Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity

Juto, Alexander; Fink, Katharina; Nimer, Faiez Al; Piehl, Fredrik

doi:10.1016/j.msard.2019.101468

Cited by 48 publications

(55 citation statements)

References 15 publications

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“…Whether our immunological observations lead to clinical reactivation of the disease remains open. A large observational study did not find evidence of accentuated disease reappearance in a large patient cohort (32), while it is possible that individual patients may react differently. Regarding a possible transition of RRMS patients to secondary progressive MS, it was shown that rituximab may not necessarily prevent it (33).…”

Section: Discussionmentioning

confidence: 90%

B cells reappear less mature and more activated after their anti-CD20–mediated depletion in multiple sclerosis

Nissimov

Hajiyeva²,

Torke

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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B cell depletion via anti-CD20 antibodies is a highly effective treatment for multiple sclerosis (MS). However, little is known about the maturation/activation stage of the returning B cell population after treatment cessation and the wider effects on other immune cells. In the present study, 15 relapsing-remitting MS patients receiving 1,000 mg of rituximab were included. B, T, and myeloid cells were analyzed before anti-CD20 administration and in different time intervals thereafter over a period of 24 mo. In comparison to the phenotype before anti-CD20 treatment, the reappearing B cell pool revealed a less mature and more activated phenotype: 1) reappearing B cells were significantly enriched in transitional (before: 10.1 ± 1.9%, after: 58.8 ± 5.2%) and mature naive phenotypes (before: 45.5 ± 3.1%, after: 25.1 ± 3.5%); 2) the frequency of memory B cells was reduced (before: 36.7 ± 3.1%, after: 8.9 ± 1.7%); and 3) reappearing B cells showed an enhanced expression of activation markers CD25 (before: 2.1 ± 0.4%, after: 9.3 ± 2.1%) and CD69 (before: 5.9 ± 1.0%, after: 21.4 ± 3.0%), and expressed significantly higher levels of costimulatory CD40 and CD86. T cells showed 1) a persistent increase in naive (CD4+: before: 11.8 ± 1.3%, after: 18.4 ± 3.4%; CD8+: before: 12.5 ± 1.4%, after: 16.5 ± 2.3%) and 2) a decrease in terminally differentiated subsets (CD4+: before: 47.3 ± 3.2%, after: 34.4 ± 3.7%; CD8+: before: 53.7 ± 2.1%, after: 49.1 ± 2.7%).

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Section: Discussionmentioning

confidence: 90%

B cells reappear less mature and more activated after their anti-CD20–mediated depletion in multiple sclerosis

Nissimov

Hajiyeva²,

Torke

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Even if it acts as an IRT, based on memory B cell depletion and slow repopulation characteristics (Palanichamy et al, 2014;Baker et al, 2018), it may provide some comfort to suggest that delays of 6-12 months may be feasible without MS disease activity reoccurring. The latter is based on information from off-label and phase I/II studies with rituximab in MS ( Bar-Or et al, 2008;Juto et al, 2020) and phase II extension trial data of ocrelizumab (Kappos et al, 2012;Baker et al, 2020a). As such retreatment to maintain remission based on repopulation of CD27+ memory B cell population, after 3-4 cycles it seems that doses, at least with rituximab, can be extended to less than once a year (Novi et al, 2019).…”

