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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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Introduction: In the general population, maternal SARS-CoV-2 infection during pregnancy is associated with an increased risk of several adverse maternal and fetal outcomes. In patients with Multiple Sclerosis (PwMS) an increased risk of severe COVID- 19 was reported after treatment with antiCD20 or corticosteroid close to COVID-19 onset. However, no data are currently available about maternal and fetal outcomes in pregnant women with MS who contracted COVID-19 during gestation. Objective(s): To evaluate maternal and fetal outcomes and their predictors in a population of pregnant women with MS with COVID-19 diagnosis selected from two large national registries and compared with matched control pregnancies extracted from a historical Italian MS cohort. Method(s): We recruited pregnant pwMS who contracted SARSCoV- 2 infection after conception and were prospectively followed- up in Italian and Turkish MS Centres, in the period 2020-2022. All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders, including disease modifying treatments. A historical matched control group was extracted from a previous Italian multicenter cohort. Data on pregnancy outcomes were compared using logistic and linear multivariable regression analyses, when appropriate. Result(s): So far clinical characteristics and data on COVID-19 outcomes are available for 85 pregnant MS women (mean age 35.2+/-6.4 years, 83 relapsing remitting (RR), mean disease duration 8.3+/-6.86 years, median Expanded Disability Status Scale (EDSS) 1.0 (IQR 1.0-2.5), body mass index 24.5+5.8, current smokers 10.6%, occasional or regular alcohol consumption 28.3%). As for COVID-19 course, 8 women (9.4%) were hospitalized;no one required transfer to intensive care. The historical control group consists of 232 women with RRMS (mean age 34.6+/-3.1 years, mean disease duration 8.8+/-4.8 years, median EDSS 1.5 (IQR 1.0-2.0). The collection of information on maternal and fetal outcomes is ongoing: eclampsia, maternal mortality and admission to intensive care unit, spontaneous abortion, stillbirths, congenital abnormalities, preterm delivery, child weight and length at birth, admission to neonatal intensive care unit. Conclusion(s): Our preliminary data show no increased risk of severe COVID-19 in MS patients who contracted the infection during pregnancy. The analysis on pregnancy-related maternal and fetal outcomes is ongoing.
ABSTRACT
Introduction: The patients who manifest rapid accumulation of physical and cognitive decline despite treatment with one or more disease-modifying drugs (DMTs) are accepted as highly active multiple sclerosis (HA-MS). Cladribine is an effective treatment option for HA-MS. We aimed to evaluate the efficacy and safety profiles of cladribine HA-MS patients. Method(s): HA-MS patients under cladribine from July 2020-May 2022 were included in the study. Demographic data, disease duration and progression parameters, and Covid-19 infection data were evaluated. Result(s): The study included 82 patients (64 female,18 male). The mean ages were 38.17+/-8.7 years. According to the Lublin classification, 18 (22%) patients had non-active/non-progressive, 35 (42.7%) had active/nonprogressive, 21 (25.6%) had non-active/progressive and 8 (%9.7) patients had active/progressive MS. The mean disease durations were 9.75+/-6.42 years. The mean follow-up duration under cladribine was 8.32+/-5.4 months. The median EDSS score both before and after treatment was 2.5 (0-7) (p=0.086). Fifty (61%) of the patients were switched from first-line DMT, 27 (32.9%) from second-line DMT, and cladribine was the first drug in 4 patients. Most of the patients were switched from interferon/glatiramer acetate (24.4%), teriflunomide (20.7%), and fingolimod (19.5%). 12 (14.6%) of the patients had grade 1, 14 (17.1%) had grade 2, 2 (2.4%) had grade 3 lymphopenia. None of the patients observed had grade 4 lymphopenia. Overall, 24 (29.2%) patients had mild complaints under cladribine. Most common side effects were hair loss (n=8;9,75%), mild ALT/ AST elevation (n=5;6.1%);headaches (n=3;3.7%), mild skin reactions (n=5;6.1%). One patient had a zona zoster infection, while 2 complained of frequent urinary infections. No serious infection, allergic reactions, and malignancy were observed. 8 (9.75%) patients developed attacks under cladribine while under cladribine for at least one month, and the symptoms resolved after intravenous methylprednisolone. 18 (21.95%) patients had Covid-19 infection, and all but 1 had mild symptoms. One patient had a mild MS attack one month after the Covid-19 infection. None of the patients experienced any attacks or severe side effects after the Covid-19 vaccination. Conclusion(s): Cladribine therapy is a well-tolerated and so far effective treatment option for HA-MS patients. Long-term efficacy and safety studies are still needed.
