Rituximab for treatment of refractory multiple sclerosis relapses during pregnancy

Introduction

During pregnancy, relapse rate declines, reaching a nadir during the third trimester followed by an increase during the initial 3 months post-partum, and recent analyses suggest that this paradigm continues despite overall reductions in relapse rates, optimization of MS diagnostics, and the use of new therapies.^1,2 Relapses during pregnancy often do not require treatment, but in rare cases, the potential risks of other treatments, such as rituximab, must be weighed against the complications of a severe relapse.

Case 1

A 41-year-old woman at 13 weeks gestation presented with a 1-week history of right hemi-body numbness, ataxia, diplopia, and dysarthria. Examination revealed a left internuclear ophthalmoplegia (INO). Magnetic resonance imaging (MRI) brain without contrast demonstrated multiple periventricular and juxtacortical FLAIR-hyperintense lesions along with lesions of the left corona radiata, left brachium pontis, and left superior colliculus that restricted diffusion (Figure 1(a)–(d)). A lumbar puncture was performed with cerebrospinal fluid (CSF) cell counts, glucose, and protein within normal limits and >3 CSF-specific oligoclonal bands. Serum neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibody testing was negative. She met criteria for diagnosis of MS as per the 2017 McDonald Criteria. She received 5 days of intravenous (IV) methylprednisolone followed by plasma exchange every-other-day for five exchanges with no improvement. Repeat MRI demonstrated enlargement of lesions within the left pons and cerebellar peduncle. After discussing the risks and benefits, 1000 mg IV rituximab was given. Her symptoms improved 1 week after the infusion. She experienced hyperemesis gravidarum, had premature rupture of membranes at 36 weeks, and had an uncomplicated spontaneous vaginal delivery. The neonate weighed 5.5 lbs and was otherwise healthy. Infant CD19 levels were not obtained; indicated vaccinations were given as scheduled. At 12-month follow-up, the infant was meeting all developmental milestones with no behavioral abnormalities or opportunistic infections. Our patient has continued to receive anti-CD20 therapy with ocrelizumab with no further relapses as of follow-up at 18 months postpartum.

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Figure 1.

(a, b) Case 1, FLAIR hyperintensities of the inferior colliculus, brachium pontis, and periventricular subcortex, (c) Case 1, diffusion restriction of the lesions of the inferior colliculus, brachium pontis, (d) Case 1, peripheral diffusion restriction of the periventricular lesions (arrows), (e, f) Case 2, MRI at presentation showed extensive multifocal FLAIR hyperintensities with involvement of the corpus collosum (g, h) Case 2, MRI following treatment with methylprednisolone and IVIG showed an increase in FLAIR hyperintensities which were becoming more confluent both in the brain stem and frontal lobes.

Case 2

A 24-year-old woman with a 4-year history of MS presented at 15 weeks gestation with acute-onset right-leg weakness. She had discontinued natalizumab infusions 4 months prior to presentation due to high JC virus antibody index of 3.14. She declined to restart disease-modifying therapy (DMT) because of her desire to conceive. Exam showed 4/5 strength in the right lower extremity. MRI showed extensive new areas of FLAIR hyperintensity within the frontal, parietal, and temporal lobes and involvement of the corpus collosum (Figure 1(e) and (f)). Several lesions also exhibited peripheral restricted diffusion suggesting acute demyelination. She was treated with 5 days of 1000 mg IV methylprednisolone and her strength began to modestly improve. She was subsequently treated for this relapse with IVIG 2 g/kg over 5 days. The patient opted to start glatiramer acetate during pregnancy due to the minimal risk of side effects. She returned at 21 weeks gestation with bilateral optic neuritis, right arm weakness, and bilateral leg weakness. MRI showed more confluent and numerous FLAIR hyperintense lesions involving the pons, corpus callosum, and frontal horns (Figure 1(g) and (h)). She again received 5 days of 1000 mg IV methylprednisolone followed by plasma exchange. Due to the frequency and severity of her MS relapses, she was treated with rituximab 1000 mg IV followed by an additional 1000 mg dose after 2 weeks. She had no further relapses after initiating rituximab. She had an uncomplicated vaginal delivery at 37 weeks. The infant weighed 5.5 lbs; infant CD19 levels were not obtained. Vaccinations were given as scheduled. At 12-month follow-up, the infant was meeting all developmental milestones with no behavioral abnormalities or opportunistic infections. Our patient’s expanded disability status scale (EDSS) was 4.0 (EDSS was 2.0 pre-pregnancy) at her most recent 2-year postpartum follow-up with 20/200 visual acuity in the right eye and mild ataxia.

