Rheumatoid arthritis (RA) is one of the most common autoimmune disease in the world, characterized by persistent inflammation of the synovial joints, severe pain, joint erosion, and also functional impairment. RA may be diagnosed according to a set of diagnostic criteria established in 1987 by the American College of Rheumatology (ACR).¹ Recently, ACR and European League Against Rheumatism (EULAR) both reported new criterias for the diagnosis of RA in 2010. In 1987, the therapeutic options were limited and the accepted approach for the treatment of RA was defined as “pyramid” or “start low and go slow” but, nowadays, especially during the last two decades, the therapeutic approach and also options for RA has been changed a lot.² Some randomized controlled trials have shown that early aggressive therapy may improve clinical outcomes as well as disease-associated morbidity such as functional disability in RA. Early aggressive therapy may decrease mortality and provide remission by slowing down the damage via suppression of disease activity. ^3–7,8

The mainstay of RA treatment is the usage of disease-modifying antirheumatic drugs (DMARDs). Methotrexate (Mtx) is the most effective and widely used DMARD therapy mostly combined with glucocorticosteroids in the initial step of the treatment.⁹ On the other hand, nearly 20% of RA patients are resistant to this combination; therefore, newer strategies were searched for these group of patients.¹⁰ The first triple DMARD combination therapy was reported in 1982, and cyclophosphamide, azathioprine, and hydroxychloroquine (HCQ) were the components of this combination. During the last 2 decades, the effectiveness of Mtx, sulfasalazine (SLZ), and HCQ were reported to be better than the other combinations and also better than the mono- and double combination therapies.¹¹ But, there are still a group of patients resistant to this triple combination therapy, and according to the reports in the literature, the ratio of these patient differ between 10% and 40%.¹² For these patients, alternative therapies as anti-TNFs or rituximab may be used.

Herein, we report our experience with tetrad DMARD combination with methotrexate, HCQ, SLZ, and leflunomide for the patients resistant to both dual (Mtx and glucocorticoid) and triple (Mtx, HCQ, and SLZ) combination.

MATERIAL AND METHODS

Patient Characteristics

Totally, the data of 435 patients with RA who were diagnosed as RA in our clinic between 1985 and 2009 were analyzed retrospectively. There were totally 70 patients with resistant RA under triple DMARD combination. Sixty-three (90%) were female and the median age at diagnosis was 56 (29–82) years. Of all, 66 (94.3%) have used steroid therapy in the past. The median time between the diagnosis and beginning of tetrad therapy was 60 (25–216) months. The mean DAS 28 score at the diagnosis and before the beginning of the tetrad therapy was 5.051 and 4222, respectively. The patient characteristics and the laboratory features at the beginning of the tetrad therapy were shown in Table 1.

Treatment Protocol

Patients who applied to our outpatient unit with a diagnosis of RA or were diagnosed as RA in our clinic were first treated with triple DMARD therapy (Mtx 10–15 mg/wk, SLZ 1500–3000 mg/d, and HCQ 200–400 mg/d). Corticosteroids were all discontinued before tetrad therapy. All patients were checked for disease activity every month for the following 6 months. If no remission could be held, tetrad therapy was prescribed to the patient (Mtx 7.5–15 mg/wk, SLZ 1500–3000 mg/d, HCQ 200–400 mg/d, and leflunomide 10–20 mg/d). Again the patients were checked for disease activity and also side effects or toxicities every month for the following 6 months, and according to the disease activity, further protocols were planned.

Statistical Analysis

Fischer's exact and chi square test were used for nominal variables, Mann-Whitney U test was used for the numeric variables. Kaplan-Meier method was used for censored data and log rank test was to compare survival. All the P values were two-sided and a value less than or equal to .05 was considered significant. Statistical Package for Social Sciences version 16.0 (SPSS 16.0) software was used for analysis.

RESULTS

A total of 435 patients who were in regular follow-up were involved in this retrospective study; DMARD treatment strategies were categorized as triple, tetrad, and biological. Seventy patients on tetrad therapy protocol who were resistant to triple therapy according to clinical and laboratory assesment were evaluated. The mean DAS 28 score at the diagnosis, before the beginning of the tetrad therapy, and 12 months after tetrad therapy was 5.051, 4222, and 3026, respectively. The decrease in DAS 28 score after 12 months therapy with tetrad protocol was statistically significant (P<.05). The median follow-up period of patients with tetrad therapy was 98 (12–132) months. The mean and the median number of tender joints before and after tetrad therapy were 4.38, 3 (2–24) and 1, 1 (0–3), respectively. Similarly, the mean and median number of swollen joints before and after tetrad therapy were 1, 1 (0–6) and 0.16, 0 (0–2), respectively. The decrease of the DAS 28 score at the time of analysis when compared with the beginning was also statistically significant (4222 to 3180, respectively, P<.05) (Table 2). According to the DAS28 scores 29 (41.4%) patients held remission after tetrad therapy although there were no patients previously. The laboratory features at the beginning and at the time of analysis are shown on Table 3. The costs of the DMARDs, anti-TNFs, and biologic agents are also shown in Table 4.

Toxicity

The patients were regularly (every month for the first 6 months than every 6 months) evaluated for side effects and toxicities. The blood biochemistry for glucose levels, liver and renal function tests, and complete blood count for hemoglobin and leucocyte levels were studied on every control. The doses of the DMARDs were adjusted according to the results. No serious side effects were observed (Table 3). But 12 (17.14%) patients reported mild nausea and vomitting, four (5.71%) patients presented with mild leucopenia (3000–5000/mm³), and four patients presented with mild liver function test impairment (lower than three times) after tetrad therapy. During the follow-up period, malignancies, severe infections, cardiac or renal failure, and cirrhosis were not observed.

DISCUSSION

The treatment of RA with Mtx, SLZ, and HCQ combination is named as triple therapy. Previous reports have shown that triple therapy is superior to MTX alone or SLZ and HCQ combination.¹³ But remission may not be held in all patients with RA with triple thrapy, and further therapies are necessary. Anti-TNFs, rutiximab, tocilizumab, and abatacept are not only the newer and effective but also very expensive options for these patients with resistant disease. Because of the cost and the side effects of these biologic agents, alternative treatment protocols are necessary for these patients. Therefore, we report our experince with tetrad DMARD therapy. We totally reported results in 70 patients and significant decrease in CRP and DAS 28 scores was seen. According to the DAS 28 scores, 59 (74.28%) of the patients had high or moderate disease activity before tetrad therapy, but after tetrad therapy, 43 (60.4%) patients had held remission or low disease activity. Although the difference was not statistically significant, the need for further therapies have been decreased. The most frightening point in any combination therapy is the probable toxicity. In our trial, close monitoring of the liver and renal function tests with hemoglobin and leucocyte counts were done, and no severe side affect was observed. The second important point in planning a new treatment protocol is the cost effectiveness. As seen in Table 4, newer agents are very expensive, therefore should be preffered only for patients who have resistant RA to DMARD combinations. Tetrad therapy to our study decreases the need for anti-TNF and also other biologic agents, which means saving money and less patients facing the serious side affects of the anti-TNF and the biologic agents. But herein, we must state that anti-TNF and also other biologic agents are very effective options for patients with resistant RA and the newer trials report that the increase in the serious and opportunistic infections are very small and the risk for malignancies do not increase.¹⁴

In conclusion, we report a new DMARD combination for resistant RA patients, which is safe and decrease the need for anti-TNF and also other biologic agents.

Disclosure: There is no conflict of interest.

REFERENCES

It is well known that in hemophilia, the knees tend to bleed beginning at an early age of 2–5 years. The synovium is only able to reabsorb a small amount of intra-articular blood; if the amount of blood is excessive, the synovium will hypertrophy as a compensating mechamism, so that eventually the affected joint will show an increase in the size of the synovium: so-called hypertrophic chronic hemophilic synovitis (Figure 1) The hypertrophic synovium is very richly vascularized, so that small injuries will easily make the joint rebleed. The final result will be the classic vicious cycle of hemarthrosis-synovitis-hemarthrosis ^{1, 2}.

In developing and undeveloped countries—in which around 75% of the global population lives—the knee is a very commonly affected joint (target joint). In other words, most hemophilia persons in these countries suffer a severe involvement of the knee joint from craddle to adulthood, due to severe recurrent knee hemartroses related to the lack of adequate hematological treatment (nontreatment or on-demand treatment instead of primary prophylaxis). However, in developed countries, in which primary or at least secondary prophylaxis is commonly used despite their high economical cost, the knee is the second most affected joint after the ankle, but in a moderate to severe degree of involvement.

In more severely involved knees of patients with hemophilia, flexion contracture is a common deformity. In addition, valgus, the external rotation deformity and posterior subluxation of the tibia, may exist. In painful and advanced cases, a total knee arthroplasty may become necessary. In this article we will review the most important therapeutic modalities for the hemophilic knee.

HEMARTHROSIS (ARTHROCENTESIS)

An arthrocentesis of the knee is a very single and efficient procedure that many times can be carried out at an outpatient clinic or in the patient's bed^{1, 2}. Articular punctions must be used in hemophilia for the evacuation of knee hemarthroses.

RADIOSYNOVECTOMY

Radiosynovectomy consists of the destruction of synovial tissue by an intra-articular injection of a radioactive agent. Radioactive substances have been used for the treatment of chronic hemophilic synovitis of the knee for many years. Radiation causes fibrosis within the subsynovial connective tissue of the joint capsule and synovium. It also affects the complex vascular system, in that some vessels become obstructed; however, articular cartilage is not affected by radiation. Radioactive substances, therefore, have a radionecrotic effect ^1–3. The indication for a radiosynovectomy is chronic hemophilic synovitis causing recurrent hemarthroses, unresponsive to hematological treatment. Synoviorthesis is the intra-articular injection of a certain material to diminish the degree of synovial hypertrophy, decreasing the number and frequency of hemarthroses. There are three basic types of synovectomies: chemical, radiosynovectomy, and arthroscopic synovectomy. On average, the efficacy of the procedure ranges from 76%–80%, and can be performed at any age. The procedure slows the cartilaginous damage, which intra-articular blood tends to produce in the long-term.

Radiosynovectomy can be repeated up to three times with 3-month intervals if radioactive materials are used (Yttrium-90, Phosphorus-32, and Rhenium-186), or weekly up to 10–15 times if rifampicin (chemical synovectomy) is used. After 35 years of using radiosynovectomy worldwide, no damage has been reported in relation to the radioactive materials. Radiosynovectomy is currently the preferred procedure when radioactive materials are available, however, rifampicin is an effective alternative method if radioactive materials are not available ⁴.

With radiosynovectomy no damage has been reported in relation to the radioactive materials. The only potential complication is a cutaneous radioactive burn if the radioactive material is injected out of the joint, which has been described in less than 10 cases in the literature. Therefore a careful technique of injection is recommended when performing a radiosynovectomy. So far, osteonecrosis has not been described as a complication of radiosynovectomy.

REHABILITATION

The importance of preoperative and postoperative rehabilitation of the knee joint in hemophilia must be emphasized. Children must utilize the resources available and seek early consultation with their center rehabilitation physician and/or physiotherapist. Using the techniques available, rehabilitation has been shown to speed recovery, reduce pain, and prevent contractures. Physiotherapy is important in knee rehabilitation of patients following surgical procedures and the physiotherapist must work closely with the orthopedic surgeon.

ARTHROSCOPIC SYNOVECTOMY

Regarding knee surgical synovectomy, it may be done through an open technique or by arthroscopic means ⁵. At the knee, the arthroscopic synovectomy is preferred and the open procedure is reserved for when the arthroscopic technique fails to control the synovium. Open synovectomy should be performed through a medial parapatellar approach, and as complete a synovectomy as possible should be carried out. It is well known that it is impossible to perform a complete synovectomy by a medial parapatellar approach; however, a complete synovectomy is not mandatory in hemophiliacs because it has been shown that a wide partial synovectomy is enough to decrease the amount of bleeding synovium in order to decrease the number of articular bleedings. Suction drainage must be used for 24–48 h after operation and patients are discharged with a home exercise regime.

Arthroscopic synovectomy should be done through three portals (anterolateral, anteromedial, and lateral or medial suprapatellar portals). In other words, at least three portals are needed to perform a “complete” synovectomy. As complete a synovectomy as possible should be performed with the use of a motorized resector. After surgical synovectomy (by any method) the knee should be immobilized in a Robert Jones dressing for 3 days and active movement encouraged. The Holmium:Yag laser would appear to be superior to conventional arthroscopic synovectomy, which utilizes mechanical devices, because a laser might improve the quality of a local hemostasis and the rapidity of postoperative recovery.

SEVERE HEMOPHILIC ARTHROPATHY

There is a number of orthopedic procedures that can be carried out in the hemophilic knee when a severe degree of arthropathy is reached ^{1, 2, 6}.

Curetagge of subchondral bone cysts

Some hemophilic patients present great subchondral cysts on the proximal tibia (Figure 2). When such cysts are symptomatic, its curetagge and filling with fibrin glue and/or a cancellous bone graft should be recommended ^{1, 2}.

Alignment osteotomies

Sometimes during childhood, adolescence, or early adulthood, some hemophilic knee joints suffer from an alteration of its normal axis. It is common that their knees show varus, valgus, and flexion deformities. When the malaligned joint is painful the patient will need an alignment osteotomy ⁷. The most commont osteotomies performed in hemopiliacs at the knee are: proximal tibial valgus osteotomy, supracondylar femoral varus osteotomy, and knee extension osteotomy.

In all of them the rationale is to produce a fracture at an adequate area in order to realign the joint to a normal axis. After the osteotomy, it would be necessary to get an adequate bone fixation by any kind of internal fixation device. It is interesting to note that sometimes this author has corrected a flexion contracture of the knee at the same time of a spontaneous supracondylar fracture of the femur. When an axial malalignment occurs in a joint with severe hemophilic arthropathy, a total joint arthroplasty would be commonly indicated, and, hence, at the same time both problems can be solved.

Arthroscopic debridement

A joint débridement is commonly performed in young patients suffering from severe hemophilic arthropathy, in the cases when the orthopedic surgeon in charge considers a patient too young to indicate a total joint replacement. In other words, débridement is a procedure that can alleviate articular pain and bleeding for a number of years, and that delays the need for a total joint arthroplasty ^{1, 2}. A joint débridement consists of the opening of the joint in order to remove the existing osteophytes, to resect the synovium, and to make curettage to the articular cartilage of femoral condyles, tibial plateaus, and patella. Some authors do not believe in the efficacy of débridement and therefore when facing a severe degree of arthropathy in a young patient they directly indicate a total joint replacement. It should be emphasized that if débridement fails, a joint arthroplasty can be performed by the same approach. Some authors perform joint débridement by arthroscopic means with similar results than by open surgery. In many occasions a synovectomy and a débridement are performed together, because hemophilic synovitis and early arthropathy commonly coexist. Again, postoperative rehabilitation is paramount to avoid loss of range of motion, and therefore it should be associated to an adequate hematological control in order to avoid rebleedings.

Total knee arthroplasty

Between the second and fourth decades, many hemophilic patients develop severe articular destruction. For the knee, the best solution is a total knee arthroplasty. The role of total knee replacement in persons with hemophilia is very important ^{1, 2}. Hemophilic patients infected by the human immunodeficiency virus are at risk of bacterial and opportunistic infection because of worsening immunodepression. In these patients, the risk of infection after orthopedic surgery is of considerable concern. Arthroplasty appeared to have seven times the risk of infection than other procedures ⁸.

Total knee replacement for advanced hemophilic arthropathy has very good results in about 85% of cases (Figure 3). The principle risk is late infection that can occur regardless of HIV status. However, this risk appears increased in the patient with a CD4 count under 200. It should not be inferred that a total knee arthroplasty (TKA) should be avoided in an HIV-positive hemophilia patient today, but that the orthopedic surgeon, treatment team, and the patient should weigh the risks and benefits carefully.

KNEE FLEXION CONTRACTURES

The management of an articular contracture in a patient with hemophilia represents a major challenge. The problems that arise are complex, and require a range of knowledge from an understanding of basic biological events to fine details of the surgical technique. The treatments available are physiotherapy, orthotics and corrective devices, and surgical procedures. End-stage arthropathy of the knee is the most frequent cause of severe pain and disability in hemophiliacs. Some patients have such severe arthropathy that a total joint arthroplasty is required ^{1, 2}.

Physiotherapy and orthotic and corrective devices

The aim of physiotherapy is to maintain muscle power and a good range of joint movement. The problems of the hemophiliacs are unique and complicated and the assignment of a special physiotherapist to their care is an invaluable aid. Several specific devices have been used to overcome hemophilic contractures.

Serial casting

The most basic of these is the serial application of plaster of paris casts, which are changed approximately weekly as the deformity is gradually overcome. Serial casting can be complicated by skin necrosis, joint cartilage compression, and joint subluxation.

Reversed dynamic slings and inflatable splints

More recently, serial casting has been supplemented by the use of reversed dynamic slings and inflatable splints (Flowtron machine, Huntleigh Medical, Luton, England). Reversed dynamic slings require admission to hospital and close supervision, whereas the Flowtron is easy to use and suitable for home treatment. These noninvasive methods are generally successful in only mild contractures, or are used as adjuncts after radical soft-tissue release gradually stretching the tight neurovascular structures. The amount of corrective force that may be applied with casts, splints, and braces is limited by the inability of skin to tolerate direct pressure. Additionally these methods can cause articular subluxation.

Extension/desubluxation hinge (EDH) devices

An extension-only hinge device between cylinder casts on a thigh and calf can be used for the treatment of severe knee flexion contractures.

Surgical procedures

Late or severe cases may require surgical correction in the form of soft-tissue procedures, osteotomies, or mechanical distraction using external fixators.

Soft-tissue procedures

The soft-tissue procedures (hamstring release at the knee) are often insufficient to gain full correction. In this situation, the chronically contracted vessels and nerves prevent full correction.

Osteotomies

Supracondylar extension osteotomy of the femur creates a secondary deformity (angulation and shortening) instead of correcting the deformity, and may lead to abnormal joint-loading forces in the ambulatory patient.

Mechanical distraction using external fixators

Russian investigators have developed external fixators to produce gradual joint distraction and to allow ambulatory treatment. These fixators represent a more efficient way to apply forces to the skeletal deformity. Advantages of these techniques include versatility and minimized risk of neurovascular complications. Problems encountered included a rebound phenomena after frame removal, with loss of the temporarily increased total arc of motion.

Experimental evidence suggests that low-load prolonged stretch is preferred to high-load brief intermittent stretch in the elongation of collagen. There are still two unanswered questions: Why does the muscle stretch? and How can the rebound phenomena be minimized? Continued combined clinical and basic research will hopefully provide answers to these questions. The results obtained with mechanical distraction external fixators warrant its wider application.

PATIENTS WITH INHIBITORS

The development of an inhibitor against factor VIII or factor IX is the most common and most serious complication of replacement therapy in patients with hemophilia A or B, resulting from the exclusive use of virus-inactivated, plasma-derived concentrates, or recombinant products. When present, the inhibitor inactivates the biological activity of the infused factor (F) VIII or IX, making the patient refractory to treatment. Between 10 and 30% of patients with severe hemophilia A, and 2%–5% of patients with severe hemophilia B or mild/moderate hemophilia A, develop an inhibitor against FVIII or FIX after treatment with either plasma-derived or recombinant products. Inhibitor detection using the Bethesda assay, measured in Bethesda units (BU), is part of the regular follow-up for all hemophilic patients treated with such products. After the development of the inhibitor, the inhibitor titer decreases if no FVIII- or FIX-containing products are used for a long period so that the inhibitor may become undetectable. However, the inhibitor usually reappears after a new challenge with FVIII- or FIX-containing products (anamnestic response).

Two approaches for the management of patients with inhibitors have been proposed. Immune tolerance induction using a high dose of FVIII or FIX daily or twice daily for a period of a few months to several years may completely eliminate the inhibitor, allowing the patient to again be treated efficiently with FVIII or FIX. However, immune tolerance induction fails in around 20% of cases and is not proposed for all patients due to the high probability of failure or adverse events. Furthermore, this procedure is very costly. The other possibility is to treat bleeding episodes with prothrombin complex concentrates (PCCs), activated prothrombin complex concentrates (aPCCs, Autoplex, Feiba) or, more recently, with recombinant-activated factor VIIa (rFVIIa, NovoSeven). In the case of failure of aPCC or rFVIIa in life- or limb-threatening bleeds or as first-line treatment for major bleeds, the high-dose human or porcine FVIII or human FIX may be efficacious if the inhibitor is low or is lowered using plasmapheresis or protein A immunoadsorption. However, the anamnestic rise of the inhibitor will render treatment with FVIII or FIX ineffective within a few days, making the patient resistant to rescue with FVIII or FIX for months or even years.

Recombinant FVIIa has made major elective orthopedic surgery possible in patients with high-titer inhibitors. Most of these procedures would not have been possible without rFVIIa, as it would have been difficult to overcome the inhibitor even with high doses of human or porcine FVIII or FIX. The reported experience with aPCC, for example, is minimal despite aPCCs being available for more than 20 years. The rFVIIa is a novel and real alternative for major elective orthopedic surgery in inhibitor patients. The standard regimen is 90µg/kg body weight every 2 h for the first 48 h with an increasing interval between doses after this first postoperative period. Lower doses are much less efficient and administration by continuous infusion is not yet approved for rFVIIa, as a few bleeds and one episode of disseminated intravascular coagulation have been reported with a continuous infusion of rFVIIa.

Previous reports have shown that current hematological advances allows hemophilic patients with inhibitors to undergo surgery with a greater expectation of success, leading to an improved quality of life ^9–11. Thorough analysis of each case as part of a multidisciplinary team will help to identify further inhibitor patients in whom surgery can be performed both safely and effectively (Figure 4). In a recent publication a consensus was reached regarding the definition of the type of surgical procedures, a scale for evaluating the degree of perioperative bleeding, the recommended doses of FEIBA and rFVIIa for surgery, and the blood tests required before and after surgery. The need for prospective studies was also emphasized.

THE INFECTIOUS RISK OF THE HIV-POSITIVE PATIENTS

In this section we will emphasize spontaneous septic arthritis and postoperative infection.

Spontaneous septic arthritis (arthrotomy)

Immunodepressed patients may suffer a spontaneous septic arthritis of the knee that sometimes can mimic a hemarthrosis. Pyrexia and culture of the intra-articular fluid will help us to reach a diagnosis. Intravenous antibiotics many times can solve the problem, but other times it will be necessary to perform surgical drainage and joint lavage through an arthrotomy.

Postoperative infection

Taking into account that a majority of our adult hemophilic population are HIV-positive, their immunological status is likely to be deficient when surgery is considered. Furthermore, most of them are also positive for hepatitic C. In fact, when undertaking surgery on hemophilic patients, the risk of postoperative infection is higher than in normal population because of their immunodepression. However, some controversy exists on this particular point since some authors have reported a much higher postoperative infection risk in patients with a CD4 count lower than 200/mm³, while others have not found such a high level of infection. There is no doubt that immunosupression somehow increases the risk of postoperative infection, specially when performing joint arthroplasties, and such a risk should be known by the patient. Nonetheless, modern treatments against immunodeficiency can make it possible for hemophilia patients to undertake orthopedic surgery with a relatively satisfactory immunological status.

AUTHORS’ EXPERIENCE

When medical management fails to prevent arthropathy, we have several options for the nonmedical management of chronic synovitis: radiosynovectomy, chemical synoviorthesis, and arthroscopic synovectomy. In cases with severe arthropathy, the role of the orthopedic surgeon in improving surgical outcomes is paramount.

The most appropriate molecules for use in radiosynovectomy are Yttrium-90 at a dose of 185 MBq for the knees and Rhenium-186 at a dose of 56-74 MBq and 74 MBq for the elbows and ankles, respectively, based on measures of the radioactive half-life and therapeutic penetration power. The usual treatment regimen is a maximum of three injections given at 3- to 6-month intervals. The technique is highly cost effective in comparison to arthroscopic synovectomy, and in 448 procedures (298 patients) performed at our center, we were able to reduce bleeding frequency by a median of 85%. In other studies, radiosynovectomy was found to reduce hemarthrosis by 59% to 100% in 53% to 100% of the patients ^12–15.

Chemical synoviorthesis is most commonly performed using rifampicin or oxytetracycline chlorhydrate. The technique is not widely used due to patient inconvenience; however, it may have some utility in developing countries where the radioactive substances required for radiosynovectomy are not available ¹⁶.

There are mixed views as to whether arthroscopic synovectomy should be considered as first- or second-line therapy in patients with chronic synovitis. In a study of 20 children with moderate or severe hemophilia, synovectomy significantly reduced the frequency of hemarthrosis in the first year. In addition, 76% of patients had stable or improved joint function at their most recent comprehensive clinic visit ¹⁷. In a further study of 44 pediatric patients undergoing synovectomy as first-line therapy, a median hemarthrosis frequency decline of 84% was reported (P<.001). The median arc of motion was stable or improved in the year after surgery in ankles, elbows, and shoulders; however, radiographic scores worsened slightly ¹⁸. At our center, arthroscopic synovectomy is used only as a second-line therapy after the failure of three radiosynoviortheses with 3- to 6-month intervals ¹⁹. This technique has so far only been required in 15 of 448 joints injected in 298 patients.

total knee arthroplasty (TKA) is indicated if a patient suffers severe pain and disability after the failure of a conservative treatment such as prophylaxis, physiotherapy, or radiosynoviorthesis. The presence of HIV, HCV, or inhibitors is not a contraindication. In a series of 45 patients undergoing TKA, 42 procedures were considered to be excellent and/or good according to the Knee Society scoring system; postoperative radiographs can be seen in Figure 3. Four patients suffered complications. These included three deep infections (two early and one late), which required a two-stage revision arthroplasty in two patients, and one case of pseudoaneurysm that required embolization (in one of the two patients with inhibitors). Survival of the prostheses at 7.5 years postsurgery was 95.5%.

The medical status, physical disability, age, and projected activity levels are the major factors in determining treatment for the patient with unilateral or bilateral hemophilic arthropathy of the knee. The surgeon must have the expertise and experience to correct these deformities sufficiently when performing a total knee arthroplasty. A properly performed soft-tissue release that achieves balance between the medial and lateral ligamentous structures and posterior capsule can provide stability to the knee with a semiconstrained prosthesis. In hemophiliacs, we routinely perform posterior stabilized prosthesis, using an antibiotic cement and resurfacing of the patella. In extremely deformed knees, a CCK (constrained condylar knee) prosthesis may be necessary or even a rotational-hinge prosthesis. It is common in hemophilia patients for the tibia and distal femur to be quite small, which may require small prosthetic components (preoperative planning as usual is very important).

At this point in time, TKA should be indicated in hemophilia patients suffering from severe knee pain and disability. However, the expected high risk of infection and other postoperative complications is a concern. The orthopedic surgeon should weigh the risks and benefits carefully. Clinical and immunological status should be considered before suggesting total knee replacement to a hemophilia patient.

CONCLUSIONS

Continuous prophylaxis could halt or slow the development of the orthopedic complications of hemophilia that we still see today. However, this has not been achieved so far, not even in developed countries; therefore, orthopedic surgeons are still needed to carry out many different surgical procedures in the knee. The HIV infection has made the immunodepressed have a high risk of postoperative infection after any surgical procedure, specially a joint arthroplasty. Current hematological advances allow hemophilic patients with inhibitors to undergo surgery with a greater expectation of success.

Keywords

hemophilia, knee, management, review

Disclosure: The authors declare no conflict of interest.

REFERENCES

1. Rodriguez-Merchan EC, Goddard NJ, Lee CA Musculoskeletal Aspects of Haemophilia. Oxford: Blackwell Science Ltd; 2000.
2. Rodriguez-Merchan EC. The Haemophilic Joints: New Perspectives. Oxford: Blackwell Science Ltd; 2003.
3. Rivard GE, Girard M, Bélanger R, et al. Synoviorthesis with colloidal 32P chromic phosphate for the treatment of hemophilic arthropathy. J Bone Joint Surg Am. 1994;76A:482–488.
4. Caviglia HA, Fernandez-Palazzi F, Maffei E, Galatro G, Barrionuevo A. Chemical synoviorthesis for hemophilic synovitis. Clin Orthop Relat Res. 1997;343:30–36.
5. Wiedel JD. Arthroscopic synovectomy of the knee in hemophilia: 10- to 15-year follow-up. Clin Orthop Relat Res. 1996;328:46–53.
6. Luck JV, Kasper CK. Surgical management of advanced hemophilic arthropathy: an overview of 20 years experience. Clin Orthop Relat Res. 1989;242:60–68.
7. Smith MA, Urquhart DR, Savidge GF. The surgical management of varus deformity in haemophilic arthropathy of the knee. J Bone Joint Surg Br. 1981;63B:261–265.
8. Ragni MV, Crossett LS, Herndon JH. Postoperative infection following orthopaedic surgery in human immunodeficiency virus-infected hemophiliacs with CD4 counts < or = 200/mm3. J Arthroplasty. 1995; 10:716–721.
9. Rodriguez-Merchan EC, Lee CA. Inhibitors in Patients with Haemophilia. Oxford: Blackwell Science Ltd; 2002.
10. Rodriguez-Merchan EC, Wiedel JD, Wallny T., et al. lective orthopaedic surgery for inhibitors patients. Haemophilia. 2003;9:625–631.
11. Rodriguez-Merchan EC, Rocino A, Ewenstein B, et al. Consensus perspectives on surgery in haemophilia patients with inhibitors: summary statement. Haemophilia. 2004;10(suppl 2):50–52.
12. Silva M, Luck JV Jr, Siegel ME. 32P chromic phosphate radiosynovectomy for chronic haemophilic synovitis. Haemophilia. 2001;7(suppl 2):40–49.
13. Manco-Johnson MJ, Nuss R, Lear J, et al. 32P radiosynoviorthesis in children with hemophilia. J Pediatr Hematol Oncol. 2002;24:534–539.
14. Chew EM, Tien SL, Sundram FX, Ho YK, Howe TS. Radionuclide synovectomy and chronic haemophilic synovitis in asians: a retrospective study. Haemophilia. 2003;9:632–637.
15. Grmek M, Milcinski M, Fettich J, Benedik-Dolnicar M, Brecelj J. Radiosynoviorthesis for treatment of hemophilic hemarthrosis—Slovenian experience. Cancer Biother Radiopharm. 2005;20:338–343.
16. Fernandez-Palazzi F, Cedeno M, Maldonado JC, et al. Chemical synoviorthesis with oxytetracycline clorhydrate (emicine) in recurrent haemarthrosis. Haemophilia. 2008;14:21–24.
17. Journeycake JM, Miller KL, Anderson AM, Buchanan GR, Finnegan M. Arthroscopic synovectomy in children and adolescents with hemophilia. J Pediatr Hematol Oncol. 2003;25:726–731.
18. Dunn AL, Busch MT, Wyly JB, Sullivan KM, Abshire TC. Arthroscopic synovectomy for hemophilic joint disease in a pediatric population. J Pediatr Orthop. 2004;24:414–426.
19. Rodriguez-Merchan EC, Quintana M, De la Corte-Rodriguez H, Coya J. Radioactive synoviorthesis for the treatment of haemophilic synovitis. Haemophilia. 2007;13(suppl 3):32–37.

Classically FM has been defined by two criteria: (1) pain in at least three of four body quadrants including some part of the axial spine for the past ≥3 months (eg widespread pain) and (2) at least 11 of 18 specified tender points on physical exam.² Although the diagnosis is based on pain, the typical patient with FM is polysymptomatic; commonly reporting fatigue, disrupted sleep, stiffness, cognitive dysfunction (“fibrofog”), and often mood disorders.³ Emerging research demonstrates a physiologic overlap between FM and other central sensitivity syndromes such as irritable bowel syndrome, painful bladder syndrome, chronic headaches, temporomandibular dysfunction, and pelvic pain syndromes.^{4, 5} These comorbid diagnoses in persons with FM increase the complexity of maximizing symptom management and quality of life.

The purpose of this article is to present practical, evidence-based self-management strategies for clinicians to pair with pharmacologic management. Self-management is defined here as therapies that the patient can learn to enact without the assistance of a therapist or practitioner, as would be needed for acupuncture, chiropractic adjustments, massage, and similar therapies. Evidence-based self-management therapies for FM include lifestyle and dietary changes, exercise, and a wide range of self-administered cognitive behavioral strategies.¹ Encouraging patients to employ these strategies in addition to standard care promotes better management of pain, fatigue, cognitive dysfunction, sleep problems, and physical deconditioning and can reverse unhelpful thought processes.⁶

MAXIMIZING THE RELATIONSHIP WITH THE HEALTH CARE CLINICIAN

In order to maximize the FM patient's self-management, the clinician first needs to establish trust and build a therapeutic alliance with the patient.^{6, 7} Most importantly, clinicians need to recognize that it may require more time to establish this therapeutic relationship with patients who have FM compared to patients with other chronic illnesses. Many people with FM are distrustful of clinicians, based on prior negative experiences. For example, many patients have been told that FM is simply depression or that the diagnosis is “all in their heads.” It is easy, for both clinician and patient to become frustrated with the lack of available effective treatments, but research demonstrates that collaborative patient–clinician interactions are associated with increased patient satisfaction and improved health outcomes.^{8, 9}

Clinicians may choose to adopt a method whereby symptoms can be tracked and prioritized. Russell¹⁰ promotes a practice management strategy whereby patients identify their three most bothersome symptoms on points of a triangle. Clinicians and patients can then target therapies most likely to impact those specific symptoms. At follow-up, the patient and provider focus on progress made on the three selected symptoms, ultimately moving on to new symptoms as others become better managed. Similarly, questionnaires such as the Fibromyalgia Impact Questionnaire-Revised (FIQ-R) can be completed by patients at each visit to systematically identify particularly problematic symptoms or physical function deficits. Like the triangle method, the FIQR can be completed at each visit with changes monitored over time.¹¹

One challenging topic for providers is discussing alternative therapies for the management of FM. Although there is a need for more evidence to establish the long-term benefit of complementary and alternative therapies (CAM) in FM treatment, patients are overwhelmingly seeking these modalities.¹² Between 60% and 90% of patients with FM in the United States have used at least one CAM treatment.¹³ One study found that individuals with FM were more likely to discuss CAM use with their clinician as compared to individuals with other rheumatologic conditions, indicating that patients with FM have a desire to initiate this conversation.¹⁴ Some common alternative therapies such as acupuncture,^{15, 16} massage,^{17, 18} yoga,¹⁹ and tai chi²⁰ do show some evidence based benefits, pose very little risk, and can be safely recommended to patients. Other less traditional treatments, such as IV lidocaine^{21, 22} and aggressive thyroid supplementation²³ have limited research supporting their use and present significant safety concerns.

The overall dearth of methodologically rigorous evidence for many (CAM) therapies in FM treatment,¹² can make it difficult to answer patients’ questions on this subject. In order to preserve therapeutic alliance, it is important to be nonjudgmental about CAM therapies, while still using good clinic judgment in regards to safety. It is okay to acknowledge one's lack of expertise in this area, but try to guide patients to reliable resources such as PubMed and Natural Standard so they can be informed consumers before starting any new alternative therapy.

Practical strategies for clinicians to consider:

• During the initial evaluation, consider basic laboratory testing to rule out other causes of widespread pain and fatigue (CBC, chemistry profile, sedimentation rate, hepatitis C serology, vitamin D [OH] 25, insulin-like gowth-factor-1).²⁴

• Make the diagnosis of FM as soon as possible using a body pain diagram and tender point exam. Appropriately assigning a label of FM leads to improved health satisfaction and decreased symptom severity.²⁵

• Validate the diagnosis of FM if a patient comes to you with this diagnosis.

• Schedule visits every 6 weeks initially then quarterly when therapies are stabilized.

• Schedule regular follow-up appointments to avoid visits that are only scheduled during flares or pain crises.

• Allow for longer appointment times at each visit; code at a level four to account for extended counseling time.

• Ask patients to write a list of the top three issues they wish to discuss before each visit.

• Enhance self-efficacy by reinforcing gains made by the patient.

• Be conscious of memory and cognitive deficits during the office visit and encourage patients to take notes, bring a companion, or record the discussion with a tape recorder.

• Remain open-minded and supportive about patients’ use of unproven, but non-harmful CAM therapies. At a minimum they may evoke the placebo response and be conducive to maintaining a therapeutic alliance.

• Provide realistic expectations; for example, FDA approved drug therapies are generally only 30–40% effective in relieving symptoms and 20–30% effective in improving function.²⁶

• Reassure patients that FM is not progressive in the same way that neurodegenerative diseases such as multiple sclerosis are (eg, they will not likely progress to needing a wheelchair).

• Follow-up with referrals for treatment of recalcitrant comorbidities (eg, psychiatry for mood, urology for irritable bladder, sleep medicine for potential sleep apnea, endocrine for severe growth hormone deficiency).

• Acknowledge frustration with currently available medical therapies.

• Provide hope for the future by sharing scientific advances and success stories from other patients.

PAIN MANAGEMENT

Widespread pain over much of the body is the core symptom of FM and is often the presenting symptom for which patients with FM seek help from their clinicians. The physiological mechanisms underlying the pain of FM arise from disordered pain processing in the central nervous system.^{27, 28} The resulting central and peripheral sensitization leads to the characteristic pain-amplification that causes mildly painful stimuli to be interpreted as severely painful (hyperalgesia) and even nonpainful stimuli, such as clothing or a blanket against the skin, to cause discomfort (allodynia). Although central sensitization produces widespread neuropathic-type pain, many people with FM also have other pain generators (eg, osteoarthritis, myofascial pain syndrome, tempromandibular disorder, joint hypermobility syndrome, headaches, restless leg syndrome, or irritable bowel or bladder syndrome) that may require additional treatments.^{29, 30} These peripheral sources of pain provide increased input into an already sensitized nervous system producing an enhanced pain experience, which maintains central sensitization. Therefore, treating both centrally and peripherally maintained pain is of utmost importance.^{31, 32} Although medications aimed at treating both types of pain have proven somewhat beneficial,³³ self-management strategies should be used to augment the pain not controlled with medications.¹² Books, web, and media resources can help reduce pain and promote self-management (see Table 1).

Practical strategies for patients to employ:

• Seek to understand the altered pain processing that underlies FM.

• Treat pain before it becomes severe. This will minimize flares that are often refractory to standard interventions.

• Use of multiple small strategies frequently throughout the day can add up to provide greater relief. Some of these strategies include:³⁴ heat, transcutaneous electrical nerve stimulation,³⁵ topical analgesics or capsaicin,³⁶ regular stretching to maintain flexibility,³⁷ warm water aquatherapy (balneotherapy),³⁸ or biofeedback.^{39, 40}

• Try self-acupressure. Many patients with FM present with myofascial pain syndrome and have associated trigger points that may promote ongoing nociception.⁴¹ Although controversial in the medical literature, trigger point injections are used by many clinicians.³¹ Patients can also self-treat by gradually placing firm pressure on the trigger point, holding the pressure for 60 seconds, then gradually releasing the pressure.

• Alternate positions every 20–30 min to avoid staying in one position for too long, which shortens and tightens muscle.

• Practice range of motion movements to prevent stiffness if needing to sit for an extended period of time.

• Use pillows or supports to maintain a neutral body position while sitting or lying down. This will minimize strain to muscles of the spine and extremities.

• Pay attention to persistent new types or areas of pain since a majority of patients with FM report concurrent painful comorbidities.⁴² Although new symptoms are often chalked up to “just the FM,” they might represent a change in a comorbid condition or the onset of a non-FM related condition.

