The coronavirus disease 2019 (COVID-19) pandemic is concerning for patients with neuroimmunological diseases who are receiving immunotherapy. Uncertainty remains about whether immunotherapies increase the risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or increase the risk of severe disease and death upon infection. National and international societies have developed guidelines and statements, but consensus does not exist in several areas. In this Review, we attempt to clarify where consensus exists and where uncertainty remains to inform management approaches based on the first principles of neuroimmunology. We identified key questions that have been addressed in the literature and collated the recommendations to generate a consensus calculation in a Delphi-like approach to summarize the information. We summarize the international recommendations, discuss them in light of the first available data from patients with COVID-19 receiving immunotherapy and provide an overview of management approaches in the COVID-19 era. We stress the principles of medicine in general and neuroimmunology in particular because, although the risk of viral infection has become more relevant, most of the considerations apply to the general management of neurological immunotherapy. We also give special consideration to immunosuppressive treatment and cell-depleting therapies that might increase susceptibility to SARS-CoV-2 infection but reduce the risk of severe COVID-19.

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Neurological immunotherapy in the era of COVID-19 - looking for consensus in the literature.

Background and Objectives To report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or treated in real-world postmarketing settings. Methods Safety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections (SIs) and malignancies were contextualized using multiple epidemiologic sources. Results At data cutoff (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient-years [PY] of exposure) in clinical trials. Rates per 100 PY (95% confidence interval) of AEs (248; 246–251), serious AEs (7.3; 7.0–7.7), infusion-related reactions (25.9; 25.1–26.6), and infections (76.2; 74.9–77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81–2.23) and malignancies (0.46; 0.37–0.57), were consistent with the ranges reported in epidemiologic data. Discussion Continuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns, in a heterogeneous MS population. Classification of Evidence This analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls.

https://n.neurology.org/content/neurology/97/16/e1546.full.pdf

Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease affecting the central nervous system (CNS), often characterized by the accumulation of irreversible clinical disability over time. During last years, there has been a dramatic evolution in several key concepts of immune pathophysiology of MS and in the treatment of this disease. The demonstration of the strong efficacy and good safety profile of selective B-cell-depleting therapies (such as anti-CD20 monoclonal antibodies) has significantly expanded the therapeutic scenario for both relapsing and progressive MS patients with the identification of a new therapeutic target. The key role of B cells in triggering MS disease has been also pointed out, determining a shift from the traditional view of MS activity as largely being ‘T-cell mediated’ to the notion that MS-related pathological processes involve bi-directional interactions between several immune cell types, including B cells, both in the periphery and in the CNS. This review provides an updated overview of the involvement of B cells in the immune pathophysiology and pathology of MS. We summarize the rationale regarding the use of anti-CD20 therapies and the results of the main randomized controlled trials and observational studies investigating the efficacy and safety profile of rituximab, ocrelizumab, ofatumumab and ublituximab. Suggestions regarding vaccinations and management of MS patients during COVID-19 pandemic with anti-CD20 therapies are also discussed. Finally, therapies under investigation and future perspectives of anti-CD20 therapies are taken into consideration.

/pdf/anti-cd20-therapies-for-multiple-sclerosis-current-status-3kpn6fub4i.pdf

Anti-CD20 therapies for multiple sclerosis: current status and future perspectives.

Multiple sclerosis (MS) is an autoimmune and chronic inflammatory demyelinating disease of the central nervous system (CNS), which gives rise to focal lesion in CNS and cause physical disorders. Although environmental factors and susceptibility genes are reported to play a role in the pathogenesis of MS, its etiology still remains unclear. At present, there is no complete cure, but there are drugs that decelerate the progression of MS. Traditional therapies are disease-modifying drugs that control disease severity. MS drugs that are currently marketed mainly aim at the immune system; however, increasing attention is being paid to the development of new treatment strategies targeting the CNS. Further, the number of neuroprotective drugs is presently undergoing clinical trials and may prove useful for the improvement of neuronal function and survival. In this review, we have summarized the recent application of drugs used in MS treatment, mainly introducing new drugs with immunomodulatory, neuroprotective, or regenerative properties and their possible treatment strategies for MS. Additionally, we have presented Food and Drug Administration-approved MS treatment drugs and their administration methods, mechanisms of action, safety, and effectiveness, thereby evaluating their treatment efficacy.

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Progress in the Application of Drugs for the Treatment of Multiple Sclerosis

Anti-CD20 therapies have demonstrated considerable efficacy in the treatment of relapsing multiple sclerosis, constituting a high-efficacy treatment approach for reducing relapse risk and mitigating disability progression. These therapies have been shown to strongly deplete circulating B cells and small subsets of CD3+ CD4 and CD8 T cells that express low levels of CD20. While the clinical profiles of the various anti-CD20 monoclonal antibodies used in treating multiple sclerosis are well-described in the literature, greater understanding of the implications of their distinct molecular and pharmacological attributes is needed. In this review, we focus on four anti-CD20 monoclonal antibodies-rituximab, ocrelizumab, ofatumumab, and ublituximab-that are currently used, approved, or in late-stage clinical development for the treatment of multiple sclerosis. We provide clinical perspectives on the potential implications of differences in molecular structures, target epitopes, dosing regimens, mechanisms and impact on B-cell depletion and reconstitution, immunogenicity, administration-related reactions, and infection risks.

