Background

Retinoid acid X receptor [RXR] gamma agonists promote oligodendrocyte progenitor cell differentiation and remyelination following experimental demyelination.

Objectives

To assess the safety and efficacy of bexarotene, a non-specific RXR agonist licensed for cutaneous T-cell lymphoma, as a remyelinating therapy in people with relapsing remitting multiple sclerosis.

Methods

In a double-blind, placebo-controlled, phase 2a trial (Cambridge Centre for Myelin Repair: CCMR-One), participants aged 18-50 years with relapsing remitting multiple sclerosis, stable on dimethyl fumarate for at least 6 months, were randomised to bexarotene 300mg/m² or placebo for 6 months. The primary efficacy outcome was change in mean lesional magnetisation transfer ratio (MTR) for lesions whose baseline MTR was below the median lesional MTR for that patient. The secondary efficacy outcome was change in full-field visual evoked potential (VEP) latency in eyes with electrophysiological evidence of optic neuropathy (baseline latency >118ms). We analysed by intention to treat.

Results

52 patients were randomised 1:1 to receive six months of bexarotene or placebo. Two placebo patients withdrew before receiving study drug and one bexarotene patient withdrew consent during the trial. All bexarotene patients experienced adverse effects, notably central hypothyroidism (26 [100%]) and hypertriglyceridaemia (24 [92%, mean maximum of 6.79 mmol/L ,SD 4.4]; as well as rash (13 [50%]) and neutropenia (10 [38%]). Two discontinued placebo because of adverse events and five discontinued bexarotene because of rash [2], neutropenia, triglyceridaemia and mood disturbance. The primary efficacy outcome was negative (mean submedian lesion MTR change was 0.25pu in the bexarotene group versus 0.09pu in the placebo group, p=0.54), but in an exploratory, lesion-level analysis, though treatment difference in submedian lesions was too small to achieve significance, it was statistically significantly greater than in supermedian lesions (p=0·007). This suggests that bexarotene has a biological effect on MTR and that this effect is dependent on baseline lesional MTR. This interpretation is supported by the finding that bexarotene treatment reduced full field visual evoked potential latency compared to placebo in the 52 eyes with delayed VEPS at baseline, by 4·66 ms/eye (95% CI -8·38 -0·93; p=0·014) and in all eyes, by a per-protocol analysis, by 4.02ms/eye (P=0.015).

Conclusions

Despite a negative primary efficacy outcome, evidence from both magnetisation transfer ratio imaging and visual evoked potentials suggest that a retinoic X receptor agonist, bexarotene, promotes remyelination in people with multiple sclerosis. We have also a heterogeneous response of MS lesions to a drug promoting remyelination. Although bexarotene’s safety profile precludes its widespread use, these data support efforts to develop a selective RXR-gamma agonist.

Background

The Coronavirus Disease 2019 (COVID-19) pandemic has introduced uncertainties into the multiple sclerosis (MS) community and the focus so far has been the severity of infection among people with MS (pwMS) who have COVID-19. This approach has left questions about the risk of contracting disease in pwMS unanswered which has implications as society gradually returns to normal.

Objectives

To evaluate the trend of COVID-19 incidence in pwMS, their behaviour in response to the outbreak, and the effect of their demographic and clinical characteristics on the likelihood of contracting COVID-19.

Methods

The United Kingdom MS Register (UKMSR) has been collecting demographic and MS related data since 2011 from pwMS all over the UK. On 17 March 2020, existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this on-going study, pwMS answer a COVID-19 related survey at participation and a different follow-up survey every two weeks depending on whether they report COVID-19.

