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

Guillaume Jouvenot; Guilhem Courbon; Mathilde Lefort; Fabien Rollot; Romain Casey; Emmanuelle Le Page; Laure Michel; Gilles Edan; Jérome de Seze; Laurent Kremer; Kevin Bigaut; Sandra Vukusic; Guillaume Mathey; Jonathan Ciron; Aurélie Ruet; Elisabeth Maillart; Pierre Labauge; Hélène Zephir; Caroline Papeix; Gilles Defer; Christine Lebrun-Frenay; Thibault Moreau; David Axel Laplaud; Eric Berger; Bruno Stankoff; Pierre Clavelou; Eric Thouvenot; Olivier Heinzlef; Jean Pelletier; Abdullatif Al-Khedr; Olivier Casez; Bertrand Bourre; Philippe Cabre; Abir Wahab; Laurent Magy; Jean-Philippe Camdessanché; Ines Doghri; Solène Moulin; Haifa Ben-Nasr; Céline Labeyrie; Karolina Hankiewicz; Jean-Philippe Neau; Corinne Pottier; Chantal Nifle; Nicolas Collongues; Anne Kerbrat

doi:10.1001/jamaneurol.2024.0395

. 2024 Mar 25;81(5):490–498. doi: 10.1001/jamaneurol.2024.0395

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

Guillaume Jouvenot ^1,², Guilhem Courbon ³, Mathilde Lefort ⁴, Fabien Rollot ^5,^6,^7,⁸, Romain Casey ^5,^6,^7,⁸, Emmanuelle Le Page ^3,⁹, Laure Michel ^3,⁹, Gilles Edan ^3,⁹, Jérome de Seze ^1,^2,¹⁰, Laurent Kremer ^2,¹⁰, Kevin Bigaut ^2,¹⁰, Sandra Vukusic ^5,^6,^7,⁸, Guillaume Mathey ^11,¹², Jonathan Ciron ¹³, Aurélie Ruet ¹⁴, Elisabeth Maillart ¹⁵, Pierre Labauge ¹⁶, Hélène Zephir ¹⁷, Caroline Papeix ¹⁸, Gilles Defer ¹⁹, Christine Lebrun-Frenay ²⁰, Thibault Moreau ²¹, David Axel Laplaud ^22,²³, Eric Berger ²⁴, Bruno Stankoff ²⁵, Pierre Clavelou ²⁶, Eric Thouvenot ²⁷, Olivier Heinzlef ²⁸, Jean Pelletier ²⁹, Abdullatif Al-Khedr ³⁰, Olivier Casez ³¹, Bertrand Bourre ³², Philippe Cabre ³³, Abir Wahab ³⁴, Laurent Magy ³⁵, Jean-Philippe Camdessanché ³⁶, Ines Doghri ³⁷, Solène Moulin ³⁸, Haifa Ben-Nasr ³⁹, Céline Labeyrie ⁴⁰, Karolina Hankiewicz ⁴¹, Jean-Philippe Neau ⁴², Corinne Pottier ⁴³, Chantal Nifle ⁴⁴, Nicolas Collongues ^1,^2,^10,⁴⁵, Anne Kerbrat ^3,^9,^46,^✉, for the OFSEP Investigators

¹Center for Clinical Investigation, INSERM U1434, Strasbourg, France

²Biopathology of Myelin, Neuroprotection and Therapeutic Strategy, INSERM U1119, Strasbourg, France

³Department of Neurology, University Hospital of Rennes, Rennes, France.

⁴University of Rennes, EHESP, CNRS, INSERM, Arènes—UMR 6051, RSMS (Recherche sur les Services et Management en Santé)—U 1309, Rennes, France

⁵Université de Lyon, Université Claude Bernard, Lyon, France

⁶Department of Neurology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Bron, France

⁷Centre de Recherche en Neurosciences de Lyon, Observatoire Français de La Sclérose en Plaques, INSERM 1028 and CNRS UMR 5292, Lyon, France

⁸Eugène Devic EDMUS Foundation Against Multiple Sclerosis, State-Approved Foundation, Bron, France

⁹CIC-P 1414 INSERM, University Hospital of Rennes, Rennes, France

¹⁰Department of Neurology, University Hospital of Strasbourg, Strasbourg, France

¹¹Department of Neurology, Nancy University Hospital, Nancy, France

¹²Université de Lorraine, APEMAC, Nancy, France

¹³CRC-SEP, Department of Neurology, CHU de Toulouse, Toulouse, France

¹⁴Department of Neurology, CHU de Bordeaux, CIC Bordeaux CIC1401, Bordeaux, France

¹⁵Département de Neurologie, Hôpital Pitié-Salpêtrière, APHP, Centre de Ressources et de Compétences SEP, Paris, France

¹⁶MS Unit, CHU de Montpellier, Montpellier, France

¹⁷CRC-SEP Lille, CHU Lille, Lille, France

¹⁸Department of Neurology, Fondation Rothschild, Paris, France

¹⁹Department of Neurology, MS Expert Centre, CHU de Caen, Caen, France

²⁰Neurology, UR2CA-URRIS, Centre Hospitalier Universitaire Pasteur2, Université Nice Côte d’Azur, Nice, France

