From Western University, Department of Clinical Neurological Sciences, London Health Sciences Centre, London, ON, Canada (SAM); Hoffmann-La Roche, Mississauga, ON, Canada (VG, SS, JR); F. Hoffmann-La Roche, Basel, Switzerland (NP, KF); Fraser Health Multiple Sclerosis Clinic, Burnaby, BC, Canada (GV). 

: Sarah A. Morrow, MD, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada; 

 A wearing-off effect has been reported in people with multiple sclerosis (MS) receiving ocrelizumab and other monoclonal antibodies. We sought to describe the real-world occurrence of wearing-off effect among people with MS in Canada treated with ocrelizumab.

 Canadian self-reports coded to the Medical Dictionary for Regulatory Activities preferred term 

) between November 5, 2008, and March 15, 2023, were identified from the Roche Global Safety Database. Cases were then linked to patient-level data from the Canadian Roche Patient Support Program (COMPASS). Only people with MS who had received 3 or more doses of ocrelizumab were included.

 A total of 10,055 people with MS in Canada received 3 or more doses of ocrelizumab within COMPASS. 

was reported 140 times among 138 unique cases (1.3%) over an average of 7.4 infusions. Discontinuation of ocrelizumab was generally uncommon. In the overall COMPASS population, 11.4% (1143 of 10,055) discontinued ocrelizumab. Among those who reported 

, 15.9% (22 of 138) discontinued while the majority (116 of 138; 84.1%) continued ocrelizumab treatment. Of individuals reporting the adverse event of interest, those with relapsing-remitting MS more frequently remained on therapy (98 of 112; 87.5%) compared with those with primary progressive MS (18 of 26; 69.2%).

 A wearing-off effect was infrequently reported and did not limit treatment among people with MS in the real-world COMPASS patient support program.

 The authors thank all people with MS enrolled in Roche Canada COMPASS. The medical writing support provided by Stevie Kenyon of Placencia Holdings (Hamilton, Ontario, Canada) is also appreciated.

In the past 3 years, Sarah A. Morrow, MD, has served on advisory boards/had speaking engagements for Biogen Idec, Bristol Myers Squibb/Celgene, EMD Serono, Greenwich Biosciences, Novartis, Roche, Sanofi Genzyme, and Teva Neurosciences; has received investigator-initiated grant funds from Biogen Idec, Novartis, Roche, and Sanofi Genzyme; and has acted as site primary investigator for multicenter trials funded by Bristol Myers Squibb/Celgene, EMD Serono, Novartis, roche, and Sanofi Genzyme. Victor Gitman, PharmD; Sofija Spasojevic, PhD; Jessica Rassi, MSc; Noemi Pasquarelli, PhD; and Kocho Fitovski, MD, are employees and shareholders of Hoffmann-La Roche/F. Hoffmann-La Roche. Galina Vorobeychik, MD, has received research support, educational grants, and/or honoraria from Alexion, Berlex, Biogen Idec, Bristol Myers Squibb/Celgene, EMD Serono, Novartis, Roche, Sanofi Genzyme, and Teva Neurosciences.

Hoffmann-La Roche (Mississauga, Ontario, Canada) sponsored this research and writing services for the preparation of the manuscript. The company, in collaboration with independent authors, was also involved in the study design, collection, analysis, and interpretation of data; writing the report; and the decision to submit the article for publication.

Presented as an abstract/poster at the European Committee for Treatment and Research in Multiple Sclerosis 2022; October 26 to 28, 2022; Amsterdam, Netherlands.

Sarah A. Morrow, MD, MS, FRCPC

Victor Gitman, PharmD, MSc

Sofija Spasojevic, PhD

Jessica Rassi, MSc

Noemi Pasquarelli, PhD

Kocho Fitovski, MD

Galina Vorobeychik, MD

Unsolicited reports of the wearing-off effect related to ocrelizumab were infrequent (< 2%).

Symptoms reported with the wearing-off effect were nonserious.

The majority of patients reporting the wearing-off effect continued with ocrelizumab.

Multiple sclerosis (MS) is a chronic, neurologic, inflammatory disease affecting approximately 90,000 Canadians.