SELF-ADMINISTERED COGNITIVE BEHAVIORAL STRATEGIES

Treatment of FM with cognitive behavioral therapy is designed to identify and subsequently modify behavioral and thinking patterns that interfere with the optimal management of this chronic condition.⁴³ This therapy assists patients in recognizing habits or patterns that perpetuate symptoms of pain, fatigue, and psychological distress. The goal of cognitive behavioral therapy is to promote adaptation to new ways of performing activities and modifying thought patterns to gain better control of symptoms. Once patients learn these cognitive and behavioral strategies, they can employ these techniques on their own with successful utilization evidenced by sustained improvements up to 1 year after learning these techniques.^{44, 45} Employment of these strategies has been shown to produce improvements in physical functioning, pain, fatigue, mood, sleeplessness, and stress management with evidence that patients sustain improvements months after completing a cognitive behavioral therapy intervention.³⁴ Cognitive behavioral therapy encompasses several components, usually employed in concert. Pacing, graded activation, relaxation, and pleasant activity scheduling will be discussed individually.

Pacing

Many patients with FM report that one of the most difficult aspects of their condition is adjusting to the limitations placed upon them by pain and fatigue. An Internet study by Bennett and colleagues⁴² reported on results from over 2500 individuals with FM who indicated that pain and fatigue were among their most bothersome symptoms. These limitations require that patients adjust the way they perform their daily activities. Pacing describes strategies to modulate the rate with which one performs activities.⁴⁶ Strategies such as interspersing rest periods, breaking larger tasks into more manageable pieces, and slowing down allow patients more time for recovery in a typical day. Activity pacing is a common component of pain management programs and has been associated with reduced levels of disability in patients with FM.^{47, 48} Although learning to pace takes time and commitment, the use of pacing is associated with decreased physical impairment.⁴⁷ The practitioner can speak to the patient about pacing strategies discussed below.

Practical strategies for patients to employ:

• Engage in consistent amounts of physical activity each day. By avoiding the temptation to engage in excess amounts of physical activity on days that patients feel good, the pattern of over-activity followed by under-activity that exacerbates FM symptoms will be prevented.⁴⁹

• Alternate physical activity with periods of rest.

• Vary positions and exertion levels. Alternate types of activities that use varying levels of physical exertion.

• Prevent flares of pain before they occur. Mild to moderate pain is much more responsive to interventions than severe pain.

• Use time-based pacing to learn what the body can tolerate. Start with a period of time that will not cause excessive pain or fatigue and slowly increase activity duration over weeks to months.

• Use a timer to monitor the amount of time spent on a certain activity.

• Break down large tasks into smaller ones to achieve a greater level of productivity over time.

• Use a pedometer as a way of monitoring and quantifying activity.

Graded Activation

Researchers have demonstrated that an overactive lifestyle is a frequent premorbid characteristic of individuals with FM and chronic fatigue syndrome.⁵⁰ Following the onset of the illness, it can be difficult to reverse this pattern of behavior, particularly when one's self-esteem has been dependent on high achievement and productivity. In fact, in a metasynthesis of qualitative studies in FM,⁵¹ two major themes that arose in regards to the psychological impact of FM included losing control of one's life and the loss of one's former self. Another study highlighted the significant frustration of the inability of individuals with FM to live up to their own expectations.⁵² In an attempt to return to a lifestyle of high productivity, patients with FM will have periodic bursts of activity when feeling better⁵⁰ followed by several days of inactivity due to pain, fatigue, and lack of sleep. This pattern leads to significant levels of day to day variability in symptoms and perpetuates the patient's feelings of frustration and disability. Although it can seem counterintuitive to patients, maintaining the same level of activity day to day can mitigate this cycle of over-activity followed by inactivity. Finding a level of activity that the patient can sustain and still maintain some reserve for the following day will help achieve more balance in terms of pain, fatigue, and mood.⁵³

Practical strategies for patients to employ:

• Make a list of all the activities that need to be accomplished on a certain day. Divide this list in half, leaving half of the items on today's list and placing half on tomorrow's list.

• Pay attention to your level of fatigue at the end of the day. If you go to bed completely exhausted, you are likely overexerting during the day. Nighttime sleep is more effective when preparing a person for the next day's activities instead of being used to recover from the previous day's events.⁵⁴

• Reflect on how you define yourself or gain self-worth. Many people identify themselves by how much they accomplish or base their self-worth on fulfilling the tasks associated with their role in the family.⁵⁵

Relaxation

Relaxation techniques for the management of chronic pain and mood disorders have been used for years as a common component of successful cognitive behavioral interventions.^{56, 57} Although neurobiological models describing the effects of relaxation and meditation are underdeveloped, pain modulation likely occurs through increased activity in the sympathetic branch of the autonomic nervous system, which serves to downregulate activity in the stress system, leading to a reduction in pain.⁵⁸ Along with altering pain perception, strategies such as deep breathing, relaxation, and meditation serve to enhance emotional regulation and moderate negative effect. These propositions are supported by data from studies that investigate the effects of meditation on experimental pain response, demonstrating decreased pain thresholds and tolerance following meditation training.^{59, 60} Although few researchers have tested the effects of relaxation alone in FM,¹² most cognitive therapy interventions used in FM include relaxation training.⁶¹ Relaxation training is well suited for patients with FM, as muscle relaxation can combat symptoms of muscle soreness; periods of physical and emotional rest can counteract fatigue; using relaxation before bed can promote sleep induction; and mindfully gaining control of one's symptoms can counteract feelings of depression and anxiety.

Practical strategies for patients to employ:

• Use simple relaxation strategies such as slow, deep breathing if building a formal relaxation period into your self-care routine seems daunting.⁵⁹

• Practice progressive muscle relaxation (purposefully and sequentially relaxing each muscle group), which can be effective for people who have difficulty creating images in their mind or regularly experience intrusive thoughts.

• Try relaxation tapes or compact discs that provide a guide through a relaxation sequence; these are useful for people new to using relaxation.

• Employ mindfulness meditation (focusing one's attention on the present moment) or passive disregard for thought (allowing thoughts to enter one's mind but then letting those thoughts go without judgment or attachment), which can promote enhanced coping.⁶²

• Moving meditation may be preferred to sitting/lying meditation by some patients²⁰

• Master imagery (imagining oneself in a pleasant or peaceful experience), which can promote feelings of calm and safety.

• Be patient. Relaxation is a skill that develops over time.

Pleasant Activity Scheduling

Although many types of chronic illnesses can lead to a decreased life satisfaction, patients with FM seem to be especially prone to a decreased sense of well being. One study found that women with FM presented with lower quality of life as compared to women with rheumatoid arthritis, osteoarthritis, permanent ostomies, chronic obstructive pulmonary disease, and insulin dependent diabetes.⁶³ In studies investigating quality of life in chronic disease, patients described quality of life in terms of their ability to care for themselves, to function independently, to have a sense of security, to be able to engage in recreational activities, and to have meaning in their life; all aspects that can be affected by living with FM. As patients with FM struggle with daily functioning, fulfilling role expectations, and performing work functions,⁶⁴ this burden can take a toll on the individual's mood. Patients can feel overwhelmed by the amount of work needed to manage their illness. This responsibility combined with their normal duties for their job and families can leave patients feeling unfulfilled and over burdened. Purposefully scheduling pleasant activities may help patients take time for joyful experiences. Over time they may recognize that engaging in activities that bring them joy can help them feel more fulfilled and might make them more effective in their daily self-care, care for others, or in their work environment.

Practical strategies for patients to employ:

• Make a list of pleasant activities that are enjoyable, will not aggravate pain or fatigue, and are relatively inexpensive.

• Schedule one of these activities into your calendar once, twice, or three times per week.

• Schedule time with others to combat isolation that often occurs in people with pain, fatigue, and/or depression.

• Engage in gentle, movement-oriented pleasant activities. These can increase physical activity while pain is buffered by pleasant affect.

• Modify previous hobbies. Activities that were enjoyable before FM became so intrusive can still be a part of life with some modification.

• Develop new interests that are congruent with FM limitations (eg, hand crafts, bird watching, photography, Internet blogging unrelated to FM).

Exercise

More than 90 exercise interventions have been published in the FM literature.⁶⁵ Their consistent message is that most subjects enrolled had poor aerobic fitness, strength, flexibility, and balance. The message for patients to hear is that is that muscle in FM appears to be fully retrainable, unlike conditions such as multiple sclerosis. The challenge is to find an exercise program that is individualized to the person with FM and sensitive to the disease's physiological underpinnings. For example, FM is known to be associated with enhanced awareness of pain arising from muscle, skin, and joints.^{66, 67} Hyperalgesia and allodynia are by-products of enhanced central sensitivity and require alterations to the FM exercise prescription. Moreover, 90% of people with FM tested to date demonstrate a lack of growth hormone (GH) in response to exercise to V02 max and some other drug stimulations to the hypothalamic pituitary growth hormone axis.⁶⁸ In adulthood, GH is thought to repair muscle microtrauma after exercise. Eighty percent of GH is made during deep sleep, which has been repeatedly demonstrated to be deficient in people with FM.⁶⁹ Similarly prolonged muscle contraction and activation of active and latent myofascial tender points may add to pain burden during higher intensity exercise.^70–74 Additionally, multiple defects in the autonomic nervous system, neuroendocrine pathways, and cytokine regulation have been identified that could account for fatigue, dizziness and poor exercise tolerance.^{75, 76} Lastly, exercising muscle in FM has less blood flow and a slower rate of return to baseline resting state compared to healthy controls.^{77, 78}

Given these limitations, it is not surprising that interventions that were lower-intensity, used nonrepetitive movements, and enhanced self-efficacy demonstrated the greatest improvement in FM symptoms and physical conditioning.⁷⁹ Studies that tested high impact movements such as running or fast dancing resulted in worsening symptoms and resulted in higher attrition.^{80, 81} Higher intensity exercise with Nordic walking poles recently demonstrated significant increase in physical fitness without a symptom flare in women with FM.⁸² Likewise, gentle exercise that includes a mind–body component such as Tai chi, Yoga, and Pilates have been demonstrated to be effective in overall functioning as well as pain management.^{19, 20, 83} Self-management exercise guidelines include the following practical strategies.

Practical strategies for patients to employ:

• Start low—go slow. Ease into an exercise program and progress at a slower rate than people without FM.

• Keep work near the midline of the body and minimize overhead work to decrease eccentric muscle work. Eccentric muscle work occurs when a lengthened muscle is loaded. For example curl the bicep up slowly and down more rapidly.

• Rest hand weights on a table between short repetitions to allow the muscle to return to complete resting state.

• Take smaller steps when walking downhill or use walking poles.

• Conserve energy during activities of daily living in order to participate in structured exercise.

• Consider exercising during peak hours (10 am–3 pm, rather than after a long day of work).

• Exercise near a bathroom if irritable bowel or bladder syndromes are a problem.

• Avoid prolonged motionless standing to minimize fatigue and near-syncopal episodes.

• Change sides (arm/leg movements) frequently to minimize repetitive work.

• Avoid fast turns (pivots) to minimize dizziness and postural instability.

• Work near a wall, in a chair, with a cane or with a partner to reduce the risk of falls.

• Keep joints in the normal joint line, especially if hypermobility exists.

• Consider using pain medication before exercise. Although NSAIDs are generally not effective for overall FM management, some find them helpful short-term when initiating an exercise program.⁸⁴

Dietary Approaches

Although less evidence exists regarding dietary interventions compared to exercise interventions, advice can be gleaned from the literature. A recent review outlines the existing studies investigating the impact of dietary modifications and weight loss on FM.⁸⁵ There is no single diet that best treats FM, but weight loss and avoiding certain food additives may be helpful.

Many people with chronic illnesses in the United States are overweight; FM is no exception. However, presence of comorbidities can guide a dietary prescription. For example, if obesity is a comorbidity, gradual caloric reduction paired with gentle exercise is key. One study found that a Weight Watchers-type approach of behavioral strategies was successful and well tolerated.⁸⁶ Another study found that significant weight loss, postbariatric surgery improved FM.⁸⁷ The Living Foods Diet has been found to be beneficial in persons with FM who can tolerate a diet limited to fresh fruits, vegetables, and unprocessed foods.^{88, 89} These studies propose that certain food additives, such as unbound glutamate, which is removed in the Living Foods Diet, enhance central pain in FM since the gut is a potent vehicle for pain generation. This hypothesis was tested recently in 57 people with FM by employing a diet that eliminated food additives that are classified as “excitatory neuroexcitotoxins.” After 4 weeks, FM and IBS symptoms were significantly decreased. In a randomized, double-blind acute dosing follow-up, subjects receiving an oral MSG acute challenge compared to placebo, reported significant return of the number and severity of multiple symptoms.⁹⁰ Self-management dietary change includes the following practical strategies.

Practical strategies for patients to employ:

• Buy precut fruits and vegetables to minimize fatigue and curb impulse eating of low nutrient, high calorie foods.

• Keep a food diary.

• Limit eating out. Start by decreasing the consumption of food prepared outside the home by 50% each month.

• Consider a challenge/elimination trial by removing dietary excitotoxins that may act on NMDA receptors, then adding them back to evaluate symptom severity.

• Minimize sources of MSG (unbound glutamate). These include: meals from fast food restaurants, most canned foods, broths, soups, many spice mixes including dehydrated noodle seasonings, flavored potato chips, soy sauce, and parmesan cheese.

• Consume a diet high in fruits and vegetables. Start by adding one new serving of fruit or vegetable each week until five servings a day is reached. Diets higher in fruits and vegetables may encourage less reliance on processed, packaged foods that are more likely to contain excitatory neurotoxins.

• Choose lower fat protein sources including meats and skim dairy products.

• Choose complex, less refined carbohydrates such as whole grain breads (without dough conditioners such as l-cystine), cereals, and pastas.

• Weigh weekly unless a registered dietician or psychiatric clinician discourages this.

Sleep Management

A majority of people with FM demonstrate poor sleep quality, latency, duration, and efficiency. These poor sleep attributes have been shown to affect pain, physical functioning, and depression in FM.⁹¹ In fact, sleep abnormalities were the first objective laboratory finding in FM.⁹² People with FM spend little time in deep (stages 3 and 4) sleep, often have alpha intrusion into delta-sleep, have extended stage 1 sleep, have frequent arousals, and take longer to fall asleep.⁹³ Moreover, auditory sensations are amplified due to central sensitization,⁹⁴ providing further opportunity for disrupted sleep. This sleep pattern, sometimes termed poor sleep efficiency, leaves people feeling that they have “cat-napped” all night.⁹⁵ Sleep disruption plays a critical role in exacerbating many core FM symptoms⁹¹ to the extent that it has been recommended that insomnia be treated as if it were a comorbid condition.⁹⁶

Experimental sleep deprivation results in worsening pain, perhaps through alterations in both ascending and descending inhibitory pain control.⁹⁷ Enhancing sleep in FM by utilizing pharmacologic agents will also improve pain.⁹⁸ Improving sleep requires three major steps: (1) rule out sleep-related pathologies such as sleep apnea, narcolepsy, cataplexy, and restless leg syndrome; (2) consider as needed or long-term prescribing of sleep agents (tricyclics, short acting hyponotics, or recommended most recently, sodium oxybate),⁹⁹ and (3) couple pharmacologic agents with sleep hygiene to reduce the total dose of medication and maximize high quality sleep. Self-management sleep hygiene includes the following practical strategies.

Practical strategies for patients to employ:

• Get pets out of the bedroom.

• Consider a private bedroom if the bed partner snores.

• Use silicon earplugs.

• Go to bed at a regular time on both weeknights and weekends.

• Avoid strenuous exercise within 3 hours of bedtime.

• When traveling, request hotel rooms on higher floors, away from elevators and ice machines.

• Stop smoking, as night time awakenings can be associated with physiologic nicotine cravings.

• Soak in a hot tub 30 min prior to bedtime.

• Avoid the temptation to watch news or stimulating television in bed.

• Remove computers or other nonsleep related items from the bedroom.

• Use black-out curtains to reduce early morning awakenings from light.

Self-management therapies employed by people with FM may maximize their physical functioning, decrease symptoms, and improve quality of life.^{1, 12, 100} Clinicians who embrace such strategies by promoting them to their patients may further enjoy a greater therapeutic alliance. Patients may then begin to share their self-management strategies with clinicians, who can in turn, pass them on to better serve all persons in their practice.

Taken as a whole, the self-management strategies discussed here can be used by clinicians to assist their patients with FM in successfully managing their symptoms and maximizing physical function. Moreover, engaging in rational, nonthreatening discussions of these nonpharmacologic ideas can enhance the therapeutic relationship between the clinician and patient.

Keywords

Fibromyalgia, Self-help, Fibromyalgia Impact Questionnaire-Revised

Acknowledgements: This work was supported by the Fibromyalgia Information Foundation (www.myalgia.com).

Disclosure: The authors have no conflict of interest to report.

REFERENCES

1. Iversen MD, Hammond A, Betteridge N. Self-management of rheumatic diseases: state of the art and future perspectives. Ann Rheum Dis. 2010;69(6):955–963.
2. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis Rheum. 1990;33(2):160–172.
3. Mease PJ, Arnold LM, Crofford LJ, et al. Identifying the clinical domains of fibromyalgia: contributions from clinician and patient Delphi exercises. Arthritis Rheum. 2008;59(7):952–960.
4. Yunus MB. Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness. Semin Arthritis Rheum. 2008;37(6):339– 352.
5. Kindler LL, Bennett RM, Jones KD. Central sensitivity syndromes: mounting pathophysiologic evidence to link fibromyalgia with other common chronic pain disorders. Pain Manage Nurs. 2011 Mar;12(1):15– 24. Epub 2009 Dec 2. PMID:21349445.
6. Cymet TC. A practical approach to fibromyalgia. J Natl Med Assoc. 2003;95(4):278–285.
7. Steihaug S, Malterud K. Part process analysis: a qualitative method for studying provider-patient interaction. Scand J Public Health. 2003;31(2):107–112.
8. Frantsve LM, Kerns RD. Patient-provider interactions in the management of chronic pain: current findings within the context of shared medical decision making. Pain Med. 2007;8(1):25–35.
9. Buetow S. The scope for the involvement of patients in their consultations with health professionals: rights, responsibilities and preferences of patients. J Med Ethics. 1998;24(4):243–247.
10. Russell IJ. Fibromyalgia syndrome: case-based learning. CNS Spectrums. 2009;14(10, suppl 8):4–7; discussion 17–18.
11. Bennett RM, Friend R, Jones KD, Ward R, Han BK, Ross RL. The Revised Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric properties. Arthritis Res Ther. 2009;11(4):R120.
12. Hassett AL, Gevirtz RN. Nonpharmacologic treatment for fibromyalgia: patient education, cognitive-behavioral therapy, relaxation techniques, and complementary and alternative medicine. Rheum Dis Clin N Am. 2009;35(2):393–407.
13. Dimmock S, Troughton PR, Bird HA. Factors predisposing to the resort of complementary therapies in patients with fibromyalgia. Clin Rheum. 1996;15(5):478–482.
14. Rao JK, Mihaliak K, Kroenke K, Bradley J, Tierney WM, Weinberger M. Use of complementary therapies for arthritis among patients of rheumatologists. Ann Intern Med. 1999;131(6):409–416.
15. Cao H, Liu J, Lewith GT. Traditional Chinese medicine for treatment of fibromyalgia: a systematic review of randomized controlled trials. J Alternative Complementary Med. 2010;16(4):397–409.
16. Harris RE, Tian X, Williams DA, et al. Treatment of fibromyalgia with formula acupuncture: investigation of needle placement, needle stimulation, and treatment frequency. J Alternative Complementary Med. 2005;11(4):663–671.
17. Field T, Diego M, Cullen C, Hernandez-Reif M, Sunshine W, Douglas S. Fibromyalgia pain and substance P decrease and sleep improves after massage therapy. J Clin Rheum. 2002;8(2):72–76.
18. Kalichman L. Massage therapy for fibromyalgia symptoms. Rheum Int. 2010;30(9):1151–1157.
19. Carson JW, Carson KM, Jones KD, Bennett RM, Wright CL, Mist SD. A pilot randomized controlled trial of the Yoga of Awareness program in the management of fibromyalgia. Pain. 2010;151(2):530–539.
20. Wang C, Schmid CH, Rones R, et al. A randomized trial of Tai Chi for fibromyalgia. N Engl J Med. 2010;363(8):743–754.
21. Raphael JH, Southall JL, Kitas GD. Adverse effects of intravenous lignocaine therapy in fibromyalgia syndrome. Rheumatology. 2003;42(1):185–186.
22. Schafranski MD, Malucelli T, Machado F, et al. Intravenous lidocaine for fibromyalgia syndrome: an open trial. Clin Rheum. 2009;28(7):853–855.
23. Lowe JC, Garrison RL, Reichmand AJ, Yellin J, Thompson M, Kaufman D. Effectiveness and safety of T3 (triiodothyronine) therapy for euthyroid fibromyalgia: a double-blind placebo-controlled responsedriven crossover study. Clin Bull Myofascial Ther. 1997;2(2/3):31–58.
24. Goldenberg DL. Diagnosis and differential diagnosis of fibromyalgia. Am J Med. 2009;122(12 suppl):S14–S21.
25. White KP, Nielson WR, Harth M, Ostbye T, Speechley M. Does the label ‘‘fibromyalgia’’ alter health status, function, and health service utilization? A prospective, within-group comparison in a community cohort of adults with chronic widespread pain. Arthritis Rheum. 2002;47(3):260– 265.
26. Russell IJ, Mease PJ, Smith TR, et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: results from a 6-month, randomized, double-blind, placebocontrolled, fixed-dose trial. Pain. 2008;136(3):432–444.
27. Staud R, Domingo M. Evidence for abnormal pain processing in fibromyalgia syndrome. Pain Med. 2001;2(3):208–215.
28. Julien N, Goffaux P, Arsenault P, Marchand S. Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain. 2005;114:295–302.
29. Aggarwal VR, McBeth J, Zakrzewska JM, Lunt M, Macfarlane GJ. The epidemiology of chronic syndromes that are frequently unexplained: do they have common associated factors? Int J Epidemiol. 2006; 35(2):468–476.
30. Clauw D. Fibromyalgia associated syndromes. J Musculoskeletal Pain. 2002;10(1–2):201–214.
31. Affaitati G, Costantini R, Fabrizio A, Lapenna D, Tafuri E, Giamberardino MA. Effects of treatment of peripheral pain generators in fibromyalgia patients. Eur J Pain. 2011;15(1):61–69.
32. Staud R, Vierck CJ, Robinson ME, Price DD. Overall fibromyalgia pain is predicted by ratings of local pain and pain-related negative affectpossible role of peripheral tissues [published online ahead of print April 18, 2006]. Rheumatology. 2006. DOI 10.1093/rheumatology/kel121
33. Arnold LM, Keck PE Jr, Welge JA. Antidepressant treatment of fibromyalgia. A meta-analysis and review. Psychosomatics. 2000; 41(2):104–113.
34. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. J Am Med Assoc. 2004;292(19):2388–2395.
35. Lofgren M, Norrbrink C. Pain relief in women with fibromyalgia: a cross-over study of superficial warmth stimulation and transcutaneous electrical nerve stimulation. J Rehabil Med. 2009;41(7):557–562.
36. McCarty DJ, Csuka M, McCarthy G, Trotter D. Treatment of pain due to fibromyalgia with topical capsaicin: a pilot study. Semin Arthritis Rheum. 1994;23(6, suppl 3):41–47.
37. Matsutani LA, Marques AP, Ferreira EA, et al. Effectiveness of muscle stretching exercises with and without laser therapy at tender points for patients with fibromyalgia. Clin Exp Rheum. 2007;25(3):410–415.
38. Langhorst J, Musial F, Klose P, Hauser W. Efficacy of hydrotherapy in fibromyalgia syndrome—a meta-analysis of randomized controlled clinical trials. Rheumatology. 2009;48(9):1155–1159.
39. Hassett AL, Radvanski DC, Vaschillo EG, et al. A pilot study of the efficacy of heart rate variability (HRV) biofeedback in patients with fibromyalgia. Appl Psychophysiol Biofeedback. 2007;32(1):1–10.
40. Babu AS, Mathew E, Danda D, Prakash H. Management of patients with fibromyalgia using biofeedback: a randomized control trial. Indian J Med Sci. 2007;61(8):455–461.
41. Staud R. Are tender point injections beneficial: the role of tonic nociception in fibromyalgia. Curr Pharm Design. 2006;12(1):23–27.
42. Bennett R, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people with fibromyalgia. BioMed Cent Musculoskeletal Disord. 2007;8:27.
43. Bernardy K, Fuber N, Kollner V, Hauser W. Efficacy of cognitivebehavioral therapies in fibromyalgia syndrome—a systematic review and meta-analysis of randomized controlled trials. J Rheum. 2010; 37(10):1991–2005.
44. Pfeiffer A, Thompson JM, Nelson A, et al. Effects of a 1.5-day multidisciplinary outpatient treatment program for fibromyalgia: a pilot study. Am J Phys Med Rehabil. 2003;82(3):186–191.
45. Thieme K, Flor H, Turk DC. Psychological pain treatment in fibromyalgia syndrome: efficacy of operant behavioural and cognitive behavioural treatments. Arthritis Res Ther. 2006;8(4):R121.
46. Karsdorp PA, Vlaeyen JW. Active avoidance but not activity pacing is associated with disability in fibromyalgia. Pain. 2009;147(1–3):29–35.
47. Nielson WR, Jensen MP, Hill ML. An activity pacing scale for the chronic pain coping inventory: development in a sample of patients with fibromyalgia syndrome. Pain. 2001;89(2–3):111–115.
48. Nielson WR, Jensen MP. Relationship between changes in coping and treatment outcome in patients with fibromyalgia syndrome. Pain. 2004;109(3):233–241.
49. Goldenberg DL. Multidisciplinary modalities in the treatment of fibromyalgia. J Clin Psychiatry. 2008;69(suppl 2):30–34.
50. Van Houdenhove B, Neerinckx E, Onghena P, Lysens R, Vertommen H. Premorbid ‘‘overactive’’ lifestyle in chronic fatigue syndrome and fibromyalgia: an etiological factor or proof of good citizenship? J Psychosom Res. 2001;51(4):571–576.
51. Sim J, Madden S. Illness experience in fibromyalgia syndrome: a metasynthesis of qualitative studies. Soc Sci Med. 2008;67(1):57–67.
52. Cudney SA, Butler MR, Weinert C, Sullivan T. Ten rural women living with fibromyalgia tell it like it is. Holistic Nurs Pract. 2002;16(3):35–45.
53. Fontaine KR, Conn L, Clauw DJ. Effects of lifestyle physical activity on perceived symptoms and physical function in adults with fibromyalgia: results of a randomized trial. Arthritis Res Ther. 2010;12(2):R55.
54. Togo F, Natelson BH, Cherniack NS, FitzGibbons J, Garcon C, Rapoport DM. Sleep structure and sleepiness in chronic fatigue syndrome with or without coexisting fibromyalgia. Arthritis Res Ther. 2008;10(3):R56.
55. Kalitskus V, Matthiessen PF. Personal growth in chronic illness—a biographical case study of living with fibromyalgia. Forsch Komplementmed. 2010;17(4):203–208.
56. Williams DA, Cary MA, Groner KH, et al. Improving physical functional status in patients with fibromyalgia: a brief cognitive behavioral intervention. J Rheum. 2002;29(6):1280–1286.
57. Allen LA, Woolfolk RL, Escobar JI, Gara MA, Hamer RM. Cognitivebehavioral therapy for somatization disorder: a randomized controlled trial. Arch Intern Med. 2006;166(14):1512–1518.
58. Zautra AJ, Fasman R, Davis MC, Craig AD. The effects of slow breathing on affective responses to pain stimuli: an experimental study. Pain. 2010;149(1):12–18.
59. Zeidan F, Gordon NS, Merchant J, Goolkasian P. The effects of brief mindfulness meditation training on experimentally induced pain. J Pain. 2010;11(3):199–209.
60. Kingston J, Chadwick P, Meron D, Skinner TC. A pilot randomized control trial investigating the effect of mindfulness practice on pain tolerance, psychological well-being, and physiological activity. J Psychosom Res. 2007;62(3):297–300.
61. Holdcraft LC, Assefi N, Buchwald D. Complementary and alternative medicine in fibromyalgia and related syndromes. Best Pract Res Clin Rheum. 2003;17(4):667–683.
62. Kabat-Zinn J, Lipworth L, Burney R. The clinical use of mindfulness meditation for the self-regulation of chronic pain. J Behav Med. 1985;8(2):163–190.
63. Burckhardt CS, Clark SR, Bennett RM. Fibromyalgia and quality of life: a comparative analysis. J Rheum. 1993;20:475–479.
64. Henriksson C, Burckhardt C. Impact of fibromyalgia on everyday life: a study of women in the USA and Sweden. Disability Rehabil. 1996; 18(5):241–248.
65. Jones KD, Liptan GL. Exercise interventions in fibromyalgia: clinical applications from the evidence. Rheum Dis Clin N Am. 2009;35(2):373– 391.
66. Ge HY. Prevalence of myofascial trigger points in fibromyalgia: the overlap of two common problems. Curr Pain Headache Rep. 2010;14(5):339–345.
67. Kim SH, Kim DH, Oh DH, Clauw DJ. Characteristic electron microscopic findings in the skin of patients with fibromyalgia—preliminary study. Clin Rheum. 2008;27(2):219–223.
68. Jones KD, Burckhardt CS, Deodhar AA, Perrin NA, Hanson GC, Bennett RM. A six-month randomized controlled trial of exercise and pyridostigmine in the treatment of fibromyalgia. Arthritis Rheum. 2008;58(2):612–622.
69. Jones KD, Deodhar P, Lorentzen A, Bennett RM, Deodhar AA. Growth hormone perturbations in fibromyalgia: a review. Semin Arthritis Rheum. 2007;36(6):357–379.
70. Staud R, Robinson ME, Weyl EE, Price DD. Pain variability in fibromyalgia is related to activity and rest: role of peripheral tissue impulse input. J Pain. 2010;11(12):1376–1383.
71. Ge HY, Nie H, Madeleine P, Danneskiold-Samsoe B, Graven-Nielsen T, Arendt-Nielsen L. Contribution of the local and referred pain from active myofascial trigger points in fibromyalgia syndrome. Pain. 2009;147(1–3):233–240.
72. Staud R, Nagel S, Robinson ME, Price DD. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double-blind, placebo-controlled study. Pain. 2009;145(1–2):96–104.
73. Staud R, Robinson ME, Price DD. Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls. Pain. 2005;118(1–2):176–184.
74. Staud R. Is it all central sensitization? Role of peripheral tissue nociception in chronic musculoskeletal pain. Curr Rheum Rep. 2010;12(6):448–454.
75. Martinez-Lavin M. Biology and therapy of fibromyalgia—stress, the stress response system, and fibromyalgia. Arthritis Res Ther. 2007;9(4):7.
76. Ross RL, Jones KD, Bennett RM, Ward RL, Druker BJ, Wood LJ. Preliminary evidence of increased pain and elevated cytokines in fibromyalgia patients with defective growth hormone response to exercise. Open Immunol. 2010;3:9–18.
77. Elvin A, Sioteen AK, Nilsson A, Kosek E. Decreased muscle blood flow in fibromyalgia patients during standardised muscle exercise: a contrast media enhanced colour doppler study. Eur J Pain. 2006;10(2):137–144.
78. Elert J, Kendall SA, Larsson B, Mansson B, Gerdle B. Chronic pain and difficulty in relaxing postural muscles in patients with fibromyalgia and chronic whiplash associated disorders. J Rheum. 2001;28(6):1361–1368.
79. Hauser W, Bernardy K, Arnold B, Offenbacher M, Schiltenwolf M. Efficacy of multicomponent treatment in fibromyalgia syndrome: a meta-analysis of randomized controlled clinical trials. Arthritis Rheum. 2009;61(2):216–224.
80. Norregaard J, Bulow PM, Lykkegaard JJ, Mehlsen J, Danneskiold- Samsooe B. Muscle strength, working capacity and effort in patients with fibromyalgia. Scand J Rehabil Med. 1997;29(2):97–102.
81. van Santen M, Bolwijn P, Landewe R, et al. High or low intensity aerobic fitness training in fibromyalgia: does it matter? J Rheum. 2002;29(3):582–587.
82. Mannerkorpi K, Nordeman L, Cider A, Jonsson G. Does moderate-tohigh intensity nordic walking improve functional capacity and pain in fibromyalgia? A prospective randomized controlled trial. Arthritis Res Ther. 2010;12(5):R189.
83. Altan L, Korkmaz N, Bingol U, Gunay B. Effect of pilates training on people with fibromyalgia syndrome: a pilot study. Arch Phys Med Rehabil. 2009;90(12):1983–1988.
84. Paiva ES, Jones KD. Rational treatment of fibromyalgia for a solo practitioner. Best Pract Res Clin Rheum. 2010;24(3):341–352.
85. Holton KF, Kindler LL, Jones KD. Potential dietary links to central sensitization in fibromyalgia: past reports and future directions. Rheum Dis Clin N Am. 2009;35(2):409–420.
86. Shapiro JR, Anderson DA, Danoff-Burg S. A pilot study of the effects of behavioral weight loss treatment on fibromyalgia symptoms. J Psychosom Res. 2005;59(5):275–282.
87. Hooper MM, Stellato TA, Hallowell PT, Seitz BA, Moskowitz RW. Musculoskeletal findings in obese subjects before and after weight loss following bariatric surgery. Int J Obes. 2007;31(1):114–120.
88. Hanninen O, Kaartinen K, Rauma AL, et al. Antioxidants in vegan diet and rheumatic disorders. Toxicology. 2000;155(1–3):45–53.
89. Kaartinen K, Lammi K, Hypen M, Nenonen M, Hanninen O, Rauma AL. Vegan diet alleviates fibromyalgia symptoms. Scand J Rheum. 2000;29(5):308–313.
90. Holton K, Naas S, Griffin T, et al. Preliminary results of a novel dietary intervention in fibromyalgia patients with irritable bowel syndrome. J Pain. 2010;11(4, suppl 1):S53.
91. Bigatti SM, Hernandez AM, Cronan TA, Rand KL. Sleep disturbances in fibromyalgia syndrome: relationship to pain and depression. Arthritis Rheum. 2008;59(7):961–967.
92. Moldofsky H, Scarisbrick P. Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosomatic Med. 1976;38(1):35–44.
93. Harding SM. Sleep in fibromyalgia patients: subjective and objective findings. Am J Med Sci. 1998;315(6):367–376.
94. Geisser ME, Glass JM, Rajcevska LD, et al. A psychophysical study of auditory and pressure sensitivity in patients with fibromyalgia and healthy controls. J Pain. 2008;9(5):417–422.
95. Theadom A, Cropley M. This constant being woken up is the worst thing: experiences of sleep in fibromyalgia syndrome. Disability Rehabil. 2010;32(23):1939–1947.
96. Krakow B. Potential impact of sleep disorder treatment in fibromyalgia patients. Arch Intern Med. 2006;166(12):1323; author reply 1323–1324.
97. Tiede W, Magerl W, Baumgartner U, Durrer B, Ehlert U. Sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain ratings in healthy volunteers. Pain. 2010;148(1):36–42.
98. Moldofsky H, Inhaber NH, Guinta DR, Alvarez-Horine SB. Effects of sodium oxybate on sleep physiology and sleep/wake related symptoms in patients with fibromyalgia syndrome: a double blind, randomized, placebo-controlled study. J Rheum. 2010;37(10):2156–2166.
99. Arnold LM. Strategies for managing fibromyalgia. Am J Med. 2009;122(12 suppl):S31–S43.
100. Jensen MP, Nielson WR, Turner JA, Romano JM, Hill ML. Changes in readiness to self-manage pain are associated with improvement in multidisciplinary pain treatment and pain coping. Pain. 2004;111(1– 2):84–95.

Primary Sjögren's syndrome (pSS) is a chronic multisystem disease affecting 0.3%–0.5% of the adult population.^{1, 2} Women are nine times more likely to be affected than men.^1–4 The disease is characterized by oral and ocular dryness, fatigue, and musculoskeletal pain. PSS can affect other organ systems including the skin, nervous system, lungs, and kidneys.^{3, 4} Patients with pSS have a greater than 40-fold increased risk of developing B-cell mucosa-associated lymphoid tissue (MALT) lymphoma.^{4, 5} Patients with pSS have poor health-related quality of life and a significant proportion of pSS patients are unable to work due to their condition.^{2, 6–17} Both direct and indirect health care costs are higher in pSS than in the general population.^{17, 18} PSS is not, therefore a benign condition, but has a significant health and economic burden to patients and society.

The cause of pSS is unknown but the hallmark of the condition is the presence of inflammatory infiltrates in the affected exocrine glands and the presence of characteristic autoantibodies against RNA-binding proteins Ro and La. This, along with a frequently raised total IgG level, raised levels of B-cell survival factors such as BlyS/BAFF¹⁹ and the increased risk of B-cell lymphoma suggests an important role for B-cell hyper-reactivity. In addition, histological, molecular and genetic data from clinical studies and animal models have implicated dysregulation of other components of the immune system (eg, cytokines, chemokines, T-cells, and the innate immune system) in driving the disease process.

At present, treatment is symptomatic based on careful oral hygiene, the use of artificial tears and saliva and glandular stimulants such as pilocarpine. There is a modest role for conventional immunosuppressants in patients with systemic disease. The management of pSS-associated fatigue and poor health-related quality of life remains a considerable challenge.²⁰ Recent advances in the understanding of pSS pathogenesis have opened up new avenues of more targeted therapeutic strategies. For instance, a potential role for anti-B-cell therapies is a current area of active clinical research.

In parallel, significant progress has been made in a number of areas of clinical research. Probably the biggest single advance has been a consensus on classification criteria—the American–European Consensus Group (AECG) criteria.²¹ Another area of significant progress has been the development of patient symptom questionnaires and disease assessment tools.^22–30 In the UK, these projects have galvanized the formation of the UK Sjögren's Interest Group (UKSIG), a network of clinicians and scientists with an interest in pSS. Over the past 2 years, a further European and International collaboration is developing consensus on these questionnaires and tools^{27, 28} and, as a result, standardized approaches to data collection and analysis are now possible.

Advances in clinical and laboratory investigative technologies including the emergence of high-throughput technologies such as proteomics and genomics that allow systematic analysis of genome composition and gene expression profiling has also opened up new avenues in dissecting the molecular basis of pSS and thus the potential for future, targeted drug development.

The provision of additional infrastructure support through the creation of a large cohort of clinically well-characterized patients with pSS and the creation of a research biobank could provide a timely and much needed resource and catalyst for pSS research.

The UK Primary Sjögren's Syndrome Registry

The UK primary Sjögren's syndrome registry (UKPSSR) is a planned cohort of 500 clinically well-characterized patients with pSS fulfilling the AECG consensus criteria.³¹ The UKPSSR is funded by the Medical Research Council, UK. The primary objective of the UKPSSR is to promote high-quality clinical research and facilitate clinical trials of pSS. In addition, it is hoped that the establishment of the UKPSSR will foster collaborative research and enhance the profile of pSS research within the wider community.

All patients recruited are assessed for disease activity and damage, together with other detailed, relevant clinical information including data on quality of life using appropriate validated instruments. All clinical information are collected using a standardized pro forma, which is available on the UKPSSR website (www.sjogrensregistry.org) to registered users. The clinical data are summarized in Table 1. In addition to clinical data collection, peripheral blood samples from the participants are stored for future research. Therefore, the UKPSSR is more than a patient cohort, but also an epidemiological research project as well as a research biobank. There are also a few potential weaknesses in its design, which has been discussed in a recent article.³¹

To date, nearly 400 patients have been recruited from 19 recruitment centers across the UK, with several additional centers expected to commence recruitment in the near future. We anticipate that recruitment will be completed by the summer of 2011.

