SPECIAL REPORT

The following summarizes some of the key data on multiple sclerosis presented at the European Academy of Neurology meeting, held 29 June – 2 July, in Oslo, Norway.

Cancer and mortality among MS patients: An analysis of MS and cancer registries in Norway compared cancer risk in MS patients, non-MS siblings and the general population over a 58-year observation period (Grytten et al. EAN 2019; abstract O1204). The overall cancer risk was 12% higher in MS patients compared to the general population. Cancer risk was highest for respiratory (hazard ratio 1.64), urinary (HR 1.50) and CNS (HR 1.51) malignancies. However, cancer risk was highest in non-MS siblings compared to MS patients and population controls.

Two separate studies of malignancies in MS patients reported mixed results. An analysis of cancer registries during the DMT era (1995-2015) reported no excess in malignancies in Denmark (standardized incidence ratio 0.96), but a higher rate in the Netherlands (SIR 1.8) (Kuiper et al. EAN 2019; abstract EPO2202). The most common malignancy was breast cancer in both countries (Norgaard et al. EAN 2019; abstract EPO2226). A U.S. analysis reported that the incidence rate for all-cause mortality was two-fold higher in MS patients compared to the general population (Persson et al. EAN 2019; abstract O1206). The most common cause of death was pneumonia; the incidence of cancer deaths was not elevated in MS patients.

Sustained NEDA with cladribine: In the CLARITY study, 47% of patients treated with cladribine 3.5 mg/kg achieved no evidence of disease activity (NEDA) at 96 weeks (Giovannoni et al. Lancet Neurol 2011;10:329-37). A retrospective analysis of the extension phase found that NEDA is sustained for up to five years from treatment start (Giovannoni et al. EAN 2019; abstract EPO1244). In the group switched from cladribine 3.5 mg/kg to placebo for the extension, the NEDA rate was 46% in the 12 months up to the end of year 4 and 35% to the end of year 5. For patients receiving a second treatment course (cumulative 7.0 mg/kg), the NEDA rate was 48% to the end of years 4 and 5.

Trial of fingolimod vs. glatiramer acetate: ASSESS is the first head-to-head study to compare fingolimod with glatiramer acetate. RRMS patients were randomized to fingolimod 0.5 mg/day or glatiramer acetate 20 mg/day for one year (Cree et al. EAN 2019; abstract EPR1084). At 12 months, there was a significant 40.7% reduction in annualized relapse rate with fingolimod compared to glatiramer acetate, and significant reductions in the number of new/enlarging T2 lesions, T2 lesion volume, Gd+ lesion number and Gd+ lesion volume versus the injectable.

Cognitive impairment and recovery: A study examined the longitudinal course of cognitive impairment in 59 CIS/RRMS patients evaluated at two time points 10-13 years apart (Katsari et al. EAN 2019; abstract EPO2199). Patients who performed normally on memory tasks at baseline showed significant declines at long-term follow-up. Those with impaired working memory at baseline showed significant improvements over time. The domains of verbal and visual memory showed no further declines from baseline. The authors concluded that some domains of cognitive function may not show progressive worsening during the course of MS.

HPV infection and alemtuzumab: Annual screening for human papillomavirus (HPV) is recommended for females treated with alemtuzumab but more frequent screening may not be required, according to a UK study (Ruffer et al. EAN 2019; abstract EPO3190). An analysis of 80 female patients (mean age 39.1 years) who had received at least one course of alemtuzumab found that 5.0% had dyskaryosis and 1.25% were HPV-positive at baseline. After treatment, abnormal cervical screening was seen in 6.9%; 1.39% of patients were HPV+ at one year. No additional HPV cases were observed in years 3 and 4 although the sample size was small.

Lymphocyte kinetics with cladribine: A small study examined the kinetics of lymphocyte subpopulations in patients treated with oral cladribine 3.5 mg/kg dosed in week 1 and 5 (Ruggieri et al. EAN 2019; abstract EPO1241). After two months, there was a significant 79% decrease in memory B cells, a decrease in regulatory B cells (CD19+CD38+: 56.9%; CD19+CD25+: 74.9%), and a 16% increase in regulatory T cells. The authors suggested that cladribine may restore immune tolerance by increasing the Treg population early in treatment.

Update on evobrutinib: Phase II data for evobrutinib, a novel inhibitor of Bruton’s tyrosine kinase in development for relapsing MS, are now available (see ECTRIMS 2018 Daily Report, NeuroSens, October 10, 2018; https://neuro-sens.com/ectrims-2018-daily-report-wednesday-edition/). The 48-week study randomized relapsing MS patients to placebo or one of three doses of evobrutinib (25 mg OD, 75 mg OD, 75 mg BID); a reference arm of dimethyl fumarate 240 mg BID was included (Montalban et al. EAN 2019; abstract O1205). Placebo-treated patients were switched to evobrutinib 25 mg OD after 24 weeks. The primary endpoint was the number of Gd+ lesions. There was a significant reduction in Gd+ lesion number with evobrutinib 75 mg OD and 75 mg BID, and a significant reduction in new/enlarging T2 lesions with the 75 mg BID dose over weeks 12-24. The annualized relapse rate at 48 weeks was 0.25 and 0.11 with the 75 mg OD and BID doses, respectively. The most common adverse effects were nasopharyngitis and asymptomatic elevations in liver enzymes.

Ig deficiency common in MS: A retrospective study examined Ig deficiency in two cohorts of MS patients in Bern and Athens (n=337) (Zoehner et al. EAN 2019; abstract EPR3107). Ig deficiency was defined as IgG < 7.0 g/L, IgM < 0.4 g/L, and IgA < 0.7 g/L). Deficiencies were common at both centres for IgG (Bern 15.5%, Athens 14.9%), IgM (Bern 16.9%, Athens 7.0%) and IgA (Bern 3.9%, Athens 2.0%). The rates of Ig deficiency were also elevated in untreated MS patients (IgG 7.9%, 8.6%; IgM 12.5%, 5.2%; IgA 0%/1.7%). Serum IgG concentrations were lower in SPMS vs. RRMS or PPMS patients. IgG concentrations were significantly lower in patients treated with rituximab, natalizumab, fingolimod, or IV steroids < 4 weeks before sampling. The authors suggested that Ig deficiency may be associated with an increased infection risk and may confound serological antibody testing (e.g. for JCV or VZV).

Impaired neurotransmitter networks in MS: A study evaluating neurotransmitter network dysfunction in MS reported evidence of diffuse damage to serotonergic, cholinergic, noradrenergic and dopaminergic networks in patients with MS compared to age/sex-matched healthy controls (Carotenuto et al. EAN 2019; abstract EPR1081). Serotonergic, noradrenergic and cholinergic network impairment was significantly associated with disease duration, EDSS score and symptoms of depression. Serotonergic, noradrenergic, cholinergic and dopaminergic network impairment was significantly associated with cognitive dysfunction. Functional changes in neurotransmitter systems may be due to neuronal damage and reorganization which could be amenable to symptomatic treatments that target neurotransmitters.

Is gadolinium necessary? An analysis of MRI scans obtained from 255 treated MS patients over a four-year period found that gadolinium enhancement added little information (Tsantes et al. EAN 2019; abstract EPO3207). Overall, new/enlarging T2 lesions were detected in 13.7% of cases. Only 1.3% of scans detected Gd+ lesions without a T2 lesion equivalent.