Featured Articles from the Journal of Clinical Rheumatology and Musculoskeletal Medicine (JCRMM)

Knee Problems in Severe Hemophilia: Orthopedic Management

E. Carlos Rodriguez-Merchan¹, Victor Jimenez-Yuste², Primitivo Gomez-Cardero¹, M. Teresa Alvarez-Roman², Monica Martin-Salces² and Ana Rodríguez de la Rua²

Affiliations: ¹Department of Orthopaedic Surgery, La Paz University Hospital, Madrid, Spain and ²Department of Haematology, La Paz University Hospital, Madrid, Spain

Correspondence: E. Carlos Rodriguez-Merchan, Department of Orthopaedic Surgery, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain. Tel: +34-606 712 724; Fax: +34 91 571 28 71; e-mail: ecrmerchan@gmx.es

ABSTRACT

Contemporary knowledge appears to demonstrate that radiosynovectomy is a very effective procedure, which decreases both the frequency and the intensity of recurrent intra-articular bleeds related to knee synovitis. The procedure should be performed as soon as possible to minimize the degree of articular cartilage damage. It can also be used in patients with inhibitors and with a minimal risk of complications. No damage has been reported in relation to the radioactive materials. Radiosynovectomy is currently the preferred procedure when radioactive materials are available; however, chemical synovectomy is an effective alternative method if radioactive materials are not available. Radiosynovectomy is the best choice for patients with persistent synovitis. Personal experience and the general recommendation is that when three early consecutive radiosynovectomies (repeated every 3 to 6 months) fail to halt synovitis, an arthroscopic synovectomy should be immediately considered. For advanced hemophilic arthropathy of the knee, the best solution is a total knee replacement. Other surgical and nonsurgical procedures are less commonly needed for the hemophilic knee.

Psoriatic Disease: A Systemic Pathology, Structured by Psoriasis, Psoriatic Arthritis and Comorbidities

Department of Research & development, Astralis Ltd, 1076 Stuyvesant Ave. Irvington, NJ, USA.

Correspondence: J. A. O'Daly, Department of Research & development, Astralis Ltd, 1076 Stuyvesant Ave. Irvington, USA. Tel: 1-973-224-5723; e-mail: joseodaly@aol.com

ABSTRACT

While injecting volunteers in Venezuela with a vaccine for prevention of leishmaniasis, we observed 100% clinical remission of a psoriatic lesion in one subject. A single center study evaluated the safety and efficacy of multiple 500 µg doses of AS100 on psoriatic arthritis (PsA). Approximately, 2599 subjects (83%) experienced at least one adverse event, injection site related and including: pain 43%, nodule formation 23%, heat 21%, and erythema 14%. When baseline Psoriasis Area and Severity Index (PASI) values in the group with PsA (n=508) were compared with post-treatment 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 number of AS100 doses required to induce 100% remission was 9.9±4.8. Higher percentage frequency in PsA than psoriasis patients was found in hypertension, vascular diseases, intestinal diseases, infections, gastritis, cardiac arrhythmia, gallstones in gallbladder, osteoporosis, hyperuricemia, and epilepsy. Up to 7–8 comorbidities were found in both psoriasis and PsA patients together in the same subject: thus, psoriasis is a systemic disease, induced by cytokines in all body organs, being expressed in each tissue according to genetic and environmental factors due to shared inflammatory pathways. Development of psoriasis and PsA is centered in the blood vessels’ behavior. Both diseases start by proliferation of blood vessels after up-regulation of vascular endothelial growth factor, transforming growth factor β, and other angiogenic factors. Clinical remission in psoriatic lesions also starts by decreased proliferation of blood vessels, after treatment with leishmania antigens.

The Interferon-Signature of Sjögren's Syndrome: What Does It Say About the Etiopathology of Autoimmunity?

INTRODUCTION

Sjögren's syndrome (SS) of humans and SS-like (SjS-like) diseases in mouse models are characterized by chronic immune attacks against the salivary and lacrimal glands leading to exocrine dysfunction. One characteristic of SS is an upregulated expression of interferon (IFN) and IFN-responsive genes, designating SS as an “interferon-signature” disease.

