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The wearing-off phenomenon of ocrelizumab in patients with multiple sclerosis

  • A.A. Toorop
    Correspondence
    Corresponding author.
    Affiliations
    Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurology Outpatient Clinic, De Boelelaan 1118, 1081 HV, Amsterdam, the Netherlands
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  • Z.Y.G.J. van Lierop
    Affiliations
    Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurology Outpatient Clinic, De Boelelaan 1118, 1081 HV, Amsterdam, the Netherlands
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  • E.M.M. Strijbis
    Affiliations
    Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurology Outpatient Clinic, De Boelelaan 1118, 1081 HV, Amsterdam, the Netherlands
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  • C.E. Teunissen
    Affiliations
    Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
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  • F. Barkhof
    Affiliations
    Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam, the Netherlands

    Queen Square MS Center, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, United Kingdom,

    National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Center, London, United Kingdom
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  • B.M.J. Uitdehaag
    Affiliations
    Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurology Outpatient Clinic, De Boelelaan 1118, 1081 HV, Amsterdam, the Netherlands
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  • Z.L.E. van Kempen
    Affiliations
    Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurology Outpatient Clinic, De Boelelaan 1118, 1081 HV, Amsterdam, the Netherlands
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  • J. Killestein
    Affiliations
    Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurology Outpatient Clinic, De Boelelaan 1118, 1081 HV, Amsterdam, the Netherlands
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Open AccessPublished:November 01, 2021DOI:https://doi.org/10.1016/j.msard.2021.103364

      Highlights

      • The wearing-off phenomenon is reported by more than half of patients with MS using ocrelizumab.
      • Only BMI was identified as a predicting factor.
      • The wearing-off phenomenon was not elicited by extending infusion intervals or higher B-cell counts.
      • The wearing-off phenomenon of ocrelizumab does not seem to reflect suboptimal control of MS disease activity.

      Abstract

      Background

      Patients with multiple sclerosis (MS) who are treated with monoclonal antibodies frequently report an increase of MS-related symptoms prior to the next dose known as the wearing-off phenomenon. The objective of this study was to assess the prevalence and predicting factors of the wearing-off phenomenon in patients with MS using ocrelizumab.

      Methods

      This was a prospective cohort study in patients with MS receiving ocrelizumab ≥1 year. Most participants received B-cell guided personalized extended interval dosing to limit ocrelizumab exposure and hospital visits during the COVID-19 pandemic (cut-off ≥ 10 cells/µL). Participants completed questionnaires during ocrelizumab infusion and 2 weeks thereafter. Demographics, clinical and radiological characteristics, CD19 B-cell counts, and serum neurofilament light (sNfL) levels were collected. Data were analyzed using logistic regression analyses.

      Results

      Seventy-one (61%) out of 117 participants reported the wearing-off phenomenon during ocrelizumab treatment. The most frequently reported symptoms were fatigue, cognitive disability and sensory symptoms. Wearing-off symptoms started < 1 week (11%), 1–4 weeks (49%) or more than 4 weeks (37%) before ocrelizumab infusion. Fifty participants (43%) reported a current wearing-off phenomenon at the first questionnaire. Higher body mass index (threshold BMI ≥ 25) increased the odds of reporting a current wearing-off phenomenon (OR 2.70, 95% CI 1.26 to 5.80, p = .011). Infusion interval, EDSS score, MRI disease activity, clinical relapses, CD19 B-cell counts, and sNfL levels were no predictors. Disappearance of the wearing-off phenomenon occurred in the first week after ocrelizumab infusion in most participants. Participants with a current wearing-off phenomenon significantly improved in self-reported physical and psychological functioning after ocrelizumab infusion. Reporting the wearing-off phenomenon did not influence treatment satisfaction. Forty of 109 participants (37%) reported post-infusion symptoms, such as fatigue, flu-like symptoms or walking difficulties. These post-infusion symptoms started directly or in the first week after ocrelizumab infusion and disappeared within 2 weeks.

      Conclusions

      The wearing-off phenomenon is reported by more than half of patients with MS using ocrelizumab. Only BMI was identified as a predicting factor. The wearing-off phenomenon was not elicited by extending infusion intervals or higher B-cell counts. The wearing-off phenomenon of ocrelizumab therefore does not seem to reflect suboptimal control of MS disease activity.
      MS (Multiple Sclerosis), BMI (Body Mass Index), COVID (Coronavirus Disease), MSIS (Multiple Sclerosis Impact Scale), MRI (Magnetic Resonance Imaging), EDSS (Expanded Disability Status Scale), sNfL (serum Neurofilament Light), OCR (Ocrelizumab), EID (Extended Interval Dosing)

