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Influence of delaying ocrelizumab dosing in multiple sclerosis due to COVID-19 pandemics on clinical and laboratory effectiveness

Published:December 21, 2020DOI:https://doi.org/10.1016/j.msard.2020.102704

      Highlights

      • We found no clinical consequences of delaying ocrelizumab due to COVID-19 pandemics.
      • Positive correlation between the time of lymphocyte sampling and levels of CD19+ B cells was found for patients who received only one prior ocrelizumab cycle.
      • The delay in dosing of ocrelizumab was an independent predictor of repopulation of B cells.

      Abstract

      Objective

      To evaluate clinical and laboratory effects of delaying ocrelizumab infusions during the COVID-19 pandemics in people with multiple sclerosis (pwMS).

      Methods

      We have retrospectively searched our electronic database and identified 33 pwMS who had a delay in treatment due to COVID-19 pandemics. The following data were extracted: age, sex, multiple sclerosis (MS) phenotype: relapsing-remitting (RRMS) or primary progressive multiple sclerosis (PPMS), disease duration, Expanded Disability Status scale (EDSS), previous disease modifying therapy (DMT), number of ocrelizumab cycles prior to the lockdown, dates of first ocrelizumab infusion, last ocrelizumab infusion prior to the lockdown and delayed ocrelizumab infusion after the lockdown. Flow cytometry results, relapses and EDSS progression prior to the delayed ocrelizumab infusion after the lockdown were extracted.

      Results

      The mean time between two ocrelizumab infusion during the lockdown was 7.72±0.64 (range 6.07 to 8.92) months. The mean time between last ocrelizumab infusion and the lymphocyte sampling prior to post COVID infusion was 6.59±0.95 (range 5.18 to 8.49) months. In this period, none of the studied patients had a relapse. In a multivariable linear regression analysis, time from last ocrelizumab infusion to lymphocyte sampling prior to the next infusion was the only significant predictor for CD19+ B cells count, when corrected for the number of previous ocrelizumab cycles and MS phenotype (RRMS or PPMS) (B=7.981, 95% C.I. 3.277-12.686, p=0.002).

      Conclusions

      We have not shown clinical consequences of delaying ocrelizumab due to COVID-19 pandemics. However, the delay in dosing of ocrelizumab was an independent predictor of repopulation of B cells.

      Keywords

      Introduction

      Ocrelizumab is a humanized anti-CD20 monoclonal antibody approved for the treatment of adults with relapsing-remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis (PPMS). (
      • Syed YY.
      Ocrelizumab: A Review in Multiple Sclerosis.
      ) Ocrelizumab binds to CD20 and selectively depletes CD20-expressing B cells through antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, and apoptosis. (
      • Sorensen PS
      • Blinkenberg M.
      The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects.
      ) In people with RRMS, ocrelizumab has significantly reduced annualized relapse rates, while in people with PPMS, ocrelizumab significantly reduced the risk of ≥ 12-week confirmed disability progression. (
      • Hauser SL
      • Bar-Or A
      • Comi G
      • Giovannoni G
      • Hartung HP
      • Hemmer B
      • Lublin F
      • Montalban X
      • Rammohan KW
      • Selmaj K
      • Traboulsee A
      • Wolinsky JS
      • Arnold DL
      • Klingelschmitt G
      • Masterman D
      • Fontoura P
      • Belachew S
      • Chin P
      • Mairon N
      • Garren H
      Kappos L; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.
      ,
      • Montalban X
      • Hauser SL
      • Kappos L
      • Arnold DL
      • Bar-Or A
      • Comi G
      • de Seze J
      • Giovannoni G
      • Hartung HP
      • Hemmer B
      • Lublin F
      • Rammohan KW
      • Selmaj K
      • Traboulsee A
      • Sauter A
      • Masterman D
      • Fontoura P
      • Belachew S
      • Garren H
      • Mairon N
      • Chin P
      • Wolinsky JS
      ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis.
      )
      As ocrelizumab's mechanism of action is closely associated with depletion of B lymphocytes, it has been suggested that B-cell repopulation latency may serve as surrogate marker for individualized treatment strategies in people with MS (pwMS). (
      • Ellrichmann G
      • Bolz J
      • Peschke M
      • Duscha A
      • Hellwig K
      • Lee DH
      • Linker RA
      • Gold R
      • Haghikia A.
      Peripheral CD19+ B-cell counts and infusion intervals as a surrogate for long-term B-cell depleting therapy in multiple sclerosis and neuromyelitis optica/neuromyelitis optica spectrum disorders.
      ) This may have significant implications on the effectiveness of treatment during the COVID-19 pandemics when many, especially second line disease modifying therapies (DMTs), have been postponed or delayed either due to COVID-19 infection in an individual patient or due to the worsening epidemiological situation in certain areas of the world. Furthermore, most of the international and national recommendations regarding DMT management during the COVID-19 pandemic, including recommendation from the Croatian neurological society, initially recommended considering the delay of dosing for cell-depleting therapies, including CD20 monoclonal antibodies. (
      • Thakolwiboon S
      • Zhao-Fleming H
      • Pan J
      • Scott JK
      • Shoji E
      • Sohn G
      • Avila M.
      Disease-Modifying Therapies During the COVID-19 Outbreak: A Narrative Review of International and National Recommendations.
      )
      Therefore, the aim of this study was to evaluate clinical and laboratory effects of delaying ocrelizumab infusions during the COVID-19 pandemics.

