Multiple Sclerosis and the Risk of Infection: A Consensus Guideline

Multiple sclerosis (MS) is an inflammatory condition affecting the central nervous system. Infection is a major consideration in the MS population due to its relevance to several stages of the disease process: (i) it has been suggested that infective processes may be 'triggering' or aetiological factors for MS, (ii) concurrent infection is known to exacerbate symptoms in MS, (iii) people with MS are at higher risk of infection when compared to the general population, and this risk is exaggerated in those receiving disease modifying therapies (DMTs). This guidance document was developed by specialists in the field of MS, Immunology, Infectious Disease and Pharmacy. A modified Delphi approach was used to develop clinically relevant, evidence-based consensus guidelines to help physicians navigate the complex interaction between DMTs and infectious diseases. We focus on specific risks predisposing people with MS to infection and how to manage these risks. We also provide recommendations on how to screen for, prevent, and manage infection in this population, in particular tuberculosis, progressive multifocal leukoencephalopathy, hepatitis B, human papillomavirus, herpetic and other opportunistic infections. We also discuss vaccination and the COVID-19 pandemic in people on DMTs.

Extended Interval Dosing of Ocrelizumab Reduces Risk of Developing Hypogammaglobulinaemia

Introduction Disruption to clinical services, triggered by the COVID-19 pandemic, led to extended intervals between ocrelizumab treatments for some patients. Objectives To assess the rates of developing low immunoglobulin levels and timing of CD19+ B-cell count repopulation in a real-world clinical population. To assess for evidence of clinical or radiological MS disease activity with extended interval dosing of ocrelizumab. Methods We audited 712 patients given ocrelizumab by our seven clinical services. All monitoring of immunoglobulin levels and CD19+ cell counts were recorded. Disease activity was defined as on treatment clinical relapse, radiological activity, and EDSS progression. Results Low immunoglobulin levels developed in 102 patients, the odds ratio for developing hypogam- maglobulinaemia comparing extended to standard interval dosing was 0.42 (CI 0.22-0.81). Disease activity included 20 participants with clinical relapses and 72 with new MRI lesions. There was no evidence of excess clinical or radiological disease activity on switching to extended interval dosing. 38 had EDSS progression, giving an odds ratio comparing extended to standard interval dosing of 0.77 (CI 0.38-1.56). Conclusions This real-world data of extended interval dosing of ocrelizumab indicates lower rates of hypogammaglobulinaemia and no detrimental effect on short-term treatment efficacy.

Humoral and T- cell response to multiple COVID-19 booster vaccinations in people with MS

Introduction: People with multiple sclerosis (PwMS) treated with anti-CD20 therapies and fingolimod are less likely to successfully produce a humoral response to COVID-19 vaccines 1 and 2. Objective(s): To measure the humoral and/or cellular response to COVID-19 booster vaccinations in a cohort of PwMS who were previously seronegative after their initial COVID vaccine course. Aim(s): To determine whether there is a benefit of COVID-19 booster vaccinations for people with MS who are known to have had an attenuated response to initial vaccines. Method(s): We studied a cohort of PwMS all of whom were seronegative for anti-SARS-CoV-2 spike protein IgG after the 1st and 2nd COVID-19 vaccines, including PwMS treated with ocrelizumab (n=53), fingolimod (n=15), other DMTs (n=9) and no DMT (n=2). Dried blood spot +/- whole blood samples were obtained from participants at 2-8 weeks after their 3rd (n=79) and 4th (n=40) COVID-19 vaccines. Samples were used to measure anti-SARS-CoV-2 spike protein IgG (ELISA) and T-cell response (IFN-g release assay measured on whole blood). Result(s): Overall 27/79 (34%) who were seronegative after COVID vaccine 2 seroconverted after vaccine 3. Seroconversion rates were 17% for PwMS treated with ocrelizumab, 47% for fingolimod and 100% for other DMTs. A further 2/30 (7%) of those who remained seronegative after vaccine 3 seroconverted after vaccine 4. Anti-SARS-CoV-2 T-cell responses were measurable in 26/40 (65%) after vaccine 3 and 13/19 (68%) after vaccine 4 but were conspicuously absent in people treated with fingolimod. Overall, 75% of participants showed either humoral or cellular response after receiving 4 COVID vaccinations. PwMS with laboratory evidence of prior COVID-19 infection had higher measurable T-cell responses. Conclusion(s): Booster vaccinations for COVID-19 are associated with incremental benefits in measurable immunity in those with attenuated responses to the initial vaccine course. Overall, three quarters of those who were seronegative after COVID vaccines 1 & 2 had a measurable immune response after COVID vaccine 4. This data supports the use of booster vaccinations in pwMS at risk of attenuated vaccine response.

