Discontinuation of dimethyl fumarate in multiple sclerosis - a nationwide study.

BACKGROUND: Adherence is a prerequisite for the efficacy of any drug, and previous studies have shown that non-adherence is associated with disease activity and increased health care cost in multiple sclerosis (MS). The aim of this study was to investigate rates and reasons for discontinuation of dimethyl fumarate (DMF) among people with MS on a national level and differences between clinics in Denmark. METHODS: This was a nationwide, registry and population study of patients treated with DMF. We calculated standard residuals (SR) demonstrate differences between clinics. For survival analysis regarding discontinuation rates and discontinuation due to specific AEs we used log-rank test Cox-proportional hazards and plotted Kaplan-Meier graphics. RESULTS: We included 2,448 people with MS, treated with DMF from 2013 to 2020. Average treatment duration was 26 months (5,382 treatment years). 49.2 % of patients who initiated treatment with DMF (n = 1205) were continuously treated. Reasons for discontinuation were adverse events (54.5 %, n = 656), active disease (26.1 %, n = 315), pregnancy (9.4 %, n = 113) or other reasons (13.2 %, n = 159). We compared SR to the mean regarding reasons for discontinuation and found significant differences between sites regarding gastrointestinal adverse events, flushing and lymphopenia. Discontinuation due to all adverse events, flushing and lymphopenia were more frequent in female than male patients. CONCLUSION: In this population-based study, we found major differences between the MS clinics in rates and reason for discontinuation of DMF. Our results suggest that management strategies during DMF treatment can reduce discontinuation rates.

AMPA and NMDA receptor antibody autoimmune encephalitis preceded by ocular myasthenia gravis: a case report.

BACKGROUND: α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the brain and may be targeted by autoantibodies, leading to autoimmune synaptic encephalitis (AE). AE can be associated with other autoimmune diseases. However, the cooccurrence of anti-AMPA and NMDA receptor AE together with myasthenia gravis (MG) is unusual. CASE PRESENTATION: A 24-year-old previously healthy male presented with seronegative ocular MG, the diagnosis of which was supported by single-fiber electrophysiology findings. Three months later, he developed AE, initially being positive for AMPA receptor antibodies and subsequently for NMDA receptor antibodies. No underlying malignancy was found. In response to aggressive immunosuppressive treatment, he recovered (modified Rankin Scale (mRS) score change from 5 to 1). Despite some cognitive problems at the 1-year follow-up, which were not revealed using the mRS, he was able to return to his studies. CONCLUSIONS: AE may coexist with other autoimmune disorders. Patients with seronegative MG, including ocular MG, may develop autoimmune encephalitis with more than one cell-surface antibody.

Real-world experience of cladribine treatment in relapsing-remitting multiple sclerosis: A Danish nationwide study.

BACKGROUND: Cladribine is a nucleoside analogue interfering with synthesis and repair of DNA. Treatment with cladribine leads to a preferential reduction in lymphocytes, resulting in profound depletion of B-cells with a rapid recovery of naïve B-cells, while T-cell show a lesser but long-lasting depletion It is approved for treatment of relapsing multiple sclerosis (MS). Cladribine tablets 3.5 mg/kg bodyweight are administered in two yearly treatment courses, each including two treatment series lasting 4 or 5 days, one at the start of the first month and the other at the start of the second month. OBJECTIVE: To describe treatment patterns of cladribine in a real-world setting. METHODS: Registry based observational cohort study with prospectively enrolled cases from December 2017 through June 2021. The data source is The Danish Multiple Sclerosis Registry, which is a near complete nationwide population-based registry. Outcomes were length of the treatment, preceding and following treatments, treatment response, and safety data. RESULTS: In total 268 patients had started therapy with cladribine tablets, 89 men and 179 women, with a median age of 40 years (interquartile range (IQR) 32-48. The disease course was relapsing-remitting MS in 97.8% of the patients, and at treatment start the median time from disease onset was 8.1 years (IQR 4.2-14.5) and EDSS 2.5 (IQR 1.5-3.5). Thirty-four patients (12.7%) were treatment naïve while 56 (20.9%) had received one previous disease-modifying therapy (DMT), 67 (25.0%) two, and 111 (41.4%) three or more previous DMTs. In total, 214 (80.0%) patients had completed the full treatment of two courses of cladribine, while 54 (20.0%) had received only one course of cladribine tablets. The median follow-up time after cladribine initiation was 34.7 months (IQR 23.3-43.7). Compared with an annualized relapse rate (ARR) of 0.67 (95% CI [0.56, 0.79]) in the year prior to start of cladribine, ARR was reduced to 0.11 (95% CI [0.08, 0.15]) in year 0-2 after 3-month re-baseline with cladribine (84.8% reduction). Adverse events, reported in 44 (16.4%) of the patients, were mild or moderate, and herpes zoster was only reported in 2 patients. In total, 30 (11.2%) patients discontinued cladribine treatment, of whom 7 (2.6%) discontinued because of adverse effects and 12 (4.5%) discontinued because of disease activity. CONCLUSION: In this nationwide review of all Danish patients starting therapy with cladribine tablets in a real-world setting, cladribine treatment was safe, and the therapeutic response was as expected from previous clinical trials. A prolonged observation period is necessary to assess the long-term benefit and risk of cladribine.

