Serious safety events in rituximab‐treated multiple sclerosis and related disorders

Abstract

Introduction Studies investigating rates and risk factors for serious safety events (SSEs) during rituximab treatment of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and related disorders are limited. Methods Rituximab‐treated patients with MS, NMOSD, or related disorders at the Rocky Mountain and New York University MS Care Centers were included. The follow‐up period was defined as the time from the initial dose of rituximab up to 12 months of last dose of rituximab or ocrelizumab (in patients who switched). Clinician‐reported and laboratory data were retrospectively collected from electronic medical records. Results One‐thousand patients were included comprising 907 MS, 77 NMOSD, and 16 related disorders. Patients had a mean follow‐up of 31.1 months and a mean cumulative rituximab dose of 4012 mg. Of the 169 patients who switched to ocrelizumab, the mean ocrelizumab dose was 1141 mg. Crude incidence rate per 1000 person‐years (PY) for lymphopenia was 19.2, neutropenia 5.6, and hypogammaglobulinemia 17.8. Infections resulting in either hospitalization, IV antibiotics, or using antibiotics ≥14 days occurred at a rate of 38.6/1000 PY. Risk factors for infection were duration of therapy, male gender, increased disability, prior exposure to immunosuppression/chemotherapy, lymphopenia, and hypogammaglobulinemia. Particularly, wheelchair‐bound patients had 8.56‐fold increased odds of infections. Crude incidence rates of malignant cancer were 3.5, new autoimmune disease 2.3, thromboembolic event 3.1, and mortality of 5.4 per 1000 PY. Interpretation Rates of SSEs in patients with MS, NMOSD, and related disorders were low. Through properly assessing risk:benefit of B‐cell depleting therapy in neuroinflammatory disorders and continual monitoring, clinicians may decrease the risk of serious infections.

Rituximab-Induced Hypogammaglobulinemia and Infections in AQP4 and MOG Antibody–Associated Diseases

“…The effect of RTX-induced hypogammaglobulinemia on the rate of infection was reported recently in 2 retrospective studies including large cohorts of patients with autoimmune rheumatic diseases 2 and CNS inflammatory diseases. 18 Similarly, these studies revealed an association between the reduced IgG level and the rate of infection. In patients with CNS inflammatory diseases, Vollmer et al 18 found several other factors associated with risk of infection, including duration of RTX therapy, male sex, increased disability, prior exposure to immunosuppression, and lymphopenia.…”

“… 18 Similarly, these studies revealed an association between the reduced IgG level and the rate of infection. In patients with CNS inflammatory diseases, Vollmer et al 18 found several other factors associated with risk of infection, including duration of RTX therapy, male sex, increased disability, prior exposure to immunosuppression, and lymphopenia. In the present study, prior exposure to immunosuppression and male sex were associated with only reduced IgG level during RTX treatment but not infection risk.…”

Targeting B cells to modify MS, NMOSD, and MOGAD

“…50 In the US study referred to above, neutropenia of less than 500 cells/mm 3 was noted in 1.2% of patients on rituximab. 48 The same group of investigators observed low values of IgG evolving over a mean treatment period of 31.1 months and a mean cumulative dose of 4,012 mg in 6%. 48 When the FDA Adverse Event Reporting Database was recently interrogated, 51 623 and 7,984 reports for rituximab and ocrelizumab, respectively, were identified.…”

“…48 The same group of investigators observed low values of IgG evolving over a mean treatment period of 31.1 months and a mean cumulative dose of 4,012 mg in 6%. 48 When the FDA Adverse Event Reporting Database was recently interrogated, 51 623 and 7,984 reports for rituximab and ocrelizumab, respectively, were identified. Serious adverse events were more commonly reported for rituximab as were adverse events related to blood, lymphatic, and immune system.…”

Infection Mitigation Strategies for Multiple Sclerosis Patients on Oral and Monoclonal Disease-Modifying Therapies

“…Long-term rituximab and ocrelizumab use can cause hypogammaglobulinemia [86,87] and, less commonly, lymphopenia and neutropenia, which are risk factors for severe infections [86,[88][89][90][91][92]. Therefore, baseline blood cell counts with differential and immunoglobulin levels should be checked before starting anti-CD20 therapy and at regular intervals thereafter [19].…”