A longitudinal analysis of SLE patients treated with rituximab (anti-CD20): Factors associated with B lymphocyte recovery☆
Introduction
Rituximab, a chimeric anti-CD20 monoclonal antibody, was first approved in 1997 as an effective treatment for a subpopulation of CD20+ B cell non-Hodgkin's lymphoma [1], [2]. It is now also being used to treat autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus in which B cells are thought to play a pathogenic role. It has been hypothesized that elimination of pre-plasma B cells in patients with a preferential recurrence of naive cells will reestablish B cell tolerance during reconstitution [3], [4], [5].
Recent studies have described the pattern of depletion and reconstitution of the circulating B cell compartment following the treatment of patients with both rheumatoid arthritis and SLE with rituximab [6], [7], [8], [9], [10]. In patients with rheumatoid arthritis, depletion of B lymphocytes occurs uniformly and regeneration follows a characteristic pattern with an early presence of immature cells in addition to recirculating plasma cells [6]. The repopulation of the memory B cell compartment is delayed in these patients. In contrast, B cell depletion is highly variable among SLE patients ranging from complete and prolonged to transient to incomplete with an increase in the percentage of naive B cells after reconstitution [9].
Given the documented variability in the biological response to B-cell-targeted therapy in SLE patients, the current study employed a longitudinal analysis of B, T and NK lymphocytes in individual patients to gain further insight into the kinetics of B cell depletion and the factors associated with subsequent auto-reconstitution. Findings included (1) three out of four patients with a high proportion of circulating transitional B lymphocytes at baseline exhibited short-lived B cell depletion, suggesting that the baseline phenotype may predict the length of depletion in some patients. (2) Transitional B lymphocytes were usually the first cells to return, irrespective of the baseline phenotype. (3) A variable kappa:lambda light chain ratio (κ:λ) was observed when the B cells first returned. (4) A relative and absolute increase of circulating natural killer cells was observed during B lymphocyte depletion in 8 out of 12 patients.
Section snippets
Patients/Clinical parameters
Patients, aged 23–56 years, who fulfilled the American College of Rheumatology criteria for SLE [11] were recruited from the University of Pennsylvania to receive rituximab as part of a multi-center phase 1, open label trial aimed to assess the safety and efficacy of rituximab in the management of SLE. All patients had SLE for at least 6 months prior to the start of the study, had failed a least one immunosuppressive drug and had active disease. Each patient underwent a 1-month washout period
Overview of the study design
Patients with SLE tend to be heterogeneous with respect to disease activity and their immunologic profiles, including the composition of their lymphocyte subsets [12], [13], [14]. Therefore, this study utilized a longitudinal analysis of peripheral blood lymphocytes in 12 patients with SLE in which a baseline sample from each patient was compared to all subsequent samples from the same patient. In addition, the baseline phenotype of the SLE subjects was compared to the phenotype of 13 control
Discussion
This study suggests that the biological response to rituximab in patients with SLE is positively correlated with the length and depth of B cell depletion. However, alterations in the B cell compartment varied between patients. Based on these data, three factors were identified that may serve as candidate biomarkers in the setting of B cell depletion: the proportion of transitional B cells at baseline may predict the longevity of depletion, the κ:λ ratio may give insight into clonal expansion
Acknowledgments
We are grateful for the contributions of our patients and to Felicia Barnack and Sadia Kahn, MD, for their help with the clinical trial, to Noah Goodman for his help with flow cytometry and the University of Pennsylvania flow cytometry core facility.
Disclosures: R.E. and E.L.P. serve as consultants to Genentech. R.E. has also received support for clinical and basic research from Genentech.
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J.S. is supported by NIDDK T32 DK63688. R.E. and E.L.P. are supported by an innovative research grant from the Alliance for Lupus Research. Additional funding for this study was provided by Genentech, Inc.