Multiple Sclerosis Research Repository

115)  “Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis: A Systematic Review” by Jannis Muller, MD et al

-”In this systematic review of 48 studies, PIRA was found to be the most common form of disability accumulation across all traditional MS phenotypes, including clinically isolated syndrome and early relapsing-remitting MS.”

116)  “Does initial high efficacy therapy in multiple sclerosis surpass escalation treatment strategy?  A comparison of patients with relapsing-remitting multiple sclerosis in the Czech and Swedish national multiple sclerosis registries” by Tereza Hrnciarova

-”In contrast to the previous comparison between the Swedish and Danish cohorts (Spelman et al, 2021), the primary outcome (CDW) did not show a significant difference in favor of the Swedish cohort (…p-value 0.2764)

-”it is reasonable to ask why such a significant reduction in the risk of relapse did not translate into a change in the long-term outcome of CDW”

117)  “Contribution of relapse-associated worsening in overall disability accrual in patients with relapsing-onset multiple sclerosis: A mediation analysis” by Bo Chen et al

-”In relapsing-onset MS, PIRA is the major contributor to the irreversible disability accrual throughout the whole disease course…”

-”Nonetheless,

with more and more disease-modifying treatments (DMTs) available to

reduce the attack frequency, substantial evidence has shown that

disability progression in most treated patients can still develop slowly

over time, independent of relapses and whatever medications applied, in

whether relapsing-remitting or progressive cases (Cree et al., 2016;

Reich et al., 2018; Signori et al., 2016).”

-”Even in the population with

relapsing MS who initially received ocrelizumab, a B cell-depleting

agent, the cumulative proportion with disability progression climbed

at a slow rate in the case of nearly complete and sustained suppression of

new brain MRI lesion activity (Hauser et al., 2017; Hauser et al., 2020),

with the similar findings observed in patients treated with other

high-efficacy DMTs (Coles et al., 2012; Kapoor et al., 2018), implying

that the neurological deterioration seems unavoidable in this life-long

Disease.”

-”On the other hand, compared to that in the early phase, the disability accrual in the later one is not significantly slowed by the reduced relapse frequency, suggesting that the effect of RAW on the disabled outcome may vary in different stages of the disease.“

-”Annualized relapse rate (ARR), a marker for disease activity, cannot

reflect the neurological deterioration in patients with MS…”

-”The key findings were that clinical attack number partly mediated less than half (0.414) of the positive relationship between disease duration and disability worsening in the early phase (i.e., RAW accounted for 41.4% of the disability accrual while PIRA for 58.6%), whereas it was not associated with the disabled outcome in the later phase (i.e., PIRA contributed to the majority of the progression).”

-”…supporting an immune-mediated or triggered neurodegenerative nature of MS and underlining the importance of the treatment on PIRA even in the initial phase.”

-”A significant and partial mediator effect of clinical attack number on

the relationship between disease duration and neurological disability

accrual was observed in the early phase but not in the later phase herein

(Table 3), suggesting that the role of RAW on disability accumulation

differs in different stages of the disease, in line with previous studies

(Leray et al., 2010; Scalfari et al., 2010; Weinshenker et al., 1989).”

-”In previous research, when comparing untreated “natural history” and DMT-treated cohorts of patients, Tilling K et al. found that although disability progression was slowed by treatment, the treated patients still worsened considerably over time (Tilling et al., 2016).”

-”These findings imply that RAW only partly rather than entirely contributes to the irreversible disability accumulation in relapsing MS, and disability would inevitably accrue in the long term, even the relapses are controlled, in keeping with our results that attack number partly mediates the relationship between duration and EDSS scores in the early phase.”

-”once the patients enter the later phase, the contribution of relapse or RAW to the disabled outcome becomes negligible (indirect/total effect < 10%)…”

-”In contrast, the disability of the individuals with NMOSD is mainly contributed by one or more severe episodes of attacks and less accumulates over time (Wingerchuk et al., 2007), which

is one of the pivotal differences between the two diseases. This difference, on the other hand, implies that demyelination alone seems insufficient to explain the entire disability in MS.”

