Please be kindly advised that the articles posted here are the accepted articles for the Journal of Clinical Rheumatology & Musculoskeletal Medicine (JCRMM) in lieu of their proper inclusion in a particular issue. Once the article is formally lined-up for an issue, it will be reflected on the particular journal issue i.e. JCRMM volume 3 issue 1.
Reactive arthritis as the presenting feature of systemic lupus erythematosus
Metin Işik, Meral Çalgüneri
Affiliation: Division of Rheumatology, Department of Internal Medicine, Hacettepe University Hospital, Ankara, Turkey
Abstract
Patients with reactive arthritis frequently present with polyarthritis, conjunctivitis, and urethritis. On the other hand, in patients with systemic lupus erythematosus (SLE), polyarthritis is a frequent and conjunctivitis is a rare manifestation. Also, patients with SLE face with infections more often.
In conclusion, SLE may mimic a lot of diseases at the time of onset. Therefore, a better evaluation and a close follow-up is necessary.
Correspondence: Metin Işik, MD, Division of Rheumatology, Department of Internal Medicine, Hacettepe University Hospital, Sihhiye Ankara 06100, Turkey. Tel: 90-312-3051450; Fax: 90-312-3051348; e-mail: metin1721978@yahoo.com
Amit Kumar1, Timothy W R Briggs2,3, Robert U Ashford3–5
Affiliations:1Trauma & Orthopaedics, East Midlands (South) Rotation, Leicester General Hospital, Leicester, United Kingdom; 2Royal National Orthopaedic Hospital, London, United Kingdom; 3British Orthopaedic Oncology Society, United Kingdom; 4East Midlands Sarcoma Service, University Hospitals of Leicester, Leicester, United Kingdom; 5Division of Orthopaedic & Accident Surgery, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom
ABSTRACT
Sarcomas are potentially devastating tumours that can be encountered in rheumatology. With prompt diagnosis and treatment, sarcomas can successfully be treated to improve patient outcome. Delays in diagnosis of many months and even years are not uncommon in patients with sarcomas. We discuss the background of sarcomas along with the red flags that are important to aid diagnosis and mechanisms of referral to specialist sarcoma treatment centres in the United Kingdom.
Keywords: Sarcoma, bone, soft tissue, diagnosis
Correspondence: Robert Ashford, Trauma & Orthopaedics, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW. e-mail: robert.ashford@uhl-tr.nhs.uk
Affiliations:1Division of Rheumatology, Department of Internal Medicine, Hacettepe University, Ankara, Turkey; 2Department of Internal Medicine, Hacettepe University, Ankara, Turkey
ABSTRACT
Chorea gravidarum (CG) may be observed after rheumatic fever, systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome, syphilis, and encephalitis. Herein, we present a case with CG and SLE.
Affiliations: Metin Isık, MD, Department of Rheumatology, Hacettepe University Hospital, Sihhiye Ankara 06100, Turkey. Tel: 90-312-3051450; Fax: 90-312-3051348; e-mail: metin1721978@yahoo.com
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.
United Kingdom Primary Sjögren's Syndrome Registry (UKPSSR): How Should We Evaluate Its Outcome?
Wan-Fai Ng1, Simon J. Bowman2 and Bridget Griffiths3
Affiliations:1Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; 2Rheumatology Department, University Hospital Birmingham (Selly Oak), Birmingham, UK and 3Musculoskeletal Directorate, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
ABSTRACT
INTRODUCTION
Primary Sjögren's syndrome (pSS) is an immune-mediated rheumatic disease with a disease impact for patients comparable to that for rheumatoid arthritis (RA). However, pSS research has lagged behind that of RA. In 2009 recruitment opened to the Medical Research Council-funded United Kingdom Primary Sjögren's Syndrome Registry (UKPSSR).
OBJECTIVES
The UKPSSR was established to collect detailed clinical data from 500 patients with pSS and to establish a research biobank in order to facilitate high-quality research into this condition. In this article we will principally discuss how we should evaluate success and whether it has achieved its objectives.
METHODS
Mapping of the activities of the UKPSSR against published and proposed criteria.
RESULTS
We discuss the design of the registry and describe the utilization to date of the Registry data and biobank samples across a number of projects that have already started. We consider issues of process and quality assurance and the future utilization and maintenance of the UKPSSR.
CONCLUSIONS
The UKPSSR offers a significant opportunity to expand research into pSS in the UK and elsewhere. In its early phase alone it has already provided a valuable resource that is facilitating basic science projects, outcomes research, and clinical trial recruitment.
Keywords: primary Sjögren's syndrome, registry, research biobank, patient cohort
Correspondence: Simon J. Bowman, Rheumatology Department, Selly Oak Hospital, Birmingham B29 6JD, UK. Tel: +44-121 627 1627; Fax: +44-121 627 8480; e-mail: simon.bowman@uhb.nhs.uk
A Multicentric Prospective Analysis of 344 Ceramic on Ceramic Bearing in Total Hip Arthroplasty
R Beya1, D Dagrenat2, V Souillac3, J Tonetti4, B Vasse1 and L Devun5
Affiliations:1Orthopaedic & Trauma Department, La Rochelle Hospital, La Rochelle, France; 2Orthopaedic Unit, L’Orangerie Clinic, Strasbourg, France; 3Orthopaedic Unit, Pellegrin-Tripode Academic Hospital, Bordeaux, France; 4Orthopaedic & Trauma Department, Michallon Academic Hospital, Grenoble, France; 5Tural Implant Research Lab, Marignier, France
ABSTRACT
Total hip arthroplasty (THA) components have been developed now for 40 years and provide excellent and reliable clinical results. Ceramics was selected for the bearing couple for its biocompatibility and tribological performance with the lowest wear rate. With a ceramic on ceramic bearing, wear is no longer an issue but dislocation remains a complication in THA; therefore, big femoral ball heads are currently in high demand. However, increasing the ball head diameter has some surgical consequences. Specific complications related to impacting a ceramic liner into an acetabular shell include the risk of deforming the shell itself and the risk of not seating the liner correctly. In order to secure the ceramic insert, a preassembled cup has been developed; the aim of this clinical prospective study is to evaluate the benefit of this innovative device in THA. Between January 2008 and June 2010, 344 patients received a non-cemented THA using 32- or 36-mm femoral ball heads with a preassembled ceramic EXCLUSIF® cup. (ATF Marignier, France) The average follow-up was 20 months. The main age average was 62.75 years with 57% male and 43% female. An independent surgeon reviewed the x-rays and found no radiolucent lines, osteolysis or loosening. No ceramic liner breakage was observed, or ball head fracture, no patients required revision for instability, infection or pain. Preassembled inserts and metal-backs eliminate the risk of misalignment or third body at the interface. The ceramic insert is secured by the metal-back; this would not be possible during surgery, giving complete seating and superior strength both to the interface and the assembled cup. This technique also enables to avoid chipping on the edge of the ceramic insert as the insert is placed correctly in the metal-back. The risk of breakage should be avoided, as the cup is not deformed. The preassembled cup secures the ceramic insert with a quick and simple implantation technique and avoids complications in relation with the conical fixation of the insert into the metal-back. Results should be confirmed by further follow-ups in a larger population.
