Melinda Magyari

Reproduction and the risk of multiple sclerosis.

Background: The incidence of multiple sclerosis (MS) in Denmark has doubled in women since 1970, whereas it has been almost unchanged in men. Objectives: To investigate whether age at first childbirth and number of births have an effect on the risk of developing MS. Methods: The cohort consisted of 1403 patients with MS of both sexes, identified through the Danish Multiple Sclerosis Registry, with clinical onset between 2000 and 2004. For each case, 25 control persons were drawn by random from the Danish Civil Registration System matched by sex, year of birth, and residential municipality. Results: More female cases than controls had no childbirths or fewer births before clinical onset (p=0.018) but only in the last five years preceding onset (p<0.0001). Childbirths within five years before clinical onset reduced the risk of MS onset in women: OR=0.54 (95% CI 0.41–0.70, p<0.0001) for one child and OR=0.68 (95% CI 0.53–0.87, p=0.002) for more than one child. Parental age at first childbirth had no effect on the risk of MS. Conclusions: The data did not suggest reversed causality between childbirth and MS.

Neonatal vitamin D status and risk of multiple sclerosis A population-based case-control study

Objective: As previous research has suggested that exposure to vitamin D insufficiency in utero may have relevance for the risk of multiple sclerosis (MS), we aimed to examine the direct association between level of neonatal vitamin D and risk of MS. Methods: We carried out a matched case-control study. Dried blood spots samples (DBSS) belonging to 521 patients with MS were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1–2 controls with the same sex and birth date were retrieved from the Biobank (n = 972). Level of 25-hydroxyvitamin D (25[OH]D) in the DBSS was measured using liquid chromatography tandem mass spectroscopy. The association between different levels of 25(OH)D and risk of MS was evaluated by odds ratios (OR) calculated in conditional logistic regression models. Results: We observed that lower levels of 25(OH)D in neonates were associated with an increased risk of MS. In the analysis by quintiles, MS risk was highest among individuals in the bottom quintile (<20.7 nmol/L) and lowest among those in the top quintile of 25(OH)D (≥48.9 nmol/L), with an OR for top vs bottom of 0.53 (95% confidence interval [CI] 0.36–0.78). In the analysis treating 25(OH)D as a continuous variable, a 25 nmol/L increase in neonatal 25(OH)D resulted in a 30% reduced risk of MS (OR 0.70, 95% CI 0.57–0.84). Conclusion: Low concentrations of neonatal vitamin D are associated with an increased risk of MS. In light of the high prevalence of vitamin D insufficiency among pregnant women, our observation may have importance for public health.

Demyelinizing neurological disease after treatment with tumor necrosis factor alpha-inhibiting agents in a rheumatological outpatient clinic: description of six cases.

Biological treatment with inhibitors of the pro-inflammatory cytokine TNF-alpha has dramatically improved the disease course of several chronic rheumatologic conditions. Adverse events (AEs) are primarily infections and hypersensitivity reactions. Demyelinizing neurological symptoms resembling multiple sclerosis (MS) have been described as a rare AE. During about 10-year use of anti TNF-alpha, the Danish Medicines Agency has recorded eight cases of MS like AEs. The objective of this study was to estimate the incidence of demyelinizing AEs both in the central and peripheral nervous system after treatment with anti TNF-alpha in a cohort of patients from a large rheumatologic outpatient clinic in Copenhagen. In a 4-year period from January 2008 to December 2011, approximately 550 patients annually were undergoing treatment with anti TNF-alpha inhibitors in our department. We collected data on all patients who developed neurological symptoms during this time period. We found six patients with signs of demyelinizing neurological disorders: four resembling MS, one MS-like condition, and one multifocal motor neuropathy. During a relatively short time period, we found a remarkably high number of neurological demyelinizing AEs probably linked to anti TNF-alpha treatment. The AEs were not associated with a single anti TNF-alpha agent and were thus presumably a class effect. The data presented suggest that neurological AEs may be underreported. We advocate that physicians handling patients during treatment with TNF inhibitors are aware of this potentially serious AE and report these events to the proper medical authorities.