      Methods

      Patients

      All pwMS treated with ocrelizumab according to the local reimbursement guidelines at the University Hospital Center Zagreb were eligible for the study. The criteria for reimbursement for RRMS include only patients who failed 1st line treatment (interferons, glatiramer acetate, teriflunomide or dimethyl fumarate) or patients who had adverse event on any of the 2nd line treatments (natalizumab, fingolimod, alemtuzumab, cladribine). The diagnosis of PPMS and Expanded Disability Status scale (EDSS) <6.5 are criteria for the reimbursement of ocrelizumab in pwPPMS.
      All patients received ocrelizumab 600 mg every 6 months (two 300 mg infusions 14 days apart for the first dose and a single 600 mg infusion thereafter).
      The laboratory work-up before each scheduled ocrelizumab infusion consisted of complete blood count (CBC), IgG, IgM and IgA levels and flow cytometry data (CD4+, CD8+ and CD19+ lymphocytes) performed at least 2 weeks prior to ocrelizumab infusion.
      The first case of documented COVID-19 case in Croatia occurred in February 2020 (), and very soon Croatian neurological society issued recommendations on the use of disease-modifying therapies in MS during the COVID-19 pandemics. (
      • Adamec I
      • Barun B
      • Gabelić T
      • Habek M.
      Preporuke o uzimanju lijekova koji modificiraju tijek bolesti u osoba s multiplom sklerozom u uvjetima epidemije koronavirusa.
      ) These guidelines recommended delaying the next ocrelizumab infusion during the pandemics, which resulted in stopping all ocrelizumab infusions in the period from March 16th to April 30th 2020.
      We have retrospectively searched our electronic database and identified all patients who had a delay in treatment due to COVID-19 pandemics. The following data were extracted: age, sex, MS phenotype (RRMS or PPMS), disease duration, EDSS, previous DMT, number of ocrelizumab cycles prior to the lockdown, dates of first ocrelizumab infusion, last ocrelizumab infusion prior to the lockdown and delayed ocrelizumab infusion after the lockdown. Furthermore, flow cytometry results, relapses and EDSS progression prior the delayed ocrelizumab infusion after the lockdown were extracted.

      Flow cytometry

      The four-color flow cytometry analysis of peripheral blood samples was carried out by staining the cells with appropriate fluorochrome-conjugated antibodies in two separate tubes, one for T and one for B cells. The antibodies used were CD20-FITC (clone L27), CD45-PerCP (clone 2D1), CD19-APC (clone SJ25C1), CD8-FITC (clone SK1), CD4 -PE (clone SK3) and CD3-APC (clone SK7) purchased from BD Biosciences (San Jose, USA). One hundred microliters of whole blood per tube were stained for 15 min with fluorochrome-conjugated antibodies according to manufacturer's recommendations and were afterwards incubated for 10 min with BD FACS Lysing solution for lysing red blood cells (BD Biosciences, San Jose, USA). Finally, leukocytes were washed in phosphate-buffered saline (PBS) and resuspended in 300 μL of PBS. The FACS Lyric (BD Biosciences, San Jose, USA) was used for acquisition of samples and data were analyzed by FACSuite ver1.2 software (BD Biosciences, San Jose, USA). The absolute count of lymphocyte subsets (per μL of blood) was obtained by using absolute lymphocyte count (ALC) derived from the hematological analyzer Sysmex XN-3000 (Sysmex Corporation, Kobe, Japan).

