Risk of T2 lesions when discontinuing fingolimod: a nationwide predictive and comparative study.

Fingolimod is a frequently used disease-modifying therapy in relapsing-remitting multiple sclerosis. However, case reports and small observational studies indicate a highly increased risk of disease reactivation after discontinuation. We aimed to investigate the risk of radiological disease reactivation in patients discontinuing fingolimod. We performed a nationwide cohort study in Denmark, including patients who discontinued fingolimod between January 2014 and January 2023. Eligibility was a diagnosis with relapsing-remitting multiple sclerosis and two MRIs performed respectively within 1 year before and after discontinuing fingolimod. The included patients were compared with those discontinuing dimethyl fumarate with the same eligibility criteria in an unadjusted and matched propensity score analysis. Matching was done on age, sex, Expanded Disability Status Scale, MRI data, cause for treatment discontinuation, treatment duration and relapse rate. The main outcome was the presence of new T2 lesions on the first MRI after treatment discontinuation. To identify high-risk patients among those discontinuing fingolimod, we made a predictive model assessing risk factors for obtaining new T2 lesions. Of 1324 patients discontinuing fingolimod in the study period, 752 were eligible for inclusion [mean age (standard deviation), years, 41 (10); 552 females (73%); median Expanded Disability Status Scale (Q1-Q3), 2.5 (2.0-3.5); mean disease duration (standard deviation), years, 12 (8)]. Of 2044 patients discontinuing dimethyl fumarate in the study period, 957 were eligible for inclusion, presenting similar baseline characteristics. Among patients discontinuing fingolimod, 127 (17%) had 1-2 new T2 lesions, and 124 (17%) had ≥3 new T2 lesions compared with 114 (12%) and 45 (5%), respectively, for those discontinuing dimethyl fumarate, corresponding to odds ratios (95% confidence interval) of 1.8 (1.3-2.3) and 4.4 (3.1-6.3). The predictive model, including 509 of the 752 patients discontinuing fingolimod, showed a highly increased risk of new T2 lesions among those with disease activity during fingolimod treatment and among females under 40 years. This nationwide study suggests that discontinuing fingolimod in some cases carries a risk of developing new T2 lesions, emphasizing the importance of clinical awareness. If feasible, clinicians should prioritize the prompt initiation of new disease-modifying therapies, particularly among young females.

Comorbidity in the aging population with multiple sclerosis: a Danish nationwide study.

Introduction: Multiple sclerosis (MS) is a neurodegenerative disease accumulating disabilities over time. However, the mean age of individuals with MS is increasing, consequently elevating their risk of developing comorbidities. Comorbidities' impact on MS is widely debated. Yet very few countries possess population-based registries, which provide unique opportunities for individual-level data linkage. This study aims to assess acute and chronic comorbidities among elderly patients with MS, comparing them to matched controls. Additionally, this study seeks to investigate the influence of chronic comorbidities on all-cause mortality. Methods: A nationwide register-based study using the Danish Multiple Sclerosis Registry to identify all living patients with MS older than 50 years at the reference date (January 1st, 2022). Patients were matched 1:10 with individuals from the general population. Comprehensive healthcare data within the Danish hospital system were obtained. Chronic comorbidities were classified according to the Charlson Comorbidity Index, while acute comorbidities were based on ICD-10 codes and an "acute" admission type. To investigate all-cause mortality, a Cox regression analysis was conducted. Results: The study encompassed a total of 8,688 individuals with MS, matched with 86,880 controls. The mean age was 63.5 years, with females constituting 68.3%. Individuals with MS exhibited a higher frequency of acute hospitalizations (OR: 2.1, 95% CI: 1.9-2.2), primarily due to various infectious diseases, along with longer median hospital stays (4 vs. 3 days, p < 0.001). When assessed using the Charlson Comorbidity Index, individuals with MS carried a significantly greater burden of chronic comorbidities (p < 0.001). The most prevalent chronic comorbidity among individuals with MS was "Uncomplicated Diabetes" (20.1%). Notably, while individuals with MS displayed an overall lower 5-year survival rate, this difference ceased to be statistically significant among those with a high Charlson Comorbidity Index score of ≥4 (p = 0.32). Conclusion: This study highlights a heightened prevalence of both acute and chronic comorbidities among individuals with MS, with chronic comorbidities significantly increasing the risk of mortality. These findings underscore the critical importance of factoring in comorbidities when devising treatment strategies for individuals living with MS.

