Discontinuation of disease-modifying therapy for patients with relapsing-remitting multiple sclerosis: Effect on clinical and MRI outcomes

Yano, Hajime; Gonzalez, Cindy; Healy, Brian C.; Glanz, Bonnie I.; Weiner, Howard L.; Chitnis, Tanuja

doi:10.1016/j.msard.2019.07.021

Cited by 39 publications

(27 citation statements)

References 31 publications

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“…Our results are in line with studies investigating the risk of disease reactivation after DMT discontinuation, which have found older age at discontinuation (mostly >45–50 years), longer periods without relapses, and absence of MRI activity at discontinuation to be associated with lower likelihood of recurrence of relapse after DMT discontinuation [6–8,16,17]. Adding to this, DMT continuation yields <0.02 quality‐adjusted life years above the age of 55 years, which is considered clinically insignificant [18].…”

Section: Discussionsupporting

confidence: 87%

Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: The VIAADISC score

Bsteh

Hegen

Riedl

et al. 2021

Euro J of Neurology

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Background and purpose There is a lack of evidence guiding discontinuation of disease‐modifying therapy (DMT) in relapsing multiple sclerosis (RMS). Thus, the objective of this study was to generate and validate a risk score for disease reactivation after DMT discontinuation in RMS. Methods We drew a generation and validation dataset from two separate prospectively collected observational databases including RMS patients who received interferon‐β or glatiramer acetate for ≥12 months, then discontinued DMT for ≥6 months and had ≥2 years of follow‐up available. In the generation sample (n = 168), regression analysis was performed to identify clinical or magnetic resonance imaging (MRI) variables independently predicting disease reactivation after DMT discontinuation. A predictive score was calculated using the variables included in the multivariable model and applied to the validation sample (n = 98). Results The variables included in the final model as independent predictors of disease reactivation were age at discontinuation, MRI activity at discontinuation, and duration of clinical stability (all p < 0.001). The resulting score was able to robustly identify patients at high (83%–85%), moderate (36%–38%), and low risk (7%) of disease reactivation within 5 years after DMT discontinuation in both cohorts. Conclusions The composite VIAADISC score is a valuable tool to inform and support patients and neurologists in the process of decision making to discontinue injectable DMTs.

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Section: Discussionsupporting

confidence: 87%

Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: The VIAADISC score

Bsteh

Hegen

Riedl

et al. 2021

Euro J of Neurology

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“…Younger age in this older population was associated with an increased risk of relapse and/or MRI disease activity after DMT discontinuation. Taken together with previous studies, [9][10][11] these findings suggest that for those with 2 or more lifetime relapses, benign/burn-out MS is best reserved for those aged 55 years and older and that MRI evidence of spinal cord involvement does not preclude the possibility of benign/burnt-out MS. Our 2020 consensus case definition for benign/burnt-out MS are presented in table 2.…”

Section: Resultssupporting

confidence: 73%

“…Some experts have raised concerns that DMT discontinuation, even in patients with potentially benign/burnt-out MS, will lead to rebound disease activity resulting in irreversible disability. In this respect, findings from our and prior studies 9 – 11 are reassuring, with none finding evidence of uncontrolled inflammatory disease activity following discontinuation of DMTs in older patients, regardless of MS subtype. Previous observational studies that have compared patients with MS who continued on DMTs to those who discontinued showed no difference in the risk of relapses.…”

Section: Discussionsupporting

confidence: 68%

“…Previous observational studies that have compared patients with MS who continued on DMTs to those who discontinued showed no difference in the risk of relapses. [9][10][11] Even with the very generous assumption that continuing DMTs would have prevented all relapses and/or MRI disease activity, the NNT of 27 over 5 years to prevent 1 relapse in this population underscores the low value of continuing DMTs in these patients with benign/burnt-out MS.…”

Section: Resultsmentioning

confidence: 95%

“…8 Several observational studies suggest that discontinuing DMTs, particularly in older patients, 9 does not lead to inflammatory disease activity in excess of those who remain on DMTs. [9][10][11] These results are reassuring but do not specifically address patients with suspected benign/burnt-out MS, as the studies included young patients 10,11 in whom a benign disease course cannot be accurately predicted and/or patients with progressive MS 9,11 in whom randomized controlled trials of most DMTs have failed to demonstrate benefit. 12 The purpose of this study was to assess the safety of discontinuing DMTs in patients with suspected benign/burnt-out MS and develop a consensus case definition based on the results.…”

mentioning

confidence: 99%

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Defining Benign/Burnt-Out MS and Discontinuing Disease-Modifying Therapies

McFaul

Hakopian

Smith

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo determine whether MS disease-modifying therapies (DMTs) can be safely discontinued in patients aged 50 years or older with suspected benign/burnt-out MS and to define criteria to identify such patients.MethodsWe conducted a retrospective cohort study of 136 patients with suspected benign/burnt-out MS who discontinued DMTs from the electronic health record (EHR) at Kaiser Permanente Southern California.ResultsThe majority discontinued an injectable DMT (n = 131, 96%). At the time of DMT discontinuation, mean and SD for age was 60.6 (6.2) years, disease duration 19.5 (10.7) years, and time since last relapse 11.0 (7.2) years. After a mean duration of follow-up of 5.0 years post-DMT discontinuation, 5 (3.7%) patients had a relapse, 2 (1.5%) had mild residual deficits, and 3 (2.2%) had asymptomatic MRI disease activity. Patients with MS disease activity following DMT discontinuation were younger (median = 53.6 years) than those who remained disease activity free. Fifty patients (36.8%) had only 1 lifetime relapse, of whom 1 relapsed post-DMT discontinuation. Sixty (56.6%) of 106 patients with spinal cord MRIs before discontinuation showed demyelinating lesions.ConclusionsDMT discontinuation in older patients with suspected benign/burnt-out MS appears safe. Our findings suggest that MRI evidence of spinal cord involvement does not preclude the possibility of benign/burnt-out MS, and for those with 2 or more lifetime relapses, a benign/burn-out classification is best reserved for those aged 55 years and older. Future studies to determine whether DMT discontinuation is safe at a younger age in patients with a single lifetime relapse are needed.Classification of EvidenceThe study provides Class IV evidence that DMTs can be safely discontinued in older patients with suspected benign/burnt-out MS.

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High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS

Jouvenot,

Courbon,

Lefort

et al. 2024

JAMA Neurol

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ImportanceA recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity.ObjectiveTo determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET.Design, Setting, and ParticipantsThis observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022.ExposuresNatalizumab, fingolimod, rituximab, and ocrelizumab.Main Outcomes and MeasuresTime to first relapse.ResultsOf 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P &lt; .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy.Conclusion and RelevanceAs in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

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Discontinuation of disease-modifying therapy for patients with relapsing-remitting multiple sclerosis: Effect on clinical and MRI outcomes

Cited by 39 publications

References 31 publications

Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: The VIAADISC score

Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: The VIAADISC score

Defining Benign/Burnt-Out MS and Discontinuing Disease-Modifying Therapies

High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS

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