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

The research, led by Yan Xie and Shaolong Wu of Henan Provincial People’s Hospital and Tongji Hospital in China, together with colleagues including Yi Wang at Weill Cornell Medicine and Meiyun Wang as senior author, compared 119 patients with relapsing–remitting multiple sclerosis, 47 patients with neuromyelitis optica spectrum disorders, and 93 healthy controls. The choice of comparison group matters. Neuromyelitis optica spectrum disorder was once lumped together with multiple sclerosis as a variant of the same disease, but it is now understood to be a fundamentally different condition, driven by antibodies against a water channel protein called aquaporin-4 rather than by the immune-mediated destruction of myelin that characterizes multiple sclerosis. Contrasting the two diseases in the same imaging framework therefore provides a kind of natural experiment: if a signal appears in multiple sclerosis but not in neuromyelitis optica, it likely reflects processes specific to multiple sclerosis pathology.

The technical heart of the study is an advanced magnetic resonance imaging method called susceptibility separation imaging, sometimes referred to as chi-separation. Conventional MRI is superb at revealing lesions, the bright scars that dot the brains of people with multiple sclerosis, but it says little about the underlying chemistry. Quantitative susceptibility mapping, a technique refined over the past decade, goes further by converting subtle distortions in the magnetic field measured by the scanner into maps of magnetic susceptibility, a physical property tied to the concentration of substances such as iron and myelin. Iron, sequestered in ferritin and heme within cells, is strongly paramagnetic and pushes susceptibility in the positive direction, while myelin, with its lipid-rich sheaths, is diamagnetic and pulls susceptibility negative. The trouble is that ordinary susceptibility maps blend these contributions into a single number, making it impossible to say whether a change reflects iron, myelin, or both.

Susceptibility separation imaging tackles this ambiguity head-on. Reconstructed from standard three-dimensional multi-echo gradient echo acquisitions, the method mathematically decomposes the total susceptibility signal into a positive component, denoted chi-pos, and a negative component, chi-neg. Histological validation work by other groups has shown that the positive component corresponds predominantly to iron stores, whereas the negative component is dominated by myelin. In effect, the technique gives researchers two separate dials, one roughly tracking tissue iron and the other tracking myelin integrity, from data that can be collected on conventional clinical scanners in a single session. That combination of chemical specificity and clinical practicality is what makes the approach attractive for large patient studies.

To focus on the U-fibers, the team defined the region of interest as the white matter lying within four millimeters beneath the gray-white matter boundary, and then divided this thin ribbon into a set of subregions across the whole brain. From each subregion they extracted total susceptibility as well as the positive and negative components, and used general linear models to compare the three groups while partial correlation analyses probed links with clinical measures. The results were strikingly asymmetric. In the multiple sclerosis patients, the positive susceptibility component, the putative iron signal, was significantly decreased in multiple temporal and limbic U-fiber regions relative to healthy controls. The negative component, associated with myelin, was significantly increased across a far more widespread set of U-fiber subregions.

The direction of these changes is as informative as their presence. A decrease in the iron-related signal in superficial white matter fits with a growing body of work suggesting that multiple sclerosis involves not just iron accumulation in deep gray matter structures but actual iron loss in certain tissue compartments, possibly reflecting the death of iron-rich glial cells, efflux of iron from damaged tissue, or dilution as tissue shrinks. Meanwhile, an increase in the negative, myelin-related component across broad U-fiber territories is consistent with demyelination and the inflammatory remodeling of myelin sheaths, processes that alter the diamagnetic signature of the tissue even outside visible lesions. That the myelin signal was abnormal across so many regions underscores a point that neuropathologists have made for decades: the damage in multiple sclerosis extends well beyond the discrete scars that radiologists can see on standard scans.

Perhaps the most consequential finding, however, is what the researchers did not find. When they compared the neuromyelitis optica spectrum disorder patients with healthy controls, no U-fiber subregion showed a significant difference in any susceptibility metric. In other words, the iron and myelin chemistry of the superficial white matter appeared essentially preserved in this disease, despite the fact that patients with neuromyelitis optica can carry a substantial burden of brain lesions and neurological impairment. This dissociation strengthens the argument that the susceptibility changes seen in multiple sclerosis are not a generic consequence of having an inflammatory brain disease, but instead reflect disease-specific processes, most plausibly the primary demyelination that defines multiple sclerosis pathology.

The story acquires an important caveat when the two patient groups are compared directly with each other. After the researchers adjusted for potential confounding effects of disease severity and lesion burden, the significant differences in susceptibility metrics between the multiple sclerosis and neuromyelitis optica groups disappeared. This suggests that part of the apparent disease-specificity may be explained by the fact that the multiple sclerosis patients in this cohort had greater lesion loads or more advanced disease. The U-fiber changes, in this reading, scale with the overall amount of tissue injury rather than being uniquely programmed by multiple sclerosis biology. Disentangling whether superficial white matter chemistry is a cause, a consequence, or simply a barometer of lesion burden will require longitudinal studies that follow patients from the earliest stages of disease.

What the study does establish firmly is a link to clinical disability. Within the multiple sclerosis group, the negative susceptibility component in U-fiber subregions correlated significantly with scores on the Expanded Disability Status Scale, the standard clinical measure of neurological impairment, with the strongest association in the left superior frontal region. That region houses short association fibers serving frontal lobe networks involved in executive function and cognitive control, domains that are frequently impaired in multiple sclerosis even when physical disability seems modest. The finding dovetails with prior work showing that U-fiber diffusion and susceptibility abnormalities relate to cognitive deficits and neurodegeneration, and it raises the possibility that susceptibility metrics could serve as surrogate markers, bridging the persistent gap between what radiologists see on conventional scans and what patients actually experience.

The implications reach toward clinical practice. Because susceptibility separation imaging can be reconstructed from gradient echo data already acquired in routine protocols, it could in principle be added to existing MRI examinations without new scan time, offering clinicians a quantitative readout of iron and myelin status in tissue that conventional sequences render as unremarkable. Such markers could eventually help monitor disease progression, evaluate whether experimental remyelinating therapies are working, and distinguish multiple sclerosis from its mimics at earlier stages. For now, the study’s authors are careful to frame the metrics as suggestive surrogate markers rather than diagnostic tests, and the cross-sectional design leaves open the question of whether the U-fiber changes precede visible lesions or follow them. Still, the work adds a compelling piece to a rapidly growing picture in which the brain’s thinnest, most overlooked layer of wiring, the short fibers hugging the cortical surface, turns out to be a sensitive mirror of the disease process, and a potential window into the biology of disability in multiple sclerosis.

Subject of Research: Iron and myelin susceptibility changes in U-fiber white matter in relapsing–remitting multiple sclerosis versus neuromyelitis optica spectrum disorders

Article Title: Comparison of iron and myelin changes in U‑fiber regions of relapsing–remitting multiple sclerosis and neuromyelitis optica spectrum disorders

Article References: Xie, Y., Wu, S., Zhang, Y., Ju, C., Zhang, S., Wang, Y., Zhu, W., & Wang, M. (2026). Comparison of iron and myelin changes in U‑fiber regions of relapsing–remitting multiple sclerosis and neuromyelitis optica spectrum disorders. Journal of Neurology, 273(10), Article 596. https://doi.org/10.1007/s00415-026-14054-y

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14054-y

Keywords: multiple sclerosis, neuromyelitis optica spectrum disorder, U-fibers, susceptibility separation imaging, quantitative susceptibility mapping, iron, myelin, white matter, MRI, Expanded Disability Status Scale, demyelination, superficial white matter