Keywords: ceramic, preassembled ceramic insert, large diameter femoral ball head, total hip replacement
Correspondence: L Devun, Tural Implant Research Lab, Marignier, France. e-mail: devun@tural.fr
Effect of percutaneous needle fasciotomy on hand function in patients with Dupuytren's disease
Liesbeth J Corporaal1, Johanna P Aussems1, J Daniel Moolenburgh2, Rens L Huisinga3, Tjeerd van der Ploeg4 Johannes PJ Bakker4
Affiliations:1Department of Rehabilitation Medicine, Medical Center Alkmaar, Alkmaar, the Netherlands; 2Department of Rheumatology, Medical Center Alkmaar, Alkmaar, the Netherlands; 3Department of Plastic Surgery, Medical Center Alkmaar, Alkmaar, the Netherlands; 4Foreest Medical School, Medical Center Alkmaar, Alkmaar, the Netherlands
ABSTRACT
Introduction
Few studies have assessed the effect of treatment on hand function in Dupuytren's disease. In most of these studies, no distinction was made between patients who underwent a percutaneous needle fasciotomy (PNF) or a fasciectomy.
Objectives
To assess the change in hand function after PNF in combination with a rehabilitation program.
Methods
Thirty-six patients with Dupuytren's disease were included[AQ]. Hand function and passive range of joint motion were measured before treatment and 3 and 12 months after treatment. Hand function was measured with the sequential occupational dexterity assessment (SODA) and the Michigan Hand Outcomes Questionnaire-Dutch Language Version (MHQ-DLV). Joint motion was noted in degrees of angulation. A mean total passive extension deficit (TPED) was calculated.
Results
A mean TPED of 52° (range: −10° to 120°) before PNF was corrected to 0° after 3 months (range: −30° to 30°) and to 12° after 12 months (range: −20° to 90°). The mean SODA score significantly improved from 100 (out of 108) before PNF to 107 after 3 and 12 months. The mean total MHQ score changed significantly from 81 (out of 100) to 91 after 3 months. At 12 months, the MHQ score was 92.
Conclusion
In patients with Dupuytren's disease, PNF in combination with a rehabilitation program results in a significant improvement of hand function after 3 months. After 12 months, the hand function remains good. Although there is an increase in TPED compared to the 3 months results, it remains less than that of before treatment.
Keywords: Dupuytren’s contracture, hand function, percutaneous needle fasciotomy
Affiliations: 1Rheumatologist at the Medisch Centrum Alkmaar, Alkmaar, The Netherlands and 2Rheumatologist at the Medical Unit, Thermal Center, 1400 Yverdon-Les-bains, Switzerland
ABSTRACT
Dupuytren's disease (DD) is a proliferative fibrodysplasia of the superficial palmar aponeurosis of the hands, leading to flexion contracture (FC) of the fingers and to incapacity. In this editorial history, pathoanatomy, etiology, related conditions, and epidemiology will be reviewed with consideration of the newest insights. Several treatments have been proposed for symptomatic DD, of which the main objectives are the reduction of fixed extension deficits of the fingers and the specific associated disability. Generally, systemic and local pharmacological treatments have been disappointing. Other proven treatments will be reviewed in detail, including the latest treatment with injectable collagenase.
Correspondence: G. Rappoport, Medical Association, 22, av. des Bains, 1400 Yverdon-les-Bains, Switzerland. Tel: +41244230202; Fax: +41244230222; e-mail: g.rappoport@bluewin.ch
Collagenase in Dupuytren's Disease: A Review of the Literature and Suggested Clinical Use
Tommy R Lindau1-3, Dan Armstrong1, Ernest A Azzopardi4, Dean E Boyce4
Affiliations:1Pulvertaft Hand Centre, Royal Derby Hospital, Derby, United Kingdom; 2University of Derby, United Kingdom; 3University of Bergen, Norway and 4The Welsh Centre for Plastic Surgery, Morriston Hospital, Swansea, Wales, United Kingdom
Abstract
Dupuytren's contracture is a common disabling condition of the hand in which recurrent and progressive disease leads to significant morbidity and cost-of care but not life-threatening problems. Until recently, surgery was the only viable management option. A significant complication rate may be associated with surgical treatment, especially for fasciectomy and revision surgery.
We have in this review article collated all evidence in the understanding and use of Collagenase Clostridium histolyticum (CCH) from a collagenase enzyme into licensed drugs: as Xiaflex® by Auxillium in the United States, with Food and Drug Administration (FDA) approval, and as Xiapex® by Pfizer in Europe with European Medicines Agency (EMA) approval.
Collagenase has proven to be an effective non-surgical alternative that results in comparable correction rates, and rates of recurrence, when compared to surgery. The precise role this treatment may play in the treatment of Dupuytren's disease is yet to be defined.
Randomised controlled trials are needed comparing outcome, recurrence rate and complication rate of comparable treatment groups treated with surgery, percutaneous needle fasciotomies and collagenase. Such studies may further refine where and when collagenase is the treatment of choice.
Correspondence: Tommy Lindau, MD, PhD, Pulvertaft Hand Centre, Royal Derby Hospital, Uttoxeter Road, Derby DE22 3NE, United Kingdom. e-mail: tommy.lindau@derbyhospitals.nhs.uk
B Cell Therapies in Patients With an Inadequate Response to Traditional Immunomodulatory Therapies
Philip Mease
Affiliation: Swedish Medical Center, University of Washington School of Medicine, Seattle, USA
ABSTRACT
Autoreactive B cells and autoantibodies are strongly implicated in the pathogenesis of rheumatoid arthritis and other autoimmune diseases, providing a strong rationale for the use of B cell-targeted therapies in these diseases. This article reviews the efficacy and safety of B cell-targeted therapies that are approved or in clinical development for the treatment of specific autoimmune diseases. At present, rituximab, a monoclonal antibody that selectively targets the CD20 surface marker on B cells, is approved for the treatment of rheumatoid arthritis, Wegener's granulomatosis, and microscopic polyangiitis, and is in clinical development for the treatment of Sjögren's syndrome and idiopathic membranous nephropathy. Belimumab, a monoclonal antibody directed against B lymphocyte stimulator (B cell activating factor), is approved for the treatment of systemic lupus erythematosus. Other B cell-targeted therapies currently in clinical development are also covered.
