Rheumatoid Arthritis: Gabay C

Gabay C, So A. · No affiliation provided · Rev Med Suisse. · Pubmed #17458148 No free full text.

This publication has no abstract.

Palmer G, Gabay C, Imhof BA. · No affiliation provided · Arthritis Rheum. · Pubmed #16948054 links to  free full text

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Finckh A, Gabay C. · Division of Rheumatology, University Hospitals of Geneva and University of Geneva, Switzerland. · Curr Opin Rheumatol. · Pubmed #18388517 No free full text.

Abstract: PURPOSE OF REVIEW: To review the rational and the results regarding the use of novel biologic agents in inflammatory rheumatic diseases. RECENT FINDINGS: Recent findings show that excessive IL-1 processing and release contribute to different rheumatic conditions, including periodic fever syndromes, systemic-onset juvenile idiopathic arthritis, adult Still's disease, and crystal-induced arthritis. Preliminary results indicate that administration of IL-1 receptor antagonist and other IL-1 inhibitors improves these conditions. IL-6 also plays a major role in the control of inflammatory responses. Several clinical trials have shown that inhibition of IL-6 by a monoclonal antibody against its receptor is efficacious in rheumatoid arthritis and systemic-onset juvenile idiopathic arthritis patients. Accumulating evidence indicates that other cytokines, including IL-15, IL-18, and IL-21 may also play an important role in rheumatoid arthritis. Several signaling pathways involved in the immune and inflammatory responses may also constitute novel targets. Preliminary data on an agent targeting the Janus kinase/Signal transducer and activators of transcription pathway are encouraging. SUMMARY: Beyond tumor necrosis factor alpha targeting, the use of inhibitors against other cytokines and cytokine-induced intracellular responses is leading to a promising therapy in the future.

Emery P, Gabay C, Kraan M, Gomez-Reino J. · Academic Unit of Musculoskeletal Disease, Leeds University, Chapel Town Road, Leeds, LS7 4S, UK. · Rheumatol Int. · Pubmed #17505829 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease characterised by inflammation resulting in structural joint damage and functional disability. Tumour necrosis factor-alpha (TNFalpha) is a pivotal mediator and driver of inflammation in RA. Inflammation is closely related to the production of C-reactive protein (CRP), and a close correlation exists between serum CRP and TNFalpha levels. CRP levels are therefore a convenient, objective biomarker of disease activity. CRP correlates closely with changes in inflammation/disease activity, radiological damage and progression and functional disability. Identification of TNFalpha as a driver of RA progression has led to the introduction of TNFalpha-blocking agents and, subsequently, improvement of disease management. TNFalpha-blocking agents provide rapid, profound and sustained suppression of disease activity in correspondence with a marked reduction in CRP levels. A reduction in CRP level correlates closely with the positive clinical response to TNFalpha-blocking therapy. Thus, CRP levels can be used to predict, assess and monitor response to treatment with TNFalpha-blocking agents, and may be helpful in determining the optimal TNFalpha-blocker dosage. Given the close correlation between inflammation and disease progression and the relation between inflammation and CRP, the latter, if used effectively in clinical practice, may be means to identify patients likely to progress rapidly and who require intensive anti-TNFalpha therapy. The purpose of this review is to identify how CRP levels may be useful for monitoring the effect of therapy on halting disease progression and why monitoring CRP levels at baseline and after treatment should become a routine part of clinical practice.

Jacques C, Gosset M, Berenbaum F, Gabay C. · UMR 7079 CNRS, Physiology and Physiopathology Laboratory, University Paris 6, Paris, 75252 Cedex 5, France. · Vitam Horm. · Pubmed #17027524 No free full text.