Registers of multiple sclerosis in Denmark

There are two nationwide population‐based registers for multiple sclerosis (MS) in Denmark. The oldest register is The Danish Multiple Sclerosis Registry (DMSR), which is an epidemiological register for estimation of prevalence and incidence of MS and survival, and for identifying exposures earlier in life that may affect the risk of MS. This register has no systematic follow‐up data except for survival. The DMSR has over the years published nationwide incidence‐ and prevalence data from Denmark and has been involved in a number of ‘historical prospective’ studies to elucidate the association between a number of different environmental exposures in the past and the subsequent risk of MS. Some of these studies have been able to exonerate suspected risk factors. The other register, the nationwide Danish Multiple Sclerosis Treatment Register, is a follow‐up register for all patients who have received disease‐modifying treatments since 1996. It has, in particular, contributed to the knowledge of the role of antibodies against the biological drugs used for the treatment of MS.

A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod

Background: Natalizumab and fingolimod were approved for treatment of active relapsing-remitting multiple sclerosis (RRMS) in Denmark in 2006 and 2011, respectively. There have been no randomized head-to-head studies comparing the two drugs. Objective: To compare the clinical efficacy of natalizumab and fingolimod. Methods: Data on all Danish RRMS patients who started their first second-line treatment with natalizumab or fingolimod from July 2011 to March 2015 were prospectively recorded in the Danish Multiple Sclerosis (MS) Treatment Register. The two treatment arms were 1:1 propensity score matched by baseline covariates using ‘nearest neighbour’ method. Results: Propensity score matching left 928 of 1309 RRMS cases, 464 in each treatment group. The on-treatment annualized relapse rate was 0.296 (95% confidence interval (CI): 0.26–0.34) for natalizumab and 0.307 (95% CI: 0.27–0.35) for fingolimod. The adjusted relapse rate ratio was 0.93 (95% CI: 0.74–1.17; p = 0.53). Mean time to first relapse was 2.55 and 2.56 years, respectively (p = 0.76). There was no difference in change of Expanded Disability Status Scale (EDSS). Conclusion: We found no differences in clinical disease activity between natalizumab- and fingolimod-treated RRMS patients in this real-life observational study. However, the lack of magnetic resonance imaging (MRI) data for the propensity score matching may conceal a higher efficacy of natalizumab.

High-dose erythropoietin in patients with progressive multiple sclerosis: A randomized, placebo-controlled, phase 2 trial

Background: Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). Objective: To evaluate a treatment effect of EPO on progressive MS. Methods: This was a single-center, randomized, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6.5 and clinical progression without relapses in the 2 preceding years. The primary outcome was the change in a composite measure of maximum gait distance, hand dexterity, and cognition from baseline to 24 weeks. Results: A total of 50 patients completed the study. Venesection was performed often but no thromboembolic events occurred. We found no difference in the primary outcome between the EPO and the placebo group using the intention-to-treat principle (p = 0.22). None of the secondary outcomes, neither clinical nor magnetic resonance imaging (MRI) measures showed any significant differences. Conclusion: This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS.

Gender and autoimmune comorbidity in multiple sclerosis

Background: The female preponderance in incidence of multiple sclerosis (MS) calls for investigations into sex differences in comorbidity with other autoimmune diseases (ADs). Objectives: To determine whether male and female patients with MS have a higher frequency of autoimmune comorbidity than controls, and to describe the type and frequency of ADs that are associated with MS. Methods: Our database was established by linkage of the Danish MS Registry to The Danish National Patient Register and consisted of 1403 patients of both sexes with clinical onset of MS between 2000 and 2004, and 25 matched controls for every case. Results: None of the ADs occurred more frequently in female cases than in controls. Male cases were more likely to have Type I diabetes mellitus (odds ratio (OR) = 3.34; 95% CI 1.40 – 7.02; p < 0.008), Crohn’s disease (OR = 5.03; 95% CI 1.18 – 16.10; p = 0.03) and systemic lupus erythematosus (OR = 12.55; 95% CI 1.62 – 69.95; p = 0.02) than male controls. Conclusions: Autoimmune disorders are rare, but some of them tend to occur together with MS at a higher rate than in controls. Although women are generally more prone to ADs than men, significantly increased occurrence of other ADs were only found in male MS patients.

