A multiple sclerosis disease progression measure based on cumulative disability

BACKGROUND: Existing severity measurements in multiple sclerosis (MS) are often cross-sectional, making longitudinal comparisons of disease course between individuals difficult. OBJECTIVE: The objective of this study is to create a severity metric that can reliably summarize a patient's disease course. METHODS: We developed the nARMSS - normalized ARMSS (age-related MS severity score) over follow-up, using the deviation of individual ARMSS scores from the expected value and integrated over the corresponding time period. The nARMSS scales from -5 to +5; a positive value indicates a more severe disease course for a patient when compared to other patients with similar disease timings. RESULTS: Using Swedish MS registry data, the nARMSS was tested using data at 2 and 4 years of follow-up to predict the most severe quartile during the subsequent period up to 10 years total follow-up. The metric used was area under the curve of the receiver operating characteristic (AUC-ROC). This resulted in measurements of 0.929 and 0.941. In an external Canadian validation cohort, the equivalent AUC-ROCs were 0.901 and 0.908. CONCLUSION: The nARMSS provides a reliable, generalizable and easily measurable metric which makes longitudinal comparison of disease course between individuals feasible

Accurate classification of secondary progression in multiple sclerosis using a decision tree

BACKGROUND: The absence of reliable imaging or biological markers of phenotype transition in multiple sclerosis (MS) makes assignment of current phenotype status difficult. OBJECTIVE: The authors sought to determine whether clinical information can be used to accurately assign current disease phenotypes. METHODS: Data from the clinical visits of 14,387 MS patients in Sweden were collected. Classifying algorithms based on several demographic and clinical factors were examined. Results obtained from the best classifier when predicting neurologist recorded disease classification were replicated in an independent cohort from British Columbia and were compared to a previously published algorithm and clinical judgment of three neurologists. RESULTS: A decision tree (the classifier) containing only most recently available expanded disability scale status score and age obtained 89.3% (95% confidence intervals (CIs): 88.8-89.8) classification accuracy, defined as concordance with the latest reported status. Validation in the independent cohort resulted in 82.0% (95% CI: 81.0-83.1) accuracy. A previously published classification algorithm with slight modifications achieved 77.8% (95% CI: 77.1-78.4) accuracy. With complete patient history of 100 patients, three neurologists obtained 84.3% accuracy compared with 85% for the classifier using the same data. CONCLUSION: The classifier can be used to standardize definitions of disease phenotype across different cohorts. Clinically, this model could assist neurologists by providing additional information

Disease-Modifying Drugs for Multiple Sclerosis and Association With Survival

BACKGROUND AND OBJECTIVES: We examined the association between the disease-modifying drugs (DMDs) for multiple sclerosis (MS) and survival in a multiregion population-based study. METHODS: We accessed multiple administrative health databases from 4 Canadian provinces. Persons with MS were identified and followed from the most recent of the first MS or demyelinating event or January 1, 1996 (index date), until death, emigration, or December 31, 2017. Association between the first-generation and second-generation DMDs and all-cause mortality was examined using stratified Cox proportional hazard models, reported as adjusted hazard ratios (aHRs). Timing of DMD initiation was explored, with findings reported at 2, 5, or 10 years postindex date, representing very early, early, or late initiation. RESULTS: We identified 35,894 persons with MS; 72% were female. The mean age at index date was 44.5 years (SD = 13.6). The total person-years of follow-up while DMD-exposed was 89,180, and total person-years while unexposed was 342,217. Compared with no exposure, exposure to any DMD or to any first-generation DMD was associated with a 26% lower hazard of mortality (both aHRs 0.74; 95% CI 0.56-0.98), while any second-generation DMD exposure was associated with a 33% lower hazard (aHR 0.67; 95% CI 0.46-0.98). Earlier DMD initiation (beta-interferon or glatiramer acetate vs no exposure) was associated with a significant mortality effect (p < 0.05), while later initiation was not (95% CIs included 1). However, the survival advantage with earlier initiation diminished over time, no longer reaching statistical significance at 15 years postindex date. DISCUSSION: Our study demonstrates an association between the DMDs for MS and improved survival in the real-world setting

