SPECIAL REPORT
Progression independent of relapse activity (PIRA)
Use of ofatumumab in patients with low disease activity
Safety in pregnancy
Effect of treatment on biomarkers
There is a growing consensus that initiating treatment with a high-efficacy disease-modifying therapy (DMT) may be the optimal strategy to target the progressive biology and improve long-term outcomes in patients with multiple sclerosis. This was among the key topics addressed at the 11th annual Americas Committee for Treatment and Research in MS (ACTRIMS) Forum, held February 5-7, 2026, in San Diego, California. The following summarizes new data with a special emphasis on the early use of the anti-CD20 monoclonal antibody ofatumumab.
Progression independent of relapse activity (PIRA)
Progression independent of relapse activity (PIRA) or relapse and MRI activity (PIRMA) has emerged as a marker of the chronic neurodegeneration that is evident during relapse-free periods. A real-world study of RRMS patients (median age 32 years) treated during the period 2011 to 2019 reported that initiating therapy with a low- or moderate-efficacy DMT was associated with an increased risk of a PIRMA event (hazard ratio 7.36) compared to starting with a high-efficacy DMT (Guarnaschelli et al. ACTRIMS Forum 2026;P421). Moreover, the risk of PIRMA remained elevated in patients who did not adequately respond to a lower-efficacy agent and were then switched to a high-efficacy DMT (HR 2.56), underscoring the importance of early use of a high-efficacy therapy. These results were supported by a post-hoc analysis of the Argentine MS Registry, which found that the prevalence of PIRA was lower (odds ratio 0.10) among patients started on a high-efficacy DMT (Alonso et al. Mult Scler Relat Disord 2025:104:106775).
Use of ofatumumab in patients with low disease activity
Several studies presented at the ACTRIMS Forum examined the efficacy and safety of initiating treatment with ofatumumab in patients with low disease activity. A post-hoc study of the pivotal ASCLEPIOS I/II trials analysed data for the subgroup of newly-diagnosed treatment-naïve patients (n=261) (Wiendl et al. ACTRIMS Forum 2026;P134). Low disease activity was defined as only one relapse in the two years prior to entry. The rates of no evidence of disease activity (NEDA) were lower for the ofatumumab versus teriflunomide group at Year 1 (43.9% vs. 28.9%, OR 2.38) and Year 2 (89.9% vs. 34.4%, OR 18.27). There were also significant relative reductions in Gd+ lesions (92%), new/enlarging T2 lesions (82.7%) and six-month confirmed disability progression (CDP) (36.0%) with ofatumumab. Mean IgG levels remained stable during treatment with ofatumumab; IgM levels initially declined but remained above the lower limit of normal (LLN).
These findings were supported by a real-world observational study of treatment-naïve patients (N=514) without highly active disease who were started on a self-administered injectable (ofatumumab, interferon-beta or glatiramer acetate) (Nelles et al. ACTRIMS Forum 2026;P426). According to the interim analysis (n=497), initial treatment with ofatumumab was associated with a 30% reduction in the annualized relapse rate (ARR) and fewer relapses requiring hospitalization or corticosteroids. The rate of treatment discontinuation at 24 months was 4% with ofatumumab, 25% for interferon-beta and 35% for glatiramer acetate. There were fewer serious adverse events and treatment discontinuations due to adverse effects with ofatumumab compared to the other injectables. The risk of >2 infections was also lower with ofatumumab.
Safety in pregnancy
Effective contraception is recommended for six months after the last dose of ofatumumab for female patients considering pregnancy. However, as pregnancies can occur during this period, a new analysis examined pregnancy outcomes for patients treated with ofatumumab immediately before or during pregnancy (Bove et al. ACTRIMS Forum 2026;P425). Outcomes data for 232 patients exposed to ofatumumab up to 180 days prior to their last menstrual period were obtained from the international Pregnancy Outcomes Intensive Monitoring (PRIM) program. Overall, pregnancy outcomes and the rates of major and minor malformations following maternal drug exposure were in line with those seen in the general population. There were 16 (6.8%) induced terminations, 33 (14.2%) spontaneous abortions, 1 (0.4%) stillbirth and 2 (0.8%) ectopic pregnancies. There were 8 cases (3.4%) of congenital anomalies. The rates of spontaneous abortion, stillbirth, ectopic pregnancies and congenital anomalies in the Canadian population are 15-25%, 0.9%, 1-2% and 4.3%, respectively (https://www.canada.ca/en/public-health/services/publications/healthy-living/infographic-perinatal-loss-canada.html).
Effect of treatment on biomarkers
In the ASCLEPIOS I/II trials, ofatumumab resulted in a 23-24% lower serum neurofilament light (sNfL) concentration at month 24 compared to teriflunomide (Hauser et al. N Engl J Med 2020;383:546-557). The relative reduction was 20% at 24 months in the recently diagnosed treatment-naïve subgroup (Gartner et al. Mult Scler 2022;28:1562-1575).
The AGNOS study (N=180) has now examined serum biomarker changes in treatment-naïve patients with early MS started on ofatumumab compared to healthy controls (Hendin et al. ACTRIMS Forum 2026;P067). Mean sNfL at baseline was 20.66 pg/mL in the ofatumumab group and 7.96 pg/mL in healthy controls. In the ofatumumab group, mean sNfL declined to 10.54 pg/mL at month 6 and remained stable thereafter (10.20 pg/mL at month 18). In healthy controls, mean sNfL remained stable at 8.03 at month 6, and 8.32 pg/mL at month 18. There were similar changes for serum glial fibrillary acidic protein (GFAP). Mean sGFAP declined from 23.17 to 20.36 pg/mL at month 6 in the ofatumumab group and remained stable thereafter (21.22 pg/mL at month 18). sGFAP concentrations in healthy controls were 15.35 pg/mL at baseline, 15.25 pg/mL at month 6 and 14.58 pg/mL at month 18. The results indicate that early treatment with ofatumumab may normalize serum biomarkers of inflammation and neurodegeneration. The NeofiLos program in Germany is now assessing the clinical usefulness of serial sNfL testing in neurology practice (Akguen et al. ACTRIMS Forum 2026;V035).