Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis

Abstract

ImportanceProgression independent of relapse activity (PIRA) is the main event responsible for irreversible disability accumulation in relapsing multiple sclerosis (MS).ObjectiveTo investigate clinical and neuroimaging predictors of PIRA at the time of the first demyelinating attack and factors associated with long-term clinical outcomes of people who present with PIRA.Design, Setting, and ParticipantsThis cohort study, conducted from January 1, 1994, to July 31, 2021, included patients with a first demyelinating attack from multiple sclerosis; patients were recruited from 1 study center in Spain. Patients were excluded if they refused to participate, had alternative diagnoses, did not meet protocol requirements, had inconsistent demographic information, or had less than 3 clinical assessments.ExposuresExposures included (1) clinical and neuroimaging features at the first demyelinating attack and (2) presenting PIRA, ie, confirmed disability accumulation (CDA) in a free-relapse period at any time after symptom onset, within (vs after) the first 5 years of the disease (ie, early/late PIRA), and in the presence (vs absence) of new T2 lesions in the previous 2 years (ie, active/nonactive PIRA).Main Outcomes and MeasuresExpanded Disability Status Scale (EDSS) yearly increase rates since the first attack and adjusted hazard ratios (HRs) for predictors of time to PIRA and time to EDSS 6.0.ResultsOf the 1128 patients (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]) included in the study, 277 (25%) developed 1 or more PIRA events at a median (IQR) follow-up time of 7.2 (4.6-12.4) years (for first PIRA). Of all patients with PIRA, 86 of 277 (31%) developed early PIRA, and 73 of 144 (51%) developed active PIRA. Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Older age at the first attack was the only predictor of PIRA (HR, 1.43; 95% CI, 1.23-1.65; P < .001 for each older decade). Patients with PIRA had steeper EDSS yearly increase rates (0.18; 95% CI, 0.16-0.20 vs 0.04; 95% CI, 0.02-0.05; P < .001) and an 8-fold greater risk of reaching EDSS 6.0 (HR, 7.93; 95% CI, 2.25-27.96; P = .001) than those without PIRA. Early PIRA had steeper EDSS yearly increase rates than late PIRA (0.31; 95% CI, 0.26-0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) and a 26-fold greater risk of reaching EDSS 6.0 from the first attack (HR, 26.21; 95% CI, 2.26-303.95; P = .009).Conclusions and RelevanceResults of this cohort study suggest that for patients with multiple sclerosis, presenting with PIRA after a first demyelinating event was not uncommon and suggests an unfavorable long-term prognosis, especially if it occurs early in the disease course.

Time to Change the Current Clinical Classification of Multiple Sclerosis?

“…Despite this limitation, both studies leave no doubt that PIRA is a common feature of MS from the earliest stages and contradict the conceptual distinction between relapsing and progressive disease courses or stages. Tur et al also provide solid evidence that experiencing PIRA is a predictor of accelerated accumulation of disability; patients with PIRA had an 8-fold higher risk of reaching an EDSS score of 6.0 than patients without PIRA. Prognostically, early PIRA seems to portend a worse outcome: participants who developed PIRA within 5 years had significantly higher annual EDSS score increase rates than those who developed PIRA later and a 26-fold greater risk of reaching an EDSS score of 6.0.…”

“…On the other hand, despite coming to recognize the presence of PIRA from the earliest stages of MS, we learn disappointingly little from this study of patients with CIS about the predictors of PIRA. 6 Only age at first demyelinating event emerged as a statistically robust, although not particularly strong, risk factor for early development of PIRA (hazard ratio for each older decade, 1.43; 95% CI, 1.23-1.65; P < .001). In patients who had sufficient magnetic resonance imaging (MRI) documentation, the number of spinal cord lesions was also a risk factor, confirming the data reported previously in a smaller cohort.…”

“…13 Much remains to be done to advance our understanding of the factors underlying disability accumulation in people with MS and to improve our quantification and prevention of this disability. The study by Tur et al 6 brings us a step closer by documenting that accumulation of disability starts early in the disease course and by underlining the detrimental consequences of early PIRA in people with MS. Altogether, these clinical observations and our current-growing but still incomplete-knowledge about the factors that contribute to disability accumulation suggest that we should revisit our traditional categorization of MS into relapsing and progressive courses.…”

“…In addition, our recognition of PIRA was critically facilitated by the availability of treatments that effectively suppress or even completely abrogate relapse activity-thus reducing the noise that may interfere with the detection of subtle signs of progression. In this issue of JAMA Neurology, Tur et al 6 expand the findings obtained in RRMS to people with MS presenting with a very first demyelinating event, classified as a clinically isolated syndrome (CIS). In the setting of the prospectively followed and thoroughly documented Barcelona inception cohort, these investigators assessed the frequency of PIRA vs relapse-associated worsening (RAW) in 1128 participants, all enrolled within 3 months from the first clinical episode.…”

Are highly active and aggressive multiple sclerosis the same entity?

“…PIRA is critically determined by age, being more frequent in older patients (23). Furthermore, the presence of PIRA suggests an unfavorable longterm prognosis, mainly if it occurs early in the course of the disease (25).…”