      Outcomes

      The primary outcome was to investigate clinical effectiveness by assessing whether delaying ocrelizumab infusions has an impact on
      • a)
        Occurrence of relapse and
      • b)
        EDSS progression.
      The secondary outcomes were to investigate laboratory effectiveness by assessing whether delaying ocrelizumab infusions has an impact on:
      • a)
        Repopulation of CD19+ B cells
      • b)
        Repopulation of CD19+ B cells depending on the number of prior ocrelizumab infusions
      • c)
        To investigate possible predictors of CD19+ B cells count prior to next ocrelizumab infusion

      Statistical analysis

      Statistical analysis was performed with IBM SPSS 25 software. Due to relatively small number of participants, the differences between the two groups were assessed using the Mann-Whitney test, and the associations between the groups were determined with the Spearman's correlation analysis. Univariable and multivariable linear regression analysis was performed to determine which variables are independent predictors of the count of the CD19+ B cells. P values of less than 0.5 were regarded as statistically significant.

      Results

      The electronic database retrieved 33 pwMS which fulfilled the inclusion criteria. The flow-chart of the study is provided in Figure 1. As some of the patients had flow cytometry performed in a period of 2 weeks prior to the lockdown, a 6.5 months delay in the laboratory was set as a cut-off value for further analysis. Demographic characteristics of the cohort are presented in Table 1.
      Table 1Demographic characteristics of the cohort.
      Age42.2±10.4
      Sex (females)22 (66.7%)
      MS phenotype
      RRMS23 (69.7%)
      PPMS10 (30.3%)
      Disease duration (years)10.24±7.12
      EDSS4.5 (0-8.0)
      Previous DMTs
      Treatment naïve8 (24.2%)
      1 previous DMT16 (48.5%)
      2previous DMTs6 (18.2%)
      ≥3previous DMTs3 (9.1%)
      Previous DMTs
      1st line injectables19 (57.6%)
      1st line orals7 (21.2%)
      Fingolimod4 (12.1%)
      Natalizumab2 (6.1%)
      Alemtuzumab1 (3.0%)
      Number of ocrelizumab cycles prior to the lockdown
      114 (42.4%)
      212 (36.4%)
      36 (18.2%)
      51 (3.0%)

      Primary outcomes

      The mean time between two ocrelizumab infusion during the lockdown was 7.72±0.64 (range 6.07 to 8.92) months. The mean time between last ocrelizumab infusion and the lymphocyte sampling prior to post COVID infusion was 6.59±0.95 (range 5.18 to 8.49) months.
      In this period, none of the studied patients had a relapse. As well, none of the patients experienced worsening of the EDSS in the studied period.

