Rheumatoid Arthritis: Vratsanos G

Weisman MH, Durez P, Hallegua D, Aranda R, Becker JC, Nuamah I, Vratsanos G, Zhou Y, Moreland LW. · Division of Rheumatology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., B-131, Los Angeles, CA 90048, USA. · J Rheumatol. · Pubmed #17014006 No free full text.

Abstract: OBJECTIVE: Abatacept, a soluble selective costimulation modulator, selectively modulates T cell activation via the CD80/CD86:CD28 costimulation pathway. Data from a Phase II trial showed efficacy in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate when treated with abatacept (10 mg/kg or 2 mg/kg). To determine the mechanism of action of abatacept, we analyzed changes in the serum levels of inflammatory biomarkers in the patients enrolled in this trial. RESULTS: Following 12 months' treatment, serum levels of interleukin 6 (IL-6), soluble IL-2 receptor, C-reactive protein, soluble E-selectin, and soluble intercellular adhesion molecule-1 were significantly lower in patients receiving abatacept 10 mg/kg versus placebo. Smaller reductions in tumor necrosis factor-a and rheumatoid factor were also observed in the abatacept 10 mg/kg group compared with the placebo group. Although there was no evidence for efficacy of the 2 mg/kg dose, small reductions in inflammatory biomarkers at this dosage support the biologic effect of this therapy. CONCLUSION: These findings reveal the antiinflammatory and immunomodulatory effects of abatacept in patients with RA, and are consistent with the concept that modulating T cell activation improves clinical signs and symptoms and inhibits the progression of structural damage. These data suggest that selective modulation of the CD80/CD86:CD28 pathway with abatacept may affect several inflammatory cell types and cytokines that are involved in the proinflammatory cascade.

Buch MH, Boyle DL, Rosengren S, Saleem B, Reece RJ, Rhodes LA, Radjenovic A, English A, Tang H, Vratsanos G, O'Connor P, Firestein GS, Emery P. · Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, UK. · Ann Rheum Dis. · Pubmed #18772191 links to  free full text

Abstract: OBJECTIVES: Abatacept is the only agent currently approved to treat rheumatoid arthritis (RA) that targets the co-stimulatory signal required for full T-cell activation. No studies have been conducted on its effect on the synovium, the primary site of pathology. The aim of this study was to determine the synovial effect of abatacept in patients with RA and an inadequate response to tumour necrosis factor alpha (TNFalpha) blocking therapy. METHODS: This first mechanistic study incorporated both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and arthroscopy-acquired synovial biopsies before and 16 weeks after therapy, providing tissue for immunohistochemistry and quantitative real-time PCR analyses. RESULTS: Sixteen patients (13 women) were studied; all had previously failed TNFalpha-blocking therapy. Fifteen patients completed the study. Synovial biopsies showed a small reduction in cellular content, which was significant only for B cells. The quantitative PCR showed a reduction in expression for most inflammatory genes (Wald statistic of p<0.01 indicating a significant treatment effect), with particular reduction in IFNgamma of -52% (95% CI -73 to -15, p<0.05); this correlated well with MRI improvements. In addition, favourable changes in the osteoprotegerin and receptor activator of nuclear factor kappa B levels were noted. DCE-MRI showed a reduction of 15-40% in MRI parameters. CONCLUSION: These results indicate that abatacept reduces the inflammatory status of the synovium without disrupting cellular homeostasis. The reductions in gene expression influence bone positively and suggest a basis for the recently demonstrated radiological improvements that have been seen with abatacept treatment in patients with RA.

Genant HK, Peterfy CG, Westhovens R, Becker JC, Aranda R, Vratsanos G, Teng J, Kremer JM. · University of California, San Francisco, San Francisco, CA, USA. · Ann Rheum Dis. · Pubmed #18086727 links to  free full text

Abstract: OBJECTIVE: Assess the effect of abatacept on progression of structural damage over 2 years in patients with rheumatoid arthritis who had an inadequate response to methotrexate. METHODS: 539 patients entered an open-label extension of the AIM (Abatacept in Inadequate responders to Methotrexate) trial and received abatacept. Radiographic assessment of the hands and feet was performed at baseline, year 1 and year 2. At year 2, each patient's radiographs were scored for progression blinded to sequence and treatment allocation. RESULTS: In patients treated with abatacept for 2 years, greater reduction in progression of structural damage was observed in year 2 than in year 1. The mean change in total Genant-modified Sharp scores was reduced from 1.07 units in year 1 to 0.46 units in year 2. Similar reductions were observed in erosion and joint space narrowing scores. Following 2 years of treatment with abatacept, 50% of patients had no progression of structural damage as defined by a change in the total score of < or =0 compared with baseline. 56% of patients treated with abatacept had no progression during the first year compared with 45% of patients treated with placebo. In their second year of treatment with abatacept, more patients had no progression than in the first year (66% vs 56%). CONCLUSIONS: Abatacept has a sustained effect that inhibits progression of structural damage. Furthermore, the mean change in radiographic progression in patients treated with abatacept for 2 years was significantly lower in year 2 versus year 1, suggesting that abatacept may have an increasing disease-modifying effect on structural damage over time.

Bigbee CL, Gonchoroff DG, Vratsanos G, Nadler SG, Haggerty HG, Flynn JL. · University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA. · Arthritis Rheum. · Pubmed #17665452 links to  free full text

Abstract: OBJECTIVE: Treatment of rheumatoid arthritis and other autoimmune disorders with anti-tumor necrosis factor (anti-TNF) agents is associated with an increased risk of reactivation of latent Mycobacterium tuberculosis. While the mechanism of action of abatacept is fundamentally different from that of anti-TNF therapies, its effect on the protective response to latent tuberculosis is not known. We undertook this study to determine the effect of abatacept treatment in a murine model of chronic M tuberculosis infection. METHODS: Chronic M tuberculosis infection was established in C57BL/6 mice. Four months after infection, mice were treated for up to 16 weeks with abatacept, anti-murine TNF antibody, or vehicle. The primary end point was survival; body weight, bacterial load, histologic features, interferon-gamma (IFNgamma) production by T cells, and cellular infiltration were also assessed. RESULTS: Abatacept- and vehicle-treated groups both maintained control of M tuberculosis infection, with 100% survival after 16 weeks of treatment. These 2 groups had no significant differences in body weight, no clinically relevant differences in bacterial load in the lungs, lymph nodes, or spleen, and no differences in the mean percentage of total or activated T cells, macrophages, neutrophils, or B cells, or in IFNgamma production in the lung or lymph nodes. In contrast, 100% mortality was seen in the anti-TNF antibody-treated group by week 9, with significant body weight loss and increased bacterial load in the lungs, lymph nodes, and spleen. Furthermore, the anti-TNF antibody-treated group had increased pathology consistent with the exacerbation of M tuberculosis infection. CONCLUSION: Abatacept did not impair the ability of mice to control a chronic M tuberculosis infection. In contrast, mice treated with anti-TNF therapy showed increased pathology and bacterial load, with 100% mortality by week 9. The clinical significance of these findings has not yet been determined.