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Background: Early high-efficacy treatment of multiple sclerosis (MS) may provide long-term clinical benefits, improving disease outcomes and patient quality of life. ENSEMBLE is a multicentre, open-label, single-arm Phase IIIb study, evaluating the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting MS (RRMS). Aim(s): To report 2-year interim efficacy and safety data of the full cohort of patients with early-stage RRMS from the ENSEMBLE trial (NCT03085810), using no evidence of disease activity (NEDA)-3 as the primary endpoint. Method(s): Treatment-naive patients with early-stage RRMS (age 18-55 years;disease duration <=3 years;Expanded Disability Status Scale [EDSS] <=3.5;with one or more clinically reported relapse(s) or one or more signs of MRI activity in the prior 12 months) received OCR 600 mg every 24 weeks for 192 weeks (planned study duration). Key endpoints were NEDA-3 (defined as no relapses, 24-week [W] confirmed disability progression [CDP] and MRI activity [T1-weighted contract enhanced images or new/enlarging T2-weighted lesions, with MRI measurements rebaselined at W8]), annualised relapse rate (ARR), mean change in EDSS score from baseline (BL) and a safety overview. Result(s): BL demographics and disease characteristics of the ENSEMBLE population (N=1,225) were consistent with earlystage RRMS disease (patients <=40 years, 78.9%;female, 64.0%;median: Age, 32.0 years;duration since MS symptom onset, 0.74 years;duration since RRMS diagnosis, 0.22 years;BL EDSS score, 1.75;mean BL EDSS score [SD], 1.80 [0.93]). At W96, the majority of patients (n=857, 77.3%) had NEDA, 88.9% had no MRI activity, 93.4% had no relapses and 90.7% had no 24W-CDP. The adjusted ARR at W96 was low, 0.033 (95% CI, 0.026-0.042), and the mean (SD) EDSS score showed a statistically significant improvement between BL and W96, decreasing by 0.13 (0.89;p<0.0001), from 1.80 (0.93) to 1.67 (1.12). Safety results were consistent with prior OCR studies. Infections were reported by 760 (62.0%) patients;rates of serious infections were low (n=33 [2.7%] patients);32 (2.6%) of patients contracted a COVID-19 infection. Conclusion(s): In the ENSEMBLE study of treatment-naive patients with early-stage RRMS, disease activity based on clinical and MRI measures was minimal in most patients treated with ocrelizumab over 2 years;safety was consistent with prior ocrelizumab experience, with no new safety signals.
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Background: Attenuated antibody and robust T-cell responses following SARS-CoV-2 vaccines have been reported in people with multiple sclerosis (PwMS) treated with ocrelizumab (OCR). Factors influencing humoral and cellular responses and how these relate to clinical protection are not well understood. Aim(s): To investigate the effect of OCR on antibody and T-cell responses to SARS-CoV-2 vaccines, and characterise clinical outcomes of breakthrough COVID-19 infections in PwMS. Method(s): Patients participating in three ongoing Phase IIIb studies evaluating the effectiveness and safety of OCR, who decided to receive a SARS-CoV-2 vaccine as part of national immunisation programmes, were invited to undergo optional exploratory assessment. Antibody responses to SARS-CoV-2 spike and nucleocapsid proteins were assessed using the Elecsys electrochemiluminescence assay. Interferon-gamma ELISpot (ImmunoSpot) was used to detect SARS-CoV-2-specific T cells against 4 different peptide pools of the spike protein. Vaccine breakthrough cases were defined as suspected or laboratory-confirmed COVID-19 infections occurring >=14 days after completion of the recommended primary immunisation schedule. Result(s): Up to Sept 2021, 111 patients provided samples for assessment of response to SARS-CoV-2 vaccination. Mean (SD) age was 41.7 (11.8) years;63.1% were female;72.1% had relapsing- remitting MS, 15.3% secondary progressive MS and 12.6% primary progressive MS.Most patients had been on treatment with OCR for at least 2 years. Mean (SD) of 78.5 (41.4) days elapsed between the first vaccine dose and last OCR infusion. 94/111 patients received an mRNA vaccine and 15 patients an adenoviral vaccine. Most samples were collected within 80 days following completion of the primary vaccine schedule. Antibody response was detected in 22/103 (21%) patients and T-cell responses to >=1 of the 4 different peptide pools in 83/95 (87%) patients. Four breakthrough infections were reported. Conclusion(s): In preliminary analysis, frequency of patients with an antibody and T-cell response were in line with published data for PwMS on OCR. Expanded analyses with a larger set of patients (approximately 450 patients, up to March 2022), including longitudinal responses, booster data, differences between vaccine platforms and assessment of factors that may affect immune responses will be presented. Correlations between level of immune responses and breakthrough infection diagnosis and severity will be explored.
