Rituximab Versus Mycophenolate Mofetil for Infection Risk in Systemic Sclerosis

To the Editor:

Despite widespread first-line use of mycophenolate mofetil (MMF) and the growing adoption of rituximab (RTX) for systemic sclerosis (SSc), comparative data on their relative infection risks remain scarce.^1,2 Investigating how these treatments may affect infection risk is crucial to establish comprehensive safety and efficacy profiles and guide treatment selection.²

We conducted an emulated trial with patients across 121 healthcare organizations using medical record data from a deidentified database, TriNetX, comparing infection risk among patients with SSc treated with either MMF or RTX as monotherapy.

We included patients aged ≥ 18 years with a new diagnosis of SSc between 2016 and 2020 with a first prescription for either agent within a year of diagnosis, and without prior diagnosis of any cancer or HIV. To emulate an intention-to-treat analysis, patients were analyzed according to their initial treatment assignment. For each cohort, combination therapy with any other study medication was excluded to prevent confounding from treatment switching and mixed exposure effects. Outcomes (infection risks) were observed over 1 year, with a landmark set at 1 month to preclude outcomes occurring prior to or within 1 month after treatment initiation. Laceration and varicose vein diagnoses served as negative control outcomes. Previously validated and used International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10), and RxNorm-based algorithms (positive predictive value ≥ 87% for SSc), further confirmed by medication prescription, were used for cohort selection and outcome identification (Supplementary Material, available with the online version of this article).^3-5 Randomization was emulated through 1:1 propensity score matching with a greedy nearest-neighbor algorithm to balance groups on demographics, comorbidities, pulmonary function testing, and medication use. Hazard ratios (HRs) for all outcomes were estimated using Cox regression models on weighted samples. Full details on cohort, covariate, and outcome definitions and target trial specifications are available in the Supplementary Material.

After propensity score matching, 1649 patients were included in each group, with minimal baseline characteristic differences between groups (standardized mean difference [SMD] < 0.10; Table 1); the median follow-up time for both groups was 365 days. RTX treatment was associated with a higher risk of serious infections compared to MMF treatment (HR 1.29; 95% CI 1.03-1.64), primarily driven by an increased risk of pulmonary infections (HR 1.46; 95% CI 1.13-1.89; Table 2). There were no significant differences in risk between groups for any other infectious outcome types, nor diagnoses of trauma (laceration) or varicose veins (negative control outcomes).

Study strengths include extensive covariate matching, landmark analysis to mitigate immortal time and reverse causation bias, and negative control analysis. Study limitations include inability to evaluate combination therapy outcomes or SSc subtypes due to insufficient sample sizes, misclassification risk due to reliance on structured clinical data, and confounding by indication, though controlling for pulmonary function testing and comorbidities may reduce disease severity-related bias and other unmeasured confounders. For instance, infection risk in SSc may be correlated with impaired pulmonary function, which may contribute to residual confounding.⁶ Prospective randomized trials directly comparing these agents are warranted to validate study findings and further elucidate their relative efficacy and safety.

The observed increased risk of serious infections with RTX treatment, predominantly pulmonary in etiology, represents a novel and important consideration for clinical decision making that must be carefully weighed against emerging efficacy data in the individualized treatment of patients with SSc.^1,2

• Copyright © 2026 by the Journal of Rheumatology