 MS can affect various parts of the central nervous system, leading to a range of possible symptoms (eg, fatigue, lack of coordination, sensory symptoms, vision problems, bladder problems, cognitive impairment, mood changes). In Canada, approximately 90% of MS cases are relapsing-remitting (RRMS),

 characterized by reversible episodes of neurological dysfunction and disability. However, damage from these events can accumulate over time, with resulting lesions in the brain and spinal cord.

 In 10% of Canadian people with MS, the disease is progressive from onset (primary progressive MS [PPMS]).

Although there is no cure for MS, current therapies support people with MS in reducing disease activity, delaying progression, and gaining better symptom control.

 Among a broad class of disease-modifying therapies (DMTs) are the higher-efficacy monoclonal antibodies (mAbs) alemtuzumab, natalizumab, and 3 anti-CD20s: ocrelizumab, ofatumumab, and ublituximab.

 Each has a unique structure, mechanism of action, dosing regimen, and safety profile.

 Ocrelizumab, a humanized mAb that selectively targets CD20-expressing B cells, is approved in Canada for the treatment of RRMS and PPMS.

 After initial dosing of a split, twice-administered 300-mg infusion, ocrelizumab is administered at a single fixed dose (600 mg) every 6 months.

Natalizumab, ocrelizumab, and ofatumumab have been linked with reports of a therapeutic phenomenon called 

 A wearing-off effect is described as the experience of MS symptoms, such as fatigue, in the days or weeks prior to the next scheduled mAb infusion and a disappearance of such symptoms following receipt of the treatment.

 It has been reported at varying frequencies (16%-67%), which may be a result of different case definitions and/or assessment methods.

 The wearing-off effect is often referred to as a phenomenon for which research has failed to elucidate either the true cause or consequence of the effect.

 This is notably different from disease reactivation or rebound, which has been reported and studied extensively following natalizumab and fingolimod discontinuation.

 For natalizumab, findings from a study of the wearing-off effect associated the event with lower α

-integrin receptor occupancy on circulating leukocytes, suggesting a decreased treatment effect.

 For ocrelizumab, research suggests that the reported wearing-off phenomenon is not related to dose interval, B-cell count (remains depleted), symptom burden, or clinical efficacy but may be correlated with higher body mass index (BMI).

Considering the differences in reported frequency as well as within patient variability of wearing-off effect reports among people with MS treated with ocrelizumab, further investigation was deemed worthwhile. In Canada, the provision of ocrelizumab for MS through a national patient support program presented an opportunity to further study wearing-off effect events in a large population of people with MS treated with ocrelizumab in a real-world setting. The primary objective of this study was to determine the frequency with which the wearing-off effect occurs during real-world treatment with ocrelizumab and, secondarily, to characterize how the event affected the course of treatment, if at all.

This is a retrospective, observational study of Canadian people with MS treated with ocrelizumab enrolled in the Canadian Roche Patient Support Program (COMPASS) and reporting wearing-off effect (within the Roche Global Safety Database).

COMPASS is a patient support program in Canada, sponsored by the manufacturer of ocrelizumab, that supports the provision of the drug to people with MS. All people with MS in Canada receiving ocrelizumab would at some point in their care be enrolled in COMPASS. The Roche Global Safety Database is a centralized repository for reports of adverse events (AEs) received for products manufactured by F. Hoffmann-La Roche Ltd.

AEs were voluntarily reported, meaning event information was volunteered in an unprompted manner. 

) was the Medical Dictionary for Regulatory Activities v24.1 (MedDRA) highest-level preferred term used in the analysis to capture wearing-off events. Aligned with routine pharmacovigilance processes, medical coders selected the most appropriate lowest-level term from the MedDRA that accurately reflected the reported verbatim information. Medical judgment was applied to assign a MedDRA term that represented the reported concept when the verbatim term was not an exact match to 

 Examples of verbatim terms that were coded to the preferred term (

. Individual case safety reports coded to the MedDRA preferred term 

were extracted from the Roche Global Safety Database (collected from November 5, 2008, to March 15, 2023) and linked with data from the COMPASS program using unique patient identification numbers or initials and date of birth (

 Study Participant Eligibility and Selection

There was no imputation of data; cases with missing identifying information were excluded from the analysis. Reports not linked to the COMPASS program (eg, those from clinical trials) were excluded from this study. Only adults (aged ≥ 18 years) with MS who had received at least 3 doses of ocrelizumab were included in the analysis of TRS. This ensured those included in the analysis had received 2 initial doses (300 mg each) and, approximately 6 months later, a third dose (600 mg; full dose), allowing for at least one 6-month dosing interval in which TRS might occur. TRS events are herein referred to as 

in keeping with the common literature, as terms synonymous with reports of wearing-off events were coded to TRS as per MedDRA.