      Secondary outcomes

      In 13 pwMS, CD19+ B cell counts were determined in the period of <6.5 months and in 20 patients they were determined in the period of ≥6.5 months after the prior ocrelizumab infusion (Figure 1). In 20 patients, in which CD19+ B cell counts were determined in the period of ≥6.5 months after the prior ocrelizumab infusion, we found no correlation between time of delay and number of CD19+ B cells (rs=0.191, p=0.420). The graphical presentation of CD19+ counts depending on the time of the delay is presented in Figure 2.
      Figure 2
      Figure 2Graphical presentation of CD19+ counts depending on the time of the delay.
      We than divided the pwMS in the group which received 2nd cycle (Group 1) and group which received 3rd or subsequent cycle (Group 2). Values of CD19+ lymphocytes depending on the cycle and time of sampling (<6.5 months vs ≥6.5 months after the prior ocrelizumab infusion) are presented in the Table 2. Group 2 had a statistically significant higher levels of CD19+ lymphocytes, if measured ≥6.5 months after the last ocrelizumab infusion. For the group who received only 1 prior cycle of ocrelizumab infusion and who had the time of lymphocyte sampling of ≥6.5 months (7 patients), we found positive correlation between the time of lymphocyte sampling and levels of CD19+ B cells (rs=0.847, p=0.016). No correlation was found between the time of lymphocyte sampling and the levels of CD19+B cells for patients who received 3rd or subsequent cycle if measured ≥6.5 months after the prior ocrelizumab infusion (rs=-0.148, p=0.630).
      Table 2Comparison of values of CD19+ B cells for Group 1 (2nd cycle) and Group 2 (≥3rd cycle) depending on the time of sampling (<6.5 months vs ≥6.5 months after the prior ocrelizumab infusion).
      Ocrelizumab cycleTime of samplingCD19+ cells/μL, median (range)p value
      2nd<6.5 months0 (0-3)0.053
      ≥6.5 months7 (0-62)
      ≥3rd<6.5 months0 (0-3)0.012
      ≥6.5 months9 (0-35)
      In order to investigate possible predictors of CD19+ B cell count, univariable and multivariable linear regression analyses were performed (Table 3). Time from last ocrelizumab infusion to lymphocyte sampling prior to the next infusion was the only significant predictor for CD19+ B cell count in a univariable linear regression analysis. In a multivariable linear regression analysis, this finding persisted when corrected for the number of previous ocrelizumab cycles and MS phenotype (RRMS or PPMS).
      Table 3Results of the univariable and multivariable linear regression model.
      Univariable linear regressionMultivariable linear regression
      B95% C.I. for Bp valueB95% C.I. for Bp value
      CD19+ B cell counts
      Age0.079-0.412-0.5700.746
      Sex-0.409-11.102-10.2830.938
      EDSS1.081-1.654-3.8170.426
      MS phenotype (RRMS or PPMS)-2.491-13.422-8.4400.645-1.562-11.110-7.9850.740
      Number of previous Ocrelizumab cycles (1 or >1)-0.135-10.335-10.0640.979-0.148-9.012-8.7150.973
      CD19+ B cells count prior to the last ocrelizumab cycle-0.007-0.060-0.0460.784
      Time from last ocrelizumab infusion to lymphocyte sampling prior to the next infusion8.0253.486-12.5640.0017.9813.277-12.6860.002

