Update: B-Cells in Rheumatic Disease

Volume 6 | April 1, 2007 - June 30, 2007

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Highest Rated Articles

Finckh A, Ciurea A, Brulhart L, et al, for the Physicians of the Swiss Clinical Quality Management Program for Rheumatoid Arthritis. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum 2007;56(5):1417-23.

An obvious but important question is whether we should switch RA patients failing anti-TNF to rituximab or abatacept rather than trying an alternative anti-TNF. Finckh and colleagues in the Swiss Clinical Quality Management Program for RA compared patients failing anti-TNF therapy who were started on rituximab against those started on an additional anti-TNF. They conclude that RA patients failing may respond better to rituximab. Since this was an open observational study rather than a blinded, randomized, controlled trial, the results cannot be considered conclusive. It would have been especially useful to have response rates rather than just mean improvement in DAS28. Nevertheless, given that we may never have a head-to-head comparison, the study makes an important contribution.   

Gunnarsson I, Sundelin B, Jonsdottir T, Jacobson SH, Henriksson EW, van Vollenhoven RF. Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide-resistant proliferative lupus nephritis. Arthritis Rheum 2007;56(4):1263-72.

Rituximab in combination with cyclophosphamide has been used by several European groups to treat SLE patients who were refractory to conventional immunosuppression. Gunnarsson and colleagues treated a small group of patients with refractory proliferative lupus nephritis with cyclophosphamide plus rituximab. An innovative and interesting outcome was comparison of renal biopsies at baseline and 6 month after therapy. The most impressive result was a decrease in renal activity index from a mean of 6.4 to 2.6 (p < 0.002) while chronicity remained unchanged. These results suggest similar biopsy studies in a randomize trial may provide important adjunctive data on efficacy.

Vos K, Thurlings RM, Wijbrandts CA, et al. Early effects of rituximab on the synovial cell infiltrate in patients with rheumatoid arthritis. Arthritis Rheum 2007;56(3):772-8.

Earlier work using human rheumatoid synovial tissue grafted onto SCID mice found rituximab treatment rapidly depleted B cells from the grafts and dramatically deceased cytokine production and infiltrating T cells. Vos et al performed the analogous study in humans by comparing baseline synovial biopsies to biopsies 1 month after treatment with rituximab. In contrast to the tissue grafted into SCID mice, treatment with rituximab in humans led overall to a modest decease in synovial B cells despite excellent depletion in peripheral blood. There was no decrease in other synovial cell populations. This result suggests that the effects of rituximab may not be due to depletion of B cells in target tissue. A problem with this interpretation is that at the time of the repeat biopsy, there were no clinical responses, and the patients were not followed to determine who responded later. In any case, it is clear that synovial B cells are relatively resistant to depletion with rituximab.

Pers JO, Devauchelle V, Daridon C, et al. BAFF-modulated repopulation of B lymphocytes in the blood and salivary glands of rituximab-treated patients with Sjogren's syndrome. Arthritis Rheum 2007;56(5):1464-77.

Sjogren’s syndrome is associated with B cell hyperactivity and elevated levels of BAFF. What was of considerable interest in the study by Pers et al was the close correlation between higher BAFF levels and shorter duration of B cell depletion. This result suggests that there should be synergy between rituximab and anti-BAFF agents in Sjogren’s syndrome and, perhaps, in other diseases with systemic or local high levels of BAFF (eg, SLE and RA synovium). In an animal model, synergy between anti-BAFF and anti-CD20 has already been reported. [Gong Q, et al. J Immunol 2005;174:817-26]

Devauchelle-Pensec V, Pennec Y, Morvan J, et al. Improvement of Sjogren's syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum 2007;57(2):310-7.

Devauchelle-Pennec and colleagues treated 16 patients with primary Sjogren’s syndrome, based on the American-European consensus criteria. In this open trial, there were impressive improvements in subjective measures including visual analog scales for global assessment, fatigue, pain, and dryness as well as in tender points and tender joints. There was also evidence for depletion of B cells from minor salivary glands at 12 weeks. (However, only six subjects had B cells infiltrating minor salivary gland.)  Objective measures of dryness (ie, Shirmer’s test and salivary gland from rates) did not corroborate the subjective response of dryness. Of note, one patient with a chronic cough and interstitial pneumonitis on CT scan improved after treatment with rituximab. This apparent response of interstitial pneumonitis is of considerable interest. The first two patients developed infusion reactions when the infusion rate was increased to 200 mg/hr. Thereafter, a slow infusion rate (100 mg/hr.) was instituted and appeared to be better tolerated. One patient with a monoclonal cryoglobulin and renal failure prior to inclusion developed a lymphplasmacytic lymphoma shortly after treatment with rituximab as part of this study. Subsequent treatment with fludarabine, mitoxantrone, and four infusions of rituximab induced remission. This study adds substantially to the experience of rituximab in Sjogren’s syndrome but also demonstrates many of the difficulties with such studies.    

Other Rated Articles

Annals of Rheumatic Disease

Four Stars Ng KP, Cambridge G, Leandro MJ, Edwards JC, Ehrenstein M, Isenberg DA. B cell depletion therapy in systemic lupus erythematosus: Long term follow up and predictors of response. Ann Rheum Dis 2007;Apr 5. [Epub ahead of print]
Four Stars Tokunaga M, Saito K, Kawabata D, et al. Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann Rheum Dis 2007;66(4):470-5.
Three Stars Lavie F, Miceli-Richard C, Ittah M, Sellam J, Gottenberg JE, Mariette X. Increase of B cell-activating factor of the TNF family (BAFF) after rituximab treatment: insights into a new regulating system of BAFF production. Ann Rheum Dis 2007;66(5):700-3.
Three Stars Toubi E, Kessel A, Slobodin G, et al. Changes in macrophage function after rituximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2007;66(6):818-20.

Rheumatology (Oxford, England)

Four Stars Popa C, Leandro MJ, Cambridge G, Edwards JC. Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 yrs. Rheumatology (Oxford) 2007;46(4):626-30.


Four Stars Withers DR, Fiorini C, Fischer RT, Ettinger R, Lipsky PE, Grammer AC. T cell-dependent survival of CD20+ and CD20- plasma cells in human secondary lymphoid tissue. Blood 2007;109(11):4856-64.

Journal of Biologic Chemistry

Three Stars Du J, Wang H, Zhong C, et al. Structural basis for recognition of CD20 by therapeutic antibody Rituximab. J Biol Chem 2007;282(20):15073-80.

Rheumatology International

Three Stars Henes JC, Richter C, Kanz L, Koetter I. B-cell depletion in patients with rheumatoid arthritis refractant to multiple TNF blockers and the interleukin 1 receptor-antagonist anakinra: Good responses in an extreme negative selection. Rheumatol Int 2007;Jun 12. [Epub ahead of print]
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Center for Continuing Education | 1950 Richmond Road, TR204, Lyndhurst, OH 44124