²¹Department of Neurology, CHU de Dijon, Dijon, France

²²Department of Neurology, CHU de Nantes, Nantes, France

²³Nantes Université, CHU Nantes, INSERM, CIC 14131413, Center for Research in Translational Immunology, UMR 1064, Nantes, France

²⁴Service de Neurologie, CHU de Besançon, Besançon, France

²⁵Department of Neurology, AP-HP, Saint-Antoine Hospital, Paris, France

²⁶Department of Neurology, CHU Clermont-Ferrand, Clermont-Ferrand, France

²⁷Department of Neurology, Nimes University Hospital, Nimes, France

²⁸Hôpital de Poissy, Department of Neurology, Poissy, France

²⁹Service de Neurologie, APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Marseille, France

³⁰CHU d’Amiens, Department of Neurology, Amiens, France

³¹CHU Grenoble Alpes, Department of Neurology, Neurology MS Clinic Grenoble, Grenoble Alpes University Hospital, Grenoble, France

³²CHU de Rouen, Department of Neurology, Rouen, France

³³Department of Neurology, CHU de la Martinique, Fort-de-France, France

³⁴Department of Neurology, APHP, Hôpital Henri Mondor, Créteil, France

³⁵Department of Neurology, CHU de Limoges, Hôpital Dupuytren, Limoges, France

³⁶Department of Neurology, CHU de Saint-Étienne, Hôpital Nord, Saint-Étienne, France

³⁷Department of Neurology, CHU de Tours, Hôpital Bretonneau, Tours, France

³⁸Department of Neurology, CHU de Reims, CRC-SEP, Reims, France

³⁹Hôpital Sud Francilien, Department of Neurology, Corbeil-Essonnes, France

⁴⁰Department of Neurology, CHU Bicêtre, Le Kremlin-Bicêtre, France

⁴¹Department of Neurology, Hôpital Pierre Delafontaine, Centre Hospitalier de Saint-Denis, Saint-Denis, France

⁴²Department of Neurology, CHU La Milétrie, Hôpital Jean Bernard, Poitiers, France

⁴³Department of Neurology, CH de Pontoise, Hôpital René Dubos, Pontoise, France

⁴⁴Departement of Neurology, Centre Hospitalier de Versailles, Le Chesnay, France

⁴⁵Department of Pharmacology, Addictology, Toxicology and Therapeutics, Strasbourg University, Strasbourg, France

⁴⁶Empenn U1228, University of Rennes, Inria, CNRS, INSERM, IRISA UMR 6074, Rennes, France

Group Information: The OFSEP Investigators appear in Supplement 2.

Accepted for Publication: January 5, 2024.

Published Online: March 25, 2024. doi:10.1001/jamaneurol.2024.0395

^✉

Corresponding Author: Anne Kerbrat, MD, PhD, Department of Neurology, University Hospital of Rennes, 2 rue Henri Le Guilloux, 35000 Rennes, France (anne.kerbrat@chu-rennes.fr).

Author Contributions: Drs Jouvenot and Kerbrat had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Jouvenot, Courbon, Collongues, and Kerbrat contributed equally to this work.

Concept and design: Courbon, Lefort, Rollot, Casey, Moreau, Laplaud, Pelletier, Collongues, Kerbrat.

Acquisition, analysis, or interpretation of data: Jouvenot, Courbon, Lefort, Casey, Le Page, Michel, Edan, de Seze, Kremer, Bigaut, Vukusic, Mathey, Ciron, Ruet, Maillart, Labauge, Zephir, Papeix, Defer, Lebrun-Frenay, Laplaud, Berger, Stankoff, Clavelou, Thouvenot, Heinzlef, Pelletier, Al-Khedr, Casez, Bourre, Cabre, Wahab, Magy, Camdessanché, Doghri, Moulin, Ben-Nasr, Labeyrie, Hankiewicz, Neau, Pottier, Nifle, Collongues, Kerbrat.

Drafting of the manuscript: Courbon, Moreau, Pelletier, Ben-Nasr, Collongues, Kerbrat.

Critical review of the manuscript for important intellectual content: Jouvenot, Courbon, Lefort, Rollot, Casey, Le Page, Michel, Edan, de Seze, Kremer, Bigaut, Vukusic, Mathey, Ciron, Ruet, Maillart, Labauge, Zephir, Papeix, Defer, Lebrun-Frenay, Laplaud, Berger, Stankoff, Clavelou, Thouvenot, Heinzlef, Al-Khedr, Casez, Bourre, Cabre, Wahab, Magy, Camdessanché, Doghri, Moulin, Labeyrie, Hankiewicz, Neau, Pottier, Nifle, Collongues, Kerbrat.

Statistical analysis: Jouvenot, Courbon, Lefort, Rollot, Collongues.

Obtained funding: Collongues.

Administrative, technical, or material support: Michel, Maillart, Labauge, Camdessanché, Collongues, Kerbrat.

Supervision: Edan, de Seze, Lebrun-Frenay, Moreau, Laplaud, Bourre, Magy, Collongues, Kerbrat.