OBJECTIVE

To determine if SjS-like disease of C57BL/6.NOD-Aec1Aec2 mice, a model of primary SjS, displays the interferon-signature of SS.

METHODS

Using oligonucleotide microarrays, temporal gene expression profiles were generated for salivary and lacrimal glands of 4–20 week old C57BL/6.NOD-Aec1Aec2 mice. Pair-wise analyses were used to identify differentially expressed IFN and IFN-responsive genes.

RESULTS

Temporal gene expression profiles of IFN genes indicated that only a single gene, Ifna5, showed an upregulated expression during development and onset of SjS-like disease. In contrast, a selective subset of IFNα/β- and/or IFNγ-responsive genes were highly upregulated, and the times at which they were maximally upregulated corresponded to the two time points defining either the innate response (8–12 weeks of age) or the adaptive immune response (16–20 weeks of age). Several upregulated IFN-responsive genes of C57BL/6.NOD-Aec1Aec2 mice overlapped significantly with genes reported to be upregulated in PBMCs and/or LSG biopsies of SS patients.

CONCLUSIONS

Although a variety of genes known to respond to the direct or indirect actions of an IFN are upregulated in SS/SjS-like disease, the genes differentially expressed represent select subsets. We hypothesize, therefore, that understanding the functions of these upregulated genes and how they interact molecularly and biologically should provide critical details of SS pathology.

How to Use Synovial Immunohistology as a Tool for the Better Understanding of the Clinical Use of Different Antirheumatic Treatments

Arthroscopy is a safe and reliable technique to obtain synovial biopsies for studies of the local inflammatory process in joint diseases such as rheumatoid arthritis. In this review we aimed to provide an overview on the use of this particular research tool in studies concerning mechanisms of action of distinct antirheumatic drugs. These studies contribute to identification of both new therapeutic targets and synovial biomarkers for prediction of disease outcome and therapy response. We conclude that further development and standardization as well as efforts to organize large synovial tissue biobanks are warranted.

New Insights in Fibromyalgia: A Review

When Mrs. Blomberg, a 52-year-old fibromyalgia patient, meets her health care providers such as a physician, nurse, or physiotherapist, she asks many questions: What kind of a disease is this? What is the cause and is it common? What can be done regarding treatment and what is the prognosis?

The present review article summarizes up-to-date evidence-based facts in order to provide answers to these questions and to have a good scientific basis when discussing fibromyalgia with the patient as well as with health care colleagues, researchers, and others.

Ultrasound in Rheumatoid Arthritis: Association Between the Polymorphism -308 A/G of Tumor Necrosis Factor and the Severity of Bone Erosive Damage

INTRODUCTION

Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive bone damage. The tumor necrosis factor (TNF) -308A/G polymorphism was associated with erosive radiographic progression. Musculoskeletal ultrasound (US) was found superior to radiography to identify bone erosions within small joints (metacarpophalangeal [MCP], hand proximal interphalangeal [PIP], metatarsophalangeal [MTP]) in patients affected with RA.

OBJECTIVES

To evaluate the association of TNF -308G/A with bone erosions assessed with an ultrasound.

STUDY DESIGN

Fifty-two patients affected by RA criteria were genotyped for TNF -308G/A. Disease activity was measured with the disease activity score in 28-joints (DAS28) and the clinical response was evaluated according to the European League Against Rheumatism (EULAR) response criteria. Rheumatoid factor (RF) and anticitrullinated protein/peptides antibodies (ACPA) were detected. The analysis of the TNF -308G/A polymorphism was made by polymerase chain reaction amplification. An ultrasound was performed to assess bone surfaces of metacarpophalengeal (MCP), proximal interphalangeal (PIP), and metatarsophalangeal (MTP) joints by multiplanar scans. According to the number of erosions per joint, a semiquantitative score (range 0–3) was applied. A score in each anatomical district was calculated obtaining MCP-total erosion score (TES), PIP-TES, and MTP-TES, ranging from 0 to 30, and a global TES-patient from the sum of these scores (range 0–90).

