A comprehensive Norwegian observational study has demonstrated that rituximab provides superior disease control compared to cladribine in patients with relapsing-remitting multiple sclerosis (RRMS), offering new insights for clinicians managing aggressive disease presentations. The research, conducted over a median follow-up of 4.5 years, analyzed 285 patients from two geographically distinct university hospitals using a target trial emulation framework.
Study Design and Patient Population
The study leveraged treatment preferences at two Norwegian institutions: Haukeland University Hospital, which favored rituximab (Rituxan; Genentech), and Oslo University Hospital, which preferred cladribine (Mavenclad; Merck KGaA). Treatment assignment was largely based on patient residence, creating a quasi-random allocation that reduced selection bias. Researchers used propensity scores to match patients on key characteristics including age, sex, disease duration, past treatments, MRI markers, disability scores, and relapse history.
Significant Differences in Disease Activity Control
The primary endpoint of new MRI disease activity over 4 years strongly favored rituximab. Only 17% of rituximab-treated patients (95% CI: 11-23) developed new MRI activity compared to 57% of cladribine-treated patients (95% CI: 44-66), representing an absolute risk difference of approximately 40 percentage points (95% CI: 28-50). Patients receiving rituximab remained free from new MRI activity for an average of 16.8 months longer than those on cladribine.
The study also revealed substantial differences in clinical outcomes. Rituximab demonstrated superior performance in relapse prevention, with only 6% of patients experiencing relapses versus 17% in the cladribine group, showing a risk difference of approximately 12 percentage points. Treatment discontinuation rates also favored rituximab at 7% compared to 21% for cladribine, with a risk difference of about 15 percentage points.
Disability Outcomes and Biomarker Analysis
Beyond disease activity control, rituximab showed advantages in disability outcomes. While the overall change in disability scores did not differ significantly between groups, 21% of rituximab patients experienced disability improvement compared to only 4% of cladribine patients, representing a risk difference of approximately 18% (95% CI: 4-29).
Patients treated with rituximab demonstrated a substantially higher likelihood of achieving NEDA-3 status (no evidence of disease activity), with an odds ratio of 15.9 (95% CI: 3.8-92.4) compared to cladribine. Biomarker analysis revealed that serum glial fibrillary acidic protein (GFAP), a potential indicator of disease progression, was significantly lower in the rituximab group, while neurofilament light chain levels remained similar between treatments.
Safety Profile Comparison
The safety analysis showed comparable hospitalization rates for adverse effects between the two treatments: 6 per 100 patient-years for rituximab versus 4.1 per 100 for cladribine. However, more rituximab patients were hospitalized for COVID-19 (16 versus 2), potentially indicating increased susceptibility to infection or closer monitoring during the pandemic period. No deaths were reported in either group, and overall infection rates were similar between treatments.
Clinical Implications
The study's findings provide valuable real-world evidence supporting rituximab as a more efficacious treatment option for RRMS patients requiring aggressive therapy. The research demonstrates rituximab's superior ability to reduce radiologic disease activity, lower relapse rates, improve disability outcomes, and achieve comprehensive disease control while maintaining a comparable safety profile to cladribine.
These insights from real-world practice offer important guidance for clinicians weighing treatment options in RRMS management. The ongoing NOR-MS randomized controlled trial (NCT04121403) is expected to provide additional confirmation of these findings in a fully randomized setting.