Multiple sclerosis and COVID-19: Assessing risk perception, patient behaviors and access to disease-modifying therapies.

BACKGROUND: Following the outbreak of COVID-19, global healthcare systems have had to rapidly adapt. People with multiple sclerosis (pwMS) were required to make decisions about their individual risk and consequent work and social behaviors. This study aimed to evaluate risk perception and patterns of shielding behavior amongst pwMS at the onset of the COVID-19 pandemic and the subsequent impact on patients' employment and access to disease modifying therapies (DMTs). METHODS: Postal surveys were sent to 1690 people within a UK population-based MS cohort during the first wave of the COVID-19 pandemic. Patients were surveyed on: (i) perceived vulnerability to COVID-19; (ii) isolation behavior; (iii) interruption to DMT; (iv) employment status; (v) level of satisfaction with their current working arrangement. RESULTS: Responses were received from 1000 pwMS. Two thirds of patients reported isolating at home during the first wave of the pandemic. This behavior was associated with increased age (p<0.0001), higher disability (p<0.0001) and use of high-efficacy DMTs (p = 0.02). The majority of patients reported feeling vulnerable (82%) with perceived vulnerability associated with higher EDSS (p<0.0001) and receiving a high-efficacy DMT (p = 0.04). Clinician-defined risk was associated with shielding behavior, with those at high-risk more likely to self-isolate/shield (p<0.0001). Patients on high-efficacy DMTs were more likely to have an interruption to their treatment (50%) during the first wave of the pandemic. Most pwMS experienced a change to their working environment, and most were satisfied with the adjustments. CONCLUSION: This study highlights the risk perception, social behavioral practices and changes to treatment experienced by pwMS during the first wave of the COVID-19 pandemic in a large, well-described UK cohort. The results may help inform management of pwMS during future pandemic waves.

Self-diagnosed COVID-19 in people with multiple sclerosis: a community-based cohort of the UK MS Register

The COVID-19 study (clinicaltrials.gov:NCT04354519) is a prospective observational cohort launched on 17 March 2020 as part of the UKMSR. As of 24 April, out of 3910 participants, 237 (6.1% (95% CI 5.3% to 6.8%)) reported self-diagnosed COVID-19 among whom 54 (22.8% (17.5% to 28.2%)) also had a diagnosis by a healthcare professional based on symptoms and 37 (15.6% (11.2% to 20.6%)) a confirmed diagnosis by testing. Three participants reported hospitalisation due to COVID-19. No deaths were reported. Among 1283 siblings without MS, 79 (6.2%) had a reported diagnosis of COVID-19. Adjusting for age and gender, the likelihood of contracting COVID-19 in pwMS was similar to siblings (OR 1.180 (0.888 to 1.569)). Seven hundred and fifty-nine of 3812 participants reported that they were self-isolating and that they had been self-isolating for at least 2 weeks before symptom onset if they had COVID-19. Of these, 2 (0.3% (0% to 0.7%)) had self-diagnosed COVID-19 whereas 137 of 3053 participants not self-isolating (4.5% (3.8% to 5.2%)) had the disease. Participants on DMTs were less likely to have self-diagnosed COVID-19 (OR 0.640 (CI 0.428 to 0.957)), which remained significant after removing self-isolating participants (OR 0.633 (0.402 to 0.998)). High-efficacy DMTs reduced the likelihood of self-diagnosed COVID-19 compared with no DMTs (OR 0.540 (0.311 to 0.938)) but not compared with moderate-efficacy DMTs. Including webEDSS (n=2808) and physical MSIS-29v2 (n=3192) as additional predictors in the analysis showed no significant association with the likelihood of contracting COVID-19. The gender distribution was similar between participants with and without COVID-19. More participants with self-diagnosed COVID-19 reported themselves as having any ethnicity other than white compared with those without the disease (6.9% (3.9% to 10.1%) vs 3.8% (3.2% to 4.4%), p=0.019). Gender and ethnicity did not affect the likelihood of having COVID-19.