Microbiological Etiology in Patients with IE Undergoing Surgery and for Patients with Medical Treatment Only: A Nationwide Study from 2010 to 2020.

Microbiological etiology has been associated with surgery for infective endocarditis (IE) during admission, especially Staphylococcus aureus. We aimed to compare patient characteristics, microbiological characteristics, and outcomes by treatment choice (surgery or not). We identified patients with first-time IE between 2010 and 2020 and examined the microbiological etiology of IE according to treatment choice. To identify factors associated with surgery during initial admission, we used the Aalen-Johansen estimator and an adjusted cause-specific Cox model. One-year mortality stratified by microbiological etiology and treatment choice was assessed using unadjusted Kaplan-Meier estimates and an adjusted Cox proportional hazard model. A total of 6255 patients were included, of which 1276 (20.4%) underwent surgery during admission. Patients who underwent surgery were younger (65 vs. 74 years) and less frequently had cerebrovascular disease, cardiovascular disease, diabetes, and chronic kidney disease. Patients with Staphylococcus aureus IE were less likely to undergo surgery during admission (13.6%) compared to all other microbiological etiologies. One-year mortality according to microbiological etiology in patients who underwent surgery was 7.0%, 5.3%, 5.5%, 9.6%, 13.2, and 11.2% compared with 24.2%, 19.1%, 27,6%, 25.2%, 21%, and 16.9% in patients who received medical therapy for Staphylococcus aureus, Streptococcus spp., Enterococcus spp., coagulase-negative Staphylococci, "other microbiological etiologies", and blood culture-negative infective endocarditis, respectively. Patients with IE who underwent surgery differed in terms of microbiology, more often having Streptococci than those who received medical therapy. Contrary to expectations, Staphylococcus aureus was more common among patients who received medical therapy only.

Socioeconomic status of the elderly MS population compared to the general population: a nationwide Danish matched cross-sectional study.

Introduction/objectives: Multiple sclerosis (MS) leads to physical and cognitive disability, which in turn impacts the socioeconomic status of the individual. The altered socioeconomic trajectory combined with the critical role of aging in MS progression could potentially lead to pronounced differences between MS patients and the general population. Few nations have the ability to connect long-term clinical and socioeconomic data at the individual level, and Denmark's robust population-based registries offer unique insights. This study aimed to examine the socioeconomic aspects of elderly Danish MS patients in comparison to matched controls from the general population. Methods: A nationwide population-based study in Denmark was conducted, comprising all living MS patients aged 50 years or older as of 1 January 2021. Patients were matched 1:10 based on sex, age, ethnicity, and residence with a 25% sample of the total Danish population. Demographic and clinical information was sourced from the Danish Multiple Sclerosis Registry, while socioeconomic data were derived from national population-based registries containing details on education, employment, social services, and household characteristics. Univariate comparisons between MS patients and matched controls were then carried out. Results: The study included 8,215 MS patients and 82,150 matched individuals, with a mean age of 63.4 years (SD: 8.9) and a 2:1 female-to-male ratio. For those aged 50-64 years, MS patients demonstrated lower educational attainment (high education: 28.3 vs. 34.4%, P < 0.001) and fewer received income from employment (46.0 vs. 78.9%, P < 0.001), and working individuals had a lower annual income (48,500 vs. 53,500€, P < 0.001) in comparison to the controls. Additionally, MS patients within this age group were more likely to receive publicly funded practical assistance (14.3 vs. 1.6%, P < 0.001) and personal care (10.5 vs. 0.8%, P < 0.001). Across the entire population, MS patients were more likely to live alone (38.7 vs. 33.8%, P < 0.001) and less likely to have one or more children (84.2 vs. 87.0%, P < 0.001). Conclusion: MS presents significant socioeconomic challenges among the elderly population, such as unemployment, reduced income, and increased dependence on social care. These findings underscore the pervasive impact of MS on an individual's life course, extending beyond the clinical symptoms of cognitive and physical impairment.