The primary variables of interest for this study included reports of wearing-off effect, indication for treatment, therapy status (collected by COMPASS; eg, 

[within the 6-month dosing interval and intends to receive the next ocrelizumab infusion] or 

[exceeded the 6-month dosing interval or does not intend to receive the next ocrelizumab infusion]), and reason for treatment discontinuation (eg, unknown reason, physician recommendation, AE with program drug, financial reason, switched to another therapy, or other). The Roche Global Safety Database served as the primary source for the following data: AE information (seriousness and outcome), sex at birth, and age. The COMPASS program provided baseline demographics, including data related to treatment history, current therapy status, ocrelizumab dosage, dosing interval treatment indication, and supplementary information on sex and age if unavailable in the AE report. Individuals were stratified by indication for ocrelizumab therapy (ie, RRMS or PPMS). Standard follow-up conducted by case managers in the COMPASS program includes a call after the individual is medically cleared by their neurologist, a call 5 business days prior to the scheduled infusion, a call 2 business days after the infusion, and a 4-month check-in call after the last infusion (ie, 2 months before the next).

This study involved the secondary use of personal data; hence, informed consent was not feasible nor required. A waiver of consent was granted by Advarra (May 3, 2022). All people with MS participating in the COMPASS program consented to sharing their personal information (including personal health information) with Roche and the possibility that this information would be used in an aggregated manner for publication. Still, precautions were taken to protect participant anonymity, including aggregating and anonymizing/pseudonymizing final data and ensuring linkage back to the individual participant was impossible or tightly controlled. The study protocol was reviewed and approved by the Advarra Institutional Review Board (approval number: MOD01320274).

Analyses were conducted using Python 3.8.8. For continuous variables, measures of central tendency (medians and means) and dispersion (SD and range) are reported. The COMPASS database provided a total number of individuals exposed to ocrelizumab (a denominator), and the Roche Global Safety Database, after exclusions, provided the number of individuals affected (the numerator). This enabled the reporting of frequencies and percentages for each categorical variable. All data are reported using descriptive statistics.

As of March 15, 2023, a total of 10,567 people with MS had received at least 1 administration of ocrelizumab through the COMPASS program, with 10,055 having received at least 1 full dose. Of those, 138 unique cases and 140 reports of wearing-off effect (2 individuals reported wearing-off effect twice) were identified in the safety database and linked to COMPASS, representing 1.3% of the estimated total exposed population (Figure S1). Reports were primarily received by patients or other non–health care professionals (see 

Characteristics of the study and source cohorts are outlined in 

Characteristics of People With MS in COMPASS Exposed to Full-Dose Ocrelizumab and People With MS in Study Exposed to Full-Dose Ocrelizumab and Reporting Wearing-Off Effect

Patients reporting a wearing-off effect received an average of 7.4 infusions, with a mean time between full doses of 6.2 months. Generally, people with MS treated with ocrelizumab reporting wearing-off effect had similar disease and treatment characteristics as those of the total exposed population (Table 1). The wearing-off effect occurred in people with PPMS and RRMS in proportions similar to the overall study makeup (Table 1). The majority of individuals with PPMS were treatment naive prior to receiving ocrelizumab. Mean ocrelizumab dosing interval was similar between the groups, with the majority receiving ocrelizumab every 6 months with no variation (IQR, 0; Table 1). Duration of therapy and number of infusions received were higher in the group reporting wearing-off effect (Table 1).

All reports of wearing-off effect were nonserious (

 Detailed Analysis of Wearing-Off Effect Reports

Overall, 11.4% of the total exposed population and 15.9% of people with MS reporting wearing-off effect discontinued treatment (

Ocrelizumab Therapy Status and Reasons for Discontinuation: Source and Study Populations

The discontinuation rate was higher in those with wearing-off effect and PPMS vs RRMS (30.8% vs 12.5%, respectively; Table 3). Reasons for discontinuation in people with MS reporting wearing-off effect were similar to those of the overall COMPASS population (Table 3).