      Keywords

      1. Introduction

      Ocrelizumab is an anti-CD20 monoclonal antibody used for the treatment of relapsing remitting multiple sclerosis (MS) and primary progressive MS. (
      • Hauser S.L.
      • Bar-Or A.
      • Comi G.
      • et al.
      Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.
      ) (
      • Montalban X.
      • Hauser S.L.
      • Kappos L.
      • et al.
      Ocrelizumab versus placebo in primary progressive multiple sclerosis.
      ) Ocrelizumab causes complete depletion of CD20-expressing B cells by phagocytosis and cell death. (
      • Sorensen P.S.
      • Blinkenberg M.
      The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects.
      )  Patients with MS using monoclonal antibodies can experience wearing-off at the end of a treatment cycle prior to the next dose. (
      • van Kempen Z.L.E.
      • Doesburg D.
      • Dekker I.
      • et al.
      The natalizumab wearing-off effect: end of natalizumab cycle, recurrence of MS symptoms.
      ;
      • Bringeland G.H.
      • Blaser N.
      • Myhr K.M.
      • et al.
      Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy.
      ;
      • Catherine D.
      • Annelien P.
      • Anne S.
      • et al.
      End of dose interval symptoms in patients treated with natalizumab: a role for serum cytokines?.
      ;
      • Ratchford J.N.
      • Brock-Simmons R.
      • Augsburger A.
      • et al.
      Multiple sclerosis symptom recrudescence at the end of the natalizumab dosing cycle.
      ) The wearing-off phenomenon usually consists of an increase of MS-related symptoms such as fatigue, cognitive disability, balance problems, motor function problems or sensory symptoms, which disappear immediately or in the next days after infusion. The wearing-off phenomenon is reported by 50–70% of patients with MS using natalizumab, another monoclonal antibody registered for MS. (
      • van Kempen Z.L.E.
      • Doesburg D.
      • Dekker I.
      • et al.
      The natalizumab wearing-off effect: end of natalizumab cycle, recurrence of MS symptoms.
      ;
      • Bringeland G.H.
      • Blaser N.
      • Myhr K.M.
      • et al.
      Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy.
      ;
      • Catherine D.
      • Annelien P.
      • Anne S.
      • et al.
      End of dose interval symptoms in patients treated with natalizumab: a role for serum cytokines?.
      ;
      • Ratchford J.N.
      • Brock-Simmons R.
      • Augsburger A.
      • et al.
      Multiple sclerosis symptom recrudescence at the end of the natalizumab dosing cycle.
      ) Regarding the natalizumab wearing-off phenomenon, an association with low natalizumab receptor occupancy was found. (
      • Bringeland G.H.
      • Blaser N.
      • Myhr K.M.
      • et al.
      Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy.
      ) However, other studies only reported body mass index (BMI) as a predicting factor, and concluded that the natalizumab wearing-off phenomenon is unlikely to reflect a non-optimal pharmacokinetic or pharmacodynamic state. (
      • van Kempen Z.L.E.
      • Doesburg D.
      • Dekker I.
      • et al.
      The natalizumab wearing-off effect: end of natalizumab cycle, recurrence of MS symptoms.
      ;
      • Catherine D.
      • Annelien P.
      • Anne S.
      • et al.
      End of dose interval symptoms in patients treated with natalizumab: a role for serum cytokines?.
      ) The exact etiology of the wearing-off phenomenon is unknown.
      So far, the ocrelizumab wearing-off phenomenon was not reported. As the wearing-off phenomenon could influence patient satisfaction, it is of importance to understand the etiology and detect possible risk factors. Furthermore, as personalized extended interval dosing (EID) of monoclonal antibodies is gaining ground, and an increasing number of trials on EID are conducted, studying the effect of EID on the wearing-off phenomenon is a timely matter. (
      • Barun B.
      • Gabelić T.
      • Adamec I.
      • et al.
      Influence of delaying ocrelizumab dosing in multiple sclerosis due to COVID-19 pandemics on clinical and laboratory effectiveness.
      ;
      • van Kempen Z.L.E.
      • Hoogervorst E.L.J.
      • Wattjes M.P.
      • et al.
      Personalized extended interval dosing of natalizumab in MS: a prospective multicenter trial.
      ;
      • van Lierop Z.Y.
      • Toorop A.A.
      • van Ballegoij W.J.
      • et al.
      Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic.
      ;
      • Tazza F.
      • Lapucci C.
      • Cellerino M.
      • et al.
      Personalizing ocrelizumab treatment in Multiple Sclerosis: what can we learn from Sars-Cov2 pandemic?.
      ;
      • Rolfes L.
      • Pawlitzki M.
      • Pfeuffer S.
      • et al.
      Ocrelizumab extended interval dosing in multiple sclerosis in times of COVID-19.
      ).
      The objectives of this study were to investigate the prevalence of the wearing-off phenomenon in patients with MS using ocrelizumab, to detect possible risk factors and to evaluate if the wearing-off phenomenon is also reflected in physical or psychological changes after ocrelizumab infusion.

      2. Methods

      2.1 Patient inclusion

      This was a prospective monocenter cohort study executed in the MS center Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands. Participants were included in the study between May 2020 and March 2021. Patients were eligible for inclusion if they had a current diagnosis of MS, (
      • Thompson A.J.
      • Banwell B.L.
      • Barkhof F.
      • et al.
      Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.
      ) if they were treated with ocrelizumab for a minimum of one year and if they were able to answer questionnaires in Dutch. Patients were excluded if they received a different infusion protocol during the previous ocrelizumab infusion (e.g. 300 mg of ocrelizumab instead of 600 mg). Patients were asked to participate in the study at their routine blood test consultation 22–24 weeks after the previous ocrelizumab infusion. Between March-December 2020, most patients received personalized B-cell guided dosing of ocrelizumab to limit ocrelizumab exposure and hospital visits during the COVID-19 pandemic. (
      • van Lierop Z.Y.
      • Toorop A.A.
      • van Ballegoij W.J.
      • et al.
      Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic.
      ) During this period, the consecutive infusion of ocrelizumab was extended when CD19 B-cell count was below 10 cells/µL. Follow-up lymphocyte counts were repeated every 4 weeks. The next infusion was aimed to be scheduled within 2–4 weeks as soon as CD19 B-cells repopulated to ≥ 10 cells/µL.

