ROCHESTER, New York—A subgroup of systemic lupus erythematosus (SLE) patients treated with B-cell depletion using rituximab have prolonged clinical responses and autoantibody normalization. Jennifer H. Anolik, MD, PhD, and colleagues report in Arthritis & Rheumatism that these patients also have delayed memory B-cell recovery in peripheral blood and lymphoid tissue.¹

"Although the broader applicability of these findings should be confirmed in a larger group of patients, the possibility is raised that profound B-cell depletion and subsequent de novo reconstitution may provide the autoimmune system with a chance to re-form. It is important to bear in mind, however, that this may be at the expense of a treatment-induced immunodeficiency," Dr. Anolik noted.

41-month follow-up in rituximab-treated SLE patients

Fifteen SLE patients were treated with rituximab as part of a phase I/II dose-ranging study. At a mean follow-up time of 41 months, Dr. Anolik used multicolor flow cytometry to assess B-cells from peripheral blood and tonsils with regard to expression of defined surface markers.

In patients with clinical responses lasting >5 years and autoantibody normalization, the researchers found that

• reconstitution of peripheral blood CD27+ memory B-cells was delayed for several years
• peripheral blood memory B-cell delay correlated with the expansion of transitional B-cells (which are in developmental transition between immature B-cells in the bone marrow and mature naïve B-cells in the periphery)
• peripheral blood memory B-cell delay correlated with absence of antinuclear autoantibodies
• lymphoid tissue had active germinal center (GC) reactions, and
• lymphoid tissue had decreased numbers of memory B-cells with the Fc receptor homolog-4 (FcRH-4) marker
• normal total serum IgG and IgM levels

In these patients, lymphoid tissue recovered slowly after B-cell depletion therapy and peripheral blood memory B-cells recovered even more slowly.

"The presence of GC reactions, but with altered memory B-cell subpopulations in tonsils suggests that peripheral blood memory cell reconstitution lags behind a slow secondary lymphoid tissue recovery, with important implications for immunologic competence and tolerance," Dr. Anolik said.

Patients with less durable clinical responses or with no clinical response had faster memory B-cell recovery, particularly "a rapid and selective expansion of postswitched memory B-cells," the researchers reported. This indicates faster peripheral blood expansion of post-GC memory cells than of memory B-cells arising from the marginal zone.

These differences point to the heterogeneity of the human memory B-cell population. "Our observation that this [FcRH-4] memory cell subpopulation is strikingly decreased during recovery from B-cell depletion therapy is consistent with the idea that it represents a different sublineage of memory B-cells," Dr. Anolik added.

These findings may have both clinical and theoretical implications. The investigators suggest that a reconstitution profile dominated by memory B-cells rather than transitional B-cells might indicate incomplete or inadequate response to rituximab.

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