Other Sjögren's Syndrome Registries

The Sjögren's International Collaborative Clinical Alliance (SICCA) is setting up a research biobank and registry of patients and family members with sicca symptoms or other autoimmune features without requiring participants to fulfill the classification criteria of the AECG,³² it will be interesting to compare the data generated by the UKPSSR and that of the SICCA registry. Other pSS cohorts are also being identified in Italy,^{33, 34} Spain,³⁵, France,³⁶ Sweden,³⁷ and Greece.³⁸ By combining forces in international collaborating studies, cohorts numbering several thousand patients can be generated and these will facilitate epidemiological and genetic studies³⁹ where such large numbers are required to perform definitive studies.

ASSESSMENT OF THE UKPSSR

A number of criteria have been proposed to assist in the evaluation of Disease Research Registries.^40–44 We now describe the UKPSSR in relation to a number of these areas.

Process and Quality Assurance

Clear aims and objectives

The creation of a patient cohort and research biobank requires considerable human efforts and financial resources, therefore such a project should have clear aims and objectives that justify the work. These aims and objectives set the standards for assessing the success of the project. The aims and objectives of the UKPSSR and the needs and value of such infrastructure in Sjögren's syndrome research have been discussed above.

Leadership and multidisciplinary team

Due to the complexity of designing and managing a successful registry and research biobank, the skills required will rarely be found in one individual. Instead, a multidisciplinary team is needed. The UKPSSR is led by four investigators. Each offers different skill sets that are important for the success of the project. Dr Wan-fai Ng is an academic rheumatologist with expertise in immune tolerance and autoimmunity and is responsible for the overall management and development of the registry. He also co-ordinates the scientific development of the UKPSSR. Dr Simon Bowman is an experienced rheumatologist who has a long-standing interest and international reputation in clinical research in pSS. He has founded the UKSIG and developed several key outcome measurement tools for pSS. Dr Ian Griffiths (now retired) and Dr Bridget Griffiths are experienced clinicians who have developed a regional cohort of patients with pSS and had utilized the cohort for a number of clinical studies. Dr Ian Griffiths was also the rheumatology adviser to the chief medical officer and the chairman of the British Society for Rheumatology Biologics Registry, a highly successful registry that informs clinical practice and provides an invaluable resource for research. Therefore, this team of investigators has combined clinical and scientific expertise in pSS, experience and leadership in patient cohort, and clinical database management, a network of clinicians and scientists with an interest in pSS, as well as a strong commitment, drive and desire to promote pSS research.

Information technology

In addition to strong leadership, expertise in information technology, biostatistics, clinical database and research biobank management including quality assurance as well as publicity and public engagement are also needed.

At the outset, the UKPSSR has been supported by a software development company, which has a strong background in software development in partnership with the NHS institutions. The company has developed the registry website and the database including the online portals for recruitment centers. Throughout the development process, the staff of the UKPSSR worked closely with the staff of the software company to ensure that the final product is fit for purpose. Furthermore, the UKPSSR is also supported by a part-time data manager who assists in day-to-day data management as well as updating the registry website.

Biobanking

In order to provide a reliable and efficient management structure for the processing and storage of high-quality biological materials, the UKPSSR is supported by a dedicated biobank manager at the University of Newcastle with leadership experience in pharmaceutical industry biobanking.

Biostatistics

Access to biostatistics support for the UKPSSR is provided by the Institute of Health and Society at the University of Newcastle and funding for such biostatistics service is available.

Steering committee

A steering committee consisting of seven clinical and scientific experts in pSS has been set up to review the applications for using the UKPSSR data and biological samples as well as to advice on the creation, management, and future development of the UKPSSR.

Funding

The Medical Research Council UK has provided the funding for the establishment of the UKPSSR, which is budgeted at full economic cost for the entire duration of the project. This funding was obtained through a competitive application process in 2008 to support the development of clinically well-characterized patient cohorts. This financial support has provided a stable and sufficient financial support to ensure the success of this project. “The MRC believes that disease registries offer valuable research opportunities, particularly when linked with other health, economic, social and demographic data”.⁴⁰

Patient representation

Patient representatives from the British Sjögren's Syndrome Association (BSSA) contributed to the design, recruitment strategies, and management of the UKPSSR. We provide regular updates on the progress of recruitment and utilization of the UKPSSR to the BSSA and local pSS patient support groups.

Simplicity and flexibility

The recruitment is designed in a manner that can be carried out during a routine appointment or as a dedicated appointment depending on the availability of support from other clinical or nursing staff in the recruitment process. All the materials required for the data and sample collection are provided for the recruiting centers. A fully trained senior research nurse is available to answer any queries relating to the protocol of recruitment. Recruiting clinicians are given flexibility in their methods of identifying candidate patients for the UKPSSR. We also provided a choice of courier companies for the transfer of samples that best suit the individual recruitment centers.

Access to samples and data

Since the ultimate goal of the UKPSSR is to facilitate high-quality pSS research, it is important that all the resources of the UKPSSR (ie, the biological materials and the corresponding anonymized clinical data) are widely accessible by researchers while at the same time to put in place a robust mechanism to ensure that the quality of the research utilizing the UKPSSR resources is high. This is particularly important when considering applications for utilizing resources that are finite (eg, serum and RNA).

Review of research project requests

In order to quality-assure the research proposals utilizing the UKPSSR resources, formal application for the use of the UKPSSR data or biological materials are mandatory. All the applications are reviewed by the steering committee and are assessed on the scientific merits and clinical relevance of the proposed research. Samples and data will only be released after evidence of adequate financial support and when all regulatory approvals are obtained. Furthermore, material transfer agreements will be made between the UKPSSR and the receiving organization to ensure that the data and samples are used for the proposed project and that the data and samples will be handled appropriately and in strict confidence.

Publicizing the UKPSSR to the research community

To widen the accessibility of the UKPSSR resources, we will consider applications from academic organizations as well as their industrial partners irrespective of their geographical location. It is also important that the UKPSSR is well publicized in order to attract high-quality scientific applications. In addition, the investigators also engage directly with researchers who have the expertise and interest in pSS research to develop research proposals.

Informed consent was explicitly obtained from all participants that their biological samples and data can be used for future research projects provided the research proposals satisfy certain conditions including the approval by the steering committee and that the proposal must be directly related to pSS. Such an approach has been approved by the UK research ethics committee (REC). In other words, it is possible to use the UKPSSR resources for pSS research without obtaining separate project-specific REC approvals.

Sample quality assurance

A major challenge is to quality assure the UKPSSR data and samples especially when a large number of centers are involved in recruitment. To ensure the establishment of a research biobank of high-quality samples, standard operation procedures are in place covering sample procurement, sample transfer from recruitment sites to the UKPSSR, as well as processing, storage, and catalogue of the samples at the UKPSSR. In addition, supply agreements are set up between the UKPSSR and the recruitment centers defining the standards expected of the procurement procedures and the transfer of the samples as well as the responsibility of the recruiting sites and the receiving organization. All samples are processed (extraction of serum and peripheral blood mononuclear cells) and stored within 24 hours upon collection. Any unexpected delay in the receipt or processing of the samples or missing or inadequate sampling will be documented and replacement samples will be obtained if possible.

All UKPSSR samples are stored in storage vessels with a monitoring alarm to detect temperature rising above or falling below the acceptable ranges. All incidents of the storage temperature falling outside the acceptable range will be recorded, and samples will be moved to emergency storage vessels with the correct temperature setting if the storage temperature did not return to the desirable range within 4 hours.

A dedicated database is set up to record the nature and quantity of the samples, the storage location, the number of freeze-thaw cycles that the samples has undergone, and any incidents that have led to the violation of protocol. In order to maintain a clear audit trail, all entries and changes to the database are recorded.

Data quality assessment and missing data

Several measures are used to ensure the robustness of our data. Firstly, during the set-up phase of the registry, we held a series of meetings inviting all the recruiting clinicians and patient representatives to discuss all aspects of the recruitment process such as the design of the proforma and database, patient identification and selection, the organization of recruitment, data and sample collection, and strategies to secure research infrastructure support. This consultation process helped to develop a protocol that is as feasible and practical as possible without compromising the design of the registry. Nevertheless, in this project, comprehensive clinical information is being collected that can be particularly challenging if patients are recruited during routine outpatient appointments. To facilitate clinical data collection, all data, including subjective and objective clinical assessments and patient reported outcomes, are being collected using a standardized proforma, or directly onto the web-based database via a secured online portal. This online portal allows the clinicians to enter data directly at source and could reduce the risk of data loss during transfer and improve the efficiency of clinical data collection. Nevertheless, the collection of high-quality data still require highly motivated, vigilant, and dedicated recruiting clinical staff. The quality of the clinical data will also depend on the quality of the medical records available at source.

Validation of data

Another key measure for quality assurance of the data is monitoring and audit. All the data will be checked for accuracy and completeness. The database will also detect and highlight clinical data that are significantly outside the normal ranges as well as highlight missing entries. These measures will help the staff of the UKPSSR to validate the data collected. In addition, a formal audit will be carried out at least once during the lifetime of the project.

Compliance with regulatory requirements

Compliance with the regulatory requirements is an essential element of the UKPSSR, which not only safeguards the interests of the UKPSSR participants, but also ensures that the UKPSSR resources are not misused. The relevant regulatory requirements include the Human Tissue Act (HTA) 2004 for the storage of biological materials, research ethics approval, and data protection.

The collection and storage of biological materials for the UKPSSR is covered by the license granted under the HTA 2004 to Newcastle University, where the samples are processed and stored. Research ethics committee (REC) approvals have been obtained for the establishment of the registry and the subsequent use of the data and biological samples collected for research directly relevant to pSS. Annual reports on the progress of recruitment and the summary and titles of projects that have utilized the UKPSSR resources are submitted to the REC and to the MRC.

Data protection

The UKPSSR is compliant with the Data Protection Act 1998, which regulates the use of computerized information and paper records of identifiable individuals. All recruiting sites have approvals from their corresponding Caldicott Guardian for the transfer of clinical and personal data to the registry. All personal identifiable data are transferred to and stored at the UKPSSR separately from the clinical data. Data collected via the online portal are fully encrypted and access is limited to registered users only. The database is installed onto a password-protected computer in a locked office. Access to the database requires an additional password, which is given only to the staff of the UKPSSR with responsibility for the data management.

Staff training and appraisal

Adequate training and support for recruiting staff is an essential component of the quality assurance process. This is accomplished through group training sessions, one-to-one training during site initiation visits, and opportunity for recruiting staff to “shadow” the recruitment process.

Publicity and public engagement

A website (www.sjogrensregistry.org) has been set up to increase the public awareness and provide information of the registry. We have included on the website different sections tailored for patients, clinicians, scientific researchers, as well as the general public. The website also establishes an Internet presence and strengthens our brand identification. Furthermore, we produce regular newsletters and circulate to clinicians and scientists as well as patient associations and support groups. We also give presentations at meetings of appropriate medical and scientific learned societies as well as meetings of patient support groups. In addition, two of the investigators are members of the medical council of the BSSA, the largest patient association for pSS in the UK. This has provided a unique opportunity to promote the UKPSSR and engage with the patient users.

Outputs

Recruitment

We are on track to recruit the 500 pSS patients as proposed in the study application. This will be the largest cohort of patients with pSS recruited in the UK. The recruitment of matched controls is desirable but perhaps arguably not “central” to the success of the registry and is not in our original proposal. The recruitment of comparator controls is proceeding more slowly and will be considered further by the Steering Committee in the context of strategies to improve the utilization of the Registry.

Research studies

To date, the cohort is being used for a mixture of new and ongoing clinical and academic projects (Table 2), including the award of several additional grants. What is particularly encouraging is that these research projects involve collaborations between a number of research organizations.

In our original proposal, a key milestone is that the UKPSSR will be available for pSS research within 12 months. In that regard, the UKPSSR data and biological samples are being utilized for three research projects (including two new projects and one ongoing projects) within 1 year since recruitment has started. Taking into account the relatively short period of time since the UKPSSR project has started, the utilization of the UKPSSR is encouraging to date. However, efforts must continue to be made to develop high-quality research projects utilizing the cohort that are competitive nationally and internationally. Involvement of appropriate industrial partners should be encouraged.

Future development

Our vision is that the UKPSSR will be the foundation of a long-term collaborative project. Therefore, it is important that we look ahead to the future development of the registry. Firstly, we plan to collect longitudinal data at 3–5 years after the inception, and every 5 years subsequently. In this regard, the UKPSSR is modeled on a successful rheumatology cohort, the Norfolk Arthritis Register.⁴⁵ Longitudinal study of the cohort will not only generate valuable data on the natural history of pSS, which is at present poorly understood, but also important in the evaluation of systemic features such as pulmonary manifestations, peripheral neuropathy, and lymphomas that are more common in patients with longer disease duration.^{37, 38} In order to address some of the potential biases relating to the sampling methods of UKPSSR, creation of additional smaller pSS cohorts such as an “inception cohort” of newly diagnosed pSS patients, cohort of pSS negative for anti-Ro/La autoantibodies, or a cohort of pSS patients based on systematic sampling within a population. The potential added values of such cohorts, however, will be better assessed after the recruitment of the UKPSSR has been completed and the full data set has been analyzed. A longer-term challenge for the UKPSSR is the maintenance and development of the cohort as well as the long-term storage of the samples that will require securing further funding to support the necessary personnel and consumables cost. In this regard, the proposal of the development of a nationwide research database and biobank of rheumatic diseases, the INBANK, by the Arthritis Research UK could provide an opportunity for the UKPSSR to contribute and collaborate.

In addition to cohort development, we also envisage that the data from the UKPSSR will guide the development of a simplified version of the database that is suitable for using in the day-to-day management of pSS patients. Such a database will not only improve the standard of care of pSS patients but also facilitate standardization of data collection, which in turn will benefit future research and clinical audits.

Furthermore, we hope to establish a collaborative network with other pSS registries across the world and to reach a consensus on a core data set that is important for all pSS registries. Such a consensus can further promote data sharing, increase the power of the data analysis and ultimately benefits pSS research and patient care.

Conclusions

The UKPSSR will enhance pSS research by facilitating clinical and academic studies as well as generating an invaluable set of epidemiological data. The key challenge for the UKPSSR is ensuring that the quality standards of the data and biological samples are high. The establishment of the UKPSSR depends on the enthusiasm, commitment, and hard work of all the UKPSSR contributors. The ultimate success of the UKPSSR will be measured by its utilization for high-quality pSS research. In the longer term, it is hoped that the UKPSSR will serve as a platform for the creation of a more extensive collaborative research network for pSS.

Keywords

primary Sjögren's syndrome, registry, research biobank, patient cohort

Acknowledgements: We wish to thank all the patients that have taken part in the UKPSSR.

WFN, SJB, BG are investigators of the UKPSSR, the other contributors to the UKPSSR as of November 2010 (but additional centers are still joining) include, in alphabetical order of their affiliations:

Elalaine Bacabac, Robert Moots, (Aintree University Hospitals); Michele Bombardieri, Constantino Pitzalis, Nurhan Sutcliffe (Barts and the London NHS Trust); Nagui Gendi (Basildon Hospital); John Hamburger, Andrea Richards (Birmingham Dental Hospital); Saaeha Rauz (Birmingham & Midland Eye Centre); Paul Allcoat, John McLaren (Whyteman's Brae Hospital, Fife); Julie Edwards, Diarmuid Mulherin (Cannock Chase Hospital); Jacqueline Andrews, Paul Emery, Colin Pease (Chapel Allerton Hospital, Leeds); Alison Booth, Marian Regan (Derbyshire Royal Infirmary); Monica Gupta, John Hunter, Lesley Stirton (Gartnavel General Hospital, Glasgow); Gill Ortiz, Elizabeth Price (Great Western Hospital, Swindon); Beverley Jones, Susan Knight, Deborah Symmons (Macclesfield District General Hospital & Arthritis Research UK Epidemiology Unit, Manchester); Marco Carrozzo, Suzanne Edgar, Francisco Figuereido, Heather Foggo, Ian D Griffiths, Dennis Lendrem, Iain Macleod, Sheryl Mitchell, (Newcastle upon Tyne Hospitals NHS Foundation Trust); Adrian Jones, Peter Lanyon (Nottingham University Hospital); Steven Young-Min (Queen Alexandra Hospital, Portsmouth); Susan Pugmire, Saravanan Vadivelu (Queen's Elizabeth Hospital, Gateshead); Annie Cooper (Royal Hampshire County Hospital); David Coady, Elizabeth Kidd (Sunderland Royal Hospital); Bhaskar Dasgupta, Pamela Long (Southend University Hospital), Ian Giles, David Isenberg, Ada Ferenkah-Koroma (University College Hospital).

Disclosure: SJB has consulted for Roche, UCB, Chugai, Medimmune and Genentech. The other individual authors have declared no conflict of interest.

Funding: Medical Research Council, UK (Grant No. G0800629). The cardiovascular substudy of the UKPSSR also receives support from the British Sjögren's Syndrome Association.

REFERENCES

1. Gabriel SE, Michaud K. Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther. 2009;11:229.
2. Thomas E, Hay EM, Hajeer A, Silman AJ. Sjögren’s syndrome: a community-based study of prevalence and impact. Br J Rheumatol. 1998;37:1069–1076.
3. Fox RI. Sjögren’s syndrome. Lancet. 2005;366:321–331.
4. Voulgarelis M, Tzioufas AG, Moutsopoulos HM. Mortality in Sjögren’s syndrome. Clin Exp Rheumatol. 2008;26:S66–S71.
5. Kassan SS, Thomas TL, Moutsopoulos HM, et al. Increased risk of lymphoma in sicca syndrome. Ann Intern Med. 1978;89:888–892.
6. Strömbeck B, Ekdahl C, Manthorpe R, Wikström I, Jacobsson L. Healthrelated quality of life in primary Sjögren’s syndrome, rheumatoid arthritis and fibromyalgia compared to normal population data using SF-36. Scand J Rheumatol. 2000;29:20–28.
7. Tensing EK, Solovieva SA, Tervahartiala T, et al. Fatigue and health profile in sicca syndrome of Sjögren’s and non-Sjögren’s syndrome origin. Clin Exp Rheumatol. 2001;19:313–316.
8. Rostron J, Rogers S, Longman L, Kaney S, Field EA. Health-related quality of life in patients with primary Sjögren’s syndrome and xerostomia: a comparative study. Gerodontology. 2002;19:53–59.
9. Bowman SJ, Booth DA, Platts RG; UK Sjögren’s Interest Group. Measurement of fatigue and discomfort in primary Sjögren’s syndrome using a new questionnaire tool. Rheumatology. 2004;43:758–764.
10. Belenguer R, Ramos-Casals M, Brito-Zerón P, et al. Influence of clinical and immunological parameters on the health-related quality of life in patients with primary Sjögren’s syndrome. Clin Exp Rheumatol. 2005;23: 351–356.
11. Champey J, Corruble E, Gottenberg JE, et al. Quality of life and psychological status in patients with primary Sjögren’s syndrome and sicca symptoms without autoimmune features. Arthritis Rheum. 2006; 55:451–457.
12. Stewart CM, Berg KM, Cha S, Reeves WH. Salivary dysfunction and quality of life in Sjögren’s syndrome: a critical oral-systemic connection. J Am Dent Assoc. 2008;139:291–299.
13. López-Jornet P, Camacho-Alonso F. Quality of life in patients with Sjögren’s syndrome and sicca complex. J Oral Rehabil. 2008;35:875–881.
14. Meijer JM, Meiners PM, Huddleston Slater JJ, et al. Health-related quality of life, employment and disability in patients with Sjögren’s syndrome. Rheumatology. 2009;48:1077–1082.
15. Segal B, Bowman SJ, Fox PC, et al. Primary Sjögren’s syndrome: health experiences and predictors of health quality among patients in the United States. Health Qual Life Outcomes. 2009;7:46.
16. Baturone R, Soto M, Marquez M, et al. Health-related quality of life in patients with primary Sjögren’s syndrome: relationship with serum levels of proinflammatory cytokines. Scand J Rheumatol. 2009;2:1–4.
17. Callaghan R, Prabu A, Allan RB, et al. Direct healthcare costs and predictors of costs in patients with primary Sjögren’s syndrome. Rheumatology. 2007;46:105–111.
18. Bowman SJ, St. Pierre Y, Sutcliffe N, et al. Estimating indirect costs in primary Sjögren’s syndrome. J Rheumatol. 2010;37:1010–1015.
19. Mariette X, Roux S, Zhang J, et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren’s syndrome. Ann Rheum Dis. 2003;62(2):168–171.
20. Ng WF, Bowman SJ. Primary Sjogren’s syndrome: too dry and too tired. Rheumatology (Oxford). 2010;49(5):844–853.
21. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61: 554–558.
22. Bowman SJ, Hamburger J, Richards A, Barry RJ, Rauz S. Patient-reported outcomes in primary Sjögren’s syndrome: comparison of the long and short versions of the Profile of Fatigue and Discomfort—Sicca Symptoms Inventory. Rheumatology. 2009;48:140–143.
23. Barry RJ, Sutcliffe N, Isenberg DA, et al. The Sjögren’s Syndrome Damage Index: a damage index for use in clinical trials and observational studies in primary Sjögren’s syndrome. Rheumatology. 2008;47:1193–1198.
24. Bowman SJ, Sutcliffe N, Isenberg DA, et al. Sjögren’s Systemic Clinical Activity Index (SCAI)—a systemic disease activity measure for use in clinical trials in primary Sjögren’s syndrome. Rheumatology. 2007;46: 1845–1851.
25. Bowman SJ, Booth DA, Platts RG, Field A, Rostron J; UK Sjögren’s Interest Group. Validation of the Sicca Symptoms Inventory for clinical studies of Sjögren’s syndrome. J Rheumatol. 2003;30:1259–1266.
26. Vitali C, Palombi G, Baldini C, et al. Sjögren’s Syndrome Disease Damage Index and disease activity index: scoring systems for the assessment of disease damage and disease activity in Sjögren’s syndrome, derived from an analysis of a cohort of Italian patients. Arthritis Rheum. 2007;56:2223– 2231.
27. Seror R, Ravaud P, Bowman S, et al. EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI): development of a consensus systemic disease activity index in primary Sjögren’s syndrome. Ann Rheum Dis. 2010; 69(6):1103–1109.
28. Seror R, Mariette X, Bowman S, et al. Accurate detection of changes in disease activity in primary Sjogren’s syndrome by the European League against Rheumatism Sjogren’s Syndrome Disease Activity Index. Arthritis Care Res. 2010;62(4):551–558.
29. Bowman SJ, Pillemer S, Jonsson R, et al. Revisiting Sjogren’s syndrome in the new millennium: perspectives on assessment and outcome measures. Report of a workshop held on 23 March 2000 at Oxford, UK. Rheumatology. 2001;40(10):1180–1188.
30. Pillemer SR, Smith J, Fox PC, Bowman SJ. Outcome measures for Sjogren’s syndrome, April 10–11, 2003, Bethesda, Maryland, USA. J Rheumatol. 2005;32(1):143–149.
31. Ng WF, Bowman SJ, Griffiths B; UKPSSR study group. United Kingdom Primary Sjogren’s Syndrome Registry – a united effort to tackle an orphan rheumatic disease. Rheumatology (Oxford). 2011 Jan;50(1):32–39.
32. Whitcher JP, Shiboski CH, Shiboski SC, et al. A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjögren’s Syndrome International Registry. Am J Ophthalmol. 2010;149(3):405–415.
33. Botsios C, Furlan A, Ostuni P, Sfriso P, Andretta M, Ometto F, Raffeiner B, Todesco S, Punzi L. Elderly onset of primary Sjögren’s syndrome: clinical manifestations, serological features and oral/ocular diagnostic tests. Comparison with adult and young onset of the disease in a cohort of 336 Italian patients. Joint Bone Spine. 2011 Mar;78(2):171–174.
34. Massara A, Bonazza S, Castellino G, et al. Central nervous system involvement in Sjogren’s syndrome: unusual, but not unremarkable— clinical, serological characteristics and outcomes in a large cohort of Italian patients. Rheumatology. 2010;49(8):1540–1549.
35. Ramos-Casals M, Solans R, Rosas J, et al. Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients. Medicine. 2008;87:210–219.
36. Gestermann N, Mekinian A, Comets E, et al. STAT 4 is a confirmed genetic risk factor for Sjogren’s syndrome and could be involved in type 1 interferon pathway signalling. Genes Immun. 2010;11(5):432–438.
37. Theander E, Henriksson G, Ljungberg O, Mandl T, Manthorpe R, Jacobsson LT. Lymphoma and other malignancies in primary Sjögren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65:796–803.
38. Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren’s syndrome. Arthritis Rheum. 2002;46:741–747.
39. Cobb BL, Fei Y, Jonsson R, et al. Genetic association between methyl- CpG binding protein 2 (MECP2) and primary Sjogren’s syndrome. Ann Rheum Dis. 2010;69(9):1731–1732.
40. Newton J, Garner S; Disease Registers in England. A report commissioned by the Department of Health Policy Research Programme in support of the White Paper entitled Saving Lives: Our Healthier Nation. Oxford: Institute of Health Sciences, University of Oxford.
41. Pryor D, Califf R, Harrell F, et al. Clinical databases: accomplishments and unrealised potential. Medical Care. 1985;23(5):623–647.
42. Klaucke D, Buehler J, Thacker S, Parrish R, Trowbridge F, Berkelman R. Guidelines for evaluating surveillance systems. MMMR. 1988;37(S5): 1–18.
43. Buehler JW. Surveillance. In: Rothman KJ, Greenland S. Modern Epidemiology. 2nd ed. Philadelphia, PA: Lippincott-Raven; 1998:435–457.
44. Goldberg J, Gelfand HM, Levy PS. Registry evaluation methods: a review and case study. Epidemiologic Rev. 1980;2:210–220.
45. www.medicine.manchester.ac.uk/epidemiology/research/arc/inflamma torymusculoskeletal/outcomestudies/noar/noarinfo/

Over the last decades, the introduction of the anti-TNF agents has dramatically changed the world of rheumatology by tremendously improving the prognosis of rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). Five anti-TNF agents have now been marketed and they have all demonstrated major improvements in pain, swelling, function, quality of life, and radiographic damage. Nevertheless, there are still an important proportion of patients who fail to respond adequately, loose efficacy over time, or develop toxicity. One of the reasons may be the development of antidrug antibodies. Immunogenicity is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response. In this case, patients develop antibody toward the anti-TNF agents. We will here review the mechanisms for this phenomenon, its clinical impact on efficacy and side effects, and how to manage this issue.

METHODS

For the purpose of this review, we performed a Medline search from 1990 to January 2010. Search terms were “immunogenicity,” “antiantibody,” “anti-TNF,” “infliximab,” “etanercept,” “adalimumab,” “golimumab,” and “certolizumab.” We also hand searched relevant references of retrieved articles as well as abstracts from ACR and EULAR 2009–2010. The search was limited to publications in the English language. Studies on immunogenicity of anti-TNF in nonrheumatologic diseases such as Crohn's disease (CD) were also included if they had relevant information not otherwise available.

REVIEW

What is Immunogenicity?

The currently available anti-TNF agents differ in their construct but some share common structures such as the IgG1 Fc portion except for certolizumab that has two polyethylene glycol molecules (Figure 1). Individuals who receive anti-TNF agents may develop antibodies against different parts of the molecule recognized as a foreign antigen. Antibodies can develop against the isotype (class of immunoglobulin), the allotype (allelic form of the same proteins that vary amongst individuals), or the idiotype (the specific antigene binding site region).¹ Antiallotype, but more so anti-idiotype antibodies, may interfere with the combining site of the antigen thus preventing its binding and action and can be called neutralizing antibodies. However, antibodies may bind with the framework area of the antibody or for anti-isotype with the constant domain that does not prevent binding of the antibody with it⁵ antigen and therefore its function. These antibodies are hence called non-neutralizing but could still reduce the efficacy of the drug by increasing its clearance.

A number of factors can influence the development of antibodies as not all patient receiving anti-TNF agents will mount an immune response. First, its structure is important. Infliximab, the first anti-TNF to be marketed is a chimeric monoclonal antibody, made of both murine and human proteins. Because of these murine particles, infliximab is more likely to induce formation of antibodies than fully humanized anti-TNF such as of adalimumab or golimumab. However, antibodies against those drugs can still develop. Since antibodies to TNF are not naturally occurring it is recognized that even full human antibodies can be recognized as foreign proteins. This can be explained by the fact that the antigen-binding region, that comes from transgenic mice producing human immunoglobulin upon immunization, never have a completely germline structure and are therefore inherently immunogenic.² Etanercept is a fusion protein and does not contain nonhuman elements; however, the hinge part between the two P75 receptors and the Fc portion of the molecule may contain new epitopes that can be recognized as foreign, which explains that antibodies to etanercept have also been detected.

Factors inherent to the patient such as genetic background, age, and immune status may also influence development of antibodies. In order for antibodies to be produced, a drug or protein needs not only to be recognized as foreign but needs to be seen in an inflammatory context to stimulate the immune system. A patient with an infection will be more prone to develop an immune response while a patient receiving immunosuppressive therapy may be less likely to do so.³

Innate antibodies against TNF have been demonstrated in patients with CD. Although these had no impact on the clinical response to infliximab, nonresponders had innate anti-TNF antibodies with greater neutralizing activity than antibodies from responders.⁴ This has not been correlated with the development of anti-infliximab antibodies (AIA) but suggests that intrinsic individuals’ factors may be important on the potential effect of those antibodies. No such observation was made in patients with RA.

The mode of administration, as well as dose and schedule of treatment are also likely to play a role in the development of antidrug antibodies. Higher dosages of infliximab have been associated with lower AIA formation. In a study of 101 RA patients, only 7% of those receiving infliximab 10 mg/kg developed antibodies while it was observed in 21% and 53% of patients receiving 3 and 1 mg/kg of infliximab, respectively.⁵ As opposed to the treatment schedule in rheumatology where the anti-TNF is given at a fixed interval, in CD the anti-TNF agents are sometimes given intermittently, which increases the likelihood of immunogenicity Table 1.⁶

Concomitant immunosuppressive medications also impact on frequency of development of these antibodies and will be discussed in detail later.

Review

How to Measure Immunogenicity

Different assays for immunogenicity have led to the confusion about their clinical relevance and make it difficult to do comparisons across studies.The most commonly used is the enzyme-linked immunoabsorbent assay (ELISA) as it is easily available. Other techniques include the two-site (bridging) assay and the antigen binding test, a radioimmunoassay (RIA). The ELISA is more prone to nonspecific binding.⁷ The two-site assay is more specific and sensitive but does not detect IgG4. Assays to detect humanized/human monoclonal antibodies are less reliable as they are vulnerable to interference from rheumatoid factor.⁸

More importantly, other factors need to be considered when interpreting the result of antidrug antibodies measurements.

The timing of the measurement in relation to the schedule of drug administration is of great importance as detection of the antidrug antibodies depends on the proportional amount of both antidrug antibodies and the persistent serum drug levels.⁹ If the amount of drug exceeds the levels of antidrug antibodies, they will not be detected. If equal amounts of drug and antibody are present, both drug and antibodies will not be measurable. Antidrug antibody can only be detected if they are in excess of the drug or if the drug has been completely cleared. When intending to test a patient for the presence of antidrug antibody, it is advised to always measure circulating drug levels in order to be able to interpret the results of the antidrug testing. Whenever antibodies are detected the test is positive; if both antibodies and drug are not detected the test is deemed negative; but if antibodies are not detected in the presence of detectable drug, the test is defined as nonconclusive as antibodies may exist but are bound to the drug preventing their detection. Another solution is the development of assays that can measure antidrug antibodies despite the presence of the drug in question. Van Schouwenburg et al¹⁰ have recently described a method to detect anti-adalimumab antibodies in the presence of drug by using a pH-shift-anti-idiotype antigen binding test.

Moreover, as already mentioned, antibodies can be neutralizing or non-neutralizing. Neutralizing antibodies will generally be directed against the idiotype of the drug, hence, affecting its binding with TNF while non-neutralizing antibodies will target different part of the molecule and may not interfere with its action. However clearance of the drug bound to its antibody may be increased, thus reducing its efficacy. Differentiating between neutralizing and non-neutralizing antibodies could be important when assessing their effect on clinical efficacy and/or safety.

Even when detected, the meaning and implication of these antibodies is not fully understood. Immunogenicity is an evolving process that will change over time. Some authors have reported that antibodies to infliximab or adalimumab can become undetectable when the drug is pursued or its dose increased.^{11, 12} Prevalence of AIA decreased from 30% to 7% in a study of 573 patients with CD after maintenance of infliximab.¹³

Clinical Impact

Antibodies to anti-TNF agents may have significant efficacy and safety consequences.

Infliximab

Infliximab has been the most studied anti-TNF agent in terms of immunogenicity. Studies in RA report AIA prevalence ranging from 12% to 44%.^{7, 9, 11, 14, 15} They have also been reported in AS, psoriatic arthritis, and systemic sclerosis. They can occur early with 45% of cases developing their AIA within 4 weeks of the first infliximab infusion in a group of patients with CD.¹⁶

The presence of AIA has been associated with decreased infliximab serum levels and an increasing number of studies are reporting an association between development of AIA and nonresponse or diminished response to infliximab. In a study of 51 RA patients, presence and concentrations of AIA were significantly higher in 32 patients needing escalation of infliximab to obtain or maintain a clinical response compared to patients achieving it on 3 mg/kg.¹⁴ In another study, levels of AIA and infliximab were measured and correlated with clinical response in 51 RA patients. Forty-three percent of patients developed AIA and were less often classified as responders defined by DAS28 than patients without detectable antibodies (36% vs 69%, p=.04).¹¹ Bendtzen et al¹⁵ monitored 106 RA patients that had recently started infliximab by measuring infliximab serum levels, AIA, disease activity, and the occurrence of infusion reactions as well as treatment failure. Diminished serum-through levels of infliximab at 1.5 months predicted antibody development and later treatment failure. High levels of antibodies were significantly associated with later dose increases, side effects, and cessation of therapy. Radstake et al¹⁷ also reported that clinical responses correlated with serum-through infliximab levels and AIA formation in 35 RA patients receiving infliximab. De Vries et al¹⁸ have reported similar findings in AS. In 38 AS patients treated with infliximab, the frequency of AIA was significantly higher in patients who did not show treatment response.

Etanercept

Etanercept is a fusion protein of two extracellular domains of the P75 TNF receptor linked to the Fc portion of IgG1. It is a fully human molecule, which means it is less immunogenic than infliximab and other monoclonal antibodies. Anti-etanercept antibodies have been reported in some studies with a prevalence ranging between 2% and 5.6% in RA but up to 18.3% in other diseases.^19–22 However, they do not seem to be associated with decreased clinical efficacy or side effects. In a study of adults with active RA receiving etanercept 50 mg subcutaneously once weekly for 24 weeks, antibodies to etanercept, were detected in 12 of 214 patients (5.6%) but they were all non-neutralizing and their presence did not appear to affect clinical safety or efficacy.²² In another study where 53 patients with AS were treated with etanercept 25 mg twice weekly, no antibodies were detected after 6 months of treatment. Moreover, serum levels of etanercept did not differ between responders and nonresponders.²³ Anti-etanercept antibodies detected in other disease such as psoriasis and juvenile inflammatory arthritis have also shown not to impact the clinical response or adverse events.^{19, 20}

Adalimumab

Adalimumab was the first fully human monoclonal antibody against TNF. Although it is less immunogenic than infliximab, development of anti-adalimumab antibodies (AAA) is not uncommon. Cumulative incidence of these AAA has been reported between 1% and 42% using various detection methods.^{12, 24–26}

The clinical significance of AAA is not as clear as for AIA. In the ARMADA trial that involved 271 patients randomized to adalimumab 20mg, 40mg, 80mg, or placebo, only three patients tested positive for AAA and no correlation with treatment response was observed²⁴. Moreover, there was no significant difference in the ACR20 between patients positive and negative for AAA when adalimumab was used at 40 mg every 2 weeks in a placebo-controlled trial involving 544 patients with RA.²⁵ However, more recent trials have reported different findings. Bartelds et al¹² studied an observational cohort of 121 RA patients on adalimumab to evaluate the relationship between AAA and clinical response. Serum adalimumab concentrations and AAA were measured together with clinical response variables before and up to 28 weeks after the start of treatment. Twenty-one patients (17%) developed AAA and had lower serum adalimumab levels compared with patients who did not have antibodies. Thirty-four percent of patients who failed to achieve a EULAR good response had detectable AAA compared to only 5% of the EULAR responders (p=.032). Patients with antibodies showed less improvement in disease activity (mean [SD] delta DAS28 0.65 [1.35]) than patients without antibodies (mean delta DAS28 1.70 [1.35]) (p=.001). The CHANGE study, a randomized placebo-controlled trial evaluating three doses of adalimumab monotherapy in Japanese patients reported similar findings.²⁷ The cumulative incidence of AAA during the study was 42%, 44%, and 26% for the 20, 40, and 80 mg adalimumab groups, respectively. Anti-adalimumab antibody-positive patients had lower ACR20 rates than AAA-negative patients for all dosage of adalimumab (14%, 28%, and 35% vs 39%, 57%, and 56% for the 20, 40, and 80 mg adalimumab groups, respectively).

Golimumab and certolizumab-pegol

As they have only been recently marketed, less evidence is available for these two drugs but we have some data from the phase III trials.

Golimumab is a fully humanized monoclonal antibody. Antibodies to golimumab were detected in 4% of patients across the phase III RA, PsA, and AS trials through week 24 with similar rates for each diagnosis. No conclusions about relationship with clinical efficacy and adverse events were reported.²⁸

Certolizumab-pegol is a PEGylated Fab′ fragment of a humanized TNF inhibitor monoclonal antibody. In the RA placebo-controlled trials, the overall percentage of patients with antibodies to certolizumab pegol detectable on at least one occasion was 7% (l05 of 1509). Antibody formation was associated with lowered drug plasma concentration and reduced efficacy. In patients receiving the recommended dosage of 200 mg every other week with concomitant methotrexate, the ACR20 response was lower among antibody-positive patients than among antibody-negative patients (Study RAPID1, 48% vs 60%; Study RAPID2, 35% vs 59%, respectively).²⁹

Adverse Events

The association between antidrug antibodies and adverse events is not as strong as for clinical efficacy. Few studies report an association between AIA and infliximab infusion-related reactions. In one study, 11 out of 71 patients receiving infliximab for various diagnoses (RA, AS, vasculitis) developed AIA. Antibodies developed before the second and third infusion and their appearance was strictly related to the timing of the infusion reaction.³⁰ In 442 patients with CD, incidence of infusion reactions was 16% in AIA-positive patients compared to 8% in negative ones.³¹ Development of anti-infliximab antibodies preceded infusion reactions in all 6 out of 38 patients (16%) with AS treated with infliximab in the report by de Vries et al.¹⁸

There is less data for other anti-TNF agents. In a small study, 7 out of 15 RA patients treated with adalimumab developed adverse drug reactions and five of them (71%) had detectable AAA.³². On the opposite, antidrug antibodies have not been associated with adverse events for etanercept and certolizumab-pegol²⁹ and no data is available for golimumab.