Abstract: Interleukin (IL)-1 is a cytokine that plays a major role in inflammatory responses in the context of infections and immune-mediated diseases. IL-1 refers to two different cytokines, termed IL-1alpha and IL-1beta, produced from two genes. IL-1alpha and IL-1beta are produced by different cell types following stimulation by bacterial products, cytokines, and immune complexes. Monocytes/macrophages are the primary source of IL-1beta. Both cytokines do not possess leader peptide sequences and do not follow a classical secretory pathway. IL-1alpha is mainly cell associated, whereas IL-1beta can be released from activated cells after cleavage of its amino-terminal region by caspase-1. IL-1 is present in the synovial tissue and fluids of patients with rheumatoid arthritis. Several in vitro studies have shown that IL-1 stimulates the production of mediators such as prostaglandin E(2), nitric oxide, cytokines, chemokines, and adhesion molecules that are involved in articular inflammation. Furthermore, IL-1 stimulates the synthesis and activity of matrix metalloproteinases and other enzymes involved in cartilage destruction in rheumatoid arthritis and osteoarthritis. The effects of IL-1 are inhibited in vitro and in vivo by natural inhibitors such as IL-1 receptor antagonist and soluble receptors. IL-1 receptor antagonist belongs to the IL-1 family of cytokines and binds to IL-1 receptors but does not induce any intracellular response. IL-1 receptor antagonist inhibits the effect of IL-1 by blocking its interaction with cell surface receptors. The use of IL-1 inhibitors in experimental models of inflammatory arthritis and osteoarthritis has provided a strong support for the role of IL-1 in the pathogeny of these diseases. Most importantly, these findings have been confirmed in clinical trials in patients with rheumatic diseases. Additional strategies aimed to block the effect of IL-1 are tested in clinical trials.

Genta MS, Genta RM, Gabay C. · Division of Rheumatology, Geneva University Hospitals, Geneva, Switzerland. · Semin Arthritis Rheum. · Pubmed #17023257 No free full text.

Abstract: OBJECTIVES: To review the most recent information on the incidence, clinical course, pathology, pathogenesis, diagnosis, and treatment of rheumatoid vasculitis (RV), including the still scanty data on the use of biologics. METHODS: PubMed and MEDLINE databases (1950-2006) were searched for the key words "vasculitis" and "rheumatoid arthritis"; and "rheumatoid arthritis" and "extra-articular manifestations." All relevant articles in English and French were reviewed. Additional words used in follow-up research include "anti-TNF," "rituximab," "IL-1 receptor antagonists," and "CTLA-4 Ig," all in conjunction with "vasculitis." Pertinent secondary references were also retrieved. RESULTS: RV is an inflammatory condition of the small- and medium-sized vessels that affects a subset of patients with established rheumatoid arthritis (RA) (approximately 1 to approximately 5%). It has a vast array of clinical manifestations with a predilection for the skin (peripheral gangrene, deep cutaneous ulcers) and the peripheral nervous system (mononeuritis multiplex). Because of the lack of specific signs and symptoms, the diagnosis relies on the exclusion of other causes of similar lesions (diabetes, atherosclerosis, drug reactions, infection, neoplasias) and, ideally, on the histopathological demonstration of necrotizing vasculitis. Despite the availability of a host of promising new drugs for the treatment of RA, no clinical trials have tested their efficacy in RV; therefore, its management remains largely empirical. CONCLUSIONS: Although RV has apparently been decreasing over the last 2 decades, possibly as a consequence of the more energetic approach to the management of RA currently used, it remains an important complication of RA that needs to be promptly recognized and treated.

Burger D, Dayer JM, Palmer G, Gabay C. · Clinical Immunology Unit, Division of Immunology and Allergy, Department of Internal Medicine, University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. · Best Pract Res Clin Rheumatol. · Pubmed #16980212 No free full text.

