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Stopping Disease-Modifying Treatments in Multiple Sclerosis: A Systematic Review and Meta-Analysis of Real-World Studies

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Abstract

Background

The question of whether multiple sclerosis requires life-long disease-modifying treatments (DMTs) remains unanswered. Some studies suggest that older patients with stable disease may safely discontinue their DMTs, yet comprehensive evidence-based data are scarce and real-world studies have provided mixed results.

Objective

The aim of this study was to assess the rate of disease reactivation and associated risk factors after discontinuation of DMTs in patients with multiple sclerosis.

Methods

We searched scientific databases (PubMed/MEDLINE, Scopus and Google Scholar) to identify real-world studies published until 31 July, 2023 that reported the number of patients who experienced relapses and/or disability accrual (outcomes of interest) following a therapy discontinuation longer than 12 months. Magnetic resonance activity and treatment re-start after DMT discontinuation were also considered as additional outcomes. We excluded studies where therapy discontinuation was explicitly related to an unintended or planned pregnancy or preceded a treatment switch. We ran random-effects meta-analyses, subgroup analyses and meta-regression models to provide pooled estimates of post-discontinuation relapse and disability events, and to identify their potential moderators (predictors).

Results

After an independent screening, 22 articles met the eligibility criteria, yielding a pooled sample size of 2942 patients followed for 1–7 years after discontinuation (11,689 patient-years). The pooled rates for relapse and disability events were 6.7 and 5.8 per 100 patient-years, respectively. However, available data did not allow us to disentangle isolated disability accrual from relapse-associated worsening. Studies including older patients (β = −0.65, p = 0.006), patients with a longer exposure to DMTs (β = −2.22, p = 0.001) and patients with a longer period of disease stability (β = −2.74, p = 0.002) showed a lower risk of relapse events. According to meta-regression equations, the risk of relapse events after DMT discontinuation became negligible (arbitrarily set at < 1% per year) at approximately 60 years of age, and after either 10 years of DMT exposure, or 8 years of disease stability. Additional analyses showed pooled rates for magnetic resonance imaging activity and re-start events of 16.7 and 17.5 per 100 patient-years, respectively.

Conclusions

Based on our quantitative synthesis of real-world data, in the absence of definitive answers from clinical trials, DMT discontinuation appears feasible with a high degree of certainty in selected patients. While our findings are robust regarding relapse events, future efforts are warranted to determine if DMT discontinuation is associated with isolated disability accrual.

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Acknowledgements

We thank Dr. Dejan Jamowski, Prof. Giacomo Lus, Dr. Manuel Salavisa and Dr. Elisabetta Signoriello for data sharing.

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Authors and Affiliations

  1. Department of Neurology, S. Camillo-Forlanini Hospital, C.ne Gianicolense 87, 00152, Rome, Italy

    Luca Prosperini, Shalom Haggiag, Carla Tortorella & Claudio Gasperini

  2. Department of Human Neurosciences, Sapienza University, Viale dell’Università 30, 00185, Rome, Italy

    Serena Ruggieri

  3. Neuroimmunology Unit, Santa Lucia Foundation, Via del Fosso di Fiorano 64/65, 00143, Rome, Italy

    Serena Ruggieri

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  1. Luca Prosperini
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Correspondence to Luca Prosperini.

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Funding

No sources of funding were used to conduct this study or prepare this article.

Conflicts of Interest

Luca Prosperini, Shalom Haggiag, Serena Ruggieri, Carla Tortorella and Claudio Gasperini have no conflicts of interest that are directly relevant to the content of this article. Financial disclosure (outside this work): Luca Prosperini: consulting fees and/or speaker honoraria from Biogen, Celgene, Genzyme, Merck-Serono, Novartis and Teva; travel grants from Biogen, Genzyme, Novartis and Teva and research grants from the Italian MS Society (Associazione Italiana Sclerosi Multipla) and Genzyme. Carla Tortorella: honoraria for speaking and travel grants from Biogen, Sanofi-Aventis, Merck Serono, Bayer-Schering, Teva, Genzyme, Almirall and Novartis. Shalom Haggiag: travel funding and/or speaker honoraria from Biogen, Roche, Genzyme, Novartis, CSL Behring. Serena Ruggieri: personal fees and non-financial support from Biogen, Genzyme, Merck-Serono, Novartis, and Teva. Claudio Gasperini: fees as invited speaker or travel expenses for attending meeting from Biogen, Merck-Serono, Teva, Sanofi, Novartis, Genzyme.

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The data that support the findings of this study are available in the supplementary information.

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Authors’ Contributions

Conception and design of the study, drafting a significant portion of the manuscript/figures: LP, SH, SR. Acquisition and analysis of data, revision of manuscript content: LP, SR, CT. Supervision and drafting the final version of the manuscript: LP, CT, CG. All authors read and approved the final version of the manuscript.

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Prosperini, L., Haggiag, S., Ruggieri, S. et al. Stopping Disease-Modifying Treatments in Multiple Sclerosis: A Systematic Review and Meta-Analysis of Real-World Studies. CNS Drugs 37, 915–927 (2023). https://doi.org/10.1007/s40263-023-01038-z

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