Conflict of Interest Disclosures: Dr de Seze reported personal fees from Roche, Biogen, Novartis, Sanofi, Merck, Alexion, Horizon/Amgen, Sandoz, UCB, LFB, and Argenx outside the submitted work. Dr Bigaut reported personal fees from Biogen, Novartis, Roche, and Sanofi outside the submitted work. Dr Vukusic reported grants from Biogen, Merck, Novartis, Roche, and Sanofi as well as fees paid to her institution from Bristol Myers Squibb/Celgene and Sandoz outside the submitted work. Dr Mathey reported grants from Novartis, Biogen, Roche, Bayer, Actelion, Alexion, Teva, and Sanofi Genzyme during the conduct of the study. Dr Ciron reported personal fees from Biogen, from Novartis, Merck, Sanofi, and Roche outside the submitted work. Dr Ruet reported grants from Biogen, Roche, Sanofi Genzyme, and Bristol Myers Squibb; personal fees from Biogen, Sanofi Genzyme, and Merck; and nonfinancial support from Biogen, Novartis, and Merck outside the submitted work. Dr Maillart reported grants from Biogen as well as personal fees from Biogen, Roche, Sanofi Genzyme, Teva, Novartis, Merck, and Janssen outside the submitted work. Dr Papeix reported personal fees from Biogen during the conduct of the study as well as personal fees from Alexion outside the submitted work. Dr Defer reported personal fees from Roche, Novartis, Genzyme, Biogen, Bristol Myers Squibb, and Merck Serono outside the submitted work. Dr Laplaud reported grants from Roche, Fondation Association pour la Recherche Contre la Sclérose en Plaques, Fondation European Database for Multiple Sclerosis, and Association Nationale pour la Recherche as well as personal fees from Alexion, Biogen, Merck, Sanofi, Novartis, Bristol Myers Squibb, and Merck Sharp & Dohme outside the submitted work. Dr Berger reported personal fees from Biogen Idec, Novartis, and Merck outside the submitted work. Dr Stankoff reported grants from Roche, Novartis, and Merck as well as personal fees from Janssen, Merck, and Novartis outside the submitted work. Dr Thouvenot reported grants from Biogen, Novartis, and Merck as well as personal fees from Merck, Biogen, Novartis, Janssen, Sanofi, Roche, and Bristol Myers Squibb outside the submitted work. Dr Casez reported personal fees from Biogen, Roche, Novartis, and Merck during the conduct of the study. Dr Bourre reported Alexion, Biogen, Merck, Novartis, Roche, Sanofi, Sandoz, Horizon, and Janssen outside the submitted work. Dr Wahab reported personal fees from Novartis, Merck, and Roche outside the submitted work. Dr Magy reported personal fees from Biogen, Novartis, Merck, Roche, and Sanofi outside the submitted work. Dr Doghri reported personal fees from Merck and Novartis as well as nonfinancial support from Merck, Sanofi, and Novartis outside the submitted work. Dr Collongues reported personal fees from Alexion, Biogen, Bristol Myers Squibb, Horizon Therapeutics, Merck, Novartis, Roche, and Sanofi outside the submitted work. No other disclosures were reported.

Funding/Support: Data collection was supported by a grant provided by the French State and handled by the Agence Nationale de la Recherche within the framework of the France 2030 program, under the reference ANR-10-COHO-002, Observatoire Français de la Sclérose en Plaques (OFSEP).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The OFSEP Investigators appear in Supplement 2.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the Eugène Devic EDMUS Foundation against Multiple Sclerosis for support.

^✉

Corresponding author.

PMCID: PMC10964164 PMID: 38526462

Key Points

Question

Is it possible to stop a high-efficacy therapy (HET) in patients 50 years and older with nonactive multiple sclerosis (MS) without risk of a resumption of focal inflammatory activity?

Findings

In this cohort study including 1620 patients, among the propensity score–matched groups, the risk of relapse was significantly higher in the HET discontinuation group (n = 154) vs HET continuation group (n = 154). This risk varied according to the HET used and was particularly high for natalizumab and fingolimod but not for anti-CD20 therapy.

Meaning

Stopping fingolimod or natalizumab without relay therapy in patients 50 years and older with nonactive MS may be associated with a resumption of relapses.

This cohort study evaluates whether discontinuing high-efficacy therapy in patients 50 years and older with nonactive multiple sclerosis (MS) is associated with an increased risk of relapse compared with continuing high-efficacy therapy.

Abstract

Importance

A 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.

Objective

To 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 Participants

This 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.

Exposures

Natalizumab, fingolimod, rituximab, and ocrelizumab.

Main Outcomes and Measures

Time to first relapse.

Results

Of 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 < .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 Relevance

As 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.

Introduction

It is widely accepted that high-efficacy therapy (HET) should be initiated as early as possible after the diagnosis of relapsing-remitting multiple sclerosis (MS), at least in patients with poor prognostic factors.^1,2 However, despite the increasing use of HET, there is a lack of data concerning the possibility of discontinuing these therapies in older patients with nonactive disease.^3,4 In younger patients, a risk of rebound of disease activity has been widely described after stopping natalizumab^5,6,7,8 and fingolimod,^9,10,11,12 while data suggest the possibility of discontinuing anti-CD20 therapy without rebound.^13,14 In favor of the possibility of stopping HET in older patients, several studies have confirmed an age-dependent decrease in relapse rate^15,16 and magnetic resonance imaging (MRI) activity.^17,18 Accordingly, the effectiveness of treatments declines as patients age,¹⁹ whereas the risk of treatment-related adverse effects increases.^20,21,22 Moreover, most of the retrospective studies on medium-efficacy therapy (MET) discontinuation including older patients with nonactive MS are reassuring.^{23,24,25,26,27,28,29,30,31,32,33} A recent randomized clinical trial, the Discontinuation of Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS) (DISCOMS) trial, focused on treatment discontinuation among patients older than 55 years with nonactive disease.³⁴ It concluded that therapy discontinuation may be a reasonable option, although it might be associated with a small increased risk of new MRI activity. However, the study included a limited proportion of patients undergoing HET (9%), which makes it impossible to draw any conclusions about this population. A dedicated study is therefore essential to inform decisions for clinical practice.

