The authors have declared that no competing interests exist.
Conceived and designed the experiments: FBVS VFMT. Performed the experiments: FBVS GJMP BNGA VFMT. Analyzed the data: FBVS GJMP VFMT. Contributed reagents/materials/analysis tools: FBVS GJMP JVA BNGA VFMT. Wrote the paper: FBVS JVA.
Primary Sjögren’s Syndrome (pSS) is a systemic autoimmune disease that involves the exocrine glands and internal organs. pSS leads to destruction and loss of secretory function due to intense lymphoplasmacytic infiltration. Therapeutic options include mainly symptomatic and supportive measures, and traditional immunosuppressant drugs have shown no effectiveness in randomized trials. Rituximab (RTX) is a chimeric antibody anti-CD20 that leads to B cell depletion by diverse mechanisms. There is evidence that this drug may be effective for treating pSS. The objective of this systematic review was to evaluate Rituximab effectiveness and safety for treating pSS.
We conducted a systematic review of RCTs published until December 2015, with no language restriction. We registered a protocol on
According to moderate quality evidence, the treatment with a single RTX course in patients with SSp presents discrete effect for improving lacrimal gland function. Low-quality evidence indicates the potential of this drug for improving salivary flow. According to low quality evidence, no differences were observed in the evaluation after 24 weeks regarding fatigue reduction (30% VAS), serious adverse events occurrence, quality of life improvement and disease activity. With a very low level of evidence, there was no improvement in oral dryness VAS evaluation.
Primary Sjögren’s Syndrome (pSS) is a systemic autoimmune disease that involves the exocrine glands and internal organs. pSS leads to destruction and loss of secretory function due to intense lymphoplasmacytic infiltration [
Around 50% of individuals with pSS may have systemic involvement including the pulmonary, renal, hepatic, pancreatic, vascular, central nervous and peripheral nervous systems [
Rituximab (RTX) is a chimeric antibody anti-CD20 that leads to B cell depletion by diverse mechanisms. There is evidence that this drug may be effective for treating pSS [
The objective of this systematic review was to evaluate the effectiveness and safety of Rituximab for treating pSS.
We conducted a systematic review of the literature in the Department of Evidence-Based Health of the São Paulo Federal University (UNIFESP). We registered the protocol on the
We developed search strategies including the following terms and synonyms: “rituximab”, “CD20 antibody rituximab”, “Mabthera”, “Roche brand of rituximab”, “rituxan”, “Hoffmann-La Roche brand of rituximab”, “IDEC brand of rituximab”, “Genentech brand of rituximab”, “IDEC-C2B8 antibody”, “IDEC-C2B8”, “Sjogren's Syndrome”, “Sjogren Syndrome”, “Sjogrens Syndrome”, “Syndrome Sjogren's”, “Sicca Syndrome” and “Syndrome Sicca”. We ran the search strategies until December 2015 with filters for RCTs in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via PubMed), EMBASE and LILACS.
Two authors (FBVS and GJMP) independently screened titles and abstracts and evaluated the eligibility of the identified studies. They read the studies classified as possibly eligible in full text and decided which studies to include in the review. In case of language barrier, the authors submitted articles to a qualified translator, and in case of eligibility disagreements, a third author (VMFT) made the final decision. We discarded the non-eligible studies due to specified reasons.
We included only randomized controlled trials (RCTs) and excluded cluster or cross-over trials. We selected RCTs with participants over 18 years of age and with an established pSS diagnosis according to the 2002 American-European Revised Classification Criteria [
We considered the following primary outcomes: lacrimal gland function, evaluated through the Schirmer test, lissamine green or fluorescin test and VAS; salivary gland function, evaluated through salivary flow rate and VAS; and fatigue evaluated through the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), VAS and the Profile of Fatigue and Discomfort (PROFAD). We also analysed the adverse events reported by authors.
We considered the following secondary outcomes: quality of life, measured through the Short Form-36 (SF-36) health survey or other validated instruments; disease activity, evaluated through the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) [
Two authors (FBVS and GJMP) extracted data from the studies through a standardized form with information about the participants, intervention, comparison, outcomes and characteristics. We assessed the risk of bias in each included study as high, low or unclear through the Cochrane Collaboration's tool for assessing risk of bias [
We included the data assessed at week 24 from baseline on the Review Manager (Revman) 5.3.4 software. We analysed continuum data through mean difference and dichotomous data through risk ratio. We calculated all the effect measures with a 95% confidence interval. We assessed the statistical heterogeneity between studies through the I2 statistic [
We planned subgroup analyses considering the organ specific commitment, intervention protocol (cycle, dosage, comparison to other drugs), time of disease and age. We also planned sensitivity analyses considering the risk of bias and heterogeneity between studies and the statistical model used in the meta-analyses. We evaluated the quality of evidence through the GRADE approach.