      2.2 Study protocol

      Participants completed two questionnaires before ocrelizumab infusion. The Multiple Sclerosis Impact Scale (MSIS-29) questionnaire evaluates the influence of MS-related symptoms on physical and psychological functioning in daily life and contains 29 questions. (
      • Hobart J.
      • Lamping D.
      • Fitzpatrick R.
      • et al.
      The Multiple sclerosis impact scale (MSIS-29): a new patient-based outcome measure.
      ) Physical and psychological scale scores (range 0–100) increase when more disability is present. The wearing-off questionnaire part I was designed for this study and contains questions regarding the wearing-off phenomenon and treatment satisfaction (appendix). A similar questionnaire was used in a previous study about the wearing-off phenomenon in patients using natalizumab. (
      • van Kempen Z.L.E.
      • Doesburg D.
      • Dekker I.
      • et al.
      The natalizumab wearing-off effect: end of natalizumab cycle, recurrence of MS symptoms.
      ) Participants were asked if they ever experienced a wearing-off phenomenon (never, sometimes, usually or always). Participants could specify wearing-off symptoms and how many weeks before the ocrelizumab infusion these symptoms usually appear. In addition, participants were asked if they currently felt the need for the next ocrelizumab infusion when completing the first questionnaires. Participants were asked about treatment satisfaction based on three multiple-choice questions (confidence about using ocrelizumab, benefits of ocrelizumab and overall treatment satisfaction).The answers were converted into scores between 0 and 100, with higher scores indicating higher treatment satisfaction. Two weeks after ocrelizumab infusion, two additional questionnaires were sent by e-mail to the participants. The MSIS-29 questionnaire was used to evaluate changes in self-reported physical and psychological disability after ocrelizumab infusion. The wearing-off questionnaire part II (appendix) was used to evaluate disappearance of wearing-off symptoms if applicable and to evaluate post-infusion symptoms (new symptoms emerging after ocrelizumab infusion).
      Exact body weight of the participants was measured. Other patient characteristics (age, height, sex) and information regarding MS were collected (time since diagnosis, duration of ocrelizumab treatment, infusion interval prior to the questionnaires, magnetic resonance imaging (MRI) disease activity, clinical relapses, and expanded disability status scale (EDSS) score). Blood volume was calculated using the Nadler formula. (
      • Nadler S.B.
      • Hidalgo J.H.
      • Bloch T.
      Prediction of blood volume in normal human adults.
      ) MRI disease activity was defined as time between the current ocrelizumab infusion and the last brain MRI scan with new or enlarged T2 lesions and/or gadolinium-enhancing lesions. Participants received annual 3D-FLAIR brain MRI scans according to international guidelines. (
      • Wattjes M.P.
      • Rovira À.
      • Miller D.
      • et al.
      Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis–establishing disease prognosis and monitoring patients.
      ) Clinical relapses were defined as time between the current ocrelizumab infusion and the last new clinical relapse (new neurological symptoms lasting > 24 h that were evaluated by a neurologist and were not attributable to other causes than MS). EDSS scores were assessed on a yearly basis as part of routine healthcare. EDSS scores at the current ocrelizumab infusion were the most recent EDSS scores extracted from the patient records. During the COVID-19 pandemic in 2020, most EDSS scores were assessed by telephone.
      Laboratory measurements (CD19 B-cell counts and serum neurofilament light (sNfL) levels) were performed at the routine blood test consultation 22–24 weeks after the previous ocrelizumab infusion, and repeated every 4 weeks until ocrelizumab infusion was scheduled based on B-cell counts. Lymphocyte counts were measured by flow cytometry (Gallios Flow Cytometer, Beckman Coulter). Beads were used as calibrator (BD Trucount, BD bioscience). sNfL levels were used as a biomarker for neuroaxonal damage (using Simoa technology (Quanterix)). (
      • Khalil M.
      • Teunissen C.E.
      • Otto M.
      • et al.
      Neurofilaments as biomarkers in neurological disorders.
      )

      2.3 Statistical analyses

      Participants were divided into two groups based on the presence of a current wearing-off phenomenon at the time of the first questionnaires. Baseline characteristics were compared between the groups using the independent samples t-test for normally distributed continuous data (age, body weight, BMI, blood volume, time since diagnosis, duration of ocrelizumab treatment, infusion interval) and the Mann-Whitney U test for not normally distributed continuous data (MRI disease activity, clinical relapses, EDSS score, CD19 B-cell counts and sNfL levels). A Pearson χ2 test was used for nominal data when minimum expected count was sufficient (sex). The likelihood ratio test was used if expected count was not sufficient (MS type).
      A forward selection procedure (cut-off p < 0.05) was used to identify predicting variables for a current wearing-off phenomenon (age, sex, BMI, blood volume, MS type, time since diagnosis, duration of ocrelizumab treatment, infusion interval, MRI disease activity, clinical relapses, current EDSS score, CD19 B-cell count prior to the first questionnaires and sNfL levels prior to the first questionnaires). Linearity was investigated by dividing continuous variables into quartiles. When linearity was violated, clinically relevant groups or quartiles were added to the logistic regression analyses. Treatment satisfaction was compared using the Mann-Whitney U test. Physical and psychological scale scores of the MSIS-29 questionnaires during and 2–4 weeks after ocrelizumab infusion were compared using the Wilcoxon signed-rank test. Median delta scores were calculated by subtracting the scores of the second MSIS-29 questionnaires from the first MSIS-29 questionnaires. Median delta scores and MSIS-29 scale scores were compared using the Mann-Whitney U test. SPSS statistic software version 26.0 (IBM, Armonk, NY) was used for all statistical analyses. A p-value < 0.05 was considered statistically significant.

