Blood and salivary-gland BAFF-driven B-cell hyperactivity is associated to rituximab inefficacy in primary Sjögren's syndrome

J Autoimmun. 2016 Feb:67:102-110. doi: 10.1016/j.jaut.2015.11.002. Epub 2015 Dec 10.

Abstract

Objectives: To determine whether B-cell markers (blood and minor salivary gland [SG] B-cell depletion [BCD], autoantibodies, B-cell-activating factor [BAFF]) are associated with clinical response to rituximab in patients with primary Sjögren's syndrome (pSS).

Methods: 45 patients with pSS were included: in group I, 14 received low-dose rituximab (two 375-mg/m(2) infusions) in an open-labelled study; in group II, 17 received full-dose rituximab (two 1000-mg infusions) and 14 received a placebo in a randomized, controlled study. The proportion of SG B cells was assessed using pixel-based software analyses of digitized double-immunostained (CD3/CD20) whole SGs. Response was defined at week-24 according to the Sjögren's Syndrome Responder Index (SSRI)-30.

Results: Response rate was 50% in both groups of rituximab-treated patients. Duration of blood BCD was similar in both groups despite the difference in rituximab dosage, and was highly correlated with residual serum-rituximab levels at week-16. SG B-cell dynamics mirrored blood B-cell levels, with a drastic decrease in SG B-cells at week-12 (group I), but an increase in ∼ 50% of patients in group II by week-24, in whom blood B cells had already returned. Duration of BCD was not associated with the clinical response, but responders had lower baseline proportions of SG B cells. Baseline serum BAFF level was correlated with the proportion of SG B-cells and other B-cell-activation markers, and was associated with the clinical response with higher levels in non-responders.

Conclusions: In pSS, half of the patients display an intense BAFF-driven B-cell activation and do not respond to a single course of rituximab.

Keywords: B cells; BAFF; Histology; Primary; Rituximab; Sjögren's syndrome; Treatment efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • B-Cell Activating Factor / metabolism*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Biomarkers
  • Female
  • Humans
  • Immunologic Factors / administration & dosage
  • Immunologic Factors / pharmacokinetics
  • Immunologic Factors / therapeutic use*
  • Lymphocyte Activation* / immunology
  • Lymphocyte Depletion
  • Male
  • Middle Aged
  • Rituximab / administration & dosage
  • Rituximab / pharmacokinetics
  • Rituximab / therapeutic use*
  • Salivary Glands / immunology
  • Salivary Glands / metabolism*
  • Sjogren's Syndrome / diagnosis
  • Sjogren's Syndrome / drug therapy*
  • Sjogren's Syndrome / etiology
  • Sjogren's Syndrome / metabolism*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Treatment Failure
  • Treatment Outcome

Substances

  • B-Cell Activating Factor
  • Biomarkers
  • Immunologic Factors
  • TNFSF13B protein, human
  • Rituximab