A comparison of people who reported wearing-off effect and continued vs discontinued ocrelizumab is outlined in 

Characteristics of Patients Who Reported Wearing-Off Effect Stratified by Continuation or Discontinuation of Ocrelizumab

The groups had a similar ocrelizumab dosing interval (every 6 months). People who reported wearing-off effect and discontinued ocrelizumab were more likely to be older, were more likely to be men, and had a lower overall duration of treatment than those who continued ocrelizumab.

AEs reported in conjunction with the wearing-off effect are detailed in 

 Select Adverse Event Frequencies in Study Population

We investigated reports of a wearing-off effect in people with MS in Canada by combining events from the global safety database with patient-level data from the national COMPASS database. Given that all people with MS receiving ocrelizumab outside of clinical trials in Canada receive it via COMPASS, the data set allowed for a reliable estimate of total Canadian exposure. This database, coupled with the Roche Global Safety Database, provided a useful means of analyzing the wearing-off effect phenomenon in Canada. We observed that wearing-off effects coded to 

were reported by 1.3% of the studied population and were generally not treatment limiting, with 15.9% of people with MS who reported wearing-off effect discontinuing ocrelizumab.

Studies of wearing-off effect published to date have ranged from case series

 to prospective, phase 4, nonrandomized, multicenter trials (N = 376).

 When surveyed, people with MS treated with natalizumab have reported a wearing-off effect at a frequency of 37% to 67%.

 Similarly, a wearing-off effect has been reported in 51% to 61% of people with MS receiving ocrelizumab.

 These prospective studies related to ocrelizumab (88-100 participants) used a wearing-off questionnaire and noted the potential for overreporting due to enhanced recall and reporting bias.

In contrast, our study presents the largest cohort of people with MS yet studied for the wearing-off effect (N = 10,055) using spontaneous AE reporting rather than topic-specific questionnaires. Spontaneous AE reporting has been shown to underrepresent the prevalence of an AE compared with active monitoring (or true incidence).

 Although in some cases, rare AEs may be subject to less underreporting,

 in the case of wearing off, underreporting may be amplified given its subjective nature and relative nonseriousness. Interestingly, a retrospective chart review from British Columbia, Canada, found a wearing-off phenomenon recorded in 16% (11 of 69) of patient charts.

 Our data show that the spontaneous reporting of wearing off in a large real-world population is lower than that found in prospective studies. We suspect the true incidence of wearing off lies somewhere between the rate of spontaneous reports seen in our study and the frequency of reports solicited in prospective studies.

In the prospective study by Toorop and colleagues, treatment satisfaction did not differ between those reporting wearing off and those not reporting it

; however, in the multi-mAB study noted previously, wearing off was associated with reduced treatment satisfaction scores, and 20% of participants noted they had considered switching to another DMT.

 Uniquely, our data report on treatment status and reasons for ocrelizumab discontinuation. Importantly, wearing-off events were not reported as the reason for ocrelizumab discontinuation, and most people with MS affected remained on treatment (84.1%). Furthermore, wearing-off events were confirmed to be nonserious in nature for all in our study. The majority received ocrelizumab at 6-month intervals, and overall duration of therapy was similar in the total COMPASS population as it was among those who reported wearing off and discontinued treatment.

The potential cause of wearing off remains unknown. Findings from studies related to ocrelizumab used at extended dosing intervals have shown a maintenance of clinical efficacy, even with altered B-cell repopulation.

 In our study, a median dosing interval of 6 months was observed in both people with MS reporting wearing-off effect as well as the total exposed population, which is in line with the recommended dosing interval of every 6 months.

Given this consistency between groups, we were unable to observe any impact of dosing interval on wearing off.

Another theory to explain wearing off that has been explored is a decreased pharmacological effect. In the SymBOLS study (NCT04855617), no correlation was found between serum neurofilament light chain (sNfL) or ocrelizumab serum levels and symptom burden, suggesting wearing off is not a result of subclinical disease activity.

 found wearing-off reports were associated with higher levels of CD8 and CD3/CD27 lymphocytes (ie, reduced immunomodulation) and increased plasma NfL levels (ie, neuroaxonal damage); however, these were not correlated with clinical or radiological disease activity nor ocrelizumab serum levels, so a causal effect was not established. Results from a cross-sectional study by Meca-Lallana et al found no correlation between sNfL, CD19+, baseline Expanded Disability Status Scale score, age, progression, or relapse in people with MS treated with ocrelizumab experiencing a wearing-off effect.