      Discussion

      Although delaying the next ocrelizumab dose did not have any effect on the relapses and EDSS progression, we have found significant effect on the repopulation of B cells. Similar finding was observed in a study which investigated the repopulation rate of peripheral CD19+ B cells as a potential surrogate marker for individual application intervals in pwMS and neuromyelitis optica spectrum disorders treated with rituximab, another anti-CD20 monoclonal antibody. (
      • Ellrichmann G
      • Bolz J
      • Peschke M
      • Duscha A
      • Hellwig K
      • Lee DH
      • Linker RA
      • Gold R
      • Haghikia A.
      Peripheral CD19+ B-cell counts and infusion intervals as a surrogate for long-term B-cell depleting therapy in multiple sclerosis and neuromyelitis optica/neuromyelitis optica spectrum disorders.
      ) Despite the fact that the therapeutic effect in their cohort has been closely associated with the absence of CD19+ B cells, no correlation between B cell counts at the time-point of reinfusion and clinical course or MRI outcome in patients in whom relapses did occur were observed. (
      • Ellrichmann G
      • Bolz J
      • Peschke M
      • Duscha A
      • Hellwig K
      • Lee DH
      • Linker RA
      • Gold R
      • Haghikia A.
      Peripheral CD19+ B-cell counts and infusion intervals as a surrogate for long-term B-cell depleting therapy in multiple sclerosis and neuromyelitis optica/neuromyelitis optica spectrum disorders.
      ) However, given the large inter-individual range of B cell recovery time, authors suggest that the CD19+ B-cell repopulation rate may serve as surrogate marker to appraise individually adapted therapy intervals. (
      • Ellrichmann G
      • Bolz J
      • Peschke M
      • Duscha A
      • Hellwig K
      • Lee DH
      • Linker RA
      • Gold R
      • Haghikia A.
      Peripheral CD19+ B-cell counts and infusion intervals as a surrogate for long-term B-cell depleting therapy in multiple sclerosis and neuromyelitis optica/neuromyelitis optica spectrum disorders.
      ) This is supported by the results of the recently published study which showed that the memory B cell–based rituximab reinfusion protocol is able to reduce the mean number of rituximab reinfusions with persistent reduction of disease activity. (
      • Novi G
      • Bovis F
      • Fabbri S
      • Tazza F
      • Gazzola P
      • Maietta I
      • Currò D
      • Bruschi N
      • Roccatagliata L
      • Boffa G
      • Lapucci C
      • Pesce G
      • Cellerino M
      • Solaro C
      • Laroni A
      • Capello E
      • Mancardi G
      • Sormani M
      • Inglese M
      • Uccelli A.
      Tailoring B cell depletion therapy in MS according to memory B cell monitoring.
      ) Similar findings are observed in the present study, where we have not found increased occurrence of relapses despite higher repopulation of B cells.
      Treatment regiments differ between rituximab and ocrelizumab, with ocrelizumab treatment having fixed 6 months intervals with a long-lasting depletive effect. Repopulation of B cells is defined when CD19+ cells reach 1% of lymphocyte counts, after which a rapid increase occurs. (
      • Pellkofer HL
      • Krumbholz M
      • Berthele A
      • Hemmer B
      • Gerdes LA
      • Havla J
      • Bittner R
      • Canis M
      • Meinl E
      • Hohlfeld R
      • Kuempfel T.
      Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab.
      ,
      • Yang CS
      • Yang L
      • Li T
      • Zhang DQ
      • Jin WN
      • Li MS
      • Su N
      • Zhangning N
      • Liu Q
      • Shao ZH
      • Yu C
      • Shi FD.
      Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis optica.
      ) The median time to B-cell replenishment for ocrelizumab is about 62 weeks after 3 treatment cycles and 72 weeks after 4 treatment cycles. (
      • Baker D
      • Roberts CAK
      • Pryce G
      • Kang AS
      • Marta M
      • Reyes S
      • Schmierer K
      • Giovannoni G
      • Amor S
      COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.
      ,

      Kappos L, Li D, Calabresi PA, et al. Long-term safety and efficacy of ocrelizumab in patients with relapsing-remitting multiple sclerosis: week 144 results of a phase II, randomised, multicentre trial [abstract no. P362 and poster]. Presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 11 October 2012, Lyon, France.

      ) In contrast, in rituximab-treated patients, B-cell repopulation has considerable intraindividual variation which may be a consequence of different regiments applied, with average intervals being 8.3 months. (
      • Ellwardt E
      • Ellwardt L
      • Bittner S
      • Zipp F.
      Monitoring B-cell repopulation after depletion therapy in neurologic patients.
      ) Studies investigating repopulation of B cells in ocrelizumab treated patients are scarce. A recently published study observed a significant depletion of CD19+ cells after six months and one year of treatment, but an incomplete depletion was detected in 41.8% of patients and in 24% of patients a significant reappearance of this B cells (2%) has been achieved. (
      • Signoriello E
      • Bonavita S
      • Di Pietro A
      • Abbadessa G
      • Rossi F
      • Miele G
      • Casertano S
      • Lus G.
      BMI influences CD20 kinetics in multiple sclerosis patients treated with ocrelizumab.
      ) One of the factors that may be responsible for these variations in repopulation of CD19+ cells identified in this study is body mass index.
      The COVID-19 pandemic has created concerns about immunosuppression in pwMS, leading to cessation or a delay in disease modifying treatments. Although most reports suggest that DMTs should not necessarily expose people to severe SARS-CoV-2-related issues, recently presented data has shown that compared with dimethyl fumarate, rituximab was associated with significantly higher risk of hospitalization, ICU admission, and ventilation. (

      Simpson-Yap S, De Brouwer E, Kalincik T, Rijke N, Hillert J, Walton C, Edan G, Moreau Y, Spelman T, Geys L, Parciak T, Gautrais C, Lazovski N, Pirmani A, Ardeshirdavani A, Forsberg L, Glaser A, McBurney R, Schmidt H, Bergmann A, Braune S, Stahmann A, Middleton R, Salter A, Van Der Walt A, Rojas J, Van Der Mei I, Ivanov R, Sciascia Do Olival G, Dias A, Magyari M, Brum D, Mendes M, Alonso R, Nicholas R, Bauer J, Chertcoff A, Zabalza A, Arrambide G, Comi G, Peeters L. First results of the COVID-19 in MS Global Data Sharing Initiative suggest anti-CD20 DMTs are associated with worse COVID-19 outcomes" MSVirtual 2020 Encore; Abstract SS02.04.

