Predictors of hypogammaglobulinemia and serious infections among patients receiving ocrelizumab or rituximab for treatment of MS and NMOSD.

BACKGROUND AND OBJECTIVES: Ocrelizumab and rituximab are monoclonal antibodies targeting the CD20 marker on B lymphocytes. The enhanced efficacy of B lymphocyte depleting therapies poses a greater risk of decreased immunoglobulin (Ig) levels. The rate and risk factors of hypogammaglobulinemia in MS and NMOSD patients treated with anti-CD20 therapies are unknown. METHODS: A retrospective study was conducted among patients who received anti-CD20 therapy for the treatment of MS, NMOSD, and other related neurological disorders. The goal was to determine the incidence and risk factors of hypogammaglobulinemia and serious infections in patients receiving ocrelizumab versus rituximab. The secondary goals were to determine the rates of lymphopenia, neutropenia, and early B cell repopulation among patients on anti-CD20 therapy. RESULTS: Overall, 184 patients (mean age 48.4 ± 13.7, 66.8% female) met inclusion criteria; 152 patients received ocrelizumab and 32 patients received rituximab. A total of 22 patients (12%) developed hypogammaglobulinemia. Patients who developed hypogammaglobulinemia were more likely to have been ≥50 years of age (p = .0275) with lower baseline IgG (p = .001) and IgA (p = .0038) levels. Serious infections were observed in 21 patients (11%) and seen more commonly in those that developed total lymphopenia (<1.0 × 109/L) and had longer duration of B-cell therapy. Multivariate analysis identified age ≥ 50 years, white race, and rituximab as independent predictors of hypogammaglobulinemia, and absolute lymphopenia as an independent risk factor for serious infections. DISCUSSION: Among patients receiving anti-CD20 therapy, 12% of patients experienced hypogammaglobulinemia which was seen more commonly in white patients, at least 50 years old, with lower baseline IgG and IgA levels and in those treated with rituximab. Serious infections were seen more commonly in patients with total lymphopenia and longer exposure to anti-CD20 therapy.

The humoral response to SARS-COV-2 vaccines in MS patients: A case series exploring the impact of DMT, lymphocyte count, immunoglobulins, and vaccine type.

BACKGROUND & OBJECTIVES: Certain disease modifying therapies may negatively impact the humoral response to SARS-CoV-2 vaccines. Many MS related clinical, demographic, and immunological characteristics can also affect vaccine response but those have not been fully explored. This study aimed to investigate potential correlations between clinical, demographic, and immunological variables in MS patients to post-vaccination spike protein antibody positivity rates and levels. METHODS: Patients with MS and related neuroimmunological disorders who requested verification of the immune response to the SARS-COV-2 vaccine were tested for the spike protein antibody from January to October 2021. We performed an exploratory analysis to compare patients with positive versus negative spike protein antibody. RESULTS: Fifty patients (mean age 53 ±12, 78% females) were included. There were 29 patients with positive post-vaccination spike protein antibody (58%) and 21 with negative antibody (42%). Patients with negative antibody were more likely to have been on B-cell therapy (86% vs 31%, P=.001) while positive patients were more likely to have been on a fumarate (31% vs 4.8%, P=.03). Thirty percent of positive patients on fumarate therapy had mild lymphopenia. No differences existed between groups in gender, age, race, disease phenotype, vaccine brand, and lymphocyte counts. Among patients on B-cell therapy, 33% had a positive spike protein antibody. There was an association between detectable CD19 cells at time of vaccination and positive humoral response to vaccination (P=0.049). There was no relationship between subgroups in terms of vaccine timing relative to B-cell therapy dose. Hypogammaglobulinemia was not associated with seroconversion rates, however it was associated with decreased quantitative spike protein antibody levels (p=0.045). DISCUSSION: B-cell therapy is associated with a negative humoral response to SARS-COV-2 vaccines. Patients on B-cell depleting therapy with detectable CD19 counts at the time of vaccination were associated with a positive humoral response. There was no relationship between hypogammaglobinemia and seroconversion rate, however it was associated with decreased spike protein antibody levels. The fumarates are associated with positive humoral response even in the presence of mild lymphopenia.

Multiple Sclerosis Disease-Modifying Therapy and the COVID-19 Pandemic: Implications on the Risk of Infection and Future Vaccination.

The coronavirus 2019 (COVID-19) pandemic is expected to linger. Decisions regarding initiation or continuation of disease-modifying therapy for multiple sclerosis have to consider the potential relevance to the pandemic. Understanding the mechanism of action and the possible idiosyncratic effects of each therapeutic agent on the immune system is imperative during this special time. The infectious side-effect profile as well as the route and frequency of administration of each therapeutic agent should be carefully considered when selecting a new treatment or deciding on risk mitigation strategies for existing therapy. More importantly, the impact of each agent on the future severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) vaccine should be carefully considered in treatment decisions. Moreover, some multiple sclerosis therapies may have beneficial antiviral effects against SARS-CoV-2 while others may have beneficial immune-modulating effects against the cytokine storm and hyperinflammatory phase of the disease. Conventional injectables have a favorable immune profile without an increased exposure risk and therefore may be suitable for mild multiple sclerosis during the pandemic. However, moderate and highly active multiple sclerosis will continue to require treatment with oral or intravenous high-potency agents but a number of risk mitigation strategies may have to be implemented. Immune-modulating therapies such as the fumerates, sphinogosine-1P modulators, and natalizumab may be anecdotally preferred over cell-depleting immunosuppressants during the pandemic from the immune profile standpoint. Within the cell-depleting agents, selective (ocrelizumab) or preferential (cladribine) depletion of B cells may be relatively safer than non-selective depletion of lymphocytes and innate immune cells (alemtuzumab). Patients who develop severe iatrogenic or idiosyncratic lymphopenia should be advised to maintain social distancing even in areas where lockdown has been removed or ameliorated. Patients with iatrogenic hypogammaglobulinemia may require prophylactic intravenous immunoglobulin therapy in certain situations. When the future SARS-CoV-2 vaccine becomes available, patients with multiple sclerosis should be advised that certain therapies may interfere with mounting a protective immune response to the vaccine and that serological confirmation of a response may be required after vaccination. They should also be aware that most multiple sclerosis therapies are incompatible with live vaccines if a live SARS-CoV-2 vaccine is developed. In this article, we review and compare disease-modifying therapies in terms of their effect on the immune system, published infection rates, potential impact on SARS-CoV-2 susceptibility, and vaccine-related implications. We propose risk mitigation strategies and practical approaches to disease-modifying therapy during the COVID-19 pandemic.