The research, led by Leonardo Palazzo and colleagues at the IRCCS San Raffaele Scientific Institute in Milan, drew on the Italian MS Registry, a nationwide repository of clinical data from people living with multiple sclerosis across the country. The team focused on patients with relapsing-remitting disease who had been treated for at least five years with one of four so-called platform therapies: the oral agents dimethyl fumarate and teriflunomide, and the injectable treatments interferon beta and glatiramer acetate. These drugs represent the long-standing backbone of first-line MS care, prescribed to hundreds of thousands of patients worldwide, yet head-to-head evidence on their effects against relapse-independent progression has remained strikingly thin.

Defining PIRA precisely is a technical challenge that has occupied the field in recent years. In this study, the investigators adopted a stringent operational definition: a confirmed worsening of disability on the Expanded Disability Status Scale that persisted for at least twelve months and occurred in the complete absence of any relapse during the relevant window. This twelve-month confirmation requirement helps filter out transient fluctuations in neurological function that can follow infections, fatigue, or heat, ensuring that the events counted as PIRA reflect genuine, sustained accumulation of impairment rather than temporary pseudoexacerbations.

From an initial pool of 1,910 eligible patients, the researchers constructed carefully balanced comparison groups using propensity score matching, a statistical technique that pairs treated individuals who share similar baseline characteristics such as age, sex, disease duration, and prior treatment history. Matching was performed separately for each drug comparison, yielding 174 matched pairs of dimethyl fumarate versus teriflunomide users and 404 matched pairs of interferon beta versus glatiramer acetate users. This design approximates the conditions of a randomized trial in a real-world setting, where treatment assignment is driven by clinical judgment rather than a protocol, and it helps reduce the confounding that typically plagues observational comparisons of therapies.

The statistical machinery applied to these matched cohorts was correspondingly rigorous. Negative binomial regression was used to model the cumulative number of PIRA events in each group, while Cox proportional hazards models estimated the time to a patient’s first PIRA event. Both approaches are standard tools in survival and event-count analysis, and their convergence strengthens the reliability of the findings. Across every comparison, the confidence intervals for the risk ratios and hazard ratios comfortably spanned the null value of one, indicating no statistically detectable difference between the therapies under study.

Specifically, teriflunomide-treated patients showed a cumulative PIRA risk ratio of 0.82 relative to those on dimethyl fumarate, with a 95 percent confidence interval of 0.47 to 1.40, and a hazard ratio of 0.81 for time to first event, with a confidence interval of 0.47 to 1.37. In the injectable comparison, glatiramer acetate versus interferon beta produced a risk ratio of 1.04 and a hazard ratio of 0.86, both similarly non-significant. When the investigators pooled the oral and injectable cohorts into a broader class-level comparison, the results again revealed no meaningful divergence, with a risk ratio of 0.79 and a hazard ratio of 1.06. In plain terms, none of the four platform drugs demonstrated a measurable advantage in shielding patients from relapse-independent disability accumulation.

The significance of this null result extends beyond the four drugs themselves. PIRA has emerged as a central concept in modern MS research because pooled analyses of clinical trial data have suggested that the majority of confirmed disability worsening in treated relapsing patients is, in fact, relapse-independent. Landmark work published in JAMA Neurology in 2020 estimated that relapse-independent progression contributes substantially to overall disability accumulation in typical relapsing disease, and subsequent cohort studies have confirmed that PIRA begins early, sometimes even after a first demyelinating event, and predicts long-term disability outcomes. If the inflammatory attacks are being controlled but patients continue to worsen silently, then understanding which therapies, if any, can modify this process becomes a question of enormous clinical weight.

The biological substrate of PIRA is thought to lie in mechanisms that conventional anti-inflammatory drugs reach only imperfectly: compartmentalized inflammation within the central nervous system, smoldering lesions with slowly expanding rims of microglial activation, meningeal inflammatory aggregates, diffuse gray matter damage, and progressive neurodegeneration that unfolds independently of peripheral immune attacks. Platform therapies such as interferon beta, glatiramer acetate, dimethyl fumarate, and teriflunomide were all developed primarily as modulators of peripheral immune activity, and the new findings are consistent with the idea that their shared mechanism of action leaves the smoldering intrathecal disease process largely untouched. Whether higher-efficacy agents, such as B-cell-depleting antibodies or potent immunosuppressants, offer better protection against PIRA remains an active area of investigation, with recent observational studies in Swiss and other cohorts beginning to explore these comparisons.

For clinicians and patients, the practical message of the Milan study is one of reassurance and clarity in therapeutic decision-making. Because the platform therapies appear equivalent with respect to PIRA risk, the choice among them can legitimately be guided by other considerations: safety profiles, tolerability, monitoring requirements, pregnancy planning, comorbidities, patient preference, and cost. Dimethyl fumarate requires regular lymphocyte and renal function monitoring; teriflunomide carries teratogenic risk and demands careful contraception counseling; interferon beta produces flu-like side effects and injection-site reactions; glatiramer acetate is generally well tolerated but demands frequent injections. None of these trade-offs, the study suggests, is offset by a differential ability to prevent silent progression.

The authors are careful to acknowledge the inherent limits of their design. Retrospective registry data, however carefully matched, cannot eliminate all confounding, and the five-year minimum treatment requirement may select for patients with milder disease courses who tolerate their therapy well. The confidence intervals, while centered near the null, are not narrow enough to exclude moderate differences between drugs, and the number of matched pairs in the oral comparison was comparatively modest. Nonetheless, the study represents one of the most direct real-world examinations of platform therapy effects on PIRA to date, and its conclusions align with a growing consensus, reflected in recent efforts to standardize PIRA definitions across the field, that relapse-independent progression is a distinct therapeutic target. As the MS treatment landscape shifts toward early use of high-efficacy agents, this work provides a sober benchmark: the older, gentler drugs, whatever their virtues, appear to stand shoulder to shoulder when it comes to the quiet accumulation of disability that no relapse ever announces.

Subject of Research: Comparative incidence of progression independent of relapse activity (PIRA) under platform disease-modifying therapies in relapsing-remitting multiple sclerosis

Article Title: Incidence of Progression Independent of Relapse Activity (PIRA) under platform disease-modifying treatment in multiple sclerosis

Article References: Palazzo, L., Clarelli, F., Giordano, A., Ferré, L., Moiola, L., Rocca, M. A., Esposito, F., Filippi, M., Clinical SanRaf MS Study Group, Missaglia, M., Visentin, G., Guido, G., Marino, V., De Simone, A., Viti, V., Zanetta, C., Margoni, M., Guerrieri, S., Petza, E., … Rossi, L. (2026). Incidence of Progression Independent of Relapse Activity (PIRA) under platform disease-modifying treatment in multiple sclerosis. Journal of Neurology, 273(10), Article 640. https://doi.org/10.1007/s00415-026-14171-8

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14171-8

Keywords: multiple sclerosis, PIRA, disease-modifying therapy, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate, disability progression, Italian MS Registry, propensity score matching, relapsing-remitting multiple sclerosis, neuroimmunology