The uncertainty period preceding the clinical defined SPMS diagnosis and the applicability of objective classifiers - A Danish single center study.

BACKGROUND: The clinical transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) is often related to a period of diagnostic uncertainty delaying diagnosis. With emerging treatment options for SPMS how to identify RRMS patients at risk of SPMS and when to assign a SPMS diagnosis has become a matter of growing clinical concern. This study aimed to determine the period of diagnostic uncertainty among Danish MS patients. Secondly, this study examined the performance of two objective classifiers in a longitudinal setting regarding their ability to shorten the period of diagnostic uncertainty. METHODS: By using the Danish Multiple Sclerosis Registry, we identified all patients linked to Rigshospitalet with clinically assigned SPMS from 2010 to 2021. We reviewed all patient records and identified the first mentioned sign of progression (FMP). The time between the dates of FMP and clinically assigned SPMS was defined as the period of diagnostic uncertainty. Secondly, we applied two objective classifiers (the Karolinska Decision tree and the MSBase criteria) to generate suggested transition dates and compared them to the ones obtain from the patient records. Detailed descriptions of the population were made at all mentioned timepoints. RESULTS: In total 138 patients were included. We found a median period of diagnostic uncertainty of 2.12 years. The objective classifiers generated a median suggested transition date 3.44 and 4.48 years earlier than the date of clinically assigned SPMS, but they only provided an earlier SPMS transition date in 50.72% and 55.80% of cases. CONCLUSIONS: Our findings emphasize the uncertainty related to the transition from RRMS to SPMS illustrating the need of an improved diagnostic approach. Objective classifiers might have the potential to help reduce the period of diagnostic uncertainty in the future, but in their current form they do not perform satisfactorily enough to solve all difficulties related to detecting SPMS-transition.

Transition of cluster headache phenotype: An interview-based study.

Background Cluster headache exists diagnostically in a chronic and episodic variant between which patients can convert. We aimed to describe how many patients change phenotype, elucidate possible factors associated with this transition and identify differences in clinical features between primary and secondary phenotypes.Methods 540 well-defined cluster headache patients according to current ICHD-criteria completed a cross-sectional semi-structured interview.Results Total transition-incidence for the cohort was 20.7%. Conversion from chronic to episodic was reported by 6.3% and transition from episodic to chronic by 14.4% with attack side shift as a possible predictor (p = 0.007). Compared to primary chronic patients, secondary chronic patients had more frequent (60 vs 34 per month, p = 0.0487), but shorter (60 vs 90 minutes, p = 0.041) attacks. Secondary episodic patients experienced shorter remission periods than primary episodic patients (6 vs 11 months, p = 0.010). Treatment response was poor in all groups and only one third had effective prevention.Conclusion Cluster headache is a fluctuating disorder with a fifth of our cohort having experienced at least one phenotype change during course of disease. Apart from attack side shifts, no predictors for transition were identified. Severity differed between primary and secondary subtypes. Overall, there is an urgent need for better understanding of cluster headache.

Intravenous ofatumumab treatment of multiple sclerosis and related disorders: An observational study.

