Elsevier

Joint Bone Spine

Volume 85, Issue 1, January 2018, Pages 15-22
Joint Bone Spine

Recommendations and metaanalyses
Efficacy and safety of biological DMARDs modulating B cells in primary Sjögren's syndrome: Systematic review and meta-analysis

https://doi.org/10.1016/j.jbspin.2017.06.004Get rights and content

Abstract

Objective

In this review, we summarise the clinical efficacy and safety of B-cell targeted therapies for primary Sjögren's syndrome (pSS).

Methods

A systematic literature review was conducted using databases including MEDLINE, EMBASE and Cochrane. Only articles reporting controlled or prospective studies of b-DMARDs modulating B cells in treatment of pSS were selected. The highest-quality studies were selected for meta-analysis. The primary outcome of interest was clinical efficacy at week 24 on fatigue, dryness, Schirmer test, salivary flow rate and the full ESSDAI score including biological domain. For the efficacy criteria used, the difference between rituximab and placebo groups was expressed as mean difference (MD).

Results

Eighteen articles (13 of rituximab, 3 of belimumab, 1 of epratuzumab and 1 of baminercept) were identified for detailed evaluation. 4 controlled randomised trials of rituximab treatment vs. placebo involving 300 patients were included for quantitative analysis. No significant differences were observed between groups in the meta-analysis of mean improvements between baseline and week 24 in fatigue VAS [MD −3,24 95% CI (−30,21 to 23,72)], oral dryness VAS [MD −8,41 95% CI (−35,06 to 18,24)], salivary flow rate [MD 0,04 95% CI (−0,03 to 0,11)] and Schirmer test [MD 0,35 95% CI (−2,13 to 2,82)]. Rituximab was relatively safe compared to placebo.

Conclusion

Our review shows that rituximab is not effective in pSS with the designs and outcomes proposed in the trials. Controlled randomised trials are needed to prove the efficacy of belimumab and epratuzumab in this indication. The randomised controlled trial evaluating baminercept failed to achieve its primary endpoint.

Introduction

Sjögren's syndrome is a systemic autoimmune disease, characterised by lymphoplasmocytic infiltration of exocrine glands leading to a progressive functional impairment. Fatigue, articular pain, ocular and oral dryness are the main symptoms and these often reduce quality of life. However, for about one third of the patients, the disease is accompanied by systemic manifestations that can be serious and involve the musculoskeletal system, nervous system, lungs, kidneys, skin and blood vessels skin [1], [2]. Also about 5 to 10% of pSS patients are estimated to develop a B-cell lymphoma [3], [4].

Increasing evidence supports that B-cell hyperactivity plays a central role in pSS physiopathology as reflected by the presence of autoantibodies (rheumatoid factor (RF), anti-SSA/Ro and anti-SSB/La), cryoglobulins and hypergammaglobulinemia [5]. Cytokines playing a key role in B-cell homeostasis, such as BAFF and IL6 [5], are increased in this disease. Until today, the treatment of the Sjögren syndrome has been mainly based on symptomatic measures. Recently, guidelines have been published and the use of rituximab was considered as a therapeutic option in selected clinical settings for oral and ocular dryness and for certain systemic manifestations [6]. However, a recent review [2] suggests that rituximab should probably not be used in pSS, except in patients with severe disease and no other treatment options. Studies on rituximab and other B-cell targeted therapies showed conflicting results and their place in the management of pSS remains controversial. [7]. A recent meta-analysis of the results of randomised trials evaluating rituximab was performed [8]. However, this study has many methodological and statistical limitations.

The purpose of this systematic review and meta-analysis was to analyse and summarise the evidence on b-DMARDs modulating B cells for the main clinico-biological manifestations of primary Sjögren syndrome (sicca symptoms, fatigue, pain, ESSDAI) for adults.

Section snippets

Methods

This study was conducted in line with the guidelines of the Cochrane Collaboration and our findings are reported according to the Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The following sources were used: the Cochrane, Medline (from 1946) and Embase databases (from 1947) and the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) annual meetings’ databases up to April 12, 2016. The keywords used were Sjögren's

Literature research and study characteristics

The literature retrieving strategy is shown in the flowchart (Fig. 1). There were 416 potentially relevant papers and two ACR abstracts. After screening the title and reading the abstract and full-length article, 16 published articles [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [28] and two abstracts [25], [26] with a total of 636 patients were included in this review. The highest-quality studies, i.e. the randomised controlled trials, were selected

Discussion

Rituximab has shown encouraging results in open studies and two randomised controlled trials regarding the reported symptoms. However, our meta-analysis showed that neither statistical nor clinical significance was found in pooled results. The limits of our meta-analysis were the heterogeneity of endpoints between articles. Therefore, we could combine the results of two or three different studies for each criterion assessed. Moreover, the number of patients in each study was low, notably

Disclosure of interest

Supported by AbbVie: AbbVie France pharmaceutical company provided logistic support by organizing a meta-analysis methods workshop but played no further role in the project. No fund was received to carry out this study.

Pr Lukas, MD, PhD, has received honoraria from Roche-Chugai and UCB less than 8000€.

Pr Gaujoux-Viala, MD, PhD, has received honoraria from Roche-Chugai and UCB less than 8000€.

Pr Combe, MD, PhD, has received honoraria from Roche-Chugai and UCB less than 8000€.

Pr Morel, MD, PhD,

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