Rheumatology Advance Access originally published online on November 22, 2005
Rheumatology 2006 45(1):122-123; doi:10.1093/rheumatology/kei189
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LETTER TO THE EDITOR |
Rituximab reduces both quantity and quality of B cells in SLE: reply
First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
Correspondence to: Y. Tanaka, First Department of Internal Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu 807-8555, Japan. E-mail: tanaka{at}med.uoeh-u.ac.jp
SLE is an autoimmune disease characterized by autoreactive T cells and polyclonal activation of B cells. We reported that five SLE patients with organ-threatening disorders, resistant to intensive conventional therapies, were treated by weekly use of rituximab (375 mg/m2, twice), and that sufficient evidence of excellent tolerability and high efficacy of rituximab therapy was obtained. Moreover, a rapid and marked reduction in the expression of the costimulatory molecules CD40 and CD80 on B cells was found on serial phenotypic assessments of residual B cells in all five patients. Such down-regulation was seen for more than 7 months in two patients, implying that reduction of both the quantity and the quality of B cells by rituximab could improve the disease course in refractory SLE [1].
Furthermore, we have recently found that the expression of CD40L, a ligand for CD40, and inducible T cell co-simulator (ICOS), a ligand for CD80 and CD86, was also down-regulated on CD4+ T cells in some of SLE patients (unpublished data by MT and YT). Sfikakis et al. [2] also reported that rituximab consistently decreased CD40L-bearing CD4+ T cells by 4-fold as early as 1 month from baseline in 10 patients with lupus nephritis, and that the expression of CD40L was almost blocked when partial remission was clinically evident. On the other hand, Anolik et al. [3] reported that rituximab improved abnormalities in B-cell homeostasis, with a decreased proportion of autoreactive memory B cells after treatment. Therefore, rituximab-induced depletion of memory B cells could also prevent the activation of autoreactive T cells through interactions with B cells, resulting in the down-regulation of CD40L and ICOS on CD4+ T cells.
Dr Okamoto's comments that rituximab might suppress Th1-dominant disorders by reducing interactions between CD40–CD40L and CD80–CD28 are a fascinating explanation of the dramatic efficacy of the therapy for neuropsychiatric SLE, in which Th1 dominance has been reported. However, although rituximab completely down-regulated CD40 and CD80 expression on B cells in all 10 recently assessed SLE patients, it decreased CD40L on CD4+ T cells in only half of the patients (unpublished data by MT and YT). Thus, the effects of rituximab on the Th1–Th2 balance remain unclear and further studies are required. Alternatively, rituximab might change the proportions of helper or autoreactive T cells and regulatory T cells, since following rituximab treatment some patients displayed sharp increases in their CD25+/CD4+ cell counts [2]. However, this was observed in only some SLE patients and further studies are again needed.
The CD40–CD40L pathway is known to play a central role in the B cell–T cell interactions that provide the pathological autoimmune responses, and overexpression of CD40L always correlates with disease activity of SLE. A reduction in both the quantity and the quality of B cells interacting with T cells through CD40–CD40L was observed with rituximab, implying that rituximab may improve the disease course of SLE by partially resetting the autoimmune responses. Thus, therapeutic B-cell depletion by rituximab has not only provided an opportunity to learn more about the biology of B cells and their roles in the pathogenesis of SLE and other autoimmune diseases, but has also brought a promising treatment a step closer to the clinic [4].
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No conflict of interest has been declared.
References
- Tokunaga M, Fujii K, Saito K et al. Down-regulation of CD40 and CD80 on B cells in patients with life-threatening systemic lupus erythematosus after successful treatment with rituximab. Rheumatology 2005;44:176–82.
[Abstract/Free Full Text] - Sfikakis PP, Boletis JN, Lionaki S et al. Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheum 2005;52:501–13.[CrossRef][Web of Science][Medline]
- Anolik JH, Barnard J, Cappione A et al. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 2004;50:3580–90.[CrossRef][Web of Science][Medline]
- Silverman GJ. Anti-CD20 therapy in systemic lupus erythematosus: a step closer to the clinic. Arthritis Rheum 2005;52:371–7.[CrossRef][Web of Science][Medline]
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