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Early use of HE-DMTs
Use in pregnancy
Noteworthy studies in 2025
Switching between anti-CD20 agents
The year 2025 saw an increasing early use of high-efficacy disease-modifying therapies (HE-DMT) in patients with multiple sclerosis, either as the first-choice agent or for the first switch. The rationale for this change in practice patterns derived from the accumulating efficacy and safety data from clinical trials, database analyses and real-world studies on the use of anti-CD20 monoclonal antibodies.
Early use of HE-DMTs
Phase III trials such as OPERA I/II with ocrelizumab and ASCLEPIOS I/II with ofatumumab demonstrated that anti-CD20 agents were more effective in reducing inflammatory disease activity than interferon beta-1a and teriflunomide, respectively (Hauser et al. N Engl J Med 2017;376:221-234. Hauser et al. N Engl J Med 2020;383:546-557). A recent meta-analysis reported that ofatumumab and ocrelizumab were the most efficacious therapies for reducing six-month confirmed disability progression (CDP) (Samjoo et al. J Comp Eff Res 2023;12:e230016). There is also some preliminary evidence suggesting that HE-DMTs are more effective in reducing progression independent of disease activity (PIRA) (Spelman et al. Mult Scler 2024;30(3S):651-652. Diras et al. ECTRIMS 2025;P842). In addition, a post-hoc analysis of the OPERA I/II trials reported that cognitive outcomes as assessed by the Symbol Digit Modalities Test (SDMT) were superior with ocrelizumab versus interferon beta-1a; ocrelizumab was associated with greater improvement in cognitive scores and a lower risk of cognitive decline (Benedict et al. Mult Scler Relat Disord 2025:95:106310).
In support of this more aggressive approach to therapy, a Canadian expert panel published consensus recommendations on the use of HE-DMTs (Freedman et al. Can J Neurol Sci 2025; 9:1-10). The group stated that HE-DMTs should be the first choice for all patients with more aggressive or severe disease at presentation, noting that early intensive therapy is associated with better long-term outcomes (Harding et al. JAMA Neurol 2019;76:536-541). [Full disclosure: NeuroSens’ parent company provided editorial support.]
Further evidence supporting this approach was provided in the AGNOS study on the first-line use of ofatumumab in early MS (Hendin et al. ECTRIMS 2025;P428). At 18 months, 98.9% of ofatumumab-treated patients were relapse-free, 90.5% had no three-month CDP, and the rate of brain volume loss was stabilized. A study of ocrelizumab as first-line therapy in highly active RRMS also found that treatment was effective in reducing relapse rates and stabilizing EDSS scores (Kvartskhava et al. J Neurol Sci 2025:475:123577). A separate observational study found that treatment-naïve patients started on a HE-DMT had a 94% lower risk of relapse and a 30% lower EDSS score in the first year of treatment compared to patients started on a lower-efficacy agent (Al-Araji et al. Ann Clin Transl Neurol 2025;12:2077-2085).
Also noteworthy was a meta-analysis this year that showed that ofatumumab and alemtuzumab were the most effective therapies for reducing the endpoints of CDP and brain volume loss (Cagol et al. Lancet Reg Health Eur 2025:59:101476).
Use in pregnancy
Three studies published or presented this year looked at the safety of anti-CD20 agents during pregnancy. The MINORE and SOPRANINO studies reported minimal ocrelizumab transfer across the placenta and in breast milk, respectively (Bove et al. ECTRIMS 2025;O102). Infant B cell levels were within the normal range in 97% at one year and most infants were able to mount a seroprotective humoral response to vaccinations. Similarly, a small study of ofatumumab administered during breastfeeding found no abnormalities in B cell counts, and no increase in infections, antibiotic use or hospitalizations with drug exposure (Witt et al. Mult Scler 2025;31:338-351).
Noteworthy studies in 2025
Several HE-DMT studies this year were noteworthy for their potential relevance to clinical practice. Five-year data from the ALITHIOS extension study reported that >80% of patients receiving ofatumumab remained free of six-month CDP and new MRI activity was almost completely suppressed (Hauser et al. Neurol Ther 2025;14:1975-1992). The rate of serious infections (1.63/100 patient-years) and malignancies (0.32/100 PY) was low. In a follow-up reported at ECTRIMS, the rate of no evidence of disease activity (NEDA) was >90% at seven years in ofatumumab-treated patients (Hauser et al. ECTRIMS 2025;P804). Mean IgG levels were above the lower limit of normal in 96.8% of patients at all assessments.
The efficacy of anti-CD20 therapy in patients with severe disability (median EDSS 6.0) was evaluated in the ORATORIO-HAND study (Giovannoni et al. ECTRIMS 2025;O128). Ocrelizumab significantly reduced composite CDP, which comprised EDSS and 9HPT, versus placebo. The greatest benefit was seen in patients with EDSS >6.5, indicating that even severely disabled patients can still benefit from treatment.
The OPERETTA 2 study reported that ocrelizumab (300 mg or 600 mg IV q24wk) was superior to fingolimod (0.25 or 0.5 mg/day) in pediatric-onset MS with respect to relapse reduction and the rate of new/enlarging T2 lesions (Banwell et al. ECTRIMS 2025;O130). At present, fingolimod is the only DMT approved for pediatric-onset MS in Canada.
The RIDOSE-MS study found that low-dose rituximab (500 mg/year) was non-inferior to a higher dose (500 mg q6months) with respect to the rate of disease activity (26% in both groups) (Svenningsson et al. ECTRIMS 2025;O131.) However, the lower dose provided no benefits in terms of IgG levels or infection rates. Similarly, a meta-analysis found a reduced rate of B cell depletion but no loss of efficacy with extended-interval ocrelizumab, suggesting that a lower dose exposure may be appropriate in some cases (Cruciani et al. ECTRIMS 2025;P361). The mean delay in ocrelizumab dosing was 15 weeks.
B cell repopulation was also not predictive of disease reactivation in a study of finite-course ocrelizumab (Salazar-Camelo et al. Mult Scler 2025;31:1338-1347). The finite course limited treatment to two courses (300 mg × 2 followed 6 months later by 600 mg). The mean time to disease reactivation was 40.5 months and patients remained clinically stable for >3 years. These preliminary findings suggest that sustained benefits may be achieved with short-course anti-CD20 therapy in older patients who are considering treatment de-escalation or discontinuation.
Switching between anti-CD20 agents
Anti-CD20 therapies appear to have comparable efficacy (Meuth et al. Ann Neurol 2025;97:583-595), however, a lateral switch may be required due to adverse effects (e.g. infusion reactions) or patient preference (e.g. convenience). Two studies this year investigated lateral switches from one B cell-depleting agent to another.
A matched-cohort study compared patients who switched anti-CD20 therapies (ocrelizumab to ofatumumab or the reverse) to those who remaining on their initial anti-CD20 therapy (Axhausen et al. Mult Scler 2025;31:1110-1120). Treatment efficacy was comparable after a switch. However, switching from ofatumumab to ocrelizumab resulted in a slight increase in B cell depletion. There was also a persistent decline in IgG levels following a switch.
In the phase IIIb OLIKOS study, treatment efficacy and safety were maintained after switching from ocrelizumab to ofatumumab (Hua et al. J Neurol 2025;272:725). There were no Gd+ lesions and no change in the median EDSS score from baseline to month 12 of ofatumumab. Treatment satisfaction improved following the switch to ofatumumab, most notably for convenience, with patients preferring self-injection at home rather than treatment at an infusion centre.