Rheumatoid Arthritis: Inman RD

Zhang X, Pacheco-Tena C, Inman RD. · No affiliation provided · Arthritis Rheum. · Pubmed #12910552 links to  free full text

This publication has no abstract.

Ichim TE, Zheng X, Suzuki M, Kubo N, Zhang X, Min LR, Beduhn ME, Riordan NH, Inman RD, Min WP. · University of Western Ontario, Departments of Surgery, Pathology, Microbiology & Immunology, 339 Windermere Road, University Hospital C9-136, London, Ontario, N6A 5A5, Canada. · Expert Opin Biol Ther. · Pubmed #18194075 No free full text.

Abstract: BACKGROUND: Immunotherapy offers the promise of antigen-specific suppression of pathological immune responses in conditions such as autoimmunity and organ transplantation. Substantial advances have been made in recent years in terms of understanding basic immunological mechanisms of autoreactivity, as well as clinically implementing immune-based therapies that are antigen nonspecific. OBJECTIVE: To provide an integrated overview of the current state of the art in terms of antigen-specific tolerance induction, as well as to predict future directions for the field. METHODS: Examples of successes and failures of antigen-specific immunotherapy were sought. Particular attention was paid to the well-established collagen II-induced model of arthritis. RESULTS/CONCLUSIONS: Previous failures of antigen-specific immunotherapy were associated with lack of identification of clinically relevant antigens, as well as inappropriate tolerogenic methodologies. The advances in proteomics combined with novel gene-specific immune modulatory techniques place today's translational researchers in a unique position to tackle the problem of antigen-specific immunotherapeutic protocols.

Keeling SO, Landewe R, van der Heijde D, Bathon J, Boers M, Garnero P, Geusens P, El-Gabalawy H, Inman RD, Kraus VB, Kvien TK, Mease PJ, Ostergaard M, Ritchlin C, Syversen SW, Maksymowych WP. · Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. · J Rheumatol. · Pubmed #17343310 No free full text.

Abstract: OBJECTIVE: A list of 14 criteria for guiding the validation of a soluble biomarker as reflecting structural damage endpoints in rheumatoid arthritis (RA) clinical trials was drafted by an international working group after a Delphi consensus exercise. C-reactive protein (CRP), a soluble biomarker extensively studied in RA, was then used to test these criteria. Our objectives were: (1) To assess the strength of evidence in support of CRP as a soluble biomarker reflecting structural damage in RA according to the draft validation criteria. (2) To assess the strength of recommendation for inclusion of individual criteria in the draft set. METHODS: A systematic literature review was conducted to elicit evidence in support of each specific criterion composing the 14-criteria draft set. A summary of the key literature findings per criterion was presented to both the working group and to participants in a special interest soluble biomarker group at OMERACT 8. Participants at OMERACT 8 were asked to rate the strength of evidence and the strength of the recommendation in support of each individual criterion on a 0-10 numerical rating scale. Working group members not present at OMERACT voted by a Web-based survey. RESULTS: Minimal data were extracted from the literature pertaining to those criteria listed under the category of truth. Ratings for strength of evidence were moderate to low (< 7) for CRP as a biomarker reflecting structural damage in RA; this was true for all criteria except those listed under the category of feasibility and 2 listed under the category of discrimination pertaining to assay reproducibility and evidence regarding sources of variability. Ratings for strength of recommendation for inclusion of each of the 14 criteria in the draft set were high (> 7) except for those criteria listed under the category of truth. CONCLUSION: The draft criteria serve as a useful template in the evaluation of the strength of evidence in support of a particular soluble biomarker as reflecting structural damage in RA.

Maksymowych WP, Inman RD, Gladman D, Thomson G, Stone M, Karsh J, Russell AS, Anonymous00134. · The University of Alberta, Edmonton, Canada. · J Rheumatol. · Pubmed #12784417 No free full text.