/pdf/clinical-perspectives-on-the-molecular-and-pharmacological-2tca6ps6w2.pdf

Clinical Perspectives on the Molecular and Pharmacological Attributes of Anti-CD20 Therapies for Multiple Sclerosis

Importance Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus that has no proven effective treatment. Although rare cases of PML have occurred with other anti-CD20 therapies, there had been no prior cases associated with ocrelizumab. Objective To report the first ever case of PML occurring with ocrelizumab monotherapy in a patient with progressive multiple sclerosis without prior immunomodulation. Design, Setting, and Participant This case was reported from an academic medical center. The patient had multiple sclerosis while receiving ocrelizumab monotherapy. Exposures Ocrelizumab monotherapy. Results A 78-year-old man with progressive multiple sclerosis treated with ocrelizumab monotherapy for 2 years presented with 2 weeks of progressive visual disturbance and confusion. Examination demonstrated a right homonymous hemianopia, and magnetic resonance imaging revealed an enlarging nonenhancing left parietal lesion without mass effect. Cerebrospinal fluid revealed 1000 copies/mL of JC virus, confirming the diagnosis of PML. Blood work on diagnosis revealed grade 2 lymphopenia, with absolute lymphocyte count of 710/μL, CD4 of 294/μL (reference range, 325-1251/μL), CD8 of 85/μL (reference range, 90-775/μL), CD19 of 1/μL, preserved CD4/CD8 ratio (3.45), and negative HIV serology. Retrospective absolute lymphocyte count revealed intermittent grade 1 lymphopenia that preceded ocrelizumab (absolute lymphocyte count range, 800-1200/μL). The patient’s symptoms progressed over weeks to involve bilateral visual loss, right-sided facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated. The patient nevertheless declined rapidly and ultimately died. PML was confirmed at autopsy. Conclusions and Relevance In this case report, PML occurrence was likely a result of the immunomodulatory function of ocrelizumab as well as age-related immunosenescence. This case report emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections such as elderly patients.

Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy.

Objective: To report a case of progressive multifocal leukoencephalopathy (PML) occurring after two years of ocrelizumab monotherapy in a patient with progressive multiple sclerosis (MS) without prior immunomodulatory medication. Background: PML is an untreatable, life-threatening, opportunistic infection caused by the JC virus (JCV), occurring in individuals with impaired cell-mediated immunity. While anti-CD20 therapies primarily target B-cells, they also mildly decrease CD4 and CD8 levels. Though rare cases of PML have occurred with rituximab, there had been no prior PML cases associated with ocrelizumab. Previous PML cases after ocrelizumab initiation were “carry-over” cases related to prior natalizumab or fingolimod use, and ocrelizumab was deemed non-contributory. Design/Methods: Case report: A 78-year-old man with progressive MS treated with ocrelizumab monotherapy for two years without prior immunomodulatory medications presented with two weeks of progressive visual disturbance and confusion. Exam demonstrated a right homonymous hemianopia and MRI revealed an enlarging non-enhancing left parietal lesion without mass effect. CSF PCR revealed 1,000 copies/ml of JCV, confirming the diagnosis of PML. Blood work upon diagnosis revealed grade-2 lymphopenia, with absolute lymphocyte count (ALC) 710/uL, CD4 294/uL (reference 325–1251), CD8 85/uL (reference 90–775), CD19 1/uL, preserved CD4/CD8 ratio (3.45), and negative HIV serology. Retrospective analysis revealed intermittent grade-1 lymphopenia that preceded ocrelizumab therapy (ALC range 800–1200/uL). The patient’s symptoms progressed over weeks to involve bilateral visual loss, right facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated. Results: This is the first occurrence of PML directly associated with ocrelizumab monotherapy. Subsequent course will be presented. Conclusions: PML occurrence may have been multifactorial, due to a combination of the immunomodulatory function of ocrelizumab, possible immune senescence, and preceding mild lymphopenia. This case emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections, such as the elderly. Disclosure: Dr. Sul has nothing to disclose. Dr. Patel has nothing to disclose. Dr. Gordon has received research support from MSD (Merck), Eisai, AbbVie, and Janssen. Dr. Steinklein has nothing to disclose. Dr. Sanguinetti has nothing to disclose. Dr. Pramanik has nothing to disclose. Dr. Orban has nothing to disclose. Dr. Koralnik has nothing to disclose. Dr. Harel has nothing to disclose.

Progressive Multifocal Leukoencephalopathy in a Patient on Ocrelizumab Monotherapy (4875)

A middle-aged woman with idiopathic longitudinally extensive myelitis underwent repeat MR scan of cervical spine at 5-month follow-up, which showed new non-enhancing T2 hyperintensities, initially reported as myelitis recurrence. However, the hyperintensities involved both lateral corticospinal tracts caudal to the initial lesion and both dorsal columns rostral to the initial lesion and were therefore compatible with Wallerian degeneration. This radiological mimic should be considered in the differential of recurrence of myelitis.

https://pn.bmj.com/content/practneurol/21/3/235.full.pdf

Wallerian degeneration as a mimic of recurrence of myelitis.

Summary Background Moyamoya disease (MMD) is a rare vasculopathy and Multiple Sclerosis (MS) is an autoimmune disease which causes CNS demyelination. While most literature has focused on misdiagnosis of MMD as an “MS-mimic”, we present a patient in which both co-existed. Methods Case Report Results A 57-year-old woman presented with gait dysfunction and paresthesias in both feet. MRI revealed brain and spinal cord lesions consistent with MS. Vessel imaging revealed multivessel stenosis consistent with MMD. Lumbar puncture demonstrated oligoclonal bands, leading to two diagnoses, MS and MMD. Conclusions MS can exist concurrently with MMD, potentially due to underlying propensity for autoimmunity.

Arpan Patel

Papers

Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy.

Progressive Multifocal Leukoencephalopathy in a Patient on Ocrelizumab Monotherapy (4875)

Wallerian degeneration as a mimic of recurrence of myelitis.

A patient with concurrent multiple sclerosis and moyamoya disease.