      2.4 Ethics approval, registrations, and patient consent

      The medical ethics committee approved the study protocol (Amsterdam UMC Ethics committee number 2020.191). Oral and written informed consent was obtained from all participants. This study was registered at Clinicaltrials.gov with identifier NCT04478591.

      2.5 Data sharing statement

      Anonymized data will be shared by reasonable request from any qualified investigator.

      3. Results

      A total of 117 participants were included in the study. The majority of patients (84%) treated with ocrelizumab at the MS center Amsterdam who were eligible for inclusion were willing to participate (Fig. 1). Mean duration between infusions was 36.1 ± 8.6 weeks due to personalized B-cell guided dosing of ocrelizumab during the COVID-19 pandemic. Patients were treated with ocrelizumab for 1.7 ± 0.5 years at completion of the first questionnaires. Characteristics of the participants are presented in Table 1.
      Fig 1
      Fig. 1Flowchart of the inclusion process.
      *Patients were not asked to participate if they received ocrelizumab at the Neurology ward instead of the outpatient clinic. **Two patients received 300 mg of ocrelizumab instead of 600 mg after recovering from progressive multifocal leukoencephalopathy (
      • Toorop A.A.
      • van Lierop Z.Y.G.
      • Strijbis E.E.M.
      • et al.
      Mild progressive multifocal leukoencephalopathy after switching from natalizumab to ocrelizumab.
      ).
      Table 1Patient characteristics at the first questionnaires.
      Current wearing-off phenomenon
      Participants were divided into two groups based on the presence of a current wearing-off phenomenon when completing the first questionnaires.


      (n = 50)
      No current wearing-off phenomenon

      (n = 67)
      Total (n = 117)
      Age, years42.8 ± 11.042.5 ± 10.542.6 ± 10.7
      Sex, female31 (62.0)39 (58.2)70 (59.8)
      Body mass index, kg/m225.4 ± 3.4*23.6 ± 3.624.4 ± 3.6
      - BMI <2523 (46.0)46 (69.7)69 (59.5)
      - BMI ≥2527 (54.0)20 (30.3)47 (40.5)
      Blood volume, liters
      Blood volume was calculated using the Nadler formula (for males: 0.3669 * height3 + 0.03219 * weight + 0.6041; for females: 0.3561 * height3 + 0.03308 * weight + 0.1833) (Nadler et al., 1962).
      4.8 ± 0.74.7 ± 0.84.8 ± 0.7
      MS type

      - RRMS

      - PPMS

      - SPMS


      39 (78.0)

      9 (18.0)

      2 (4.0)


      53 (79.1)

      12 (17.9)

      2 (3.0)


      92 (78.6)

      21 (17.9)