Correspondence: Philip Mease, Seattle Rheumatology Associates, 1101 Madison Suite 1000, Seattle WA 98104, USA. Tel: +1 (206) 386 2000; Fax: +1 (206) 386 2083; e-mail: pmease@philipmease.com
Keywords: Autoantibodies, autoimmune disease, B cell, B cell-targeted therapy, monoclonal antibody, rheumatoid arthritis, rituximab
Kim D. Jones1, Lindsay L. Kindler2, and Ginevra L. Liptan3
Affiliations:1School of Nursing and Medicine, Oregon Health & Science University, Portland, OR, USA; 2Schools of Nursing, Oregon Health & Science University and University of Portland, Portland, OR and 3Division of Arthritis and Rheumatic Medicine, Oregon Health & Science University, Portland, OR, USA
ABSTRACT
Fibromyalgia (FM) is a common disorder increasingly recognized in clinical practice. The veracity of the disorder is bolstered by three decades of objective evidence regarding central, peripheral, autonomic and endocrine dysfunction. Recently the US Food and Drug Administration have approved agents specifically for the treatment of fibromyalgia. What is less clear is how maximize outcomes in FM by promoting self-management activities in this population. The purpose of this article is to present practical, evidence-based self-management strategies for clinicians to pair with pharmacologic management. The therapies presented here are chosen if patients can enact them without the assistance of a therapist or practitioner and they are supported by extant literature. These include maximizing the relationship with the practitioner, pain management, self-administered cognitive behavioral strategies, exercise, dietary approaches and sleep management.
Correspondence: Kim D. Jones, PhD, RN, FNP, FAAN, Oregon Health & Science University School of Nursing 3455 SW US Veterans Road, SN-ORD Portland, OR 97239, USA. Tel: +503-494-3837; Fax: +503-418-0903; e-mail: joneskim@ohsu.edu
Affiliation: Division of rheumatoloy, Centre Hospitalies de l'Université de Montréal
ABSTRACT
The introduction of anti-TNF agents has considerably improved the prognosis of many of our rheumatologic conditions over the recent years. Unfortunately, not all patients respond adequately and some will develop adverse events leading to stopping of therapy. This can be in part explained by the immunogenicity associated with anti-TNF agents. Antibodies directed against different anti-TNF agents have been documented in clinical trials and in real life settings with differences between agents in the incidence and the impact on efficacy and safety. Agents with a monoclonal antibody construct, especially infliximab that has been the most widely studied one seems to be the most immunogenic. This problem has clinical and financial implications and needs to be recognized. Strategies to address it in a real life setting need to be developed.
Correspondence: Edith Villeneuve, Centres Hospitalier de l’Universite de Montreal, Hopital Notre-Dame, Service de rhumatologie, 4e etage, Pavillon Mailloux 1560 Sherbrooke Est, Montreal, Qc, H2L 4M1, Canada. Tel: +1-514-890-8000 28800; Fax: +1-514-412-7630; e-mail: ed.villeneuve@gmail.com
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
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.
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
Psoriatic Disease: A Systemic Pathology, Structured by Psoriasis, Psoriatic Arthritis and Comorbidities
J A O’Daly
Affiliation: Department of Research & development, Astralis Ltd, 1076 Stuyvesant Ave. Irvington, NJ, USA
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.
Correspondence: J. A. O’Daly, Department of Research & development, Astralis Ltd, 1076 Stuyvesant Ave. Irvington, NJ 07111, USA. Tel: 1-973-224-5723; e-mail:joseodaly@aol.com
Affiliations: 1Department of Rheumatology, Hacettepe University, Ankara, Turkey and 2Department of Internal Medicine, Hacettepe University, Ankara, Turkey
(Submission Date: 20 October 2011; Acceptance Date: 10 April 2012; Publication Date: 27 April 2012)
ABSTRACT
Objectives
The mainstay of rheumatoid arthritis (RA) treatment is the disease-modifying antirheumatic drugs (DMARD) and triple DMARD combination is now known to be better than monotherapies. Our aim in this trial was to report a new, safe, and cheap combination therapy for patients with RA resistant to triple DMARD therapy.
Methods
Totally 70 patients with RA resistant to triple DMARD therapy was analyzed. All were treated with leflunomide, methotrexate sulfasalazine, and hydroxychloroquine combination for a median period of 98 months.
Results
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 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).
Conclusion
Tetrad DMARD therapy is a safe, cheap, and an effective option for patients with resistant RA.
Correspondence: Metin Işık, MD, Division of Rheumatology, Department of Internal Medicine, Hacettepe University Hospital, Sihhiye Ankara 06100, Turkey. Tel: +90-312-3051450; Fax: +90-312-3051348; e-mail: metin1721978@yahoo.com
Awakening Research on Sleep and Spondyloarthropathy
Allen J Lehman1, Kierla Ireland2, and Deborah Da Costa2,3
Affiliations:1The Arthritis Research Centre of Canada, Vancouver, British Columbia, Canada; 2Division of Clinical Epidemiology, McGill University Health Centre, Montreal, Quebec, Canada and 3Department of Medicine, McGill University, Montreal, Quebec, Canada
Correspondence: Deborah Da Costa, Division of Clinical Epidemiology, McGill University Health Centre, 1025 Pine Ave, Montreal (Quebec), H3A 1A1 Canada. Tel: 514 934-1934; ext: 44723; Fax: 514 934-8293; e-mail: Deborah.DaCosta@mcgill.ca
ABSTRACT
Sleep problems are common in persons living with spondyloathropathy (SpA). Approximately 55%–66% of individuals living with SpA report poor sleep quality, characterized mainly by difficulties initiating and/or maintaining sleep. Emerging data also indicate that sleep and respiratory disorders are prevalent in patients with SpA. Despite their prevalence and potential to negatively impact health and quality of life, sleep problems remain underrecognized, undertreated, and understudied in this patient population. Only a handful of studies have been conducted to investigate determinants of sleep problems in SpA. The findings suggest that disease expression (activity, pain) and psychosocial factors, including depressed mood and stress contribute to sleep problems in SpA. Future studies, integrating a biopsychosocial approach, are needed to clarify the specific factors and underlying mechanisms that trigger and maintain sleep problems in SpA. The course of sleep problems in SpA remains unknown as studies have been cross sectional. Directions for future research are discussed herein. Routine assessment andmanagement of sleep problems in SpA should be part of the comprehensive care of patients with SpA. While effective pharmacological and nonpharmacological treatments are available to manage sleep problems, few studies have specifically evaluated these strategies for persons living with SpA. Given the complex interplay of factors contributing to sleep problems in SpA, a multimodal treatment approach combining nonpharmacological strategies and medication for more chronic and difficult cases should be utilized for the management of sleep difficulties in SpA.
