Exposure to passive smoking during adolescence is associated with an increased risk of developing multiple sclerosis.

BACKGROUND: Environmental factors are associated with acquiring multiple sclerosis (MS) particularly in adolescence. OBJECTIVE: To test for association between MS and exposure to passive smoking at the age of 10-19. METHODS: A total of 919 patients from the Danish MS Registry and Biobank and 3419 healthy blood donors who had not smoked before the age of 19 were targeted. We analyzed separately for each sex and for those never-smokers (cohort 1) and active smokers above the age of 19 (cohort 2). All participants completed standardized questionnaires about smoking and lifestyle. We matched cases and controls in the ratio of 1:2 by propensity scores discarding unmatchable individuals and used logistic regression adjusted for all covariates and interactions. RESULTS: After matching, we included 110/213 male cases/controls and 232/377 female case/controls in cohort 1. In cohort 2, the numbers were 160/320 and 417/760, respectively. Among women in cohort 1, the odds ratio (OR) for MS by passive smoking at the age of 10-19 was 1.432 (p = 0.037) but in men it was 1.232 (p = 0.39). Among men in cohort 2, OR was 1.593 (p = 0.022) but among women it was only 1.102 (p = 0.44). CONCLUSION: Among never smokers, female MS cases were more often than female controls reported with passive smoking between the age of 10 and 19, and among smokers above the age of 19, male MS patients were more often than male controls reported with passive smoking.

Incidence of MS has increased markedly over six decades in Denmark particularly with late onset and in women.

OBJECTIVE: To describe the pattern of development of incidence of multiple sclerosis (MS) over 60 years in Denmark with age-period-cohort analyses and seasonality of birth. METHODS: Data on virtually all patients with onset of MS have since 1950 been prospectively recorded and kept in the Danish Multiple Sclerosis Registry with multiple sources of notification. Annualized incidence rates per 100,000 were directly standardized to the European Standard Population. RESULTS: We have registered 19,536 cases with clinical onset of confirmed MS in Denmark from 1950 to 2009. From the 1950-1959 to the 2000-2009 onset period, incidence more than doubled in women, with an increase from 5.91 (95% confidence interval [CI]: 5.60-6.24) to 12.33 (95% CI: 11.91-12.75) per 100,000 per year compared with a modest 24% increase in men from 4.52 (95% CI: 4.24-4.81) to 6.08 (95% CI: 5.79-6.38). With age at onset of 50 years and older, incidence increased with a factor 4.30 in women and 2.72 in men. The female/male sex ratio increased over time and with year of birth. Age-period-cohort analysis revealed a significant birth cohort effect in addition to the age and period effect. We found no statistically significant seasonality of births. CONCLUSION: The incidence of MS has doubled in women, most pronounced with late onset, and has only modestly increased in men. Lifestyle changes in the female population that could include fewer childbirths, increased occurrence of obesity, and increased cigarette consumption may have a role.

Smoking affects the interferon beta treatment response in multiple sclerosis.

OBJECTIVE: To investigate whether smoking in patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta (IFN-ß) is associated with the relapse rate and whether there is an interaction between smoking and human leukocyte antigen (HLA)-DRB1*15:01, HLA-A*02:01, and the N-acetyltransferase-1 (NAT1) variant rs7388368A. METHODS: DNA from 834 IFN-ß-treated patients with RRMS from the Danish Multiple Sclerosis Biobank was extracted for genotyping. Information about relapses from 2 years before the start of treatment to either the end of treatment or the last follow-up visit was obtained from the Danish Multiple Sclerosis Treatment Register. Smoking information came from a comprehensive questionnaire. RESULTS: We found that the relapse rate in patients with RRMS during IFN-ß treatment was higher in smokers compared to nonsmokers, with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 1.021-1.416, p = 0.027) and with an IRR increase of 27% per pack of cigarettes per day (IRR 1.27, 95% CI 1.056-1.537, p = 0.012). We found no association or interaction with HLA and the NAT1 variant. CONCLUSION: In this observational cohort study, we found that smoking is associated with increased relapse activity in patients with RRMS treated with IFN-ß, but we found no association or interaction with HLA or the NAT1 variant.