Management of Immunogenicity

Prevention

The use of concomitant DMARD has been shown to reduce the potential immunogenicity of anti-TNF agents. Maini et al⁵ reported that none of the patients receiving infliximab in combination with methotrexate 7.5mg/week developed AIA, while they were found in 7% of patients receiving infliximab monotherapy. Similar findings have been described for adalimumab. In a cohort study of 121 patients treated with adalimumab, concomitant methotrexate use was lower in the group with AAA (52%) than in the group without antibodies (84%) (p=.003).¹² Lower rates of antibodies development have also been reported for golimumab and certolizumab-pegol when used in combination with methotrexate.^28–29 Methotrexate was also shown to decrease the incidence of AIA in studies involving patients with CDs.^{13, 16, 33, 34}

Evidence for the influence of other DMARDS is less clear however. Cyclosporine, azathioprine, and sulfasalazine have not been shown to prevent the development of AIA in RA.⁴ In contrast, in CD, azathioprine in association with infliximab did significantly decrease the development of AIA.¹⁶

The influence of corticosteroids has shown conflicting results. In one study of 51 RA patients on infliximab, the ones developing AIA used steroids in lower doses.¹⁴ However, in a randomized-controlled trial of 53 patients with CD, the use of hydrocortisone prior to the first infliximab infusion was associated with less AIA development than with placebo (26% vs 42%, p=.06).³⁴ No association was found between steroids and prevalence of AIA in the study by Bendtzen et al.¹⁵

Therapeutic monitoring

Including drug and antibody levels to the monitoring of patient's treatment could potentially lead to a better use of these drugs. At the moment, although some adjustments are being made based on clinical judgment, most patients will receive the same drug regimen. However, as discussed earlier, there are multiple factors that will determine the development and clinical implication of antidrug antibodies at the individual's level.

In responders, dosage or drug interval could possibly be adjusted according to the drug levels. A study assessing infliximab serum-through levels and AIA in patients with low disease activity (DAS28 ≤3.2) in clinical practice has demonstrated that 31% of patients had low serum-through infliximab levels and 11% had AIA.³⁵ Correlation of serum-through levels between two consecutive visits was very high, which led the authors to conclude that both AIA and serum-through measurements are promising candidates in predicting successful doses de-escalation. In nonresponders, patients with high level antidrug antibodies could be switched to another TNF agent while nonresponders with no antibodies would benefit from switching to a biological agent with a different mechanism of action such as rituximab, abatacept, or tocilizumab Table 2. Some studies support this strategy. In a cohort study of 292 RA patients starting etanercept, 89 patients (30%) who previously failed infliximab or adalimumab (switchers) were compared to anti-TNF-naïve patients.³⁶ Switchers without antidrug antibodies had a decreased treatment response (ΔDAS28=1.2) compared to both anti-TNF naïve patients (ΔDAS28=2.1, p=.001) and switchers with antibodies (ΔDAS28=2.0, p=.017). However, in an open-label study evaluating the effectiveness of adalimumab in RA patients having failed infliximab, baseline AIA status did not significantly impact effectiveness.³⁷

Tolerance induction

Tremendous efforts have been made to create drugs that are less immunogenic by trying to identify and replace the epitopes that are triggering the immune response. Unfortunately, it is not always possible to change an epitope without changing the function of the protein. As described previously, to date, all anti-TNF have demonstrated some degree of immunogenicity and a solution to reduce its effects is the induction of tolerance to the anti-TNF used. A variety of approaches have been developed including the use of gene therapy.³ Although, these remain experimental for the use of anti-TNF, we can hope to see them in clinical practice in the near future.

CONCLUSION

With the increasing number of biological molecules being available for the treatment of rheumatic diseases, immunogenicity will definitely remain a topic of interest. Although, more research is needed, our knowledge of how to interpret and assess antidrug antibodies has greatly improved over the past years. Newer methods of testing for immunogenicity are being developed. There is also accumulating evidence of its clinical impact: while anti-etanercept antibodies do not appear to have an impact on the efficacy and safety of etanercept, antidrug antibodies to adalimumab and even more so infliximab can lead to decreased clinical response, more frequent need of treatment escalation, and more adverse events.

This knowledge impacts clinicians’ practice. While waiting for tolerance induction protocol to become reality, concomitant use of methotrexate (and possibly other DMARDs) is advisable in order to reduce the frequency and impact of antidrug antibodies. One advantage of the reduced immunogenicity of certain agents such as etanercept compared to others is their potential use as monotherapy in patients with contraindications or intolerance to DMARDs. Moreover, if easy to use, assays can be developed; routine dosing of antidrug antibodies and drug serum-through levels may lead to more rational treatment strategies.

Immunogenicity is not unique to anti-TNF agents and with the increasing use of biological agents with different mechanisms of actions such as rituximab, abatacept, and tocilzumab it will also be interesting to see how immunogenicity will impact their efficacy and safety.

Keywords

immunogenicity, anti-drug antibodies, anti-TNF agents, inflammatory arthritis

REFERENCES

1. Coico R SGaBE. Immunology: A Short Course. 5th ed. Hoboken, NJ: John Wiley and Sons; 2003.
2. Clark M. Antibody humanization: a case of the ‘‘Emperor’s new clothes’’? Immunol Today. 2000;21(8):397–402.
3. Scott DW, De Groot AS. Can we prevent immunogenicity of human protein drugs? Ann Rheum Dis. 2010;69(Suppl 1):i72–i76.
4. Ebert EC, Das KM, Mehta V, Rezac C. Non-response to infliximab may be due to innate neutralizing anti-tumour necrosis factor-alpha antibodies. Clin Exp Immunol. 2008;154(3):325–331.
5. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41(9):1552–1563.
6. Cassinotti A, Travis S. Incidence and clinical significance of immunogenicity to infliximab in Crohn’s disease: a critical systematic review. Inflamm Bowel Dis. 2009;15(8):1264–1275.
7. Svenson M, Geborek P, Saxne T, Bendtzen K. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology (Oxford). 2007;46(12): 1828–1834.
8. Tatarewicz S, Miller JM, Swanson SJ, Moxness MS. Rheumatoid factor interference in immunogenicity assays for human monoclonal antibody therapeutics. J Immunol Methods. 2010;357(1–2):10–16.
9. Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of biologicals: assessment and clinical relevance. Curr Opin Rheumatol. 2009;21(3):211–215.
10. van Schouwenburg PA, Bartelds GM, Hart MH, Aarden L, Wolbink GJ, Wouters D. A novel method for the detection of antibodies to adalimumab in the presence of drug reveals ‘‘hidden’’ immunogenicity in rheumatoid arthritis patients. J Immunol Methods. 2010;362(1–2):82–88.
11. Wolbink GJ, Vis M, Lems W, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54(3):711–715.
12. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66(7):921–926.
13. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol. 2004;2(7):542–553.
14. Haraoui B, Cameron L, Ouellet M, White B. Anti-infliximab antibodies in patients with rheumatoid arthritis who require higher doses of infliximab to achieve or maintain a clinical response. J Rheumatol. 2006;33(1):31–36.
15. Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne T. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum. 2006;54(12):3782–3789.
16. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003; 348(7):601–608.
17. Radstake TR, Svenson M, Eijsbouts AM, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1739–1745.
18. de Vries MK, Wolbink GJ, Stapel SO, et al. Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation. Ann Rheum Dis. 2007;66(9):1252–1254.
19. Tyring S, Gordon KB, Poulin Y, et al. Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol. 2007;143(6):719–726.
20. Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med. 2000;342(11):763–769.
21. Keystone EC, Schiff MH, Kremer JM, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50(2):353–363.
22. Dore RK, Mathews S, Schechtman J, et al. The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2007;25(1):40–46.
23. de Vries MK, van der Horst-Bruinsma IE, Nurmohamed MT, et al. Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis. Ann Rheum Dis. 2009;68(4):531–535.
24. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48(1):35–45.
25. van de Putte LB, Atkins C, Malaise M, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis. 2004;63(5):508–516.
26. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50(5):1400–1411.
27. Miyasaka N. Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study. Mod Rheumatol. 2008;18(3): 252–262.
28. Simponi^TM (golimumab) Prescribing information. Horsham, PA: Centocor Ortho Biotech Inc.; 2010.
29. Cimzia^TM (certolizumab-pegol) Prescribing information. Smyma, GA: UBC Inc.; 2010.
30. Vultaggio A, Matucci A, Nencini F, et al. Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions. Allergy. 2010;65(5):657–661.
31. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359 (9317):1541–1549.
32. Bender NK, Heilig CE, Droll B, Wohlgemuth J, Armbruster FP, Heilig B. Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol Int. 2007;27(3):269–274.
33. Vermeire S, Noman M, Van Assche G, Baert F, D’Haens G, Rutgeerts P. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56(9):1226–1231.
34. Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology. 2003;124(4):917–924.
35. van der Maas A DBA, Wolbink GJ, van den Hoogen FHJ, van Riel PLCM, van den Bernt BJF. Prevalence an persistence of low infliximab serum through levels in RA patients with low disease activity in daily clinical practice. Arthritis Rheum. 2010;62(Suppl 10):S763.
36. Jamnitski A, Bartelds GM, Nurmohamed MT, et al. The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis. 2010;70(2):284–288.
37. van der Bijl AE, Breedveld FC, Antoni CE, et al. An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status. Clin Rheumatol. 2008;27(8):1021–1028.

Louis Aliberti, in 1818, first noted the relationship between psoriasis and arthritis. Pierre Bazin then described “Psoriasis Arthritique” in 1860, followed by Charles Bourdillon in 1888 with “Psoriasis et Arthropathies.” Jeghers and Robinson in 1937 and Vilanova and Piñol in 1951 described psoriatic arthritis (PsA) as a unique entity. PsA was recognized after Verna Wright published a comparative study of rheumatoid arthritis (RA), psoriasis, and arthritis associated with psoriasis in 1956 and 1959. The American College of Rheumatology recognized PsA as a distinct entity in 1964.¹

Prevalence of PsA varies in several studies (5%–40%). A large study conducted in the UK, Italy, France, Spain, and Germany in 2006 found 8.1% prevalence of PsA in patients with psoriasis. Survival analysis indicated that the incidence of PsA among plaque psoriasis patients remained constant at 74 per 100 person/years, whereas the prevalence increased with time since diagnosis of psoriasis, reaching 20.5% after 30 years.²

A population based study in Minnesota USA reported the annual incidence of PsA per 100,000 to be 7.2. The incidence increased from 3.6 between 1970 and 1979 to 9.8 between 1990 and 2000, providing the first evidence that the incidence of psoriasis increased during recent decades.³ A second study from 1982 to 1992 in the same community revealed an incidence rate of 6.59% per 100,000 US population.⁴

PsA is characterized by stiffness, pain, swelling, and tenderness of the joints as well as adjacent tendons and ligaments with a penetrance from 6% to 42% in the population with psoriasis. A clinical trial demonstrated that 84% of patients with PsA had only skin disease for an average of 12 years before the development of PsA.⁵

The psoriatic disease is a multifocal and chronic systemic inflammation in which genes and environment play a role. Erosive and deforming arthritis occurs in 40%–60% of patients with PsA. Psoriasis has not been interpreted in the past as a systemic disease; thus, comorbidities have not been well evaluated by the dermatologist.⁶

T-helper cell type 1 (Th1) lymphocytes secreting cytokines, including interleukin (IL)-17, IL-2, IL-6, IL-10, IL-1β, interferon γ (IFN γ), and tumor necrosis factor α (TNFα) among many cytokines, are found in psoriatic synovium and skin plaques and are provoking not only proliferation and abnormal differentiation of keratinocytes and synoviocytes but also a systemic reaction cause of many inflammatory diseases in the same patient, where the cytokine TNFα plays the most relevant role.⁷ Such comorbidities include PsA, metabolic syndrome (MS), palm-plantar pustulosis, inflammatory bowel disease, cardiovascular disease (CVD), hypertension (HTA), myocardial infarct (MI), autoimmune diseases, psychiatric illness, diabetes mellitus (DM), liver disease, smoking, cancer at specific sites, obesity, chronic obstructive pulmonary disease, sleep apnea, alcohol abuse, and depression.⁸

The Classification of Psoriatic Arthritis (CASPAR) study group was established as classification criteria for PsA. The CASPAR criteria comprised: (1) Evidence of psoriasis as judged by a rheumatologist or dermatologist, personal and family history from patient, (2) psoriatic nail dystrophy, including onycholysis, pitting, and hyperkeratosis, (3) a negative test for rheumatoid factor (RF), (4) dactylitis, current swelling of an entire digit, or history of dactylitis, and (5) radiological evidence of juxta-articular new bone formation as ill-defined ossification near joint margins on hand or foot. Using the CASPAR criteria, the combination of psoriasis and inflammatory arthritis gave .96 for sensitivity and .97 for specificity, respectively.^9–11

Three main clinical patterns have been identified in PsA: (1) oligoarticular (≤4 involved joints) or polyarticular (≥5 involved joints), (2) peripheral disease, and (3) axial disease with or without associated peripheral arthritis. Distal interphalangeal arthritis and arthritis mutilans may also occur. Asymmetric oligoarthritis is the most frequent pattern at onset. Axial disease has been estimated between 5% and 36% of patients, characterized by predilection for the cervical spine. Recurrent episodes of enthesitis and dactylitis represent a hallmark of PsA. In 20% of cases, distal extremity swelling with pitting edema of the hands or feet is observed. Unilateral acute iridocyclitis, usually recurrent in alternate fashion, is the most frequent extra-articular manifestation (2%–25%), and accelerated atherosclerosis is the prominent comorbidity.¹²

Development of blood vessels from in situ-differentiating endothelial cells (EC) is called vasculogenesis; whereas, sprouting of new blood vessels from the preexisting ones is termed angiogenesis or neovascularization. Angiogenesis is essential for tissue repair, fetal development, and female reproductive cycle.^{13, 14} One of the most specific and critical regulators of angiogenesis is vascular endothelial growth factor (VEGF) that regulates endothelial proliferation, permeability, and cell survival.^{15, 16} Microvascular alterations are essential for the development and persistence of the psoriatic lesions as they provide cellular and tissue nutrition to hyperplastic keratinocytes and promote inflammatory cell migration. Dilated and tortuous blood vessels within dermal papillae represent one of the earliest detectable histological changes for all stages of lesional development in psoriasis.¹⁷ Dysregulation of angiogenesis and lymphangiogenesis participates in psoriasis pathogenesis. Expansion of lymphatic vessels occurs after blood vascular development in psoriasis.¹⁸ A balance between proangiogenic and antiangiogenic growth factors and cytokines tightly controls angiogenesis. Up-regulation of VEGF and transforming growth factor β (TGFβ), providing the distinctive tortuous vessels noted in psoriatic skin and synovium, has been found in early psoriasis and PsA.^19–21

Concentration of serum VEGF and VEGF receptors (sVEGF-R1, -R2) demonstrated significant correlation with psoriasis area and severity index (PASI). Levels of serum VEGF and sVEGF R1 were the highest in patients with PASI>20.²² In vitro culture studies revealed that VEGF and other cytokines in the skin are secreted predominantly by keratinocytes and its concentration is enhanced in both involved and uninvolved skin of patients with psoriasis suggesting that the epidermis is capable of inducing vascular proliferation.^{23, 24} VEGF receptors are also overexpressed in lesional psoriatic epidermal keratinocytes, are stimulated by VEGF itself, and are capable of binding VEGF, preventing proangiogenic signal transduction that can be a clinically relevant strategy for the inhibition of angiogenesis.²⁵

In skin and synovium of PsA, there is infiltration of neutrophils, positive for receptors VEGF-R1, -R2, together with a prominent T cells infiltrate, localized in epidermis, dermal papillae, and to the sublining stroma in the joints as well as the inflamed enthesis.²⁶ TNFα activates EC, leading to expression of adhesion molecules, including vascular cell adhesion molecule-1 (VCAM1), intercellular adhesion molecule-1 (ICAM1), and E-selectin, all molecules responsible for lymphocyte migration to sites of inflammation.²⁷ TNFα also plays a role in cartilage degradation via increased production of matrix metalloproteinases that are thought to mediate cartilage erosion.^{28, 29}

A predominance of CD8+ T lymphocytes has been noted in both the synovial fluid and entheses of patients with PsA.³⁰ PsA is associated with clonally expanded CD8+ T cells independently from the participation of CD4+ T cells.³¹ PsA explants in vitro released elevated levels of interleukin IL-1β, IL-2, IL-10, IFNγ, and TNFα but not IL-4 or IL-5. A similar pattern of gene expression was detected in whole synovial tissue. Levels of IFNγ, IL1β, and IL-10 were higher in psoriatic synovium than psoriatic dermal plaques.³²

The chronic inflammatory state of PsA and psoriasis contributes to the accelerated atherosclerosis. Aortic pulse wave velocity was reduced after treatment with TNFα antagonists in parallel to decrease in C-reactive protein (CRP) and PASI values.³³ The theory of passive lipid artery accumulation leading to plaque formation has changed because it has been demonstrated that systemic inflammation, involving inflammatory activity in the vascular wall, is fundamental in the pathogenesis of atherosclerosis. Many inflammatory cells and cytokines, including TNFα, play an active role in atherosclerosis, similar to their role on PsA and psoriasis.³⁴ The mean serum VEGF concentration was higher in patients with active PsA (394.4 pg/ml), in contrast to lower values in inactive PsA (200.4 pg/ml) and controls (214.3 pg/ml).³⁵ PsA patients (35%) had a higher prevalence of subclinical atherosclerosis, with significantly increased sugar, total triglyceride levels, white cell count, and patients’ global assessment score compared with those without subclinical atherosclerosis.³⁶

Diabetes mellitus and HTA were found in a higher proportion in PsA patients, who had a significantly lower prevalence of low HDL cholesterol than controls, whereas the prevalence of hypercholesterolemia and hypertriglyceridaemia was similar in both PsA and control groups. The total cholesterol and low-density lipoproteins (LDL) cholesterol levels were significantly lower; in PsA patients.³⁷ These facts underline the role of the vessel wall inflammation in atherosclerosis.

Cardiovascular disease is more prevalent in those with moderate to severe psoriasis than in the general population. A large cohort study revealed a greater than normal incidence of MI in patients with mild and severe psoriasis. Patients with psoriasis are at high risk of developing DM, HTA, obesity, hyperlipidemia, MI, angina, atherosclerosis, peripheral vascular disease and stroke, reinforcing a connection between psoriasis, the systemic inflammation, and heart disease.³⁸ A follow-up study demonstrated similar results in psoriatic patients: HTA (60.1%), obesity (6.3%), DM (27.3%), dyslipidemia, (31.6%), smoking (9.9%), and mortality (19.6%). Psoriasis is an independent risk factor for mortality; with a higher percentage of deaths among patients with psoriasis (19.6%) than among patients without psoriasis (9.9%).³⁹

The increased CVD depends on the inflammatory nature of psoriasis that plays a significant role in atherogenesis and in the formation of early fatty streaks. The immune response in atherosclerosis is modulated by two anti-inflammatory cytokines IL-10 and TGFβ, both play a critical role. Proinflammatory cytokines implicated in the generation of atherosclerotic plaques are mainly produced by macrophages that also activate smooth muscle cells (SMC) and EC similar to cytokines described in psoriasis and PsA.⁴⁰

The lipid-laden foam cells of the fatty streak comprises an area of intimal thickening composed of macrophages distended by lipid droplets (foam cells), T lymphocytes, and SMC. Plaques develop after accumulation of LDL in the subendothelial space, followed by the diapedesis of leukocytes, formation of foam cells, and production of connective tissue.⁴¹ Psoriasis is the most common Th1 immunological disease. Evidence has linked Th1 diseases to MI. A cohort was followed up for a mean of 5.4 years. There were 2.0% MI within the control population and 1.8% and 2.9% MI within the mild and severe psoriasis groups, respectively. The incidences for MI per 1000 person-years for control patients, patients with mild and severe psoriasis were 3.58, 4.04, and 5.13, respectively.^42–44

T lymphocytes (20%) are found surrounding the plaque and in the fibrous cap, pointing to a role of immunity in atherosclerosis.⁴⁵ The NF-κB pathway is one of the main signaling pathways activated in response to proinflammatory cytokines, including TNFα, IL-1, and IL-18, as well as following activation of the Toll-like receptors (TLR) by the pattern recognition of pathogen-associated molecular patterns (PAMPs), and also enzymes such as cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS).^{46, 47}

Animal models of atherosclerosis have shown a very early role for heat shock protein 60 (HsP60) in the development of the disease. Enhanced levels of circulating HsP60 are associated with early atherosclerosis in clinically normal subjects. More than 95% sequence homology exists on both the DNA and protein levels, basis for extensive immunological cross reactions between pathogens including parasites and autologous HsP60. The first cell types found in the arterial intima at atherosclerotic lesions are lymphoid cells followed by macrophages and SMC. Within the T cell population in these early lesions, activated CD4+ HLA-DR+CD25+ T cells prevail over CD8+ cells T cells.⁴¹

The MS is a constellation of interrelated risk factors of metabolic origin that appear to directly promote the development of atherosclerotic CVD and type II DM. MS is defined as a state of chronic systemic inflammation and the presence of abdominal obesity, increased insulin resistance, elevated fasting glucose level, impaired glucose regulation, decreased high-density lipoprotein, hypertriglyceridemia, and HTA.^{48, 49} Increased incidence of MS and CVD has been found in PsA compared with the general population. Studies report that plasma acute phase proteins were significantly elevated in patients with psoriasis compared with healthy controls.^{37, 42}

Cohort analyses followed up from 1978 to 2004 revealed a malignancy in PsA at an average age of 62.4 years. The most frequent were breast (20.6%), lung (13.2%), and prostate (8.8%) cancer. However, the incidence of malignancy did not differ from that in the general population.⁵⁰

MATERIALS AND METHODS

Safety Criteria for the Treatment of Psoriasis and Psoriatic Arthritis

In all trial subjects, safety was evaluated by assessing vital signs (including heart rate and blood pressure), injection site reactions, and physical examinations. In a selected group of subjects, safety was further assessed by clinical laboratory tests (comprehensive hematology and metabolic profile).

Efficacy Criteria Before and After Treatment

Efficacy of AS100 vaccines was assessed by performing skin examinations and recording PASI parameters at each visit as published.^51–54 PASI reduction was calculated as follows: [(PASI at base line)—(PASI at each visit)/PASI at baseline]×100. The primary efficacy parameters were the percentage reduction in PASI score at each visit and the comparative proportions of subjects with 100%, 75%, and 50% PASI improvement in each treatment group. For analysis of LS data before treatment, PASI groups I, II, and III were analyzed in patients with 1–34 years of evolution with psoriasis. PASI score changes after each dose of the active products were classified as follows: <10% PASI reduction (PASI between 1 and 9); ≥10% PASI reduction (PASI between 10 and 49); ≥50% PASI reduction (PASI between 50 and 74); ≥75% PASI reduction (PASI between 75 and 89): and 100% PASI reduction (PASI between 90% and 100%) as previously published^51–54 The total number of subjects with Psoriasis was 3132 volunteers. From that group, 508 subjects (16.22%) had PsA that meet the CASPAR criteria^9–11 and were chosen for the analysis and comparison with 2624 volunteers with skin psoriasis but no arthritis. The study was conducted at one medical center from March 1992 through May 2002 and included all nine types of psoriasis: plaque (79%), guttate (10%), plaque and guttate (10%), palm/plantar (.3%), erythrodermia (1.8%), inverse (.8%), plaque and arthritis (3.4%), and nail psoriasis (.3%) as published.⁵¹ The study group had average age 40.5±15.0 years old, 2894 (92.4%) were between 26 and 65 years of age with a range of 5–88 years old. One thousand ninety six subjects (35%) had family histories of psoriasis. The average duration of disease in all subjects was 11.5±10.3 years, ranging from 2 to 62 years, similar in both males and females. The 508 group with PsA had average age 44.9±14.3 years old, range 5–83 years, time with psoriasis 13.2±12.4 years, range .4–64 years, 53% females. RFs determined in 3% of patients (n=15) with PsA were negative, a low number, due to economic reasons. Eleven percent (53/508) had diagnosis of psoriasis by skin biopsy, the rest by clinical criteria by an experienced dermatologist, checked by a rheumatologist in 15% of cases.⁵² Clinical examination of patients was performed at the clinical site, and comorbidities were recorded at the first visit as in Tables 1 and 2.

Inclusion and Exclusion Criteria

The AS100 trial, main criteria for trial inclusion and exclusion were one and the same as previously published criteria. Briefly, the inclusion criteria were as follows. Eligible subjects included males and females five years of age or older with active but clinically stable plaque psoriasis present for at least three months. Additional inclusion criteria were use of a medically accepted form of contraception throughout the study and a negative pregnancy test (females of child-bearing potential). The exclusion criteria consisted of a positive leishmania infection status and a positive intradermal reaction skin test for leishmania at screening. Any female subject pregnant or lactating was excluded from the trial. Documented immunodeficiency, HIV status, opportunistic infections, or ongoing uncontrolled infections were a basis for trial exclusion. Subjects whose medication involved any vaccines, allergy desensitization products, or use of topical therapy (except emollients) for psoriasis within two weeks preceding the first administration of the study medication were excluded from trial participation. The use of systemic retinoids, corticosteroids, cyclosporine A, methotrexate, phototherapy, coal tar treatments, or receipt of any investigational drug therapy within four weeks preceding the administration of the study medication was also a cause for exclusion. Subjects with a known hypersensitivity to gentamicin or local anesthesia, or diagnostic agents used for tests pertaining to the trial protocol, and a documented history of alcohol abuse were excluded from trial participation as published.^51–54

Preparation of the Polyvalent Immunogen (AS100)

The first-generation polyvalent vaccine AS100 was prepared with four leishmania species: L.(L)amazonensis, L.(L)venezuelensis, L.(V)brasiliensis, and L.(L)chagasi. The final polyvalent first generation immunogen preparation, AS100 drug substance, contained 1 mg/ml or 250 µg of each Leishmania spp. in PBS supplemented with Rehydragel and 4 µg/ml of gentamicin. The placebo dose contained .125 ml of Rehydragel in .5 ml of PBS; the same amount of alumina is present in the 500 µg dose of the polyvalent vaccine. Each step in the preparation of the immunogen was checked for sterility as previously published.^51–54 The concentration of alumina was .25 ml per mg (v/w) of parasitic protein. Protein concentration was determined by Lowry or BCA.^{55, 56}

Preparation of AS200 Purified Vaccine

Preparation of second-generation AS200 immunogen from leishmania protein (DEAE) fractions was as follows: Individual Leishmania species from AS100 polyvalent vaccine were separated by DEAE chromatography. The chromatographic separation resulted in seven protein fractions per each AS100 vaccine component for a total of 28 protein fractions (leishmania protein [DEAE] fractions). The fractions were in turn used to formulate the second-generation immunogen (AS200). Each AS200 vaccine was prepared from each discrete protein fraction; hence, each Leishmania species (La, Lb, Lch, and Lv) potentially had seven AS200 formulations as previously published.⁵⁴ The final immunogen preparation contained 400 µg/ml of each of the antigenic fraction in PBS and Rehydragel at a concentration of .25 ml/mg (v/w) of protein. Protein content was determined by the method of Lowry or BCA.^{55, 56}

AS200 Trial

The AS200 study was a single-blind, controlled trial. The AS200 trial included 53 subjects, 62% females average 40.6±18.6-years-old, age range 7–78 years of age, initial PASI 26.4±19.2, time with psoriasis 15.0±12 years. The treatment subjects received four 200 µg/dose injections of AS200 (Lb) and control subjects received four 500 µg/dose of AS1001.⁵⁴

Statistical Methods

The analysis was similar to previously published guidelines used for AS100-1 trials.^51–54 The ANOVA assumption of normality and homogeneity of variances was tested and, where appropriate, a nonparametric approach (Tukey's test) or Mann–Whitney's test was used to compare treatment groups. A last-observation-carried forward algorithm was used to replace missing observations. D'Agostino & Pearson omnibus normality test and Wilcoxon Signed Rank Test were used to compare column statistics. All calculations were done with GraphPad Prism software.

RESULTS

AS100 Trial

This study was an open label, single-center study that evaluated the safety and efficacy of multiple 500 µg doses of AS100 on PsA. Approximately 2599 subjects (83%) experienced at least one adverse event (AE). The most frequent AE was injection site related, and included the following: pain 43%, nodule formation 23%, heat 21%, and erythema 14%, as previously published.^51–54 When baseline PASI values in the group with PsA (n=508) were compared with posttreatment values, clinical remissions were: PASI 100 in 275 (54.1%), PASI 75 in 117 (23%), PASI 50 in 73 (14.4%), and PASI 10 in 43 (8.5%) of subjects, respectively. The average number of AS100 doses required to induce 100% remission of psoriasis was 9.9±4.8.⁵²

Single Blind Trial With AS200 (L.(V)brasiliensis) and an Active Control (AS100)

All subjects had PASI scores determined prior to treatment, prior to each injection, and at follow-up for two weeks after the last injection Of the 51 subjects treated, 45% experienced no AEs, of the AE observed, most were local in nature. The most frequent AEs of a local nature were injection site pain (39%), erythema (12%), heat (12%), and nodule formation of a short duration (8%). The most common events of a systemic nature were general discomfort (6%) and/or a low-grade fever (16%), sleepiness (6%), and headache (4%). Almost all AE were characterized as mild or moderate. No AE was rated as “serious.” Kruskal–Wallis test between the six Lb AS200 (Lb) treatment groups and AS100 control had a p=.495, and no significant variation between medians (p=.05) was observed. Student's t tests comparing PASI reduction in each of the six treatment arms and the active control resulted in a nonsignificant difference (average p=.310±.22). All AS200 (Lb) vaccines induced PASI reductions in the same range as the active control.⁵⁴

Analysis of Comorbidities in Patients With Psoriasis and PsA

Comorbidities are presented (Table 1) in decreasing percentages of frequency in PsA and compared with the frequency in patients with psoriasis. Less than 1% frequency in both groups was found in the following comorbidities: Hepatitis, Glaucoma, cataracts, amaurosis fugax, prostate hyperplasia, prostatitis, inguinal hernia, pitiriasis versicolor, or alba, hypercholesterolemia, depression, anxiety, psychosis, vitiligo, obesity, alcohol consumption, intercostals neuritis, herpes zoster, anemia, Down syndrome, lipomas, HIV+, amebiasis, leishmaniasis, and toxoplasmosis.

The morbidity statistics in Venezuela were very scarce, only small groups in several localities could be found. Values were 22%–23.3% for HTA (n=952), .17%–.65% for vascular diseases, and 4.4% for diabetes (n=669). For comparison, the mortality percentages in 2008 were included, the only statistics published so far in last five years. Higher percentage frequency in PsA (underline) than psoriasis patients was found in HTA, vascular diseases, intestinal diseases, infections, gastritis, cardiac arrhythmia, gallstones in gallbladder, osteoporosis, hyperuricemia, and epilepsy (Table 1).

Several comorbidities were found in both psoriasis and PsA patients in several cases up to 7–8 comorbidities together in the same subject (Table 2). This fact points out that psoriasis is a systemic disease, induced by inflammatory cytokines in all organs of the body being expressed in each tissue according to genetic and environmental factors due to shared inflammatory pathways.

Column statistitics between 19 values in PsA and skin psoriasis comorbidities frequencies were significant. D'Agostino & Pearson omnibus normality test had p<.0001(two tailed), a similar p value found with the Wilcoxon Signed Rank Test (significant α value=.05). One sample t-test had p=.0019 with 95% CI of discrepancy from 2.055 to 7.661 for PsA and p=.0079 with 95% CI of discrepancy from 1.063 to 6.116 for psoriasis (α value=.05 for both columns).

Clinical Regression of Skin Lesions in AS100 Trial

The first sign of clinical regression in skin psoriasis after treatment with leishmania antigens polyvalent vaccine AS100-1 is the disappearance of itching followed by significant decrease in redness in the plaque from the periphery to the center (Figure 1a), from the center to the periphery, (Figure 1b) indicative of a gradual decrease in angiogenesis, until the whole plaque is white without redness (Figure 1c)

DISCUSSION

We believe that the development and maintenance of psoriasis and PsA since the beginning of lesions is centered in the blood vessels’ behavior. Both diseases start with redness in the skin and joints by proliferation of blood vessels and angiogenesis after up-regulation of VEGF and TGFβ and other angiogenic factors. TNFα is a key cytokine in the inflammatory process because it activates EC, leading to expression of adhesion molecules, VCAM1, ICAM1, and E-selectin, opening the door to cells migration to sites of inflammation.²⁷ A multimolecular complex named immunological synapse is formed between antigen presenting cells (APC) and T cells. At the beginning of lesion formation, APC travel from the skin to the lymph nodes and after activation, CD4+CD8−, CD3+CD8−, CD8+CD3+, CD8+CD4−, and CD8+HLA− decreased in PBMC as PASI increased, suggesting migration from the blood to the skin. Contrary to the previous finding, the following LS: CD8+HLA+ and HLA+CD8−, and membrane surface immunoglobulin IgA+, IgD+, and IgM+ increased in PBMC as PASI increased, suggesting activation and proliferation by unknown antigens, maintaining a cycle between skin and peripheral blood.⁵³ A different picture was observed in PsA, CD4+, CD8+HLA−, CD8+HLA+, CD8+CD3−, CD8+CD3+ decreased in PBMC as PASI increased, suggesting migration from the blood to the skin. On the other hand, the following LS: CD8+CD4−, CD3+CD8−, HLA+CD8−, CD19, CD8+CD4+, and membrane surface immunoglobulin IgA+, IgD+, IgM+, IgE+, and IgG+ increased in PBMC as PASI increased, suggesting activation and proliferation by unknown antigens creating a homeostatic cycle between skin/joints and peripheral blood.⁵² After treatment with leishmania antigens, both homeostatic cycles are stopped, by many possible mechanisms under study, to explain PASI decrease and clinical remission of lesions. One first mechanism may be blocking the CD2+ receptor in the immunological synapse and subsequently the inflammatory process in skin and joints as postulated previously.^51–53

All mentioned comorbidities in psoriasis and PsA have a common cause, an inflammatory process in the respective organs. The old hypothesis of passive lipid artery accumulation has been substituted by low-grade inflammatory activity in the vascular wall, key in the pathogenesis of atherosclerosis. CVD present endothelial dysfunction³⁵ with formation of early fatty streaks. T cells (20%) are found surrounding the plaque and in the fibrous cap, pointing to a role of immunity in atherosclerosis similar to the process in psoriasis skin and PsA joints.^{40, 41, 45} In our work, we found DEAE fractions from leishmania amastigote antigens, suppressing psoriasis by stimulating lymphocytes, a mechanism of action contrary to the immunosuppressive mechanisms of most therapeutic products used today. In our studies, we have postulated that antigenic fractions could be stimulating regulatory CD8+ T cells in skin, synovium, and vascular wall lesions; an alternative mechanism to the inhibition of the immunological synapse, to control the inflammatory process in the affected tissues mentioned above.^{52, 54, 57}

The inflammatory component of atherosclerosis involves cellular and humoral immunity to the phylogenetically highly conserved antigen heat shock protein 60 (Hsp60) postulated as the autoantigen initiating mechanism in atherosclerosis that might play a role in triggering an autoreactive T-cell response. The first cells invading the intima have been identified as Hsp60-reactive T cells, followed by macrophages and SMC.⁴¹ Leishmania antigens are produced after a heat shock in promastigotes that become amastigotes in a liquid culture medium.⁵⁸ The molecular weight of leishmania vaccine AS200 is similar to the range of most Hsp host ligands (50–70 kDa) for TLR2 and could be competing with peptides in RASF receptors or Hsp60 reactive T-cell receptors in the vascular wall, another mechanism suggested for inhibiting the inflammation of psoriasis, PsA, and CIA.^{54, 57} Further support for T-cell cross-recognition of Hsp regions shared by the host and pathogen comes from epitope-mapping studies with a T-cell clone derived from mice primed with mycobacterial HsP60. Data from several arthritis models such as adjuvant arthritis and collagen type II-induced arthritis favor a role for Hsp60 autoimmune T cells in disease protection.⁵⁹ To induce CIA, complete Freund's adjuvant and M. tuberculosis was used; it is possible that treatment with leishmania vaccine AS200 is acting in a beneficial way similar to mycobacterial Hsp60 epitope cross reacting with self-determinants, and also by competing with ligands for TLR2 thereby, decreasing CIA as found in our work, a model for human RA.^{57, 60}

Intra-abdominal fat is not an inert mass of tissue but a vigorous endocrine organ, secreting bioactive proteins promoting inflammation. Chronic inflammation in obesity (BMI ≥ 30 kg m⁻²) is promoted by secretion of cytokines such as: TNFα that induces insulin resistance by increasing free fatty acid production, leptin that stimulates T cells, (IL)-6, and adiponectin. In this process, a balance is produced by adiponectin that reduces TNFα production, monocyte cell adhesion, macrophage phagocytic activity, and transformation of macrophages to foam cells.⁶¹ In our work, we found that leishmania amastigote antigens decreased production of TNFα, IL-1β, CRP, complement 5a (C5a), and PASI values in human psoriasis. This effect is similar to adiponectin, and is another possible mechanism to explain decrease of inflammation in psoriasis and PsA after vaccination with the amastigotes vaccine.^{57, 60}

TNFα plays a central role in the defense against intracellular infections with leishmania, a disease, that ends fatally in TNFα^−/− mice. Resolution of an established infection is mediated by IFN-γ produced by CD4+ T cells in C57BL/6-resistant mouse strain. In contrast, BALB/c susceptible strain develops anti-inflammatory IL-4 and IL-10 mediated CD4+ T cell response with dissemination of parasites and animal death. Analyses of immune responses in natural and experimental (healthy human volunteers) infections show that the clear Th1/Th2 T cell responses to L(L.)major seen in murine studies do not occur. Instead, a typical mixed Th1/Th2 response is observed with PBMC from patients secreting varying amounts of IFNγ, IL-10, and IL-4 depending on the clinical stage of the disease.⁶⁰ In our work, TLCK-treated and NP-40-extracted amastigote antigens contrary to live parasites induced decrease of TNFα and inflammatory markers. The parasite antigens did not induce humoral immunity in psoriatic patients up to six doses of AS100.⁵¹ This suggests that cellular immunity is another alternative mechanism for control of psoriatic systemic disease by inducing regulatory T cells in peripheral tissues in psoriasis and PsA.^{52, 54, 57}

Another relevant point to consider is that amastigotes inhibit antigen presentation by repressing the expression of Class I and Class II MHC gene products, both basally and following stimulation with IFNγ.^{62, 63} On the other hand, macrophages infected with L(L)major may express normal levels of MHC class II molecules, but parasites inhibit antigen presentation by interfering with the loading of antigens onto the MHC class II molecule.⁶⁴ An alternative suppression technique used by several leishmania species is to sequester the MHC II molecules and/or antigens within the phagolysosome.⁶⁵ This is another probable mechanism to explain the effect of leishmania antigens from AS100 and AS200 vaccines on psoriasis and PsA. They could be inhibiting MHC molecules in APC inducing subsequent deactivation of the synaptic complex formed with autoreactive T cells, stopping the inflammatory process by the unknown psoriasis and PsA antigen.

Iridocyclitis (acute anterior uveitis) represents the most frequent extra-articular feature in psoriasis with an estimated prevalence of 2%–25% of cases, characterized by inflammation of the anterior chamber with presence of leukocyte precipitates; another example of the systemic inflammation in psoriasis.¹² Double blind trials must be performed to analyze the effect of amastigote antigens on this comorbidity.

