Monoclonal antibodies have become a mainstay in the treatment of patients with relapsing multiple sclerosis (RMS) and provide some benefit to patients with primary progressive MS. They are highly precise by specifically targeting molecules displayed on cells involved in distinct immune mechanisms of MS pathophysiology. They not only differ in the target antigen they recognize but also by the mode of action that generates their therapeutic effect. Natalizumab, an [Formula: see text]4[Formula: see text]1 integrin antagonist, works via binding to cell surface receptors, blocking the interaction with their ligands and, in that way, preventing the migration of leukocytes across the blood-brain barrier. On the other hand, the anti-CD52 monoclonal antibody alemtuzumab and the anti-CD20 monoclonal antibodies rituximab, ocrelizumab, ofatumumab, and ublituximab work via eliminating selected pathogenic cell populations. However, potential adverse effects may be serious and can necessitate treatment discontinuation. Most importantly, those are the risk for (opportunistic) infections, but also secondary autoimmune diseases or malignancies. Monoclonal antibodies also carry the risk of infusion/injection-related reactions, primarily in early phases of treatment. By careful patient selection and monitoring during therapy, the occurrence of these potentially serious adverse effects can be minimized. Monoclonal antibodies are characterized by a relatively long pharmacologic half-life and pharmacodynamic effects, which provides advantages such as permitting infrequent dosing, but also creates disadvantages regarding vaccination and family planning. This review presents an overview of currently available monoclonal antibodies for the treatment of RMS, including their mechanism of action, efficacy and safety profile. Furthermore, we provide practical recommendations for risk management, vaccination, and family planning.

• Keywords
• Alemtuzumab, Disease-modifying therapy, Monoclonal antibodies, Multiple sclerosis, Natalizumab, Ocrelizumab, Ofatumumab, Rituximab, Ublituximab,
• MeSH
• Humans MeSH
• Antibodies, Monoclonal therapeutic use   MeSH
• Natalizumab therapeutic use   MeSH
• Antineoplastic Agents, Immunological * therapeutic use   MeSH
• Risk Management MeSH
• Multiple Sclerosis * therapy   MeSH
• Pregnancy MeSH
• Vaccination MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antibodies, Monoclonal MeSH
• Natalizumab MeSH
• Antineoplastic Agents, Immunological * MeSH

Secondary immunodeficiencies (SIDs) are acquired conditions that may occur as sequelae of immune therapy. In recent years a number of disease-modifying therapies (DMTs) has been approved for multiple sclerosis and related disorders such as neuromyelitis optica spectrum disorders, some of which are frequently also used in- or off-label to treat conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, myositis, and encephalitis. In this review, we focus on currently available immune therapeutics in neurology to explore their specific modes of action that might contribute to SID, with particular emphasis on their potential to induce secondary antibody deficiency. Considering evidence from clinical trials as well as long-term observational studies related to the patients' immune status and risks of severe infections, we delineate long-term anti-CD20 therapy, with the greatest data availability for rituximab, as a major risk factor for the development of SID, particularly through secondary antibody deficiency. Alemtuzumab and cladribine have relevant effects on circulating B-cell counts; however, evidence for SID mediated by antibody deficiency appears limited and urgently warrants further systematic evaluation. To date, there has been no evidence suggesting that treatment with fingolimod, dimethyl fumarate, or natalizumab leads to antibody deficiency. Risk factors predisposing to development of SID include duration of therapy, increasing age, and pre-existing low immunoglobulin (Ig) levels. Prevention strategies of SID comprise awareness of risk factors, individualized treatment protocols, and vaccination concepts. Immune supplementation employing Ig replacement therapy might reduce morbidity and mortality associated with SIDs in neurological conditions. In light of the broad range of existing and emerging therapies, the potential for SID warrants urgent consideration among neurologists and other healthcare professionals.

• MeSH
• Alemtuzumab administration & dosage   adverse effects   MeSH
• Dimethyl Fumarate administration & dosage   adverse effects   MeSH
• Fingolimod Hydrochloride administration & dosage   adverse effects   MeSH
• Immunoglobulin G blood   immunology   MeSH
• Immunologic Factors administration & dosage   adverse effects   MeSH
• Immunosuppressive Agents administration & dosage   adverse effects   MeSH
• Immunotherapy adverse effects   MeSH
• Infections blood   chemically induced   immunology   MeSH
• Coinfection MeSH
• Humans MeSH
• Natalizumab administration & dosage   adverse effects   MeSH
• Neurology methods   trends   MeSH
• Rituximab administration & dosage   adverse effects   MeSH
• Risk Factors MeSH
• Age Factors MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Alemtuzumab MeSH
• Dimethyl Fumarate MeSH
• Fingolimod Hydrochloride MeSH
• Immunoglobulin G MeSH
• Immunologic Factors MeSH
• Immunosuppressive Agents MeSH
• Natalizumab MeSH
• Rituximab MeSH

BACKGROUND: Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. OBJECTIVE: Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. METHODS: Patients (N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. RESULTS: Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%-4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and analysis of core study subcutaneous interferon beta-1a-treated patients who received alemtuzumab in the extension. Patients converting to secondary progressive MS were older, and had higher EDSS scores and greater brain lesion volumes at baseline, but did not need additional alemtuzumab or other therapies. CONCLUSIONS: The 6-year conversion rate to secondary progressive MS was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression.ClinicalTrials.gov identifiers: NCT00530348, NCT00548405, NCT00930553.

• Keywords
• Relapsing-remitting multiple sclerosis, alemtuzumab, disease progression, secondary progressive multiple sclerosis,
• Publication type
• Journal Article MeSH

Since the introduction of the interferons in the 1990s, a multitude of different immunomodulatory and immunosuppressant disease-modifying therapies for multiple sclerosis (MS) have been developed. They have all shown positive effects on clinical endpoints such as relapse rate and disease progression and are a heterogeneous group of therapeutics comprising recombinant pegylated and non-pegylated interferon-β variants, peptide combinations, monoclonal antibodies, and small molecules. However, they have relevant side effect profiles, which necessitate thorough monitoring and straightforward patient education. In individual cases, side effects can be severe and potentially life-threatening, which is why knowledge about (neurological and non-neurological) adverse drug reactions is essential for prescribing neurologists as well as general practitioners. This paper aims to provide an overview of currently available MS therapies, their modes of action and safety profiles, and the necessary therapy monitoring.

• MeSH
• Immunologic Factors adverse effects   therapeutic use   MeSH
• Immunomodulation * MeSH
• Immunosuppressive Agents adverse effects   therapeutic use   MeSH
• Humans MeSH
• Multiple Sclerosis drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Immunologic Factors MeSH
• Immunosuppressive Agents MeSH