Progression independent of relapse (clinical & Imaging) drives disability and is the basis for progression of disability. Natalizumab has its main action outside of the brain so any influence on progression would be due to stopping the consequences of damaging immune attack from entering into the CNS. Once sufficient damage is accumulated then a slow nerve loss is generated that will not quickly respond to the effects of natalizumab because they are driven by events occuring in the CNS. These events will generate because one has not controlled disease well enough, early enough…i.e. Not starting with an effective high efficacy therapy early, by which time damage has accumulated. This is one reason why some therapies should be retired or used only for special considerations and also a reason why all treatments should be on the table at the start of disease rather than waiting for failure. This is what occurs in Poundland Britain, but not in other parts of the World. The regulators are slowly waking up and the advent of B cell depleters has woken them up. B cell depleters are not just anti-CD20 antibodies
Puthenparampil M, Passamonti M, Rozzi M, Basili E, Mauceri VA, Nosadini M, Sartori S, Di Paola A, Gallo P, Rinaldi F, Perini P. EDSS and disease duration associate with progression independent of relapse and MRI activity in natalizumab-treated multiple sclerosis patients. Mult Scler Relat Disord. 2026 Mar 17;109:107148.
Background: Clinical, biological and radiological data that may help in predicting and managing the Progression Independent of Relapse and MRI Activity (PIRMA) in multiple sclerosis (MS). We designed a retrospective, longitudinal study to identify prognostic factors of PIRMA in natalizumab (NTZ) treated patients with MS (pwMS).
Methods: Clinical and radiological data from pwMS starting NTZ in the period July 2007 to February 2017 were retrospectively collected.
Results: 238 patients (age of 29.1 ± 8.5 years) were followed up for 5.5 ± 4.3 years. PIRMA was observed in 70 patients (29.4%). PIRMA was predicted by both EDSS (Cox regression analysis: H.R.= 1.7, p < 0.0001) and disease duration at NTZ first administration (H.R.= 1.0, p = 0.025). Combining disease duration (138 months) and EDSS (4.0) cut-offs, pwMS with lower and disease duration had lower probability of PIRMA compared to patients with 1 risk factor (disease duration ≥138 months or EDSS ≥ 4, H.R. 5.321, 95%IC 2.943 – 9.622, p < 0.0001) or 2 risk factors (H.R. 6.100, 95%IC 2.100 – 17.730, p < 0.0001). To evaluate the effect of age on PIRMA, we focused the analysis on patients that reached at least the age of 45 during the follow-up (age at follow-up end: 51.8 ± 5.7; range: 45-75). Higher baseline EDSS was independently associated with an increased risk of PIRMA (HR 1.65, 95% CI 1.24-2.24, p = 0.0005). Conversely, older age at natalizumab initiation was associated with a lower risk of PIRMA (HR 0.87 per year, 95% CI 0.81-0.95, p = 0.0007).
Conclusions: PIRMA was identified as the main driver of disability progression in RRMS treated with NTZ and is predicted by disease duration and EDSS at therapy initiation.
Source: multiple-sclerosis-research.org