Results

We estimate the nationwide overall incidence of COVID-19 in pwMS as 10% (n=522) among 5237 participants until 24 June 2020. The weekly incidence peaked during the 2^nd week after lockdown started on 23 March 2020 (13.2%) and remained high until it dropped to 3.5% in the 10^th week. The mean (standard deviation) age of the study population was 52.4 (11.9), 76.1% (n=3985) were female, and 95.7% (n=5012) were of white ethnicity. PwMS with a higher web-based Expanded Disability Status Scale (EDSS) score are more likely to self-isolate (odds ratio [OR] 1.389, 95%CI [confidence interval] 1.333−1.447). PwMS who are taking disease modifying therapies (DMTs) and those with progressive MS tend to self-isolate more (OR 1.259, 95%CI 1.059−1.497 and OR 1.245, 95% CI 1.013−1.531, respectively). Older age, progressive MS, and white ethnicity were associated with a lower likelihood of having COVID-19 (OR 0.969, 95%CI 0.957−0.982 and OR 0.595, 95% 0.422−0.838 and OR 0.495, 95%CI 0.347−0.705, respectively). Gender, EDSS, MS Impact Scale version 29 scores and DMTs did not alter the likelihood of contracting COVID-19.

Conclusions

To our knowledge, this is the largest community-based study of COVID-19 in pwMS worldwide. The trend of COVID-19 in pwMS is comparable to that of the UK general population. During a period with strict physical distancing measures, pwMS are not at an increased risk of contracting COVID-19.

Background

Anxiety and depression are more common in people with multiple sclerosis (pwMS) compared to people without MS. The unpredictable nature of the COVID-19 pandemic has caused widespread distress, but it is unknown if it would affect pwMS disproportionately.

Objectives

To evaluate the impact of the COVID-19 pandemic on the mood and well-being of pwMS in the UK and compare it to that of controls.

Methods

The UK MS Register has been collecting Hospital Anxiety and Depression Scale (HADS) data of pwMS since 2011. In the mood and well-being UKMSR COVID-19 study, we asked pwMS (n=5240) and controls (n=376) to answer questions on General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9) for depression and Revised Impact of Event Scale (IES-R) for post-traumatic stress disorder (PTSD) in addition to changes in their lifestyle and well-being during the COVID-19 outbreak.

Results

The HADS score of pwMS (n=2225) during the COVID-19 outbreak had not changed compared to the year before (mean difference 0.004, 95%CI -0.11−0.12, p=0.952 for anxiety and mean difference 0.05, 95%CI -0.05−0.15, p=0.283 for depression). The rate of anxiety (GAD-7>5) in male pwMS (37.2%) was more than controls (24.3%) (p=0.032) but was similar in female pwMS and controls. More male pwMS had moderate to severe depression (PHQ-9>9) compared to controls (28.5.4% vs 12.2%, p=0.003), but again, the rate was similar in females. More pwMS who had COVID-19, experienced anxiety or PTSD (IES-R>32) compared to those without the infection (54% vs 44%, p=0.018; 30.5% vs 22.5%, p=0.024, respectively). The rate of depression was similar in pwMS with or without symptoms of the disease. Anxiety, compared to the actual infection, was more strongly associated with subjective worsening of general health (57.1% vs 37.3%, with anxiety or COVID-19 respectively, p=0.008) or MS symptoms (61% vs 31.3%, p<0.001).

A high proportion of both pwMS and controls did not experience any change in the quality of their relationships. However, more pwMS reported worsening of their relationships compared to controls (21.4% vs 16.7%, p<0.001). The change in loneliness was similar between the two groups with 4 in 10 pwMS and controls feeling lonelier during the outbreak.

Conclusions

Anxiety during the COVID-19 pandemic is having a more profound effect on the general well-being of most patients compared to the infection itself.

Background

Ocrelizumab, an anti-CD20 monoclonal antibody similar in action to rituximab, has demonstrated efficacy in relapsing and primary progressive MS. Late onset neutropenia (LON) is a rare, but serious side-effect of rituximab occurring in 1.3% of patients. There only 2 reported cases of LON related to ocrelizumab. A single case of grade 4 LON occurred during the phase three studies.