-”the percent of the direct effect of disease duration on EDSS scores (PIRA) soars from 58.6% in the early phase to 90.8% in the later one (Table 3).”

-”As demonstrated in Table 3, the significant direct effect of duration on EDSS scores in both early and later phases implies that PIRA may begin as early as the commencement

of the disease and account for the leading cause of the irreversible disabled outcome. From this point of view, the benefit from most current DMTs may be attained with ease in the first few years and become limited in preventing the disability exacerbation in the long term, consistent with previous studies (Kingwell et al., 2019; Manouchehrinia et al., 2017; Tilling et al., 2016).”

-”Prior studies have shown that in the early stage, patients with late-onset age are vulnerable to disability accumulation after several relapses, while the young-onset can rehabilitate with little neurological deficit (Cierny et al., 2017; D’Amico et al., 2018; Guillemin et al., 2017).  Nevertheless, we found that the disability accrual accelerated with the increase of onset age only in the early phase (significant total effect of onset age on EDSS scores with adjusting for the duration, Table 3), fully independent of clinical attack number (the direct effect was significant while the indirect effect was not), while the statistical association between onset age and disability progression was absent after that, which is also observed previously (Leray et al., 2010; Scalfari et al., 2011). The exact potential mechanisms remain elusive but may involve the

age-related decrease in the repair capacity of the CNS (Stankoff et al., 2007) and age-related altered immune response (Ditamo et al., 2005; Weiner, 2009). Of note, although significant, the standardized total effect of onset age on EDSS scores in the early phase was merely 0.205, much smaller than that of duration (0.542) (Table 3), even the effect of attack number/RAW (0.224) or PIRA (0.318), implying that in terms of disability accrual, the cont

118)  “Real-world evidence of ocrelizumab-treated relapsing multiple sclerosis cohort shows changes in progression independent of relapse activity mirroring phase 3 trials” by J Ingwersen et al

-”Mean follow-up time was 29 months (range 6 to 51 months). 23.5% developed CDA under ocrelizumab therapy (n = 23). Of those, the majority developed PIRA (87.0% of CDA, n = 20) rather than RAW (13.0% of CDA, n = 3). An exploratory investigation using Cox proportional hazards ratios revealed two possible factors associated with an increased probability of developing PIRA: a shorter disease duration prior to ocrelizumab (p = 0.02) and a lower number of previous DMTs prior to ocrelizumab (p = 0.04). Our data show that in ocrelizumab-treated RRMS patients, the main driver of disability accumulation is PIRA rather than RAW.”

-”Using data from the pivotal phase 3 randomized controlled trials (RCTs) OPERA I and OPERA II, Kappos et al. investigated RAW and PIRA contributions to the disability accumulation of ocrelizumab-treated vs. interferon-treated patients.  They found that (A) PIRA was responsible for most of the disability accumulation rather than RAW irrespective of the treatment arm (later confirmed by the findings of Lublin et al.) and (B) ocrelizumab was superior in preventing PIRA compared to interferon. However, it was less effective in preventing PIRA than RAW.”

-”In both the interferon and ocrelizumab groups, PIRA (rather than RAW) was responsible for 80–90% of the clinical worsening…”

-”our data contributes to the notion that in typical RRMS patients under effective, immune-directed therapy PIRA is the primary driver of disability progression rather than RAW.”

119)  “Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in Multiple Sclerosis Patients Diagnosed in Different Eras” by Noemi Montobbio, PhdD et al

-”The average contribution of PIRA to overall EDSS progression, already predominant in patients diagnosed in 1980-1996 (78%)…and in 1997-2008 (76%)…was significantly increased….in patients diagnosed in later years (87%…)”

-”However, although clinical relapses are almost completely eliminated by modern high-efficacy DMTs, the underlying disability progression independent of relapse activity is far from being halted or reversed.  Our results showed a progressive shift toward a mostly relapse-independent progression”