Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies

Abstract

IMPORTANCE Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden. OBJECTIVE To examine the risk of serious infections associated with disease-modifying treatments for MS. DESIGN, SETTING, AND PARTICIPANTS This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included. EXPOSURES Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA. MAIN OUTCOMES AND MEASURES Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions. RESULTS A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]). CONCLUSIONS AND RELEVANCE Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles sh...

COVID-19 and MS disease-modifying therapies

“…27,28 Interferon-β may be protective against respiratory viruses, 29 and of all the DMTs, interferon-β and glatiramer acetate are associated with the lowest risk of infections. 30 One study in an MS population showed a salutary effect of interferon-β on human herpes virus type 6 compared with control groups. 30,31 Similarly, 1 study found that JC virus (JCV) DNA was detected less frequently in the blood of interferon-β-treated patients 32 ; however, another study found no effect of interferons on urinary JCV excretion.…”

“…30 One study in an MS population showed a salutary effect of interferon-β on human herpes virus type 6 compared with control groups. 30,31 Similarly, 1 study found that JC virus (JCV) DNA was detected less frequently in the blood of interferon-β-treated patients 32 ; however, another study found no effect of interferons on urinary JCV excretion. 33 On rare occasions, leukopenia and lymphopenia may occur with interferon-β, 34 which could increase the morbidity of SARS-CoV-2 infection, but in their absence, there is low concern with respect to interferon-β administration in MS during the COVID-19 pandemic.…”

“…e1 (links.lww.com/NXI/A258) There is no evidence of enhanced infectious risk during treatment with glatiramer acetate. 30 The shift from a Th1 (proinflammatory) to a Th2 response with glatiramer acetate e2 could be beneficial in COVID-19. Furthermore, glatiramer acetate has been shown to block IFNγ-mediated activation of macrophages, e3 which are thought to be essential for the development of COVID-19 ARDS.…”

“…A large register-based cohort study from Sweden with data on 6,421 patients collected over 7 years indicated that the risk of infection with fingolimod did not appear to be significantly higher than with platform therapies when adjusted for confounders, e.g., age, sex, and disability. 30 There is some concern for increased risk due to SARS-CoV-2 infection with S1P modulator treatment mainly because of sequestration of crucial lymphocyte populations, but also, possibly to a lesser degree, related to effects on pulmonary function e37 (mild dose-dependent decreases in lung function and exhaled volumes in the first month after therapy initiation). The potential for aggressive rebound of MS activity with cessation of S1P modulator therapy should be balanced against any risk in the face of SARS-CoV-2.…”

COVID-19 infection in a patient with multiple sclerosis treated with fingolimod

“…1 Multiple sclerosis (MS) is an immune-mediated neurologic disease which requires long-term treatment with immunotherapies that have been shown to increase the risk of infections. 2 As a result, there is significant anxiety among patients and neurologists during the pandemic regarding the infection outcome in this patient population. We present a patient with MS treated with fingolimod who was diagnosed with COVID-19 and had a favorable outcome.…”