 Finally, Toorop and colleagues observed a correlation between higher BMI and a wearing-off effect that did not appear correlated with B-cell count.

They speculated that higher rates of clinical disability experienced by people with MS and obesity may be responsible for greater MS symptom fluctuation.

The prevailing hypothesis, based on current evidence, is that the wearing-off phenomenon may be a subjectively perceived lack of effect or disease-related symptom fluctuations misattributed to treatment.

The low rates of unprompted reports observed in our study support this. In CASTING, a phase 3b study (NCT02861014), the patient-reported outcome tool SymptoMScreen, which includes elements such as fatigue, cognitive function, and sensory symptoms—all in common with wearing-off effect symptoms—was applied.

 People with MS who previously had a suboptimal response to 1 or 2 DMTs had significant improvement in SymptoMScreen scores, which were observed 24 weeks into ocrelizumab treatment and maintained over 96 weeks.

 Furthermore, results from the SymBOLS study of 103 people with MS treated with ocrelizumab failed to show correlation between wearing off and meaningful symptom changes throughout the infusion cycle as measured by Quality of Life in Neurological Disorders short forms, SymptoMScreen, and the Work Productivity and Activity Impairment Questionnaire at the beginning, middle, and end of the ocrelizumab treatment cycle.

 Importantly, the significant intra- and interindividual symptom variability associated with the MS disease course (regardless of treatment)

 is likely to affect the ability of prospective studies to objectively and consistently capture wearing-off phenomenon within a group over time. Results from a recent study of wearing-off effect with 4 mAbs found wearing off to be associated with symptoms of depression, which may support the theory that it is a psychological rather than biological phenomenon.

The present work is characterized by some limitations. Inherent to the nature of safety databases, the extracted data require careful interpretation due to the varying quality of AE reports, which could in some instances have missing, nonverifiable, and/or incomplete information. This also precluded the analysis of comorbidities (such as BMI and laboratory parameters) that may overlap with wearing-off effect. However, the COMPASS data supplement many other data points potentially missing from AE reports.

The calculation of population-based AE rates was not feasible because voluntary AE reporting is unprompted and, particularly for nonserious events, prone to be underreported.

 Given the unsolicited and voluntary nature of the information retrieval, there is a possibility that some wearing-off symptoms were not reported, potentially leading to an underestimation of the true frequency as discussed previously. Furthermore, although the preferred term 

captured a broad range of synonymous terms, other common MS symptoms (eg, fatigue) reported independently of the analyzed preferred term may not have been coded in the Roche Global Safety Database as 

, further contributing to the potential underestimation of the frequency of wearing off.

Despite the above considerations, our data provide insights into a phenomenon that is difficult to objectively measure. Wearing-off event analysis can vary by the definition of the reported event, use of a biological/symptomatic surrogate, timing/interval of data collection, study design and resulting biases, and individual awareness of the effect. These are all factors at play when considering the results of this study in the context of the limited literature on the topic.

Although these findings support the provision of ocrelizumab according to the recommended dosing schedule, with no observed impact due to wearing-off effect, an opportunity to better understand the phenomenon remains. In addition to routine pharmacovigilance assessment for lack of efficacy (including wearing-off effect), longitudinal studies designed to minimize reporting bias and monitor symptom recrudescence and biological markers over the course of treatment may be insightful. Two ongoing phase 3 studies investigating ocrelizumab administered at higher doses may provide additional insights into symptom control under other clinical circumstances.

In this large and representative population of people with MS in Canada treated with ocrelizumab, reports of wearing-off effect were infrequent (< 2%). Observed symptoms and treatment patterns in people with MS reporting wearing-off effect were nonserious and support the continuation of therapy according to label recommendations.

What is multiple sclerosis? MS Canada. Accessed June 7, 2023. https://mscanada.ca /intro-to-ms/what-is-multiple-sclerosis

Filippi M, Bar-Or A, Piehl F, et al. Multiple sclerosis. 

. 2018;4(1):43. doi:10.1038/s41572-018-0041-4

Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. 

. 2018;90(17):777-788. doi:10.1212/WNL.0000000000005347

Freeman L, Longbrake EE, Coyle PK, Hendin B, Vollmer T. High-efficacy therapies for treatment-naïve individuals with relapsing-remitting multiple sclerosis. 