The primary objective of this study was to compare time to first relapse between 2 matched groups of patients 50 years and older with nonactive MS: patients who discontinued HET and patients who continued to receive HET. The secondary objectives were to compare time to first inflammatory activity (relapse and/or MRI activity) and time to confirmed disability progression (CDP) between the 2 groups. These objectives were investigated in the entire population and again in subgroups according to the HET used (fingolimod, natalizumab, or anti-CD20 therapy) and the disease phenotype. Additional secondary objectives were to identify predictors of recurrence of inflammatory activity in the HET discontinuation group and to describe the dynamic of this recurrence in the year after discontinuation.

Methods

Study Design

This was an observational cohort study using data extracted in June 2022 from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). The OFSEP database includes clinical and imaging data from 38 expert MS centers in France³⁵ collected during patients’ routine follow-up visits using dedicated software.³⁶

All patients had given written informed consent for the use of their medical data for research purposes.³⁷ The study was approved by the local ethics committee at University Hospital of Rennes. Data confidentiality and security were consistent with the recommendations of the French Data Protection Agency (CNIL). This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Patients

We included all patients who met the inclusion criteria: diagnosis of relapsing-remitting MS or secondary progressive MS³⁸; age of 50 years or older; no evidence of relapse or MRI activity in 2 years or more; HET duration of 1 year or more; and medical follow-up of 6 months or more after inclusion. The inclusion date corresponded to the first visit including an Expanded Disability Status Scale (EDSS) evaluation where a patient met these criteria and ranged from February 2008 to November 2021. Patients were then classified into 2 groups according to whether they stopped or continued their HET.

For the HET discontinuation group, patients had to have stopped their HET without any initial plan to switch to another therapy. As a scheduled discontinuation resulting in a resumption of treatment due to a recurrence of inflammatory activity is difficult to distinguish in the database from a treatment switch planned in advance, a systematic review of the patient’s file was carried out in all cases of treatment resumption within a period of more than 1 month and less than 6 months after treatment discontinuation.

Exposures

The HETs included rituximab, ocrelizumab, natalizumab, and fingolimod. They were administered according to published protocols.^39,40,41,42 For rituximab, the dose was between 500 and 1000 mg intravenously every 6 to 9 months. Rituximab and ocrelizumab were grouped together as anti-CD20 therapies for the analyses. For patients treated with anti-CD20 therapy, the date of discontinuation was considered to be 6 months after the last infusion. For patients treated with fingolimod and natalizumab, the discontinuation date was considered to be the date of the last oral dose and the last infusion.

Outcomes

The primary outcome was time to first relapse, defined as the appearance, recurrence, or aggravation of neurological symptoms for a period of at least 24 hours without fever, validated by the treating neurologist at each center and reported in the database. Secondary outcomes included time to first inflammatory activity (relapse and/or MRI activity) and time to CDP. These outcomes were determined for the whole study population and in an exploratory analysis according to the treatment used (fingolimod, natalizumab, or anti-CD20 therapy) and the disease phenotype (relapsing-remitting or secondary progressive MS). Additional secondary outcomes were the predictors of recurrence of a relapse or inflammatory activity in the HET discontinuation group and the relapse rates during each 4-month period before and after HET discontinuation. CDP was defined as an increase in EDSS score of 1 point (or 0.5 points if baseline EDSS score was 5.5 or greater) confirmed for at least 6 months and until the end of patient follow-up. MRI activity was defined as new or enlarged T2 lesions compared with the previous brain MRI scan or gadolinium-enhancing lesions.

Statistical Analysis

Patient Matching

We used a dynamic propensity score (PS), as proposed by Lu⁴³ and recently used in MS,⁴⁴ to match the patients who stopped treatment with patients who had the same probability of stopping treatment at the same time but who had not yet stopped. The first step consisted of modeling the time from inclusion in the study to treatment discontinuation using a cause-specific updated Cox model. This model was adjusted for type of HET, number of previous treatments, age, sex, disease duration, disease phenotype, EDSS score, and time since last focal inflammatory activity (relapse and/or MRI activity) at inclusion. Additionally, the number of relapses, MRI activity, disability worsening, and change in disease phenotype were considered as time-dependent covariates and were updated for every year. The time-dependent PS was defined as the linear predictor of this Cox model with time-dependent covariates. The second step consisted of matching a patient who had stopped treatment with another patient who had not yet stopped treatment at the same time and with a comparable PS value at that time. Nearest-neighbor 1:1 matching at random, with a caliper of 0.1 without replacement, was used. Baseline was the time of matching, ie, the decision to stop treatment for patients matched as discontinuation and the corresponding time for patients matched as continuation. To check the balance in the matched cohort, standardized mean differences were computed.³⁵

