The development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has been highly successful in recent decades. It is now widely accepted that early initiation of DMTs after disease onset is associated with a better long-term prognosis. However, the question of when and how to de-escalate or discontinue DMTs remains open and critical. This topic was discussed during an international focused workshop organized by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in 2023. The aim was to review the current evidence on the rationale for, and the potential pitfalls of, treatment de-escalation in MS. Several clinical scenarios emerged, mainly driven by a change in the benefit-risk ratio of DMTs over the course of the disease and with ageing. The workshop also addressed the issue of de-escalation by the type of DMT used and in specific situations, including pregnancy and paediatric onset MS. Finally, we provide practical guidelines for selecting appropriate patients, defining de-escalation and monitoring modalities and outlining unmet needs in this field.

• Keywords
• ageing, de-escalation, discontinuation, disease-modifying therapy, multiple sclerosis, pregnancy,
• MeSH
• Immunologic Factors * administration & dosage   MeSH
• Immunosuppressive Agents administration & dosage   MeSH
• Humans MeSH
• Multiple Sclerosis * drug therapy   MeSH
• Pregnancy MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Immunologic Factors * MeSH
• Immunosuppressive Agents MeSH

This review addresses current changes in the approach to treating patients with multiple sclerosis (MS). The widely practiced approach of utilizing agents with lower treatment efficacy (LETA) at onset with subsequent escalation has been challenged by new data suggesting that MS patients derive greater benefit when therapy is initiated with high-efficacy treatment agents (HETA). Several recent studies compared treatment efficacy and safety of early administration of HETA versus LETA. The results of randomized, double blind, phase III studies with LETA as a control arm and population-based larger and longer studies using propensity scoring, marginal structural modeling and weighted cumulative exposure analysis support the benefit of early treatment with HETA. Patients initiating their treatment with HETA, regardless of prognostic factors and MRI burden at baseline, showed significantly lower annualized relapse rate (ARR) and reduced disability progression in follow-up periods of up to 10-15 years. Moreover, the safety profile of recently approved HETA ameliorates concerns about off-target effects associated with a number of earlier high-efficacy drugs. Patient perception has also changed with an increasing preference for medication profiles that both improve symptoms and prevent disease progression. Accumulating data from randomized studies and the results of large population-based studies demonstrating short-term and longer-term patient benefits support the view that HETA should be more widely used. The adoption of early treatment with HETA capitalizes on a window of opportunity for anti-inflammatory drugs to maximally impact disease pathology and heralds a sea change in clinical practice toward pro-active management and away from a philosophy routed in generating clinical benefit as a consequence of treatment failure.

• Keywords
• Escalation therapy, High-efficacy drugs, Multiple sclerosis, Safety,
• MeSH
• Pharmaceutical Preparations MeSH
• Humans MeSH
• Randomized Controlled Trials as Topic MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   MeSH
• Multiple Sclerosis * diagnostic imaging   drug therapy   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Pharmaceutical Preparations MeSH

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