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Assessment of rituximab's immunomodulatory synovial effects (the ARISE trial). I: clinical and synovial biomarker results
  1. Arthur Kavanaugh (akavanaugh{at}ucsd.edu)
  1. Div of Rheumatology, United States
    1. Sanna Rosengren
    1. UCSD, United States
      1. Susan J Lee
      1. UCSD, United States
        1. Deepa Hammaker
        1. UCSD, United States
          1. Gary S Firestein
          1. University of California, United States
            1. Kenneth Kalunian
            1. UCSD, United States
              1. Nathan Wei
              1. Arthritis and Osteoporosis Center of Maryland, United States
                1. David L Boyle
                1. UCSD, United States

                  Abstract

                  Abstract Objective: Treatment with the anti-CD20 mAb rituximab has proven efficacious in patients with rheumatoid arthritis (RA). Marked depletion of circulating CD 20+ B cells is observed in almost all treated patients, but does not show a direct relationship with efficacy. While studies have begun to address the cellular constitution in the synovium following rituximab therapy, potential immunomodulatory effects of rituximab on B cell functions including antibody and autoantibody production and cytokine expression in the synovium have not been defined. Methods: ARISE is an open label, serial synovial biopsy study of active, Rheumatoid factor positive (RF+) RA patients on concomitant methotrexate. Thirteen patients had baseline arthroscopic synovial biopsy of an affected knee or wrist, followed by rituximab (1 gram intravenously on days 0 and 14; without peri-infusional steroids. Post treatment biopsies of the same joint were obtained at week 8. Tissue was analyzed for various features including infiltrating cells by immunohistochemistry with digital image analysis, inflammation by histologic score, and gene expression by real time-PCR. Results: The average patient age was 53.4 years and the duration of RA 12.2 years. The mean dose of methotrexate used was 17.3 mg/week. Of note, 11/13 patients had failed prior TNF inhibitor therapy. Patients had active RA with a mean pre-treatment DAS28 score of 6.5±0.4. With treatment, all patients experienced near complete depletion of circulating B cell numbers. During the 6 months after treatment, 7/13 patients achieved an ACR20 response, 3/13 an ACR50 response and 2/13 an ACR70 response. With treatment, serum IgM RF and total IgM decreased in nearly all patients whereas serum IgG and anti-CCP IgG were largely unchanged. In the synovium, there was a significant decrease in B cells after treatment; however, there was only a small trend towards a greater reduction in B cells among clinical responders. Overall architecture, which was diverse among patients pre-treatment, and synovial inflammation were not altered by therapy. Among the 3 patients with higher levels of response (≥ACR50) there was a significant decrease in synovial immunoglobulin synthesis. Conclusions: These data suggest that unlike those in circulation, synovial B cells may be decreased but are not eliminated by rituximab therapy. Patients with higher levels of response may have more consistent depletion of synovial B cells. There may be also an association between changes in synovial B cell function and clinical response, as indicated by decreases in synovial immunoglobulin synthesis. Thus, effects on synovial B cells may be necessary but not sufficient for inducing clinical efficacy, and other effects, such as on primary lymph organ B cell antigen presentation or cytokine production, may be operative. Registered through ClinicalTrials.Gov September 2, 2005; Registration NCT00147966

                  • B cells
                  • Rheumatoid Arthritis,
                  • biomarker,
                  • rituximab
                  • synovium,

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