Abstract: Inflammation is an important homeostatic mechanism that limits the effects of infectious agents. However, inflammation might be self-damaging and therefore has to be tightly controlled or even abolished by the organism. Interleukin 1 (IL-1) is a crucial mediator of the inflammatory response, playing an important part in the body's natural responses and the development of pathological conditions leading to chronic inflammation. While IL-1 production may be decreased or its effects limited by so-called anti-inflammatory cytokines, in vitro IL-1 inflammatory effects are inhibited and can be abolished by one particularly powerful inhibitor, IL-1 receptor antagonist (IL-1Ra). Recent research has shown that in the processes of rheumatoid arthritis (RA) IL-1 is one of the pivotal cytokines in initiating disease, and IL-1Ra has been shown conclusively to block its effects. In laboratory and animal studies the inhibition of IL-1 by either antibodies to IL-1 or IL-1Ra proved beneficial to the outcome. Because of its beneficial effects in many animal disease models, IL-1Ra has been used as a therapeutic agent in human patients. The recombinant form of IL-1Ra, anakinra (Kineret, Amgen) failed to show beneficial effects in septic shock and displays weak effects in RA patients. However, IL-1 blockade by anakinra is dramatically effective in systemic-onset juvenile idiopathic arthritis, in adult Still's disease and in several autoinflammatory disorders, most of the latter being caused by mutations of proteins controlling IL-1beta secretion. Importantly, to be efficacious, anakinra required daily injections, suggesting that administered IL-1Ra displays very short-term effects. Better IL-1 antagonists are in the process of being developed.

Gabay C. · Division of Rheumatology, University Hospital of Geneva, Switzerland. · Arthritis Res Ther. · Pubmed #16899107 No free full text.

Abstract: Interleukin (IL)-6 is produced at the site of inflammation and plays a key role in the acute phase response as defined by a variety of clinical and biological features such as the production of acute phase proteins. IL-6 in combination with its soluble receptor sIL-6Ralpha, dictates the transition from acute to chonic inflammation by changing the nature of leucocyte infiltrate (from polymorphonuclear neutrophils to monocyte/macrophages). In addition, IL-6 exerts stimulatory effects on T- and B-cells, thus favoring chronic inflammatory responses. Strategies targeting IL-6 and IL-6 signaling led to effective prevention and treatment of models of rheumatoid arthritis and other chronic inflammatory diseases.

Ghavami A, Genevay S, Fulpius T, Gabay C. · No affiliation provided · Ann Rheum Dis. · Pubmed #15958767 links to  free full text

This publication has no abstract.

Finckh A, Gabay C, Guerne PA. · Arthritis & Musculoskeletal Clinical Research Center, Department of Medicine, Brigham & Women's Hospital, Boston, USA. · Rev Med Suisse Romande. · Pubmed #15552748 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic in-flammatory disease with progressive joint damage, generally considered irreversible. A more aggressive therapeutic approach is promoted. Progression of joint damage, gradual functional disability and rate of mortality are lowered by disease modifying antirheumatic drugs (DMARD). Among these, we discuss the relative role of TNF inhibitors and their efficacy on preventing radiographic progression of joint damage. We also touch on the notion of a therapeutic window of opportunity early in the course of RA, as early initiation of aggressive treatment seems to provide a sustained benefit on radiographic progression.

Gabay C. · Division of Rheumatology, University Hospital of Geneva, 26 Avenue Beau-Séjour, 1211 Geneva 14, Switzerland. · Curr Opin Investig Drugs. · Pubmed #12833655 No free full text.

Abstract: Regeneron and Novartis are co-developing the interleukin (IL)-1 antagonist IL-1 trap for the potential treatment of rheumatoid arthritis. In July 2002, a phase II trial was initiated and results are expected mid-2003.

Gabay C. · Division of Rheumatology, University Hospital of Geneva, 26 Avenue Beau-Séjour, 1211 Geneva 14, Switzerland. · Expert Opin Biol Ther. · Pubmed #11849114 No free full text.

Abstract: Rheumatoid arthritis (RA) is an immune-mediated disease characterised by articular inflammation and subsequent tissue damage leading to severe disability and increased mortality. A variety of cytokines are produced locally in the rheumatoid joints. Numerous studies have demonstrated that IL-1 and TNF-alpha, two prototypic pro-inflammatory cytokines, play an important role in the mechanisms involved in synovial inflammation and in progressive joint destruction. Indeed, the administration of TNF-alpha and IL-1 inhibitors in patients with RA led to a dramatic improvement of clinical and biological signs of inflammation and a reduction of radiological signs of bone erosion and cartilage destruction. However, despite these encouraging results, a significant percentage of patients do not respond to these agents, suggesting that other mediators are also involved in the pathophysiology of arthritis. This review describes the results of clinical trials with TNF-alpha inhibitors and a specific IL-1 inhibitor (IL-1 receptor antagonist [IL-1Ra]). In addition, other therapeutic strategies are also discussed.