Disease-modifying drugs for multiple sclerosis and subsequent health service use

OBJECTIVE: We assessed the relationship between the multiple sclerosis (MS) disease-modifying drugs (DMDs) and healthcare use. METHODS: Persons with MS (aged ⩾18 years) were identified using linked population-based health administrative data in four Canadian provinces and were followed from the most recent of their first MS/demyelinating event or 1 January 1996 until the earliest of death, emigration, or study end (31 December 2017 or 31 March 2018). Prescription records captured DMD exposure, examined as any DMD, then by generation (first-generation (the injectables) or second-generation (orals/infusions)) and individual DMD. The associations with subsequent all-cause hospitalizations and physician visits were examined using proportional means model and negative binomial regression. RESULTS: Of 35,894 MS cases (72% female), mean follow-up was 12.0 years, with person-years of DMD exposure for any, or any first- or second-generation DMD being 63,290, 54,605 and 8685, respectively. Any DMD or any first-generation DMD exposure (versus non-exposure) was associated with a 24% lower hazard of hospitalization (adjusted hazard ratio, aHR: 0.76; 95% confidence intervals (CIs): 0.71–0.82), rising to 29% for the second-generation DMDs (aHR: 0.71; 95% CI: 0.58–0.88). This ranged from 18% for teriflunomide (aHR: 0.82; 95% CI: 0.67–1.00) to 44% for fingolimod (aHR: 0.56; 95% CI: 0.36–0.87). In contrast, DMD exposure was generally not associated with substantial differences in physician visits. CONCLUSION: Findings provide real-world evidence of a beneficial relationship between DMD exposure and hospitalizations

Disease-Modifying Drug Uptake and Health Service Use in the Ageing MS Population

Background: Evidence regarding the efficacy or effectiveness of the disease-modifying drugs (DMDs) in the older multiple sclerosis (MS) population is scarce. This has contributed to a lack of evidence-based treatment recommendations for the ageing MS population in practice guidelines. We examined the relationship between age (<55 and ≥55 years), DMD exposure and health service use in the MS population. Methods: We conducted a population-based observational study using linked administrative health data from British Columbia, Canada. We selected all persons with MS and followed from the most recent of their first MS or demyelinating event, 18th birthday or 01-January-1996 (index date) until the earliest of emigration, death or 31-December-2017 (study end). We assessed DMD exposure status over time, initially as any versus no DMD, then by generation (first or second) and finally by each individual DMD. Age-specific analyses were conducted with all-cause hospitalizations and number of physician visits assessed using proportional means model and negative binomial regression with generalized estimating equations. Results: We included 19,360 persons with MS (72% were women); 10,741/19,360 (56%) had ever reached their 55th birthday. Person-years of follow-up whilst aged <55 was 132,283, and 93,594 whilst aged ≥55. Any DMD, versus no DMD in the <55-year-olds was associated with a 23% lower hazard of hospitalization (adjusted hazard ratio, aHR0.77; 95%CI 0.72-0.82), but not in the ≥55-year-olds (aHR0.95; 95%CI 0.87-1.04). Similar patterns were observed for the first and second generation DMDs. Exposure to any (versus no) DMD was not associated with rates of physician visits in either age group (<55 years: adjusted rate ratio, aRR1.02; 95%CI 1.00-1.04 and ≥55 years: aRR1.00; 95%CI 0.96-1.03), but variation in aRR was observed across the individual DMDs. Conclusion: Our study showed beneficial effects of the DMDs used to treat MS on hospitalizations for those aged <55 at the time of exposure. In contrast, for individuals ≥55 years of age exposed to a DMD, the hazard of hospitalization was not significantly lowered. Our study contributes to the broader understanding of the potential benefits and risks of DMD use in the ageing MS population

Age Related Multiple Sclerosis Severity Score: Disability ranked by age.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS) is obtained by normalising the Expanded Disability Status Scale (EDSS) score for disease duration and has been a valuable tool in cross-sectional studies. OBJECTIVE: To assess whether use of age rather than the inherently ambiguous disease duration was a feasible approach. METHOD: We pooled disability data from three population-based cohorts and developed an Age Related Multiple Sclerosis Severity (ARMSS) score by ranking EDSS scores based on the patient's age at the time of assessment. We established the power to detect a difference between groups afforded by the ARMSS score and assessed its relative consistency over time. RESULTS: The study population included 26058 patients from Sweden ( n = 11846), Canada ( n = 6179) and the United Kingdom ( n = 8033). There was a moderate correlation between EDSS and disease duration ( r = 0.46, 95% confidence interval (CI): 0.45-0.47) and between EDSS and age ( r = 0.44, 95% CI: 0.43-0.45). The ARMSS scores showed comparable power to detect disability differences between groups to the updated and original MSSS. CONCLUSION: Since age is typically unbiased and readily obtained, and the ARMSS and MSSS were comparable, the ARMSS may provide a more versatile tool and could minimise study biases and loss of statistical power caused by inaccurate or missing onset dates.Biogen, Neuro Sweden (Neuroförbundet), Cambridge NIHR Biomedical Research Centr

Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 × 10-8, odds ratio = 8.3, 95% confidence interval = 3.6-19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 × 10-5) and alkaline phosphatase (P = 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2):a multicentre observational cohort study

Background: Cerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack. Methods: Our observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316. Findings: Between Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0–20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1–5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27–10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29–0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53–0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60–0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07–0·43, p=0·0065; and 0·33, 0·14–0·51, p=0·00059, respectively). Interpretation: In patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from oral anticoagulation. Funding: The Stroke Association and the British Heart Foundation