Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic  Encephalopathy/Chronic Fatigue Syndrome.

Abstract

Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We have previously suggested clinical benefit from B-cell depletion  using the monoclonal anti-CD20 antibody rituximab in a randomized and  placebo-controlled study. Prolonged responses were then demonstrated in an  open-label phase-II study with maintenance rituximab treatment. Using blood  samples from patients in the previous two clinical trials, we investigated  quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum  levels of two B-cell regulating cytokines during follow-up. B-lymphocyte  activating factor of the tumor necrosis family (BAFF) in baseline serum samples  was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p =  0.011). There were no significant differences in baseline serum BAFF levels  between patients with mild, moderate, or severe ME/CFS, or between responders and  non-responders to rituximab. A proliferation-inducing ligand (APRIL) serum levels  were not significantly different in ME/CFS patients compared to healthy controls  at baseline, and no changes in serum levels were seen during follow-up.  Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation  markers at multiple time points during follow-up showed no significant  differences over time, between rituximab and placebo groups, or between  responders and non-responders to rituximab. Baseline serum IgG levels were  significantly lower in patients with subsequent response after rituximab therapy  compared to non-responders (p = 0.03). In the maintenance study, slight but  significant reductions in mean serum immunoglobulin levels were observed at 24  months compared to baseline; IgG 10.6-9.5 g/L, IgA 1.8-1.5 g/L, and IgM 0.97-0.70  g/L. Although no functional assays were performed, the lack of significant  associations of T- and NK-cell subset numbers with B-cell depletion, as well as  the lack of associations to clinical responses, suggest that B-cell regulatory  effects on T-cell or NK-cell subsets are not the main mechanisms for the observed  improvements in ME/CFS symptoms observed in the two previous trials. The modest  increase in serum BAFF levels at baseline may indicate an activated B-lymphocyte  system in a subgroup of ME/CFS patients.