Arend WP, Gabay C. · Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. · Arthritis Res. · Pubmed #11094434 links to  free full text

Abstract: Recent studies have described the spontaneous development of arthritis or vasculitis in IL-1 receptor antagonist (IL-1Ra) knockout mice bred on specific and different genetic backgrounds. The levels of both secreted and intracellular isoforms of IL-1Ra produced in the rheumatoid joint or in the arterial wall may not be adequate to effectively inhibit the excess amounts of locally produced IL-1. Thus, an imbalance between IL-1 and IL-1Ra may predispose to local inflammatory disease in particular tissues in the presence of other as yet unknown genetically influenced factors.

Gabay C. · Division of Rheumatology, University Hospital of Geneva, 26 Avenue Beau-Sejour, 1211 Geneva 14, Switzerland. · Expert Opin Investig Drugs. · Pubmed #11060665 No free full text.

Abstract: IL-1 is a pleiotropic cytokine shown to play a major role in synovitis and in the mechanisms that lead to the progressive joint destruction of rheumatoid arthritis (RA). IL-1 receptor antagonist (IL-1Ra), a member of the IL-1 family, binds IL-1 receptors but does not induce a cellular response. IL-1Ra competitively inhibits the binding of IL-1 to its cell surface receptors and thus acts as an endogenous anti-inflammatory mediator. In different experimental animal models of arthritis systemic administration of IL-1Ra, or local delivery into the joints by gene therapy attenuated the severity of the inflammatory response and reduced articular destruction. In addition, treatment of RA patients with IL-1Ra led to an improvement in different clinical and biological parameters and to a reduction in the radiological signs of joint erosions. Recently, interesting results were obtained using IL-1Ra in combination with methotrexate, a well-known antirheumatic drug, or in combination with other strategies designed to block the effects of tumour necrosis factor (TNF)-alpha. Encouraging results also have been reported in both in vitro and in vivo experimental models of arthritis by using other strategies designed to block the effects of IL-1.

Gabay C. · Département de médecine interne, Hôpital cantonal universitaire, Genève. · Rev Med Suisse Romande. · Pubmed #11014098 No free full text.

This publication has no abstract.

Brulhart L, Ciurea A, Finckh A, Notter A, Waldburger JM, Kyburz D, Gabay C. · No affiliation provided · Ann Rheum Dis. · Pubmed #16540545 No free full text.

This publication has no abstract.

Finckh A, Simard JF, Duryea J, Liang MH, Huang J, Daneel S, Forster A, Gabay C, Guerne PA. · Robert B. Brigham Atthritis and Musculoskeletal Diseases Clinical Research Center, Brigham & Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. · Arthritis Rheum. · Pubmed #16385495 links to  free full text

Abstract: OBJECTIVE: To compare the effectiveness of 3 therapeutic strategies in preventing progressive joint damage, in a population-based cohort. The 3 strategies were infliximab with concomitant disease-modifying antirheumatic drugs (DMARDs), etanercept with concomitant DMARDs, and etanercept alone. METHODS: We used sequential radiographs to assess all patients who were treated with infliximab or etanercept for >10 months. The rates of erosion progression and joint space narrowing (JSN) were analyzed using multivariate regression models for longitudinal data, with adjustment for potential confounders. RESULTS: A total of 372 patients treated with anti-tumor necrosis factor (TNF) therapies met the inclusion criteria. The baseline characteristics of the patients assigned to the 3 strategies were not significantly different, except that, as expected, more patients were receiving combination therapy with infliximab. The combination of infliximab plus DMARDs was significantly more effective than etanercept alone for controlling erosion progression (P < 0.001), but the effectiveness of the 2 combination-treatment strategies was similar (P = 0.07). The combination of infliximab plus DMARDs was also more effective at controlling progressive JSN compared with etanercept alone (P = 0.04) or etanercept plus DMARDs (P = 0.02). Treatment with anti-TNF agents (infliximab or etanercept) plus concomitant DMARDs was more effective than treatment with etanercept alone for controlling erosion progression (P = 0.045). CONCLUSION: When combined with traditional DMARDs, both etanercept and infliximab appear to offer similar protection against progressive structural joint damage, and combination therapy with either of these agents appears to be more effective than treatment with etanercept alone.

