Tur C. High-efficacy therapy and progression independent of relapse and MRI activity in multiple sclerosis. Brain. 2026:awag175. https://doi.org/10.1093/brain/awag175

They say “The main mechanism through which patients with multiple sclerosis (MS) acquire disability is progression independent of relapse activity (PIRA)” (Yep a widely held view)…..”However, PIRA events may also be preceded by acute inflammatory activity, as indicated by the presence of new or enlarging T2 lesions on MRI in up to 50% of cases”. (Eh therefore PIRA is not independent of relapse i.e. lesion formation = clinical or sub-clinical relapse, especially as MRI will not find all lesions everywhere, as they seldom look in the spinal cord for example) “Preventing PIRA from occurring in the first place—by targeting the processes that ultimately drive it—therefore appears crucial for limiting long-term disability”. Yep so it seems obvious that we need anti-inflammatory treatment as the base of all approaches and this needs to be effectively instigated as soon as possible.

I seem to be missing the point of PIRA, I been talking PIRMA. Progression independent of both relapses and MRI activity (PIRMA).

This is the editorial that surrounds this study

Rollot F, Casey R, Kerbrat A, Edan G, Le Page E, Vukusic S, Mathey G, Maillart E, De Sèze J, Ciron J, Ruet A, Labauge P, Papeix C, Zephir H, Lebrun-Frenay C, Defer G, Moreau T, Berger E, Clavelou P, Heinzlef O, Thouvenot E, Pelletier J, Casez O, Bourre B, Wahab A, Moulin S, Kwiatkowski A, David T, Magy L, Camdessanché JP, Doghri I, Dos Santos A, Hankiewicz K, Sarov Riviere M, Manchon E, Pottier C, Tchikviladze M, Scherer Gagou C, Dahan C, Durozard P, Laplaud DA, Michel L. Progression independent of relapse and MRI activity and treatment strategies in multiple sclerosis. Brain. 2026. doi: 10.1093/brain/awag060.

The impact of high-efficacy therapies (HET) on progression independent of relapse and MRI activity (PIRMA) remains poorly defined. In this context, using the French MS registry, we aimed to assess the real-life effectiveness of HET compared with moderate efficacy therapies (MET) on PIRMA in relapsing-onset MS (RMS) patients. Data were collected from RMS patients of the French MS Registry, between January, 2010 and June, 2023, with a mean follow-up of 3.7 years. RMS patients were included in the analysis if they were treated first with HET (2666 included) or MET (7833 included), and had EDSS and MRI follow-up every two years. Each outcome was studied using a propensity score framework. The primary outcome was time-to-first PIRMA. Secondary outcomes were PIRMA incidence, time-to-first confirmed disability progression (CDP), relapse-associated worsening (RAW), MRI-associated worsening (MAW) and identification of risk factors associated with PIRMA. A total of 10499 patients fulfilled the inclusion criteria. The mean (SD) age at treatment initiation was 36.4 (10.3) years, with a mean (SD) disease duration of 3.1 (5.1) years. The restricted mean survival (SD) time to first PIRMA was slightly significantly shorter in the HET group compared to the MET group (8.7 yrs (0.08) vs. 8.9 yrs (0.05) p=0.017). However, when looking at time-to-first CDP, it tended to be longer in the HET group compared to the MET group (7.6 (0.10) vs. 7.3 years (0.06); p=0.071), and it was probably linked to the shorter time-to-first RAW and MAW in the MET group (9.2 (0.06) vs 8.7 years (0.05); p<0.001 for RAW and 9.0 (0.05) vs 8.5 (0.07); p<0.001 for MAW). Baseline risk factors associated with increased PIRMA incidence in the whole population were: high EDSS, higher age at baseline and the presence of spinal cord lesions. Even if HET has a better control on disability accumulation related to disease activity than MET, our real-life study suggests that PIRMA-related mechanisms are not differentially affected by HET versus MET.

While High Efficacy Treatments were associated with longer times to confirmed disability worsening. It seemed that the time to PIRMA was similar.

“High Efficacy Treatments were consistently superior to Moderately Efficacy Treatments in delaying confirmed disability worsening, relapse-associated worsening (RAW), and MRI-associated worsening (MAW), confirming their strong anti-inflammatory effects”

In secondary analyses, the authors found that the risk of PIRMA varied by treatment: natalizumab (n = 888) and anti-CD20 therapies (n = 991) were associated with shorter time to first PIRMA compared with MET”

The consistency of findings across therapies such as natalizumab and anti-CD20 agents further suggests that current treatments, including anti-CD20 therapies, may have limited impact on the chronic inflammatory processes driving progression (NSS. We need therapies that actually enter the CNS and target responses not currently effectively targeted by the lymphocyte-targeting drugs that we seem to be solely focussing on. In this context all HETS and METS target lymphocytes, one needs to target the neurodegenerative mechanisms that are not driven by the lymphocytes).

One of the problems is the data comes from 2010-2023 and in 2010 the only high efficacy drug was natalizumab and you typically have to fail a treatment before you get it….now you can get anti-CD20 as a first line treatment. The issue about measuring progression is that the root biology is not a single entity and so the measures are detecting composite processes

COI: None relevant

Disclaimer my views

Source: multiple-sclerosis-research.org