. 2022;36(12):1285-1299. doi:10.1007/s40263-022-00965-7

Carlson AK, Amin M, Cohen JA. Drugs targeting CD20 in multiple sclerosis: pharmacology, efficacy, safety, and tolerability. 

. 2024;84(3):285-304. doi:10.1007/s40265-024-02011-w

. Health Canada. 2023. Accessed June 8, 2023. https://pdf.hres.ca/dpd_pm/00033852.PDF

. Health Canada. 2017. Accessed June 8, 2023. https://pdf.hres.ca/dpd_pm/00039755.PDF

. Health Canada. 2017. Accessed June 7, 2023. https://pdf.hres.ca/dpd_pm/00040681.PDF

. Health Canada. 2021. Updated June 15, 2022. Accessed June 7, 2023. https://pdf.hres.ca/dpd_pm/00066349.PDF

Hauser SL, Bar-Or A, Comi G, et al; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. 

. 2017;376(3):221-234. doi:10.1056/NEJMoa1601277

Montalban X, Hauser SL, Kappos L, et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. 

. 2017;376(3):209-220. doi:10.1056/NEJMoa1606468

van Kempen ZLE, Doesburg D, Dekker I, et al. The natalizumab wearing-off effect: end of natalizumab cycle, recurrence of MS symptoms. 

. 2019;93(17):e1579-e1586. doi:10.1212/WNL.0000000000008357

Ratchford JN, Brock-Simmons R, Augsburger A, et al. Multiple sclerosis symptom recrudescence at the end of the natalizumab dosing cycle. 

. 2014;16(2):92-98. doi:10.7224/1537-2073.2013-017

Cathérine D, Annelien DP, Anne S, et al. End of dose interval symptoms in patients treated with natalizumab: a role for serum cytokines? 

. 2020;41:102020. doi:10.1016/j.msard.2020.102020

Toorop AA, van Lierop ZYGJ, Strijbis EMM, et al. The wearing-off phenomenon of ocrelizumab in patients with multiple sclerosis. 

. 2022;57:103364. doi:10.1016/j.msard.2021.103364

Akgün K, Kretschmann N, Haase R, et al. Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS. 

. 2019;6(3):e555. doi:10.1212/NXI.0000000000000555

Labani A, Becker D. Wearing-off phenomenon in multiple sclerosis patients on ofatumumab: a case series. 

. 2023;3:100167. doi:10.1016 /j.nerep.2023.100167

Bringeland GH, Myhr KM, Vedeler CA, Gavasso S. Wearing-off at the end of natalizumab dosing interval and risk of MS disease activity: a prospective 1-year follow-up study. 

. 2020;415:116880. doi:10.1016/j.jns.2020.116880

Reznik JJ, Kin B, Bergeron-Vitez H, Nelson J, Kazimirchik A, Vorobeychik G. A retrospective study on B-cell depleting therapies in multiple sclerosis patients: frequency of the wearing off phenomenon. 

. 2022;28(supp 3):873-874. doi:10.1177/13524585221123682

Mowry EM, Bourdette D. Natalizumab wearing-off symptoms: patients with MS on extended interval dosing may not “mind the gap”. 

. 2019;93(17):735-736. doi:10.1212/WNL.0000000000008358

Foley JF, Stuve O. Natalizumab wearing-off effect: the hunt for the elusive pharmacodynamic biomarker. 

. 2020;7(3):e706. doi:10.1212/NXI.0000000000000706

Prosperini L, Kinkel RP, Miravalle AA, Iaffaldano P, Fantaccini S. Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis. 

. 2019;12:1756286419837809. doi:10.1177/1756286419837809

FDA warns about severe worsening of multiple sclerosis after stopping the medicine Gilenya (fingolimod). US Food and Drug Administration. November 20, 2018. Accessed October 2, 2023. https://www.fda.gov/drugs/drug-safety-and-availability /fda-warns-about-severe-worsening-multiple-sclerosis-after-stopping-medicine -gilenya-fingolimod

Bringeland GH, Blaser N, Myhr KM, Vedeler CA, Gavasso S. Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy. 