The NFκB pathway is one of the main signaling pathways activated in response to proinflammatory cytokines, including TNFα, IL-1, and IL-18 as well as by ligation of the TLR by the pattern recognition of PAMPs. The NF-κB pathway induces genes encoding proinflammatory cytokines, adhesion molecules, chemokines, growth factors, and enzymes such as COX2 and iNOS. A substantial number of similar proinflammatory cytokines are also found in skin psoriasis, PsA synovium, and EC of human atherosclerotic lesions.⁴⁰ In our work, inflammatory markers CRP and C5a decreased significantly in serum after treatment with six doses of AS200 DEAE leishmania amastigote antigens. The leishmania antigens decreased markedly the TNFα concentration in supernatants from PBMC from psoriatic patients.⁶⁰ In mice ConA-induced hepatitis, leishmania antigens decreased serum TNFα and IL-1β compared with placebo inducing significant reduction of CIA.^{57, 60} It would be interesting to determine urinary excretion of nitric oxide by iNOS in psoriasis and PsA as a marker for the evolution of the disease before and after treatment with amastigote antigens.

Diabetes mellitus and HTA frequency increased in PsA patients together with CRP level, platelet, and white cell counts. Inflammation, as reflected by the CRP level, was associated with a higher BMI, waist circumference, systolic and diastolic blood pressure, sugar and insulin resistance, dyslipidemia, and increased thrombotic tendency.³⁷ As explained above, we found CRP and C5a decreased significantly in serum after treatment with six doses of AS200 DEAE leishmania amastigote antigens. Double blind clinical trials must be done to confirm their effect in these comorbidities.⁶⁰

It is clear that all the comorbidities have as substratum, an inflammatory process in the respective tissue, due to a cytokine cascade, similar to the immunological process found in skin psoriasis and PsA joints, starting by inflammation in vascular structures with key changes in the endothelial intima, a process that can be stopped with leishmania antigens as found in our work.

The first sign of clinical regression in skin psoriasis after treatment with leishmania antigens polyvalent vaccine AS100-1 is the disappearance of itching followed by significant decrease in redness in the plaque from the center to the periphery, or the periphery to the center (Figure 1a, b), indicative of a gradual decrease in angiogenesis until the whole plaque is white without redness (Figure 1c). It is noteworthy that the regression of lesions begins at the blood vessels, the vascular tissue origin of the plaques where lesions started. Probably, leishmania antigen peptides blocked VEGF receptors preventing proangiogenic signal transduction and angiogenesis by VEGF cytokine. This effect is helped by decrease in CRP, C5a, TNFα, in patients and also TNFα, and IL1β in ConA-induced hepatitis in mice, after treatment with leishmania antigens, all cytokines involved in PsA, Psoriasis, and comorbidities.⁶⁰

Some comorbidities such as HTA and diabetes decreased with leishmania antigens in few patients with no specific treatment (antihypertensive, oral diabetics), but to confirm the action of the vaccine on this processes, double blind placebo control studies must be done before reaching any conclusion.

CONCLUSION

The development and maintenance of psoriasis and PsA since the beginning of lesions is centered in the blood vessels. Both diseases start with redness in the skin and joints by proliferation of blood vessels and angiogenesis after up-regulation of VEGF and TGFβ and other angiogenic factors. TNFα is a key cytokine in the inflammatory process because it activates EC, leading to expression of adhesion molecules, opening the door to cells migration to sites of inflammation. Higher percentage frequency in PsA than psoriasis patients was found in HTA, vascular diseases, intestinal diseases, infections, gastritis, cardiac arrhythmia, gallstones in gallbladder, osteoporosis, hyperuricemia, and epilepsy. Several comorbidities were found in both psoriasis and PsA patients up to 7–8 comorbidities together in the same subject. Psoriasis is a systemic disease, induced by inflammatory cytokines in all organs of the body being expressed in each tissue according to genetic and environmental factors due to shared inflammatory pathways. Several mechanisms for clinical remission are proposed as: blocking the CD2+ receptor in the immunological synapse; stimulation of regulatory CD8+ T cells in skin, synovium and vascular lesions; leishmania peptides cross reacting with Hsp60 epitopes; decreased production of TNFα, IL-1β, CRP, complement 5a (C5a); inhibition of MHC molecules in APC inducing subsequent deactivation of the synaptic complex with autoreactive T cells; and blocking VEGF receptors preventing proangiogenic signal transduction and angiogenesis by VEGF cytokine.

ETHIC COMMISSION

The clinical investigations were conducted in accordance with the Declaration of Helsinki. The Ethic Commission of the National Academy of Medicine of Venezuela approved the protocols for the field trial for leishmaniasis as well as the trials for psoriasis. Dr Blas Bruni Celli was appointed as trial monitor and oversaw all subsequent follow-up work on the trials. All volunteers signed an informed consent authorizing treatment.

Keywords

psoriasis systemic disease, psoriasis comorbidities, psoriatic arthritis, psoriasis vascular disease

Acknowledgements: We would like to thank Dr Jose Rafael Lopez Padrino, Professor at Harvard University, for critical discussions, and for suggesting useful ideas for the article, and to Dr Jose Felix Oletta for providing the data on prevalence and mortality of diseases in Venezuela. Jose A. O'Daly Astralis CSO, CEO and Chairman, would also like to thank The Technology Business Tax Certificate Transfer Program of the Greater State of New Jersey, Economic Development Authority (eda) for their support.

Disclosure: The authors declare no conflicts of interest.

REFERENCES

1. Gladman DD. Psoriatic Arthritis from Wright’s Era until today. J Rheumatol. 2009;36(Suppl 83):4–8.
2. Christophers E, Barker JN, Griffthy CE, Dauden E, Milligan G, Motta C, et al. The risk of psoriatic arthritis remains constant following initial diagnosis of psoriasis among patients seen in European dermatology clinics. J Eur Acad Dermatol Venereol. 2010;24(5):548–554.
3. Wilson FC, Icen M, Crowson CS, McEvoy MT, Gabriel SE, Kremers HM. Time trends in epidemiology and characteristics of psoriatic arthritis over 3 decades: a population based study. J Rheumatol. 2009;36(2):361–367.
4. Shbeeb M, Uramoto KM, Gibson LE, O’Fallon WM, Gabriel SE. The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA, 1982–1991. J Rheumatol. 2000;27(5):1247–1250.
5. Kim N, Thrash B, Menter A. Comorbidities in psoriasis patients. Semin Cutan Med Surg. 2010;29(1):10–15.
6. Gottlieb A, Korman NJ, Gordon KB, Feldman SR, Lebwohl M, Koo JY, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58(5):851–864.
7. Lotti T, Hercogova J, Prignano F. The concept of psoriatic disease: can cutaneous psoriasis any longer be separated by the systemic comorbidities? Dermatol Ther. 2010;23(2):119–122.
8. Naldi L, Mercuri SR. Epidemiology of comorbidities in psoriasis. Dermatol Ther. 2010;23(2):114–118.
9. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006;54(8):2665–2673.
10. Chandran V, Schentag CT, Gladman DD. Sensitivity of the classification of psoriatic arthritis criteria in early psoriatic arthritis. Arthritis Rheum. 2007;57(8):1560–1563.
11. Coates LC, Helliwell PS. Classification and categorization of psoriatic arthritis. Clin Rheumatol. 2008;27(10):1211–1216.
12. Cantini F, Niccoli I, Nannini C, Kaloudi O, Bertoni M, Cassara E. Psoriatic arthritis: a systematic review. Int J Rheum Dis. 2010;13(4): 300–317.
13. Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis? Cell. 1996;87(7):1153–1155.
14. Folkman J. Angiogenesis and angiogenesis inhibition: an overview. EXS. 1997;79:1–8.
15. Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 1998;91(10):3527–3561.
16. Pandya NM, Dhalla NS, Santani DD. Angiogenesis–a new target for future therapy. Vascul Pharmacol. 2006;44(5):265–274.
17. Micoli G, Lacarrubba F, Musumeci ML, Massimino D, Nasca MR. Cutaneous vascular patterns in psoriasis. Int J Dermatol. 2010;49(3):249– 256.
18. Henno A, Blacher S, Lambert CA, Deroanne C, Noel A, Lapiere C, et al. Histological and transcriptional study of angiogenesis and lymphangiogenesis in uninvolved skin, acute pinpoint lesions and established psoriasis plaques: an approach of vascular development chronology in psoriasis. J Dermatol Sci. 2010;57(3):162–169.
19. Turkiewics AM, Moreland LW. Psoriatic arthritis. Current concepts on pathogenesis-oriented therapeutic options. Arthritis Rheum. 2007;56(4): 1051–1066.
20. Fearon U, Reece R, Smith J, Emery P, Veale DJ. Synovial cytokine and growth factor regulation of MMPs/TIMPs: implications for erosions and angiogenesis in early rheumatoid and psoriatic arthritis patients. Ann NY Acad Sci. 1999;878:619–621.
21. Fearon U, Griosios K, Fraser A, Reece R, Emery P, Jones PF, et al. Angiopoietins, growth factors, and vascular morphology in early arthritis. J Rheumatol. 2003;30(2):260–268.
22. Flisiak I, Zaniewski P, Rosalska M, Mysliwiec H, Jaroszewicz J, Chodynicka B. Effect of psoriasis activity on VEGF and its soluble receptors concentrations in serum and plaque scales. Cytokine. 2010;52(3):225–229.
23. Canavese M, Altruda F, Ruzicka T, Schauber J. Vascular endothelial growth factor (VEGF) in the pathogenesis of psoriasis – a possible target for novel therapies? J Dermatol Sci. 2010;58(3):171–176.
24. Kiselyov A, Balakin KV, Tkachenko SE. VEGF/VEGFR signalling as a target for inhibiting angiogenesis. Expert Opin Invest Drugs. 2007; 16(1):83–107.
25. Man XY, Yang XH, Cai SQ, Bu ZY, Zheng M. Overexpression of vascular endothelial growth factor (VEGF) receptors on keratinocytes in psoriasis regulated by calcium independent of VEGF. J Cell Mol Med. 2008;12(2):649–660.
26. Veale D, Yanni G, Rogers S, Barnes L, Bresnihan B, Fitzgerald O. Reduced synovial membrane macrophage numbers, ELAM-1 expression, and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis. Arthritis Rheum. 1993;36(7):893–900.
27. Veale D, Rogers S, Fitzgerald O. Immunolocalization of adhesion molecules in psoriatic arthritis, psoriatic and normal skin. Br J Dermatol. 1995;132(1):32–38.
28. Fraser A, Fearon U, Billinghurst RC, Ionescu M, Reece R, Barwick T, et al. Turnover of type II collagen and aggrecan in cartilage matrix at the onset of inflammatory arthritis in humans: relationship to mediators of systemic and local inflammation. Arthritis Rheum. 2003;48(11):3085–3095.
29. Yost J, Gudjonsson JE. The role of TNF inhibitors in psoriasis therapy: new implications for associated comorbidities. F1000 Med Rep. 2009;8:1–30.
30. Costello P, Bresnihan B, O’Farrelly C, Fitzgerald O. Predominance of CD8T lymphocytes in psoriatic arthritis. J Rheumatol. 1999;26(5): 1117–1124.
31. Laloux I, Voisin MC, Allain J, Martin N, Kerboull L, Chevalier X, et al. Immunohistological study of entheses in spondyloarthropathies: comparison in rheumatoid arthritis and osteoarthritis. Ann Rheum Dis. 2001;60(4):316–321.
32. Ritchlin C, Haas-Smith SA, Hicks D, Capuccio J, Oesterland CK, Looney RJ. Patterns of cytokine production in psoriatic synovium. J Rheumatol. 1998;25(8):1544–1552.
33. Angel K, Provan SA, Gulseth HL, Mowinckel P, Kvien TK, Atar D. Tumor necrosis factor alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: a controlled study. Hypertension. 2010;55(2):333–338.
34. Husni ME, Mease PJ. Managing comorbid disease in patients with psoriatic arthritis. Curr Rheumatol Rep. 2010;12(4):281–287.
35. Fink AM, Cauza E, Hassfeld W, Dunky A, Bayer PM, Jurecka W, et al. Vascular endothelial growth factor in patients with psoriatic arthritis. Clin Exp Rheumatol. 2007;25(2):305–308.
36. Tam LS, Shang Q, Li EK, Tomlinson B, Chu TT, Li M, et al. Subclinical carotid atherosclerosis in patients with psoriatic arthritis. Arthritis Rheum. 2008;59(9):1322–1331.
37. Tam LS, Tomlison B, Chu TT, Li M, Leung YY, Kwok LW, et al. Cardiovascular risk profile of patients with psoriatic arthritis compared to controls—the role of inflammation. Rheumatology. 2008;47(5): 718–723.
38. Kaye JA, Li L, Jick SS. Incidence of risk factors for myocardial infarction and other vascular diseases in patients with psoriasis. Br J Dermatol. 2008;159(4):895–902.
39. Prodanovich S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Federman DG. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol. 2009; 145(6):700–703.
40. Tedgui A, Mallat Z. Cytokines in atherosclerosis: Pathogenic and regulatory pathways. Physiol Rev. 2006;86(2):515–581.
41. Wick G, Knoflach M, Xu Q. Autoimmune and inflammatory mechanisms in atherosclerosis. Annu Rev Immunol. 2004;22:361–403.
42. Gelfand JM, Neimannn AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735–1741.
43. Gottlieb AB, Dann F. Comorbidities in patients with psoriasis. Am J Med. 2009;122(12):1150e1–9.
44. Brauchli YB, Jick SS, Miret M, Meier CR. Psoriasis and risk of incident myocardial infarction, stroke or transient ischaemic attack: an inception cohort study with a nested case-control analysis. Br J Dermatol. 2009;160(5):1048–1056.
45. Han C, Robinson DW Jr, Hackett MV, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol. 2006;33(11):2167–2172.
46. Gisondi P, Del Giglio M, Cozzi A, Girolomoni G. Psoriasis, the liver, and the gastrointestinal tract. Dermatol Ther. 2010;23(2):155–159.
47. Ayala F, Ayala F. Clinical aspects and comorbidities of psoriasis. J Rheumatol. 2009;83(Suppl):19–20.
48. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735–2752.
49. Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol. 2006;47(6):1093–1100.
50. Rohekar S, Tom BDM, Hassa A, Schentag CT, Farewell VT, Gladman DD. Prevalence of Malignancy in Psoriatic arthritis. Arthritis Rheum. 2008;58(1):82–87.
51. O’Daly JA, Lezama R, Rodriguez PJ, Silva E, Indriago NR, Pena G, et al. Antigens from Leishmania amastigotes induced clinical remission of psoriasis. Arch Dermatol Res. 2009;301(1):1–13.
52. O’Daly JA, Gleason J, Lezama R, Rodriguez PJ, Silva E, Indriago NR. Antigens from Leishmania amastigotes inducing clinical remission of psoriatic arthritis. Arch Dermatol Res. 2011; DOI 10.1007/s00403-011-1133-0
53. O’Daly JA, Rodriguez B, Ovalles T, Pelaez C. Lymphocyte subsets in peripheral blood of patients with psoriasis before and after treatment with leishmania antigens. Arch Dermatol Res. 2010;302(2):95–104.
54. O’Daly JA, Lezama R, Gleason J. Isolation of Leishmania amastigotes protein fractions which induced lymphocyte stimulation and remission of psoriasis. Arch Dermatol Res. 2009;301(6):1–17.
55. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem. 1951;193(1):265–275.
56. Smith PK, Krohn RJ, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, et al. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985;150(1):76–85.
57. O’Daly JA, Gleason JP, Pen˜a G, Colorado I. Purified proteins from leishmania amastigotes-induced delayed type hypersensitivity reactions and remission of collagen-induced arthritis in animal models. Arch Dermatol Res. 2010;302(8):567–581.
58. O’Daly JA, Rodrý´guez MB. Differential growth requirement of several Leishmania spp in chemically defined culture media. Acta Trop. 1988;45(2):109–126.
59. Zügel U, Kaufmann SHE. Role of heat shock proteins in protection from and pathogenesis of infectious diseases. Clin Microbiol Rev. 1999; 12(1):19–39.
60. O’Daly JA, Gleason J. Antigens from Leishmania amastigotes inducing clinical remission of psoriasis: Relationship between Leishmaniasis and psoriasis. J Clin Dermatol. 2010;1:47–57.
61. Sterry W, Strober BE, Menter A. Obesity in psoriasis. The metabolic, clinical and therapeutic implications. Report of an interdisciplinary conference and review. Br J Dermatol. 2007;157(4):649–655.
62. Reiner NE, Ng W, McMaster WR. Parasite-accessory cell-interactions inmurine leishmaniasis. Leishmania donovani suppresses macrophage expression of Class-I and class-II major histocompatibility complex geneproducts. J Immunol. 1987;138(6):1926–1932.
63. Reiner NE, Ng W, McMaster WR. Kinetics of gamma interferon binding and induction of major histocompatibility complex class II mRNA in leishmania infected macrophages. Proc Natl Acad Sci USA. 1988; 85(12):4330–4334.
64. Fruth U, Solioz N, Louis JA. Leishmania major interferes with antigen presentation by infected macrophages. J Immunol. 1993;150(5): 1857–1864.
65. Kima PE, Soong L, Chicharro C, Ruddle NH, McMahon-Pratt D. Leishmania-infected macrophages sequester endogenously synthesized parasite antigens from presentation to CD4+ T cell. Eur J Immunol. 1996;26(12):3163–3169.

The spondyloarthropathies (SpA) encompass a group of chronic inflammatory rheumatic conditions, including ankylosing spondylitis (AS), psoriatic arthritis reactive arthritis (ReA), arthritis associated with irritable bowel disease, and undifferentiated SpA.^{1, 2} The primary pathological sites include the entheses (the bony insertion of ligament and tendons), the axial skeleton, sacroiliac and limbic joints, and some nonarticular structures.^3–5 Severity of symptoms varies widely among patients, and the clinical course of the disease is largely unpredictable. While considerable research has been dedicated to pain and stiffness in SpA, much less is known about the prevalence and factors associated with sleep difficulties among persons living with this disease.

Sleep problems are relatively common in North America. Community-based epidemiological surveys suggest that up to one-third of the general population report insomnia symptoms such as difficulties falling asleep or staying asleep and/or nonrestorative sleep.^6–12 Moreover, insomnia symptoms can persist for years if left untreated, particularly in individuals with more severe symptoms.^{10, 11}

The prevalence of sleep difficulties among patients with chronic medical conditions is much higher than that of the general population.⁶ While rates vary considerably, likely due to differences in defining and assessing sleep problems, estimates range from 25% to 88%.^13–17 In the general population, insomnia has been associated with significant daytime dysfunction, including cognitive impairments, fatigue, depression, and poorer health-related quality of life.^18–21 Sleep disturbances, including insomnia, have been associated with poorer physical health status,¹⁴ less adherence to medical treatment,²² symptom amplification,²³ greater functional disability,⁸ decreased work productivity, increased risk of accidents, more work absenteeism, and more health care utilization.^24–26 These problems may be amplified in individuals whose symptoms persist for years.^{25, 22} Despite the high prevalence and long-term negative consequences, insomnia remains underrecognized and inadequately treated.

Sleep disruptions have been observed in rheumatic diseases.^{13 ; 15 ; 27–30} However, studies examining sleep in rheumatic conditions have either focused on specific forms of arthritis ¹⁷ or have not distinguished between various forms of arthritis (ie, osteoarthritis).¹⁵ A recent exploratory analysis of 2138 patients with inflammatory arthropathies found that those with AS rated sleep problems as a significantly higher priority for improvement than those with other inflammatory arthropathies.³¹ Moreover, “Sleep Functions” were deemed a core health outcome in patients with AS by an expert panel of the International Classification of Functioning, Disability and Health and the World Health Organization, thus highlighting the importance and encouraging further study of sleep in this patient population.³²

While the occurrence of sleep disturbances in patients with SpA has become increasingly recognized as an important problem, compared to other arthritic conditions, sleep has received little research attention in this patient population. We identified only three studies that were designed to examine sleep quality in patients with SpA.^33–35 A handful of studies on fatigue in SpA have also assessed and reported rates of sleep disturbance to better understand its contribution to fatigue severity.^{35, 36}

Sleep disturbances are commonly experienced by individuals living with SpA, even when their condition is well controlled. This literature review aims to provide a better understanding of the nature of sleep difficulties in persons with SpA and the factors associated with poor sleep. Sleep disturbances are multidetermined, modulated by factors such as disease status, behavioral and psychosocial variables.^{15, 37} However, their relative importance in SpA remains unclear. Determinants of sleep difficulties emerging from published SpA studies will be described, along with potential physiological and psychological mechanisms that may explain sleep difficulties in SpA. Although there are no evidence-based guidelines for managing sleep problems in patients with SpA, assessment methods and treatment strategies will be addressed. Finally, we conclude with recommendations for future empirical studies.

SPA SLEEP DIFFICULTIES

Sleep disturbances are more common among individuals living with chronic conditions than among those without chronic illness.⁶ Patient reports in clinical settings frequently substantiate claims of people living with SpA that “[s]leep is elusive, and going to bed is a positive chore.”³⁸ Despite sleep problems burdening people with SpA and the probable negative impact of sleep disturbance on daily functioning and quality of life, sleep problems in SpA remain underrecognized, understudied, and undertreated. Sleep disturbances in SpA include insomnia, poor sleep quality, and awakening difficulties.^{33, 34, 39–42} These sleep problems in SpA need the enlightenment of research to improve health interventions and quality of life.

The Nature of Sleep Difficulties in SpA

Insomnia syndrome, characterized as a persistent problem with sleep onset and/or sleep maintenance, is the most common sleep disturbance both in the general population and in individuals with chronic illnesses.¹¹ Other sleep disturbances include sleep-related breathing disorders and restless leg syndrome (RLS). Sleep apnea refers to periodic cessation of breathing during sleep either by disruptions of the respiratory drive or by intermittent obstruction of the airway, affecting 1%–5% of the adult population.⁴³ RLS is characterized by twitching or aching in the legs and difficulty falling asleep.⁴⁴ Although other sleep disorders certainly do occur and impact the quality of life of individuals with SpA, this article focuses primarily on insomnia syndrome because its support is strongest in extant literature.^{6, 9}

Only three studies in SpA have been conducted to specifically examine sleep quality, ^{33, 34, 39} two used standardized sleep assessment measures,^{34, 39} and one accounted for the potential interplay of behavioral and psychosocial factors.³⁹ These studies found evidence to indicate that sleep difficulties are commonly experienced by persons living with SpA (Table 1).

Sleep fragmentation refers to the disruption of continuous sleep by frequent and often lengthy awakenings at night. Using the Pittsburgh Sleep Quality Index (PSQI),⁴⁵ a standardized self-report measure of subjective sleep quality, evidence of sleep fragmentation, with reduced total sleep time (TST; 6.5 hours±1.5) has been reported in SpA.³⁹ A similar duration (6.9 hours± 1.7) was found in a recent study with AS patients conducted in Turkey.³⁴ While a TST in the range of 5–7 hours may not be uncommon in the general population, it is lower than the 8 hours recommended as ideal.⁴⁶ Da Costa and colleagues ³⁹ also found evidence of sleep fragmentation in patients with SpA, as 66% of the sample reported awakening at least 3 nights per week, which is significantly higher than what has been reported in the general population (35.5%).⁴⁷ Others have shown that a considerable proportion of AS patients complaining of fatigue (41%) awaken more than 3 times per night.⁴⁸

Sleep efficiency is the ratio of total sleel time (TST) to time in bed (TIB) [TST/TIB×100) and represents an overall index of how well a person sleeps.⁴⁹ A sleep efficiency greater than 90% is indicative of good sleep.⁵⁰ The mean sleep efficiency has been found to be 79.5% (SD=17.0) in patients with SpA,³⁹ which is considerably lower than the 90% cutoff. In the same sample of 125 individuals, 88% reported difficulties with sleep maintenance, including 66.4% reporting awakenings three or more times per week.

Sleep latency reflects time elapsed between going to bed and the onset of sleep. The little data published on sleep latency in SpA provide initial evidence suggesting that it appears to be more prolonged in persons with SpA. Using the PSQI, Da Costa and colleagues³⁹ found a mean sleep latency of 31.0 minutes±34.5 in SpA patients, which is more prolonged than the 10–12 minutes reported by healthy persons.^{49, 51} In this study, poor sleep quality was found in 69% of SpA patients.³⁹ In other studies with AS patients, sleep disturbances have been observed in approximately 55% of patients.^{36, 41} These initial findings suggest that sleep disturbance is more prevalent in SpA compared to the general population (10%–30%),^{8, 12, 19, 52} but similar to what has been reported in other chronic conditions.^{17, 53, 54}

A recent study comparing gender differences in SpA found sleep disturbances to be more commonly reported in women than men.⁵⁵ These findings are consistent with other studies in the general population and in arthritis that have also found sleep disturbances, including inadequate sleep duration and insomnia, to be more common in women across the lifespan.^56–58 These gender differences are likely attributable to a number of factors including differences in hormones, risk factors for sleep problems, and clinical manifestations of sleep problems.⁴⁴

Evidence for respiratory disorders during sleep has been reported in SpA. One prospective observational study of 17 AS patients in the United Kingdom found that two people (12%) had sleep apnea.⁵⁹ Another study conducted in Turkey with 31 AS patients found that seven of the 31 patients (22.6%) had sleep apnea.⁶⁰ The limited published research to date suggests that respiratory disorders and sleep difficulties may be prevalent among individuals living with SpA as compared to the general population.

DETERMINANTS OF SLEEP DIFFICULTIES

Sleep problems for people with SpA are most likely modulated by multiple factors including disease status and behavioral and psychosocial variables. Evidence for each of these factors will be examined, along with a biopsychosocial model using the existing knowledge base in SpA and other rheumatological conditions, to understand the relationship between potential contributing factors and sleep disturbance.

Disease-Related Factors

Localized or generalized pain is a common clinical symptom associated with chronic inflammatory rheumatic conditions, including SpA. In arthritis, the relationship between pain intensity and sleep problems has been firmly documented.^{15, 61} The relationship between pain and sleep disturbance is complex but likely reciprocal. While chronic pain can disrupt and exacerbate sleep problems, sleep disturbances can also exacerbate pain intensity ^{62, 63} and related dysfunction, including fatigue and reduced daily activities.^{35, 36, 64, 65} The results of two separate national surveys in adults with a diagnosis of arthritis, conducted in Canada ¹⁵ and the United States,⁶¹ have shown that the relationship between arthritis and sleep disturbances is largely mediated by pain. Although pain severity is likely to be a significant contributor to sleep disturbances in SpA, well-controlled studies are lacking.

Several studies, mostly aimed at better understanding fatigue have indirectly examined the relationship between disease activity and sleep problems in SpA. Disease activity and functional status have been assessed in these studies with standardized measures, including the Bath Ankylosing Spondylitis Disease Activity Index⁶⁶ and Bath Ankylosing Spondylitis Functional Index.⁶⁷ Both disease activity and worse functional status have been found to be correlated with various sleep parameters, including sleep latency, duration, efficiency, and daytime sleepiness.^{34, 39} In the study by Da Costa et al., ³⁹ only the association between functional status and various sleep parameters, including sleep latency, duration, and efficiency, remained significant in the multivariate analysis. Disease activity did not remain significant in the multivariate model, suggesting that its relationship to sleep may be weak and nonlinear.

The main treatment goals in SpA are to reduce pain and spine stiffness, to manage peripheral arthritis, enthesitis, and to prevent extra-articular disease manifestations such as uveitis.⁶⁸ Conventional pharmacological treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), disease modifying antirheumatic agents (DMARDs) such as sulfasalazine, and antitumor necrosis factors (TNF)-α agents.^{68, 69} The study by Karadag ³⁴ found that patients using NSAIDs and/or DMARDs had higher scores on sleep disturbances, awakening short of breath and daytime somnolence compared to controls. Patients on these medications also had more disease activity, making it difficult to disentangle the nature of the relationship between these agents, pain, and sleep problems.

In summary, the limited studies published to date suggest that disease-related parameters are related to sleep difficulties in persons with SpA. However, it is likely that other factors in addition to disease expression influence the sleep problems experienced by persons with this condition.

Behavioral and Psychosocial Factors

Physical activity

The general belief that regular physical activity enhances sleep quality is shared among sleep experts,^{70, 71} primary care physicians, exercise scientists, ^{72, 73} and the general public.⁷⁴ Only in the last decade have the potentially health-promoting effects of exercise on sleep become the focus of investigations. Reviews have concluded that there is a lack of compelling empirical evidence supporting sleep-promoting effects of exercise.^75–77 This conclusion is likely attributable to the numerous methodological limitations in published experimental studies to date.^75–78 It has been noted that most of the existing trials have been conducted with good sleepers who are unlikely to demonstrate significant improvements due to ceiling effects.⁷⁶ Clinical trials with individuals experiencing insomnia have demonstrated significant beneficial effects of exercise on sleep parameters, including sleep quality, latency, and total sleep time.^79–83 We are aware of only one study that examined the impact of a 6-week group and a home-based exercise program on disease activity, sleep, and quality of life on patients with AS.⁸⁴ The study found significant improvements in both exercise groups on measures of disease activity, sleep, and quality of life.⁸⁴ While the link between regular exercise and physical and mental well-being is established, ^85–87 the relationship between physical activity and sleep difficulties in people living with SpA requires further investigation.

Depression

The comorbidity of sleep disturbances and depression has been well documented⁸⁸ and is likely bidirectional. Epidemiological studies estimate that 50%–90% of persons diagnosed with depression report impaired sleep quality.^{88, 89} Sleep impairments commonly reported by depressed patients include sleep fragmentation and prolonged sleep latency.⁹⁰ Research has also consistently demonstrated that disturbed sleep is an important independent risk factor for a new or recurrent depressive episode.^90–93

Depression is the most common psychological symptom emerging secondary to a chronic medical condition. In patients with SpA, estimates of the prevalence of depression range between 20% and 36%.^{36, 39, 41, 94, 95} Depression in SpA is likely related to multiple factors including more active disease and poor functional and health status.^{96, 97} Depressed mood in relation to sleep disturbance in SpA has only been examined in one study. Da Costa et al. ³⁹ found that depression is independently associated with each of sleep quality, duration, and efficiency.

Stress

Limited research has examined the link between stress and sleep quality in people with SpA. One recent study of 125 people with SpA found an association between higher levels of stress and poorer sleep quality,³⁹ consistent with findings in other arthritis studies involving heterogeneous samples.^{15, 98–98, 98}

Collectively, these findings highlight the need to further investigate the role of depression and stress on sleep problems in people living with SpA. Sleep disturbance in SpA, as with other types of inflammatory arthritis, appears to be multifaceted involving behavioral and psychosocial factors central in maintaining sleep difficulties. Although specific disease-related, behavioral, and psychosocial factors have been associated with sleep problems in SpA, the specific mechanisms underlying the observed relationships remain at an embryonic state of knowledge. The promising results of a limited number of studies investigating psychosocial predictors of sleep quality in SpA underscore the need for more rigorous, multivariate, prospective studies assessing sleep parameters and potential contributing biopsychosocial factors to elucidate the potential role of disease-related, behavioral, and psychosocial factors in predicting sleep difficulties in people with SpA (Figure 1).

Proposed Biopsychosocial Model of Sleep Disturbance in SpA

Figure 1 depicts a model guided by a biopsychosocial conceptual framework that can be applied to help elucidate variables influencing sleep disturbance in SpA. The variables included in this model were derived from limited sleep studies in SpA, from existing sleep research in inflammatory arthritis, and from studies in the sleep area. The model includes three broad components that can trigger and/or influence the maintenance of sleep problems. Certain relationships in the model are considered to be more hypothetical than others, and the strength of the relationships are not assumed to be equivalent. The model depicts the complex interplay between variables and sleep disturbance in SpA. It is important to note that given the current state of knowledge, it is unknown whether these components directly or indirectly influence sleep disturbance through their impact on other variables. For instance, disease activity may directly result in disturbed sleep. Alternatively, disease activity may influence sleep indirectly by decreasing physical activity participation, increasing depressed mood, and stress. Finally, a factor may moderate the effect of a specific variable on sleep. For example, pain severity may influence sleep only for patients who are physically inactive.

Clearly, more studies are needed to clarify the factors that influence sleep in SpA. A biopsychosocial approach should be used to guide future sleep studies in SpA. Clinically, the model also depicts the importance of assessing and addressing potentially important behavioral and psychosocial factors to better manage sleep disturbance in SpA.

RECOGNIZING AND MANAGING SLEEP DIFFICULTIES IN SpA

Patient complaints of sleep problems tend to be dismissed by primary care physicians,^104–106 who may be less aware of the current evidence base for treatment options.¹⁰⁷ Only about 11%–30% of patients with sleep disturbances discuss their sleep problems with their primary care providers.^{108, 109} Results of the 2009 Sleep in America Poll(¹¹⁰) found that 32% of participants had ever been asked by their physicians about their sleep problems.¹¹⁰ Ohayon ¹⁰⁹ recently reported that among the 90% of persons with nocturnal awakenings who had not reported their sleep disturbances to their physician but who had consulted him or her in the prior year, only 6% were prescribed a medication, compared with 33% among those who had spoken to their physician about their sleep problem. These findings highlight the importance for both patients and health care providers to initiate inquiry into sleep to ensure that any difficulties are adequately assessed and treated.

Given the numerous and complex symptom manifestations that can arise in SpA, it is not surprising that sleep complaints tend to be underrecognized and undertreated in this patient population. However, health care providers involved in the care of SpA patients should recognize that sleep problems can complicate the management of SpA by further impairing patient quality of life,⁴⁸ increasing pain and fatigue,^{14–16, 35, 63, 91} increasing work absenteeism,²⁵ and increasing health care costs.⁷ Taken together, these findings suggest that adequate sleep is essential to the maintenance of health status and quality of life in persons with SpA.

Routine screening and adequate treatment of sleep problems should be an important component of the comprehensive care of SpA patients. A clinical assessment can be done to ascertain the nature of the sleep problem. Culpepper¹⁰⁵ and Schutte-Rodin and colleagues¹⁰⁶ outlined key questions to ask patients in order to better define the sleep problem and the need to proceed further with assessment and treatment. These include:

1. Does the patient have difficulty falling asleep or maintaining sleep?

2. Does the patient feel refreshed upon awakening in the morning?

3. Is the sleep problem occurring every night or is it occasional?

4. Is the problem recent?

5. How has the patient coped with the problem?

6. What does the patient perceive to be the cause of the problem?

7. Does the patient feel an intervention is required?

Qualitative and quantitative self-report scales of sleep can also be administered to further clarify the nature of the problem. For example, The PSQI ⁴⁵ assesses sleep quality and disturbances over a 1-month interval. It includes subscales assessing subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. By summing the subscales, a global score is generated to represent a composite of sleep quality and quantity.⁴⁵ The PSQI has previously been used in systemic lupus erythamatesus (SLE) patients.^{36, 39} Screening for depression, stress, and anxiety with brief standardized measures, such as the Beck Depression Scale ¹¹¹, Perceived Stress Scale,¹¹² and State-Trait Anxiety Inventory,¹¹³ should also be performed for patients reporting sleep problems. A comprehensive sleep assessment should also inquire about any agents that could impair sleep, including caffeine, tobacco, alcohol, and certain medication classes.^{105, 106} Referral to a sleep clinic for an overnight polysomnography (PSG) is useful for providing objective evidence for the complaint of unrefreshing sleep, to ascertain diagnosis when there is uncertainty, or if the patient has failed to respond to treatment.^{105, 106, 114}

To date, there has been no study systematically targeting sleep as a primary outcome measure in SpA or more specifically AS; however, compelling post hoc evidence exists for pharmacological treatment of sleep problems in this population.¹¹⁵ TNF-α inhibitors are a useful alternative for AS patients with minimal response or intolerance to standard treatment with NSAIDs.¹¹⁶ Adalimumab, a newer TNF-α inhibitor, has demonstrated significant improvement in sleep disturbances in patients with active AS in the short term,¹¹⁷ with significant reductions in clinical symptoms and disease activity, and increases in patient-reported quality of life outcomes, in the long term.¹¹⁸ Similarly, golimumab, a more recently approved TNF-α inhibitor, has been shown to reduce sleep disturbances in AS patients,¹¹⁵ with associated reductions in disease activity and improved physical function, and increased quality of life.¹¹⁹ Moreover, its pharmacological properties allow for less frequent dosing than adalimumab¹¹⁹ and for reduced discomfort upon administration.¹²⁰ The durability of these effects in the long term on sleep outcomes in patients with SpA is unknown and requires further study. Nonpharmacological interventions may also be an effective and feasible treatment option for the management of sleep problems in SpA.

Nonpharmacological treatments that may be useful include sleep hygiene, cognitive behavioral therapy, relaxation, and aerobic exercise.^121–123 Controlled studies with SpA patients are needed to determine whether the benefits of these sleep-enhancing interventions extend to this patient population. Cognitive behavioral therapy for Insomnia (CBT-I) has been shown to improve sleep quality in adults with comorbid medical conditions.¹²⁴ Recently, CBT-I has been shown to significantly improve sleep and reduce pain, without the intervention directly targeting pain control, in older patients with osteoarthritis.¹²⁵ Importantly, both these improvements were maintained at the 1-year follow-up, suggesting the durability of CBT-I effects for comorbid insomnia. As suggested by the authors, these findings underscore the need for future RCTs in other populations, including SpA, where chronic pain and sleep disturbances typically co-occur. Given that sleep disturbances in patients with SpA are likely to be multifactorial, a multidisciplinary treatment approach combining pharmacological and nonpharmacological methods may be required, particularly for more chronic cases.

FUTURE STUDIES

It is clear that more studies using objective measures of sleep parameters are needed to better characterize sleep patterns in SpA. To date, all the sleep studies in SpA have assessed sleep at one single point in time. Hence, the temporal stability and severity of sleep problems in SpA remains to be investigated. Furthermore, prospective designs would also allow for clarification of the factors that contribute to the maintenance and improvement of sleep in SpA. Although PSG is considered the gold standard, the actigraph that estimates sleep parameters based on limb motor movement, compared to PSG is less expensive, less invasive, and more conducive to repeated measures in ambulatory settings.^{126, 127} Moreover, the actigraph in other populations has been extensively used in interventions studies to track changes in sleep over time.¹²⁸ A comparison of subjectively and objectively derived sleep parameters such as the actigraph, in a large enough sample of SpA patients with repeated assessments over a number of days, is needed to fully understand sleep problems in SpA and to evaluate the strength and stability of the relationship between these two methods. Validation of this sleep assessment method could provide a useful adjunct in clinical and empirical evaluations of sleep problems in SpA. Future studies should apply a comprehensive biopsychosocial framework to more clearly elucidate the complex interplay between disease-related, behavioral, and psychosocial factors to sleep disturbance in SpA. Clinical trials are needed to evaluate the effects of the newer pharmacological agents (ie, TNF-α inhibitors) and nonpharmacological interventions for improving sleep in this patient population, and the associated mechanisms. There is also a need to examine more comprehensively the impact of disturbed sleep in SpA and how these disturbances independently influence disease activity, pain, fatigue, and quality of life.

CONCLUSION

Sleep problems are highly prevalent among patients with SpA. Most patients rarely discuss sleep problems with their physicians, making it imperative that sleep be routinely assessed, along with possible contributing factors, in order to better guide management. SpA patients report sleep problems as a health need that remains unmet,³⁹ suggesting inadequate management in cases where sleep problems are reported to health care providers. As such, there is a need for educational initiatives to inform both patients and physicians on the nature of sleep problems in SpA, their consequences, and possible treatments. Although the specific mechanisms involved remain to be clarified, numerous factors that can interact among each other contribute to sleep problems in SpA. Disease expression, most notably pain, is likely an important factor triggering sleep problems in SpA. Additionally, an array of behavioral and psychosocial factors, including physical inactivity, depressed mood, and stress likely contribute to the sleep disturbances experienced by patients with SpA. Given the importance of depressed mood to sleep disturbances in SpA, treatment strategies aimed at alleviating depression have the potential to improve sleep and its negative impact on quality of life. A biopsychosocial approach should be used to guide future sleep studies in SpA. A better understanding of the factors involved in triggering, maintaining, and improving sleep problems in SpA will help improve detection and management and will also guide the development of evidence-based interventions tailored specifically to this patient population.