RESULTS

TNF -308GG genotype was present in 43 patients while TNF -308AG/AA was present in 9 patients. No significant differences within the two groups were observed for mean age (56±13.8 vs 56.8±16.1 years), disease duration (141.6±117.6 vs 140.4±72.3 months), rheumatoid factor (33/76.7 vs 8/88.8 [N/%]), ACPA (38/88.4 vs 8/88.8 [N/%]), ESR (32.4±26.9 vs 29.4±19.9 mm/h), DAS28 (5.5±1.0 vs 4.6±1.3), HAQ (1.5±.9 vs 1.1±.7). A significant association was found between TNF -308AG/AA genotypes and higher TES patient (28.5±23.7 vs 38.1±17.1 [P<.05]), MCP TES (11.2±8.2 vs 18±8.4 [P=.027]), MTP TES (8.2±8 vs 11.2±6 [P<.05]), and no differences for PIP TES (8.7±8.9 vs 8.9±6.2).

CONCLUSION

This study showed an association between the TNF -308 A allele, linked to higher TNF expression, and bone erosive damage evaluated by ultrasound in patients with RA. This preliminary result confirms previous radiographic studies.

Pulmonary Arterial Hypertension-A Deadly Complication of Systemic Sclerosis

Pulmonary arterial hypertension (PAH) is a devastating disease with limited therapeutic options. Moreover, when PAH occurs in patients diagnosed with systemic sclerosis, worse outcomes are observed. The purpose of this review is to discuss the etiologies of PAH found in the systemic sclerosis patient, limitations of current medical therapies, and, finally, potential therapies for patients with this combination.

Screening for Hepatitis B and C in Patients with Recent-Onset Polyarthritis

Infection, metabolic, or autoimmune diseases such as rheumatoid arthritis (RA) may be the cause of recent-onset polyarthritis. The possibility to identify the etiology of recent-onset polyarthritis depends on the combination of clinical, imaging, and laboratory tests used. However, the diagnostic efficacy and the indications of several tests are not fully determined. Between these, the appropriateness of testing for hepatitis B and C viruses is still debated. In addition, only a few studies have addressed this question in patients with recent-onset polyarthritis. These studies have shown a low prevalence of anti hepatitis virus antibodies in early arthritis, quite similar to those reported in the general population. The aim of this review is to describe the diagnostic usefulness of serological test for hepatitis B and C viruses in patients with recent-onset polyarthritis compared to RA populations.

The Long-Term Effectiveness and Safety of Abatacept in Rheumatoid Arthritis

Several biological drugs with a mode of action different from TNF blockade are currently available for the treatment of rheumatoid arthritis (RA). Since there are no data in literature to compare the different biologicals head-to-head, rheumatologists currently base their treatment decisions on literature reviews and registry data. One of these drugs is Abatacept, a costimulation modulator. A careful analysis of the different extension trials of Abatacept provides interesting insights in the specific efficacy and safety profile that might contribute to the understanding and the appropriate use of this latter drug. Long-term attrition on the drug in these extensions, increasing clinical and X-ray improvements over time, important and stable responses over years, particular improvements in patient-centered outcomes, but also long-term safety, and easy administration with low rates of perfusion reactions will be discussed.

Review: Surfactant Protein D and KL-6 in Scleroderma-Related Interstitial Lung Disease

This article will review the clinical background and significance of two promising serum biomarkers that have been studied in relation to systemic sclerosis (scleroderma, SSc). Systemic sclerosis is a rare and difficult to treat connective tissue disease, with pulmonary involvement being the leading cause of mortality. The most common pulmonary manifestation in SSc is interstitial lung disease (SSc-ILD), and noninvasive serum markers to evaluate and monitor patients and their lung disease are being sought. Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are glycoproteins secreted by type II pneumocytes. Serum levels of KL-6 and SP-D have been shown in several studies to correlate with the presence of interstitial lung disease in patients with a variety of lung conditions including SSc-ILD. In this article, we will examine the background and significance of these glycoproteins and assess their role to this point as biomarkers of SSc-ILD.