Excess mortality among patients with multiple sclerosis in Denmark has dropped significantly over the past six decades: a population based study

Background Lifetime expectancy in multiple sclerosis (MS) is reduced. Few studies have had sufficient follow-up or sufficient number of patients to assess if survival has improved with time. However, a recent meta-analysis found no time-dependent change in MS excess mortality across studies over recent decades. Objective To investigate whether short-term all-cause excess mortality in patients with MS in the total Danish population has changed over the last six decades. Patients and methods We included all patients with MS recorded in the nationwide Danish MS Registry with definite or probable MS and onset from 1950 through 1999. The Danish Civil Registration System provided date of death for all deceased patients with follow-up in 2015, and Statistics Denmark supplied specific population mortality. We calculated excess number of death per 1000 person-years (EDR) and standardised mortality ratio (SMR). Results We included 18 847 patients among whom 6102 had died as opposed to 2492 expected deaths. EDR was 10.63 (95% CI 10.19 to 11.09) and a SMR was 2.45 (95% CI 2.39 to 2.51). The 15-year EDR dropped gradually from 11.29 (95% CI 9.95 to 12.73) in the 1950–1959 onset cohort to 2.56 (95% CI 1.98 to 3.18) in the 1990–1999 onset cohort, and SMR dropped from 4.48 (95% CI 4.06 to 4.92) to 1.80 (95% CI 1.62 to 1.99). Conclusion The decline in short-term excess mortality in MS started decades before disease-modifying treatment of MS became available, before use of MRI became widespread, and before the McDonald diagnostic criteria were introduced. A change in the MS cohorts with fewer malignant cases may be a significant contributor.

Risk of multiple sclerosis during tumour necrosis factor inhibitor treatment for arthritis: a population-based study from DANBIO and the Danish Multiple Sclerosis Registry

Multiple sclerosis (MS) is a chronic inflammatory neurological disease with multifactorial aetiology.1 Evidence of tumour necrosis factor (TNF)-α as an important factor in the pathogenesis of MS has emerged.2 However, attempts of treating MS with TNF-inhibitors (TNFi) have increased disease activity.3 Several case reports have indicated that demyelinating diseases could be a serious adverse event following TNFi treatment while data from the Spanish Registry of biological therapies in rheumatic diseases did not bring clarification.4 ,5 Some, but not all, studies have suggested a negative association between rheumatoid arthritis (RA) and MS.6 ,7 We aimed to investigate whether TNFi treatment in patients with arthritis is associated with an increased risk of developing MS and whether RA is associated with a decreased risk compared with the general population. The nationwide Danish DANBIO Registry started in 2000 and covers >90% of adults with rheumatological disease treated with TNFi in routine care.8 Since 2005, patients not treated with …

Acute headache and persistent headache attributed to cervical artery dissection: Field testing of ICHD-III beta

The criteria for headache attributed to cervical artery dissection have been changed in the new third edition of the International Classification of Headache Disorders (ICHD-III beta). We have retrospectively investigated 19 patients diagnosed from 2001 to 2006 with cervical artery dissection at onset and followed them up six months after dissection. At dissection onset 17/19 patients were classified as headache probably attributed to vascular disorder at the time of dissection using the ICHD second edition (ICHD-II) criteria. In contrast, 17/19 of patients fulfilled the ICHD-III beta criteria for Headache or facial or neck pain attributed to cervical carotid or vertebral artery dissection or Headache attributed to intracranial arterial dissection. Six months after dissection five of 19 patients still reported persistent headache attributed to dissection. The study demonstrates that the ICHD-III beta criteria for cervical artery dissection are useful for classifying patients at the first encounter. We show for the first time that persistent headache attributed to arterial dissection is frequent.