BACKGROUND: Ofatumumab is an anti-CD20 monoclonal antibody approved for subcutaneous administration for the treatment of relapsing multiple sclerosis (MS), but intravenously administered ofatumumab has been investigated in a phase 2 trial and used off-label. The objective of the present study was to assess disease activity and side effects in relation to longer-term intravenous ofatumumab treatment of MS and related disorders. METHODS: We conducted a retrospective study of patients treated off-label with intravenous ofatumumab for MS, neuromyelitis optica spectrum disease (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) at the Danish Multiple Sclerosis Center. Data was retrieved from the Danish Multiple Sclerosis Registry and through medical chart review. RESULTS: Fifty patients were identified with a median treatment duration of 2.2 years. Annualized relapse rate decreased from 1.03 at baseline to 0.38 during ofatumumab treatment. At 24 months, the probability of having experienced a relapse was 55% and confirmed disability worsening 7%. Frequency of infusion-related reactions was 86% during the first infusion and 42% during the last infusion. Six experienced infections requiring hospitalization. CONCLUSION: Our data indicate a reduction of relapse frequency, stabilization of disability worsening and an acceptable safety profile, although we observed a higher frequency of infusion reactions compared to data from other intravenously administered anti-CD20 monoclonal antibodies. The study supports a class effect of anti-CD20 monoclonal antibodies and the hypothesis that complement activation may be associated to a higher frequency of infusion related reactions.

Time to first treatment and risk of disability pension in relapsing-remitting multiple sclerosis.

Background Initiation of disease-modifying therapy early in the disease course of relapsing-remitting multiple sclerosis (RRMS) has demonstrated beneficial effects on clinical outcomes, but socioeconomic outcomes remain largely unexplored. Objective To investigate the association between the delay from disease onset to first treatment and the hazard of disability pension. Methods We performed a population-based cohort study with data from the nationwide Danish Multiple Sclerosis Registry and Danish nationwide registries. Patients with a disease onset between 1 January 1996 to 5 April 2016 were followed until disability pension or a competing risk/censoring event. 7859 patients were assessed for eligibility of which 5208 were included in the final cohort. Key inclusion criteria were: a diagnosis of multiple sclerosis, relapsing-remitting phenotype, treatment in history, age 18-65 years and an Expanded Disability Status Scale≤4. Patients were categorised according to time from onset to first treatment: within 1 year (early), between 1 and 4 years (intermediate) and from 4 to 8 years (late). Results Of the 5208 patients, 1922 were early, 2126 were intermediate and 1160 were late. Baseline clinical and socioeconomic variables were well balanced. The hazard of receiving disability pension increased with increasing delay of treatment initiation compared with the early group. Cox regression estimates adjusted for clinical and socioeconomic confounders: intermediate (HR, 1.37; 95% CI, 1.12 to 1.68) and late (HR, 1.97; 95% CI, 1.55 to 2.51). Conclusion Early treatment initiation is associated with a reduced risk of disability pension in patients with RRMS. This finding underlines the importance of early diagnosis and treatment on a patient-centred, socioeconomic disability milestone.

Aging With Multiple Sclerosis: Age-Related Factors and Socioeconomic Risks.

Background: Studies have demonstrated an increasing mean age of the population with multiple sclerosis (MS). The association between increased age and socioeconomic outcomes has been investigated sparsely. Objective: The purpose of this study is to describe the demographic and socioeconomic status of the current Danish population of patients with MS according to age and to assess the age-related risks of no income or losing all income from earnings or receiving disability pension. Methods: The nationwide population-based Danish Multiple Sclerosis Registry provided data linked with the Danish Income Statistics Register and the Danish Rational Economic Agents Model (DREAM) database. The prevalence of socioeconomic milestones of the current MS population was compared with healthy controls and the risks of reaching socioeconomic milestones were assessed using cause-specific Cox models and cumulative incidence functions compared to healthy controls. Results: The current Danish population of patients with MS of working age (18-65 years of age) consists of 11,287 patients, of which 29.3% was older than 55 years. In 2018, 38.0% of all patients and 18.9% of controls had no income from earnings, whereas 30.5% of all patients and 7.7% of controls received disability pension. The risk of losing all income from earnings was higher for patients with MS with a hazard ratio (HR) peaking at of 4.0 (95% CI, 3.8-4.2) for the ages of 45-54 years. The risk of receiving disability pension was much higher for patients with MS peaking at a HR of 22.6 (95% CI, 20.9-24.4) for the ages of 25-34 years. Likewise, the absolute risks of both outcomes were higher for the patients with MS at all ages. Conclusion: Danish patients with MS are at a higher risk of losing all income from earnings and at a much higher risk of receiving disability pension compared with healthy controls.

