Time to Change the Current Clinical Classification of Multiple Sclerosis?

Granziera, Cristina; Derfuss, Tobias; Kappos, Ludwig

doi:10.1001/jamaneurol.2022.4156

Cited by 16 publications

(15 citation statements)

References 16 publications

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“…Only after a certain time and continuous accumulation of damage, the brain reserve may not be able to cope with the structural injury, explaining the correlation of PIRA with higher age and/or longer disease duration . Still, PIRA may remain undetected due to the low granularity of our clinical measures, highlighting the importance of standardized, quantitated and structured assessment of patients with MS with sensitive and specific measures, allowing for more precise correlation studies with markers of progression and better targeted therapeutic interventions …”

Section: Discussionmentioning

confidence: 99%

“…33 Importantly, most studies confirmed that PIRA accounted for a higher proportion of confirmed disability accruals in patients re-ceiving DMT compared with those without or undergoing placebo treatment. 7,13,16,18,25,43 Discussion Observational and controlled clinical trials provide unequivocal evidence that PIRA is the most frequent manifestation of disability accumulation across the full spectrum of traditional MS phenotypes, including CIS and early RRMS, thus challenging the conceptual distinction between relapsing and progressive disease courses or stages. The reported proportion of patients experiencing PIRA varies depending on (1) the definition used (EDSS vs composite measures, fixed vs roving baseline), ( 2) population under study (randomized clinical trials vs observational data, CIS/early RRMS vs late RRMS vs progressive MS), and (3) length of follow-up (eTable 3 in the Supplement).…”

Section: Treatment Of Piramentioning

confidence: 99%

“…13,16 The latter observation might be attributed to more effective suppression or complete abrogation of acute relapse activity by DMT, which reduces the noise that may interfere with the detection of subtle signs of insidious progression and also prolongs the duration of PIRA risk exposure due to the reduction of relapse rates or both. 7,13,18 The structural correlates of PIRA are not yet fully defined, but it has been suggested that the same mechanisms that are responsible for the accrual of disability in progressive MS may also be responsible for PIRA. 12 This is supported by the fact that patients with RRMS, and even CIS, share qualitatively similar (but quantitatively different) pathology features as patients with progressive MS. 19 Patients with PIRA show increased brain, cortical, and spinal cord atrophy as well as an increased proportion of paramagnetic rim lesions.…”

Section: Treatment Of Piramentioning

confidence: 99%

“…36 Still, PIRA may remain undetected due to the low granularity of our clinical measures, highlighting the importance of standardized, quantitated and structured assessment of patients with MS with sensitive and specific measures, allowing for more precise correlation studies with markers of progression and better targeted therapeutic interventions. [5][6][7]18,36,64 Terminology of PIRA The identification of PIRA is complex and based on various determinants that have been used inconsistently in the literature. Therefore, in the following section, we aim to recapitulate, describe, and discuss the terminology that has been used in the context of PIRA before providing recommendations in the subsequent section.…”

Section: Treatment Of Piramentioning

confidence: 99%

“…5,15,16 Based on these findings, it was proposed that a paradigm shift is needed for the classification of MS disease courses, moving away from the current clinical phenotypic classification to a classification that takes PIRA into account and includes biomarkers extending beyond clinical and imaging measures of acute inflammatory activity. 6,[17][18][19] To date, there is no uniform, agreed-upon definition of PIRA, hereby hampering the comparability of current and future studies. Here, we (1) summarize the current knowledge on PIRA based on a systematic review of the literature, (2) discuss the terminology applied in the context of PIRA, and (3) propose a harmonized definition to use in clinical practice and future studies.…”

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confidence: 99%

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Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis

Müller,

Cagol,

Lorscheider

et al. 2023

JAMA Neurol

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ImportanceEmerging evidence suggests that progression independent of relapse activity (PIRA) is a substantial contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (RRMS). To date, there is no uniform agreed-upon definition of PIRA, limiting the comparability of published studies.ObjectiveTo summarize the current evidence about PIRA based on a systematic review, to discuss the various terminologies used in the context of PIRA, and to propose a harmonized definition for PIRA for use in clinical practice and future trials.Evidence ReviewA literature search was conducted using the search terms multiple sclerosis, PIRA, progression independent of relapse activity, silent progression, and progression unrelated to relapses in PubMed, Embase, Cochrane, and Web of Science, published between January 1990 and December 2022.FindingsOf 119 identified single records, 48 eligible studies were analyzed. PIRA was reported to occur in roughly 5% of all patients with RRMS per annum, causing at least 50% of all disability accrual events in typical RRMS. The proportion of PIRA vs relapse-associated worsening increased with age, longer disease duration, and, despite lower absolute event numbers, potent suppression of relapses by highly effective disease-modifying therapy. However, different studies used various definitions of PIRA, rendering the comparability of studies difficult.Conclusion and RelevancePIRA is the most frequent manifestation of disability accumulation across the full spectrum of traditional MS phenotypes, including clinically isolated syndrome and early RRMS. The harmonized definition suggested here may improve the comparability of results in current and future cohorts and data sets.