Jozélio Freire Carvalho1 and Solange Murta Barros2
Affiliations:1Rheumatology Division, Hospital Naval Marcílio Dias, Rio de Janeiro, RJ, Brazil and 2Rheumatology Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de Saõ Paulo, Saõ Paulo, Brazil
Correspondence: Jozélio Freire de Carvalho MD, PhD, Faculdade de Medicina da, Disciplina de Reumatologia, Universidade de Saõ Paulo, Av. Dr. Arnaldo 455, 30 andar, Sala 3105, Saõ Paulo – SP, 01246-903, Brazil. Fax: +55 1130617490; e-mail: jotafc@gmail.com
Sven K. Tschoeke1, Christoph Josten2 and Christoph E. Heyde1
Affiliations:1Department of Orthopaedic Surgery, University Hospital Leipzig, Leipzig, Germany and 2Department of Trauma and Reconstructive Surgery, University Hospital Leipzig, Leipzig, Germany
Correspondence: Christoph E. Heyde, MD, Department of Orthopaedic Surgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany. Tel: +49 341 97 23200; e-mail: christoph-eckhard.heyde@medizin.uni-leipzig.de
ABSTRACT
Over the past two decades, modern diagnostic technology and the advanced spectrum of surgical techniques as well as new supportive implants have significantly improved our possibilities in the treatment of diverse spinal pathologies. In acute spinal injuries, however, explicit definitions and clearly defined treatment algorithms remain a key matter of debate. Although numerous contradictory findings from large-scale patient studies illustrate the difficulty of establishing consensus guidelines, recent results from the second and updated Internet-based multicenter study (MCSII) of the Spine Study Group (SSG) of the German Association of Trauma Surgery (DGU) have been promising. Moreover, since acute spinal trauma is a common concomitant injury in the polytraumatized patient, diagnostic and therapeutic recommendations must adapt to the decisive injury components in sequence of their severity. This specific situation often demands treatment strategies, which may significantly differ from those applied to monotraumatic spine injury. This review aims at summarizing present day concepts of managing spine injuries in the polytraumatized patient with emphasis on key diagnostic and therapeutic procedures.
1082 (G/A) Single Nucleotide Polymorphism of the Interleukin-10 Promoter Region as Susceptible Biomarker for Systemic Lupus Erythematosus (SLE)
Usha S. Potlapuvu, Tanya Debnath, Satish Vemuri, Ratnakar S. Kamaraju and Lakshmi K. Chelluri*
Affiliation: Transplant Immunology & Stem Cell Lab, Global Hospitals, Hyderabad, Andhra Pradesh, India
Correspondence: Lakshmi Kiran Chelluri, PhD, Department of Transplant Immunology & Stem Cell Lab, Global Hospitals, Lakdi-ka-Pool, Hyderabad 500 004, Andhra Pradesh, India. Tel: 0091-40-30244501; Fax: 0091-40-2324 4455; e-mail: lkiran@globalhospitalsindia.com
ABSTRACT
Interleukin-10 (IL-10) plays a substantial role in inflammatory process of autoimmune diseases such as systemic lupus erythematosus (SLE). Several lines of evidence suggest that IL-10 gene is a candidate gene in susceptibility to SLE. In particular, single nucleotide polymorphism (SNP) of the IL-10 promoter region gene has been implicated with the ensuing cellular mechanisms. However, the SNPs in the promoter region of the IL-10 with that of SLE warrant an in-depth study and analysis. Inhibition of the immune stimulatory activities of IL-10 may provide novel approaches in the treatment of humoral autoimmune diseases and infectious diseases. The current pilot study evaluates the association of IL-10 polymorphism with SLE and the plausible role of IL-10 SNPs [1082 (G/A), 819 (C/T), 592 (C/A)] as a diagnostic marker for SLE vis-à-vis normal healthy individuals. The SNPs, -1082 (G/A), -819 (C/T), and -592 (C/A), of IL-10 upstream transcription sites were examined by using the polymerase chain reaction method with genomic DNA and allele-specific primers for possible association in a case controlled study in SLE. The frequency of IL-10 promoter 1082 (G/A) genotypes consisting of AA, AG, and GG, allele frequency in the SLE patients was significantly higher than that in the healthy controls.
Affiliations:1Department of Rheumatology, Karolinska University Hospital, S-171 76 Stockholm, SWEDEN and 2Institute of Clinical Neuroscience, Karolinska Institute, Stockholm, SWEDEN
Correspondence: Ralph Nisell, Department of Rheumatology, Karolinska University Hospital, S-171 76 Stockholm, SWEDEN. Tel: +46 73 978 91 37; Fax: +46 8 517 730 80; e-mail: ralph.nisell@karolinska.se
ABSTRACT
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.
Review: Surfactant Protein D and KL-6 in Scleroderma-Related Interstitial Lung Disease
Faye N. Hant and Richard M. Silver
Affiliation: Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA
Correspondence: Faye N. Hant, Medical University of South Carolina, Department of Medicine, Division of Rheumatology and Immunology, 96 Jonathan Lucas Street, Suite 912, Charleston, SC 29425, USA. Tel: (843) 792-1991; Fax: (843) 792-7121; e-mail: hant@musc.edu
ABSTRACT
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.
