Rheumatoid Arthritis: Martin S

Tuscano JM, Martin S, Song K, Wun T. · University of California, Davis Department of Inter Medicine, Sacramento, CA 95817, USA. · Hematology. · Pubmed #16321818 No free full text.

Abstract: The therapeutic approach to patients with autoimmune disorders is in the midst of a dramatic change. Monoclonal antibody technology has allowed us to dissect and now manipulate the human immune system with greater precision. It is now widely recognized that B lymphocytes play a role in the pathogenesis of many autoimmune diseases, though the extent and contribution is a matter of debate and active investigation. There is emerging data to suggest that both antibody-dependent and independent mechanisms contribute to disease pathogenesis. However, given the heterogeneous nature of autoimmune diseases, and the varied responses to B lymphocyte reduction, the role of B lymphocytes is likely disease-specific. The two clinical trials discussed in this review demonstrate remarkable consistency in the ability of B cell reduction to ameliorate the clinical manifestations of rheumatoid arthritis with minimal toxicity. B lymphocyte targeted approaches to autoimmune disease in general, and RA specifically, will not only provide an effective and potentially less toxic alternative treatment option, but also allow for a better understanding of the pathogenesis of these complex and morbid diseases.

Fanet-Goguet M, Martin S, Fernandez C, Fautrel B, Bourgeois P. · Service de Rhumatologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. · Therapie. · Pubmed #15559549 No free full text.

Abstract: Tumour necrosis factor (TNF)-alpha and interleukin (IL)-1 are major regulators of inflammation. TNFalpha inhibitors have been shown to be effective in treating some inflammatory diseases such as rheumatoid arthritis. TNFalpha inhibitors include soluble receptor antagonists (etanercept) and monoclonal antibodies (infliximab, adalimumab). IL-1 inhibitors (anakinra) were also developed, used in therapeutics and licensed in France. TNFalpha inhibitors can be added to background regimens of methotrexate in second-line treatments. Etanercept and adalimumab can be administered alone, especially to patients who have experienced methotrexate toxicity or who do not show clinical and/or radiological improvement. The use of these new agents may optimise rheumatoid arthritis treatment and delay disease progression, particularly when first-line treatments are disappointing. This paper reviews recent data on biological therapies for rheumatoid arthritis: tolerance and their ability to modify the course of disease and prevent radiological damage.

Weskamp G, Ford JW, Sturgill J, Martin S, Docherty AJ, Swendeman S, Broadway N, Hartmann D, Saftig P, Umland S, Sehara-Fujisawa A, Black RA, Ludwig A, Becherer JD, Conrad DH, Blobel CP. · Arthritis and Tissue Degeneration Program, Hospital for Special Surgery and Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA. · Nat Immunol. · Pubmed #17072319 No free full text.

Abstract: CD23, the low-affinity immunoglobulin E receptor, is an important modulator of the allergic response and of diseases such as rheumatoid arthritis. The proteolytic release of CD23 from cells is considered a key event in the allergic response. Here we used loss-of-function and gain-of-function experiments with cells lacking or overexpressing candidate CD23-releasing enzymes (ADAM8, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19 and ADAM33), ADAM-knockout mice and a selective inhibitor to identify ADAM10 as the main CD23-releasing enzyme in vivo. Our findings provide a likely target for the treatment of allergic reactions and set the stage for further studies of the involvement of ADAM10 in CD23-dependent pathologies.

Scaife S, Brown R, Kellie S, Filer A, Martin S, Thomas AM, Bradfield PF, Amft N, Salmon M, Buckley CD. · Yamanouchi Research Institute, Oxford, UK. · Rheumatology (Oxford). · Pubmed #15292528 links to  free full text

