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Rheumatology Advance Access published online on April 8, 2008
Rheumatology, doi:10.1093/rheumatology/ken071
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A dose-escalation study of rituximab for treatment of systemic lupus erythematosus and Evans’ syndrome: immunological analysis of B cells, T cells and cytokines

Y. Tamimoto1, T. Horiuchi1, H. Tsukamoto1, J. Otsuka1,2, H. Mitoma1, Y. Kimoto1, H. Nakashima1, K. Muta3, Y. Abe3, C. Kiyohara4, A. Ueda5, K. Nagasawa6, S. Yoshizawa7, T. Shimoda7 and M. Harada1

1Department of Medicine and Biosystemic Science, Kyushu University, Fukuoka, 2National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, 3Department of Medicine and Bioregulatory Science, 4Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 5Miyazaki Prefectural Miyazaki Hospital, Miyazaki, 6Department of Internal Medicine, Saga University, Saga and 7National Hospital Organization Fukuoka Hospital, Fukuoka, Japan.

Correspondence to: T. Horiuchi, Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. E-mail: horiuchi{at}intmed1.med.kyushu-u.ac.jp


  Abstract

Objective. Accumulating evidence suggests that B-cell depletion therapy by rituximab may be effective for autoimmune disorders. However, an optimal dose of rituximab and a mechanism of its action remain to be established. We performed a dose-escalation study for treatment of Japanese patients with autoimmune diseases including eight with SLE and one with Evans’ syndrome.

Methods. Rituximab was infused intravenously, weekly 4 times in a dose-escalating fashion at three different doses of 100, 250 or 375 mg/m2 to three patients each. Immunological parameters were monitored at certain points until 12 months after the treatment.

Results. Rituximab was well tolerated and safe in these patients. Seven out of eight SLE patients and one with Evans’ syndrome clinically responded completely or partially to the treatment. Four patients achieved long-term remission (18–30 months) without any additional treatment. In these patients, a significant decrease in circulating B cells continued for 6 months after the treatment. The mean fluorescence intensities of CD19, CD21, CD40 and BR3 on the residual B cells as well as the percentage of CD69+ CD4+ T cells decreased significantly. Serum TNF-{alpha} levels decreased significantly on day 2. The Th1/Th2 balance of CD4+ T cells gradually shifted towards a Th1 type by 6 months.

Conclusion. In addition to B-cell depletion, modification of B-cell and T-cell phenotypes as well as cytokine profiles may be involved in the action of rituximab.

KEY WORDS: SLE, Evans'syndrome, Rituximab, B-cell depletion, CD19, T cell–B cell interaction

Submitted 5 September 2007; revised version accepted 30 January 2008.
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