Systemic Lupus Erythematosus, Immunosuppression, and Vaccinations: Focus on Human Papillomavirus Vaccination
Noortje Groot, Marloes W. Heijstek and Nico M. Wulffraat
Affiliation: Department of Pediatric Immunology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, The Netherlands
Correspondence: N. M. Wulffraat, associate professor pediatric immunology, Department of Pediatric Immunology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Room number KC 03.063.0, PO BOX 85090, 3508 AB, Utrecht, The Netherlands. Tel: +31-(0)887554003; Fax: +31-(0)887555350; e-mail: n.wulffraat@umcutrecht.nl
ABSTRACT
Patients with systemic lupus erythematosus (SLE) may be at higher risk of infections, due to the underlying disease or immunosuppressive treatment. Vaccinations against several pathogens may prevent these infections. The vaccine against human papillomavirus (HPV) serotype 16 and 18 has been developed to prevent chronic HPV infections, one of the causative agents for cervical cancer and its premalignant lesions. The purpose of this study is to review the safety and efficacy of vaccination in SLE patients, especially the pneumococcal and influenza vaccines. In addition, we wanted to assess whether vaccination against HPV in women with SLE prevents cervical cancer and premalignant lesions. A literature search in Medline (PubMed) was performed. We pound that nonlive vaccines can be used safely in SLE, but several drugs used for control of the disease can reduce the immunogenicity. Cervical cancer and premalignant lesions are more prevalent in patients with SLE. This underlines the necessity of prevention of chronic HPV infections in these patients. The HPV vaccine has proven to be immunogenic and safe in the general population, although long-term efficacy in preventing cancer is still unknown. No studies have been performed on HPV vaccination in SLE patients. Circumstantial evidence in favor of HPV vaccination is that most nonlive composite vaccines appear to be immunogenic and safe in patients with quiescent SLE in conclusion. Vaccination of SLE patients with the HPV vaccine may be recommended. Studies on short-term safety and immunogenicity of the HPV vaccine in SLE patients are necessary. Subsequently, a long-term cohort study has to prove whether the HPV vaccine actually reduces the incidence of cervical cancer and premalignant lesions in patients with SLE.
The Epidemiological and Pathogenic Association of Rheumatoid Arthritis With Atherosclerotic Cardiovascular Disease
Mandana Nikpour1,2, Sharmayne RE Brady3 and Danny Liew1
Affiliations:1The University of Melbourne Department of Medicine, St. Vincent’s Hospital Melbourne, Victoria, Australia; 2Department of Rheumatology, St. Vincent’s Hospital Melbourne, Victoria, Australia and 3Alfred Hospital, Melbourne, Victoria, Australia
Correspondence: Mandana Nikpour, The University of Melbourne Department of Medicine, St. Vincent’s Hospital, 41 Victoria Parade Fitzroy, Victoria 3065, Australia. Tel: +61 3 9288 2211; Fax: +61 3 9288 3652; e-mail: mnikpour@medstv.unimelb.edu.au
ABSTRACT
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.
How to Use Synovial Immunohistology as a Tool for the Better Understanding of the Clinical Use of Different Antirheumatic Treatments
Petra Neregård and Anca Irinel Catrina
Affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institute and University Hospital, Solna, Stockholm, Sweden
Correspondence: Anca Irinel Catrina, Rheumatology Department, Karolinska University Hospital and Institute, D2:01, Solna, Stockholm, S-17176, Sweden. Tel: +46 8 5177 2475; Fax: +46 8 5177 3080.
ABSTRACT
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.
The Long-Term Effectiveness and Safety of Abatacept in Rheumatoid Arthritis
Rene Westhovens
Affiliation: Rheumatology, Department of Musculoskeletal Sciences, K.U.Leuven, Belgium
Correspondence: Rene Westhovens, MD, PhD, Department of Musculoskeletal Sciences, K.U. Leuven, Belgium. Tel: +32 16 34 25 42 and +32 16 34 25 43. e-mail: rene.westhovens@uz.kuleuven.ac.be
ABSTRACT
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.
Bernd Wiedenhöfer1, Michael Tanner1, Carl Hans Fürstenberg1, Michael Akbar1, Peter Nawroth1,2 and Christian Kasperk1,2
Affiliations:1Department of Orthopedics, Trauma Surgery and Spinal Cord Injury Center, Schlierbacher Landstraße, 69118 Heidelberg, Germany and 2Department of Internal Medicine I and Clinical Chemistry, Division of Osteology, University of Heidelberg, INF 410, 69120 Heidelberg, Germany
Correspondence: Christian Kasperk MD PhD, Department of Medicine, Division of Osteology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Tel: +49 6221 56 86 05; Fax: +49 6221 56 57 93; e-mail: christian.kasperk@med.uni-heidelberg.de
B. Wiedenhöfer and M. Tanner contributed equally.
ABSTRACT
Vertebral compression fractures (VCFs) are the most frequent osteoporotic fracture type throughout the Western societies with millions of affected women and men. These fractures severely impair the quality of life and are associated with an increased mortality, thus stating a major health and socioeconomic burden on the societies.
Vertebral compression fractures may be due to trauma, primary osteoporosis, or secondary osteoporosis as a consequence of metabolic-, endocrine-, malassimilation-, medication-, or malignancy-associated disorders of bone metabolism. Therefore an interdisciplinary approach for the proper treatment of the underlying cause and of the mechanical consequences of VCF is required. Many VCFs cause immediate or chronic pain and immobility that also needs the interdisciplinary evaluation whether conservative management, osteoplastic procedures, or major spine surgical approaches are required to improve the patient's situation. Osteoplastic procedures provide an alternative approach between conservative VCF management and reconstructive spine surgery offering the advantages of a minimally invasive procedure with a rapid pain relief, an immediate stabilization of the VCF, and a possible reheightening of an acutely compressed vertebral body. Therefore if technically feasible, osteoplastic procedures in patients with painful VCF are an option to rapidly improve quality of life and simultaneously decrease mortality—which are the ultimate goals of all medical treatment and interventions.
Treatment with Parathyroid Hormone (PTH) for Osteoporosis: Novel Methods and Benefits
John P. Bilezikian
Affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Correspondence: John P. Bilezikian, MD, Department of Medicine, College of Physicians and Surgeons, 630 W 168th Street, New York, NY 10032, USA. Tel: +(212) 305 6238; Fax: +(212) 305 6486; e-mail: jpb2@columbia.edu
ABSTRACT
The osteoanabolic era for the treatment of osteoporosis was ushered in by the advent of teriparatide [hPTH(1-34)] and then the full-length molecule, PTH(1–84). The mechanism of anabolic skeletal therapy differs fundamentally from the antiresorptives in that they directly stimulate processes associated with bone formation. The improvements in skeletal microstructure and other bone qualities distinguish these drugs from other available ones. They effectively increase bone density, bone turnover markers, and reduce fracture incidence. Their safety profile is excellent. Over the past decade, the use of anabolic therapy has been studied both as monotherapy and in various combinations. While combination therapy with an antiresorptive has theoretical attractiveness, no approach has clearly shown advantages over therapy with PTH alone. Following treatment for the recommended 18–24 months, it is necessary to follow osteoanabolic therapy with an antiresorptive to maintain the gains achieved during the treatment period. On the horizon are new forms of PTH and delivery systems that may prove to have utility.