Pan SM, Dehler S, Ciurea A, Ziswiler HR, Gabay C, Finckh A, Anonymous00060. · Geneva University Hospital, Geneva, Switzerland. · Arthritis Rheum. · Pubmed #19405000 No free full text.

Abstract: OBJECTIVE: Tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of severe rheumatoid arthritis (RA), yet drug discontinuation is common. The aim of this study was to compare treatment retention rates and specific causes of anti-TNF discontinuation in a population-based RA cohort. METHODS: All patients treated with etanercept, infliximab, or adalimumab within the Swiss Clinical Quality Management RA cohort between 1997 and 2006 were included in the study. Causes of treatment discontinuation were broadly categorized as adverse events (AEs) or nontoxic causes, and further subdivided into specific categories. Specific causes of treatment interruption were analyzed using a Cox proportional hazards model and adjusted for potential confounders. RESULTS: A total of 2,364 anti-TNF treatment courses met the inclusion criteria. Treatment discontinuation was reported 803 times: 309 with etanercept, 249 with infliximab, and 245 with adalimumab. Drug inefficacy represented the largest single cause of treatment discontinuation (55.8% of cases). The median time of receiving anti-TNF therapy was 37 months, but discontinuation rates differed between the 3 anti-TNF agents (P < 0.001), with shorter retention rates for infliximab (hazard ratio [HR] 1.24, 99% confidence interval [99% CI] 1.01-1.51). The specific causes of treatment discontinuation revealed an increased risk of AEs with infliximab (HR 1.4, 99% CI 1.003-1.96), mostly due to an increased risk of infusion or allergic reactions (HR 2.11, 99% CI 1.23-3.62). Other discontinuation causes were equally distributed between the anti-TNF agents. CONCLUSION: In this population, infliximab was associated with higher overall discontinuation rates compared with etanercept and adalimumab, which is mainly due to an increased risk of infusion or allergic reactions.

Palmer G, Talabot-Ayer D, Lamacchia C, Toy D, Seemayer CA, Viatte S, Finckh A, Smith DE, Gabay C. · University Hospital of Geneva, and University of Geneva School of Medicine, Geneva, Switzerland. · Arthritis Rheum. · Pubmed #19248109 No free full text.

Abstract: OBJECTIVE: Interleukin-33 (IL-33; or, IL-1F11) was recently identified as the ligand of the IL-1 family receptor T1/ST2. The aim of this study was to examine IL-33 production in human and mouse joints and to investigate the role of IL-33 and T1/ST2 in experimental arthritis. METHODS: IL-33 expression was examined in human synovial tissue, rheumatoid arthritis (RA) synovial fibroblasts, and arthritic mouse joints. Mice with collagen-induced arthritis (CIA) were treated with blocking anti-ST2 antibody or control antibody beginning at the onset of disease. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (LN) cell responses were examined ex vivo, and joint messenger RNA (mRNA) was used for expression profiling. RESULTS: IL-33 was highly expressed in human RA synovium. In cultured synovial fibroblasts, IL-33 expression was strongly induced by IL-1beta and/or tumor necrosis factor alpha. Furthermore, IL-33 mRNA was detected in the joints of mice with CIA and increased during the early phase of the disease. Administration of a blocking anti-ST2 antibody at the onset of disease attenuated the severity of CIA and reduced joint destruction. Anti-ST2 antibody treatment was associated with a marked decrease in interferon-gamma production as well as with a more limited reduction in IL-17 production by ex vivo-stimulated draining LN cells. Finally, RANKL mRNA levels in the joint were reduced by anti-ST2 treatment. CONCLUSION: IL-33 is produced locally in inflamed joints, and neutralization of IL-33 signaling has a therapeutic effect on the course of arthritis. These observations suggest that locally produced IL-33 may contribute to the pathogenesis of joint inflammation and destruction.