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Introduction: As a high-efficacy multiple sclerosis (MS) treatment, cladribine necessitates empirical data from diverse populations. Objective(s): To study the efficacy and safety data of cladribine treatment in a real-world setting. Method(s): Patients from eight MS clinics in Turkey were involved in the study. We retrieved the demographic, clinical, MRI, safety, laboratory, COVID-19, and pregnancy records of patients with at least six months of follow-up on cladribine treatment. Result(s): Our study included 210 MS patients (52 males, 158 females;193 relapsing and 17 relapsing-progressive MS). The mean age at MS disease onset was 27.6 years (+/-8.5). Before cladribine treatment, 56.7% of patients used first-line, and 41.9% used both first and second-line therapies. During a mean follow-up period of 13.0 months (+/-4.7) following cladribine treatment, 5.7% of patients experienced a relapse. The shortest duration of relapse following cladribine administration was one week, and the longest duration was 15.3 months. Interestingly, 50% of the relapses occurred within the first three months. Among relapsing patients, five switched from fingolimod, two from dimethylfumarate, and one from ocrelizumab and interferon-beta. The mean annualized relapse rate was 0.41 (+/-0.41) in the two years preceding cladribine and 0.11 (+/-0.55) one year following treatment. At baseline, the mean EDSS score was 2.47 (+/-1.63), and 51.9% of patients ranked below EDSS 3. EDSS progression was observed in 7.6% of patients following cladribine treatment. On cladribine, eight patients (9.4%) exhibited radiological progression. There was no difference in NEDA status between patients switching from first or second-line therapy (p=0.43). COVID was observed in 73 patients, 54 of them had a mild disease course, six had a moderate disease course, and one had a severe disease course. There have been no COVID-related fatalities. There were five pregnancies documented, three of which are currently ongoing. One of the pregnancies ended with healthy childbirth, while the other was terminated in the first trimester with a miscarriage. Conclusion(s): Despite the relatively short duration of follow-up, our study demonstrates that cladribine is effective in providing NEDA. Moreover, switching from fingolimod to cladribine may increase the likelihood of early relapse.
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Introduction: Ocrelizumab, which is approved for the treatment of progressive and relapsing forms of MS, is a CD-20 monoclonal antibody. Susceptibility to hypogammaglobulinemia has recently gained importance in patients under B-cell depleting therapies. Objectives and Aims: We aimed to evaluate the changes in immunoglobulin levels and their effect on the COVID-19 infection in a group of MS patients under ocrelizumab therapy. Methods: Patients under ocrelizumab therapy from December 2017 - May 2021 were included in the study. Immunoglobulin M (IgM), immunoglobulin G (IgG), CD19, CD20 levels were obtained cross-sectionally before the last infusion of ocrelizumab. We also evaluated COVID-19 infection ratio and severity. Results: Among 320 ocrelizumab-treated patients, we included 131 patients who had been tested for IgG, IgM, CD19 and CD20 levels. The female to male ratio was 1.4: 1 and mean age was 44.3 years. While the mean disease duration was 11 years, the mean follow-up period of patients under ocrelizumab treatment was 21 months. 13 (10%) patients had lower serum IgG levels (serum IgG<750mg/dl). Serum IgM levels were found to be low in 33 (25%) of the patients with the mean of 31.85 mg/dl (±12.1). 15 had COVID-19 infection (COVID+ group). The mean serum IgM level of the COVID+ group was 78.03mg/dl (±84.70), 101 mg/dl (±73.03) in the COVID- group (p=0.262). IgG levels of the COVID+ and COVD- groups were 948.3 (±243.4) and 1073 (±256.7) mg/dl respectively (p=0.078). Only 3 patients needed hospitalization because of COVID-19. Two of them had low IgM levels. None of the patients had been needed intensive care or mechanical ventilation. Conclusions: Almost a quarter of our patients had a low level of Ig's as expected. Ig levels should be routinely evaluated to avoid infectious complications.
ABSTRACT
BACKGROUND: The pandemic of the new type of corona virus infection 2019 [Covid-19] also affect people with Multiple Sclerosis (pwMS). Currently, the accumulating information on the effects of the infection regarding the demographic and clinical characteristics of the disease, as well as outcomes within different DMTs¸ enable us to have better practices on the management of the Covid-19 infection in pwMS. OBJECTIVE: To investigate the incidence of coronavirus disease 2019 (Covid-19) and to reveal the relationship between the demographic-clinical and therapeutic features and the outcome of Covid-19 infection in a multi-center national cohort of pwMS. METHODS: The Turkish Neurological Society-MS Study Group in association with the Italian MuSC-19 Study Group initiated this study. A web-based electronic Case Report Form (eCRF) of Study-MuSC-19 were used to collect the data. The demographic data and MS histories of the patients were obtained from the file tracking forms of the relevant clinics. RESULTS: 309 MS patients with confirmed Covid-19 infection were included in this study. Two hundred nineteen (219) were females (70.9%). The mean age was 36.9, ranging from 18 to 66, 194 of them (62.8%) were under 40. The clinical phenotype was relapsing-remitting in 277 (89.6%) and progressive in 32 (10.4%). Disease duration ranged from 0.2 years to 31.4 years. The median EDSS was 1.5, ranging from 0 to 8.5. The EDSS score was<= 1 in 134 (43%) of the patients. 91.6% of the patients were on a DMT, Fingolimod was the most frequently used drug (22.0%), followed by Interferon (20.1%). The comorbidity rate is 11.7%. We were not able to detect any significant association of DMTs with Covid-19 severity. CONCLUSION: The Turkish MS-Covid-19 cohort had confirmed that pwMS are not at risk of having a more severe COVID-19 outcome irrespective of the DMT that they are treated. In addition, due to being a younger population with less comorbidities most had a mild disease further highlight that the only associated risk factors for having a moderate to severe COVID-19 course are similar with the general population such as having comorbid conditions and being older.