Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial

Corboy, John R.; Fox, Robert J.; Kister, Ilya; Cutter, Gary; Morgan, Charity J.; Seale, Rebecca; Engebretson, Eric; Gustafson, Tarah; Miller, Aaron; Bourdette, Dennis; Yadav, Vijayshree; Goodman, Andrew; Racke, Michael K.; Fallis, Robert J.; Tornatore, Carlo; Goldman, Myla D.; Kannan, Meena; Subramaniam, Sriram; Berger, Joseph R.; Cross, Anne H.; Rammohan, Kottil; Xia, Zongqi; Leist, Thomas; Lynch, Sharon G.; Klawiter, Eric C.; Amezcua, Lilyana; Bowen, James D.

doi:10.1016/s1474-4422(23)00154-0

Cited by 55 publications

(25 citation statements)

References 28 publications

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“…Our modeling study shows similar clinical outcomes to Corboy et al 29 in disability progression as there was no significant difference in EDSS between the DMT continue and discontinue cohorts. However, scenario analysis in our model showed that while incidence of severe infections decreased as more eligible patients discontinued therapy, the incidence of severe relapses in the discontinue cohort increased as the size of this cohort increased.…”

Section: Discussionsupporting

confidence: 82%

“…2,14 A recent study investigating whether DMT discontinuation is non-inferior to continuation in eligible older patients showed a small increased risk of new MRI activity with discontinuation, but no difference between the continue and discontinue cohorts in relapses or disability progression during the mean follow-up period of 22 months. 29 Although a DMT discontinuation approach for aging MS patients has previously been suggested, 14 the cost impact of discontinuation, including adverse events and relapses, has not been examined.…”

Section: Discussionmentioning

confidence: 99%

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A US payer perspective health economic model assessing value of monitoring disease activity to inform discontinuation and re-initiation of DMT in multiple sclerosis

Jalaleddini,

Bermel,

Talente

et al. 2024

Mult Scler

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Objectives: We evaluate the potential clinical and cost impacts of discontinuing disease-modifying therapy (DMT) in people with multiple sclerosis (PwMS) when age-related immunosenescence can reduce DMT efficacy while increasing associated risks. Methods: A Markov model simulated clinical and cost impacts to the patient and payers when a proportion of eligible patients with relapsing remitting multiple sclerosis (RRMS) discontinue DMT. Eligibility was defined as age >55 years, an RRMS diagnosis of >5 years, and no history of relapses for 5 years. Increasing the proportion of eligible patients willing to discontinue therapy was also modeled. Clinical and cost inputs were from published literature. Results: Difference in EDSS progression between eligible patients who did and did not attempt discontinuation was not significant. After 1 year of eligibility, per-patient costs were $96k lower in the cohort that attempted discontinuation; however a higher proportion of relapses were seen in this group. When the proportion of patients willing to discontinue DMT increased, clinical findings remained consistent while the average cost per patient decreased. Conclusion: While there are increased clinical and cost benefits as more eligible patients attempt discontinuation, the risk of relapses can increase. Timely disease monitoring is required to manage safe DMT discontinuation.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

A US payer perspective health economic model assessing value of monitoring disease activity to inform discontinuation and re-initiation of DMT in multiple sclerosis

Jalaleddini,

Bermel,

Talente

et al. 2024

Mult Scler

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“…Previously, neuroradiology, 53 biochemistry, 54 and neuropathology 28 have shown a relative age‐associated reduction in new incident lesions, central markers of inflammation and neuro‐axonal degeneration. All told, these reports support current efforts to identify cohorts that may be suitable for de‐escalating or discontinuing immunomodulatory treatment, 55,56 which are less effective in older people 3 .…”

Section: Discussionmentioning

confidence: 54%

Comparing the Pathology, Clinical, and Demographic Characteristics of Younger and Older‐Onset Multiple Sclerosis

Knowles,

Middleton,

Cooze

et al. 2023

Annals of Neurology

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ObjectiveOlder people with multiple sclerosis (MS) have a less active radiological and clinical presentation, but many still attain significant levels of disability; but what drives worsening disability in this group?MethodsWe used data from the UK MS Register to characterize demographics and clinical features of late‐onset multiple sclerosis (LOMS; symptom onset at ≥50 years), compared with adult‐onset MS (AOMS; onset 18–49 years). We performed a pathology study of a separate MS cohort with a later onset (n = 18, mean age of onset 54 years) versus AOMS (n = 23, mean age of onset 29 years).ResultsIn the Register cohort, there were 1,608 (9.4%) with LOMS. When compared with AOMS, there was a lower proportion of women, a higher proportion of primary progressive MS, a higher level of disability at diagnosis (median MS impact scale 36.7 vs. 28.3, p < 0.001), and a higher proportion of gait‐related initial symptoms. People with LOMS were less likely to receive a high efficacy disease‐modifying treatment and attained substantial disability sooner. Controlling for age of death and sex, neuron density in the thalamus and pons decreased with onset‐age, whereas actively demyelinating lesions and compartmentalized inflammation was greatest in AOMS. Only neuron density, and not demyelination or the extent of compartmentalized inflammation, correlated with disability outcomes in older‐onset MS patients.InterpretationThe more progressive nature of older‐onset MS is associated with significant neurodegeneration, but infrequent inflammatory demyelination. These findings have implications for the assessment and treatment of MS in older people. ANN NEUROL 2023

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“…To date, the only completed randomized controlled trial assessing the risk of new disease activity in older pwMS after DMT discontinuation was DISCO-MS (ClinicalTrials.gov NCT03073603), a multicenter, randomized, rater-blinded, phase 4, noninferiority trial in the United States [34 ▪▪ ]. With an enrollment period from May 22, 2017, to February 3, 2020, some of the DISCO-MS participants completed the 2-year follow-up during the COVID-19 pandemic, which also partially contributed to the study not reaching the originally planned enrollment target of 300 participants.…”

Section: Clinical Trials Of Disease-modifying Therapy Discontinuationmentioning

confidence: 99%

Treatment discontinuation in older people with multiple sclerosis

Zhu,

Xia

2024

Current Opinion in Neurology

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Purpose of review The aim of this review was to examine the evidence for disease-modifying therapies (DMTs) discontinuation in older people with multiple sclerosis (MS). We first summarized aging-associated biological changes that influence MS progression and DMT effectiveness, and then summarized recent evidence in evaluating clinical outcomes of discontinuing DMTs in older people with MS. Recent findings Recent findings provide mixed evidence regarding the outcomes of DMT discontinuation in older people with MS. Retrospective observational studies suggested older age and longer stable duration on DMT before DMT discontinuation were associated with lower risk of relapse in people with MS. However, one randomized clinical trial did not demonstrate the noninferiority of DMT discontinuation. Summary The available clinical evidence examining DMT discontinuation in older people with MS remains inconclusive. More robust evidence from clinical trials and real-world data will be necessary to guide clinical decisions regarding DMT discontinuation in older people with MS.

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Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial

Cited by 55 publications

References 28 publications

A US payer perspective health economic model assessing value of monitoring disease activity to inform discontinuation and re-initiation of DMT in multiple sclerosis

A US payer perspective health economic model assessing value of monitoring disease activity to inform discontinuation and re-initiation of DMT in multiple sclerosis

Comparing the Pathology, Clinical, and Demographic Characteristics of Younger and Older‐Onset Multiple Sclerosis

Treatment discontinuation in older people with multiple sclerosis

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