Optimization of the Patient Undergoing Total Knee Arthroplasty – The Rapid Recovery Program

There is traditionally an unnecessary “medicalization” of the orthopedic patient undergoing total knee arthroplasty. Such procedures are commonly performed under general anesthetic with difficulties in managing postoperative analgesia requirements resulting in slow mobilization and recovery. In-patient stays of 2 weeks are commonplace and care is often disjointed with limited interaction between the different groups of health care providers. Changing demographics and an ever-increasing demand for joint replacement dictate that the processes be streamlined to maximize efficiency. Rapid Recovery is an evidence-based means of providing the best possible patient care, while at the same time optimizing the use of resources. It promotes patient centered care with a focus on patient education and prehabilitation. The preoperative, intraoperative, and postoperative stages of Rapid Recovery are described. The significant reduction in the length of in-patient stay, the considerable cost savings, and the low complication rates are discussed as well as the favorable patient satisfaction scores. Rapid Recovery should now be thought of as the gold standard for the treatment of all patients undergoing hip and knee replacement.

The Epidemiological and Pathogenic Association of Rheumatoid Arthritis With Atherosclerotic Cardiovascular Disease

Rheumatoid arthritis (RA) is associated with an approximately twofold increased risk of atherosclerotic cardiovascular disease (CVD) including myocardial infarction and stroke. The increased risk of CVD in RA is due to an interplay between traditional risk factors such as hyperlipidemia, hypertension, and smoking and disease-related variables such as the presence of rheumatoid factor and anticyclic citrullinated peptide antibodies, high erythrocyte sedimentation rate, and joint swelling. Systemic inflammation and immune mechanisms form a pathogenic link between synovitis and atherosclerosis in RA. Indeed, high levels of C-reactive protein, an inflammatory marker, predict cardiovascular mortality in RA. Furthermore, the risk of CVD is greatly diminished among patients who respond to disease modifying antirheumatic drugs and biological therapies such as tumor necrosis factor (TNF) alpha antagonists. Through adverse effects on lipid profile and blood glucose level, long-term use of high-dose glucocorticoids in RA also increases cardiovascular risk. However, through control of active disease, glucocorticoids may also indirectly attenuate cardiovascular risk. Through their lipid-lowering and immunomodulatory effects, statins may have a dual benefit in the treatment of patients with RA. However, data on cardiovascular risk reduction in RA through management of traditional risk factors remain scant. Current research efforts are directed toward elucidating the risk factors for CVD in RA and developing strategies to minimize this risk.

Current Opinions in Pathogenesis of Slipped Capital Femoral Epiphysis (SCFE) of Children

Slipped capital femoral epiphysis (SCFE) is an adolescent disorder that is characterized by slipping of the femoral head off the femoral neck. It is classified into acute, chronic, and acute on chronic types. This study examines not only the epidemiology and classification, but also the etiology and pathogenesis of SCFE. Recent studies imply that obesity, trauma, shear stress in growth plate, and hormonal disturbances are some of the contributing factors to SCFE. More studies will reveal the pathophysiological mechanisms of this multifactorial disorder that concerns both pediatrics and orthopedics.

The Role of Tumor Necrosis Factor (TNF) in the Immune Response against Hepatitis B Virus (HBV) and the Use of TNF-Blocking Agents in Patients with HBV Infection and Rheumatic Diseases

Tumor necrosis factor-α (TNF-α) plays a critical role in the control of hepatitis B virus (HBV) infection through a variety of mechanisms. It amplifies host responses recruiting and activating macrophages and supporting the proliferation of HBV-specific cytotoxic T cells. It mediates death of infected hepatocytes through proapoptotic effects. It has direct antiviral effect, inhibiting virus replication.

Information on the use of TNF-blocking agents (TNFBA) in HBV-infected individuals is based only on reports of single cases or small series. Forty patients have been described, almost all HBsAg+ inactive carriers. Published data suggest a high risk of viral reactivation in these patients as increased serum HBV-DNA was demonstrated in almost 50% of them, but this risk seems to be reduced when TNFBA were administered together with an antiviral agent (p = 0.03). One case of reactivation has been described in an occult carrier (HBsAg-, anti-HBs+, anti-HBc+).