Discussion

Rituximab is a chimeric anti-CD20 monoclonal B-cell-depleting antibody which has rarely been used for severe MS relapses during pregnancy due to a lack of safety data but should be considered in severe cases refractory to first-line agents. In severe relapses, it is most reasonable to treat with high-dose corticosteroids with or without plasma exchange.^3,4 Short-term use of corticosteroids during pregnancy is considered low-risk, and early data that suggested an increased risk of fetal malformation in the first trimester has not been supported by more recent studies. ⁵ Rebound relapses after discontinuation of natalizumab or S1P receptor modulators can be severe and refractory to corticosteroids. In these cases, resuming natalizumab can be considered but neonatal anemia and thrombocytopenia are a recognized risk. ⁶ Rituximab is an alternative that may help prevent significant neurologic disability. ⁴

In both of the cases reported above, a thorough discussion of risks/benefits was undertaken before rituximab administration. Both were refractory to treatment with corticosteroids and additional second-line treatment with plasma exchange or IVIG and neither had further relapses after receiving rituximab. MRI without contrast was sufficient for clinical decision-making in both cases. Case 2 also illustrates that glatiramer acetate, while relatively safe may not effectively reduce the risk of rebound relapses after natalizumab discontinuation. ⁷ In addition, IVIG did not appear efficacious in treatment of this MS relapse, and there is no strong evidence supporting its use in this situation.

Based on our review, only one other case of a severe MS rebound relapse during pregnancy being treated with rituximab has been reported. She was treated at 22 weeks gestation with two 1 g doses of rituximab and, as with our cases, had no further relapses during pregnancy with no apparent fetal or infant adverse outcomes. ⁸ As per the product label for rituximab, there have been no adequate and well-controlled studies of rituximab in pregnant women, though studies in cynomolgus monkeys did not show evidence of teratogenicity. ⁹ Rituximab crosses the placenta with potential fetal transfer starting in the second trimester. A systematic review of 102 patients who received rituximab for any indication within 6 months prior to conception found no major safety signal but did find low B-cell counts in 39% of newborns when checked that normalized within 6 months. Findings were reassuring for a further case series of 11 women with MS and NMO though none of these cases received rituximab infusions while pregnant. ¹⁰ Another recently reported cohort of 74 pregnancies of women with MS treated with rituximab included inadvertent rituximab exposure in nine pregnancies after conception from 0.5 to 5 weeks gestation. In this cohort, exposure during the first trimester did not significantly relate to preterm birth, miscarriage, or elective abortions. ¹¹ Although it is plausible that B-cell-directed therapy increases the risk of systemic maternal or neonatal infection, this has not been suggested by the relatively small number of cases reported, even with B lymphocyte suppression. Since the lymphopenia appears transient and without increased risk of infection, the role of routine CD19 monitoring in infants is unclear. However, decreased immune response may potentially blunt effects of neonatal vaccinations which may warrant checking infant CD19 to optimize vaccination timing.

In severe relapses during pregnancy, coordination with high-risk obstetrics and pediatrics is advisable. While concern for adverse effects to the fetus such as prematurity and neonatal infections has been raised, maternal outcomes from severe relapses can include permanent neurologic disability. Our patients improved after receiving rituximab with recovery of independent ambulation and decrease in EDSS; neither patient had further relapses following the initiation of rituximab, and there were no apparent sequelae for the infant. The amount of acceptable risk is a decision that requires thorough discussion of risks and benefits. The use of rituximab in the pregnant population should be extremely limited but is worth consideration in unique circumstances.