EDSS and disease duration associate with progression independent of relapse and MRI activity in natalizumab-treated multiple sclerosis patients.

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.