      ) Weaker but similar associations were seen for ocrelizumab, although these did not always reach statistical significance. Another potential problem with B-cell depleting therapies is formation of protective immunity following infections and vaccination. (
      • Baker D
      • Roberts CAK
      • Pryce G
      • Kang AS
      • Marta M
      • Reyes S
      • Schmierer K
      • Giovannoni G
      • Amor S
      COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.
      ) Whether extended interval dosing or dosing interruption to allow vaccination, without compromising effectiveness, remains to be investigated.
      The main limitations of this study are small number of participants and lack of MRI data. A study correlating MRI activity with repopulation of B cells would be of great interest.
      In conclusion, we have not shown clinical consequences of delaying ocrelizumab due to COVID-19 pandemics. However, the delay in dosing of ocrelizumab was an independent predictor of repopulation of B-cells. Potential long-term clinical consequences of this association remain to be determined.

      Authors’ contributions

      Study concept and design: Habek. Acquisition of data: Barun, Gabelić, Adamec, Babić, Lalić, Batinić, Krbot Skorić, Habek. Analysis and interpretation of data: Barun, Gabelić, Adamec, Babić, Lalić, Batinić, Krbot Skorić, Habek. Drafting of the manuscript: Krbot Skorić, Habek. Critical revision of the manuscript for important intellectual content: Barun, Gabelić, Adamec, Babić, Lalić, Batinić, Krbot Skorić, Habek. Administrative, technical, and material support: Barun, Gabelić, Adamec, Babić, Lalić, Batinić, Krbot Skorić, Habek.
      Financial & competing interest disclosure
      BB: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals.
      TG: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.
      IA: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.
      AB: Reports no conflict of interest.
      HL: Reports no conflict of interest.
      DB: Reports no conflict of interest.
      MKS: received consultation and/or speaker fees from: Sanofi Genzyme, Roche.
      MH: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.

      Funding

      No funding was received for this study.

      References

        • Syed YY.
        Ocrelizumab: A Review in Multiple Sclerosis.
        CNS Drugs. 2018; 32: 883-890
        • Sorensen PS
        • Blinkenberg M.
        The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects.
        Ther Adv Neurol Disord. 2016; 9: 44-52
        • Hauser SL
        • Bar-Or A
        • Comi G
        • Giovannoni G
        • Hartung HP
        • Hemmer B
        • Lublin F
        • Montalban X
        • Rammohan KW
        • Selmaj K
        • Traboulsee A
        • Wolinsky JS
        • Arnold DL
        • Klingelschmitt G
        • Masterman D
        • Fontoura P
        • Belachew S
        • Chin P
        • Mairon N
        • Garren H
        Kappos L; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.
        N Engl J Med. 2017; 376: 221-234
        • Montalban X
        • Hauser SL
        • Kappos L
        • Arnold DL
        • Bar-Or A
        • Comi G
        • de Seze J
        • Giovannoni G
        • Hartung HP
        • Hemmer B
        • Lublin F
        • Rammohan KW
        • Selmaj K
        • Traboulsee A
        • Sauter A
        • Masterman D
        • Fontoura P
        • Belachew S
        • Garren H
        • Mairon N
        • Chin P
        • Wolinsky JS
        ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis.
        N Engl J Med. 2017; 376: 209-220
        • Ellrichmann G
        • Bolz J
        • Peschke M
        • Duscha A
        • Hellwig K
        • Lee DH
        • Linker RA
        • Gold R
        • Haghikia A.
        Peripheral CD19+ B-cell counts and infusion intervals as a surrogate for long-term B-cell depleting therapy in multiple sclerosis and neuromyelitis optica/neuromyelitis optica spectrum disorders.
        J Neurol. 2019; 266: 57-67
        • Thakolwiboon S
        • Zhao-Fleming H
        • Pan J
        • Scott JK
        • Shoji E
        • Sohn G
        • Avila M.
        Disease-Modifying Therapies During the COVID-19 Outbreak: A Narrative Review of International and National Recommendations.
        Int J MS Care. 2020; 22: 151-157
      1. https://www.hzjz.hr/priopcenja-mediji/koronavirus-najnoviji-podatci/, accessed on October 2, 2020.