Comorbidity in multiple sclerosis is associated with diagnostic delays and increased mortality.

OBJECTIVE: To investigate the effect of chronic comorbidity on the time of diagnosis of multiple sclerosis (MS) and on mortality in MS. METHODS: We conducted a population-based, nationwide cohort study including all incident MS cases in Denmark with first MS symptom between 1980 and 2005. To investigate the time of diagnosis, we compared individuals with and without chronic comorbidity using multinomial logistic regression. To investigate mortality, we used Cox regression with time-dependent covariates, following study participants from clinical MS onset until endpoint (death) or to the end of the study, censuring at emigration. RESULTS: We identified 8,947 individuals with clinical onset of MS between 1980 and 2005. In the study of time of diagnosis, we found statistically significant odds ratios for longer diagnostic delays with cerebrovascular comorbidity (2.01 [1.44-2.80]; <0.0005), cardiovascular comorbidity (4.04 [2.78-5.87]; <0.0005), lung comorbidity (1.93 [1.42-2.62]; <0.0005), diabetes comorbidity (1.78 [1.04-3.06]; 0.035), and cancer comorbidity (2.10 [1.20-3.67]; 0.009). In the mortality study, we found higher hazard ratios with psychiatric comorbidity (2.42 [1.67-3.01]; <0.0005), cerebrovascular comorbidity (2.47 [2.05-2.79]; <0.0005), cardiovascular comorbidity (1.68 [1.39-2.03]; <0.0005), lung comorbidity (1.23 [1.01-1.50]; 0.036), diabetes comorbidity (1.39 [1.05-1.85]; 0.021), cancer comorbidity (3.51 [2.94-4.19]; <0.0005), and Parkinson disease comorbidity (2.85 [1.34-6.06]; 0.007). CONCLUSIONS: An increased awareness of both the necessity of neurologic evaluation of new neurologic symptoms in persons with preexisting chronic disease and of optimum treatment of comorbidity in MS is critical.

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.

Inverse comorbidity in multiple sclerosis: Findings in a complete nationwide cohort.

BACKGROUND: Inverse comorbidity is disease occurring at lower rates than expected among persons with a given index disease. The objective was to identify inverse comorbidity in MS. METHODS: We performed a combined case-control and cohort study in a total nationwide cohort of cases with clinical onset of MS 1980-2005. We randomly matched each MS-case with five population controls. Comorbidity data were obtained from multiple, independent nationwide registries. Cases and controls were followed from January 1977 to the index date, and from the index date through December 2012. We controlled for false discovery rate and investigated each of eight pre-specified comorbidity categories: psychiatric, cerebrovascular, cardiovascular, lung, and autoimmune comorbidities, diabetes, cancer, and Parkinson's disease. RESULTS: A total of 8947 MS-cases and 44,735 controls were eligible for inclusion. We found no inverse associations with MS before the index date. After the index date, we found a decreased occurrence of chronic lung disease (asthma and chronic obstructive pulmonary disease) (HR 0.80 (95% CI 0.75-0.86, p<0.00025)) and overall cancer (HR 0.88 (95% CI 0.81-0.95, p=0.0005)) among MS-cases. CONCLUSION: This study showed a decreased risk of cancers and pulmonary diseases after onset of MS. Identification of inverse comorbidity and of its underlying mechanisms may provide important new entry points into the understanding of MS.

Polymorphisms of innate pattern recognition receptors, response to interferon-beta and development of neutralizing antibodies in multiple sclerosis patients.