Abstract: OBJECTIVE: To identify differentially expressed genes in synovial fibroblasts and examine the effect on gene expression of exposure to TNF-alpha and IL-1beta. METHODS: Restriction fragment differential display was used to isolate genes using degenerate primers complementary to the lysophosphatidic acid acyl transferase gene family. Differential gene expression was confirmed by reverse transcription-polymerase chain reaction and immunohistochemistry using a variety of synovial fibroblasts, including cells from patients with osteoarthritis and self-limiting parvovirus arthritis. RESULTS: Irrespective of disease process, synovial fibroblasts constitutively produced higher levels of IL-6 and monocyte chemoattractant protein 1 (MCP-1) (CCL2) than skin fibroblasts. Seven genes were differentially expressed in synovial fibroblasts compared with skin fibroblasts. Of these genes, four [tissue factor pathway inhibitor 2 (TFPI2), growth regulatory oncogene beta (GRObeta), manganese superoxide dismutase (MnSOD) and granulocyte chemotactic protein 2 (GCP-2)] were all found to be constitutively overexpressed in synoviocytes derived from patients with osteoarthritis. These four genes were only weakly expressed in other synovial fibroblasts (rheumatoid and self-limiting parvovirus infection). However, expression in all types of fibroblasts was increased after stimulation with TNF-alpha and IL-1beta. Three other genes (aggrecan, biglycan and caldesmon) were expressed at higher levels in all types of synovial fibroblasts compared with skin fibroblasts even after stimulation with TNF-alpha and IL-1. CONCLUSIONS: Seven genes have been identified with differential expression patterns in terms of disease process (osteoarthritis vs rheumatoid arthritis), state of activation (resting vs cytokine activation) and anatomical location (synovium vs skin). Four of these genes, TFPI2, GRObeta (CXCL2), MnSOD and GCP-2 (CXCL6), were selectively overexpressed in osteoarthritis fibroblasts rather than rheumatoid fibroblasts. While these differences may represent differential behaviour of synovial fibroblasts in in vitro culture, these observations suggest that TFPI2, GRObeta (CXCL2), MnSOD and GCP-2 (CXCL6) may represent new targets for treatments specifically tailored to osteoarthritis.

Parsonage G, Falciani F, Burman A, Filer A, Ross E, Bofill M, Martin S, Salmon M, Buckley CD. · MRC Centre for Immune Regulation, Division of Immunity and Infection, Birmingham University, Birmingham, UK. · Thromb Haemost. · Pubmed #14515190 No free full text.

Abstract: We investigated the extent to which fibroblasts isolated from diverse tissues differ in their capacity to modulate inflammation by comparing the global gene expression profiles of cultured human fibroblasts from skin, acute and chronically inflamed synovium, lymph node and tonsil. The responses of these fibroblasts to TNF-alpha, IFN-gamma and IL-4 stimulation were markedly different, as revealed by hierarchical cluster analysis and principal component analysis. In the absence of exogenous cytokine, synovial and skin fibroblasts exhibited similar patterns of gene expression. However their transcriptional profiles diverged upon treatment with TNF-alpha. This proved to be biologically relevant, as TNF-alpha induced the secretion of different patterns and amounts of IL-6, IL-8 and CCL2 (MCP-1) in the two fibroblast types. Co-culture of skin or synovial fibroblasts with synovial fluid-derived mononuclear cells provided further evidence that these transcriptional differences were functionally significant in an ex vivo setting. Interestingly, the transcriptional response of skin fibroblasts to IL-4 converged with that of TNF-alpha-treated synovial fibroblasts, suggesting resident tissue fibroblasts and their blood-borne precursors may be imprinted by inflammatory cytokines that are characteristic of different tissues. Our data supports the concept that fibroblasts are heterogeneous, and that they contribute to the tissue-specificity of inflammatory reactions. Fibroblasts are therefore likely to play an active role in the persistence of chronic inflammatory reactions.

Yun AG, Martin S, Zurakowski D, Scott R. · Arthritis Institute, Inglewood, California, USA. · J Arthroplasty. · Pubmed #12478506 No free full text.

Abstract: Because controversy surrounds the management of end-stage hip disease in juvenile rheumatoid arthritis (JRA), this study evaluated the long-term outcome of bipolar hemiarthroplasty as an alternative to conventional joint arthroplasty. A total of 24 JRA patients underwent 39 hemiarthroplasties; follow-up averaged 12 years (range, 3 to 15 years). There were 14 hips (36%) revised, and 25 hips (64%) maintained the original components. Mean Harris hip scores in surviving hips improved from 29 to 69 points (P<.001). Radiographs showed progressive bipolar superomedial migration (P<.01) despite attempted augmentation. Failure defined as revision to total hip arthroplasty or definite radiographic loosening occurred in 15 hips (38%). Ten-year Kaplan-Meier survivorship for all prostheses was 78%. Independent multivariate risk factors for failure included acetabular grafting (P =.006), prosthesis type (P<.001), and unilateral replacement (P<.001).