Analyses

First, we described patients at inclusion and after matching for the whole sample and by group. Quantitative data were expressed as means with SDs or medians with IQRs. Qualitative data were expressed as counts with percentages. The matching procedure led to the exclusion of unmatched patients. Unmatched and matched patients were compared. Second, after matching, time-to-event outcomes (relapse, focal inflammatory activity, and CDP) were studied using Kaplan-Meier survival curves and compared between groups with log-rank tests for paired data. These analyses were performed in the whole matched population and by subgroups according to the HET and the disease phenotype. To evaluate the presence of a transient rebound of inflammatory activity in the months following HET discontinuation, relapse rates were also calculated during the 4 months prior to treatment discontinuation and at 4-month intervals after treatment discontinuation, expressed with 95% CIs, in each HET subgroup. Third, we performed a univariate analysis to evaluate the association between each of the potential explanatory variables (age, sex, disease duration, disease phenotype, EDSS, time since last inflammatory activity, type of HET, HET duration, and number of previous treatments) and the risk of relapse and/or focal inflammatory activity in the discontinuation group using univariate Cox models. Explanatory variables with a P value less than .20 in the univariate analysis were introduced in multivariate Cox models. Results were presented as hazard ratios (HRs) with 95% CIs. The statistical significance rate was set at P < .05, and all P values were 2-tailed. Analyses and survival curves were performed using R version 4.3.1 (The R Foundation) and the MatchIt, survival, and survminer packages.

Results

Baseline Characteristics

The study flowchart is shown in Figure 1. A total of 1857 patients fulfilling the inclusion criteria were extracted from the OFSEP database. After verification of the medical records, 1620 patients were included; of these, 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 PS (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 PS matching, 2.5 [2.1] years). The characteristics of the population before and after matching are shown in the Table, and the characteristics of patients not included in the matched cohort are shown in eTable 1 in Supplement 1.

Table. Characteristics of Patients at Inclusion and After Propensity Score Matching.

Characteristic	No. (%)
	At inclusion				After propensity score matching
	Total (N = 1620)	HET discontinuation (n = 168)	HET continuation (n = 1452)	SMD, %^a	HET discontinuation (n = 154)	HET continuation (n = 154)	SMD, %^a
Age, mean (SD), y	54.7 (4.8)	55.5 (5.8)	54.6 (4.6)	17	57.5 (5.9)	57.9 (5.2)	7.1
Disease duration, median (IQR), y	17.4 (11.4-24.1)	18.8 (12.2-23.7)	17.2 (11.3-24.1)	7.9	20.5 (14.7-26.1)	19.2 (14.6-25.8)	10.3
Sex
Female	1175 (72.5)	125 (74.4)	1050 (72.3)	4.7	114 (74.0)	106 (68.8)	11.5
Male	445 (27.5)	43 (25.6)	402 (27.7)	4.7	40 (26.0)	48 (31.2)	11.5
Disease phenotype
Secondary progressive	394 (24.3)	68 (40.5)	326 (22.5)	7.9	71 (46.1)	64 (41.6)	9.2
Relapsing-remitting	1226 (75.7)	100 (59.5)	1126 (77.5)	7.9	83 (53.9)	90 (58.4)	9.2
EDSS score, median (IQR)	4.0 (2.5-5.5)	4.5 (3.0-6.0)	4.0 (2.0-5.5)	41.9	5.0 (3.5-6.0)	4.5 (3.5-6.0)	10.8
Treatment of interest
Fingolimod	759 (46.9)	54 (32.1)	705 (48.6)	50.8	51 (33.1)	51 (33.1)	<1
Natalizumab	494 (30.5)	51 (30.4)	443 (30.5)		45 (29.2)	45 (29.2)
Ocrelizumab	83 (5.1)	4 (2.4)	79 (5.4)		3 (1.9)	3 (1.9)
Rituximab	284 (17.5)	59 (35.1)	225 (15.5)		55 (35.7)	55 (35.7)
Treatments before reference treatment
1-2	1057 (65.2)	105 (62.5)	952 (65.6)	12.6	96 (62.3)	99 (64.3)	4.0
3-4	408 (25.2)	41 (24.4)	367 (25.3)		38 (24.7)	42 (27.3)
≥5	155 (9.6)	22 (13.1)	133 (9.2)		20 (13.0)	13 (8.4)
Time since last relapse and/or MRI activity, median (IQR), y	3.0 (2.3-5.3)	2.1 (1.5-4.4)	3.0 (2.3-5.4)	20.7	4.4 (3.1-6.6)	4.7 (3.3-6.4)	4.5

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Abbreviations: EDSS, Expanded Disability Status Scale; HET, high-efficacy therapy; MRI, magnetic resonance imaging; SMD, standardized mean difference.

^{^a}

The SMD was used to compare baseline variables between groups. An SMD of 10% or less was considered an acceptable balance.