      4 (3.4)
      Time since diagnosis, years10.2 ± 6.610.3 ± 5.710.3 ± 6.1
      Duration of OCR treatment, years1.7 ± 0.51.7 ± 0.51.7 ± 0.5
      Infusion interval since previous OCR, weeks35.7 ± 8.536.4 ± 8.836.1 ± 8.6
      - <28 weeks6 (12.0)12 (17.9)18 (15.4)
      - 28–32 weeks14 (28.0)15 (22.4)29 (24.8)
      - 32–36 weeks10 (20.0)9 (13.4)19 (16.2)
      - 36–40 weeks7 (14.0)10 (14.9)17 (14.5)
      - 40–44 weeks6 (12.0)9 (13.4)15 (12.8)
      - ≥44 weeks7 (14.0)12 (17.9)19 (16.2)
      Time since last MRI disease activity, years2.1 [1.5 to 2.5]1.8 [1.2 to 2.7]2.0 [1.4 to 2.6]
      MRI disease activity during OCR treatment11 (22.0)24 (35.8)35 (29.9)
      MRI disease activity between current and previous OCR infusion1 (2.0)5 (7.5)6 (5.0)
      Time since last clinical relapse, years2.5 [1.9 to 4.0]2.8 [2.3 to 5.2]2.7 [2.1 to 4.8]
      Clinical relapse between current and previous OCR infusion0 (0)0 (0)0 (0)
      EDSS score at initiation of OCR therapy4.0 [3.0 to 5.0]3.5 [2.5 to 4.0]3.5 [2.5 to 5.0]
      Current EDSS score
      The EDSS score at the current OCR infusion was the most recent EDSS score extracted from the patient records (n = 96) with a median of 2.6 [−6.4 to 28.3] weeks between current OCR infusion and most recent EDSS score.
      3.8 [2.5 to 5.5]3.5 [2.0 to 4.6]3.5 [2.5 to 5.5]
      CD19 B-cell count 24 weeks after previous OCR infusion (standard interval dosing), cells/µL2.0 [1.0 to 5.8]2.0 [1.0 to 6.0]2.0 [1.0 to 5.5]
      CD19 B-cell count prior to questionnaires
      Median amount of weeks between measurement of last CD19 B-cell count or sNfL level and completion of the first questionnaires were 2.9 [2.0 to 4.0] and 2.9 [1.8 to 4.0] weeks.
      , cells/µL
      21.0 [10.0 to 30.8]17.0 [11.0 to 33.0]18.0 [11.0 to 33.0]
      sNfL levels prior to questionnaires
      Median amount of weeks between measurement of last CD19 B-cell count or sNfL level and completion of the first questionnaires were 2.9 [2.0 to 4.0] and 2.9 [1.8 to 4.0] weeks.
      , pg/mL
      7.1 [6.1 to 9.8]7.9 [5.5 to 11.8]7.6 [5.7 to 10.7]
      Elevated sNfL levels
      Estimated upper reference limits (97.5% percentiles) for serum NfL by ten year age intervals were used to determine whether sNfL levels were normal or elevated. (Hviid et al., 2020) RRMS = relapsing remitting multiple sclerosis; PPMS = primary progressive multiple sclerosis; SPMS = secondary progressive multiple sclerosis; OCR = ocrelizumab; EDSS = expanded disability status scale; sNfL = serum neurofilament light. Values are presented as means ± standard deviation, medians [interquartile range] or frequencies (percentages). p < .01* as tested with the independent samples t-test for normally distributed continuous data.
      1/49 (2.0)3/65 (4.6)4/114 (3.5)
      a Participants were divided into two groups based on the presence of a current wearing-off phenomenon when completing the first questionnaires.
      b Blood volume was calculated using the Nadler formula (for males: 0.3669 * height3 + 0.03219 * weight + 0.6041; for females: 0.3561 * height3 + 0.03308 * weight + 0.1833) (
      • Nadler S.B.
      • Hidalgo J.H.
      • Bloch T.
      Prediction of blood volume in normal human adults.
      ).
      c The EDSS score at the current OCR infusion was the most recent EDSS score extracted from the patient records (n = 96) with a median of 2.6 [−6.4 to 28.3] weeks between current OCR infusion and most recent EDSS score.
      d Median amount of weeks between measurement of last CD19 B-cell count or sNfL level and completion of the first questionnaires were 2.9 [2.0 to 4.0] and 2.9 [1.8 to 4.0] weeks.
      e Estimated upper reference limits (97.5% percentiles) for serum NfL by ten year age intervals were used to determine whether sNfL levels were normal or elevated. (
      • Hviid C.V.B.
      • Knudsen C.S.
      • Parkner T.
      Reference interval and preanalytical properties of serum neurofilament light chain in Scandinavian adults.
      )
      RRMS = relapsing remitting multiple sclerosis; PPMS = primary progressive multiple sclerosis; SPMS = secondary progressive multiple sclerosis; OCR = ocrelizumab; EDSS = expanded disability status scale; sNfL = serum neurofilament light. Values are presented as means ± standard deviation, medians [interquartile range] or frequencies (percentages). p < .01* as tested with the independent samples t-test for normally distributed continuous data.
      Of all participants, 71 (61%) reported the wearing-off phenomenon during their treatment with ocrelizumab (Table 2). The large majority of these participants (73%), reported to experience the wearing-off phenomenon only sometimes, 17% reported its frequency as usually and 10% as always. The most frequently reported wearing-off symptoms were fatigue (62%), cognitive disability (42%), sensory symptoms (39%) and balance problems (38%), although a larger variety of MS-related symptoms were reported (Table 2). Symptoms were mostly rated mild. The wearing-off phenomenon started < 1 week (11%), 1–4 weeks (49%) or more than 4 weeks (37%) before ocrelizumab infusion.
      Table 2Results wearing-off questionnaires.
      Total (N = 117)
      Ever experienced wearing-off phenomenon
      Never46 (39.3)
      Sometimes52 (44.4)
      Usually12 (10.3)
      Always7 (6.0)
      Start wearing-off phenomenon before OCRn = 71
      The answers sometimes (n = 52), often (n = 12) and always (n = 7) from the previous question were combined.
      <1 week before OCR8 (11.3)
      1–4 weeks before OCR35 (49.3)
      > 4 weeks before OCR26 (36.6)
      Not answered2 (2.8)
      Severity of complaints
      Mild37 (52.1)
      Moderate29 (40.8)
      Severe4 (5.6)
      Not answered1 (1.4)
      Reported symptoms
      Fatigue44 (62.0)
      Cognitive disability30 (42.3)
      Sensory symptoms28 (39.4)
      Balance problems27 (38.0)
      Walking difficulties26 (36.6)
      Coordination dysfunction21 (29.6)
      Muscle weakness20 (28.2)
      Bladder problems17 (23.9)
      Pain11 (15.5)
      Other
      Other reported symptoms were spasticity, ocular symptoms, problems with speaking, stiffness, increased falling and headache.
      16 (22.5)
      Wearing-off phenomenon at current OCR infusion
      Fifty participants (70% of participants who ever experienced the wearing-off phenomenon, 43% of total participants) reported the wearing-off phenomenon at the current ocrelizumab infusion. Values are presented as frequencies (percentages). OCR = ocrelizumab.
      Yes50 (70.4)
      No8 (11.3)
      Unsure13 (18.3)
      a The answers sometimes (n = 52), often (n = 12) and always (n = 7) from the previous question were combined.
      b Other reported symptoms were spasticity, ocular symptoms, problems with speaking, stiffness, increased falling and headache.
      c Fifty participants (70% of participants who ever experienced the wearing-off phenomenon, 43% of total participants) reported the wearing-off phenomenon at the current ocrelizumab infusion. Values are presented as frequencies (percentages). OCR = ocrelizumab.
      Fifty participants (43%) reported the wearing-off phenomenon at the current ocrelizumab infusion (Table 2). Characteristics of the different groups are presented in Table 1. BMI of participants with a current wearing-off phenomenon was higher compared to participants without a current wearing-off phenomenon. Mean infusion intervals were comparable between participants with a current wearing-off phenomenon (35.7 ± 8.5 weeks) and participants without a current wearing-off phenomenon (36.4 ± 8.8 weeks). There were no significant differences in EDSS score, MRI disease activity, and clinical relapses (Table 1). CD19 B-cell counts after a mean of 24.5 ± 2.7 weeks (standard interval dosing) and prior to the first questionnaires, as well as sNfL levels prior to the first questionnaires were similar between the groups (Table 1).
      Linearity with a current wearing-off phenomenon was violated for all continuous variables. Therefore, clinically relevant groups (EDSS 0–4.0 and 4.5–10; BMI < 25 and ≥ 25) or quartiles were added to the logistic regression analyses. The forward selection procedure only revealed BMI as a significant predictor for a current wearing-off phenomenon. When adding other variables to the model, no other predictors were found. The odds of a current wearing-off phenomenon was 2.70 (95% CI 1.26 to 5.80, p = .011) for participants with a BMI ≥ 25 compared to participants with a BMI < 25.
      Fig. 2 shows the start of the wearing-off phenomenon before the current ocrelizumab infusion, divided into groups per dosing interval. This figure shows that in the majority of the participants with a current wearing-off phenomenon, the symptoms started 1–4 weeks or >4 weeks before ocrelizumab infusion in all dosing interval groups. No clear increase of duration of the wearing-off phenomenon is seen with EID.
      Fig 2
      Fig. 2Infusion intervals of participants with a current wearing-off phenomenon and start of the wearing-off phenomenon.
      Infusion intervals of participants with a current wearing-off phenomenon are sorted into 6 groups on the x-axis (n = 48/117; two participants with a current wearing-off phenomenon did not complete the question about the start of wearing-off symptoms on the first questionnaire): < 28 weeks (5/18), 28–32 weeks (14/29), 32–36 weeks (10/19), 36–40 weeks (7/17), 40–44 weeks (5/15), ≥44 weeks (7/19). The columns display the amount of participants with a current wearing-off phenomenon per group on the y-axis. The colors indicate the start of the wearing-off phenomenon before ocrelizumab infusion. This figure shows that the wearing-off phenomenon started 1–4 weeks or > 4 weeks before ocrelizumab infusion in the majority of participants with a current wearing-off phenomenon in all infusion interval groups. No clear increase of duration of the wearing-off phenomenon is seen with extended interval dosing. OCR = ocrelizumab.
      Participants with a current wearing-off phenomenon had similar treatment satisfaction as participants without a current wearing-off phenomenon (median score 72.2, IQR [59.7 to 77.8] vs. 69.4, IQR [47.2 to 86.1], p = .22). Disappearance of the wearing-off phenomenon after ocrelizumab infusion occurred direct (12.5%), in the first week (31.3%), after 1–2 weeks (12.5%), or after > 2 weeks (25.0%). Nine (18.8%) participants reported the wearing-off phenomenon on the first questionnaires, but on the follow-up questionnaires did not recall these symptoms. Participants with a current wearing-off symptoms had significantly higher median scores of disability on the MSIS-29 questionnaire during their visit for the ocrelizumab infusion (Table 3). On the follow-up MSIS-29 questionnaire 2–4 weeks thereafter, both the median physical scale score and the median psychological scale score were lower. On the physical scale, 17 (35%) participants with a current wearing-off phenomenon improved with ≥7.5 points vs. 9 (15%) participants without a current wearing-off phenomenon (p = .12).
      Table 3Results MSIS-29 questionnaires.
      Current wearing-off phenomenon