Keywords

Spondyloarthropathy, sleep problems, biopsychosocial, depression, multimodal management

Disclosure: The authors declare no conflict of interest

Funding: Dr Lehman's work was supported by a Michael Smith Foundation for Health Research postdoctoral fellowship and the Abbott Post-doctoral Fellow in Aboriginal Arthritis Research.

REFERENCES

1. Olivieri I, van Tubergen A, Salvarani C, van der Linden S. Seronegative spondyloarthritides. Best Pract Res Clin Rheumatol. 2002;16(5):723–739.
2. Zochling J, Brandt J, Braun J. The current concept of spondyloarthritis with special emphasis on undifferentiated spondyloarthritis. Rheumatol. 2005;44(12):1483–1491.
3. Khan MA. Update on spondyloarthropathies. Ann Intern Med. 2002;136(12):896–907.
4. Braun J, Bollow M, Sieper J. Radiologic diagnosis and pathology of the spondyloarthropathies. Rheum Dis Clin North Am. 1998;24(4):697–735.
5. Landewe RB, van Tubergen A. Clinical assessment and outcome research in spondyloarthritis. Curr Rheumatol Rep. 2009;11(5):334–339.
6. Ancoli-Israel S. The impact and prevalence of chronic insomnia and other sleep disturbances associated with chronic illness. Am J Manag Care. 2006;12(8 suppl):S221–S229.
7. Daley M, Morin CM, LeBlanc M, Gregoire JP, Savard J. The economic burden of insomnia: direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms, and good sleepers. Sleep. 2009;32(1):55–64.
8. Fullerton DS. The economic impact of insomnia in managed care: a clearer picture emerges. Am J Manag Care. 2006;12(suppl 8):S246–S252.
9. Leger D, Poursain B, Neubauer D, Uchiyama M. An international survey of sleeping problems in the general population. Curr Med Res Opin. 2008;24(1):307–317.
10. Morphy H, Dunn KM, Lewis M, Boardman HF, Croft PR. Epidemiology of insomnia: a longitudinal study in a UK population. Sleep. 2007;30 (3):274–280.
11. Morin CM, Belanger L, LeBlanc M, et al. The natural history of insomnia: a population-based 3-year longitudinal study. Arch Intern Med. 2009;169(5):447–453.
12. Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 2002;6(2):97–111.
13. Da Costa D, Bernatsky S, Dritsa M, et al. Determinants of sleep quality in women with systemic lupus erythematosus. Arthritis Rheum. 2005;53 (2):272–278.
14. Katz DA, McHorney CA. The relationship between insomnia and healthrelated quality of life in patients with chronic illness. J Fam Pract. 2002;51(3):229–235.
15. Power JD, Perruccio AV, Badley EM. Pain as a mediator of sleep problems in arthritis and other chronic conditions. Arthritis Rheum. 2005;53(6):911–919.
16. Smith MT, Perlis ML, Smith MS, Giles DE, Carmody TP. Sleep quality and presleep arousal in chronic pain. J Behav Med. 2000;23(1):1–13.
17. Wilcox S, Brenes GA, Levine D, Sevick MA, Shumaker SA, Craven T. Factors related to sleep disturbance in older adults experiencing knee pain or knee pain with radiographic evidence of knee osteoarthritis. J Am Geriatr Soc. 2000;48(10):1241–1251.
18. Becker PM. Insomnia: prevalence, impact, pathogenesis, differential diagnosis, and evaluation. Psychiatr Clin North Am. 2006;29(4):855–870.
19. LeBlanc M, Beaulieu-Bonneau S, Merette C, Savard J, Ivers H, Morin CM. Psychological and health-related quality of life factors associated with insomnia in a population-based sample. J Psychosom Res. 2007;63(2):157–166.
20. Ohayon MM, Roth T. Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res. 2003;37(1):9–15.
21. Taylor DJ, Lichstein KL, Durrence HH. Insomnia as a health risk factor. Behav Sleep Med. 2003;1(4):227–247.
22. Phillips KD, Moneyham L, Murdaugh C, et al. Sleep disturbance and depression as barriers to adherence. Clin Nurs Res. 2005;14(3):273–293.
23. Haack M, Mullington JM. Sustained sleep restriction reduces emotional and physical well-being. Pain. 2005;119(1–3):56–64.
24. Leger D, Guilleminault C, Bader G, Levy E, Paillard M. Medical and socioprofessional impact of insomnia. Sleep. 2002;25(6):625–629.
25. Daley M, Morin CM, LeBlanc M, Gregoire JP, Savard J, Baillargeon L. Insomnia and its relationship to health-care utilization, work absenteeism, productivity and accidents. Sleep Med. 2009;10(4):427–438.
26. Leger D, Poursain B. An international survey of insomnia: underrecognition and under-treatment of a polysymptomatic condition. Curr Med Res Opin. 2005;21(11):1785–1792.
27. Devins GM, Edworthy SM, Paul LC, et al. Restless sleep, illness intrusiveness, and depressive symptoms in three chronic illness conditions: rheumatoid arthritis, end-stage renal disease, and multiple sclerosis. J Psychosom Res. 1993;37(2):163–170.
28. Drewes AM, Svendsen L, Taagholt SJ, Bjerregard K, Nielsen KD, Hansen B. Sleep in rheumatoid arthritis: a comparison with healthy subjects and studies of sleep/wake interactions. Br J Rheumatol. 1998;37(1):71–81.
29. Hirsch M, Carlander B, Verge M, et al. Objective and subjective sleep disturbances in patients with rheumatoid arthritis. A reappraisal. Arthritis Rheum. 1994;37(1):41–49.
30. Nicassio PM, Wallston KA. Longitudinal relationships among pain, sleep problems, and depression in rheumatoid arthritis. J Abnorm Psychol. 1992;101(3):514–520.
31. Heiberg T, Lie E, van der Heijde D, Kvien TK. Sleep problems are of higher priority for improvement for patients with ankylosing spondylitis than for patients with other inflammatory arthropathies. Ann Rheum Dis. 2011;70(5):872–873.
32. Boonen A, Braun J, van der Horst Bruinsma IE, et al. ASAS/WHO ICF Core Sets for ankylosing spondylitis (AS): how to classify the impact of AS on functioning and health. Ann Rheum Dis. 2010;69(1):102–107.
33. Hultgren S, Broman JE, Gudbjornsson B, Hetta J, Lindqvist U. Sleep disturbances in outpatients with ankylosing spondylitisa questionnaire study with gender implications. Scand J Rheumatol. 2000;29(6):365–369.
34. Karadag O, Nakas D, Kalyoncu U, Akdogan A, Kiraz S, Ertenli I. Effect of anti-TNF treatment on sleep problems in ankylosing spondylitis. Rheumatol Int. 2011. [Epub ahead of print].
35. Da Costa D, Zummer M, Fitzcharles MA. Biopsychosocial determinants of physical and mental fatigue in patients with spondyloarthropathy. Rheumatol Int. 2011;31(4):473–480.
36. Gunaydin R, Goksel KA, Cesmeli N, Kaya T. Fatigue in patients with ankylosing spondylitis: relationships with disease-specific variables, depression, and sleep disturbance. Clin Rheumatol. 2009;28(9):1045– 1051.
37. Drake CL, Roehrs T, Roth T. Insomnia causes, consequences, and therapeutics: an overview. Depress Anxiety. 2003;18(4):163–176.
38. Tanfield M. Ankylosing spondylitis and sleep. Lancet. 1978;1(8070):944– 945.
39. Da Costa D, Zummer M, Fitzcharles MA. Determinants of sleep problems in patients with spondyloarthropathy. Musculoskeletal Care. 2009;7(3):143–161.
40. Jones SD, Koh WH, Steiner A, Garrett SL, Calin A. Fatigue in ankylosing spondylitis: its prevalence and relationship to disease activity, sleep, and other factors. J Rheumatol. 1996;23(3):487–490.
41. Ward MM. Health-related quality of life in ankylosing spondylitis: a survey of 175 patients. Arthritis Care Res. 1999;12(4):247–255.
42. Jamieson AH, Alford CA, Bird HA, Hindmarch I, Wright V. The effect of sleep and nocturnal movement on stiffness, pain, and psychomotor performance in ankylosing spondylitis. Clin Exp Rheumatol. 1995;13(1):73–78.
43. Cutler MJ, Hamdan AL, Hamdan MH, Ramaswamy K, Smith ML. Sleep apnea: from the nose to the heart. J Am Board Fam Pract. 2002;15(2):128– 141.
44. Krishnan V, Collop NA. Gender differences in sleep disorders. Curr Opin Pulm Med. 2006;12(6):383–389.
45. Buysse DJ, Reynolds CF, III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193–213.
46. National Heart Lung and Blood Institute (NHLBI). Your Guide to Healthy Sleep. 2005. http://www.nhlbi.nih.gov/health/public/sleep/healthy_sleep.htm, National Institute of Health, U.S. Department of Health and Human Services. Accessed May 15, 2011.
47. Ohayon MM, Krystal A, Roehrs TA, Roth T, Vitiello MV. Using difficulty resuming sleep to define nocturnal awakenings. Sleep Med. 2010;11(3):236–241.
48. Abad VC, Sarinas PS, Guilleminault C. Sleep and rheumatologic disorders. Sleep Med Rev. 2008;12(3):211–228.
49. Hirshkowitz M. Normal human sleep: an overview. Med Clin North Am. 2004;88(3):551–565,vii.
50. Miaskowski C, Lee KA. Pain, fatigue, and sleep disturbances in oncology outpatients receiving radiation therapy for bone metastasis: a pilot study. J Pain Symptom Manage. 1999;17(5):320–332.
51. Geisler P, Tracik F, Cronlein T, et al. The influence of age and sex on sleep latency in the MSLT-30 – a normative study. Sleep. 2006;29(5):687– 692.
52. Ancoli-Israel S, Roth T. Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation Survey I. Sleep. 19991;22(suppl. 2):S347–S353.
53. Taylor DJ, Mallory LJ, Lichstein KL, Durrence HH, Riedel BW, Bush AJ. Comorbidity of chronic insomnia with medical problems. Sleep. 2007;30(2):213–218.
54. Humpel N, Iverson DC. Sleep quality, fatigue and physical activity following a cancer diagnosis. Eur J Cancer Care (Engl). 2010;19(6):761–768.
55. Roussou E, Sultana S. Spondyloarthritis in women: differences in disease onset, clinical presentation, and Bath Ankylosing Spondylitis Disease Activity and Functional indices (BASDAI and BASFI) between men and women with spondyloarthritides. Clin Rheumatol. 2011;30(1):121–127.
56. Louie GH, Tektonidou MG, Caban-Martinez AJ, Ward MM. Sleep disturbances in adults with arthritis: prevalence, mediators, and subgroups at greatest risk. Data from the 2007 National Health Interview Survey. Arthritis Care Res (Hoboken). 2011;63(2):247–260.
57. Polo-Kantola P. Sleep problems in midlife and beyond. Maturitas. 2011;68(3):224–232.
58. Zhang B, Wing YK. Sex differences in insomnia: a meta-analysis. Sleep. 2006;29(1):85–93.
59. Erb N, Karokis D, Delamere JP, Cushley MJ, Kitas GD. Obstructive sleep apnoea as a cause of fatigue in ankylosing spondylitis. Ann Rheum Dis. 2003;62(2):183–184.
60. Solak O, Fidan F, Dundar U, et al. The prevalence of obstructive sleep apnoea syndrome in ankylosing spondylitis patients. Rheumatol. 2009;48(4):433–435.
61. Louie GH, Tektonidou MG, Caban-Martinez AJ, Ward MM. Sleep disturbances in adults with arthritis: prevalence, mediators, and subgroups at greatest risk. Arthritis Care Res. 2010;63(2):247–260.
62. Lee YC, Chibnik LB, Lu B, et al. The relationship between disease activity, sleep, psychiatric distress, and pain sensitivity in rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther. 2009;11(5):R160.
63. Davies KA, Macfarlane GJ, Nicholl BI, et al. Restorative sleep predicts the resolution of chronic widespread pain: results from the EPIFUND study. Rheumatol. 2008;47(12):1809–1813.
64. Smith MT, Haythornthwaite JA. How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature. Sleep Med Rev. 2004;8(2):119–132.
65. Lautenbacher S, Kundermann B, Krieg JC. Sleep deprivation and pain perception. Sleep Med Rev. 2006;10(5):357–369.
66. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol. 1994;21(12):2286–2291.
67. Calin A, Garrett S, Whitelock H, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol. 1994;21(12):2281– 2285.
68. Toussirot E. Late-onset ankylosing spondylitis and spondylarthritis: an update on clinical manifestations, differential diagnosis, and pharmacological therapies. Drugs Ageing. 2010;27(7):523–531.
69. Braun J, Baraliakos X. Treatment of ankylosing spondylitis and other spondyloarthritides. Curr Opin Rheumatol. 2009;21(4):324–334.
70. Sleep Hygiene P Behaviors That Help Promote Better Sleep. Rochester, MN: American Sleep Disorders Association; 2005.
71. Hauri PJ. Consulting about insomnia: a method and some preliminary data. Sleep. 1993;16(4):344–350.
72. Bunnell DE, Bevier W, Horvath SM. Effects of exhaustive exercise on the sleep of men and women. Psychophysiology. 1983;20(1):50–58.
73. Dishman RK. Mental health. In: Seefeldt V, ed. , Physical Activity and Well Being.Washington, DC: Hemisphere Publishing Corporation; 1986: 303– 341.
74. Sherrill DL, Kotchou K, Quan SF. Association of physical activity and human sleep disorders. Arch Intern Med. 1998;158(17):1894–1898.
75. Youngstedt SD, O’Connor PJ, Dishman RK. The effects of acute exercise on sleep: a quantitative synthesis. Sleep. 1997;20(3):203–214.
76. Youngstedt SD. Effects of exercise on sleep. Clin Sports Med. 2005;24(2):355–365, xi.
77. Driver HS, Taylor SR. Exercise and sleep. Sleep Med Rev. 2000;4(4):387– 402.
78. O’Connor PJ, Youngstedt SD. Influence of exercise on human sleep. Exerc Sport Sci Rev. 1995;23:105–134.
79. King AC, Oman RF, Brassington GS, Bliwise DL, Haskell WL. Moderate-intensity exercise and self-rated quality of sleep in older adults. A randomized controlled trial. JAMA. 1997;277(1):32–37.
80. Singh NA, Clements KM. Fiatarone MA. A randomized controlled trial of the effect of exercise on sleep. Sleep. 1997;20(2):95–101.
81. Guilleminault C, Clerk A, Black J, Labanowski M, Pelayo R, Claman D. Nondrug treatment trials in psychophysiologic insomnia. Arch Intern Med. 1995;155(8):838–844.
82. King AC, Pruitt LA, Woo S, et al. Effects of moderate-intensity exercise on polysomnographic and subjective sleep quality in older adults with mild to moderate sleep complaints. J Gerontol A Biol Sci Med Sci. 2008;63(9):997–1004.
83. Reid KJ, Baron KG, Lu B, Naylor E, Wolfe L, Zee PC. Aerobic exercise improves self-reported sleep and quality of life in older adults with insomnia. Sleep Med. 2010;11(9):934–940.
84. Karapolat H, Akkoc Y, Sari I, et al. Comparison of group-based exercise versus home-based exercise in patients with ankylosing spondylitis: effects on Bath Ankylosing Spondylitis Indices, quality of life and depression. Clin Rheumatol. 2008;27(6):695–700.
85. Hoffman BM, Babyak MA, Craighead WE, et al. Exercise and pharmacotherapy in patients with major depression: one-year followup of the SMILE study. Psychosom Med. 2011;73(2):127–133.
86. Babyak M, Blumenthal JA, Herman S, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med. 2000;62(5):633–638.
87. Moses J, Steptoe A, Mathews A, Edwards S. The effects of exercise training on mental well-being in the normal population: a controlled trial. J Psychosom Res. 1989;33(1):47–61.
88. Tsuno N, Besset A, Ritchie K. Sleep and depression. J Clin Psychiatry. 2005;66(10):1254–1269.
89. Mendelson WB Human Sleep and its Disorders. New York: Plenum Press; 1997.
90. Riemann D, Berger M, Voderholzer U. Sleep and depression – results from psychobiological studies: an overview. Biol Psychol. 2001;57(1– 3):67–103.
91. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39(6):411–418.
92. Dew MA, Reynolds CF, III, Buysse DJ, et al. Electroencephalographic sleep profiles during depression. Effects of episode duration and other clinical and psychosocial factors in older adults. Arch Gen Psychiatry. 1996;53(2):148–156.
93. Cole MG, Dendukuri N. Risk factors for depression among elderly community subjects: a systematic review and meta-analysis. Am J Psychiatry. 2003;160(6):1147–1156.
94. Bakker C, van der Linden S, van Santen-Hoeufft M, Bolwijn P, Hidding A. Problem elicitation to assess patient priorities in ankylosing spondylitis and fibromyalgia. J Rheumatol. 1995;22(7):1304–1310.
95. Barlow JH, Macey SJ, Struthers GR. Gender, depression, and ankylosing spondylitis. Arthritis Care Res. 1993;6(1):45–51.
96. Baysal O, Durmus B, Ersoy Y, et al. Relationship between psychological status and disease activity and quality of life in ankylosing spondylitis. Rheumatol Int. 2011;31(6):795–800.
97. Martindale J, Smith J, Grennan D, Goodacre L, Goodacre JA. Outcome of active disease in ankylosing spondylitis: a prospective study. Musculoskeletal Care. 2010;8(1):10–17.
98. Hall M, Buysse DJ, Nowell PD, et al. Symptoms of stress and depression as correlates of sleep in primary insomnia. Psychosom Med. 2000;62(2):227–230.
99. Katz DA, McHorney CA. Clinical correlates of insomnia in patients with chronic illness. Arch Intern Med. 1998;158(10):1099–1107.
100. Morin CM, Rodrigue S, Ivers H. Role of stress, arousal, and coping skills in primary insomnia. Psychosom Med. 2003;65(2):259–267.
101. Sutton DA, Moldofsky H, Badley EM. Insomnia and health problems in Canadians. Sleep. 2001;24(6):665–670.
102. Treharne GJ, Lyons AC, Hale ED, et al. Sleep disruption frequency in rheumatoid arthritis: perceived stress predicts poor outcome over one year. Musculoskeletal Care. 2007;5(1):51–64.
103. Shaver JL, Johnston SK, Lentz MJ, Landis CA. Stress exposure, psychological distress, and physiological stress activation in midlife women with insomnia. Psychosom Med. 2002;64(5):793–802.
104. Baldwin CM, Ervin AM, Mays MZ, et al. Sleep disturbances, quality of life, and ethnicity: the Sleep Heart Health Study. J Clin Sleep Med. 2010;6(2):176–183.
105. Culpepper L. Insomnia: a primary care perspective. J Clin Psychiatry. 2005;66(suppl 9):14–17.
106. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487–504.
107. Siriwardena AN, Apekey T, Tilling M, Dyas JV, Middleton H, Orner R. General practitioners’ preferences for managing insomnia and opportunities for reducing hypnotic prescribing. J Eval Clin Pract. 2010;16(4):731–737.
108. Shochat T, Umphress J, Israel AG, Ancoli-Israel S. Insomnia in primary care patients. Sleep. 1999;22(suppl 2):S359–S365.
109. Ohayon MM. Observation of the natural evolution of insomnia in the American general population cohort. Sleep Med Clin. 2009;4(1):87–92.
110. National Sleep Foundation (NSF). 2009 Sleep in America Poll. 2011. Washington, DC, Available from: http://www.sleepfoundation.org/sites/ default/files/2009%20POLL%20HIGHLIGHTS.pdf. Ref Type: Pamphlet. Accessed May 15, 2011.
111. Beck AT, Steer RA Brown GK. Manual for the BDI-II. San Antonio, TX: The Psychological Corporation; 1996.
112. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav. 1983;24(4):385–396.
113. Spielberger CD, Gorsuch RL, Lushene RE Manual for the State-Trait Anxiety Inventory. Alto, CA: Consulting Psychologist Press; 1983.
114. Chesson A, Jr, Hartse K, Anderson WM, et al. Practice parameters for the evaluation of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 2000;23(2):237–241.
115. Deodhar A, Braun J, Inman RD, et al. Golimumab reduces sleep disturbance in patients with active ankylosing spondylitis: results from a randomized, placebo-controlled trial. Arthritis Care Res. 2010;62(9):1266–1271.
116. van der Heijde D, Maksymowych WP. Spondyloarthritis: state of the art and future perspectives. Ann Rheum Dis. 2010;69(6):949–954.
117. Rudwaleit M, Gooch K, Michel B, et al. Adalimumab improves sleep and sleep quality in patients with active ankylosing spondylitis. J Rheumatol. 2011;38(1):79–86.
118. van der Heijde DM, Revicki DA, Gooch KL, et al. Physical function, disease activity, and health-related quality-of-life outcomes after 3 years of adalimumab treatment in patients with ankylosing spondylitis. Arthritis Res Ther. 2009;11(4):R124.
119. Inman RD, Davis JC, Jr, Heijde D, et al. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, doubleblind, placebo-controlled, phase III trial. Arthritis Rheum. 2008;58 (11):3402–3412.
120. Kay J, Rahman MU. Golimumab: a novel human anti-TNF-alpha monoclonal antibody for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Core Evid. 2010;4:159–170.
121. Currie SR, Wilson KG, Pontefract AJ, deLaplante L. Cognitive-behavioral treatment of insomnia secondary to chronic pain. J Consult Clin Psychol. 2000;68(3):407–416.
122. Morin CM, Hauri PJ, Espie CA, Spielman AJ, Buysse DJ, Bootzin RR. Nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine review. Sleep. 1999;22(8):1134–1156.
123. Montgomery P, Dennis J. A systematic review of non-pharmacological therapies for sleep problems in later life. Sleep Med Rev. 2004;8(1):47–62.
124. Rybarczyk B, Stepanski E, Fogg L, Lopez M, Barry P, Davis A. A placebocontrolled test of cognitive-behavioral therapy for comorbid insomnia in older adults. J Consult Clin Psychol. 2005;73(6):1164–1174.
125. Vitiello MV, Rybarczyk B, Von KM, Stepanski EJ. Cognitive behavioral therapy for insomnia improves sleep and decreases pain in older adults with co-morbid insomnia and osteoarthritis. J Clin Sleep Med. 2009;5(4):355–362.
126. Mullaney DJ, Kripke DF, Messin S. Wrist-actigraphic estimation of sleep time. Sleep. 1980;3(1):83–92.
127. Ancoli-Israel S, Cole R, Alessi C, Chambers M, Moorcroft W, Pollak CP. The role of actigraphy in the study of sleep and circadian rhythms. Sleep. 2003;26(3):342–392.
128. Ancoli-isreal S. Actigraphy. In: Kryger M, Roth T, Dement W, eds. Principles and Practice of Sleep Medicine. Philadelphia: Elsevier; 2005: 1459–1467.

Recently, reports have suggested grouping different autoimmune conditions that are triggered by external stimuli as a single condition called autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This syndrome is characterized by clinical manifestations such as myalgia, myositis, muscle weakness, arthralgia or arthritis, chronic fatigue, sleep disturbances, cognitive impairment, and memory loss as well as possible emergence of either a demyelinating or systemic autoimmune disease after exposure to vaccines and adjuvants. In this article, the authors will review and give a criticism on this new syndrome.

Could it be that Gulf War Syndrome (GWS), which debilitated American and British veterans of operations Desert Shield and Desert Storm and the scleroderma-like reactions of patients who received silicone implantations in the 1990s, constitute manifestations of the same illness? What might they have in common with a rare myopathic syndrome induced by aluminum and described for the first time in France in 1998? The logical response was suggested from clinical observations and innovative research at the Tel-Hashomer Autoimmune Disease Center in Israel and it is very simple: etiopathogenesis.¹

These distinct and enigmatic autoimmune conditions, separated by time and geographic distance, have been classified as one syndrome: the autoimmune/inflammatory syndrome induced by adjuvants or ASIA. An article on ASIA was recently published in a prestigious and high-impact journal in the field, namely the Journal of Autoimmunity. ¹ ASIA is an appropriate acronym, since Asia is the largest and most populous continent on the planet whose cultures are mysterious to those who have not opened their eyes and mind to its diversity.

Adjuvants include compounds that have been recognized for decades as autoimmunity inducers in different animal models and that are used in the pharmaceutical industry to develop antigenicity and to decrease the cost of vaccine production. Adjuvants, as it is already known, can trigger the development of inflammatory or autoimmune illnesses in genetically susceptible humans.^{2, 3} Among this large group—which includes infectious fragments, hormones, aluminum, and silicone—squalene has recently been highlighted. It is a natural oil obtained from shark tissue and constitutes one of the principal adjuvants used in the anti-influenza vaccine.⁴

Gulf War Syndrome (GWS) was first described in 1998⁵ in war veterans who did not suffer from classic rheumatic illnesses, but presented with symptoms characteristic of these disorders such as arthralgia, myalgia, lymphadenopathy, chronic fatigue, facial flushing, and autoimmune thyroid disease.

A double-blind cohort study completed about 10 years ago by a New Orleans group⁶ presented a surprising outcome with respect to GWS. This study compared dosages of antisqualene antibody serum in 114 Gulf War veterans and noncombat military employees (some healthy and some ill) with a control group comprised of 48 blood donors, 40 asymptomatic patients with systematic lupus erythematosis, 34 patients with silicone breast implants, and 30 patients with chronic fatigue syndrome. None of the patients from the control group—even those with active autoimmune disease—presented detectable antisqualene antibodies in their serum, whereas 95% of the military group presented positive antibodies. Among the latter, 100% of those patients who presented with symptoms of (GWS), independent of their combat status, presented with antisqualene antibodies. On the other hand, this antibody was not detected in any of the veterans who did not present with symptoms. The authors suggested then that GWS was not the result of exposure to chemical or biological weapons or posttraumatic stress but to immune disequilibrium caused by an intense vaccine regimen that, whether they were combatants or not, all military individuals received during the conflict preparation period. This also clarifies other findings⁴ of hypergammaglobulinemia and abnormal levels of acute phase proteins found in 45% of patients with GWS.

It should be highlighted that the real health concerns of the anti-Iraqi troops in this conflict were not infectious disease epidemics such as trench illness (a fever related to ticks) or those similar to the sudden outbreak of the Spanish flu that occurred during the first and between the two World Wars. The concerns did not even include trauma from firearm and explosives as in the second war or the consequences of stimulant abuse and other substances in the Vietnam War. In the gulf, the greatest enemy was the desert heat and thirst. Maintaining the quality of available drinking water was as essential as good military strategy to ensure a low number of casualties for the Western contingent.

It is ironic that more soldiers have become ill due to an oily adjuvant injected as part of a complex immuno-protector than from braving the hostile environment and fighting against armed enemies who disputed the local petroleum reserves.

Siliconosis, as the fibrosing tissue reaction similar to a limited form of scleroderma became known with its general systemic symptoms associated with cosmetic implantations, challenged the international scientific community to unravel its pathophysiological mechanisms. In the beginning of the 1990s, silicone was considered to be an inert material and, therefore, incapable of triggering immune phenomena. Recent meta-analyses estimate the prevalence of developing connective tissue disease after silicone implantation at only 0.8%, very close to that of the general population. However, these studies only admitted patients who met criteria for known autoimmune diseases. They did not consider patients with less specific manifestations that did not fit the profile of a known condition such as arthralgia, myalgia, or even neurological manifestations.

Macrophagic myofascitis, the postvaccine muscular disease described by the French researchers Gehardi et al.⁷ in 1998, is interesting for its well-documented histopathological changes. In macrophagic myofascitis there are cytoplasmic inclusions of aluminum, which is used as an adjuvant in various vaccines. It has systemic manifestations that include marked asthenia, chronic fatigue, myalgia, arthralgia, fever and, in some cases, demyelinating polyradiculoneuropathy, which is clinically similar to Guillain-Barré disease with documented electromyography changes. The patients presented with elevated acute phase proteins and creatine kinase (CK) levels. This research group⁸ also garnered support for the theory that the rarity of complications was due to genetic susceptibility, as only patients with a HLA DRB1*01 profile developed the illness. Moreover, in 2002⁸ the persistence of aluminum adjuvant deposits in the site of application for up to 10-years postimmunization was verified, which could explain the persistence of the muscular illness in patients.

Some patients with autoimmune disease and allergic profiles showed trigger reactions with the reactivation of the base illness when they were vaccinated with the common anti-influenza H1N1 vaccine, which is rich in squalene and aluminum as adjuvants. However, those who received the vaccine without adjuvants, such as pregnant patients, did not present with such alterations. These findings also give rise to debate regarding the creation of specific vaccine security recommendations for patients with rheumatic illnesses. Finally, the work of Shoenfeld has led to the suggested ASIA diagnosis criteria (Table 1) that are as yet unvalidated but can assist immediately in the recognition of the disorder and guide future studies on it.

This editorial intends to propose a new name for ASIA, Shoenfeld syndrome, in reference to the author who studied and described in an unprecedented form the nature of these events, which were previously distinguished from one another and recognized as heterogeneous. Moreover, Shoenfeld acknowledged the important relations of the disease with environmental influence studies in the etiopathogenesis and prognosis of autoimmune diseases. The authors also propose that the diagnostic criteria for this syndrome are henceforth referred to as the Shoenfeld criteria.

Keywords

ASIA, silicone, inflammatory disease, autoimmune disease, adjuvant

Disclosure: The authors declare no conflict of interest.

Funding: J.F. de Carvalho was the recipient of grants from the Federico Foundation and CNPq (300665/2009-1).

REFERENCES

1. Shoenfeld Y, Agmon-Levin N. ‘‘ASIA’’—Autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011;36(1):4–8.
2. Shoenfeld Y, Zandman-Goddard G, Stojanovich L, et al. The mosaic of autoimmunity: hormonal and environmental factors involved in autoimmune diseases—2008. Isr Med Assoc J. 2008;10:8–12.
3. de Carvalho JF, Pereira RM, Shoenfeld Y. The mosaic of autoimmunity: the role of environmental factors. Front Biosci (Elite Ed). 2009;1:501–509.
4. Israel E, Agmon-Levin N, Blank M, Shoenfeld Y. Adjuvants and autoimmunity. Lupus. 2009;18:1217–1225.
5. Asa PB, Cao Y, Garry RF. Antibodies to squalene in Gulf War syndrome. Exp Molec Pathol. 2000;68:55–64.
6. Gehardi RK, Coquet M, Cherin P, et al. Macrofagic myofasciitis: an emerging entity. Lancet. 1998;352:347–352.
7. Guis S, Pellissier JF, Nicoli F, et al. HLA-DRB1—01 and macrofagic myofasciitis. Arthritis Rheum. 2002;46:255–257.
8. Israeli E, Agmon-Levin N, Blank M, Shoenfeld Y. Macrophagic Myofaciitis a Vaccine (alum) Autoimmune-Related Disease. Clin Rev Allergy Immunol. 2010 Sep 30. [Epub ahead of print]. Doi: 10.1007/s12016-010- 8212-4.

In patients with rheumatoid arthritis (RA), initial treatment options usually involve nonbiologic disease-modifying antirheumatic drugs (DMARDs). If patients treated with DMARDs subsequently develop an inadequate response to these therapies, the next treatment option is biologic therapy. Currently available biologic therapies target key cytokines and cells involved in immune regulation, including tumor necrosis factor (TNF) alpha, interleukin-6 (IL-6), T cells, and B cells. TNF inhibitors are usually selected as the first biologic therapy as they have demonstrated favorable long-term safety and good efficacy profiles.^{1, 2} However, although five TNF inhibitors are currently available for the treatment of RA, between 30 and 40% of patients either fail to respond to initial treatment or become refractory to these agents over time.^3–7 The two main options for patients who fail a first TNF inhibitor are to switch to an alternative TNF inhibitor or to begin treatment with a biologic therapy with a different mechanism of action. Currently available nonTNF biologics are abatacept (T cell coactivation inhibitor), rituximab (targets B cells), and tocilizumab (IL-6 receptor inhibitor). Recent evidence from several patient registries suggests that, in patients with an inadequate response to TNF inhibitors (TNFi-IR), switching to the B cell therapy rituximab may be more effective than switching to an alternative TNF inhibitor.⁸

The main purpose of this article is to examine the recent clinical data regarding the use of B cell therapies in patients with RA and an inadequate response to TNF inhibitors. The use of B cell therapies in other autoimmune diseases is also reviewed.

B CELLS IN THE PATHOGENESIS OF RA

B cells are strongly implicated in the pathogenesis of RA as they control multiple cellular signaling pathways that contribute to the development of this disease.^9–11 Survival of autoreactive B cells and the production of autoantibodies can lead to autoimmune diseases such as RA.¹² The two most widely recognized autoantibodies associated with RA are rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPAs).¹¹ The presence of RF and/or ACPAs can precede the onset of symptomatic RA. Indeed, these autoantibodies have been detected in the serum of individuals many years before the appearance of any clinical RA symptoms.¹³ Autoantibodies and immune complexes that are not cleared from the circulation become deposited on joint surfaces resulting in the activation of numerous inflammatory processes and subsequent joint destruction, leading to the development of RA.^{9, 14} In addition, new immunoglobulin (Ig) M-specific ACPA B cells are constantly recruited to the inflamed RA joint, leading to continuous activation of the antibody response and sustained joint destruction.¹⁵

The evidence linking B cells with the pathogenesis of RA has led to the development of several B cell-targeted therapies (Table 1), many of which target the CD20 surface marker that is expressed exclusively on B cells.

B CELL THERAPIES FOR THE TREATMENT OF RA

The majority of evidence supporting the efficacy of B cell-targeted therapies for the treatment of RA comes from clinical trials and real-world practice with rituximab. Other B cell therapies for RA are in varying stages of development; data from trials with these therapies are now emerging.

Rituximab

Rituximab is a chimeric mouse–human monoclonal antibody that selectively targets the CD20 surface marker on B cells. When bound to CD20, rituximab initiates B cell depletion through incompletely defined mechanisms that may include complement-dependent cytotoxicity (CDC), antibody-dependent cellular toxicity (ADCC), and apoptosis.¹⁶

Rituximab was approved by the FDA in 2006 for the treatment of RA in patients whose disease does not respond to TNF inhibitors. This approval was based on results of the Randomized Evaluation oF Long-term Ēfficacy of rituXimab in RA (REFLEX) trial, the first Phase III study to demonstrate that treatment with rituximab, in combination with methotrexate (MTX), significantly improved disease symptoms in patients with active RA compared with placebo plus MTX.¹⁷ Patients with an inadequate response to at least one TNF inhibitor were treated with rituximab (2×1000 mg given on days 1 and 15) or placebo with both treatment groups receiving MTX (10–25 mg/week). At Week 24, rituximab plus MTX was significantly superior to placebo plus MTX in terms of ACR and EULAR responses (Figure 1). In addition, significant and clinically relevant improvements in all assessed patient-reported outcomes, including fatigue, disability, and health-related quality of life, were observed in patients treated with rituximab compared with placebo.¹⁷

In a 2-year extension study of REFLEX, retreatment with rituximab significantly reduced the progression of joint damage compared with placebo (Figure. 2).¹⁸ Patients eligible for retreatment received open-label rituximab from Week 24 and joint damage progression was assessed by X-ray at baseline and Weeks 24, 56, and 104. The REFLEX extension study provided the first evidence that a B cell-targeted therapy can significantly inhibit the progression of structural joint damage in patients with active, long-standing, and treatment-resistant RA.

Retreatment With rituximab

Analyses of the open-label extension studies of the Phase II/III trials in patients with an inadequate response to MTX and/or TNF inhibitors have demonstrated that the clinical efficacy of rituximab can be sustained on retreatment.¹⁹ However, although these analyses provide useful information on rituximab retreatment, the retreatment intervals used in the individual trials were variable as they were dependent on physician-defined disease flare. Therefore, firm conclusions on the efficacy of retreating with rituximab and the optimal retreatment interval cannot be drawn from these extension studies alone. To address this, the tudy for UNderstanding RItuximab Safety and Efficacy (SUNRISE) trial compared the safety and efficacy of one vs two courses of rituximab in patients with RA refractory to TNF inhibitor therapy. Results showed that patients retreated with a second course of rituximab experienced significantly improved clinical responses compared with patients who received a single course.²⁰ Patients in SUNRISE received one course of open-label rituximab (2×1000 mg) at baseline and at Week 24 were randomized to receive an additional course of rituximab or placebo. At Week 48, the ACR20 response and mean change in DAS28 (disease activity score using 28 joint counts) in patients retreated with rituximab were significantly greater than those treated with placebo at Week 24 (ACR20: 54 vs 45%, P=.02; mean change in DAS28: –1.9 vs –1.5, P=.006). Patients with an ACR20 response at Week 24 who were retreated with placebo typically lost response by Week 32, suggesting that to maintain efficacy, retreatment should occur approximately every 6 months.

In RA, the primary aim of treatment is to achieve sustained remission with low disease activity, to improve symptoms and physical function, and reduce long-term disability.²¹ These outcomes are more likely to be achieved with aggressive early treatment, the so-called “tight control” approach.²² Results from the SUNRISE trial suggest that patients who receive early rituximab retreatment prior to loss of response to the first course of treatment have better clinical outcomes than those who do not receive retreatment.²⁰ A recent analysis published by Emery et al. ²³ supports the use of a tight control strategy for rituximab therapy. In this study, retreatment with rituximab using a treatment to target (TT) approach, in which patients were assessed 24 weeks after each course and retreated if not in remission (DAS28-ESR ≥2.6), led to improved efficacy, and tighter control of disease activity compared with a treatment as needed (PRN) approach.²³This pooled analysis of patients with an inadequate response to MTX from SERENE,²⁴MIRROR,²⁵ DANCER,^{26, 27} and the initial rituximab proof of concept study²⁸ demonstrated that the TT regimen was associated with significantly greater improvements in DAS28-ESR and lower Health Assessment Questionnaire-Disability Index scores compared with the PRN approach. The TT regimen was also associated with a significantly reduced incidence of disease flares and more patients achieved a major clinical response (defined as maintenance of ACR70 response for ≥ 6 months) compared with the PRN approach.

B cell depletion and clinical response

Treatment with rituximab is known to induce a profound depletion of circulating B cells; however, studies have demonstrated that, in spite of this, clinical response to rituximab can be variable, with some patients failing to respond to treatment despite apparent B cell depletion being achieved.²⁹

Recent insights obtained using highly sensitive flow cytometry (HSFC) that can detect B cell numbers 50–100 times lower than conventional techniques^{30, 31} may provide an explanation for observed variations in the clinical response to rituximab. Using this technique, the extent of B cell depletion was shown in one study to correlate with clinical response to rituximab therapy, with incomplete B cell depletion associated with poorer clinical outcomes.³⁰ In a follow-up study, patients with poor clinical response to an initial course of rituximab had higher circulating preplasma B cell levels prior to treatment and incomplete B cell depletion following treatment.³² These studies suggest that the detection of B cell levels by HSFC after treatment may be a marker of clinical response to rituximab and could, therefore, inform individualized treatment strategies for rituximab in RA.³⁰

Studies examining synovial biopsies in patients treated with rituximab may offer further explanation for the lack of correlation between plasma B cell levels and clinical response to rituximab. These studies have shown that B cell depletion in the synovium is rarely complete following rituximab administration, and the degree of clinical response may be associated with the extent of synovial B cell depletion.^33–35

Autoantibody seropositivity and clinical response

The presence of autoantibodies such as RF and ACPA is generally considered a marker for poor clinical prognosis in RA.^{36, 37} Several analyses have shown that patients who are seropositive for RF and/or ACPA are likely to have an enhanced clinical response to rituximab compared with patients who are seronegative for these autoantibodies.^{38, 39} For example, pooled data from 10 European registries have shown that seropositivity for RF and ACPA, and in particular ACPA, is a strong predictor of response to treatment with rituximab.³⁸ In this analysis, improvements in DAS28 at 3 and 6 months were significantly greater for RF-positive and ACPA-positive patients compared with seronegative patients.