        • Adamec I
        • Barun B
        • Gabelić T
        • Habek M.
        Preporuke o uzimanju lijekova koji modificiraju tijek bolesti u osoba s multiplom sklerozom u uvjetima epidemije koronavirusa.
        Medix. 2020; 26: 1-3
        • Novi G
        • Bovis F
        • Fabbri S
        • Tazza F
        • Gazzola P
        • Maietta I
        • Currò D
        • Bruschi N
        • Roccatagliata L
        • Boffa G
        • Lapucci C
        • Pesce G
        • Cellerino M
        • Solaro C
        • Laroni A
        • Capello E
        • Mancardi G
        • Sormani M
        • Inglese M
        • Uccelli A.
        Tailoring B cell depletion therapy in MS according to memory B cell monitoring.
        Neurol Neuroimmunol Neuroinflamm. 2020; 7: e845
        • Pellkofer HL
        • Krumbholz M
        • Berthele A
        • Hemmer B
        • Gerdes LA
        • Havla J
        • Bittner R
        • Canis M
        • Meinl E
        • Hohlfeld R
        • Kuempfel T.
        Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab.
        Neurology. 2011; 76: 1310-1315
        • Yang CS
        • Yang L
        • Li T
        • Zhang DQ
        • Jin WN
        • Li MS
        • Su N
        • Zhangning N
        • Liu Q
        • Shao ZH
        • Yu C
        • Shi FD.
        Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis optica.
        Neurology. 2013; 81: 710-713
        • Baker D
        • Roberts CAK
        • Pryce G
        • Kang AS
        • Marta M
        • Reyes S
        • Schmierer K
        • Giovannoni G
        • Amor S
        COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.
        Clin Exp Immunol. 2020 Jul; (16:10.1111/cei.13495)
      2. Kappos L, Li D, Calabresi PA, et al. Long-term safety and efficacy of ocrelizumab in patients with relapsing-remitting multiple sclerosis: week 144 results of a phase II, randomised, multicentre trial [abstract no. P362 and poster]. Presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 11 October 2012, Lyon, France.

        • Ellwardt E
        • Ellwardt L
        • Bittner S
        • Zipp F.
        Monitoring B-cell repopulation after depletion therapy in neurologic patients.
        Neurol Neuroimmunol Neuroinflamm. 2018; 5: e463
        • Signoriello E
        • Bonavita S
        • Di Pietro A
        • Abbadessa G
        • Rossi F
        • Miele G
        • Casertano S
        • Lus G.
        BMI influences CD20 kinetics in multiple sclerosis patients treated with ocrelizumab.
        Mult Scler Relat Disord. 2020; 43102186https://doi.org/10.1016/j.msard.2020.102186
      3. Simpson-Yap S, De Brouwer E, Kalincik T, Rijke N, Hillert J, Walton C, Edan G, Moreau Y, Spelman T, Geys L, Parciak T, Gautrais C, Lazovski N, Pirmani A, Ardeshirdavani A, Forsberg L, Glaser A, McBurney R, Schmidt H, Bergmann A, Braune S, Stahmann A, Middleton R, Salter A, Van Der Walt A, Rojas J, Van Der Mei I, Ivanov R, Sciascia Do Olival G, Dias A, Magyari M, Brum D, Mendes M, Alonso R, Nicholas R, Bauer J, Chertcoff A, Zabalza A, Arrambide G, Comi G, Peeters L. First results of the COVID-19 in MS Global Data Sharing Initiative suggest anti-CD20 DMTs are associated with worse COVID-19 outcomes" MSVirtual 2020 Encore; Abstract SS02.04.