Ocrelizumab treatment in multiple sclerosis: A Danish population-based cohort study.

BACKGROUND AND PURPOSE: Real-world evidence regarding the effectiveness and safety of ocrelizumab for the treatment of multiple sclerosis (MS) is limited. The aim was to evaluate the effectiveness and safety of ocrelizumab treatment for MS in a real-world setting. METHODS: A nationwide population-based cohort study was conducted where clinical and magnetic resonance imaging data of MS patients enrolled prospectively in the Danish Multiple Sclerosis Registry who initiated ocrelizumab treatment between January 2018 and November 2020 were analyzed. RESULTS: A total of 1104 patients (85.7% relapsing-remitting MS [RRMS], 8.8% secondary progressive MS [SPMS], 5.5% primary progressive MS [PPMS]) were included, with a median follow-up period of 1.3 years. At baseline, the mean age was 41.4 years in the RRMS group, 44.5 years in the PPMS group and 50.3 years in the SPMS group. Median Expanded Disability Status Scale score was 2.5, 3.5 and 5.5, respectively. Most RRMS and SPMS patients had received previous disease-modifying therapies (87.5% and 91.8%, respectively), whereas PPMS patients were mostly treatment naïve (78.7%). After ocrelizumab initiation, 9.3% of the patients experienced a relapse and 8.7% a 24 weeks confirmed disability worsening. Conversely, 16.7% showed a 24 weeks confirmed disability improvement. After ~1 year of treatment, most patients (94.5%) were free of magnetic resonance imaging activity. Ocrelizumab was generally well tolerated, as side effects were only reported for 10% of patients, mostly consisting of infusion-related reactions and infections. CONCLUSIONS: It is shown that most MS patients treated with ocrelizumab are clinically stabilized and with an adverse event profile consistent with the experience from the pivotal clinical trials.

Qualitative factors shaping MS patients' experiences of infusible disease-modifying drugs: a critical incident technique analysis.

OBJECTIVE: To explore factors shaping the experiences of patients with relapsing-remitting multiple sclerosis with infusible disease-modifying drugs in a hospital setting. DESIGN AND SETTINGS: The critical incident technique served as a framework for collecting and analysing patients' qualitative account practices involving infusible disease-modifying drugs. Data were collected through semistructured interviews and one single-case study. Participants were recruited from all five regions in Denmark. Inductive thematic analysis was used to identify and interpret factors shaping patients' infusion journey over time. PARTICIPANTS: Twenty-two patients with relapsing-remitting multiple sclerosis receiving infusion with disease-modifying drugs (natalizumab, alemtuzumab and ocrelizumab). RESULTS: Four time scenarios-preinfusion, day of infusion, long-term infusion and switch of infusion-associated with the infusion of disease-modifying drugs were analysed to reveal how different factors could both positively and negatively affect patient experience. Time taken to make the treatment decision was affected by participants' subjective perceptions of their disease activity; this may have set off a treatment dilemma in the event of a pressing need for treatment. Planning and routine made infusion practices manageable, but external and internal surroundings, including infusion room ambience and the quality of relationships with healthcare professionals and fellow patients, affected patients' cognitive state and well-being irrespective of the infusion regimen. Switching the infusion regimen can reactivate worries akin to the preinfusion scenario. CONCLUSION: This study provides novel insight into the positive and negative factors that shape patients' experience of infusion care practices. From a patient's perspective, an infusion practice is not a solitary event in time but includes planning and routine which become an integral part of their multiple sclerosis management. The quality of space and the ambience of the infusion room, combined with the relationship with healthcare professionals and fellow patients, can be a significant source of knowledge and support people with relapsing-remitting multiple sclerosis in their experience of agency in life.