A total of 51 of 154 patients (33%) were treated with fingolimod, 45 (29%) with natalizumab, and 58 (38%) with anti-CD20 therapy. The 2 matched groups were acceptably balanced in terms of baseline characteristics (standardized mean difference of approximately 10%). The reason for treatment discontinuation was available for 92 of 154 patients—mainly, progression of disability without relapse (22%), adverse effects (22%), and scheduled discontinuation (35%; ie, discontinuation with the agreement of the neurologist without progression or an adverse effect of the treatment being the primary reason).

Relapse Occurrence

The mean (SD) follow-up after PS matching was 3.0 (2.2) years in the discontinuation group vs 1.9 (1.9) years in the continuation group (P < .001), and 41 patients in the discontinuation group vs 9 patients in the continuation group experienced a relapse (32 and 5, respectively, were treated with steroids). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (HR, 4.1; 95% CI, 2.0-8.5; P < .001) (Figure 2A). This increased probability of relapse was confirmed for patients with relapsing-remitting MS (HR, 4.3; 95% CI, 2.0-9.4; P < .001) but not patients with secondary progressive MS (HR, 6.7; 95% CI, 0.9-51.9; P = .07) (eFigures 1 and 2 in Supplement 1). The risk of relapse differed according to the HET discontinued and was significantly increased for natalizumab (HR, 7.2; 95% CI, 2.1-24.5; P = .001) and fingolimod (HR, 4.5; 95% CI, 1.3-15.5; P = .02) but not for anti-CD20 therapy (HR, 1.1; 95% CI, 0.3-4.8; P = .85) (Figure 2B-D). Among those discontinuing therapy, the probability of a first relapse at 1 year was 33.6% (95% CI, 18.2-46.1) for natalizumab, 16.3% (95% CI, 5.3-26.1) for fingolimod, and 0% (95% CI, 0-0) for anti-CD20 therapy. A peak of relapses was observed between 0 and 4 months after natalizumab discontinuation (Figure 3).

Figure 2. — Rituximab and ocrelizumab were grouped together as anti-CD20 therapies. The shaded area indicates 95% CIs.

Figure 3. — Rituximab and ocrelizumab were grouped together as anti-CD20 therapies. Error lines indicate 95% CIs.

Focal Inflammatory Activity

The mean (SD) frequency of MRI scans during follow-up was 0.9 (0.9) per year per patient in the discontinuation group and 1.3 (1.1) in the continuation group (P = .11). Time to first focal inflammatory activity was significantly reduced in the HET discontinuation group compared with the HET continuation group (HR, 3.6; 95% CI, 2.0-6.5; P < .001) (eFigure 3 in Supplement 1). The probability of inflammatory activity also differed according to the HET discontinued, with an HR of 6.2 (95% CI, 1.8-21.0; P = .003) for fingolimod, 3.8 (95% CI, 1.6-8.8; P = .002) for natalizumab, and 1.8 (95% CI, 0.6-5.7; P = .34) for anti-CD20 therapy. This increased probability of focal inflammatory activity was confirmed for patients with relapsing-remitting MS (HR, 3.5; 95% CI, 1.8-6.8; P < .001) and secondary progressive MS (HR, 6.0; 95% CI, 1.4-26.0; P = .02).

Disability Progression

The mean (SD) frequency of EDSS evaluations was 1.7 (0.9) per year per patient in the discontinuation group and 3.2 (5.9) in the continuation group (P = .002). Time to CDP was significantly reduced in the HET discontinuation group compared with the HET continuation group (HR, 2.6; 95% CI, 1.5-4.4; P < .001). The increased risk of CDP was particularly marked in the natalizumab subgroup, with an HR of 5.2 (95% CI, 1.5-17.6; P = .007) compared with HRs of 2.4 (95% CI, 0.9-6.0; P = .07) for fingolimod and 1.9 (95% CI, 0.9-4.3; P = .10) for anti-CD20 therapy (Figure 4).

Figure 4. — Rituximab and ocrelizumab were grouped together as anti-CD20 therapies. The shaded area indicates 95% CIs.

Factors Associated With Relapses and Focal Inflammatory Activity

Multivariate analysis evidenced a significant association between the occurrence of relapse after treatment discontinuation and patient age (HR for each additional year of age, 0.93; 95% CI, 0.86-1.00; P = .04) and a significant association between recurrence of inflammatory activity and the type of treatment stopped (anti-CD20 therapy: 1 [reference]; natalizumab: HR, 2.5; 95% CI, 1.1-5.7; fingolimod: HR, 1.9; 95% CI, 0.9-4.2) (eTables 2 and 3 in Supplement 1).

Treatment Resumption

Of the 154 patients in the discontinuation group, 69 (44.8%) resumed treatment within a mean (SD) time of 1.8 (1.8) years. In most cases, the treatment was an HET; 32 (46.3%) resumed anti-CD20 therapy, 19 (27.5%) resumed fingolimod, and 3 (4.3%) resumed natalizumab. The probability of having resumed treatment at 1 year after HET discontinuation was 36.0% (95% CI, 20.4-48.6) after natalizumab discontinuation, 20.6% (95% CI, 8.7-30.9) after fingolimod discontinuation, and 3.6% (95% CI, 0-8.4) after anti-CD20 discontinuation.