Abstract: Spondyloarthritis (SpA) represents a group of related arthritides characterized by their association with HLA-B27 and the development of sacroiliitis and enthesitis. Functional impairment, disability, and loss of quality of life may resemble that observed in rheumatoid arthritis. The SpA Research Consortium of Canada (SPARCC) is an informal association of rheumatologist members of the Canadian Rheumatology Association (CRA) with a special interest in therapeutics and outcomes research in SpA. Recent experience with anti-tumor necrosis factor-a (anti-TNF-a) directed therapies prompted a consensus-based evaluation of the evidence supporting their efficacy, safety, and appropriate use in SpA. We evaluated the clinical evidence in support of anti-TNF-a directed therapies in SpA. Medline was searched using appropriate keywords. Abstracts of the 1999-2002 annual meetings of the American College of Rheumatology and the European Congress of Rheumatology were extracted and admitted if sufficient detail was available to determine the level of evidence. Recommendations were based on randomized placebo-controlled trials (Level A evidence) and clinical studies without randomization (Level B evidence). Where the scientific literature was incomplete, recommendations reflected the consensus of SPARCC members (Level C evidence). Following development of an original draft document, consensus for revisions was achieved among members of SPARCC. The document was then posted on the CRA website prior to its final revision. The following recommendations have been endorsed by the Therapeutics Committee of the CRA: Infliximab and etanercept are indicated for reduction of signs and symptoms of moderate to severely active SpA in patients who have had an inadequate response to maximal doses of > or = 2 nonsteroidal antiinflammatory drugs (NSAID) over a 3-month period of observation; and either sulfasalazine or methotrexate is indicated in those with predominantly active peripheral arthritis. Current evidence supports their use as monotherapy (level of evidence A) for at least one year. NSAID and/or second line therapy with either sulfasalazine or methotrexate can be continued concomitantly. There is no evidence addressing potential advantages or disadvantages of combining methotrexate with anti-TNF therapy for SpA. Recommended doses for adults are: infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter; etanercept 25 mg subcutaneously twice weekly. No therapy has been shown to slow progression of axial disease in SpA, and prognostic factors for determining response to therapy remain to be determined. It is the position of the CRA that all therapeutic options should be equally available according to the best judgments of the treating physician and the informed decision of the patient.

Hyrich KL, Inman RD. · Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Canada. · Curr Opin Rheumatol. · Pubmed #11555732 No free full text.

Abstract: The possible role of infectious microorganisms in the disease process of both arthritis and autoimmunity continue to attract both basic and clinical researchers. However, proving a causal role for these suspects is a very difficult and complicated task. This article provides an update on various mechanisms in which microbes may play roles as inciting or perpetuating factors in the pathogenesis of connective tissue disease. It also focuses on current theories that specific microorganisms may play a role in rheumatoid arthritis and ankylosing spondylitis.

Popov I, Li M, Zheng X, San H, Zhang X, Ichim TE, Suzuki M, Feng B, Vladau C, Zhong R, Garcia B, Strejan G, Inman RD, Min WP. · Department of Surgery, London Health Science Centre, London, Canada. · Arthritis Res Ther. · Pubmed #16911769 links to  free full text

Abstract: Conventional treatments for autoimmune diseases have relied heavily on nonspecific immune suppressants, which possess a variety of adverse effects without inhibiting the autoimmune process in a specific manner. In the present study we demonstrate the effectiveness of antigen-specific, maturation-resistant, tolerogenic dendritic cells (DC) in suppressing collagen-induced arthritis, a murine model of rheumatoid arthritis. Treatment of DC progenitors with the NF-kappaB inhibiting agent LF 15-0195 (LF) resulted in a population of tolerogenic DC that are characterized by low expression of MHC class II, CD40, and CD86 molecules, as well as by poor allostimulatory capacity in a mixed leukocyte reaction. Administering LF-treated DC pulsed with keyhole limpet hemocyanin antigen to naïve mice resulted hyporesponsiveness specific for this antigen. Furthermore, administration of LF-treated DC to mice with collagen-induced arthritis resulted in an improved clinical score, in an inhibited antigen-specific T-cell response, and in reduced antibody response to the collagen. The efficacy of LF-treated DC in preventing arthritis was substantiated by histological examination, which revealed a significant decrease in inflammatory cell infiltration in the joints. In conclusion, we demonstrate that in vitro-generated antigen-specific immature DC may have important potential as a tolerogenic vaccine for the treatment of autoimmune arthritis.

Hyrich KL, Kim TH, Payne U, Zhang X, Chiu B, Mehren K, Inman RD. · Division of Rheumatology, Toronto Western Hospital, Toronto, Ontario, Canada. · J Rheumatol. · Pubmed #15517649 No free full text.

Abstract: A 27-year-old female lowland gorilla developed an asymmetric oligoarthritis 3 months post-partum.There was no evidence of an antecedent gastrointestinal or genitourinary infection. Serum was negative for rheumatoid factor and antinuclear antibody. Synovial fluid revealed 2000 white blood cells with negative cultures and polarized microscopy. Studies on synoviocytes were the following: (1) FACS analysis revealed surface expression of a B27-like epitope of the cells. (2) Analysis of intracellular clearance kinetics of arthritogenic organisms showed peak intracellular colony-forming units at 48 hours after bacterial invasion, and clearance by 13 days post-invasion. (3) Interferon-y (0.1-10.0 ng/ml)accelerated intracellular microbicidal pathways in a dose-dependent fashion. These findings closely parallel those seen in human synoviocytes of patients with spondyloarthropathy. Primate and human seronegative arthritis share clinical and immunologic features, as well as aspects of host:pathogen defense mechanisms. The interplay of genetic and microbial factors underlying this arthritis appears to be conserved across these species boundaries.

