ABSTRACT
Introduction: Some multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with blunted humoral vaccination responses, but relevance for SARS-CoV-2 infection is unclear. Objective(s): To determine SARS-CoV-2 exposure rates and formation of antibody memory among participants of the COMparison Between All immunoTherapies for MS (COMBAT-MS;NCT03193866) and the Immunomodulation and MS Epidemiology (IMSE) studies. Aim(s): To determine SARS-CoV2 serological response of people living with MS (pwMS). Method(s): Using a multiplex bead-based assay we determined SARS-CoV-2 spike and nucleocapsid antibody levels in 3,723 pwMS in paired serum samples (n=7,157) donated prior (<January 31st 2020) and during the pandemic (July-October 2020);16.6% had natalizumab, 6.4% fingolimod, 9.7% dimethyl fumarate, 1.9% interferon beta, 50.4% rituximab, 1.4% cladribine, 7.6% other DMTs, and 6.1% were untreated. Median fluorescent intensity (MFI) and bead-count were determined for spike and nucleocapsid antibodies, and samples were regarded as positive only when reactive to both viral antigens. Hazard ratios, from multivariable Cox regression models, were derived to assess association between antibody levels above cut-off for each antigen, comparing exposure to rituximab or fingolimod at time of sampling vs. other reference DMTs. All models were adjusted for age, sex, treatment center, time since reported infection, MS severity, disease duration, and number of previous DMTs. Result(s): Specificity and sensitivity of the assay for SARS-CoV-2 was 100% and 99.7%, respectively. The proportion of positive samples for SARS-CoV-2 differed moderately across DMTs with the highest values among cladribine-treated (7.4%) and the lowest number among rituximab-treated pwMS (3.9%). Similarly, the proportion of positive cases not reported in the Swedish MS registry varied from 100% for cladribine to 33.3% among untreated pwMS. Comparing levels of antibodies titers showed that levels were lower among those treated with rituximab or fingolimod vs interferon treated pwMS. Point estimates indicated a similar trend comparing rituximab or fingolimod vs untreated pwMS. Conclusion(s): Overall rates of SARS-CoV-2 antibody positivity after the first COVID-19 wave differed only moderately across DMTs, while antibody levels were lower with rituximab or fingolimod compared to interferon-treated pwMS. This indicates quantitative rather than qualitative differences in the humoral response to infection.
ABSTRACT
Introduction: B-cell depleting therapies used in multiple sclerosis (MS) have been associated with higher risk of severe COVID- 19. However, more precise knowledge of how B-cell depletion affects development of humoral and cellular immunity to viruses, in particular to SARS-CoV-2, is still limited. Objectives: To determine humoral and cellular SARS-CoV-2 responses after COVID-19 infection or vaccination in MS patients treated with different disease modulatory therapies (DMTs), with a focus on B-cell depleting therapies. Aims: Understand the impact of B-cell depleting therapy on the ability to develop a specific SARS-CoV-2 immunological memory after a COVID-19 infection or vaccination. Methods: We analyzed sera from subjects (n=2800) in an ongoing observational drug trial comprising multiple MS DMTs (COMBAT-MS;NCT03193866). In a single center subcohort (n=137, including healthy controls) enriched for COVID-19-like symptoms, samples for more detailed cellular analyses were obtained. Lastly, a small cohort of patients on B-cell depleting therapies were analyzed either before (n=4) or after (n=6) being vaccinated against SARS-CoV-2. Specific antibodies were determined with electro-chemiluminescence immunoassay and multiplex bead array. T-cell memory responses were determined by FluoroSpot and flow cytometry. Results: Data on humoral responses in the entire cohort will be included in the final presentation. The subcohort patients on B-cell depleting therapies were stratified into three different groups depending on B-cell status at onset of COVID-19-like symptoms;a) completely depleted (<0.01;B-cell count x 10-9/L, n=14), b) partially repleted (0.01-0.08;B-cell count x 10-9/L, n=7) or c) completely repleted (>0.08;B-cell count x 10-9/L, n=3). Within the three groups, 50%/71%, 86%/100% and 100%/100% developed a SARS-CoV-2 specific antibody/T-cell response, respectively. Furthermore, antibody titers were not significantly different from those on other DMTs or healthy controls, and SARS-CoV-2 specific T-cells also displayed functional similarity. Lastly, in the vaccination cohort, all patients displayed a specific T-cell response after vaccination although only 50% of them also developed a humoral response. Conclusions: These findings indicate that B-cell depletion does not prevent a specific immunological memory after a COVID-19 infection or vaccination against SARS-CoV-2, and patients that do not develop humoral immunity might still have a specific T-cell response. Further studies are needed to determine the correlation between immunological parameters and clinical immunity.