      (n = 50)
      No current wearing-off phenomenon

      (n = 67)
      Total (n = 117)
      Before OCR infusion
      MSIS-29 physical score33.1* [10.9 to 55.3]18.8 [5.0 to 36.3]25.0 [7.5 to 47.5]
      MSIS-29 psychological score25.0** [11.1 to 61.1]13.9 [5.6 to 36.1]19.4 [5.6 to 44.1]
      (n = 48)(n = 61)(n = 109)
      After OCR infusion
      MSIS-29 physical score27.5† [5.3 to 45.3]23.8 [7.5 to 45.6]25.0 [6.9 to 44.4]
      Delta physical score−4.4*** [−10.9 to 1.3]1.3 [−1.9 to 6.3]0.0 [−6.3 to 4.2]
      MSIS-29 psychological score20.8† [9.0 to 47.2]19.4 [8.3 to 36.1]19.4 [8.3 to 37.5]
      Delta psychological score−1.4** [−11.1 to 2.8]0.0 [−2.8 to 6.9]0.0 [−8.3 to 3.3]
      Values are presented as medians [interquartile range]. MSIS-29 = Multiple Sclerosis Impact Scale; OCR = ocrelizumab.
      p < .05* as tested with the Mann-Whitney U test between groups.
      p < .01** as tested with the Mann-Whitney U test between groups.
      p < .001*** as tested with the Mann-Whitney U test between groups.
      p < .01† as tested with the Wilcoxon Signed Ranks test within groups before and after ocrelizumab infusion.
      After ocrelizumab infusion, 40 (37%) of 109 participants reported symptoms not present before infusion such as fatigue, flu-like symptoms and walking difficulties (Table 4). These post-infusion symptoms started directly or in the first week after ocrelizumab infusion and disappeared within 2 weeks (Table 4).
      Table 4Symptoms after ocrelizumab infusion.
      Total (N = 109)
      Symptoms after current OCR infusion
      Yes40 (36.7)
      No69 (63.3)
      n = 40
      Start symptoms after OCR
      Direct21 (52.5)
      < 1 week after OCR16 (40)
      1–2 weeks after OCR3 (7.5)
      > 2 weeks after OCR0 (0)
      Severity of complaints
      Mild21 (52.5)
      Moderate17 (42.5)
      Severe2 (5.0)
      Reported symptoms
      Fatigue30 (75)
      Walking difficulties10 (25)
      Cognitive disability8 (20)
      Sensory symptoms6 (15)
      Balance problems6 (15)
      Muscle weakness6 (15)
      Coordination dysfunction5 (12.5)
      Pain5 (12.5)
      Bladder problems2 (5)
      Other
      Other symptoms were flu-like symptoms, headache, nausea, shortness of breath, increased emotional reaction, upper airway irritation, hair loss and diarrhea. Values are presented as frequencies (percentages). OCR = ocrelizumab.
      17 (42.5)
      Disappearance symptoms
      < 1 week after OCR16 (40)
      1–2 weeks after OCR11 (27.5)
      > 2 weeks after OCR13 (32.5)
      a Other symptoms were flu-like symptoms, headache, nausea, shortness of breath, increased emotional reaction, upper airway irritation, hair loss and diarrhea. Values are presented as frequencies (percentages). OCR = ocrelizumab.

