Elsevier

Journal of Autoimmunity

Volume 67, February 2016, Pages 102-110
Journal of Autoimmunity

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

https://doi.org/10.1016/j.jaut.2015.11.002Get rights and content

Highlights

  • The clinical response to rituximab is highly heterogeneous in pSS.

  • The pattern and timing of B-cell depletion is similar in blood and salivary glands.

  • The duration of B-cell depletion is not associated with rituximab clinical efficacy.

  • BAFF drives B-cell hyperactivity and resistance to rituximab in half of the patients.

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/m2 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.

Introduction

Despite several previous studies, which support a major role for B cells in the development of primary Sjögren's syndrome (pSS) and suggest the potential efficacy of rituximab [1], the large randomized controlled TEARS trial recently failed to prove a major improvement in pSS symptoms at 6 months after a single course of rituximab [2]. However, post-hoc analyses revealed that this failure could be partly explained by the inability of the chosen primary endpoint to detect the effect of rituximab. Indeed, half of the rituximab-treated patients experienced notable improvements during the 6 months following the infusions, assessed either with the newly developed composite Sjögren's Syndrome Responder Index (SSRI)-30 [3] or with ultrasonography [4]. Therefore, it seems to be of utmost importance to determine the factors (or markers) that lead to resistance to rituximab in some patients in order to better define potential indications and to design new therapeutic strategies that can be tested in future clinical trials.

The dosage and pharmacokinetics [5] of rituximab may influence its clinical efficacy. Several studies and a recent meta-analyses suggest that, in rheumatoid arthritis (RA), a “half-dose protocol” is not inferior to a full-dose on the clinical response [6], [7]. Conversely, a higher dose (three 1000-mg infusions) could be more effective that the standard regimen when given to patients with incomplete early depletion of blood B-cells [8]. In ANCA-associated vasculitis (AAV), a low-dose rituximab protocol (500 mg every 6 months) was shown to have remarkable efficacy as a maintenance therapy [9].

The level and duration of blood B-cell depletion is another potential factor that could be associated with rituximab's clinical efficacy, but data are inconsistent in the literature. In RA, AAV or systemic lupus erythematosus (SLE), some patients experience disease flares despite persistent blood B-cell depletion, whereas others have persistent clinical remission several months after blood B-cell reconstitution [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. The level of tissue B cells is also of interest, but whether target tissue B-cell dynamics are associated with blood B-cell depletion is ill-defined. Synovial biopsy studies in RA show that rituximab treatment leads to a rapid and significant decrease in synovial B cell numbers, but not in all patients [22], [23], and that this depletion does not affect resident synovium-plasma cells [24]. In pSS, we have previously reported that salivary gland (SG) B cells were depleted early after rituximab therapy, and that this depletion could last for several months in some patients [25]. Another group described complete minor-SG B-cell depletion after very intensive rituximab therapy (five courses of two 1000-mg infusions over 2.5 years) [26]. Finally, studies using parotid biopsies show that B cells were only partially depleted at 12 weeks after rituximab therapy [27] and that immunoglobulin-producing cells were not affected [28]. However, these results are difficult to compare due to differences in the timing of biopsies and the immunohistochemistry methods. Furthermore, manual quantification of stained cells by a pathologist is long and fastidious, and cannot explore a whole specimen but focuses on specific fields on the slide, which leads to potential overlaps and duplication of counts of the same cell.

The B-cell-activating factor (BAFF) is a critical cytokine in B-cell survival and activation, and is another target factor in autoimmune diseases [29]. Indeed, several studies report on the major role of BAFF in the pathophysiology of pSS [30], [31], [32], [33], [34], [35], [36]. We have previously shown that baseline BAFF level is associated with the duration of blood B-cell depletion in pSS patients [25]. Therefore, BAFF could be a significant determinant of the efficacy of rituximab in pSS.

The aim of this study was to assess the relationships between these potential predictive factors (i.e. rituximab dose and pharmacokinetics, blood and SG B-cell depletion levels and duration, circulating B-cell activity markers), and the clinical response to rituximab in pSS patients.

Section snippets

Patients

Patients from two clinical trials on rituximab therapy in pSS were included in our analyses (Table 1). The first study, referred to as group I, was a monocentric open-labelled trial on two low-dose rituximab infusions (375 mg/m2, 1 week apart without concomitant steroids) in 16 patients fulfilling the American-European Consensus Group (AECG) criteria for pSS. The study was conducted in Brest University Hospital between 2004 and 2006 [37]. Among these patients, 14 had undergone an MSGB at

The populations of patients

Table 1 presents the general characteristics of the 45 patients. Group I patients (n = 14) were similar to the rituximab-treated patients in group II (n = 17) in terms of age at inclusion, gender-ratio, symptom intensity, frequency of systemic involvement, focus score, and autoantibodies; but they had suffered a significantly longer duration of symptoms (12.6 ± 8.5 vs 6.3 ± 4.2 respectively, p = 0.01), a higher global activity of the disease as assessed by the physician (80.8 ± 12.1 vs

Discussion

In this study, we aimed to assess the usefulness of various B-cell related biomarkers in pSS patients to predict the response to rituximab. The strength of our approach relies on the analyses of well-characterized patients from two prospective trials, but also on the use of new validated tools that better assess the clinical response (i.e. SSRI) and evaluate SG B-cell infiltration (i.e. digital quantitative procedure). We have demonstrated that rituximab-induced target tissue B-cell depletion

Conclusions

This study shows that the varied responses of pSS patients to rituximab are associated with pre-treatment BAFF levels and subsequent B-cell activation, which suggests that the role of blood and/or salivary-gland B-cell-related biomarkers in the modulation/personalization of treatments that target B-cells in pSS patients should be promptly assessed in future trials.

Disclosures

EH, VG, VDP and AS received consulting fees from Roche of <10,000 US$ each.

Funding

The TEARS study was funded by the French public funding agency Programme Hospitalier de Recherche Clinique (PHRC) 2010. Rituximab was donated by Roche.

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