Stone M, Fortin PR, Pacheco-Tena C, Inman RD. · Division of Rheumatology, Department of Medicine, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. · J Rheumatol. · Pubmed #14528503 No free full text.

Abstract: OBJECTIVE: To compare the effectiveness of tetracycline antibiotics versus control (placebo or conventional treatment) in rheumatoid arthritis (RA) for the reduction of disease activity as defined by American College of Rheumatology criteria. METHODS: We searched Medline (1966-February 2002), Embase (1980-February 2002), and the Cochrane Controlled Trials Register (Issue 1, 2002 Cochrane Library). Reference lists of published trials were searched by hand for further identification of published reports and presentations at scientific meetings. Randomized controlled trials comparing tetracyclines to control (placebo or conventional disease modifying antirheumatic therapy) were selected for inclusion if at least one of the following outcomes was reported: tender joint count (TJC), swollen joint count, patient pain score by visual analog scale, patient global assessment of disease activity, physician global assessment of disease activity, eosinophil sedimentation rate (ESR) and C-reactive protein (CRP), joint space narrowing and erosions, adverse events, and quality of life as measured by the Health Assessment Questionnaire. Subjects were required to have RA as defined by the 1987 ARA criteria. RESULTS: Ten randomized controlled trials including 535 individuals were reviewed. Only 3 trials were considered high quality; elements of bias could not be excluded in the remainder. Tetracyclines, when administered for > or = 3 months, were associated with a significant reduction in disease activity in RA as follows: for TJC, standardized mean difference (SMD) = -0.39, 95% CI -0.74, -0.05; and for acute phase reactants, ESR, SMD = -8.96, 95% CI -14.51, -3.42. The treatment effect was more marked in the subgroup of patients with disease duration < 1 year who were seropositive. There was no absolute increased risk of adverse events associated with tetracyclines: absolute risk difference = 0.10, 95% confidence interval (CI) -0.01, 0.21. No beneficial effect was seen on radiological progression of disease: for erosions, SMD = 0.17, 95% CI -0.29, 0.64. In addition, subgroup analysis excluding trials with doxycycline showed that minocycline alone had a greater effect on reduction of disease activity: for TJC, SMD = -0.69, 95% CI -0.89, -0.49; and for ESR, SMD = -10.14, 95% CI -14.72, -5.57. CONCLUSION: Tetracyclines, in particular minocycline, were associated with a clinically significant improvement in disease activity in RA with no absolute increased risk of side effects. Unfortunately, the information available was inadequate to allow a detailed analysis of individual side effects in the studies. Further research is warranted to compare these agents to newer disease modifying drugs for comparable safety, efficacy, and cost-effectiveness.

Inman RD, Payne U. · Arthritis Center of Excellence, Toronto Western Hospital Research Institute, Ontario, Canada. · J Rheumatol. · Pubmed #12784405 No free full text.

Abstract: OBJECTIVE: Persistence of intracellular organisms may play a critical role in the initiation and perpetuation of synovitis in reactive arthritis (ReA). We investigated factors that may influence local clearance of arthritogenic pathogens in ReA. METHODS: We studied 11 HLA-B27 positive patients with spondyloarthropathies and contrasted these patients with 6 HLA-B27 negative control patients with rheumatoid arthritis or osteoarthritis. We employed an ex vivo system in which human synoviocytes derived from patients with ReA are cocultured with arthritogenic pathogens, and intracellular clearance is measured by quantitating colony-forming units over time. RESULTS: The clearance kinetics of the organisms bore no relationship to the HLA-B27 status of the patient. Clearance of S. typhimurium over a 10 day period was accompanied by a progressive rise in nitric oxide (NO) production, but this appeared not to be rate-limiting, since (1) clearance kinetics were comparable between high versus low NO-producing synoviocytes; and (2) L-NMMA inhibition of NO production did not alter clearance kinetics of S. typhimurium. Interferon-g (IFN-g) was observed to have a small but measurable effect on bacterial clearance. In certain patients with ReA there was a paradoxical stimulatory response to IFN-g, in which the addition of IFN-g was accompanied by an increase in intracellular bacteria. This effect was found to be attributable to IFN-g mediated suppression of NO production in these cells. This pattern was not observed in B27 negative synoviocytes. CONCLUSION: Intracellular persistence of arthritogenic organisms may contribute to the cellular basis of ReA, but the molecular basis of the bacteriocidal pathways in synoviocytes has not been fully resolved. Our findings indicate that a direct effect of HLA-B27 on these events is unlikely, but that alterations in cytokine response profiles may play a contributory role. Characterizing these mechanisms holds the promise of more specific therapeutic interventions in this disease.