Ultrasound in Rheumatoid Arthritis: Association Between the Polymorphism -308 A/G of Tumor Necrosis Factor and the Severity of Bone Erosive Damage
Annamaria Iagnocco1, Fulvia Ceccarelli1, Carlo Perricone1, Martina Fabris2, Cristiano Alessandri1, Cinzia Fabro2, Elena Pontarini2, Salvatore De Vita2 and Guido Valesini1
Affiliations:1Dipartimento di Medicina Interna e Specialità Mediche, Division of Reumatologia, Sapienza Università di Roma, Rome and 2Cattedra di Reumatologia, DPMSC, Università degli Studi di Udine, Udine, Italy
Correspondence: Annamaria Iagnocco, MD, Dipartimento di Medicina Interna e Specialità Mediche, Rheumatology, Sapienza Università di Roma, Viale del Policlinico 155, 00161, Rome, Italy. Tel.: +39 0649974631; Fax: +39 0649974642; e-mail: annamaria.iagnocco@uniroma1.it
ABSTRACT
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.
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.
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.
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.
Affiliations: 1Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan and 2Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan
ABSTRACT
The tumor necrosis factor (TNF) antagonists (anti‐TNF biologics) infliximab (IFX), adalimumab (ADA), and etanercept (ETN) are commonly used worldwide for rheumatoid arthritis (RA), have produced clinical improvement in signs and symptoms, disability, and quality of life, and have significantly inhibited the progression of joint damage in early and long‐standing disease. However, although anti‐TNF biologics often induce rapid clinical improvement in patients with RA, 20–40% of RA patients show little or no clinical response. To maximize the clinical response to these agents, the mechanism underlying the variable response in individual patients must be understood; furthermore, a strategy is needed to predict responders and non‐responders. Recently, several reports have demonstrated that cytokines and chemokines seem to be important and sensitive mediators in RA patients treated with anti‐TNF biologics. We showed that serum CX3CL1 levels were decreased in response to IFX treatment, whereas there were no significant and uniform alterations after IFX treatment in other chemokines that have crucial roles in the pathogenesis of RA development. In addition, the most interesting result in the present study was that the lack of response in the active RA group despite treatment with IFX could be related to higher basal levels of CX3CL1 and its receptor, CX3CR1. In conclusion, the CX3CL1/CX3CR1 axis and other chemokine receptors, such as CCR3 and CCR5, in patients with active RA may be sensitive to anti‐TNF therapy. These results also suggest that basal serum CX3CL1 levels correlate with the responsiveness of RA patients to IFX therapy.
Correspondence: Tsuyoshi Kasama, Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8666, Japan. Tel: +81-33784-8942; Fax: +81-33784-8946; e-mail: tkasama@med.showa-u.ac.jp
The Use of Biomarkers to Predict and Monitor Treatment Outcomes in Rheumatoid Arthritis
REVIEW ARTICLE
Paul Emery
Affiliation: Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds. NIHR Leeds Musculoskeletal Biomedical Research Unit,Leeds Teaching Hospitals Trust, Leeds, United Kingdom
ABSTRACT
Current recommendations for the management of rheumatoid arthritis (RA) suggest a stepped approach that begins with disease‐modifying anti‐rheumatic drugs (DMARDs). These are followed by the addition of treatment with anti‐tumor necrosis factor (TNF) therapies and other disease‐modifying biological therapies, as determined by the patient’s response. Thus, patients who remain resistant to first‐ and second‐line treatments often wait many months before receiving the drugs to which they respond. Unfortunately, the patient’s condition is likely to worsen over this period. It is also possible that this delay could result in a missed therapeutic window. More sophisticated use of biomarkers could identify these treatment‐resistant patients at earlier stages. For instance, patients who are seropositive for the biomarker anti‐cyclic citrullinated peptide (anti‐CCP) have a high risk of disease progression and often display a poor response to methotrexate treatment. Abatacept, a T‐cell co‐stimulation blocker, has been recently shown as beneficial in anti‐CCP‐positive patients with undifferentiated arthritis or early RA. Because T cells are also implicated in the early pathogenesis of RA, it is possible that blockage of T‐cell co‐stimulation could help alter the progression of early RA in this subset of patients. More precise targeting of RA therapy could result in lower rates of treatment resistance, improved patient outcomes, and greater use of healthcare resources on more effective therapies.
Keywords: rheumatoid arthritis, disease-modifying anti-rheumatic drugs (DMARDs), anti-tumor necrosis factor (TNF), anti-cyclic citrullinated peptide (CCP), biomarkers, abatacept, T cells, cytokines, quality of life
Correspondence: Professor Paul Emery, Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust, Leeds, United Kingdom. Tel: +(44)113-392-4883; Fax:+(44)113-392-4991; e-mail: p.emery@leeds.ac.uk
Ultrasound Imaging of Rheumatoid Arthritis and the Importance of Image Data for the Diagnosis and Treatment of Early Disease
Review Article
Walter Grassi, Luca Di Geso and Emilio Filippucci
Affiliation: Clinica Reumatologica, Universita` Politecnica delle Marche, Ancona, Italy
ABSTRACT
Physical examinations and conventional radiography have low sensitivity for the detection of joint inflammation and damage in patients with rheumatoid arthritis, especially early in the course of the disease. New imaging modalities such as ultrasound allow for accurate and sensitive assessments of both synovitis and bone erosions. The latest generation of ultrasound systems has several advantages over other imaging methods that make them ideal tools for assessing and monitoring early disease. These advantages include reproducibility, repeatability, reduced capital expenditure, high resolution, low running costs and multi‐site examination capability. The impact of the systematic use of ultrasound in the clinical setting of early rheumatoid arthritis still needs further assessment, but there is growing evidence in favor of its value for early diagnosis and in monitoring short‐term therapy. These advantages are particularly important in light of the availability of new and effective disease‐modifying therapies that claim to rapidly induce disease remission. While very recent studies have highlighted the predictive value of sonographic signs of joint disease in terms of the progression of joint damage as documented by conventional radiography, very few reports have documented its role in the assessment of tendons and hyaline cartilage. Advances in the ultrasound field have not yet reached the plateau phase, and new technologies such as higher frequency volumetric probes and fusion imaging will further enhance the utility of ultrasound for diagnostic applications in the near future. Keywords: early rheumatoid arthritis, ultrasound, power Doppler, synovitis, bone erosion. Correspondence: Walter Grassi , MD, Clinica Reumatologica, Università Politecnica delle Marche, Ospedale “A. Murri”, Via dei Colli, 52, 60035 Jesi (Ancona), Italy. Tel: +(39)‐0731‐534125; Fax: +(39)‐0731‐534124; e‐mail: walter.grassi@univpm.it
What Are the Potential Roles Magnetic Resonance Imaging Can Play in Differentiated and Undifferentiated Arthritis?
