Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy

Abstract

Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS).

Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded.

Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades ≥2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected.

Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS.

Classification of evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective.

Figure 1. Flowchart of case ascertainment

This flowchart depicts how the 822 rituximab (RTX)–treated patients with multiple sclerosis (MS) were identified. The source population was all MS cases registered in the Swedish MS register at the 3 participating MS centers (Umeå University Hospital, Umeå, until April 12, 2015; Karolinska University Hospital, Stockholm, until February 24, 2015; and Sahlgrenska University Hospital, Gothenburg, until April 18, 2015). We excluded patients lost to follow-up and patients treated with RTX for reasons other than MS (e.g., rheumatoid arthritis, systemic lupus erythematosus, and neuromyelitis optica).

Figure 2. B-cell and immunoglobulin G (IgG) levels before and during rituximab treatment in multiple sclerosis cases

B-cell and IgG levels at samplings immediately before rituximab infusions 1–12. The numbers of cases used to estimate the means and SDs are shown below the figure for IgG (top row) and B cells (lower row). ^aAt Umeå Hospital and Sahlgrenska University Hospital, the B-cell levels are shown as mean percentage of CD19+ cells within the CD45+ cell population. ^bAt the Karolinska University Hospital, the B-cell levels are shown as mean absolute numbers (×10⁶) of CD19+ cells/mL blood. ^cInfusions 8–12 were merged due to few cases.

Figure 3. Radiologic and clinical disease activity over time, and by disease subtype, in 822 rituximab-treated Swedish patients with multiple sclerosis (MS)

The percentage of MRIs with contrast-enhancing lesions (CELs, left y-axis, blue bars), as well as the annualized relapse rate (right y-axis, green bars), for patients with MS treated with rituximab, by time period after rituximab treatment initiation, or MS subtype (x-axis). The numbers of patients at risk were calculated as the number of patients entering each time period. The person-time variable was calculated as number of years from treatment initiation to data censure, or 12 months after last infusion in case of treatment discontinuation, whichever came first. ARR = annualized relapse rate; PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis.