Nursing Management of Gastrointestinal Adverse Events Associated With Delayed-Release Dimethyl Fumarate: A Global Delphi Approach.

BACKGROUND: Gastrointestinal (GI) adverse events (AEs) are commonly encountered with delayed-release dimethyl fumarate (DMF), an approved treatment for relapsing multiple sclerosis (MS). METHODS: Two hundred thirty-nine MS nurses from 7 countries were asked to complete a 2-round Delphi survey developed by a 7-member steering committee. Questions pertained to approaches for mitigating DMF-associated GI AEs. RESULTS: Ninety-six percent of nurses followed the label recommendation for DMF dose titration in round 1, but 77% titrated the DMF dose more slowly than recommended in round 2. Although 86% of nurses advised persons with relapsing forms of MS (PWMS) to take DMF with food, patients were not routinely informed of appropriate types of food to take with DMF. Most nurses recommended both pharmacologic and nonpharmacologic symptomatic therapies for PWMS who experienced GI AEs on DMF. Pharmacologic and nonpharmacologic symptomatic therapies were regarded as equally effective at keeping PWMS on DMF. In round 2, 58% of nurses stated that less than 10% of PWMS who temporarily discontinued DMF went on to permanently discontinue treatment. Sixty-six percent of nurses stated that less than 10% of PWMS permanently discontinued DMF because of GI AEs in the first 6 months of treatment in round 1. Most nurses agreed that patient education on potential DMF-associated GI AEs contributes to adherence. CONCLUSION: This first real-world nurse-focused assessment of approaches to caring for PWMS with DMF-associated GI AEs suggests that, with implementation of slow dose titration, symptomatic therapies, and educational consultations, most PWMS can remain on DMF and, when necessary after temporary discontinuation, successfully restart DMF.

Common variation near IRF6 is associated with IFN-ß-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-ß (IFN-ß). Up to 60% of IFN-ß-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-ß-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-ß-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-ß-induced liver injury, offering insight into its safer use.

Psychiatric comorbidity is associated with disability progression in multiple sclerosis.

OBJECTIVE: Emerging evidence suggests that comorbidity may influence disability outcomes in multiple sclerosis (MS); we investigated the association between psychiatric comorbidity and MS disability progression in a large multiclinic population. METHODS: This retrospective cohort study accessed prospectively collected information from linked clinical and population-based health administrative databases in the Canadian provinces of British Columbia and Nova Scotia. Persons with MS who had depression, anxiety, or bipolar disorder were identified using validated algorithms using physician and hospital visits. Multivariable linear regression models fitted using an identity link with generalized estimating equations were used to determine the association between psychiatric comorbidity and disability using all available Expanded Disability Status Scale (EDSS) scores. RESULTS: A total of 2,312 incident cases of adult-onset MS were followed for a mean of 10.5 years, during which time 35.8% met criteria for a mood or anxiety disorder. The presence of a mood or anxiety disorder was associated with a higher EDSS score (ß coefficient = 0.28, p = 0.0002, adjusted for disease duration and course, age, sex, socioeconomic status, physical comorbidity count, and disease-modifying therapy exposure). Findings were statistically significant among women (ß coefficient = 0.31, p = 0.0004), but not men (ß coefficient 0.22, p = 0.17). CONCLUSION: Presence of psychiatric comorbidities, which were common in our incident MS cohort, increased the severity of subsequent neurologic disability. Optimizing management of psychiatric comorbidities should be explored as a means of potentially mitigating disability progression in MS.

Effects of physical comorbidities on disability progression in multiple sclerosis.

OBJECTIVE: To examine the association between physical comorbidities and disability progression in multiple sclerosis (MS). METHODS: We conducted a retrospective cohort study using linked health administrative and clinical databases in 2 Canadian provinces. Participants included adults with incident MS between 1990 and 2010 who entered the cohort at their MS symptom onset date. Comorbidity status was identified with validated algorithms for health administrative data and was measured during the 1 year before study entry and throughout the study period. The outcome was the Expanded Disability Status Scale (EDSS) score as recorded at each clinic visit. We used generalized estimating equations to examine the association between physical comorbidities and EDSS scores over time, adjusting for sex, age, cohort entry year, use of disease-modifying drugs, disease course, and socioeconomic status. Meta-analyses were used to estimate overall effects across the 2 provinces. RESULTS: We identified 3,166 individuals with incident MS. Physical comorbidity was associated with disability; with each additional comorbidity, there was a mean increase in the EDSS score of 0.18 (95% confidence interval [CI] 0.09-0.28). Among specific comorbidities, the presence of ischemic heart disease (IHD) or epilepsy was associated with higher EDSS scores (IHD 0.31, 95% CI 0.01-0.61; epilepsy 0.68, 95% CI 0.11-1.26). CONCLUSIONS: Physical comorbidities are associated with an apparent increase in MS disability progression. Appropriate management of comorbidities needs to be determined to optimize outcomes.

Determinants of non-adherence to disease-modifying therapies in multiple sclerosis: A cross-Canada prospective study.

BACKGROUND: Poor adherence to the disease-modifying therapies (DMTs) for multiple sclerosis (MS) may attenuate clinical benefit. A better understanding of characteristics associated with non-adherence could improve outcomes. OBJECTIVE: To evaluate characteristics associated with non-adherence to injectable DMTs. METHODS: Consecutive patients from four Canadian MS Clinics were assessed at three time points over two years. Clinical and demographic information included self-reported DMT use, missed doses in the previous 30 days, health behaviors, and comorbidities. Non-adherence was defined as <80% of expected doses taken. We employed generalized estimating equations to examine characteristics associated with non-adherence at all time points with findings reported as adjusted odds ratios (OR). RESULTS: In all, 485 participants reported use of an injectable DMT, of whom 107 (22.1%) were non-adherent over the study period. Non-adherence was associated with a lower Expanded Disability Status Scale score (0-2.5 vs 3.0-5.5, OR: 1.80; 95% confidence interval (CI): 1.06-3.04), disease duration (⩽5 vs <5 years, OR: 2.23; 95% CI: 1.10-4.52), alcohol dependence (OR: 2.14; 95% CI: 1.23-3.75), and self-reported cognitive difficulties, measured by the Health Utilities Index-3 (OR: 1.55; 95% CI: 1.08-2.22). CONCLUSIONS: Nearly one-quarter of participants were non-adherent during the study. Alcohol dependence, perceived cognitive difficulties, longer disease duration, and mild disability status were associated with non-adherence. These characteristics may help healthcare professionals identify patients at greatest risk of poor adherence.

Examining the effects of comorbidities on disease-modifying therapy use in multiple sclerosis.

OBJECTIVE: Comorbidities are common in multiple sclerosis (MS) and adversely affect health outcomes. However, the effect of comorbidity on treatment decisions in MS remains unknown. We aimed to examine the effects of comorbidity on initiation of injectable disease-modifying therapies (DMTs) and on the choice of the initial DMT in MS. METHODS: We conducted a retrospective observational analysis using population-based health administrative and linked clinical databases in 3 Canadian provinces. MS cases were defined as any individual with ≥3 diagnostic codes for MS. Cohort entry (index date) was the first recorded demyelinating disease-related claim. The outcomes included choice of initial first-line DMTs and time to initiating a DMT. Logistic and Cox regression models were used to examine the association between comorbidity status and study outcomes, adjusting for sex, age, year of index date, and socioeconomic status. Meta-analysis was used to estimate overall effects across the 3 provinces. RESULTS: We identified 10,698 persons with incident MS, half of whom had ≥1 comorbidities. As the total number of comorbidities increased, the likelihood of initiating a DMT decreased. Comorbid anxiety and ischemic heart disease were associated with reduced initiation of a DMT. However, patients with depression were 13% more likely to initiate a DMT compared to those without depression at the index date (adjusted hazard ratio 1.13; 95% confidence interval 1.00-1.27). CONCLUSIONS: Comorbidities are associated with treatment decisions regarding DMTs in MS. A better understanding of the effects of comorbidity on effectiveness and safety of DMTs is needed.

Characteristics associated with drug-induced liver injury from interferon beta in multiple sclerosis patients.

OBJECTIVE: To identify and characterize drug-induced liver injury (DILI) associated with IFN-ß in multiple sclerosis (MS) using recommended criteria. METHODS: This retrospective, mixed methods design included a cohort of IFN-ß exposed MS patients from British Columbia (BC), Canada and a series of DILI cases from other Canadian provinces and two adverse drug reaction (ADR) networks (USA and Sweden). Associations between sex, age and IFN-ß product, and DILI were explored in BC cohort using Cox proportional hazard analyses. Characteristics, including the time to DILI, were compared between sites. RESULTS: In BC, 18/942 (1.9%) of IFN-ß exposed MS patients met criteria for DILI, with a trend toward an increased risk for women and those exposed to IFN-ß-1a SC (44 mcg 3 × weekly) (adjusted Hazard Ratios: 3.15;95% CI:0.72 - 13.72, p = 0.13 and 6.26;95%CI:0.78 - 50.39, p = 0.08, respectively). Twenty-four additional cases were identified from other sites; the median time to DILI was comparable between BC and other Canadian cases (105 and 90 days, respectively), but longer for the ADR network cases (590 days, p = 0.006). CONCLUSIONS: Approximately 1 in 50 IFN-ß exposed patients developed DILI in BC, Canada. Identification of DILI cases from diverse sources highlighted that this reaction occurs even after years of exposure.