Based on these reports, we suggest that all patients candidate to TNFBA therapy should be tested for HBV markers, including HBsAg, anti-HBs, and anti-HBc. TNFBA should be avoided in patients with active HBV replication and should be used only with caution in HBsAg+ inactive carriers. In these patients, the risk of viral reactivation might be reduced by prophylactic antiviral drugs that should probably be prolonged for a long time after TNFBA discontinuation. In addition, potential occult carrier subjects that carry a low, but not negligible, risk of viral reactivation should be identified and monitored with particular care.

The Immune Response to Gut Bacteria in Spondyloarthritis: A Role in Pathogenesis?

A link between Ankylosing spondylitis (AS) and gut inflammation is firmly established. The gut microbiota play a crucial role in the development of Ankylosing spondylitis. A defective intestinal mucosal barrier in combination with a dysfunctional immune response to luminal antigens has also been implicated. While specific bacteria have previously been postulated as a trigger for the development of disease, current evidence suggests that this is not the case. Advances in genetic research have enabled identification of several important modifier genes that appear to influence the penetrance of AS in HLA-B27-positive individuals. The function of these genes may also help to explain the mechanism of HLA-B27 in disease pathogenesis. The discovery of shared risk genes for AS and inflammatory bowel disease, in addition to immunological evidence for a shared pathogenesis have helped to increase our understanding of these two interrelated disorders. Moreover, a greater appreciation of the nature and frequency of gastrointestinal symptoms in patients with AS may assist in identifying patients with associated inflammatory bowel disease and hence influencing treatment decisions. In this review we discuss the evidence supporting the link between AS, gut bacteria, and the bowel.

Making a Diagnosis in Rheumatology—Sometimes Easy, Sometimes Not

Rheumatological conditions present in a multitude of manners. There are different patterns of disease, natural history, and progression. Some conditions are severe and progressive while others have fluctuating or episodic symptoms. Symptoms and signs may not always coincide with the patient’s initial medical visit to the doctor, resulting in diagnostic difficulty.

Making a specific diagnosis is difficult in rheumatological conditions as many depend on heterogeneous diagnostic criteria and there are few single diagnostic tests. Many diagnoses are established based on a combination of clinical, laboratory, radiological, and histological investigations. These investigations are variable in their sensitivity and specificity. Pattern recognition appears to be the key to medical interpretation. This is dependent on the clinician’s prior experience and knowledge. Some rheumatological conditions evolve and a diagnosis is only established at a later point in time.

Making a definitive diagnosis is important to aid clinical management. It reduces the ambiguity of treatment, defines prognosis, and facilitates communication. It is also important for the patient to have that diagnosis to aid their understanding and education, and also be reassured about self-limiting conditions preventing learned behavior problems and potential chronic pain, disability, secondary gain,
and chronicity.

The probability of arriving at a diagnosis is most likely if the patient has active symptoms at the clinical assessment. Patients also prefer to be seen when they have active problems. This is not always the case if the symptoms are episodic and evanescent. Our current health system cannot ensure that this is possible in every case especially as the current trend is for nonclinicians to govern the process of arranging clinic rules. Thus, access to see a specialist when they need one is not always possible within the current UK NHS.

Within the UK, different models of follow-up and assessments are currently prevalent. They have been set up by clinicians based on the services available to facilitate making a definitive diagnosis at the earliest and improve patient care. An SOS (self-referral of symptoms) system seems to have some benefits in aiding diagnosis.