Discussion

In this observational, matched PS study, we found that in patients 50 years and older with nonactive MS, the risk of relapse was significantly higher in the HET discontinuation compared with the HET continuation group but varied greatly according to the HET. In particular, the risk was much higher after discontinuation of HETs that impact immune cell trafficking (natalizumab and fingolimod) than after discontinuation of treatments that deplete B-cells (anti-CD20 therapy), as illustrated by the probability of relapse at 1 year in each HET subgroup (natalizumab, 33.6%; 95% CI, 18.2-46.1; fingolimod, 16.3%; 95% CI, 5.3-26.1; anti-CD20 therapy, 0%; 95% CI, 0-0). In younger patients, discontinuation of fingolimod, a treatment that prevents the egress of lymphocytes from lymph nodes,⁴¹ exposes patients to a fast increase of circulating lymphocytes within 4 to 8 weeks and to a significant recurrence of relapses or even rebound in inflammatory activity.^9,10,11,12 Similarly, after discontinuing natalizumab, a treatment that transiently blocks migration of lymphocytes to the central nervous system,⁴⁰ the effects on immune cells start 8 weeks after the last natalizumab dose⁴⁵ and the risk of disease recurrence or rebound increases.^5,6,7,8 Our study confirmed these risks in an older population, suggesting that the mechanism of action of the interrupted treatment is an important factor, independent of patient age. Concerning HETs that selectively deplete CD20-expressing B-cells, recent studies suggest that there is no rebound in inflammatory activity after discontinuation.^13,14,46 Their effect on reducing relapses persists for at least 18 months after the last infusion, beyond the reconstitution of a substantial amount of circulating B-cells.^46,47 Our study confirms these results. However, our mean (SD) follow-up was short (1.9 [1.9] years). Indeed, we cannot rule out a resumption of inflammatory activity beyond 2 or 3 years after stopping anti-CD20 therapy. Moreover, a large majority of patients included in the rituximab subgroup had secondary progressive MS (86 of 116 [74%]), while patients with relapsing-remitting MS were predominant in the natalizumab (81 of 90 [90%]) and fingolimod (62 of 102 [61%]) subgroups. These differences in phenotype may have an effect on the differences in risk of relapse observed between HETs.

Our results contrast with those of a recent randomized clinical trial (DISCOMS) on treatment discontinuation among patients older than 55 years with nonactive MS, which reported a low percentage of relapses after treatment discontinuation (2%).³⁴ Patients were mainly treated by MET in that study, whereas patients taking natalizumab and fingolimod were in the minority. Other characteristics of our population may also partly explain the high risk of relapse after natalizumab and fingolimod discontinuation. First, our patients are younger than in the DISCOMS trial (mean [SD] age, 57.7 [5.5] vs 63 [5.0] years), and risk of relapse is age dependent.^15,48 Second, the patients included had a relatively high level of disability and had received 1 or more treatments prior to fingolimod or natalizumab, as these treatments are most often used as second-line therapy in France. Therefore, these patients may have had a particularly active disease in the past.

Concerning the disease phenotype, the risk of relapse within the secondary progressive MS subgroup was not significantly higher in the HET discontinuation vs HET continuation group. However, these results must be treated with caution. Indeed, the transition to the secondary progressive MS phenotype may have been underestimated in our population. Furthermore, identification of relapses was potentially more difficult in this subgroup. Interestingly, the increased risk of inflammatory activity (relapse and/or MRI activity) after HET discontinuation was confirmed in both the secondary progressive and relapsing-remitting MS subgroups. Moreover, in multivariate analysis, the relapsing-remitting MS phenotype was not associated with an increased risk of relapse compared with the secondary progressive MS phenotype after HET discontinuation. Although this point will require further investigations, our study suggests that stopping natalizumab or fingolimod without switching to another treatment exposes the patient to an increased risk of inflammatory activity, even in those with nonactive secondary progressive MS.

Strengths and Limitations

The main strength of our study is the selection of patients 50 years and older with nonactive MS for whom HET discontinuation was scheduled. This population thus corresponds to that for which the question of stopping treatment for age-related reasons arises. However, although precautions were taken to ensure that HET discontinuation did not correspond to a treatment switch, this information remains difficult to obtain in a registry-based study and constitutes a potential limitation, along with the limited availability of MRI data. More generally, despite the PS used to make patients comparable, the level of evidence provided by our study is lower than that of a randomized clinical trial. Additionally, the lower age limit of 50 years is young in view of the available data on immunosenescence.⁴⁹ In particular, only 9 patients discontinued natalizumab and 11 patients discontinued fingolimod after age 60 years. Although the risk of relapse decreased linearly with age in our study (−7% per year), we were unable to reliably estimate the risks associated with stopping these treatments after age 60 years and thus unable determine whether the risk becomes very low at a certain age.

Conclusions

Our study suggests that in patients 50 years and older with nonactive MS, discontinuation of fingolimod and natalizumab significantly increased risk of relapse compared with continuing these treatments. Further studies are needed to identify the best therapeutic strategy: switching to an anti-CD20 therapy as in younger patients⁵⁰ or deescalation to an MET. On the contrary, we did not find a higher risk of relapse in the anti-CD20 therapy discontinuation group. The possibility of stopping anti-CD20 therapy without switching or with deescalation to an MET in older patients with MS must be investigated by studies with a longer follow-up.

