CLADRIPLAS: Does cladribine Target CNS plasma cells and reduce neuro-axonal damage in people with MS?

Introduction: Cladribine is a CNS penetrant disease-modifying treatment, which - in an oral preparation (Mavenclad) - was licensed for people with highly active relapsing MS in August 2017. Our experience with cladribine dates back to 2014 when we started using subcutaneously injected cladribine as a compassionate immunotherapy in people with MS (pwMS) off-label. This programme enabled us to embed CLADRIPLAS, a mechanistic study of the effect on intrathecal B cell and plasma cell function and axonal damage focussing on progressive MS (PMS) (IRAS # 240360). Objective(s): To study the effect of cladribine on peripheral and intrathecal B and plasma cells. Aim(s): To study the effect of cladribine on oligo-clonal bands (OCB) and the level of neurofilament light (NfL) chain. Method(s): Observational study involving two lumbar punctures and phlebotomies, 6-12 months apart, to collect B cell subsets, and intrathecal plasma cell as well as neurofilament light chain (NfL) level in pwMS eligible and not eligible for cladribine treatment based on cerebro-spinal fluid (CSF) NfL, clinical and/or MRI evidence of inflammatory disease activity. Here, we report baseline cohort characteristics. Result(s): Thirty-eight pwMS were recruited (19 women, 19 men) and had their first sample collections. Eight pwMS were eligible for cladribine treatment (7 based on elevated NfL, 1 due to MRI activity). Follow-up samples have been collected in 21. Mean age at baseline was 55 years (40-76). Fourteen had primary, 24 secondary PMS. Median EDSS=6.5 (3.5-8). Twenty-one pwMS had been treated with DMT before consideration of cladribine, 17 were immunotherapy-naive. Mean CSF-NfL level was 552 (176- 2072) pg/ml. Conclusion(s): Despite restrictions due to COVID-19, 38 of 40 planned pwMS were enrolled. 7/8 were eligible based on CSFNfL level indicating the importance of using biomarkers other than MRI to establish disease activity in PMS. We expect our cohort to enable meaningful comparison between groups. CLADRIPLAS will finish in early 2023.

Did it hurt? COVID-19 vaccination experience in people with multiple sclerosis.

BACKGROUND: Current guidelines recommend vaccination against SARS-CoV2 for people with multiple sclerosis (pwMS). The long-term review of the safety and effectiveness of COVID-19 vaccines in pwMS is limited. METHODS: Service re-evaluation. PwMS using the MS service at Barts Health National Health Service Trust were sent questionnaires via email to report symptoms following first and second COVID-19 vaccinations (n = 570). A retrospective review of electronic health records was conducted for clinical and safety data post-vaccination(s); cut-off was end of September 2021. Separate logistic regressions were carried out for symptoms experienced at each vaccination. Two sets of regressions were fitted with covariates: (i) Disease-modifying therapy type and (ii) patient characteristics for symptoms experienced. RESULTS: 193/570 pwMS responded. 184 pwMS had both vaccinations. 144 received the AZD1222 and 49 the BNT162b2 vaccine. 87% and 75% of pwMS experienced any symptoms at first and second vaccinations, respectively. The majority of symptoms resolved within a short timeframe. No severe adverse effects were reported. Two pwMS subsequently died; one due to COVID-19 and one due to aspiration pneumonia. Males were at a reduced risk of reporting symptoms at first vaccination. There was evidence that pwMS in certain treatment groups were at reduced risk of reporting symptoms at second vaccination only. CONCLUSIONS: Findings are consistent with our preliminary data. Symptoms post-vaccination were similar to the non-MS population and were mostly temporary. It is important to inform the MS community of vaccine safety data.

An evaluation of remote monitoring in people with MS during the COVID-19 pandemic

Introduction: The COVID-19 pandemic caused major disruption to health services across the Globe, including the UK. Quick adaptations were required to switch from face-to-face to remote consultations and to further develop remote monitoring (RM) of people with multiple sclerosis (pwMS) in the community. Objective: To evaluate the views of pwMS under the care of our team who participated in RM. Methods: RM included completion of the nine-hole peg test, Timed 25-foot walk, ABILHAND questionnaire and WebEDSS at home. Electronic health records were queried for pwMS who participated in RM from May 2020-July 2020. Questionnaires (N=72) were sent via post or email asking about their experience of RM. Data were analysed using descriptive statistics. This service evaluation project was registered with the clinical effectiveness unit at Barts Health NHS Trust (Registration:11945). Results: 23 pwMS (mean age 49 years (SD11.7);18 women, 5 men;relapsing MS: 17;progressive MS: 6;EDSS 0-8) responded to the survey. The majority viewed RM as a way for healthcare professionals to provide pwMS with the necessary support (83%) and to manage MS symptoms (70%);65% were keen to know more about how RM scores can be used to help them manage their MS symptoms. Overall, 60% of respondents felt confident completing assessments at home;52% said they will continue with RM after the pandemic. Conclusions: RM enabled monitoring of pwMS during the pandemic. Results suggest pwMS understood and generally agreed with the intentions of RM. There is also evident potential to facilitate patient activation and self-management. The apparent reluctance to continue RM in half of our sample after the pandemic warrants further exploration. Whilst bias may play a role due to limited returns, further reasons may include lack of digital confidence and associated risk of health inequalities.