Section: Ocrelizumabmentioning

confidence: 99%

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

Baker

Amor

Kang

et al. 2020

Multiple Sclerosis and Related Disorders

104

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Background: SARS-CoV-2 viral infection causes COVID-19 that can result in severe acute respiratory distress syndrome (ARDS), which can cause significant mortality, leading to concern that immunosuppressive treatments for multiple sclerosis and other disorders have significant risks for both infection and ARDS. Objective: To examine the biology that potentially underpins immunity to the SARS-Cov-2 virus and the immunity-induced pathology related to COVID-19 and determine how this impinges on the use of current disease modifying treatments in multiple sclerosis. Observations: Although information about the mechanisms of immunity are scant, it appears that monocyte/macrophages and then CD8 T cells are important in eliminating the SARS-CoV-2 virus. This may be facilitated via anti-viral antibody responses that may prevent re-infection. However, viral escape and infection of leucocytes to promote lymphopenia, apparent CD8 T cell exhaustion coupled with a cytokine storm and vascular pathology appears to contribute to the damage in ARDS. Implications: In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD8 T cells to limit protection against COVID-19. In addition, few block the formation of immature B cells within lymphoid tissue that will provide antibody-mediated protection from (re)infection. However, adjustments to dosing schedules may help de-risk the chance of infection further and reduce the concerns of people with MS being treated during the COVID-19 pandemic. 1. SARS-Cov-2 and COVID-19 a new pandemic COVID-19 is the pandemic disease caused by severe acute respiratory syndrome (SARS) coronavirus two (SARS-CoV-2) infection (Zhu et al., 2020a; Zhou et al., 2020). About 80% of people infected with SARS-CoV-2 develop a self-limiting illness, 20% require hospitalisation, largely due to cardiovascular issues and about 5% require critical care and potential ventilatory support (Kimball et al., 2020; Day. 2020). The mortality in those requiring ventilatory support is about 40-50% (Weiss and Murdoch 2020; Zhu et al., 2020b). Death from COVID-19 is associated with older age and comorbidities such as cardiovascular disease, smoking, lung disease, obesity and diabetes (Zhu et al., 2020a; Lippi et al., 2020; Richardson et al., 2020). Mortality in young people and those without comorbidities may be related to excessive viral load (Lui et al 2020a; Chen et al., 2020a). Whilst the typical clinical features requiring self-isolation, and potentially hospitalization are fever, dry cough and shortness of breath related to respiratory tract infection, other symptoms such as headache and gastrointestinal symptoms may go unnoticed or under-appreciated leading to spreading of the virus (Zhu et al., 2020b; Richardson et al., 2020; Huang et al., 2020). People shed infective virus days before symptoms occur and continue to shed virus via the lungs and faeces whilst symptoms develo...

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“…RTX is an attractive treatment option in women with MS who desire pregnancy and require a highly effective DMT because its immunomodulatory effects last long after the drug has been eliminated, 3 and RTX is not associated with drug-cessation relapses. [4][5][6] We recommend starting RTX before pregnancy, typically 500 mg every 6 months, holding infusions during pregnancy and resuming infusions typically 6-12 months postpartum or sooner if disease activity returns or is desired by the mother.…”

mentioning

confidence: 99%

Rituximab, MS, and pregnancy

Smith

Hellwig

Fink

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo describe the safety and efficacy of rituximab (RTX) in MS and pregnancy, we conducted a retrospective cohort study of 74 pregnancies among 55 women treated with RTX for MS and their offspring.MethodsWe used prospectively collected information from the electronic health record at Kaiser Permanente Southern California between 2012 and 2019 of mother and baby to identify treatment history, pregnancy outcomes, and relapses.ResultsLast RTX exposure before conception occurred between 1.8 and 5.2 months in 32 (49%) of 65 pregnancies and accidentally during the first trimester in 9 (12%). Among 38 live births, adverse pregnancy outcomes were as follows: 3 preterm deliveries (including 1 set of twins), 1 neonatal death (preterm twin), and 1 perinatal stroke (full-term). No stillbirths, chorioamnionitis, or major malformations were found. Fifteen (27%) women had at least one first-trimester miscarriage, of whom 8 (53%) had a history of infertility. Cumulative dose or timing of last RTX infusion was not associated with an increased risk of miscarriage. Only 2 (5.4%) women experienced relapses, one during pregnancy and the other postpartum.ConclusionWe observed no increase in adverse pregnancy outcomes compared with expected national incidence rates and remarkably little disease activity in RTX-treated women with MS, particularly when compared with periconceptional natalizumab-treated cohorts. However, larger studies are needed to fully assess the safety of RTX use before pregnancy, especially risks associated with prolonged B-cell depletion and hypogammaglobulinemia. Until these data are available, we recommend restricting RTX use before pregnancy to women who require highly effective MS treatments.Classification of evidenceThis study provides Class IV evidence that for pregnant women with MS, RTX controls disease activity and does not increase adverse pregnancy outcomes.

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Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity

Cited by 48 publications

References 15 publications

B cells reappear less mature and more activated after their anti-CD20–mediated depletion in multiple sclerosis

B cells reappear less mature and more activated after their anti-CD20–mediated depletion in multiple sclerosis

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

Rituximab, MS, and pregnancy

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