      4. Discussion

      We studied the wearing-off phenomenon of ocrelizumab in patients with MS and showed that a majority (61%) of participants report these end of cycle symptoms. The most frequently reported symptom was fatigue, comparable to the natalizumab wearing-off phenomenon. (
      • van Kempen Z.L.E.
      • Doesburg D.
      • Dekker I.
      • et al.
      The natalizumab wearing-off effect: end of natalizumab cycle, recurrence of MS symptoms.
      ;
      • Bringeland G.H.
      • Blaser N.
      • Myhr K.M.
      • et al.
      Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy.
      ;
      • Catherine D.
      • Annelien P.
      • Anne S.
      • et al.
      End of dose interval symptoms in patients treated with natalizumab: a role for serum cytokines?.
      ;
      • Ratchford J.N.
      • Brock-Simmons R.
      • Augsburger A.
      • et al.
      Multiple sclerosis symptom recrudescence at the end of the natalizumab dosing cycle.
      ) Most participants received EID of ocrelizumab based on CD19 B-cell counts to limit ocrelizumab exposure during the COVID-19 pandemic (cut-off ≥ 10 cells/µL). Mean duration between infusions was 36.1 ± 8.6 weeks. MRI disease activity, clinical relapses, EDSS score, infusion interval, CD19 B-cell counts and sNfL levels were no predictors of a current wearing-off phenomenon, suggesting this phenomenon is probably not reflected by decreased efficacy of ocrelizumab or inflammation-induced axonal damage affecting standard clinical trial measures. Treatment satisfaction was similar between the groups. Participants with a current wearing-off phenomenon significantly improved in self-reported physical and psychological functioning after ocrelizumab infusion. Nevertheless, the differences in median scores were small and only reflected a clinically significant improvement on the physical scale (≥ 7.5 points) in 35% of participants with a current wearing-off phenomenon. (
      • Phillips G.A.
      • Wyrwich K.W.
      • Guo S.
      • et al.
      Responder definition of the multiple sclerosis impact scale physical impact subscale for patients with physical worsening.
      )
      We found that higher BMI was a predictor for a current wearing-off phenomenon, in line with findings of the natalizumab wearing-off phenomenon. (
      • van Kempen Z.L.E.
      • Doesburg D.
      • Dekker I.
      • et al.
      The natalizumab wearing-off effect: end of natalizumab cycle, recurrence of MS symptoms.
      ;
      • Bringeland G.H.
      • Blaser N.
      • Myhr K.M.
      • et al.
      Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy.
      ) In ocrelizumab treated patients, an increase in body weight was associated with lower ocrelizumab concentrations and higher repopulation of B cells. (
      • Gibiansky E.
      • Petry C.
      • Mercier F.
      • et al.
      Ocrelizumab in relapsing and primary progressive multiple sclerosis: pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO.
      ) In our study, CD19 B-cell count prior to the questionnaires and infusion interval were no relevant predictors of the wearing-off phenomenon. Regarding the natalizumab wearing-off phenomenon, opposing results were reported between wearing-off symptoms and low receptor occupancy in patients with higher BMI. (
      • Bringeland G.H.
      • Blaser N.
      • Myhr K.M.
      • et al.
      Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy.
      ) (
      • Catherine D.
      • Annelien P.
      • Anne S.
      • et al.
      End of dose interval symptoms in patients treated with natalizumab: a role for serum cytokines?.
      )  A positive correlation between BMI and EDSS score with increased cerebrospinal fluid levels of pro-inflammatory molecules and reduced anti-inflammatory cytokines was reported in patients with relapsing remitting MS with a BMI > 30. (
      • Stampanoni Bassi M.
      • Iezzi E.
      • Buttari F.
      • et al.
      Obesity worsens central inflammation and disability in multiple sclerosis.
      ) Higher overall clinical disability in obese patients with MS could also explain why these patients experience more MS-related symptoms. Since the cause of the wearing-off phenomenon is not evident, improvement after ocrelizumab treatment may reflect a placebo effect. (
      • van Kempen Z.L.E.
      • Doesburg D.
      • Dekker I.
      • et al.
      The natalizumab wearing-off effect: end of natalizumab cycle, recurrence of MS symptoms.
      )
      EID is rapidly evolving for patients using monoclonal antibodies. (
      • Barun B.
      • Gabelić T.
      • Adamec I.
      • et al.
      Influence of delaying ocrelizumab dosing in multiple sclerosis due to COVID-19 pandemics on clinical and laboratory effectiveness.
      ;
      • van Kempen Z.L.E.
      • Hoogervorst E.L.J.
      • Wattjes M.P.
      • et al.
      Personalized extended interval dosing of natalizumab in MS: a prospective multicenter trial.
      ;
      • van Lierop Z.Y.
      • Toorop A.A.
      • van Ballegoij W.J.
      • et al.
      Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic.
      ;
      • Tazza F.
      • Lapucci C.
      • Cellerino M.
      • et al.
      Personalizing ocrelizumab treatment in Multiple Sclerosis: what can we learn from Sars-Cov2 pandemic?.
      ;
      • Rolfes L.
      • Pawlitzki M.
      • Pfeuffer S.
      • et al.
      Ocrelizumab extended interval dosing in multiple sclerosis in times of COVID-19.
      )  Recently, patients using ocrelizumab received personalized EID at our center to limit ocrelizumab exposure and hospital visits during the COVID-19 pandemic. (
      • van Lierop Z.Y.
      • Toorop A.A.
      • van Ballegoij W.J.
      • et al.
      Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic.
      ) Median interval until re-dosing or last B-cell count was 34 [30–38] weeks. No increase in short-term disease activity was found with EID of ocrelizumab in this cohort. In the current study, a longer infusion interval was no relevant predictor of the wearing-off phenomenon. Since most of the participants (85%) in this study received personalized EID of ocrelizumab, no definite conclusion can be drawn whether EID causes a longer duration of the wearing-off phenomenon compared to standard interval dosing.
      This study has several strengths. It is the first study reporting about the wearing-off phenomenon in patients with MS using ocrelizumab. Furthermore, the group of well-documented participants treated with ocrelizumab at our MS center is relatively large. We differentiated between participants with and without a current wearing-off phenomenon to study the relation with other variables and laboratory measurements such as CD19 B-cell counts and sNfL more precisely. Participants receiving personalized EID of ocrelizumab were reported as well.
      There are also limitations that need to be discussed. First, the observational design can cause a selection bias. Since most of the participants using ocrelizumab who were eligible for inclusion at our center were included (84%), we estimate this bias is relatively small. Second, measurements of CD19 B-cell counts and sNfL levels prior to re-dosing were performed 2.9 weeks before completion of the first questionnaires. This difference can possibly influence the associations that were analyzed as CD19 B-cell counts and sNfL levels vary over time. Third, some participants (n = 9/109, 8.3%) reported the wearing-off phenomenon on the first questionnaire, but on the questionnaire 2–4 weeks later did not recall these symptoms. This recall bias can influence the results on the follow-up questionnaires. In addition, some participants were probably more aware of MS-related symptoms after receiving information about this study before completing the questionnaires.
      In conclusion, the wearing-off phenomenon in patients with MS using ocrelizumab occurs frequently. The wearing-off phenomenon was not elicited by EID, MRI disease activity, clinical relapses or higher B-cell counts, but was more frequent in patients with a higher BMI. The ocrelizumab wearing-off phenomenon therefore does not seem to reflect suboptimal control of MS disease activity.