Initial high-efficacy disease-modifying therapy in multiple sclerosis: A nationwide cohort study.

OBJECTIVE: To determine the effectiveness of high-efficacy disease-modifying therapies (heDMTs) vs medium-efficacy disease-modifying therapies (meDMT) as the first treatment choice in treatment-naive patients with multiple sclerosis (MS) on disability worsening and relapses. We assessed this using a nationwide population-based MS registry. METHODS: We identified all patients starting a heDMT as first-time treatment from the Danish Multiple Sclerosis Registry and compared treatment outcomes with a propensity score matched sample of patients starting meDMT. RESULTS: We included 388 patients in the study: 194 starting initial therapy with heDMT matched to 194 patients starting meDMT. At 4 years of follow-up, the probabilities of a 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening were 16.7% (95% confidence interval [CI] 10.4%-23.0%) and 30.1% (95% CI 23.1%-37.1%) for heDMT and meDMT initiators, respectively (hazard ratio [HR] 0.53, 95% CI 0.33-0.83, p = 0.006). Patients initiating heDMT also had a lower probability of a first relapse (HR 0.50, 95% CI 0.37-0.67). Results were similar after pairwise censoring and in subgroups with high baseline activity, diagnosis after 2006, or information on baseline T2 lesion load. CONCLUSION: We found a lower probability of 6-month confirmed EDSS score worsening and lower probability of a first relapse in patients starting a heDMT as first therapy, compared to a matched sample starting meDMT. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS, starting heDMT lowers the risk of EDSS worsening and relapses compared to starting meDMT.

Clinically stable disease is associated with a lower risk of both income loss and disability pension for patients with multiple sclerosis.

OBJECTIVE: To assess the risk of losing income from salaries and risk disability pension for multiple sclerosis patients with a clinically stable disease course 3 years after the start of disease-modifying therapy (DMT). METHODS: Data from the Danish Multiple Sclerosis Registry were linked to other Danish nationwide population-based databases. We included patients who started treatment with a DMT between 2001 and 2014. Patients were categorised into a clinically stable group (No Evidence of Disease Activity (NEDA-2)) and a clinically active group (relapse activity or 6-month confirmed Expanded Disability Status Scale worsening). Outcomes were: (1) loss of regular income from salaries and (2) a transfer payment labelled as disability pension. We used a Cox proportional hazards model to estimate confounder-adjusted HRs, and absolute risks were plotted using cumulative incidence curves accounting for competing risks. RESULTS: We included 2406 patients for the income analyses and 3123 patients for the disability pension analysis. Median follow-up from index date was ~5 years in both analyses. The NEDA-2 group had a 26% reduced rate of losing income (HR 0.74; 95% CI 0.60 to 0.92). HRs were calculated for 5-year intervals in the disability pension analysis: year 0-5: a 57% reduced rate of disability pension for the NEDA-2 group (HR 0.43; 95% CI 0.33 to 0.55) and year 5-10: a 36% reduced rate (HR 0.64; 95% CI 0.40 to 1.01). CONCLUSION: Clinically stable disease course (NEDA-2) is associated with a reduced risk of losing income from salaries and a reduced risk of disability pension.

Non-linear relationship between maternal work hours and child body weight: Evidence from the Western Australian Pregnancy Cohort (Raine) Study.

Using longitudinal data from the Western Australia Pregnancy Cohort (Raine) Study and both random-effects and fixed-effects models, this study examined the connection between maternal work hours and child overweight or obesity. Following children in two-parent families from early childhood to early adolescence, multivariate analyses revealed a non-linear and developmentally dynamic relationship. Among preschool children (ages 2 to 5), we found lower likelihood of child overweight and obesity when mothers worked 24 h or less per week, compared to when mothers worked 35 or more hours. This effect was stronger in low-to-medium income families. For older children (ages 8 to 14), compared to working 35-40 h a week, working shorter hours (1-24, 25-34) or longer hours (41 or more) was both associated with increases in child overweight and obesity. These non-linear effects were more pronounced in low-to-medium income families, particularly when fathers also worked long hours.