. 2020;7(3):e678. doi:10.1212/NXI.0000000000000678

Dutta A. MedDRA - terminologies and coding. Presented at: 6th Asia Pacific Pharmacovigilance Training Course; February 26, 2020. Accessed December 19, 2023. https://admin.meddra.org/sites/default/files/page/documents_insert/MedDRA%20-%20Terminologies%20%26%20Coding.pdf

Toorop AA, Wessels MHJ, Gelissen LMY, et al. Influence of personalized extended interval dosing on the natalizumab wearing-off effect - a sub-study of the NEXT-MS trial. 

. 2024;462:123102. doi:10.1016/j.jns.2024.123102

Bringeland GH, Blaser N, Myhr KM, Vedeler CA, Gavasso S. Wearing-off symptoms during standard and extended natalizumab dosing intervals: experiences from the COVID-19 pandemic. 

. 2021;429:117622. doi:10.1016/j.jns.2021.117622

Magro G, Barone S, Tosto F, et al. Natalizumab wearing-off symptoms: effect of extend interval dosing during Sars-CoV-2 pandemic. 

. 2023;270(2):595-600. doi:10.1007/s00415-022-11408-0

Marian LM, Harris KA, Conway DS. The patient-reported wearing-off phenomenon with monoclonal antibody treatments for multiple sclerosis. 

. 2024;10(2):20552173241251707. doi:10.1177/20552173241251707

Bernardes C, Fernandes C, Cunha C, et al. Natalizumab extended interval dosing: what about wearing-off effect? 

. 2024;458:122930. doi:10.1016/j.jns.2024.122930

Kister I, Oh C, Douglas EA, et al. No increase in symptoms toward the end of the ocrelizumab infusion cycle in patients with multiple sclerosis: symptom burden on ocrelizumab: a longitudinal study (SymBOLS). 

. 2023;13(5):e200185. doi:10.1212/CPJ.0000000000200185

Monteiro I, Nicolella V, Fiorenza M, et al. The ocrelizumab wearing-off phenomenon is associated with reduced immunomodulatory response and increased neuroaxonal damage in multiple sclerosis. 

. 2024;271(8):5012-5024. doi:10.1007/s00415-024-12434-w

Fletcher AP. Spontaneous adverse drug reaction reporting vs event monitoring: a comparison. 

. 1991;84(6):341-344. doi:10.1177/014107689108400612

Rodriguez-Mogeda C, van Lierop ZYGJ, van der Pol SMA, et al. Extended interval dosing of ocrelizumab modifies the repopulation of B cells without altering the clinical efficacy in multiple sclerosis. 

. 2023;20(1):215. doi:10.1186/s12974-023-02900-z

Schuckmann A, Steffen F, Zipp F, Bittner S, Pape K. Impact of extended interval dosing of ocrelizumab on immunoglobulin levels in multiple sclerosis. 

. 2023;4(6):361- 372.e3. doi:10.1016/j.medj.2023.05.001

Meca-Lallana J, García-Merino JA, Martínez-Yélamos S, et al. Identification of patients with relapsing multiple sclerosis eligible for high-efficacy therapies. 

. 2021;11(3):251-261. doi:10.2217/nmt-2020-0049

Kister I. Improvements in patient-reported SymptoMScreen scores among ocrelizumab-treated patients with RRMS: two-year results from the CASTING clinical trial (P1039). Poster presented at: European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis 8th Joint Conference: MS Virtual 2020; September 11, 2020

Kasser SL, Goldstein A, Wood PK, Sibold J. Symptom variability, affect and physical activity in ambulatory persons with multiple sclerosis: understanding patterns and time-bound relationships. 

. 2017;10(2):207-213. doi:10.1016/j.dhjo.2016.10.006

Hauser SL, Bar-Or A, Weber MS, et al. Association of higher ocrelizumab exposure with reduced disability progression in multiple sclerosis. 

2023;10(2). doi:10.1212/NXI.0000000000200094

Wearing-Off Effect Reports in People With Multiple Sclerosis Receiving Ocrelizumab

People with multiple sclerosis (MS) experience motor and nonmotor symptoms that affect daily life. Although regular physical activity (PA) may enhance the overall well-being of people with MS, they tend to have lower activity levels than healthy individuals. This study aims to investigate the impact of usual-care physiotherapy on PA and self-efficacy in people with MS and identify prerehabilitation factors that influence positive changes in PA with physiotherapy.