Occupational Physical Activity and Meniscal Tears: A Literature Review

The objective of this study was to conduct a systematic review of the literature examining the association between occupational physical demands and meniscal tears. A comprehensive literature search involving electronic databases (Medline, Embase, Cinahl, Web of Science, and Cochrane) was conducted along with the reference list of relevant publications. Peer-reviewed full-text articles published in English, German, or Scandinavian languages and concerning the incidence or prevalence of knee disorders, particularly meniscal pathology in different occupational trade groups, comprised the search criteria. Studies were assessed by their quality and the evidence of a causal relationship between occupational physical activity and meniscal tears evaluated using specific criteria for different levels of evidence. By merging results from the databases, a total number of 13 nonduplicate articles were found. The majority focused on occupational knee demands among workers in the construction and mining industry. Studies showed an increased prevalence of meniscal tears among workers with kneeling and squatting work tasks. The literature search revealed few relevant articles concerning the topic, and only three articles reached the level of high quality. It is concluded that evidence is still lacking of a causal relationship between occupational physical activities and meniscal tears.

Therapy for ANCA-Associated Vasculitis

The potential therapies for antineutrophil cytoplasm antibody-associated vasculitis (AAV) have increased over the past 10 years. The aims of therapy are to induce remission of disease, maintain remission, and prevent relapse. Cyclophosphamide and glucocorticoids remain the standard therapy, but the toxicity of cyclophosphamide limits its use, and it is now confined to induction of remission and treatment of relapses. Newer biological agents show promise. Results of clinical trials with rituximab suggest that rituximab is as efficacious as cyclophosphamide; however, long-term outcome data are awaited. Other agents, such as azathioprine, are considered more appropriate for remission maintenance. Induction therapies should be tailored to the severity of the disease, with more aggressive treatments reserved for severe disease, as suggested by the BSR and BHPR guidelines and EULAR recommendations. The adverse events associated with the different therapies need to be borne in mind by clinicians when selecting the appropriate type, dose, and duration of treatment in AAV. As the understanding of the pathogenesis of AAV increases, new targets for treatment have been identified. Alongside this, a change in the approach to management is needed as patients are surviving their acute disease but suffer morbidity due to disease and treatment-related damage.

Monocytic Cell Gene Regulation by the Hypoxic Synovial Environment in Juvenile Idiopathic Arthritis: Implications for Disease Pathogenesis

Review Article


Maria Carla Bosco and Luigi Varesio
Affiliation: Laboratory of Molecular Biology, G Gaslini Institute, Genova, Italy


ABSTRACT

Persistent synovial inflammation, extensive blood vessel neoformation, and uncontrolled fibroblast proliferation are hallmarks of juvenile idiopathic arthritis (JIA). Dysregulated angiogenesis leads to a dysfunctional vascular network, decreasing blood flow and impairing tissue oxygenation. Oxygen supply is further reduced by the formation of a hyperplastic inflammatory mass, which increases diffusion distances from blood vessels to cells, resulting in areas of hypoperfusion and hypoxia. Monocytic cells are an important component of the leukocyte infiltrate in the joints of patients affected by JIA, where they accumulate within the hypoxic synovial microenvironment, and recent advances have shed light on their role in JIA pathogenesis. The present article provides an overview of the phenotypic and functional changes triggered by hypoxia in monocytic cells both in vitro and in vivo within the JIA synovium. The discussion revolves around studies of gene expression profiles, which give a good representation of the exquisite sensitivity and the complexity of monocytic cell response to oxygen levels similar to those present in the JIA inflamed synovium. Experimental evidence demonstrating the strict regulatory control exerted by hypoxia on monocytic cell recruitment/retention and functional properties at pathological sites is summarized. Furthermore, we outline the existing literature on the transcription pathways underlying hypoxia‐regulated gene expression. Finally, we address the possible link between hypoxia signaling and activation of the proangiogenic and inflammatory phenotype of monocytic cells infiltrating the synovial microenvironment, and discuss the implications of these findings for the persistence of chronic inflammation associated with JIA and for the development of new therapeutic strategies.

Keywords: juvenile idiopathic arthritis, monocytes/macrophages, hypoxia, angiogenic factors, chemokines, gene regulation, inflammation
Correspondence: Maria Carla Bosco, Laboratorio di Biologia Molecolare, Istituto Giannina Gaslini, Padiglione 2, Lgo Gerolamo Gaslini 5, 16147 Genova Quarto, Italy. Tel: (39)‐010‐5636633; Fax: (39)‐010‐3733346; e‐mail: mariacarlabosco@ospedale‐gaslini.ge.it