Review Article
Y Emad 1, Y Ragab2, I Bassyouni1, H Darweesh1, A Almansari4 and JJ Rasker 3
Affiliations: 1Rheumatology and Rehabilitation Department; 2Radiology Department, Faculty of Medicine, Cairo University, Cairo, Egypt; 3University Twente, Enschede, the Netherlands and 4Internal medicine department, Dr. Erfan and Bagedo general hospital, Jeddah, KSA
ABSTRACT
Magnetic resonance imaging (MRI) has advanced our understanding of many types of arthritis, with respect to both inflammatory processes and articular damage. The role of MRI in differentiating between different forms of arthritis is still debatable and under discussion. The current available data suggest that MRI can separate subsets of early synovitis patients on the basis of two principal imaging patterns: one in which the inflammatory changes are located primarily in the synovium; and another in which the periarticular entheses are inflamed in association with intense edema of the adjacent bone. These two patterns are proposed to broadly classify patients with early synovitis into an “RA” phenotype where synovitis is the primary process, and a “spondyloarthropathy” (SpA) phenotype where enthesitis is the primary process and synovitis occurs on a secondary basis. Enthesitis is a common feature on MRI in SpA, which can help to determine the evolving pattern of patients with undifferentiated arthritis of the knee joint, and may have important clinical implications for classification purposes.
Keywords: enhanced magnetic resonance imaging (MRI), undifferentiated arthritis, knee enthesitis, rheumatoid arthritis, seronegative spondylarthropathy (SpA) Correspondence: Yasser Emad, Rheumatology and Rehabilitation Department, Faculty of Medicine, Cairo University, Cairo, Egypt. Rheumatology and Rehabilitation Department Dr Erfan and Bagedo General Hospital, Jeddah, KSA. e‐mail: Yasseremad68@yahoo.com
Sexuality of Male Adolescents and Adults with Juvenile Idiopathic Arthritis
Review Article
Cláudia Goldenstein‐Schainberg and Lilian de Avila Lima Souza
Affiliation: Rheumatology Division, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
ABSTRACT
Sexuality is an important component in a person’s life, including patients with juvenile idiopathic arthritis (JIA). This chronic inflammatory joint disease affects over 0.1% of children worldwide, and persistent chronic synovitis plays a major role in the development of joint damage, growth, and limb disturbances contributing to functional disability, which may all impair sexual life. During adulthood, signs and symptoms of active disease may remain, causing physical and psychological effects, which may influence sexual behavior. In fact, sexuality as a quality of life issue is important for a person’s complete and satisfying life as a whole. Although this subject is an often neglected area of quality of life among patients with rheumatic disorders, sexual function is influenced by many relevant disease‐associated aspects such as fatigue, pain, stiffness, functional impairment, depression, anxiety, negative body image, hormonal imbalance, drug treatment, and reduced libido. Therefore, because JIA affects not only the musculoskeletal but also other organ systems and psychological aspects, this disease may have a relevant impact and influence patients’ sexuality, especially when adolescence and adulthood are reached, which will be discussed in this review.
Keywords: Sexuality, JIA, sexual function, quality of life, functional impairment Correspondence: Claudia Goldenstein‐Schainberg, Disciplina de Reumatologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 455, sala 3133, São Paulo, SP, Brasil, 01246‐903. Tel/Fax: (55)‐11‐3061‐7490; e‐mail: cgs@usp.br; cgschain@uol.com.br
Affiliation: The Motherisk Program, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, University of Toronto, Toronto, Canada
ABSTRACT
Tumor necrosis factor (TNF)‐α inhibitors (infliximab, etanercept, and adalimumab) are marked as pregnancy category B by the US Food and Drug Administration (FDA), indicating that animal studies have not demonstrated fetal risk. Previously published limited human experience has been reassuring, showing no increased risk of congenital malformations in children born to women taking TNF inhibitors. However, recently, some concerns have been raised regarding their safety in pregnancy. This review provides the most current information on the safety of anti‐TNF therapy in pregnancy. A growing body of evidence suggests that infliximab and adalimumab are low risk in pregnancy. Regarding etanercept, the data available today do not suggest that etanercept is a major human teratogen, and it is quite possible that its teratogenic risk does not exceed the baseline rate of congenital malformations in general population.
Keywords: tumor necrosis factor (TNF) inhibitors, infliximab, etanercept, adalimumab, pregnancy, women, fetal risk Correspondence: Gideon Koren, The Motherisk Program, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. e‐mail: gkoren@sickkids.ca
Peripheral Blood Lymphocyte Subset Abnormalities in Antiphospholipid Syndrome
Review Article
Javier Carbone, Carmen Chean, Nallibe Lanio, Antonio Gallego, Nadia del Pozo and Elizabeth Sarmiento
Affiliations: Clinical Immunology Department, University Hospital Gregorio Marañon
ABSTRACT
Miscarriage and thrombosis are important causes of morbidity and mortality in patients with the antiphospholipid (Hughes) syndrome. However, the precise mechanism responsible for these complications remains unclear. Among the different immunity‐related components that could be implicated in the pathogenesis of this systemic autoimmune disease, immunophenotypic abnormalities in peripheral blood lymphocytes have rarely been sought. We review studies that have been designed to assess functionally distinct T, B, and natural killer lymphocyte subsets in patients with antiphospholipid syndrome.