Forty-one people with MS undergoing physiotherapy with a median (IQR) age of 54.00 (17.00) years and an Expanded Disability Status Scale score of 6.00 (2.00) points were assessed on the first days (T0) and last days of their rehabilitation period (T1), and 6 weeks after it ended (T2). Instrumental assessment utilized Fitbit Versa trackers, measuring daily steps and moderate/vigorous PA engagement (MVPA). Self-efficacy, perceived fatigue, walking ability, and quality of life were measured using the Self-Efficacy in Multiple Sclerosis scale (SEMS), the Fatigue Severity Scale, the 10-Meter Walk Test, and the Short Form-12 Health Survey.

Usual-care physiotherapy did not improve (P > .05) daily steps (T0: 4139 [3333]; T1: 4438 [2505] steps per day), MVPA (T0: 6.00 [15.6]; T1: 10.52 [16.30] minutes per day), or self-efficacy (SEMS: T0: 42.0 [10.8]; T1: 40.5 [8.7] points). Low perceived fatigue, better overall PA, and good physical health perception were identified as predictors of positive changes in PA after physiotherapy.

Usual-care physiotherapy focusing on mobility did not result in significant improvements in PA or self-efficacy for people with MS. Perceived fatigue and overall PA before physiotherapy impacted PA levels after rehabilitation. Future interventions may benefit from integrating motivational strategies into the rehabilitation protocol to increase PA levels.

 All authors report no conflicts of interest with any financial organization regarding the manuscript.

 This research was funded by the Italian Ministry of Health, Ricerca Corrente 2023.

Alessandro Torchio, PT

 Giulia Fusari, PsyM, SLP

Davide Cattaneo, PhD, PT

Cristina Grosso, MD

Chiara Pagliari, PhD

Valeria Crispiatico, MSc, SLP

Gloria Perini, MSc, PT

Johanna Jonsdottir, PhD

Multiple sclerosis (MS) is one of the most common neurodegenerative diseases; it is commonly diagnosed in people between 20 and 50 years of age and impacts 2.8 million people worldwide.

 People with MS experience a wide range of symptoms affecting physical, cognitive, and physiological functions. These multifaceted symptoms can potentially influence their daily activity and active participation in life, including their daily amount of physical activity (PA).

Recent literature emphasized the importance of PA for people with MS, suggesting that regular PA may limit the worsening of symptoms and improve disease prognosis.

 PA includes any bodily movement produced by skeletal muscle contraction resulting in increased energy expenditure.

 It broadly encompasses daily activities like work and home tasks, leisure activities, sports, and supervised rehabilitation and/or exercise.

 PA can be more precisely defined: It is light when it is not intense enough to prevent a person from singing, and it is moderate/vigorous when a person cannot sing or can barely speak while engaged in the activity.

 There is a general consensus that regular PA is crucial for people with MS to maintain and improve overall health and well-being, reduce fatigue, and enhance mobility and quality of life (QOL).

Recent technological advances have made it possible to objectively measure PA in daily life through the use of wearable systems that can provide accurate and ecological measures of PA levels.

 To date, studies using wearable sensors show that people with MS are mostly sedentary and have lower daily PA levels compared with individuals who do not have MS.

 Even during periods of rehabilitation, people with MS are rarely advised on how to increase their PA to the recommended levels necessary for health benefits.

 A recent study showed that people with MS do not achieve the recommended daily amount of PA, even during outpatient or inpatient rehabilitation.

Volume 27, Issue Q2

Wearing-Off Effect Reports in People With Multiple Sclerosis Receiving Ocrelizumab

Impact of Usual-Care Physiotherapy on Physical Activity and Self-Efficacy in People With Multiple Sclerosis: An Observational Longitudinal Study

You've Got a Friend in Me: The Importance of a Confidant and Its Role on Health and Well-Being Among Women With Multiple Sclerosis

Understanding Diverse Caregiver Experiences and Their Impact on Caregiver Burden in Multiple Sclerosis

Integrating Clinical Pharmacy Services Into Comprehensive Multiple Sclerosis Care Teams: A Narrative Review of 4 Models

Resilience Indirectly Affects Functional Capabilities Through Physical Activity Engagement in Individuals With Multiple Sclerosis

Developing and Piloting a Dedicated Support Group for Young Adults With Multiple Sclerosis