We identified 126 records and included four studies [
We analysed each included study through the Cochrane Collaboration’s tool for assessing risk of bias (
The included studies totalized 276 participants: 145 in the RTX group and 131 in the control group (placebo). All included studies [
Three of the included studies evaluated lacrimal gland function through the Schirmer test [
Meta-analysis of the outcome Schimer test at week 24.
Meijer et al. [
All included studies reported analysis of salivary flow data [
Meta-analysis of the outcome salivary flow rate at week 24.
Two [
Meta-analysis of the outcome oral dryness (VAS) at week 24.
All included studies evaluated fatigue through VAS. Dass et al. [
Meta-analysis of the outcome fatigue VAS 30% improvement at week 24.
We evaluated the quality of evidence through the GRADE approach. The Schirmer test meta-analysis presented moderate quality. The salivary flow rate and fatigue VAS 30% improvement meta-analyses presented low quality evidence. The oral dryness VAS meta-analysis presented very low-quality evidence.
Three of the included studies [
Meta-analysis of the outcome SF-36 mental component summary at week 24.
Devauchelle-Pensec et al. [
Meta-analysis of the outcome disease activity assessed through the ESSDAI at week 24.
Dass et al. [
Only Meijer et al. [
Two studies evaluated immunoglobulin levels [
Only Bowman et al. [
All included studies reported adverse effects. Infusion-related reactions such as shiver, macular rash and purpura were more frequent in the RTX, as well as gastrointestinal, musculoskeletal and respiratory disorders. However, Meijer et al. [
Meijer et al. [
Devauchelle-Pensec et al. [
Devauchelle-Pensec et al. [
Bowman et al. [
Serious adverse events occurred in 25 participants of the RTX group [
Meta-analysis of the outcome serious adverse events at week 24.
The number of published articles about the chimeric antibody anti-CD20 (rituximab) in the treatment of pSS has been growing over time. However, most identified studies are case reports or series of specific systemic manifestations. Of the studies found, only four met the inclusion criteria of our study, and one [
Patients with pSS present B cell hyperactivity, which suggests an important role of these cells in the pSS pathogenesis [
There is still no consensus regarding the best time interval to evaluate the pSS treatment efficacy [
Systemic manifestations were not evaluated in the studies and the follow-up period was short, therefore it was not possible to analyze bad prognostic factors of the disease. Our main results were regarding ocular gland function, salivary gland function and fatigue. Two studies [
Patients with pSS present high incidence of non-Hodgkin lymphoma, mainly mucosa lymphomas [
A significant increase in the risk of adverse effects, mainly infusion reactions and respiratory disorders, was noted for participants allocated to RTX compared to those given placebo in all included studies. However, infection rates were similar between the groups in three studies: Dass et al. [
This review highlights the difficulty and inadequacy of research in pSS since that there are only a few randomized studies about RTX that compare the effectiveness of this drug to placebo or other drugs. The included studies presented similar endpoints, however the evaluation of outcomes still needs standardization. It was not possible to perform a subgroup or sensitivity analysis considering factors other than the model of effect used in the meta-analyses.
We evaluated only one treatment cycle since the assessment at week 24 was performed in all studies. Although Bowman et al. [
The number of participants included in this study was limited, even in the meta-analyses, and there was no efficacy analysis for different systemic manifestations. Regarding the benefits observed, only the outcome salivary flow demonstrated evidence of improvement, and RTX demonstrated itself to be safe since there were no differences in the presence of serious adverse events compared to the placebo group. For clinical practice, it is necessary to ponder the benefits and harms of this intervention in the treatment of pSS.
According to moderate-quality evidence, the treatment with a single RTX course for patients with SSp presents discrete effect for improving lacrimal gland function. Low quality evidence indicates the potential of this drug for improving salivary flow. According to low quality evidence, no differences were observed in the evaluation after 24 weeks regarding fatigue reduction (30% VAS), serious adverse events occurrence, quality of life improvement and disease activity. With a very low level of evidence, there was no improvement of oral dryness VAS evaluation.
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