Early Rituximab Use in Sjögren’s Syndrome: A Meta-Analysis Review

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disorder primarily affecting exocrine glands and characterized by lymphocytic infiltration. It often leads to sicca symptoms, but its systemic involvement can include fatigue, arthralgia, and neurological or pulmonary complications. B-cell activity plays a central role in its pathogenesis, which is why rituximab (RTX), an anti-CD20 monoclonal antibody, is showing promise as a therapeutic option.

While RTX has demonstrated efficacy in other autoimmune conditions, its effectiveness in pSS remains controversial, especially when considering the timing of intervention relative to disease duration. To further examine the efficacy of RTX, a review published in the Journal of Rheumatic Diseases in July 2025 conducted a systematic evaluation and meta-analysis of both randomized and quasi-experimental studies.

Here's a quick overview of what it found.

Methods: Stratified Analysis of Trial Designs and Disease Duration
This systematic review and meta-analysis included 15 studies—4 randomized controlled trials and 11 quasi-experimental studies—evaluating RTX for pSS. The primary outcome was disease activity assessed by the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), with secondary outcomes focusing on adverse events (AEs). Meta-regression and subgroup analyses were conducted to evaluate whether disease duration modified RTX efficacy. The researchers adopted a random-effects model to address heterogeneity, with analyses standardized to the 24-week (six-month) post-treatment mark.

Results: Discordant Signals Between Study Designs
In RCTs, RTX failed to significantly reduce disease activity compared to placebo. The pooled mean difference in ESSDAI scores was just 0.09 (95 percent CI: –0.43 to 0.61), with substantial heterogeneity (I² = 76.39 percent). Conversely, quasi-experimental studies showed a significant reduction in ESSDAI (mean difference –4.36, 95 percent CI: –5.83 to –2.89), with moderate heterogeneity (I² = 73.87 percent). When both study types were combined, the overall standardized mean difference remained significant, favoring RTX (–1.12, 95 percent CI: –1.54 to –0.69), though the heterogeneity across designs was high (I² = 90.16 percent).

Disease duration did not significantly correlate with treatment effect in either meta-regression or subgroup analyses. Both subgroups—those with mean disease duration under and over 60 months—showed comparable ESSDAI reductions following RTX, suggesting that treatment timing, at least within the multi-year range examined, may not strongly influence short-term efficacy.

Safety: Low Rates of Severe Reactions with Caveats
Across RCTs, adverse event rates were similar between RTX and placebo groups. Notably, 96 percent of RTX-treated patients experienced AEs, but only 16 percent were serious, and no deaths were reported. Quasi-experimental studies showed higher variability in AE reporting, with infections and infusion reactions being most frequent. Severe infections and isolated deaths were noted, but causality remains unclear due to confounding variables such as concomitant corticosteroid use.

Interpretation: Evidence Split Along Methodological Lines
The conflicting findings between RCTs and quasi-experimental studies reflect inherent methodological and clinical differences. RCTs enrolled patients with a longer average disease duration (93.6 months versus 59.9 in observational cohorts), used stricter control protocols, and had less favorable baseline ESSDAI reductions. Observational designs may overestimate benefit due to open-label effects, publication bias, and confounding by indication. However, the consistent trend in before-after improvements cannot be dismissed outright, particularly given the consistency across multiple studies and geographic settings.

The study’s attempt to isolate disease duration as a modifier of response did not yield a clear association, yet this may reflect a narrow treatment window across included trials. None administered RTX within nine months of symptom onset, a critical limitation when assessing true early-intervention efficacy.

Direction: A Need for Earlier, Longer, and Cleaner Data
The analysis underscores a critical gap: while RTX may be effective in reducing pSS activity at six months in real-world cohorts, definitive conclusions are hampered by insufficient high-quality RCT data. Future studies must address delayed diagnosis, evaluate RTX as an early intervention (ideally within the first year post-diagnosis), and standardize outcome measures using tools like ESSDAI. Longitudinal data on safety, particularly with concurrent immunosuppressants, remains limited but essential given concerns over infection risk.

The therapeutic potential of RTX in pSS remains unresolved. This meta-analysis sharpens the lens on design-driven discrepancies and points to a more rigorous future, where early, targeted, and safety-conscious trials may finally settle the question of its clinical utility.

Reference:
Shahdadian M, Saghiri MA, Capitle E. Efficacy of early rituximab treatment in primary Sjögren’s syndrome: a systematic review and meta-analysis. J Rheum Dis. 2025;32(3):211-224. doi:10.4078/jrd.2024.0149