Du Pan SM, Gabay C, Finckh A. · Division of Rheumatology, Department of Internal Medicine, University of Geneva. · Ther Clin Risk Manag. · Pubmed #18473014 links to  free full text

Abstract: BACKGROUND: Several health authorities have recently revised the indication of infliximab (IFX) to include the treatment of early rheumatoid arthritis (RA). The aim of this systematic review of the literature was to appraise the efficacy, safety, and cost-effectiveness of early therapy with IFX. METHODS: We identified published clinical trials from 1966 to May 2006. We included randomized clinical trials (RCTs) in RA with disease duration of less than 3 years comparing the treatment of methotrexate-IFX (MTX-IFX) with methotrexate-placebo (MTX-placebo). RESULTS: A total of 8 studies met inclusion criteria. Three studies reported redundant data regarding the vdH Sharp Score. Out of the 5 remaining studies, 4 analyzed structural joint destruction (vdH Sharp Score) and demonstrated a significant reduction in radiographic damage progression in favor of the combination of MTX-IFX compared with MTX-placebo (-4.1 vdH Sharp Score units (95% CI: 3.5; 4.6). Three studies also displayed a benefit of MTX-IFX on functional outcomes of RA (HAQ score) and disease activity measures (DAS, ACR response criteria), although less markedly. CONCLUSIONS: Although data might be skewed because of only 2 existing large studies with concordant data, results from RCTs demonstrate improved efficacy of the combination MTX-IFX compared with MTX-placebo in early RA. However, many early RA patients probably do not require the addition of IFX to achieve a satisfying clinical and radiological course. So far, no evidence has established the superiority of MTX-IFX over MTX-prednisone or other combinations of traditional disease-modifying anti-rheumatic agents.

Finckh A, Dehler S, Gabay C, Anonymous00030. · Division of Rheumatology, Department of Internal Medicine, University Hospital of Geneva, 26 Av. Beau-Sejour, 1211 Geneva 14. Switzerland. · Ann Rheum Dis. · Pubmed #18230627 No free full text.

Abstract: BACKGROUND: Randomised trials have demonstrated that the efficacy of anti-tumour necrosis factor (TNF) agents is significantly increased by concomitant methotrexate (MTX) in rheumatoid arthritis (RA). In clinical routine, anti-TNF agents are commonly prescribed with other disease-modifying antirheumatic drugs (DMARDs) than MTX, however their effectiveness in combination with anti-TNF agents is not well established. OBJECTIVE: To compare the effectiveness of leflunomide (LEF) and other conventional DMARDs with MTX as co-therapy to anti-TNF agents in RA. METHODS: All patients on anti-TNF agents and conventional DMARDs within the Swiss Clinical Quality Management (SCQM)-RA database were included (n = 1218) and categorised according to the type of co-therapy into anti-TNF+MTX (n = 842), anti-TNF+LEF (n = 260) and anti-TNF+other DMARDs (n = 116). Drug discontinuation rates and incidence of toxic side effects were analysed using Cox proportional hazard models. Progression of radiographic damage, the evolution of functional disability and the improvement of RA disease activity were analysed using longitudinal regression models, adjusting for potential confounders. RESULTS: The overall discontinuation rates of anti-TNF and conventional DMARD combination therapies were relatively high with a median survival of only 16 months (interquartile range (IQR): 10-37), but they did not differ between the three regimens (p = 0.69). The progression of radiographic damage (p = 0.77), functional disability (p = 0.09) and RA disease activity (p = 0.33) were also similar between the different regimen. In addition, no significant difference in the frequency of adverse events emerged. CONCLUSION: Overall these results suggest that LEF and potentially other conventional DMARDs offer an effective and safe alternative to MTX as co-therapy in combination with anti-TNF agents.