Pregnancy outcomes following maternal or paternal exposure to teriflunomide in the Danish MS population.

Background Teriflunomide (TFL) is an oral drug used for treatment of multiple sclerosis (MS). Due to possible teratogenicity it is contraindicated in women of childbearing potential. Additionally, a low risk of male-mediated embryo-fetal toxicity has been described as the drug can be transmitted via semen. This study investigated the association of adverse perinatal outcomes in newborns with either maternal or paternal exposure to TFL. Methods The Danish Multiple Sclerosis Registry was used to identify all patients treated with teriflunomide from 1st of September 2013 to 31st of December 2018. Data were merged with other nationwide national registries to identify all pregnancies with potential exposure to TFL. Exposure was defined as conception occurring after at least 30 consecutive days of treatment either during treatment or within two years of treatment discontinuation. Exposed pregnancies were matched 1:4 with controls from the general population. Individual outcomes of adverse perinatal events, namely preterm birth, congenital malformations, small for gestational age (SGA), stillbirth or low Apgar score were used to form a composite outcome, any adverse event, which was used for the analysis. Logistic regression was used to estimate the association of having any adverse event in newborns with either maternal or paternal exposure to TFL. Results A total of 112 TFL-exposed pregnancies were included of which 49 had maternal exposure and 63 paternal exposure. Among women, 21/49 pregnancies were terminated - 18 electively and three spontaneously. The remaining 28 pregnancies resulted in healthy newborns of which ≤3 were preterm. None of the newborns presented with malformations, being SGA or with low Apgar score. Among men, all 63 pregnancies resulted in birth of which 4/63 (6.3%) were preterm. Major malformations were registered in ≤3 event, and no newborn presented with low Apgar score or being SGA. No increased association of any adverse event was found in newborns with TFL exposure relative to controls (OR 1.03, 95% CI 0.50-2.13). Conclusion We did not find an increased prevalence of spontaneous abortion, preterm birth, congenital malformations, low Apgar score of being SGA in newborns with maternal or paternal exposure to TFL when compared with the general population. However, the sample was too small to draw firm conclusions.

Pregnancy in women with MS: Impact on long-term disability accrual in a nationwide Danish Cohort.

BACKGROUND: Pregnancy is considered to influence the disease course in women with multiple sclerosis (MS). OBJECTIVE: The aim of this study was to investigate the effect of pregnancy on long-term disability accrual in women with MS. METHODS: The Danish Multiple Sclerosis Registry (DMSR) was used to identify women diagnosed with clinically isolated syndrome or relapsing-remitting MS. Cox models with pregnancy as a time-dependent exposure and propensity score (PS) models were used to evaluate time to reach confirmed Expanded Disability Status Scale (EDSS) score of 4 and 6. RESULTS: A total of 425 women became parous and 840 remained nulliparous. When including pregnancy as a time-dependent exposure, a non-significant association with time to reach EDSS 4 (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.61-1.20) and EDSS 6 (HR 0.70, 95% CI 0.40-1.20) was found. Correspondingly, the PS model showed no association with pregnancy on time to reach EDSS 4 (HR 0.85, 95% CI 0.56-1.28). CONCLUSION: This study concludes that pregnancy does not affect long-term disability accumulation.

[Christmas article: Coitus is not recommended - a systematic review].

The overall positive effects of coitus have not been estimated before. A systematic review and meta-analysis was conducted for coitus versus everything. A search was made in MEDLINE resulting in 1,121 hits. The authors screened studies and conducted a meta-analysis. Thirty publications randomising to coitus or something else were included. Pooled results showed a relative risk of 0.91 (95% CI: 0.86-0.96) favouring "everything else" over coitus. Subjective pleasure is not a primary outcome in any of the included studies, and trialists must have regarded this outcome as less important. In conclusion, coitus cannot be recommended based on the published randomised studies. Evaluation by evidence-based methodology makes it clear, that better alternatives exist.