De Meo E, Addazio I, Portaccio E, Bonacchi R, Betti M, Patti F, Guerrieri S, Foschi M, Ferraro D, Annovazzi P, Brescia Morra V, Tortorella C, Lugaresi A, Camilli F, Pozzilli C, Perini P, Granella F, De Luca G, Torri Clerici VLAM, Vianello M, Romano S, Cocco EE, Lus G, Di Sapio A, Rocca MA, Simone M, Iaffaldano P, Filippi M, Trojano M, Amato MP. Disability Worsening Phenotypes in Multiple Sclerosis and Impact of Disease-Modifying Treatments. Neurology. 2025 Dec 23;105(12):e214408. doi: 10.1212/WNL.0000000000214408.
Background and objectives: Patients with multiple sclerosis (MS) exhibit variability in disability progression and response to disease-modifying therapies (DMTs). Identifying those at greatest risk of disability worsening and most likely to benefit from high-efficacy DMTs remains challenging. We aimed to identify distinct disability worsening phenotypes, explore their mechanisms, and evaluate DMT impact across them.
Methods: In this multicenter cohort study, we analyzed clinical and MRI data from propensity-matched cohorts of treated and untreated patients with relapse-onset MS from the Italian MS Register. Inclusion criteria were as follows: ≥3 years of follow-up, ≤1 year between disease onset and first assessment, and complete clinical and baseline MRI data. Latent class mixture models were applied to Expanded Disability Status Scale (EDSS) scores from untreated patients to identify disability worsening phenotypes. We compared proportions of progression independent of relapse activity (PIRA) and relapse-associated worsening events across phenotypes.
Results: We analyzed data from 2,563 untreated (mean age 41.2 ± 10 years, 67% female) and 2,952 treated (mean age 40.8 ± 11.4 years, 66% female) patients with MS over a median follow-up of 10.1 (interquartile range: 7.0-13.0) years. Four phenotypes were identified in untreated patients: “minimal-worsening” (15%), “late-worsening” (70%), “early-worsening” (3%), and “rapid-worsening” (12%). In all phenotypes, PIRA represented the main disability accrual mechanism. “Early-worsening” and “rapid-worsening” phenotypes exhibited more brain and spinal cord T2-hyperintense and gadolinium-enhancing lesions at baseline. (So this shows what a pile of tosh they are talking about they say PIRA is the main mechanism of worsening. PIRA is progression independent of relapses.….T2 and gadolinium enhancing lesions are particularly evident in the worsening but as these MRI lesions are the basis of attacks which may be subclinical or clinical i.e relapses so progression isnt independent of relapse…OK rant over. The classification algorithm assigned phenotypes to patients receiving DMTs with 71% accuracy: “minimal-worsening” (18%), “late-worsening” (61%), “early-worsening” (13%), and “rapid-worsening” (8%). DMT exposure significantly reduced disability accrual in all phenotypes (Again DMT which inhibits relapse inhibit disability need I say more..obviously the neuros need to hear it, with high-efficacy DMTs (β = -0.16, standard error (SE) = 0.06, p < 0.001) and early escalation (β = -0.18, SE = 0.06, p < 0.001) proving especially beneficial for the “rapid-worsening” phenotype (Again NSS…say no more).
Discussion: We identified 4 clinically relevant disability worsening phenotypes in relapse-onset MS, primarily driven by PIRA, with greater CNS involvement linked to early and rapid progression. Despite reliance on EDSS alone, these phenotypes may inform personalized treatment and response assessment.
How can they inform personalised treatment properly as the phenotype is a retrospective description so if you are an early progressor you have progressed…so simplistic approach is start with high efficacy agents as soon as possible ..surely it isn’t rocket science? Maybe it is if we need to be told about this 
Source: multiple-sclerosis-research.org