Other studies have shown enhanced clinical responses to rituximab in patients who are seropositive for RF. In one study of patients with RA and an inadequate response to a single TNF inhibitor, RF was found to be a predictor of clinical response to an initial course of rituximab plus MTX.⁴⁰ RF seropositivity at baseline was also found to be predictive of clinical response to rituximab in the SUNRISE trial.²⁰

Taken together, the data published to date suggest that patients who are seropositive for ACPA and/or RF could be considered as a distinct patient population that may achieve enhanced clinical response to treatment with rituximab.

Ofatumumab

Ofatumumab is a fully humanized monoclonal antibody against CD20 that has undergone evaluation for the treatment of RA using intravenous (IV) administration in two Phase III clinical trials. However, despite positive results in one of these trials,⁴¹ clinical development of IV ofatumumab has ceased. A recently completed Phase I/IIA trial assessing a subcutaneous (SC) formulation of ofatumumab demonstrated that doses of 30, 60, and 100 mg resulted in a profound and sustained depletion of peripheral B cells in patients with RA.^{42, 43}

Ocrelizumab

Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20.⁴⁴ The epitope on CD20 targeted by ocrelizumab overlaps with but is distinct from that targeted by rituximab. In vitro studies have indicated that ocrelizumab exhibits enhanced ADCC and reduced CDC when compared with rituximab, although the clinical significance of these differences is not yet clear [Roche, data on file].

Ocrelizumab has been investigated as a treatment for RA in an extensive program of Phase III, randomized, placebo-controlled clinical trials. The two pivotal trials in this program evaluated the safety and efficacy of ocrelizumab at two doses (2×200 mg and 2×500 mg, both given as two infusions, 2 weeks apart) in patients with an inadequate response to DMARDs (the STAGE trial)⁴⁵ and in TNF-IR patients (the SCRIPT trial).⁴⁶ In each trial, both doses of ocrelizumab, in combination with MTX, resulted in a significant increase in ACR20 response at Weeks 24 and 48 (the coprimary endpoint) compared with placebo+MTX. ACR50 and ACR70 response rates were also significantly improved with ocrelizumab treatment. In STAGE, both doses of ocrelizumab resulted in a significant reduction in joint damage progression (P<.0001) compared with placebo, whereas in SCRIPT, statistically significant inhibition of joint damage progression was seen only with the higher dose of ocrelizumab. The overall incidence of adverse events and infections was similar between the ocrelizumab and placebo groups in both trials. However, a higher rate of serious infections compared with placebo was observed with ocrelizumab 2×500 mg in STAGE and with both ocrelizumab doses in SCRIPT. The overall evaluation of clinical efficacy and safety from the ocrelizumab clinical trial program concluded that the potential added value of ocrelizumab over existing therapies, such as rituximab, did not warrant further development of ocrelizumab for the treatment of RA. Ocrelizumab is currently in development for multiple sclerosis, while other indications are being considered.

TRU-015 and SBI-087

TRU-015 is a recombinant CD20-directed small modular immunopharmaceutical (SMIP). The clinical development of TRU-015 for the treatment of RA was recently discontinued in favor of SBI-087, a fully humanized CD20-directed SMIP for both IV and SC administration.

SBI-087 is in the early stages of clinical development for the treatment of RA, with three trials currently ongoing. These include two Phase I trials designed to evaluate the safety and tolerability of ascending single doses (IV and SC) of SBI-087 in patients with RA.^{47, 48} Preliminary results from one of the Phase I trials indicate that SBI-087 rapidly depleted peripheral blood B cells in a dose-dependent manner after IV and SC administration. SC doses of 100 mg and higher achieved B cell depletion to below the lower limit of detection of HSFC (<0.3 cells/µL) in 50% of patients between Weeks 2 and 4. Depletion to <5 cells/µL was maintained for at least 12 weeks in ≥60% of patients treated with SC doses of 100 mg and higher.⁴⁹

The third trial is a Phase II study that will assess the safety and efficacy of SC SBI-087 in patients with active RA who are positive for either RF or ACPA and receiving methotrexate.⁵⁰

B CELL THERAPIES IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune disease that can affect any part of the body.⁵¹ SLE is associated with B cell hyperactivity, autoantibody production, and increased concentrations of plasma B lymphocyte stimulator (BLyS). B cell-targeted therapies are, therefore, a potential therapeutic option for the treatment of this disease.

Rituximab

Results from several small, uncontrolled trials suggested that rituximab may be an effective treatment for SLE.^52–56 However, despite these promising results, two placebo-controlled trials evaluating the safety and efficacy of rituximab in patients with refractory extrarenal SLE (EXPLORER trial)⁵⁷ and lupus nephritis (LUNAR trial)⁵⁸ failed to meet their primary endpoints.

In EXPLORER, the proportion of patients achieving and maintaining a major or partial clinical response (without subsequent disease flare) at the study endpoint (Week 52) was not significantly different between the rituximab and placebo groups.⁵⁷ In LUNAR, clinical response at Week 52 was numerically higher in patients treated with rituximab compared with placebo (57 vs 46%); however, this difference did not reach statistical significance.⁵⁸ Interestingly, both trials did report a beneficial effect of rituximab in Black and Hispanic patient subgroups, suggesting that patients with these ethnic backgrounds may have enhanced responses to rituximab compared with the general SLE population.

Belimumab

Belimumab is a fully human recombinant immunoglobulin G (IgG) 1λ monoclonal antibody that binds to soluble human BLyS.⁵⁹ After promising results in early clinical studies, two Phase III trials (BLISS-52⁶⁰ and BLISS-76^{61, 62}) demonstrated that belimumab in combination with standard therapy was effective and well tolerated in patients with active SLE (Table 2). In both studies, patients were randomized to receive belimumab (1 mg/kg or 10 mg/kg) or placebo on Days 0, 14, and 28, and then every 28 days until 48 weeks (BLISS-52)⁶⁰ or 72 weeks (BLISS-72)⁶¹ with standard of care. On the basis of these results, belimumab was approved by the FDA in 2011 as a treatment for patients with active, autoantibody-positive SLE.

There are a number of possible reasons that could explain the contrasting results of B cell-targeting therapies in the BLISS, EXPLORER, and LUNAR trials. Firstly, clinical outcome measures used in lupus trials may not accurately capture the heterogeneous and complex changes that occur in disease activity following treatment and thus, may not reliably differentiate a treatment effect.⁶³ The Phase III BLISS trials utilized a responder index that was developed based on an analysis of responding patients in a previous Phase II trial with belimumab,⁶⁴ whereas the EXPLORER and LUNAR trials used previously accepted standard clinical outcome measures.^{57, 58} The new responder index used in the belimumab trials is being used as a new “standard” outcome measure in some of the ongoing SLE trials with other agents. The different responder indices should be kept in mind when comparing the outcomes of the BLISS, EXPLORER, and LUNAR trials. Indeed, in a post hoc exploratory analysis of the EXPLORER trial, reanalysis of the data indicated that when severe disease flare (instead of all disease flare) was assessed following treatment, a significant treatment effect of rituximab was observed compared with placebo.⁶⁵ These results suggest that clinical outcome measures based on severe disease flare may enable clinical efficacy of rituximab to be demonstrated in future trials. The depth of initial B cell depletion with rituximab in EXPLORER and LUNAR may also help to explain why these trials failed to meet their primary endpoints. Studies have shown that in patients with SLE, poor clinical response to rituximab is associated with incomplete B cell depletion^{31, 66} and that repeated courses of rituximab may produce a more sustained clinical response compared with a single course.⁶⁷ The inclusion of additional courses of rituximab in the design of future trials may, therefore, enable a treatment effect of rituximab to be demonstrated.

Epratuzumab

Epratuzumab is a humanized anti-CD22 monoclonal antibody in clinical development for the treatment of moderate-to-severe SLE. It is currently being evaluated in two Phase III placebo-controlled trials (EMBODY 1⁶⁸ and EMBODY 2⁶⁹) and preliminary results are expected in 2014.

B CELL THERAPIES IN RTX WEGENER'S GRANULOMATOSIS AND MICROSCOPIC POLYANGIITIS

Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are rare disorders that cause inflammation of blood vessels (vasculitis) and subsequent tissue damage. They are classified as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, as most patients have autoantibodies against proteinase 3 or myeloperoxidase.^{70, 71} Experimental evidence supports a pathogenic role for B cells in ANCA-associated vasculitis, thus providing a rationale for using B cell-targeted therapy.^{72, 73}

To date, several studies have demonstrated that sustained remission is achievable in patients with refractory ANCA-associated vasculitis when treated with rituximab.^74–77 Furthermore, retreatment with rituximab has been shown to be effective and well tolerated in patients with treatment-resistant ANCA-associated vasculitis.⁷⁸

The Phase II/III RAVE trial (Rituximab in ANCA-Associated Vasculitis) compared the safety and efficacy of rituximab with cyclophosphamide in patients with ANCA-positive WG or MPA.⁷⁹ In total, 197 patients were randomized to receive rituximab (375 mg/m²/week for 4 weeks) or cyclophosphamide (2 mg/kg daily); both treatment groups received the same background glucocorticoid regimen. Patients in the cyclophosphamide group who had a remission 3–6 months could switch from cyclophosphamide to azathioprine (2 mg/kg daily). At follow-up (6 months after treatment), 64% of patients in the rituximab group had achieved remission compared with 53% in the cyclophosphamide group; this result met the trial's criterion for noninferiority between the two treatment groups (P<0.001). In patients with relapsing disease, rituximab was more effective than cyclophosphamide in inducing remission. There were no significant differences in the rates of adverse events between the treatment groups. Based on these results, rituximab, in combination with glucocorticoids, was approved by the FDA in 2011 for the treatment of WG and MPA.

The safety and efficacy of rituximab added to cyclophosphamide as an induction regimen for patients with newly diagnosed ANCA-associated renal vasculitis was assessed in the RITUXimab vs cyclophosphamide in ANCA-associated VASculitis (RITUXVAS) trial.⁸⁰ Forty-four patients were randomized to receive rituximab (375 mg/m²/week for 4 weeks) plus cyclophosphamide (15 mg/kg with the first and third rituximab infusions) or a standard regimen of intravenous cyclophosphamide. Sustained remission was high in both treatment groups; 76 and 82% of patients achieved remission in the rituximab and control groups, respectively (P=.68). There was no reduction in the incidence rate of severe adverse events (SAEs) with the rituximab-based regimen (rituximab group, 1.00 events per patient-year; control group, 1.10 events per patient-year; 95% CI, 0.61–1.99; P=.77).

BCELL THERAPIES IN OTHER AUTOIMMUNE DISEASES

Sjögren's syndrome

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by inflammation of the salivary and lacrimal glands.⁸¹ Unlike other autoimmune diseases, treatment of patients with SS using corticosteroids, DMARDs, and TNF inhibitors has failed to show significant effects on disease progression.

There is evidence to suggest that B cells are likely to play a central role in the pathogenesis of SS: B cells have been identified in salivary gland biopsies of patients with SS,⁸² and various autoantibodies, such as anti-Ro and anti-La, are present in the serum of patients with SS.⁸³ Therefore, there is a strong rationale for exploring the use of B cell-targeted therapies for the treatment of SS.

Results of several small, open-label, uncontrolled trials with rituximab were encouraging and indicated that rituximab improved disease activity in patients with SS.^84–86 Rituximab has also been investigated as a treatment for primary SS (pSS) in two randomized, placebo-controlled trials. The first trial was a 6-month pilot study and investigated improvement in fatigue as a primary outcome.⁸⁷ A total of 17 patients with pSS and a fatigue visual analogue scale (VAS) score >50 were randomized to receive rituximab (2×1000 mg on Days 1 and 15) or placebo. Six months after treatment, 87.5% of patients receiving rituximab and 55.6% of patients receiving placebo demonstrated a greater than 20% improvement in fatigue VAS score (χ2, P=.36). Mean improvement in fatigue VAS score was significant for the rituximab group (mean improvement in fatigue VAS score (SD) 36.8 (17.9), P<0.001) but not for the placebo group (mean improvement in fatigue VAS score (SD) 17.3 (32.2), P=.147). In the second trial, 30 patients with pSS and a stimulated whole saliva secretion rate of ≥0.15 ml/minute were randomized to receive rituximab (2×1000 mg on Days 1 and 15) or placebo.⁸⁸ The study met its primary endpoint, a significant improvement in stimulated whole saliva flow rate in the rituximab group compared with placebo, at Week 5 (P<0.018) and Week 12 (P=.004) but not at Week 48, the end of the study.⁸⁸

Larger, controlled trials are still needed to determine the efficacy of rituximab for the treatment of SS. Currently, two randomized, placebo-controlled trials of rituximab in patients with SS are ongoing or planned: the TEARS study in France involving 120 patients,^{81, 89} and TRACTISS, a planned UK-based study that will enroll 100 patients and run for 5 years.^{81, 90}

Idiopathic Membranous Nephropathy

Idiopathic membranous nephropathy (IMN) is a progressive kidney disease and the most common cause of nephrotic syndrome in adults.⁹¹ The rationale for using B cell-targeted therapies for the treatment of IMN comes from preclinical experimental evidence suggesting that B cell activation results in the deposition of immunoglobulins on the glomerular basement membrane, leading to membrane damage, and subsequent proteinuria.⁹²

The safety and efficacy of rituximab therapy for the treatment of IMN have been evaluated in several small, open-label studies that have yielded promising results.^93–96 The available data suggest that rituximab, dosed at either 375 mg/m² once weekly for 4 weeks or 2×1000 mg on Days 1 and 15, can lead to complete remission in 15–20% of patients and partial remission in 35–40% of patients. Both treatment regimens appear to be well tolerated.⁹⁷

SAFETY OF B CELL THERAPIES IN AUTOIMMUNE DISEASE

Autoimmune diseases are chronic conditions requiring long-term treatment to inhibit disease progression and achieve stable disease. Therapies used must be well tolerated by patients over prolonged periods of administration. To date, the majority of guidance on the safety of B cell therapies comes from clinical trials with rituximab in patients with RA, although safety data are now becoming available for other B cell therapies.

Safety of Rituximab in Patients With RA

The safety of a single course of rituximab over a period of 6–12 months was reported for each of the placebo-controlled Phase II/III studies in RA^{17, 20, 27, 28} and open-label extension studies have provided safety data for multiple courses of rituximab.¹⁹ More recently, pooled safety data from the rituximab RA clinical trial program have been published.⁹⁸

An updated analysis, involving the pooled data from eight clinical trials and their long-term extensions, was presented at EULAR 2011.⁹⁹As of September 2010, 3194 patients had been treated with up to 17 courses of rituximab, providing 11962 patient-years of rituximab exposure and up to 9.5 years’ follow-up. The updated analysis also provided data for a subgroup of patients treated with rituximab for at least 5 years (627 patients with 4418 patient-years of exposure), and a pooled placebo population (818 patients with 1107 patient-years of exposure).

Data from the pooled analysis demonstrated that the rates of AEs and serious AEs (SAE) were similar between the rituximab all-exposure population, the pooled placebo population, and those patients with greater than 5 years’ follow-up (Table 3).The most frequent AEs experienced by patients treated with rituximab were infusion-related reactions (IRRs), most of which were reported to be of mild-to-moderate intensity. The majority of IRRs occurred during the first infusion of the first course (734/3194 patients; 23.0%). Serious IRRs were rare: 19 events were reported in 17 patients (0.5%), with the majority occurring during the first infusion of the first course. No serious IRRs occurred beyond the sixth course of rituximab and no fatal IRRs were reported.

The overall rates of infections and serious infections were comparable among the rituximab and placebo groups (Table 3). Among the serious infections reported, the most frequent was pneumonia that occurred in approximately 2% of the total population treated with rituximab. The rates of infections reported in this analysis were noted to be similar to those observed with other biologic therapies in RA.^100–103

Serious opportunistic infections in the total rituximab-treated population were rare (0.06 events/100 patient-years) and were comparable to the placebo-treated population (0.09 events/100 patient-years). Pulmonary tuberculosis (TB) occurred in two patients overall; however, there were no cases of extrapulmonary TB, atypical mycobacterial infection, or multidrug-resistant TB. Among the rituximab-treated population, there were no cases of hepatitis B reactivation and only one case of de novo hepatitis B.

The most frequent cardiac event experienced in patients treated with rituximab was myocardial infarction (MI), with 49 events reported in 42 patients, most of whom had at least one risk factor for MI.^{99, 104} The rate of MI in these patients (0.41 events/100 patient-years) was consistent with rates in the general RA population (0.48–0.59 events/100 patient-years),¹⁰⁵ indicating that retreatment with rituximab does not increase the risk of MI.

Data from the pooled analysis indicate that patients with RA retreated with rituximab are not at an increased risk of malignancy compared with other patients with RA and the general US population.^106–108 In addition, there has been no evidence of an increased risk of malignancy in patients treated with rituximab over time or with repeated courses of rituximab. As expected in a predominantly female population with a median age of approximately 50 years, the most frequently reported malignancy in patients retreated with rituximab was breast cancer. However, the incidence of breast cancer in these patients was comparable to that in the general population of patients with RA.^{104, 106, 107, 109}

The pooled analysis also demonstrated that following rituximab treatment, the use of biologic therapies, including TNF inhibitors, was not associated with an increased rate of serious infections.⁹⁹ These data indicate that patients with an inadequate response to rituximab may safely receive treatment with another biologic therapy while B cell depleted.

Based on the entire rituximab clinical experience to date, there have been five reported cases of progressive multifocal leukoencephalopathy (PML) associated with the use of rituximab in RA, involving 129000 patient exposures.¹⁰⁴ The mechanism underlying any increased risk of PML in association with rituximab therapy in RA has not been identified.

Safety of Other B Cell Therapies in Patients With RA

Limited safety information is available for ofatumumab and SBI-087 that are currently in development for the treatment of RA. In a recently completed Phase I/IIA of SC ofatumumab, single doses of up to 60 mg were well tolerated in patients with RA on a stable dose of MTX.⁴³ No unexpected safety issues were found in a Phase III study of IV ofatumumab. The most common AEs associated with ofatumumab treatment were IRRs, the majority of which were mild-to-moderate and occurred mostly during the first infusion. SAEs were reported in 5% of patients treated with ofatumumab and 3% of patients treated with placebo; infection rates were 32 and 26% for ofatumumab and placebo-treated patients, respectively.⁴¹ Preliminary results from an ongoing Phase I trial demonstrate that SBI-087, given as a single SC dose with a day-of-treatment oral steroid regimen, is generally well tolerated in patients with controlled RA.⁴⁹ The most frequently reported AEs were upper respiratory infection, headache, diarrhea, chills, fever, fatigue, and bruising at the injection site.

Safety of B Cell Therapies in Patients With SLE

Belimumab

Belimumab demonstrated a favorable safety profile in the BLISS trials; the overall rates of AEs, SAEs, deaths, and infections were comparable among patients treated with belimumab (1 mg/kg and 10 mg/kg) and those treated with placebo (Table 4). In BLISS-52, the rate of IRRs, including hypersensitivity, was comparable between belimumab and placebo treatment groups⁶⁰; however, in BLISS-76, IRRs were slightly higher in both belimumab treatment groups compared with the placebo group.⁶¹

Further insights into the safety of belimumab in patients with SLE are expected from open-label extension studies of patients completing the BLISS-52 and BLISS-76 trials.

Epratuzumab

A pooled safety analysis of 308 patients with moderate-to-severe SLE from two completed open-label pilot studies, three placebo-controlled, double-blind studies, and two ongoing long-term, open-label, follow-up studies, has demonstrated that epratuzumab is well tolerated and at the doses studied, has a safety profile similar to that of placebo.¹¹⁰ Completion of the Phase III trials in 2014 will provide additional information on the safety of epratuzumab in patients with SLE.

CONCLUSIONS

Data obtained during the clinical development of B cell-targeted therapies have provided key evidence that B cells play a pivotal role in the pathogenesis of autoimmune disease.

In RA, clinical experience has shown that rituximab, in combination with MTX, is an effective treatment in patients who have failed to respond to TNF inhibitors and may be more effective at reducing disease symptoms than switching to an alternative TNF inhibitor. Furthermore, retreatment with rituximab prior to relapse leads to improved clinical responses and tighter control of disease activity compared with a treatment as needed strategy. Recent data using HSFC have demonstrated that the extent of B cell depletion is associated with clinical response to rituximab and have also provided insight into the potential role of synovial B cells in the pathogenesis of RA. The long-term safety data with rituximab are encouraging, with rates of infections, including serious and opportunistic infections, similar to those seen with other biologic therapies used to treat RA. Rare cases of PML reported with rituximab indicate that continual monitoring of rituximab safety is essential.

B cell-targeted therapies are also proving to be effective treatments for other autoimmune diseases. Rituximab, in combination with glucocorticoids, is now approved for the treatment of ANCA-associated vasculitis and is undergoing clinical evaluation for Sjögren's syndrome and IMN. Belimumab, a B cell-targeted therapy with a different mechanism of action to rituximab, was recently approved for the treatment of SLE. Other B cell-targeted therapies are also in the early stages of clinical development for RA and other autoimmune diseases and early results indicate that these treatments may provide additional therapeutic options for patients who have failed to respond to traditional immunomodulatory agents.

Keywords

Autoantibodies, autoimmune disease, B cell, B cell-targeted therapy, monoclonal antibody, rheumatoid arthritis, rituximab

Acknowledgements: Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd.

Disclosure: The author declares no conflict of interest.

Funding: Dr Mease reports receiving research grants, consultant fees, and speaker honoraria from Abbott, Amgen, Bristol Myers Squibb, Biogen Idec, Janssen, Genentech, Pfizer, Lilly, UCB, Human Genome Sciences, and GlaxoSmithKline. Dr Mease has also received research grants and consultant fees from Novartis and Celgene.

REFERENCES

1. Nam J, Emery P. Aspects of TNF inhibitor therapy in rheumatoid arthritis. Mod Rheumatol. 2010;20(4):325–330.
2. Simsek I. TNF inhibitors-new and old agents for rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2010;68(3):204–210.
3. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000;343(22):1594–1602.
4. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48(1):35–45.
5. WeinblattME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340(4):253–259.
6. Keystone EC, Genovese MC, Klareskog L, et al. Golimumab, a human antibody to tumour necrosis factor a given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis. 2009;68(6):789–796.
7. Smolen J, Landewé RB, Mease P, et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis. 2009;68(6):797–804.
8. Finckh A, Ciurea A, Brulhart L, et al. Which subgroup of patients with rheumatoid arthritis benefits from switching to rituximab versus alternative anti-tumour necrosis factor (TNF) agents after previous failure of an anti-TNF agent? Ann Rheum Dis. 2010;69(2):387–393.
9. Low JM, Moore TL. A role for the complement system in rheumatoid arthritis. Curr Pharm Des. 2005;11(5):655–670.
10. Dörner T, Kinnman N, Tak PP. Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol Ther. 2010;125(3):464–475.
11. Silverman GJ, Carson DA. Roles of B cells in rheumatoid arthritis. Arthritis Res Ther. 2003;5(suppl 4):S1–S6.
12. Meffre E. Wardemann H. B-cell tolerance checkpoints in health and autoimmunity. Curr Opin Immunol. 2008;20(6):632–638.
13. Nielen MMJ, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004; 50(2):380–386.
14. Van Steendam K, Tilleman K, De CM, et al. Citrullinated vimentin as an important antigen in immune complexes from synovial fluid of rheumatoid arthritis patients with antibodies against citrullinated proteins. Arthritis Res Ther. 2010;12(4):R132.
15. Verpoort KN, Jol-van der Zijde CM, Papendrecht-van der Voort EA et al. Isotype distribution of anti-cyclic citrullinated peptide antibodies in undifferentiated arthritis and rheumatoid arthritis reflects an ongoing immune response. Arthritis Rheum. 2006;54(12):3799–3808.
16. Mease PJ. B cell-targeted therapy in autoimmune disease: rationale, mechanisms, and clinical application. J Rheumatol. 2008;35(7):1245.
17. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54(9):2793–2806.
18. Cohen SB, Keystone E, Genovese MC, et al. Continued inhibition of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with methotrexate. Ann Rheum Dis. 2010;69(6):1158–1161.
19. Keystone E, Fleischmann R, Emery P, et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis Rheum. 2007;56(12): 3896–3908.
20. Mease PJ, Cohen S, Gaylis NB, et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE Trial. J Rheumatol. 2010;37(5):917–927.
21. Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631–637.
22. Bakker MF, Jacobs JW, Verstappen SM, et al. Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility. Ann Rheum Dis. 2007;66(suppl 3):iii56–iii60.
23. Emery P, Mease PJ, Rubbert-Roth A, et al. Retreatment with rituximab based on a treatment-to-target approach provides better disease control than treatment as needed in patients with rheumatoid arthritis: a retrospective pooled analysis. Rheumatology (Oxford). 2011 Oct 5. [Epub ahead of print].
24. Emery P, Deodhar A, Rigby WF, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab’s Efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis. 2010;69(9):1629–1635.
25. Rubbert-Roth A, Tak PP, Zerbini C, et al. Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR). Rheumatology (Oxford). 2010;49(9):1683–1693.
26. Emery P, Fleischmann R, Martin-Mola E, et al. Prolonged efficacy of rituximab in rheumatoid arthritis patients with an inadequate response to methotrexate: 1 year follow-up of a subset of patients receiving a single course in a controlled trial (DANCER trial). Ann Rheum Dis. 2006;65(suppl 2):190 [Abstract THU0240]
27. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006;54(5):1390–1400.
28. Edwards JC, Szczepañski L, Szechiñski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350(25):2572–2581.
29. Breedveld F, Agarwal S, Yin M, et al. Rituximab pharmacokinetics in patients with rheumatoid arthritis: B-cell levels do not correlate with clinical response. J Clin Pharmacol. 2007;47(9):1119–1128.
30. Dass S, Rawstron AC, Vital EM, et al. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthritis Rheum. 2008;58(10):2993–2999.
31. Vital EM, Dass S, Buch MH, et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum. 2011;63(10):3038–3047.
32. Vital EM, Dass S, Rawstron AC, et al. Management of nonresponse to rituximab in rheumatoid arthritis: predictors and outcome of re-treatment. Arthritis Rheum. 2010;62(5):1273–1279.
33. Teng YK, Levarht EW, Hashemi M, et al. Immunohistochemical analysis as a means to predict responsiveness to rituximab treatment. Arthritis Rheum. 2007;56(12):3909–3918.
34. Thurlings RM, Vos K, Wijbrandts CA, et al. Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response. Ann Rheum Dis. 2008;67(7):917–925.
35. Kavanaugh A, Rosengren S, Lee SJ, et al. Assessment of rituximab’s immunomodulatory synovial effects (ARISE trial). 1: clinical and synovial biomarker results. Ann Rheum Dis. 2008;67(3):402–408.
36. Courvoisier N, Dougados M, Cantagrel A, et al. Prognostic factors of 10-year radiographic outcome in early rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2008;10(5):R106.
37. Emery P, McInnes IB, van Vollenhoven R, et al. Clinical identification and treatment of a rapidly progressing disease state in patients with rheumatoid arthritis. Rheumatology (Oxford). 2008;47(4):392–398.
38. Chatzidionysiou K, Lie E, Nasonov E, et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann Rheum Dis. 2011; 70(9):1575–1580.
39. Isaacs JD, Olech E, Tak PP, et al. Autoantibody-positive rheumatoid arthritis (RA) patients (pts) have enhanced clinical response to rituximab (RTX) when compared with seronegative patients. Ann Rheum Dis. 2009;68(suppl 3):442 [Abstract FRI0256]
40. Tony HP, Roll P, Mei HE, et al. Predictive factors for response to rituximab in patients with rheumatoid arthritis (FIRST). Ann Rheum Dis. 2011;70(suppl 3):292 [Abstract THU0342]
41. Taylor PC, Quattrocchi E, Mallett S, et al. Ofatumumab, a fully human anti-CD20 MAB, in the treatment of biologic-naive rheumatoid arthritis patients: a randomised, double-blind, placebo-controlled clinical trial. Ann Rheum Dis. 2011;70(suppl 3):72 [Abstract OP0019]
42. Study to evaluate SC route of administration of ofatumumab in RA patients. 2010. Available from: http://www.clinicaltrials.gov/ct2/show/ NCT00686868?term=NCT00686868&rank=1 Accessed September 1, 2011.
43. Kurrasch R, Brown JC, Chu ME, et al. Tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administered ofatumumab in rheumatoid arthritis patients on stable background methotrexate: a Phase I/II study. Ann Rheum Dis. 2011;70(suppl 3):616 [Abstract SAT0288]
44. Kausar F, Mustafa K, Sweis G, et al. Ocrelizumab: a step forward in the evolution of B-cell therapy. Expert Opin Biol Ther. 2009;9(7):889–895.
45. Rigby W, Tony HP, Oelke K, et al. Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: The Phase III STAGE trial. Arthritis Rheum. 2011 Sep 8. doi: 10.1002/art.33317. [Epub ahead of print]
46. Tak PP, Mease PJ, Genovese MC, et al. Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis with an inadequate response to at least one TNF inhibitor: the Phase III SCRIPT Trial. Arthritis Rheum. 2011 In press
47. Study evaluating single doses of SBI-087 in subjects with rheumatoid arthritis. 2011. Available from: http://www.clinicaltrials.gov/ct2/show/ NCT00641225?term=NCT00641225&rank=1. Accessed September 1, 2011.
48. Study evaluating single doses of SBI-087 in Japanese subjects with rheumatoid arthritis. 2011. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00815906?term=NCT00815906&rank=1. Accessed September 1, 2011.
49. Fleischmann R, Cohen S, Pardo P, et al. Subcutaneous (SC) administration of SBI-087 provides potent B cell depletion in subjects with controlled RA. Ann Rheum Dis. 2010;69(suppl 3):69 [Abstract OP0053].
50. Study evaluating the efficacy and safety of SBI-087 in seropositive subjects with active rheumatoid arthritis. 2011. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01008852?term=NCT01008852&rank=1. Accessed September 1, 2011.
51. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008;358(9):929–939.
52. van Vollenhoven RF, Gunnarsson I, Welin-Henriksson E, et al. Biopsy-verified response of severe lupus nephritis to treatment with rituximab (anti-CD20 monoclonal antibody) plus cyclophosphamide after biopsy-documented failure to respond to cyclophosphamide alone. Scand J Rheumatol. 2004;33(6):423–427.
53. Leandro MJ, Cambridge G, Edwards JC, et al. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford). 2005;44(12):1542–1545.
54. Smith KG, Jones RB, Burns SM, et al. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment. Arthritis Rheum. 2006; 54(9):2970–2982.
55. Tokunaga M, Saito K, Kawabata D, et al. Efficacy of rituximab (anti- CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann Rheum Dis. 2007;66(4):470–475.
56. Reynolds JA, Toescu V, Yee CS, et al. Effects of rituximab on resistant SLE disease including lung involvement. Lupus. 2009;18(1):67–73.
57. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, Phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62(1): 222–233.
58. Furie R, Looney RJ, Rovin B, et al. Efficacy and safety of rituximab in subjects with active proliferative lupus nephritis (LN): results from the randomized, double-blind Phase III LUNAR study. Arthritis Rheum. 2009;60(Suppl. 10):1149 [Abstract 1149].
59. Baker KP, Edwards BM, Main SH, et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 2003;48(11):3253–3265.
60. Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767): 721–731.
61. van Vollenhoven RF, Zamani O, Wallace DJ, et al. Belimumab, a BLySspecific inhibitor, reduces disease activity and severe flares in seropositive SLE patients: BLISS-76 study. Ann Rheum Dis. 2010;69(suppl 3):74 [Abstract OP0068].
62. Thanou-Stavraki A, Sawalha AH. An update on belimumab for the treatment of lupus. Biologics. 2011;5:33–43.
63. Calero I, Sanz I. Targeting B cells for the treatment of SLE: the beginning of the end or the end of the beginning? Discov Med. 2010;10(54):416–424.
64. Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009;61(9): 1143–1151.
65. Merrill J, Buyon J, Furie R, et al. Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER). Lupus. 2011;20(7):709–716.
66. Vital EM, Dass S, Buch MH, et al. Assocation between clinical resonse and circulating B cell subsets during B cell depletion therapy for systemic lupus erythematosus. Ann Rheum Dis. 2011;70(suppl 1):A66 [Abstract A155]
67. Turner-Stokes T, Lu TY, Ehrenstein MR, et al. The efficacy of repeated treatment with B-cell depletion therapy in systemic lupus erythematosus: an evaluation. Rheumatology (Oxford). 2011;50(8):1401–1408.
68. Study of epratuzumab versus placebo in subjects with moderate to severe general systemic lupus erythematosus (EMBODY 1). 2011. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01262365?term= nct01262365&rank=1. Accessed September 1, 2011.
69. Study of epratuzumab versus placebo in subjects with moderate to severe general systemic lupus erythematosus (SLE) (EMBODY 2). 2011. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01261793? term=nct01261793&rank=1. Accessed September 1, 2011.
70. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):187–192.
71. Finkielman JD, Lee AS, Hummel AM, et al. ANCA are detectable in nearly all patients with active severe Wegener’s granulomatosis. Am J Med. 2007;120(7):643.e9–e14.
72. Popa ER, Stegeman CA, Bos NA, et al. Differential B- and T-cell activation in Wegener’s granulomatosis. J Allergy Clin Immunol. 1999; 103(5, pt 1):885–894.
73. Krumbholz M, Specks U, Wick M, et al. BAFF is elevated in serum of patients with Wegener’s granulomatosis. J Autoimmun. 2005;25(4): 298–302.
74. Keogh KA, Wylam ME, Stone JH, et al. Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005;52(1): 262–268.
75. Keogh KA, Ytterberg SR, Fervenza FC, et al. Rituximab for refractory Wegener’s granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med. 2006;173(2):180–187.
76. Jones RB, Ferraro AJ, Chaudhry AN, et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibodyassociated vasculitis. Arthritis Rheum. 2009;60(7):2156–2168.
77. Specks U, Fervenza FC, McDonald TJ, et al. Response of Wegener’s granulomatosis to anti-CD20 chimeric monoclonal antibody therapy. Arthritis Rheum. 2001;44(12):2836–2840.
78. Stasi R, Stipa E, Del Poeta G, et al. Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology (Oxford). 2006;45(11):1432–1436.
79. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3): 221–232.
80. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010; 363(3):211–220.
81. Saraux A. The point on the ongoing B-cell depleting trials currently in progress over the world in primary Sjögren’s syndrome. Autoimmun Rev. 2010;9(9):609–614.
82. Hansen A, Odendahl M, Reiter K, et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjogren’s syndrome. Arthritis Rheum. 2002;46(8):2160–2171.
83. Harley JB, Alexander EL, Bias WB, et al. Anti-Ro (SS-A) and anti-La (SS-B) in patients with Sjogren’s syndrome. Arthritis Rheum. 1986;29(2): 196–206.
84. Pijpe J, van Imhoff GW, Spijkervet FK, et al. Rituximab treatment in patients with primary Sjögren’s syndrome: an open-label phase II study. Arthritis Rheum. 2005;52(9):2740–2750.
85. Devauchelle-Pensec V, Pennec Y, Morvan J, et al. Improvement of Sjögren’s syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum. 2007;57(2):310–317.
86. Seror R, Sordet C, Guillevin L, et al. Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjögren’s syndrome. Ann Rheum Dis. 2007; 66(3):351–357.
87. Dass S, Bowman SJ, Vital EM, et al. Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann Rheum Dis. 2008;67(11):1541–1544.
88. Meijer JM, Meiners PM, Vissink A, et al. Effectiveness of rituximab treatment in primary Sjögren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62(4):960–968.
89. Tolerance and Efficacy of Rituximab in Sjogren’s Disease (TEARS) 2011. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00740948? term=NCT00740948&rank=1. Accessed September 1, 2011.
90. Clinical trials research unit (University of Leeds). TRACTISS. Dryness and fatigue in primary Sjögren’s 2011. Available from: http://ctru.leeds.ac.uk/tractiss Accessed September 1, 2011).
91. Cattran DC. Membranous nephropathy: quo vadis? Kidney Int. 2002;61(1):349–350.
92. Kerjaschki D, Neale TJ. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis). J Am Soc Nephrol. 1996;7(12):2518–2526.
93. Remuzzi G, Chiurchiu C, Abbate M, et al. Rituximab for idiopathic membranous nephropathy. Lancet. 2002;360(9337):923–924.
94. Ruggenenti P, Chiurchiu C, Brusegan V, et al. Rituximab in idiopathic membranous nephropathy: a one-year prospective study. J Am Soc Nephrol. 2003;14(7):1851–1857.
95. Fervenza FC, Cosio FG, Erickson SB, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. 2008;73(1):117–125.
96. Fervenza FC, Abraham RS, Erickson SB, et al. Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Clin J Am Soc Nephrol. 2010;5(12):2188–2198.
97. Bomback AS, Derebail VK, McGregor JG, et al. Rituximab therapy for membranous nephropathy: a systematic review. Clin J Am Soc Nephrol. 2009;4(4):734–744.
98. van ollenhoven RF, Emery P, Bingham CO, III, et al. Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol. 2010;37(3):558–567.
99. van Vollenhoven RF, Emery P, Bingham CO, III, et al. Long-term safety profile of rituximab in rheumatoid arthritis clinical trials: pooled analysis of up to 9.5 years follow-up of the retreatment population. Ann Rheum Dis. 2011;70(suppl 3):608 [Abstract SAT0267]
100. Schiff MH, Burmester GR, Kent JM, et al. Safety analyses of adalimumab (HUMIRA†) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65(7): 889–894.
101. Moreland LW, Weinblatt ME, Keystone EC, et al. Etanercept treatment in adults with established rheumatoid arthritis: 7 years of clinical experience. J Rheumatol. 2006;33(5):854–861.
102. Genovese MC, Schiff M, Luggen M, et al. Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. Ann Rheum Dis. 2008;67(4):547–554.
103. Westhovens R, Kremer JM, Moreland LW, et al. Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended Phase IIB study. J Rheumatol. 2009;36(4):736–742.
104. Clifford DB, Ances B, Costello C, et al. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol. 2011;68(9):1156–1164.
105. Dixon WG, Watson KD, Lunt M, et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2007;56(9):2905–2912.
106. Mellemkjaer L, Linet MS, Gridley G, et al. Rheumatoid arthritis and cancer risk. Eur J Cancer. 1996;32A(10):1753–1757.
107. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum. 2007;56(9):2886–2895.
108. U.S.National Institutes of Health. Surveillance epidemiology and end results 2011. Available from: http://seer.cancer.gov/ Accessed September 1, 2011.
109. Smitten AL, Simon TA, Hochberg MC, et al. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):R45.
110. Hobbs K, Houssiau F, Kelley L, et al. Safety profile of epratuzumab in patients with moderate-to-severe systemic lupus erythematosus (SLE): preliminary results. Ann Rheum Dis. 2011;70(suppl 3):319 [Abstract THU0425]

Damage Control in Spine Surgery

The original concept of damage control surgery was developed for patients with hemodynamically unstable abdominal trauma and hemorrhagic shock. For over two decades, this surgical principle has been acknowledged and practiced in virtually all surgical specialties worldwide. The underlying rationale is to limit surgical interventions with respect to eminent life-threatening disorders and, thus, reestablish key physiological parameters (endpoints of resuscitation) to prevent the “lethal triads” of hypothermia, coagulopathy, and acidosis. The latter triads remain the most considerable risk factor in the management of the polytraumatized patient, since redundant or prolonged diagnostic and therapeutic procedures have been shown to significantly promote subsequent posttraumatic mortality, respectively.^{1, 2} Although the initial mechanical injury (first hit) remains the primary prognostic factor in the polytraumatized patient, extensive research efforts have impressively demonstrated the impact of secondary exogenous and endogenous processes (so-called “second hit phenomenon”) on both the subsequent clinical course and outcome.^{3, 4} These systemic responses and critical physiological parameters in the sequelae of interventions following multiple injuries have significantly changed our understanding of trauma management with primary focus on restoring normotension, normoxaemia, normothermia, physiological coagulation, reversal of the induced lactate acidosis, and regaining a sufficient diuresis in the early phase of treatment. In conclusion, time-consuming and complex surgical interventions should generally be omitted within the primary management of polytraumatized patients retaining an instable physiological balance despite adequate treatment of acute and life-threatening injuries.