Palmer G, Busso N, Aurrand-Lions M, Talabot-Ayer D, Chobaz-Péclat V, Zimmerli C, Hammel P, Imhof BA, Gabay C. · Division of Rheumatology, Department of Internal Medicine, University Hospital, 26 avenue Beau-Séjour, 1211 Geneva 14, Switzerland. · Arthritis Res Ther. · Pubmed #17612407 links to  free full text

Abstract: Junctional adhesion molecule-C (JAM-C) is an adhesion molecule involved in transendothelial migration of leukocytes. In this study, we examined JAM-C expression in the synovium and investigated the role of this molecule in two experimental mouse models of arthritis. JAM-C expression was investigated by reverse transcriptase-polymerase chain reaction and immunohistochemistry. The effects of a monoclonal anti-JAM-C antibody were assessed in antigen-induced arthritis (AIA) and K/BxN serum transfer-induced arthritis. JAM-C was expressed by synovial fibroblasts in the lining layer and associated with vessels in the sublining layer in human and mouse arthritic synovial tissue. In human tissue, JAM-C expression was increased in rheumatoid arthritis (RA) as compared to osteoarthritis synovial samples (12.7 +/- 1.3 arbitrary units in RA versus 3.3 +/- 1.1 in OA; p < 0.05). Treatment of mice with a monoclonal anti-JAM-C antibody decreased the severity of AIA. Neutrophil infiltration into inflamed joints was selectively reduced as compared to T-lymphocyte and macrophage infiltration (0.8 +/- 0.3 arbitrary units in anti-JAM-C-treated versus 2.3 +/- 0.6 in isotype-matched control antibody-treated mice; p < 0.05). Circulating levels of the acute-phase protein serum amyloid A as well as antigen-specific and concanavalin A-induced spleen T-cell responses were significantly decreased in anti-JAM-C antibody-treated mice. In the serum transfer-induced arthritis model, treatment with the anti-JAM-C antibody delayed the onset of arthritis. JAM-C is highly expressed by synovial fibroblasts in RA. Treatment of mice with an anti-JAM-C antibody significantly reduced the severity of AIA and delayed the onset of serum transfer-induced arthritis, suggesting a role for JAM-C in the pathogenesis of arthritis.

Genevay S, Finckh A, Ciurea A, Chamot AM, Kyburz D, Gabay C, Anonymous00144. · University Hospitals of Geneva, Geneva, Switzerland. · Arthritis Rheum. · Pubmed #17471545 links to  free full text

Abstract: OBJECTIVE: Limited data have been published on tolerance to and efficacy of classic or biologic disease-modifying antirheumatic drugs in elderly patients with rheumatoid arthritis (RA). The goal of the present study was to evaluate the tolerance to and effectiveness of anti-tumor necrosis factor (anti-TNF) agents in elderly patients (> or =65 years old) with RA (ERA) in comparison with younger patients (YRA). METHODS: The Swiss Clinical Quality Management program for RA is a longitudinal population-based cohort. All patients who had received at least 1 dose of anti-TNF agents between January 1997 and November 2005 were included and categorized according to their age. Tolerance was assessed by analyzing discontinuation rates of anti-TNF agents. Effectiveness of these agents was assessed by analyzing RA disease activity (Disease Activity Score in 28 joints [DAS28]) and functional disability (Health Assessment Questionnaire [HAQ]) after anti-TNF initiation. RESULTS: Among 1,571 patients with RA treated with anti-TNF agents, 344 were > or =65 years of age at treatment initiation. Drug discontinuation rates (median time 3 years) and mean change in DAS28 scores at 2 years (-0.65 versus -0.58) were identical in ERA and YRA. However, HAQ score improved significantly less in ERA (-0.02) than in YRA (-0.1) and a subsequent analysis revealed that this finding was essentially due to patients >75 years of age. CONCLUSION: Age in itself should not interfere with the decision to treat elderly patients with RA with anti-TNF agents. In a subset of patients ages >75 years, no functional improvement according to HAQ should be expected despite improvements in disease activity.