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Background: Concerns have been raised regarding risks of COVID-19 breakthrough infections in vaccinated patients with immune-mediated infammatory diseases (IMIDs) treated with immunosuppressants, but data on COVID-19 breakthrough infections in these patients are still scarce. Objectives: The primary objective was to compare the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 delta variant between fully vaccinated IMID patients with immunosuppressants, and controls (IMID patients without immunosuppressants and healthy controls). The secondary objective was to explore determinants of breakthrough infections. Methods: In this study we pooled data collected from two large ongoing prospective multi-center cohort studies (Target to-B! [T2B!] study and ARC study). Clinical data were collected between February and December 2021, using digital questionnaires, standardized electronic case record forms and medical files. Post-vaccination serum samples were analyzed for anti-RBD antibodies (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC study only). Logistic regression analyses were used to assess associations with the incidence of breakthrough infections. Multivariable models were adjusted for age, sex, cardiovascular disease, chronic pulmonary disease, obesity and vaccine type. Results: We included 3207 IMID patients with immunosuppressants and 1810 controls (985 IMID patients without immunosuppressants and 825 healthy controls). The incidence of COVID-19 breakthrough infections was comparable between patients with immunosuppressants (5%) and controls (5%). The absence of SARS-CoV-2 IgG antibodies after COVID-19 vaccination was independently associated with an increased incidence of breakthrough infections (P 0.044). The proportion of asymptomatic COVID-19 breakthrough cases that were additionally identifed serologically in the ARC cohort was comparable between IMID patients with immunosuppressants and controls;66 (10%) of 695 patients vs. 64 (10%) of 647 controls. Hospitalization was required in 8 (5%) of 149 IMID patients with immunosuppressants and 5 (6%) of 86 controls with a COVID-19 breakthrough infection. Hospitalized cases were generally older, and had more comorbidities compared with non-hospitalized cases (Table 1). Hospitalization rates were signifcantly higher among IMID patients treated with anti-CD20 therapy compared to IMID patients using any other immunosuppres-sant (3 [23%] of 13 patients vs. 5 [4%] of 128 patients, P 0.041;Table 1). Conclusion: The incidence of COVID-19 breakthrough infections in IMID patients with immunosuppressants was comparable to controls, and infections were mostly mild. Anti-CD20 therapy might increase patients' susceptibility to severe COVID-19 breakthrough infections, but traditional risk factors also continue to have a critical contribution to the disease course of COVID-19. Therefore, we argue that most patients with IMIDs should not necessarily be seen as a risk group for severe COVID-19, and that integrating other risk factors should become standard practice when discussing treatment options, COVID-19 vaccination, and adherence to infection prevention measures with patients.
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Background The aim of this study was to investigate the effect of various immunosuppressants on the humoral immune responses after vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods The Target to B! SARS-CoV-2 study is a multicentre study, taking place in 7 Dutch academic hospitals. Patients with the following IMIDs were recruited: Crohn’s disease (CD), ulcerative colitis (UC), auto-immune hepatitis, rheumatic (e.g. rheumatoid arthritis), neurological (e.g. multiple sclerosis) and dermatological IMIDs (e.g. atopic dermatitis). Patients were recruited based on immunosuppressants (table 1) and previous SARS-CoV-2 infection. The control group consisted of healthy subjects and IMID patients without immunosuppressants. SARS-CoV-2 receptor binding domain (RBD) antibodies were measured 28 days after completed SARS-CoV-2 vaccination. Seroconversion was defined as anti-RBD IgG >4 AU/mL. In this , we focus on therapies relevant for inflammatory bowel diseases (IBD) and present results for these treatments from patients with IBD, but also other IMIDs. Results Numbers of recruited patients with each immunosuppressant are shown in table 1. Amongst these patients, 312 patients had CD and 176 UC, the rest was diagnosed with another IMID. Seroconversion was reduced in patients receiving sphingosine 1-phosphate (S1P) modulators (all multiple sclerosis patients) while seroconversion was similar to controls in the other treatment groups. However, use of Anti-tumour necrosis factor (TNF), methotrexate, janus kinase (JAK) inhibitor monotherapy and all combination therapies (except for corticosteroids combined with other immunosuppressants) were associated with reduced Sars-CoV-2 antibody titres. Patients with a previous SARS-CoV-2 infection had higher median antibody titres after second vaccination than those without a previous SARS-CoV-2 infection. The type of IMID did not affect seroconversion rates. Conclusion No immunosuppressant, registered for IBD, reduced the rates of seroconversion after vaccination against SARS-CoV-2. Some immunosuppressants were associated with lower antibody titres. However, the clinical relevance of lower antibody titres remains unknown. S1P modulators, had a clear negative impact on the humoral response against SARS-CoV-2 after vaccination. This might be relevant in the future as this therapy is currently being approved for UC. Disease aetiology did not impair immunity against SARS-CoV-2 immunity after vaccination. Disclaimer: Absolute numbers of antibody titres and rates of seroconversion will be reported at the conference and are not reported in this as this might negatively impact the current submission process.