Supplement 1.

eTable 1. Baseline Characteristics of Excluded Patients

eFigure 1. Time to First Relapse in the Treatment Discontinuation vs Continuation Group Among Patients With RRMS

eFigure 2. Time To First Relapse in the Treatment Discontinuation vs Continuation Group Among Patients With SPMS

eFigure 3. Time To First Inflammatory Activity (Clinical and/or MRI) in the Treatment Discontinuation vs Continuation Group

eTable 2. Factors Associated With Relapse Occurrence in the Discontinuation Group

eTable 3. Factors Associated With Inflammatory Activity in the Discontinuation Group

jamaneurol-e240395-s001.pdf^{(993.6KB, pdf)}

Supplement 2.

Group Information. OFSEP Investigators

jamaneurol-e240395-s002.pdf^{(119.5KB, pdf)}

Supplement 3.

Data Sharing Statement

jamaneurol-e240395-s003.pdf^{(16.2KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Baseline Characteristics of Excluded Patients

eFigure 1. Time to First Relapse in the Treatment Discontinuation vs Continuation Group Among Patients With RRMS

eFigure 2. Time To First Relapse in the Treatment Discontinuation vs Continuation Group Among Patients With SPMS

eFigure 3. Time To First Inflammatory Activity (Clinical and/or MRI) in the Treatment Discontinuation vs Continuation Group

eTable 2. Factors Associated With Relapse Occurrence in the Discontinuation Group

eTable 3. Factors Associated With Inflammatory Activity in the Discontinuation Group

jamaneurol-e240395-s001.pdf^{(993.6KB, pdf)}

Supplement 2.

Group Information. OFSEP Investigators

jamaneurol-e240395-s002.pdf^{(119.5KB, pdf)}

Supplement 3.

Data Sharing Statement

jamaneurol-e240395-s003.pdf^{(16.2KB, pdf)}

[noi240014r1] 1.He A, Merkel B, Brown JWL, et al. ; MSBase Study Group . Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study. Lancet Neurol. 2020;19(4):307-316. doi: 10.1016/S1474-4422(20)30067-3 [DOI] [PubMed] [Google Scholar]

[noi240014r2] 2.Hauser SL, Kappos L, Arnold DL, et al. Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension. Neurology. 2020;95(13):e1854-e1867. doi: 10.1212/WNL.0000000000010376 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi240014r3] 3.Chappuis M, Rousseau C, Bajeux E, et al. Discontinuation of second- versus first-line disease-modifying treatment in middle-aged patients with multiple sclerosis. J Neurol. 2023;270(1):413-422. doi: 10.1007/s00415-022-11341-2 [DOI] [PubMed] [Google Scholar]

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PERMALINK

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

Guillaume Jouvenot, MSc

Guilhem Courbon, MD

Mathilde Lefort, PhD

Fabien Rollot, PhD

Romain Casey, PhD

Emmanuelle Le Page, MD

Laure Michel, MD, PhD

Gilles Edan, MD, PhD

Jérome de Seze, MD, PhD

Laurent Kremer, MD

Kevin Bigaut, MD

Sandra Vukusic, MD, PhD

Guillaume Mathey, MD

Jonathan Ciron, MD

Aurélie Ruet, MD, PhD

Elisabeth Maillart, MD

Pierre Labauge, MD, PhD

Hélène Zephir, MD, PhD

Caroline Papeix, MD, PhD

Gilles Defer, MD

Christine Lebrun-Frenay, MD, PhD

Thibault Moreau, MD, PhD

David Axel Laplaud, MD, PhD

Eric Berger, MD

Bruno Stankoff, MD, PhD

Pierre Clavelou, MD, PhD

Eric Thouvenot, MD, PhD

Olivier Heinzlef, MD

Jean Pelletier, MD, PhD

Abdullatif Al-Khedr, MD

Olivier Casez, MD

Bertrand Bourre, MD

Philippe Cabre, MD, PhD

Abir Wahab, MD

Laurent Magy, MD

Jean-Philippe Camdessanché, MD, PhD

Ines Doghri, MD

Solène Moulin, MD, PhD

Haifa Ben-Nasr, MD

Céline Labeyrie, MD

Karolina Hankiewicz, MD

Jean-Philippe Neau, MD, PhD

Corinne Pottier, MD

Chantal Nifle, MD

Nicolas Collongues, MD, PhD

Anne Kerbrat, MD, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusion and Relevance

Introduction

Methods

Study Design

Patients

Exposures

Outcomes

Statistical Analysis

Patient Matching

Analyses

Results

Baseline Characteristics

Figure 1. Study Flowchart.

Table. Characteristics of Patients at Inclusion and After Propensity Score Matching.

Relapse Occurrence

Figure 2. Time to First Relapse in the High-Efficacy Therapy (HET) Treatment Discontinuation vs HET Continuation Groups After Propensity Score Matching.

Figure 3. Annualized Relapse Rate in the High-Efficacy Therapy Discontinuation Group by Type of Medication Stopped (Natalizumab, Fingolimod, or Anti-CD20 Therapy).

Focal Inflammatory Activity

Disability Progression

Figure 4. Time to Confirm Disability Progression in the High-Efficacy Therapy (HET) Treatment Discontinuation vs HET Continuation Groups After Propensity Score Matching.

Factors Associated With Relapses and Focal Inflammatory Activity