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.

Sigrid Lunde,Einar K Kristoffersen,Dipak Sapkota,Øystein Fluge,Olav Dahl,Kristin Risa,Ove Bruland,Olav Mella,Mario D Cordero

doi:10.1371/journal.pone.0161226

Sigrid Lunde, Einar K Kristoffersen + Show 7 more

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https://doi.org/10.1371/journal.pone.0161226

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Journal: PloS one	Publication Date: Aug 18, 2016
Citations: 19	License type: CC BY 4.0

Affiliation: Haukeland University Hospital, University of Bergen

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.

Highlights

Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology affecting approximately 0.1–0.2% of the population [1]
In a pilot case series [10], followed by a phase II randomized and placebo-controlled trial (KTS-1-2008) [11], we found that B-cell depletion using the monoclonal anti-CD20 antibody rituximab was associated with clinical improvement in a subgroup of ME/CFS patients
There were no significant differences in the baseline serum BAFF levels between patients with mild, moderate or severe ME/CFS according to the NICE-guidelines [25], or between baseline serum BAFF levels and disease duration categorized as 2–5, 5–10 and >10 years

Summary

Introduction

Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology affecting approximately 0.1–0.2% of the population [1]. There is a growing interest in the role of the immune system in the etiology of ME/CFS. In a pilot case series [10], followed by a phase II randomized and placebo-controlled trial (KTS-1-2008) [11], we found that B-cell depletion using the monoclonal anti-CD20 antibody rituximab was associated with clinical improvement in a subgroup of ME/CFS patients. In a subsequent open-label phase II trial (KTS-2-2010) using rituximab induction and maintenance to prolong the B-cell depletion period, prolonged clinical response durations were observed [12]

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