Keywords: lymphocyte subsets, antiphospholipid syndrome, CD19, CD4, CD8, NK cell, flow cytometry Correspondence: Javier Carbone, Clinical Immunology Department, University Hospital Gregorio Marañon, Dr. Esquerdo 46, 28007 Madrid, Spain. Tel: (34)‐91 ‐4265180; Fax: (34)‐91‐5866698; e‐mail: carbone@teleline.es
Functional Roles of ANKH/Ank: Insights from CPPDD‐associated ANKH Mutations and the ank/ank Mouse
Review Article
Functional Roles of ANKH/Ank: Insights from CPPDD‐associated ANKH Mutations and the ank/ank Mouse
Florence WL Tsui1,2, Facundo Las Heras3,4, Robert D Inman1–3 and Kenneth PH Pritzker4,5 Affiliations: 1Genetics and Development Division, Toronto Western Research Institute, Canada; 2Department of Immunology and 3Institute of Medical Science, University of Toronto, Canada; 4Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada and 5Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada
ABSTRACT
Calcium pyrophosphate dihydrate crystal deposition disease (CPPD arthropathy) is a common form of degenerative arthritis afflicting the elderly. Although the relationships between CPPD crystal arthropathy and osteoarthritis are controversial, it is clear that the mechanisms of CPPD crystal deposition and the mechanisms that promote cartilage matrix changes in osteoarthritis (OA) are different. Although considerable research attention has been paid to the basic mechanisms of OA, fewer studies have been conducted in CPPD; our understanding of the underlying disease processes remains woefully deficient. Rare genetic diseases with known gene mutations are extremely informative in unraveling the underlying disease mechanisms. Rare families with multiple CPPDD patients provide a good example in this respect. Earlier genetic studies on these families mapped the disease loci to chromosome 8q and 5p. Since the molecular cloning of ANKH (human homolog of progressive ankylosis; located on chromosome 5p), several dominant ANKH mutations that co‐segregate with disease were identified in a number of CPPDD families from different countries. This short review focuses on subsequent work addressing the functional consequences of these mutant ANKH proteins in an attempt to understand how these ANKH mutations might lead to CPPDD pathogenesis. Aside from gene mutations, spontaneous mouse mutants targeting the same gene provide complementary tools for unraveling the gene functions. Our recent finding in ank/ank mice showed that the ank defect results in articular chondrocyte hypertrophy (a novel observation) and increased calcified articular cartilage matrix, all preceding overt osteophyte formation and apatite crystal deposition, consequent to a single gene defect.
Keywords: progressive ankylosis, familial calcium pyrophosphate dihydrate crystal deposition disease, ANKH mutations, ank/ank mouse, tissue non‐specific alkaline phosphatase, sodium/phosphate co‐transporter PiT‐1, inorganic phosphate and pyrophosphate metabolism Correspondence: F W L Tsui, Toronto Western Hospital, Mc14‐419, 399 Bathurst Street, Toronto, Ontario, M3T 2S8, Canada. Tel: (1)‐416‐603‐5904; Fax: (1)‐416‐603‐5745; e‐mail: ftsui@uhnres.utoronto.ca
Elena Bartoloni, Devid Biscontini, Alessia Alunno, Filippo Luccioli, Sheila Moscatelli, Gianluca Santoboni and Roberto Gerli Affiliation: Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
ABSTRACT
Acro‐osteolysis (AO) has been reported in association with different systemic diseases. Pathogenesis is not completely understood, and several mechanisms leading to this destructive process have been hypothesized. In recent years, AO has been described in patients with chronic inflammatory rheumatic and connective tissue diseases, and different mechanisms contributing to bone damage have been postulated. This review will discuss possible pathogenetic mechanisms involved in bone resorption, focusing on the description of AO in patients with rheumatic diseases. Keywords: acro‐osteolysis, rheumatic diseases, psoriatic arthritis Correspondence: Roberto Gerli, Rheumatology Unit, Department of Clinical and Experimental Medicine, Via E Dal Pozzo, I-06122 Perugia, Italy. Tel: (39)-075-578-3975; Fax: (39)-075-578-3105; e-mail: gerlir@unipg.it
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.
Osteoarthritis as the Presenting Pathology in Patients with Skeletal Dysplasias
Review Article
Peter Kannu 1 2 3, Ravi Savarirayan 2 3 and F John Bateman 3 Affiliations: 1Division of Medical Genetics, Department of Paediatrics, Queen’s University, Kingston, Canada; 2Department of Paediatrics, University of Melbourne, Parkville, Melbourne, Australia and 3Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Melbourne, Australia
ABSTRACT
The understanding of common diseases and disease mechanisms is facilitated by the study of rare disorders, in which mutations associated with a significant functional effect cause an observable phenotype. The challenge clinicians currently face is with regard to patients who are increasingly aware of the importance of genes in common disease development, and expect their physician to clarify their individual disease risks using a genetic model. This review focuses on a subset of genes that have been shown to be responsible for a range of inherited bone and cartilage disorders (chondrodysplasias), which present clinically with disproportionate short stature and/or orthopedic deformity, with the aim of illustrating the growing evidence that mutations/polymorphisms of lesser effect in these genes might predispose to osteoarthritic phenotypes in the general population. The discussion is structured to review chondrodysplasias arising from mutations in different parts of the cellular and extracellular pathways. If we are able to identify robust genetic “profiles” of individuals who are at greater risk of osteoarthritis, this might then enable preventative strategies to be tailored to these groups, as well as enhancing our understanding of this complex disease phenotype.
Keywords: complex disease, osteoarthritis, transcription factors, cell signaling, matrix enzymes, cilia, matrix proteins Correspondence: Peter Kannu, Queen’s University, Division of Medical Genetics, Kingston K7L3J6, Canada. e‐mail: kannu@queensu.ca
Prevention of Tuberculosis among Patients with Inflammatory Rheumatic Diseases receiving Tumor Necrosis Factor‐α Inhibitors
Review Article
Anand N Malaviya Affiliation: Rheumatology Services, ISIC Superspeciality Hospital, Vasant Kunj, New Delhi, India
ABSTRACT
High therapeutic efficacy of inhibitors of tumor necrosis factor‐α (iTNF‐α) in the treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS)–spondyloarthritides (SpA), and several other inflammatory rheumatic diseases (IRDs) has been well established over the past decade. Large registries on the use of these biologicals and extensive experience with their use worldwide have shown that overall these agents have a good safety profile with a highly favorable risk–benefit ratio with the exception of the problem of reactivation of tuberculosis infection (TBI) among patients with latent tuberculosis infection (LTBI) with their use. Observational studies have established that the risk of developing TB is several fold higher with monoclonal antibodies against TNF‐α than with soluble TNF‐α receptor fusion protein. It has also been observed that almost all the TB flare seen with iTNF‐α is reactivation of LTBI. Therefore, key to the prevention of TB flare associated with the use of iTNF‐α is detection of LTBI among prospective users of these agents. There is, however, no “gold standard” for the diagnosis of LTBI. Therefore, different strategies for the screening of LTBI and its treatment have been recommended in different regions of the world. This review discusses the problems related to TB screening especially among patients with IRDs who may have an inherent immunocompromised state, outlining the pros and cons of different strategies and the issues related to the treatment of LTBI prior to the use of iTNF‐α agents. The review focuses especially on TB preventive strategies in high‐burden TB regions of the world.