Disease activity and CD19+ B-cell counts with extended interval dosing of ocrelizumab

Introduction: Ocrelizumab is licenced for a fixed treatment interval of six-monthly infusions to treat multiple sclerosis (MS). Disruption in clinical services, triggered by the COVID-19 pandemic, has led to extended intervals between treatments for some patients. Increasing evidence suggests that extended interval dosing of another anti-CD20 medicine, rituximab, maintains its efficacy while reducing the risks of immunosuppression. Objectives: To assess for evidence of clinical or radiological MS disease activity with extended interval dosing of ocrelizumab. To assess the rates of developing low immunoglobulin levels and timing of CD19+ B-cell count repopulation in a real-world clinical population. Methods: We audited the clinical, radiological and immunological data of 301 patients given ocrelizumab by our clinical services. Baseline demographics included age, sex, previous disease modifying treatment (DMT), phase of MS, and Expanded Disability Status Scale (EDSS). Dates of ocrelizumab administration were recorded. Disease activity was defined as on treatment EDSS progression, radiological activity or clinical relapse. All monitoring of CD19+ cell counts and immunoglobulin levels were recorded. Results: 301 participants were included in the analysis, among whom 62% were women, the mean age was 43 years and the median baseline EDSS was 3 (IQR 1-6). Half had previously used other DMTs and six (2%) had low immunoglobulin levels at baseline. They received 966 treatment cycles, of which 70 were administered with a treatment interval of 7-8 months, 45 with an interval of 8-9 months and 14 with an interval of more than nine months. In total, 131 (44%) participants had extended interval dosing. Disease activity included 33 (11%) with EDSS progression, 16 (5%) with new MRI lesions and 4 (1%) participants had clinical relapses. The odds ratio for rates of disease activity comparing extended to standard interval dosing was 0.97. Low immunoglobulin levels developed in 22 (7%). The longest recorded suppression of CD19+ B-cells was 405 days. We will present our mixed effects linear regression model of the factors that influence CD19+ count repopulation. Conclusions: This real-world data of extended interval dosing of ocrelizumab indicates no detrimental effect on short-term treatment efficacy. Our CD19+ dataset, could inform the design of a prospective trial of individualised retreatment intervals in ocrelizumab.

COVID-19 in Multiple Sclerosis: Clinically reported outcomes from the UK Multiple Sclerosis Register.

BACKGROUND: In March 2020, the United Kingdom Multiple Sclerosis Register (UKMSR) established an electronic case return form, designed collaboratively by MS neurologists, to record data about COVID-19 infections in people with MS (pwMS). OBJECTIVES: Examine how hospital admission and mortality are affected by disability, age and disease modifying treatments (DMTs) in people with Multiple Sclerosis with COVID-19. METHODS: Anonymised data were submitted by clinical teams. Regression models were tested for predictors of hospitalisation and mortality outcomes. Separate analyzes compared the first and second 'waves' of the pandemic. RESULTS: Univariable analysis found hospitalisation and mortality were associated with increasing age, male gender, comorbidities, severe disability, and progressive MS; severe disability showed the highest magnitude of association. Being on a DMT was associated with a small, lower risk. Multivariable analysis found only age and male gender were significant. Post hoc analysis demonstrated that factors were significant for hospitalisation but not mortality. In the second wave, hospitalisation and mortality were lower. Separate models of the first and second wave using age and gender found they had a more important role in the second wave. CONCLUSIONS: Features associated with poor outcome in COVID-19 are similar to other populations and being on a DMT was not found to be associated with adverse outcomes, consistent with smaller studies. Once in hospital, no factors were predictive of mortality. Reassuringly, mortality appears lower in the second wave.