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Section: Discussionmentioning

confidence: 99%

Section: Treatment Of Piramentioning

confidence: 99%

Section: Treatment Of Piramentioning

confidence: 99%

Section: Treatment Of Piramentioning

confidence: 99%

mentioning

confidence: 99%

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Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis

Müller,

Cagol,

Lorscheider

et al. 2023

JAMA Neurol

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A comparison of natalizumab and ocrelizumab on disease progression in multiple sclerosis

Iaffaldano,

Lucisano,

Guerra

et al. 2024

Ann Clin Transl Neurol

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ObjectiveNo direct comparisons of the effect of natalizumab and ocrelizumab on progression independent of relapse activity (PIRA) and relapse‐associated worsening (RAW) events are currently available. We aimed to compare the risk of achieving first 6 months confirmed PIRA and RAW events and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 in a cohort of naïve patients treated with natalizumab or ocrelizumab from the Italian Multiple Sclerosis Register.MethodsPatients with a first visit within 1 year from onset, treated with natalizumab or ocrelizumab, and ≥3 visits were extracted. Pairwise propensity score‐matched analyses were performed. Risk of reaching the first PIRA, RAW, and EDSS 4.0 and 6.0 events were estimated using multivariable Cox proportional hazards models. Kaplan–Meier curves were used to show cumulative probabilities of reaching outcomes.ResultsIn total, 770 subjects were included (natalizumab = 568; ocrelizumab = 212) and the propensity score‐matching retrieved 195 pairs. No RAW events were found in natalizumab group and only 1 was reported in ocrelizumab group. A first PIRA event was reached by 23 natalizumab and 25 ocrelizumab exposed patients; 7 natalizumab‐ and 10 ocrelizumab‐treated patients obtained an irreversible EDSS 4.0, while 13 natalizumab‐ and 15 ocrelizumab‐treated patients reached an irreversible EDSS 6.0. No differences between the two groups were found in the risk (HR, 95%CI) of reaching a first PIRA (1.04, 0.59–1.84; p = 0.88) event, an irreversible EDSS 4.0 (1.23, 0.57–2.66; p = 0.60) and 6.0 (0.93, 0.32–2.68; p = 0.89).InterpretationBoth medications strongly suppress RAW events and, in the short term, the risk of achieving PIRA events, EDSS 4.0 and 6.0 milestones is not significantly different.

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Disability trajectories by progression independent of relapse activity status differ in pediatric, adult and late-onset multiple sclerosis

Simone,

Lucisano,

Guerra

et al. 2024

J Neurol

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Background To compare Expanded Disability Status Scale (EDSS) trajectories over time between Multiple Sclerosis (MS) groups with pediatric (POMS), adult (AOMS) and late (LOMS) onset, and between patients with and without progression independent of relapse activity (PIRA). Methods Patients with a first visit within 1 year from onset, ≥ 5-year follow-up and ≥ 1 visit every 6 months were selected from the Italian MS Register. Adjusted disability trajectories were assessed by longitudinal models for repeated measures. Comparisons between groups and between patients with and without PIRA in subgroups were performed by evaluating the yearly differences of mean EDSS score changes versus baseline (delta-EDSS). A first CDA event was defined as a 6-months confirmed disability increase from study baseline, measured by EDSS (increase ≥ 1.5 points with baseline EDSS = 0; ≥ 1.0 with baseline EDSS score ≤ 5.0 and ≥ 0.5 point with baseline EDSS > 5.5). PIRA was defined as a CDA event occurring more than 90 days after and more than 30 days before the onset of a relapse. Results 3777 MS patients (268 POMS, 3282 AOMS, 227 LOMS) were included. The slope of disability trajectories significantly diverged in AOMS vs POMS starting from the second year of follow-up (Year 2: delta2-EDSS 0.18 (0.05; 0.31), p = 0.0054) and then mean delta2-EDSS gradually increased up to 0.23 (0.07; 0.39, p = 0.004) at year 5. Patients with PIRA had significant (p < 0.0001) steeper increase in EDSS scores than those without PIRA in all groups, although in POMS, the disability trajectories began to diverge later and at a lesser extent with delta-EDSS score of 0.48 vs 0.83 in AOMS and 1.57 in LOMS, at 3 years after the first PIRA. Conclusions Age is relevant in determining disability progression in MS. POMS shows a less steep increase in EDSS scores over time than older patients. The effect of PIRA in accelerating EDSS progression is less pronounced in POMS than in AOMS and LOMS.

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Time to Change the Current Clinical Classification of Multiple Sclerosis?

Cited by 16 publications

References 16 publications

Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis

Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis

A comparison of natalizumab and ocrelizumab on disease progression in multiple sclerosis

Disability trajectories by progression independent of relapse activity status differ in pediatric, adult and late-onset multiple sclerosis

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