ABSTRACT
Introduction: B cell depletion with rituximab (RTX) is associated with high treatment efficacy in relapsing-remitting multiple sclerosis (RRMS), with low risk of rebound phenomena with treatment interruptions, but also increased risk of mainly bacterial infections. In order to reduce infection risks, further prompted by COVID19, RTX standard dosing intervals were extended up to 24 months in a single centre setting. Aims: To determine risk of disease flares in RRMS patients with extended RTX dosing intervals. Methods: We retrospectively analysed all RRMS patients (n=719) treated with RTX included in two ongoing observational drug trials, COMBAT-MS (EudraCT 2016-003587-39) and MultipleMS (2017-002634-24). Data were extracted from the Swedish MS registry for demographics, diagnosis, treatment history, clinical relapses and magnetic resonance imaging (MRI). Relapses and/or new MRI T2 lesions/contrast enhancing lesions, were recorded at first sign of clinical or MRI disease activity, or the lack thereof, at most recent visit/MRI for patients without signs of disease activity. The maximum interval (MI) between RTX doses before a registered outcome was used as a proxy for the efficacy of different treatment protocols. Results: Out of 697 patients with valid clinical data, 35 (5%) suffered a relapse, 19 of which occurred after the first RTX dose. Of the remainder, 13 patients had a relapse with a MI of 6±3 months (n=181, 7.2%), 3 with MI extended to 12±3 (n=313, 1%), and no relapse was found with MI of 18±3 or & gt;21 months (n=140 and n=63, respectively). MRI activity was detected in 54/572 subjects (including 6 after first dose), of which 24/152 (15,8%) with MI 6±3 month, 16/244 (6.5%) with MI of 12±3 months, 9/116 (7.8%) with MI of 18±3 months and 5/60 (8.3%) with MI of & gt;21 months. No major differences were found among the four groups concerning demographics, type of prior treatment and disability, except for a lower number of RTX doses in the 6±3 month MI group (mean number of RTX doses 3.3, 5.8, 6.8 and 6.1, respectively;ANOVA p<0.001). Flow cytometric B lymphocyte profiles and additional follow up data regarding treatment duration will be included in the final presentation. Conclusions: Extending the RTX dosing intervals was not associated with signs of rebound disease activity. Further studies are needed to establish if dose interval extension of B cell depleting treatments can improve the benefit-risk ratio regarding disease activity versus infections.