Finckh A, Ciurea A, Brulhart L, Kyburz D, Möller B, Dehler S, Revaz S, Dudler J, Gabay C, Anonymous00139. · University Hospital of Geneva, Geneva, Switzerland. · Arthritis Rheum. · Pubmed #17469098 links to  free full text

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) in whom the response to anti-tumor necrosis factor (anti-TNF) therapy is inadequate have several therapeutic options, such as switching to an alternative anti-TNF agent or initiating B cell-depleting therapy with rituximab (RTX). Although both therapeutic options have been proven effective in trials, no head-to-head comparisons are available. The aim of this study was to compare the effectiveness of RTX with that of an alternative anti-TNF agent in the management of patients with RA who had an inadequate response to anti-TNF therapy. METHODS: This prospective cohort study was nested within the Swiss Clinical Quality Management RA cohort and included all patients who had an inadequate response to at least 1 anti-TNF agent and subsequently received either 1 cycle of RTX or an alternative anti-TNF agent. The primary outcome was the evolution of RA disease activity (as measured on the Disease Activity Score in 28 joints [DAS28]), which was analyzed using multivariate regression models for longitudinal data. RESULTS: One hundred sixteen patients with RA were included; 50 patients received 1 cycle of RTX, and 66 patients were treated with a second or a third alternative anti-TNF agent. At baseline, there were no significant differences between the 2 groups in age, sex, disease duration, and disease activity. Evolution of the DAS28 was more favorable in the group that received RTX compared with the group that received an alternative anti-TNF agent (P = 0.01). At 6 months, the mean decrease in the DAS28 was -1.61 (95% confidence interval [95% CI] -1.97, -1.25) among patients receiving RTX and -0.98 (95% CI -1.33, -0.62) among those receiving subsequent anti-TNF therapy. CONCLUSION: The results of this observational study suggest that treatment with RTX may be more effective than switching to an alternative anti-TNF agent in patients with RA in whom active disease persists despite anti-TNF therapy.

Finckh A, Dehler S, Costenbader KH, Gabay C, Anonymous00135. · Division of Rheumatology, Department of Internal Medicine, University of Geneva, 26 Av. Beau-Sejour, 1211 Geneva 14, Switzerland. · Ann Rheum Dis. · Pubmed #17237117 No free full text.

Abstract: BACKGROUND: Smoking is a well-established environmental risk factor for the development of rheumatoid arthritis (RA). However, it remains unclear whether smoking influences RA disease progression and whether smokers have more radiographic damage progression than non-smokers over time. OBJECTIVE: To compare the rates of radiographic damage progression in current smokers and non-smokers in a large prospective RA cohort. METHODS: The SCQM-RA is a population-based registry monitoring disease activity, radiographic damage and symptoms at regular intervals. All patients in the SCQM-RA database with sequential plain radiographs were included. Joint erosions were assessed in 38 hand and foot joints with a validated scoring method. The rate of erosion progression was analysed using multivariate longitudinal regression models and adjusted for potential confounders. RESULTS: 2004 RA patients with a mean of 3.6 sequential radiographs and 3.1 years of follow-up were included. The 545 (27%) current smokers smoked on average 16 cigarettes per day and had a mean past smoking exposure of 20.6 pack-years. Radiographic joint damage progressed at a similar rate in current smokers and non-smokers (p = 0.26). However, smoking intensity was associated with a significant inverse dose-response; heavy smokers (>1 pack-day) progressed significantly less than non-smokers or moderate smokers (p<0.001). CONCLUSION: Radiographic joint damage progressed at an equivalent rate in smokers and non-smokers. Furthermore, a significant trend was observed for reduced radiographic progression and generally more favourable functional scores among heavy smokers, suggesting that cigarette smoke does not accelerate RA disease progression.