Based on this perception, the former classic orthopedic principles of “early total care” with primary definitive fracture stabilization have been abandoned. Thus, present day management of the polytraumatized and severely injured patient upholds a more simplified proceeding with life-saving interventions taking top priority in the hierarchic listing of surgical and therapeutic interventions. As such, the concept of the so-called damage control orthopadics combines least invasive fracture stabilization,^5–7 along with the two basic pillars of damage control, the acute decompression of body cavities and immediate control of hemorrhagic injuries.

However, the translation of these principles into the management of spine fractures, particularly with neurological impairment, is challenging and data analyzing the association of timing of surgery and clinical outcome are rather heterogeneous.^8–10 In line with a recent meta-analysis regarding best practice determination of timing of spine fracture fixation,¹¹ Pakzad and coworkers recently emphasized the importance of an early surgical intervention (<24 hours after injury) to decrease the risk of complications related to prolonged recumbency or other factors precipitating a delayed surgical procedure.¹² While these recommendations generally account for severely injured patients without verifiable neurological injuries, the management of patients with evident neurological impairment shall be discussed in the following sections.

SPINE TRAUMA

Epidemiology

Various studies from major level I trauma centers have demonstrated the likelihood of spinal trauma to increase with severity of the overall injury pattern.¹³ In polytraumatized patients, the incidence of spinal injury has been reported to range between 13% and 34%, with approximately 5% requiring urgent surgical treatment either due to instability or neurological impairment. In contrast to fractures associated with low energy impact or osteoporosis in the elderly patient, major causes for spinal trauma in the polytraumatized patient originate from high energy forces, including motor vehicle accidents and fall from heights,^14–16 with the fall from heights commonly related to suicidal incidents.^{17, 18} Therefore, both the trauma mechanism and the resulting injury pattern may critically indicate concomitant spine injury and give direction to respective clinical and radiographic diagnostics. For example, polytraumatized patients with severe blunt chest trauma should advert to thoracic spine fractures. Moreover, Clayton and coworkers¹⁹ highlighted the increased risk of cervical spine injury in certain injury patterns, including pelvic fracture and fall or head injury, with an estimated incidence of 2%–10% in multiply injured patients.^{15, 20} Although the early recognition of a cervical spine injury remains the top priority in acute trauma management, the rate of undetected cervical spine injuries in polytraumatized patients has been reported to range up to 20%.^{21, 22} Despite these remarkable numbers, statistical analyses of the overall level distribution have shown a predominant involvement of the thoracic and lumbar segments, with a ratio of 4:1 (thoracolumbar vs cervical) in multiply injured patients.²³

Imaging

In consideration of the aforementioned setting and algorithms within the acute management of the multiply injured patient, a spinal injury must be considered until definitively excluded otherwise.¹⁵ Although conventional X-rays of the chest and pelvis, in addition to the abdominal sonography (FAST), comprise frequent diagnostic procedures in the so-called primary survey, further imaging algorithms have been controversially discussed.^{22, 24–26} While some authors demand a simple lateral X-ray of the cervical spine for primary evaluation of stability,^{21, 27} others have emphasized the importance of a three-plane evaluation (anteroposterior, lateral, and odontoid).²⁰ Yet, in order to determine the complete cervical spine, including the cervicothoracic junction at the C7/Th1 level, longitudinal traction to both upper extremities is inevitable. This manipulative maneuver, however, may be obsolete in some injury constellations involving the upper thoracic structures and extremities. Moreover, conventional X-ray in the emergency department setting is often of poor quality and possible conspicuous features from soft-tissue radiolucency may not confirm or rule out bony or discoligamentous lesions to the cervical spine (Figure 1A). In line with these critical conclusions and our own experience in managing polytraumatized patients, present day advances in computed tomography (CT) have shown clear advantages in accelerating the diagnostic process and improving its significance (Figure 1B and 1C). Thus, the routine lateral X-ray of the cervical spine remains to be reserved for specific diagnostic purposes in monotraumatic injury to the spine and is no longer recommended when managing the multiply injured patient.

Once the patient has been hemodynamically stabilized, he or she may be transferred to the so-called secondary survey for a computertomographic body scan (spiral-CT), including a 2-D or even 3-D reconstruction of the complete vertebral column (from occiput to sacrum). The efficacy and reliability of this procedure has been underlined in multiple meta-analyses and various studies comparing the detection accuracy of cervical spine injuries by conventional X-ray versus spiral-CT.^28–31 Moreover, the advanced spectrum of CT angiography has proven to be a valuable amendment in detecting vascular compromise within the craniocervical junction, particularly at the C2 level.^{32, 33} Due to a wide variation of asymptomatic appearance and an incidence reported to range between 10% and 88%, vertebral artery injury (VAI) is an often underestimated but a serious concomitant injury component.^{32, 34–36}

However, the increased availability of CT scans in centers treating major trauma is not without controversial debate among radiologists, emergency physicians, and other medical professionals. The common uncertainty of a missed diagnosis or inappropriate imaging selection upholds the risk of a routine use of CT scans, particularly in the unconscious and intubated patient with blunt multiple trauma. Goergen introduced a useful diagnostic algorithm by combining the low risk criteria developed by the National Emergency X-Radiography Utilization Study (NEXUS low risk) with the high-risk criteria described by Blackmore and Hanson.^{37, 38} Subsequent analyses of blunt trauma patients supported this algorithm while equally emphasizing the importance of a precise clinical evaluation of both the injury mechanism and clinical presentation of the patient (Figure 2).³⁹ In line with our own experience and practice, there is increasing evidence to suggest that additional imaging techniques, such as flexion and extension radiographs or MRI of the cervical spine, may only qualify as optional diagnostics when the alert and awake trauma patient claims persisting discomfort and pain in cervical spine motion.^40–43

Stability Versus Instability

In the polytraumatized patient, the careful analyses of all initial radiographic data and conclusive determination of a stable or instable spine injury is essential to ensure both optimal timing and indication of the appropriate surgical strategy. From a biomechanical point of view, evident instability is defined as the incapability of the injured spine to maintain its normal structural condition when stressed by physiological forces.¹⁵ Instable spine injuries are prone to an imminent risk of neurological compromise and secondary instability due to delayed destruction of the respective or adjacent segment. Therefore, one of the key requirements for the reliable estimate of an instable or stable spine injury is the exact classification of its pathomorphology with respect to local anatomical characteristics. White and Panjabi⁴⁴ suggested specific criteria indicating instability of the cervical spine. These criteria included the sagittal displacement of >3.5 mm, a segmental kyphosis of >11°, when compared to the adjacent levels, the enlargement of the respective disc space of >2 mm, and subluxation of the facet joints of >50%. However, individual variants as well as constitutional and age-related pseudo-subluxations may often aggravate a secure judgement in this particular region. The latter phenomenon, more common in infantile and adolescent patients, has been primarily described for the C2/3 and C3/4 level. In arguable cases, the so-called Swishuck line,^{45, 46} defined as a homogenous line drawn from the anterior aspect of the C1-3 spinous processes, may provide orientation and support the differential diagnosis, respectively.

In contrast, injuries to the thoracic and lumbar spine demand careful analyses of the complete imaging to complement the assessment of injury severity. Based on the three-column-model initially described by Denis,⁴⁷ instability should be presumed when two or all three of the columns are involved. Furthermore, signs of rotational malalignment should be identified. Mclain and Benson⁴⁸ summarized specific indicators for instability in the thoracic and lumbar spine by including primary neurological impairment, the loss of vertebral height of >50%, obvious serial fractures, and a sagittal angulation of more than 25° when compared to the adjacent levels. Other, rather indirect signs of instability in the thoracic and lumbar spine may include retroperitoneal bleeding, luxation of the adjoining ribs, the costotransversal joints, or fractures of the lumbar transverse processes.

Fracture Classification in Spine Trauma

As outlined earlier, instable spine fractures and dislocations may give rise to devastating consequences. Thus, the optimal classification must consider major variables that influence stability with regard to morphology, integrity of the discoligamentous complex, and neurology. To date, the multitude of classifications for either cervical or thoracolumbar spine injuries are constantly modified and cross-evaluated to improve reproducibility, support optimal timing, and assess the most appropriate treatment strategy.^49–52

For fractures of the atlas vertebra, we have since applied the Gehweiler classification.⁵³ Moreover, fractures indicated as type III according to the Gehweiler classification (injury of the anterior and posterior arch) must be considered instable due to the likelihood of a concomitant ligamentous injury (lig. transversum) and dislocation. Fractures of the dens axis are classified according to the recommendations published by Anderson and D'Alonzo⁵⁴ with type II fractures indicating surgical stabilization. Traumatic spondylolysis of the axis are classified according to the recommendations by Effendi and coworkers⁵⁵ and should always alert to seek for concomitant injuries within the proximate cervical spine region. Injuries involving the intervertebral disc (type II according to the Effendi classification), particularly in combination with a lesion of the anterior longitudinal ligament, must be considered instable and ultimately presuppose surgical stabilization.⁵⁶Although we continue to favor using guided functional plain radiographs to evaluate the discoligamentous stability in the awake and alert patient presenting with ambiguous clinical and diagnostic results, its clinical reliability in the acute trauma evaluation remains a subject of warranted debate.^{41, 57, 58}

In contrast to the specifics defined for the occipitocervical spine region, injuries to the subaxial cervical spine as well as to the thoracic, thoracolumbar, and lumbar spine are commonly classified according to the recommendations published by Magerl and coworkers.⁵⁹ Based on the two-column model suggested by Whitesides,⁶⁰ the Magerl (AO) classification considers both the biomechanical characteristics and inductive forces to the respective spine region.^{49, 61, 62} In brief:

Type A injuries are defined as compression injuries to the anterior column. Compression burst fractures (type A3) demand prompt surgical stabilization when associated with a significant defective position, neurological compromise and secondary stenosis of the spinal canal due to significant fragment dislocation.

Type B injuries are characterized as distraction injuries to the anterior and posterior column. Due to the high risk of neurological impairment and instability, these type B injuries should be considered for urgent stabilization within the initial surgical management of the polytraumatized patient.

Type C injuries regard both columns and include a rotational injury component, thus, indicating severe instability and urgent surgical stabilization.

Surgical Stabilization and Timing

Optimal timing of surgical stabilization with regard to the complete injury pattern, stress-related and inflammatory disorders induced by both the traumatic event and any applied surgical procedure remains a critical and heavily discussed issue. However, in consideration of the aforementioned characteristics and criteria for instability, the concept of early stabilization with realignment of the spinal column and decompression of neurological structures in the polytraumatized patient does not differ from that applied to long-bone,⁶³ pelvic, and acetabular fractures.⁶⁴ Particularly in multiply injured patients with associated chest injury, early fracture stabilization has shown to significantly reduce morbidity, length of hospital stay, and the risk of developing posttraumatic pulmonary disorders [eg, pneumonia, adult respiratory distress syndrome (ARDS)] when performed within the initial 24 hours after admission.^{8, 12, 65} Furthermore, persisting instable spine fractures may augment inflammatory processes due to secondary tissue damage (increased pressure, hematoma, or skin irritation by destructive positions) and related pain stimuli. Therefore, the primary aim should always be the early stabilization and decompression to reduce the risk of secondary neurological damage by equally holding down stress-associated procedures to comply with the optimal requirements for intensive care.

In contrast, data on managing spine injuries in the hemodynamically unstable or borderline patient are insufficient, most likely due to the timely order of treatment priorities in a “life before limb” manner. Thus, it is obvious that hemodynamically unstable or symptomatic patients with severe concomitant thoracic or abdominal injuries, who do not respond to fluid resuscitation or show obvious organ or vascular damage on CT imaging, are subjected to immediate explorative interventions and subsequent surgical or angiographic repair. Conversely, specific spine fracture patterns should alert to carefully look for any associated visceral or mesenteric and vascular damage. These primarily involve fractures caused by distractive forced flexion (type B) mechanisms.^66–69 As such, vascular injury (eg, blunt abdominal aortic disruption) is suggested to result either directly or indirectly, via transmission of hydraulic forces through the abdominal viscera.^{70, 71}

Thus, prompt and primary surgical treatment must premise the hemodynamically stable patient and is recommended within the initial 24 hours after admission, if the following criteria are present:

• Neurological deficits, including incomplete or progressive paresis

• Significant spinal stenosis due to fragment dislocation with the imminent risk of secondary neurological compromise

• Instability

• Open spine injuries

Although some injury constellations, particularly within the cervical spine region, would otherwise allow an initially conservative treatment with external fixation methods (eg, Effendi type II traumatic spondylolysis of the axis with an intact anterior longitudinal ligament), surgical treatment should thus be amply indicated to allow optimal intensive care. In the following sections, we outline the primary surgical procedures we believe should be applied safely in the hemodynamically stable, multiply injured patient:

Primary surgery of the upper cervical spine

Instable fractures of the atlas vertebra are seldom scheduled for primary surgery in the polytraumatized patient due to infrequent neurological complications. Moreover, fractures of type III, according to the Gehweiler classification, with rupture of the transverse ligament demand a posterior approach and are therefore suggested to be applied only in the hemodynamically stabilized patient and within the tertiary phase of trauma management. In contrast, fractures of the dens axis (eg, typ II according to the classification by Anderson and D'Alonzo) are suggested to be urgently reduced and stabilized. Arguments in favor of an urgent procedure are the anterior approach in supine position, granting quick access and less wearing screw osteosynthesis of the dens axis within the initial surgical management of the polytraumatized patient. However, in cases of an anterior burst or anterior-to-posterior inclining fracture pattern of the dens axis, the recommended C1/2 arthrodesis via the posterior approach must be reevaluated, and if in doubt, scheduled for a delayed intervention. In the event of a traumatic spondylolisthesis of the axis vertebra, we recommend anterior fusion of C2/3 with additional plate fixation. Alternative procedures, including screw-and-rod fixation from a posterior approach, should remain second choice interventions and should be individually reassessed in cases where the anterior approach may be contraindicated due to the respective injury constellation (eg, traumatic rupture of the esophagus, tracheal or vascular lesions within the neck region, tracheotomy). A rare exception wherein a posterior approach is initially performed is the locked luxation of the facet joints (type III injury according to the Effendi classification). We recommend completing a posterior C2/3 spondylodesis in cases where a closed reduction and anterior fusion is obsolete or fails

Primary surgery of the subaxial cervical spine

The majority of injuries to the subaxial cervical spine may be easily managed from an anterior approach by reduction, decompression, and stabilization, either by partial corporectomy of the fractured vertebra or intersomatic fusion (Figure 3). In cases, where a concomitant injury of the discoligamentous complex is uncertain, the injury may be further objectified by fluoroscopy in the operating room (OR) setting. In the given event, we recommend a mildly dosed extension maneuver, which has proven to sufficiently reveal discoligamentous injuries in our own experience. Any additive posterior stabilization may then be performed as a second-step procedure according to the damage control guidelines outlined earlier.

Primary surgery of the thoracolumbar spine

Injuries to the thoracolumbar spine are primarily stabilized by posterior screw-and-rod fixation methods (Figure 4). Although the open approach is still considered standard with the benefit of open reduction and decompression, if necessary, the concept of minimally invasive percutaneous techniques has shown favorable results by limiting soft tissue damage in a selected trauma patient population.⁷² Regardless of choosing a standard, open or minimally invasive approach, the prone positioning of the patient may spontaneously support fracture reduction by inducing ligamentotaxis. If required, further reduction may be achieved by carefully applying forced distraction and lordosis. Furthermore, prone positioning and lordosis may indicate any concomitant discoligamentous lesions otherwise undetected in supine position while undergoing the process of primary and secondary survey. In cases where closed reduction fails to adequately realign the injured segments, the posterior approach also allows for decompression or an interlaminar fenestration to manually reduce fragments, which might have dislocated into the spinal canal. Moreover, prone positioning of the patient is on no account contraindicated in the polytraumatized patient, as its benefit has been described as “therapeutic positioning,” particularly in patients with severe chest trauma.^{73, 74} Continuative procedures, such as additive anterior stabilization (eg, corporectomy, intersomatic fusion), should always be considered for a delayed and second-step intervention, as this might exceed the surgical effort and stress impact on the patient (Figure 5).

Spine Injury with Neurological Impairment

Spine injuries associated with significant neurological impairment undoubtedly confine the patient in his or her further course of clinical recovery and often implicate devastating medical and social consequences. While the primary aim of reestablishing the immunological and physiological equilibrium in the polytraumatized patient is well documented, other research efforts have focussed on the pathophysiology of spinal cord injuries and subsequent secondary changes within this particular compartment. Allen⁷⁵ and others highlighted the importance of numerous endogenous processes, including electrolyte fluxes, vascular compromise with the likelihood of spinal cord ischemia, vasospasm, edema and formation of oxygen free radicals, to significantly alter neurocellular functions.^76–78 Moreover, the increase of these and other immunomodulatory factors (eg, cytokine and catecholamine release) was shown to correlate strongly with the duration of spinal cord compression and the degree of spinal cord injury.⁷⁹ Despite former controversies regarding optimal timing and neurological outcome, recent studies investigating this particular topic in acute traumatic spinal cord injury have clearly shown the benefit of early decompression within the initial 24 hours after injury.^80–83 Although the beneficial effect of early surgical stabilization and decompression appears to be more evident in patients with higher there is emerging evidence that early surgery may also result in shorter (ISS), there is emerging evidence that early surgery may also result in shorter hospital and intensive care unit stay, fewer days on mechanical ventilation, and ultimately lowers pulmonary complications.⁸⁴

In contrast, adjuvant pharmacological approaches to spinal injury or such in lieu of any surgical procedure have been controversial. In 2006, Tsutsumi and coworkers reported on the beneficial effects of high dose methylprednisolone sodium succinate (MPSS) in acute cervical spine cord injury within the Second National Acute Spinal Cord Injury Study (NASCIS II),⁸⁵ resembling the sequel results to a previous report by Bracken.^{86, 87} A similar study by Leypold and coworkers supported these recommendations by demonstrating reduced spinal cord hemorrhage in patients treated with MPSS after cervical spine injury, yet without statistical significance to historical controls.⁸⁸ On the other hand, a more recent cohort study by Ito and coworkers, as well as an animal study reported by Rabinowitz and coworkers, found no evidence supporting the use of high-dose MPSS and exhorted the increased incidence of pulmonary complications.^{89, 90} The latter aspect of using high-dose MPSS may therefore raise profound concerns when managing the polytraumatized patient with spinal injury. In the eminent status of trauma-induced immunosuppression, high-dose corticosteroids could promote further impairment of the already aggrieved organism and lead to detrimental organ dysfunctions. In line with the histological findings reported by Kubeck and coworkers,⁹¹, MPSS administration cannot be recommended when multiple organ injury is evident.

Although MPSS may currently be limited to monotraumatic incidents, results from other recent clinical and laboratory trials focussing on agents targeting the aforementioned secondary endogenous processes of spinal cord injury are promising and will certainly form the bias for future trials.^91–93

CONCLUSION

Despite various algorithms proven to be efficient in most major trauma centers, spinal injury remains a challenge in the acute management of polytraumatized patients. According to the ATLS® and damage control guidelines outlined earlier, the “life before limb” principle should be closely reassessed throughout the entire course of treatment (Figure 6). Particularly in the unconscious and intubated patient, spinal injury must be presumed until excluded otherwise. Therefore, both the primary and secondary survey within the ATLS algorithm should be carefully aligned to detect or prevent any associated neurological compromise. In hemodynamically stable but unconscious patients with suspected spine injury, standard diagnostics should include a mandatory spiral CT with a 2D- or 3D-reconstruction of the complete spine. In cases where cervical spine injury is evident, we recommend the amendment of a CT angiography. Provided that the polytraumatized patient presents in a hemodynamically and physiologically stable condition, instable fractures with proven compression of the spinal canal or manifest neurological deficits are subject to early damage control procedures as described earlier. With respect to the various secondary endogenous changes following multiple trauma all other surgical interventions must be staged in close dependence of the patient's physiological state and clinical course of recovery. Thus, immunological monitoring and future randomized controlled trials targeting specific endogenous parameters may improve optimal timing of surgery and elucidate adjuvant pharmacological approaches. Due to the lack of reliable evidence and significant methodical and statistical discrepancies in the past study protocols, we strongly advise against the application of MPSS in polytraumatized patients.⁹⁴

Keywords

spinal cord injury, polytrauma, damage control orthopedics, instable spine fracture

Disclosure: The authors declare no conflict of interest.

REFERENCES

1. Rotondo MF, Schwab CW, McGonigal MD, et al. ‘‘Damage control’’: an approach for improved survival in exsanguinating penetrating abdominal injury. J Trauma. 1993;35(3):375–382.
2. Schwab CW. Introduction: damage control at the start of 21st century. Injury. 2004;35(7):639–41.
3. Gebhard F, Huber-Lang M. Polytrauma—pathophysiology and management principles. Langenbecks Arch Surg. 2008;393(6):825–831.
4. Lasanianos NG, Kanakaris NK, Dimitriou R, Pape HC, Giannoudis PV. Second hit phenomenon: existing evidence of clinical implications. Injury. 2011;42(7):617–629.
5. Pape HC, Giannoudis P, Krettek C. The timing of fracture treatment in polytrauma patients: relevance of damage control orthopedic surgery. Am J Surg. 2002;183(6):622–629.
6. Scalea TM, Boswell SA, Scott JD, Mitchell KA, Kramer ME, Pollak AN. External fixation as a bridge to intramedullary nailing for patients with multiple injuries and with femur fractures: damage control orthopedics. J Trauma. 2000;48(4):613–621.
7. Trentz OL. Polytrauma: pathophysiology, priorities, and management. In: Rüedi TPM, William M, eds. AO Principles of Fracture Management. New York: Thieme; 2001:665–677.
8. Croce MA, Bee TK, Pritchard E, Miller PR, Fabian TC. Does optimal timing for spine fracture fixation exist? Ann Surg. 2001;233(6):851–858.
9. Kerwin AJ, Frykberg ER, Schinco MA, et al. The effect of early surgical treatment of traumatic spine injuries on patient mortality. J Trauma. 2007;63(6):1308–1313.
10. Schlegel J, Bayley J, Yuan H, Fredricksen B. Timing of surgical decompression and fixation of acute spinal fractures. J Orthop Trauma. 1996;10(5):323–330.
11. Kerwin AJ, Griffen MM, Tepas JJ 3rd, Schinco MA, Devin T, Frykberg ER. Best practice determination of timing of spinal fracture fixation as defined by analysis of the National Trauma Data Bank. J Trauma. 2008;65(4):824–830.
12. Pakzad H, Roffey DM, Knight H, Dagenais S, Yelle JD, Wai EK. Delay in operative stabilization of spine fractures in multitrauma patients without neurologic injuries: effects on outcomes. Can J Surg. 2011;54(4): 270–276.
13. Richter-Turtur M. [Spinal injuries in polytrauma patients]. Langenbecks Arch Chir Suppl Kongressbd. 1992:311–315.
14. Krettek C, Simon RG. Tscherne H. Management priorities in patients with polytrauma. Langenbecks Arch Surg. 1998;383(3–4):220–227.
15. Patel RV, DeLong W Jr, Vresilovic EJ. Evaluation and treatment of spinal injuries in the patient with polytrauma. Clin Orthop Relat Res. 2004;(422): 43–54.
16. Reinhold M, Knop C, Beisse R, et al. Operative treatment of 733 patients with acute thoracolumbar spinal injuries: comprehensive results from the second, prospective, Internet-based multicenter study of the Spine Study Group of the German Association of Trauma Surgery. Eur Spine J. 2010; 19(10):1657–1676.
17. Greenberg MI. Falls from heights. JACEP. 1978;7(8):300–301.
18. Welkerling H, Wening JV, Langendorff HU, Jungbluth KH. [Computerassisted data analysis of injuries of the skeletal system in polytrauma patients]. Zentralbl Chir. 1991;116(22):1263–1272.
19. Clayton JL, Harris MB, Weintraub SL, Marr AB, Timmer J, Stuke LE, et al. SL Risk factors for cervical spine injury. Injury. 2011 Jul 2. [Epub ahead of print] PMID: 21726860. [PubMed - as supplied by publisher].
20. Morris CG, McCoy E. Clearing the cervical spine in unconscious polytrauma victims, balancing risks and effective screening. Anaesthesia. 2004;59(5):464–482.
21. Blauth M. [Spinal injuries—facts and questions, opening of new horizons]. Orthopade. 1999;28(8):635–636.
22. Fisher A, Young WF. Is the lateral cervical spine x-ray obsolete during the initial evaluation of patients with acute trauma? Surg Neurol. 2008;70(1):53–57.
23. Buhren V. [Injuries to the thoracic and lumbar spine]. Unfallchirurg. 2003;106(1):55–68.
24. Harris MB, Kronlage SC, Carboni PA, et al. Evaluation of the cervical spine in the polytrauma patient. Spine (Phila Pa 1976). 2000;25(22): 2884–2891.
25. Hennessy D, Widder S, Zygun D, Hurlbert RJ, Burrowes P, Kortbeek JB. Cervical spine clearance in obtunded blunt trauma patients: a prospective study. J Trauma. 2010;68(3):576–582.
26. Sampson MA, Colquhoun KB, Hennessy NL. Computed tomography whole body imaging in multi-trauma: 7 years experience. Clin Radiol. 2006;61(4):365–369.
27. Linsenmaier U, Krotz M, Kanz KG, et al. [Evaluation of spine boards for X-Ray diagnostics]. Rofo. 2001;173(11):1041–1047.
28. Anderson PA, Gugala Z, Lindsey RW, Schoenfeld AJ, Harris MB. Clearing the cervical spine in the blunt trauma patient. J Am Acad Orthop Surg. 2010;18(3):149–159.
29. Bagley LJ. Imaging of spinal trauma. Radiol Clin North Am. 2006;44(1):1– 12, vii.
30. Saltzherr TP, Fung Kon Jin PH, Beenen LF, Vandertop WP, Goslings JC. Diagnostic imaging of cervical spine injuries following blunt trauma: a review of the literature and practical guideline. Injury. 2009;40(8):795– 800.
31. Stanescu L, Talner LB, Mann FA. Diagnostic errors in polytrauma: a structured review of the recent literature. Emerg Radiol. 2006;12(3): 119–123.
32. Ding T, Maltenfort M, Yang H, et al. Correlation of C2 fractures and vertebral artery injury. Spine (Phila Pa 1976). 2010;35(12):E520–E524.
33. Fleck SK, Langner S, Baldauf J, Kirsch M, Rosenstengel C, Schroeder HW. Blunt craniocervical artery injury in cervical spine lesions: the value of CT angiography. Acta Neurochir (Wien). 2010;152(10):1679–1686.
34. Biffl WL, Moore EE, Elliott JP, et al. The devastating potential of blunt vertebral arterial injuries. Ann Surg. 2000;231(5):672–681.
35. Parbhoo AH, Govender S, Corr P. Vertebral artery injury in cervical spine trauma. Injury. 2001;32(7):565–568.
36. Torina PJ, Flanders AE, Carrino JA, et al. Incidence of vertebral artery thrombosis in cervical spine trauma: correlation with severity of spinal cord injury. AJNR Am J Neuroradiol. 2005;26(10):2645–2651.
37. Goergen S. Imaging guideline 1: blunt cervical spine trauma. Australas Radiol. 2004;48(3):287.
38. Hanson JA, Blackmore CC, Mann FA, Wilson AJ. Cervical spine injury: a clinical decision rule to identify high-risk patients for helical CT screening. AJR Am J Roentgenol. 2000;174(3):713–717.
39. Kokabi N, Raper DM, Xing M, Giuffre BM. Application of imaging guidelines in patients with suspected cervical spine trauma: retrospective analysis and literature review. Emerg Radiol. 2011;18(1):31–38.
40. Ding A, Abujudeh H, Novelline RA. Diagnosing cervical spine instability: role of the post-computed tomography scan out-of-collar lateral radiograph. J Emerg Med. 2011;40(5):518–521.
41. Khan SN, Erickson G, Sena MJ, Gupta MC. Use of flexion and extension radiographs of the cervical spine to rule out acute instability in patients with negative computed tomography scans. J Orthop Trauma. 2011;25(1):51–56.
42. Khanna P, Chau C, Dublin A, Kim K, Wisner D. The value of cervical magnetic resonance imaging in the evaluation of the obtunded or comatose patient with cervical trauma, no other abnormal neurological findings, and a normal cervical computed tomography. J Trauma. 2011 Aug 17. [Epub ahead of print]. PMID: 21857257 [PubMed - as supplied by publisher].
43. Panczykowski DM, Tomycz ND, Okonkwo DO. Comparative effectiveness of using computed tomography alone to exclude cervical spine injuries in obtunded or intubated patients: meta-analysis of 14,327 patients with blunt trauma. J Neurosurg. 2011;115(3):541–549.
44. White AA, Panjabi MM Clinical Biomechanics of the Spine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1990.
45. Dormans JP. Evaluation of children with suspected cervical spine injury. J Bone Joint Surg Am. 2002;84-A(1):124–132.
46. Swischuk LE. Anterior displacement of C2 in children: physiologic or pathologic. Radiology. 1977;122(3):759–763.
47. Denis F. The three column spine and its significance in the classification of acute thoracolumbar spinal injuries. Spine (Phila Pa 1976). 1983;8(8):817–831.
48. McLain RF, Benson DR. Urgent surgical stabilization of spinal fractures in polytrauma patients. Spine (Phila Pa 1976). 1999;24(16):1646–1654.
49. Joaquim AF, Fernandes YB, Cavalcante RA, Fragoso RM, Honorato DC, Patel AA. Evaluation of the thoracolumbar injury classification system in thoracic and lumbar spinal trauma. Spine (Phila Pa 1976). 2011;36(1):33– 36.
50. Oner FC, Wood KB, Smith JS, Shaffrey CI. Therapeutic decision making in thoracolumbar spine trauma. Spine (Phila Pa 1976). 2010; 35(suppl 21):S235–S244.
51. Patel AA, Hurlbert RJ, Bono CM, Bessey JT, Yang N, Vaccaro AR. Classification and surgical decision making in acute subaxial cervical spine trauma. Spine (Phila Pa 1976). 2010;35(suppl 21):S228–S234.
52. Whang PG, Patel AA, Vaccaro AR. The development and evaluation of the subaxial injury classification scoring system for cervical spine trauma. Clin Orthop Relat Res. 2011;469(3):723–731.
53. Gehweiler JA, Duff DE, Martinez S, Miller MD, Clark WM. Fractures of the atlas vertebra. Skelet Radiol. 1976;1(2):97–102.
54. Anderson LD, D’Alonzo RT. Fractures of the odontoid process of the axis. J Bone Joint Surg Am. 1974;56(8):1663–1674.
55. Effendi B, Roy D, Cornish B, Dussault RG, Laurin CA. Fractures of the ring of the axis. A classification based on the analysis of 131 cases. J Bone Joint Surg Br. 1981;63-B(3):319–327.
56. Josten C. [Traumatic spondylolisthesis of the axis]. Orthopade. 1999;28(5):394–400.
57. Goodnight TJ, Helmer SD, Dort JM, Nold RJ, Smith RS. A comparison of flexion and extension radiographs with computed tomography of the cervical spine in blunt trauma. Am Surg. 2008;74(9):855–857.
58. Insko EK, Gracias VH, Gupta R, Goettler CE, Gaieski DF, Dalinka MK. Utility of flexion and extension radiographs of the cervical spine in the acute evaluation of blunt trauma. J Trauma. 2002;53(3):426–429.
59. Magerl F, Aebi M, Gertzbein SD, Harms J, Nazarian S. A comprehensive classification of thoracic and lumbar injuries. Eur Spine J. 1994;3(4): 184–201.
60. Whitesides TE Jr. Traumatic kyphosis of the thoracolumbar spine. Clin Orthop Relat Res. 1977;(128):78–92.
61. Katonis P, Pasku D, Alpantaki K, et al. Combination of the AO-magerl and load-sharing classifications for the management of thoracolumbar burst fractures. Orthopedics. 2010:158–163.
62. Schueller G. [Who is who revisited: spinal trauma]. Radiologe. 2010; 50(12):1084–1095.
63. Weninger P, Figl M, Spitaler R, Mauritz W, Hertz H. Early unreamed intramedullary nailing of femoral fractures is safe in patients with severe thoracic trauma. J Trauma. 2007;62(3):692–696.
64. Vallier HA, Cureton BA, Ekstein C, Oldenburg FP, Wilber JH. Early definitive stabilization of unstable pelvis and acetabulum fractures reduces morbidity. J Trauma. 2010;69(3):677–684.
65. Schinkel C, Frangen TM, Kmetic A, Andress HJ, Muhr G. Timing of thoracic spine stabilization in trauma patients: impact on clinical course and outcome. J Trauma. 2006;61(1):156–160.
66. Anderson PA, Rivara FP, Maier RV, Drake C. The epidemiology of seatbelt-associated injuries. J Trauma. 1991;31(1):60–67.
67. McAfee PC, Yuan HA, Fredrickson BE, Lubicky JP. The value of computed tomography in thoracolumbar fractures. An analysis of one hundred consecutive cases and a new classification. J Bone Joint Surg Am. 1983; 65(4):461–473.
68. Savitsky E, Votey S. Emergency department approach to acute thoracolumbar spine injury. J Emerg Med. 1997;15(1):49–60.
69. Inaba K, Kirkpatrick AW, Finkelstein J, et al. Blunt abdominal aortic trauma in association with thoracolumbar spine fractures. Injury. 2001;32(3):201–207.
70. Lundevall J. Traumatic rupture of the aorta, with special reference to road accidents. Acta Pathol Microbiol Scand. 1964;62:29–33.
71. Roth SM, Wheeler JR, Gregory RT, et al. Blunt injury of the abdominal aorta: a review. J Trauma. 1997;42(4):748–55.
72. Schmidt OI, Strasser S, Kaufmann V, Strasser E, Gahr RH. Role of early minimal-invasive spine fixation in acute thoracic and lumbar spine trauma. Indian J Orthop. 2007;41(4):374–380.
73. Blauth M, Knop C, Bastian L, Krettek C, Lange U. [Complex injuries of the spine]. Orthopade. 1998;27(1):17–31.
74. Michaels AJ, Wanek SM, Dreifuss BA, et al. A protocolized approach to pulmonary failure and the role of intermittent prone positioning. J Trauma. 2002;52(6):1037–1047.
75. Allen JR. Infectious complications in patients with spinal cord injury. JAMA. 1982;248(1):83–84.
76. Delamarter RB, Sherman JE, Carr JB. Volvo Award in experimental studies. Cauda equina syndrome: neurologic recovery following immediate, early, or late decompression. Spine (Phila Pa 1976). 1991;16(9): 1022–1029.
77. Fehlings MG, Tator CH. An evidence-based review of decompressive surgery in acute spinal cord injury: rationale, indications, and timing based on experimental and clinical studies. J Neurosurg. 1999;91(suppl 1):1–11.
78. Yakovlev AG, Faden AI. Molecular biology of CNS injury. J Neurotrauma. 1995;12(5):767–777.
79. Segal JL. Immunoactivation and altered intercellular communication mediate the pathophysiology of spinal cord injury. Pharmacotherapy. 2005;25(2):145–156.
80. Carreon LY, Dimar JR. Early versus late stabilization of spine injuries: a systematic review. Spine (Phila Pa 1976). 2011;36(11):E727–33.
81. Fehlings MG, Wilson JR. Timing of surgical intervention in spinal trauma: what does the evidence indicate? Spine (Phila Pa 1976). 2010;35(suppl 21):S159–S160.
82. Rahimi-Movaghar V, Saadat S, Vaccaro AR, et al. The efficacy of surgical decompression before 24 hours versus 24 to 72 hours in patients with spinal cord injury from T1 to L1—with specific consideration on ethics: a randomized controlled trial. Trials. 2009;10:77.
83. Wilson JR, Fehlings MG. Emerging approaches to the surgical management of acute traumatic spinal cord injury. Neurotherapeutics. 2011;8(2): 187–194.
84. Dimar JR, Carreon LY, Riina J, Schwartz DG, Harris MB. Early versus late stabilization of the spine in the polytrauma patient. Spine (Phila Pa 1976). 2010;35(suppl 21):S187–S192.
85. Tsutsumi S, Ueta T, Shiba K, Yamamoto S, Takagishi K. Effects of the Second National Acute Spinal Cord Injury Study of high-dose methylprednisolone therapy on acute cervical spinal cord injury-results in spinal injuries center. Spine (Phila Pa 1976). 2006;31(26):2992–2996.
86. Bracken MB. Steroids for acute spinal cord injury. Cochrane Database Syst Rev. 2002;(3):CD001046.
87. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA. 1997;277(20):1597–1604.
88. Leypold BG, Flanders AE, Schwartz ED, Burns AS. The impact of methylprednisolone on lesion severity following spinal cord injury. Spine (Phila Pa 1976). 2007;32(3):373–378.
89. Ito Y, Sugimoto Y, Tomioka M, Kai N, Tanaka M. Does high dose methylprednisolone sodium succinate really improve neurological status in patient with acute cervical cord injury? A prospective study about neurological recovery and early complications. Spine (Phila Pa 1976). 2009;34(20):2121–2124.
90. Rabinowitz RS, Eck JC, Harper CM Jr, et al. Urgent surgical decompression compared to methylprednisolone for the treatment of acute spinal cord injury: a randomized prospective study in beagle dogs. Spine (Phila Pa 1976). 2008;33(21):2260–2268.
91. Kubeck JP, Merola A, Mathur S, Brkarik M, Majid K, Shanti N, et al. End organ effects of high-dose human equivalent methylprednisolone in a spinal cord injury rat model. Spine (Phila Pa 1976). 2006;31(3):257–61.
92. Hall ED. Antioxidant therapies for acute spinal cord injury. Neurotherapeutics. 2011;8(2):152–167.
93. Hurtado A, Marcillo A, Frydel B, Bunge MB, Bramlett HM, Dietrich WD. Anti-CD11d monoclonal antibody treatment for rat spinal cord compression injury. Exp Neurol. 2010 Dec 9. [Epub ahead of print]. PMID: 21145887 [PubMed - as supplied by publisher].
94. Park S, Lee SK, Park K, et al. Beneficial effects of endogenous and exogenous melatonin on neural reconstruction and functional recovery in an animal model of spinal cord injury. J Pineal Res. 2012;52(1):107–119.
95. Stahel PF, Heyde CE, Wyrwich W, Ertel W. [Current concepts of polytrauma management: from ATLS to ‘‘damage control’’]. Orthopade. 2005;34(9):823–836.