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OBJECTIVE: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination and B-cell count. METHODS: OCR treated patients were divided into an early and a late group (cut-off time 12 weeks between infusion and first vaccination). Patients were vaccinated with mRNA-1273 (Moderna). B-cells were measured at baseline (time of first vaccination) and SARS-CoV-2 antibodies were measured at baseline, day 28, 42, 52 and 70. RESULTS: 87 patients were included (62 OCR patients, 29 patients without DMTs). At day 70, seroconversion occurred in 39.3% of OCR patients compared to 100% of MS patients without DMTs. In OCR patients, seroconversion varied between 26% (early group) to 50% (late group) and between 27% (low B-cells) to 56% (at least 1 detectable B-cell/µL). CONCLUSIONS: Low B-cell counts prior to vaccination and shorter time between OCR infusion and vaccination may negatively influence humoral response but does not preclude seroconversion. We advise OCR treated patients to get their first vaccination as soon as possible. In case of an additional booster vaccination, timing of vaccination based on B-cell count and time after last infusion may be considered.
Subject(s)
COVID-19 , Multiple Sclerosis , Antibodies, Monoclonal, Humanized , COVID-19 Vaccines , Humans , SARS-CoV-2 , VaccinationABSTRACT
Introduction: Ocrelizumab is an often used and effective anti- CD20 therapy for patients with multiple sclerosis. The disease course of coronavirus disease 2019 (COVID-19) might be more severe in patients using anti-CD20 therapies, since B-cell depletion is associated with an increased risk of severe infections. Consequently, international MS experts have advised neurologists to consider interval extension between ocrelizumab doses based on B-cell count. Objectives: To assess the safety and efficacy of B-cell tailored personalized dosing of ocrelizumab in patients with multiple sclerosis. Aims: To provide knowledge on personalized dosing of ocrelizumab in multiple sclerosis in a large, closely monitored cohort and share the B-cell tailored personalized dosing protocol as implemented at our center during the COVID-19 pandemic. Methods: We conducted an observational study of all patients who received personalized dosing of ocrelizumab at our center since March 15th 2020. The personalized dosing protocol was based on serum CD19 B-cell count measured every 4 weeks, starting 24 weeks after a 600 mg dose or 12 weeks after a 300 mg dose. The next ocrelizumab dose was scheduled as soon as CD19 B-cell count re-emerged to ≥10 cells/μL. Clinical and radiological disease activity parameters and serum neurofilament light (sNfL) levels were collected until November 1st 2020. We applied linear regression (correcting for age and BMI) and mixed models (correcting for within-subjects correlations) to assess the effect of extended intervals on log-transformed sNfL levels. Results: A total of 159 patients received personalized dosing of ocrelizumab after a 600 mg dose and 6 patients after a 300 mg dose. Median CD19 B-cell count was 2 [1-7] cells/μL at the start of the personalized dosing protocol and 15 [4-27] cells/μL prior to re-dosing. After a 600 mg dose, median interval until re-dosing or until the last available CD19 B-cell count was 34 [30-38] weeks. No clinical relapses were reported and monthly sNfL levels during extended intervals remained stable. Of the 107 patients with a follow-up MRI-scan, only 2 (1.9%) showed radiological disease activity. Conclusions: Personalized dosing of ocrelizumab based on CD19 B-cell count led to an interval extension in the majority of patients with a low short-term incidence of disease activity, encouraging future studies to confirm safety and efficacy of this protocol beyond the COVID-19 pandemic.
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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.