ABSTRACT
Introduction: Mounting evidence suggests that B-cell depleting disease-modifying therapies (DMTs) may be associated with an increased risk of a moderate to severe COVID-19. Use of rituximab (RTX) is frequent in Sweden, a country that suffered high COVID-19 rates. Objective: To explore the association between timing and dose of RTX and risk of hospitalization for COVID-19 in a well-characterized cohort of MS patients. Methods: We included participants in COMBAT-MS, (NCT03193866) with ongoing treatment with RTX. Data include detailed demographic and clinical information, DMT exposure (date and dose of all RTX infusions), COVID-19 information (dates of infection and hospitalization as reported by the patient), as well as patient-reported outcomes. Among all persons who developed COVID-19, we measured the odds of hospitalization for COVID-19 as they related to 1) the time between most recent RTX infusion and COVID-19 onset date (measured in months), and 2) the total lifetime cumulative dose of RTX received (measured in grams), using logistic regression. The reference cohort included all persons with 'mild' COVID-19, not requiring hospitalization. Models were adjusted for age and sex with results reported as odds ratios (OR) and 95% confidence intervals (CI). Results: Of 3391 persons actively enrolled in the COMBAT-MS cohort, 326 (9.6%) developed COVID-19 between March 1, 2020 and April 30, 2021. Amongst these patients, 172 (52.8%) were exposed to RTX prior to their COVID-19 onset, and 26 (15.1%) required hospitalization. No deaths occurred. Median time between last RTX infusion and COVID-19 onset was 6.1 months [interquartile range (IQR): 3.9, 11.0] among mild cases, and 4.6 months [IQR: 3.6, 5.6] among those hospitalized for COVID-19 (difference not significant, Mann-Whitney U-test p=0.16). Persons with mild COVID-19 had a median cumulative lifetime RTX dose of 3.5g [IQR: 2.5, 4.5], compared to 3.3g [IQR:2.6, 4.5] for hospitalized cases. The time between most recent DMT infusion and COVID-19 onset was not associated with altered odds of requiring hospitalization (age-and sexadjusted OR: 0.97 (95%CI: 0.90-1.03), nor was lifetime cumulative dose of RTX (age and sex-adjusted OR: 1.05 (95%CI: 0.83-1.31). Conclusions: Among COMBAT-MS participants who contracted COVID-19, there was no significant association between timing of RTX infusion nor cumulative lifetime RTX dose and the odds of hospitalization for COVID-19.
ABSTRACT
Background: Studies from COVID-19 case-repositories among patients with rheumatic diseases have assessed associations (relative risks) between characteristics of the disease and adverse COVID-19 outcomes. Such designs are susceptible to bias from selection of cases reported. Few studies have assessed absolute and relative risks for COVID-19 outcomes in population-based cohorts of patients with inflammatory joint diseases, nor compared these risks to those in the general population. Objectives: To estimate all-cause mortality, absolute and relative risks for severe COVID-19 in patients with chronic inflammatory joint diseases, compared over time and to the general population. Methods: We updated a multi-register nationwide linkage (“ARTIS”) on adults with RA, PsA, AS, SpA or JIA and population referents (matched on sex, age, and region), with data on hospitalizations, admission to intensive care (ICU), and deaths due to COVID-19. We calculated all-cause mortality March-September 2015-2020, and absolute and relative risks for COVID-19 outcomes March-September 2020. Patients were compared to population referents using hazard ratios (HR) from Cox models adjusted for comorbidities and socio-economy. Results: We identified 110567 individuals with inflammatory joint disease (53455 with RA) in Sweden on March 1st 2020, and 484277 matched general population subjects. In all cohorts, the absolute risk of death from any cause in 2020 was higher than 2015-2019 (Figure 1), with a peak in mid-April, but the relative risks of death (vs. the general population) 2020 remained similar to HRs for 2015-2019 (HR for 2020 in Table 1). Among all individuals with inflammatory joint disease in 2020, the risk for hospitalization, admission to ICU, and death due to COVID-19 was 0.5%, 0.04% and 0.1%, respectively (Table 1). HRs (vs. the general population) were elevated for almost all outcomes. HRs for COVID-19 related outcomes (Table 1) were higher than for non-COVID-19 outcomes;adjustment for co-morbidities and socio-economy explained much of these increases, somewhat less so for the former. Conclusion: Risks of severe COVID-19 were increased among patients with inflammatory joint diseases, but similar increases were seen for non-COVID-19 morbidity. Co-morbidities and socio-economy explain much of this increase.