      Declaration of Competing Interest

      AAT, ZYGJL, EMMS, ZLEK report no competing interests. CET has served on advisory boards for Roche, has received nonfinancial support in the form of research consumables from ADx NeuroSciences and Euroimmun, and has performed contract research or received grants from Probiodrug, Biogen, Esai, Toyama, Janssen Prevention Center, Boehringer, Axon Neuroscience, EIP Pharma, PeopleBio, and Roche. FB reports other from Neurology, other from Radiology, other from MSJ, other from Neuroradiology, personal fees from Springer, personal fees and other from Bayer, personal fees from Biogen, grants from Roche, grants from Merck, grants from Biogen, personal fees from IXICO Ltd, other from GeNeuro, grants from IMI-EU, grants from GE Healthcare, grants from UK MS Society, grants from Dutch Foundation MS Research, grants from NWO, grants from NIHR, personal fees from Combinostics,  outside the submitted work. BMJU reports personal fees from Genzyme, Biogen Idec, Teva Pharmaceutical Industries, Merck Serono, and Roche.  JK has accepted speaker and consulting fees from Merck Serono, Biogen, Roche, Teva Pharmaceutical Industries, Genzyme, and Novartis.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      CRediT authorship contribution statement

      A.A. Toorop: Conceptualization, Data curation, Investigation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Z.Y.G.J. van Lierop: Data curation, Investigation, Writing – review & editing. E.M.M. Strijbis: Writing – review & editing. C.E. Teunissen: Methodology, Validation, Writing – review & editing. F. Barkhof: Methodology, Validation, Writing – review & editing. B.M.J. Uitdehaag: Writing – review & editing. Z.L.E. van Kempen: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. J. Killestein: Conceptualization, Supervision, Writing – original draft, Writing – review & editing.

      Appendix. Supplementary materials

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