Objectives

Increase awareness of the features of late onset neutropenia and improve risk management of disease modifying treatments.

Methods

We discuss a case series of 3 treatment naive patients with active RRMS who developed severe LON (grade 4) after ocrelizumab treatment in MS specialist centres in the United Kingdom.

Results

A 31y female presented with neutropenic sepsis (neutrophils 0.0) 115 days after her third ocrelizumab infusion, requiring treatment with intravenous antibiotics and granulocyte colony stimulating factor (G-CSF). Subsequent multiple episodes of recurrent grade 4 neutropenia (neutrophils 0.0-0.2) occurred over the next 6 months, often requiring G-CSF treatment. Bone marrow aspiration demonstrated normocellular granulopoiesis.

A 35y male developed neutropenic sepsis (neutrophils 0.2) 119 days after the first ocrelizumab infusion which recovered rapidly with G-CSF. He received the 2^nd and 3^rd ocrelizumab doses with no recurrence of neutropenia.

A 22y female developed fever and cough with neutropenia (0.28), 150 days after initial treatment with ocrelizumab. She was treated with IV antibiotics and the neutropenia recovered spontaneously.

Conclusions

The 3 cases demonstrate the spectrum of LON with ocrelizumab. The aetiology of LON is poorly understood, but hypothesised to be mediated by autoimmune destruction, neutrophil apoptosis or failure of release from the bone marrow. The normal bone marrow aspirate suggests peripheral consumption. The cases are important to raise the clinical suspicion of this life threatening complication of disease modifying therapy and the need for serial blood monitoring. Further experience is required to understand risk of recurrence and when it is safe to re-challenge with ocrelizumab.

Background

Ocrelizumab is one of the most effective disease-modifying drugs for MS. As a potent immunosuppressor, ocrelizumab carries significant infection risk and its long-term effects on immunocompetence are not fully understood. Although ocrelizumab is given as a regular six-monthly infusion, it shares several characteristics with immune reconstitution therapies, such as alemtuzumab and cladribine. Alemtuzumab and cladribine deplete circulating lymphocytes and ocrelizumab specifically depletes circulating B-cells, with reconstitution of cells occurring from bone marrow. It is not known whether the therapeutic effect of ocrelizumab outlasts the administration period. Giving ocrelizumab in a time-limited fashion could reduce both short- and long-term side effects, as well as provide a substantial cost reduction.

Objectives

Share experience of a case in order to stimulate investigation into ocrelizumab as an immune reconstitution therapy.

Methods

1. Consent was successfully obtained to present the patient's case.

2. Case details were collated, including radiological and laboratory data.

Results

A 24-year-old female patient was diagnosed with MS following subacute onset left hemiparesis, positive CSF oligoclonal bands, exclusion of mimics and MRI showing multiple T2 lesions in the periventricular areas, corpus callosum and juxtacortical areas. Her baseline MRI performed immediately prior to treatment commencement showed five new T2 lesions with new enhancement. She was treated with five doses of ocrelizumab at six-monthly intervals between 2012-14 as part of a clinical trial. She then decided to withdraw from the study to travel, but returned to the UK in 2020. Despite cessation of all disease modifying treatment for six years the patient reported no clinical relapses, and in comparison with the MRI at treatment cessation in 2014 there were no new lesions or enhancement. Lymphocyte subset analysis showed reconstitution of B-cells (578 x 10⁶ cells/L; normal range 50-500 x 10⁶ cells/L). The patient is fit and well and suffered no side effects of treatment.

Conclusions

A patient treated early with a limited course of ocrelizumab for two years demonstrated no evidence of disease activity (NEDA2) after six years without treatment. Caution is recommended in extrapolation from a single case, however investigation of ocrelizumab as an immune reconstitution therapy is warranted. Limited duration ocrelizumab treatment could have substantial benefits in terms of side effects, cost and patient convenience whilst maintaining efficacy.