Up to 6 years follow-up of people with MS (n=250) receiving cladribine

Introduction: Oral cladribine is a licensed disease-modifying treatment (DMT) for highly active relapsing multiple sclerosis (RMS). We report clinical and paraclinical data collected as part of ongoing follow-up of our cohort of people with MS (pwMS) treated with subcutaneous (s.c.) cladribine personalised dosing (CPD). Objectives and Aims: To report follow-up data in pwMS treated using CPD (adjusted for weight and total lymphocyte count, TLC). Methods: CPD was offered to pwMS with signs of disease activity irrespective of their disease course. Cladribine 10 mg s.c. was given on three consecutive days (four in pwMS & gt;90kg) during week 1. Based on TLC at week 4, patients were given another 0-3 doses at week 5. A second cycle of CPD was administered 11 months later. Follow-up included recording of adverse events, relapses, annual EDSS, 9-hole peg, timed 25-foot walking, and symbol digit modalities tests. MRI (gadolinium enhancing T1 and T2 lesions), cerebrospinal fluid (CSF) neurofilament light chain (NfL) measurements and full blood counts were obtained. Results: 250 pwMS (113 RMS, 137 PMS) received CPD. 211/250 completed a second cycle. Baseline age 45 (17-72) years and baseline EDSS 0-8.5. The safety and tolerability profile of CPD was generally very good. Six severely disabled pwMS died (one each from influenza, encephalitis, hypoxic brain injury due to choking, COVID19 pneumonia, haemopericardium and dissecting aortic aneurysm and unknown [prior EDSS 9.5]). One myocardial infarction, two breast cancers, one pulmonary embolism occurred, and three severe allergic skin reactions without long term sequelae. Severe lymphopenia (WHO grade 3-4) occurred in 7% despite personalised dosing. In 74/155 pwMS (47.7% of those with EDSS data available), EDSS remained stable or improved at follow up (median 2.9 years). In n=37, mean pre- and post-treatment CSF-NfL measurements at -4.4 and 11.3 months, respectively, were 1079pg/ml (CI 557, 1601) and 508pg/ml (CI 330, 686). Conclusions: Our ongoing observations of this uncontrolled real world cohort suggests CPD is a safe, well tolerated treatment for pwMS with disease activity. Efficacy of cladribine in preserving upper limb function in advanced MS (EDSS 6.5-8.5) will be tested in the ChariotMS trial.

Experience with the COVID-19 AstraZeneca vaccination in people with multiple sclerosis.

BACKGROUND: Some people with multiple sclerosis (pwMS) are at increased risk of severe Coronavirus disease 19 (COVID-19) and should be rapidly vaccinated. However, vaccine supplies are limited, and there are concerns about side-effects, particularly with the ChAdOx1nCoV-19 (AstraZeneca) vaccine. OBJECTIVES: To report our first experience of pwMS receiving the AstraZeneca vaccine. METHODS: Service evaluation. pwMS using the MS service at Barts Health NHS Trust were sent questionnaires to report symptoms following vaccination. RESULTS: Thirty-three responses were returned, 29/33 pwMS received a first dose of AstraZeneca vaccine, the remaining four received a first dose of BioNTech/Pfizer vaccine. All but two patients (94%) reported any symptoms including a sore arm (70%), flu-like symptoms (64%), fever (21%), fatigue (27%), and headache (21%). In more than 2/3 patients, symptoms lasted up to 48 hours, and with the exception of two pwMS reporting symptom duration of 10 and 12 days, respectively, symptoms in the remainder resolved within seven days. No severe adverse effects occurred. CONCLUSIONS: pwMS report transient symptoms following AstraZeneca vaccination, characteristics of which were similar to those reported in the non-MS population. Symptoms may be more pronounced in pwMS due to the temperature-dependent delay in impulse propagation (Uhthoff's phenomenon) due to demyelination.