BACKGROUND: Interferon-beta therapy of patients with relapsing-remitting multiple sclerosis involves repeated 'immunizations' with exogenous protein solutions. Innate pattern recognition receptors play an important role in immune responses towards foreign substances and may thus be related to treatment outcome. OBJECTIVE: To determine the genotypes at 42 single nucleotide polymorphism loci in selected pattern recognition receptors for 567 prospectively followed relapsing-remitting multiple sclerosis patients treated with recombinant interferon-beta, and test for relationships to several outcome parameters, including formation of interferon-beta neutralizing antibodies. RESULTS: The results suggest an association between the rs5743810 polymorphism (Ser249Pro) of TLR6 and development of neutralizing antibodies after 24 months of therapy in males (p = 0.00002), but not in females (p = 0.2). This association survived crude Bonferroni correction (p (corrected) = 0.02). Additional associations were observed in carriers of the TLR2-rs5743708 and NOD2-rs3135499 SNPs (time to relapse), the TLR7-rs179008 and NOD1-rs2075820 SNPs (time to disease progression) and the TLR4-rs7873784, TLR9-rs5743836, and NOD2-rs2066842 SNPs (frequency of neutralizing antibodies development). All of these, however, failed to survive correction for multiple testing. There were no significant differences between interferon-beta responders and non-responders for any of the investigated single nucleotide polymorphisms. CONCLUSIONS: The rs5743810 polymorphism of TLR6 may be involved in development of anti-interferon-beta antibodies in males, although further studies are required to firmly establish this.

Multiple sclerosis and polymorphisms of innate pattern recognition receptors TLR1-10, NOD1-2, DDX58, and IFIH1.

Genetic factors are critical in multiple sclerosis (MS), and it is conceivable that the pattern recognition receptors of the innate immune system are of pathogenic importance. We therefore developed two novel assays capable of analyzing 42 single-nucleotide polymorphisms in the human genes encoding TLR1-10, NOD1-2, DDX58, and IFIH1. Using these assays, we genotyped 963 MS patients and 960 controls, and analyzed for possible associations to MS diagnosis, clinical course, severity, and age at onset. Our results support previous findings of associations between the IFIH1-locus and MS (IFIH1-rs3747517 and IFIH1-rs1990760 trend test: P=0.002 and P=0.014, respectively).

Cancer risk among patients with multiple sclerosis: a population-based register study.

Cancer occurrence in patients with multiple sclerosis (MS) has been little studied, but associations with brain tumours, breast cancer, Hodgkin lymphoma and nasopharyngeal carcinoma have been suggested. We took advantage of population-based registers of MS and cancer to assess the risk of cancer following diagnosis of MS. Patients registered in the Danish Multiple Sclerosis Register were linked with the Danish Cancer Register to obtain information on cancer occurrence. The ratio of the observed to the number of expected cancers based on population-based incidence rates, i.e., the standardised incidence ratio (SIR), served as measure of the relative cancer risk. A database comprising all Danish women born after April 1, 1935, with information on all live-born children, was used in the analyses of breast cancer to adjust for reproductive factors. Overall 1,037 cancers were observed in 11,817 MS patients during 153,875 person-years of follow-up vs. an expected number of 1,098 (SIR = 0.94 [95% confidence interval CI: (0.89-1.00)]. The risk of brain tumours and Hodgkin lymphoma was not increased. A 16% overall reduced cancer risk in men with MS was explained by reduced numbers of cancers of the digestive, respiratory and genital organs. Though the overall cancer risk was not increased [SIR = 1.01(0.94-1.09), n = 676], female MS patients had an increased risk of breast cancer [SIR = 1.21 (1.05-1.39), n = 193]. Adjusting for parity and age at first child delivery did not change this risk estimate materially. In general MS patients are not at increased risk of cancer. Women with MS, however, seem to have a small excess risk of breast cancer, which cannot be attributed to reduced parity or delayed first child birth.

Familial clustering of Hodgkin lymphoma and multiple sclerosis.

BACKGROUND: Epidemiologic similarities between Hodgkin lymphoma in young adults (i.e., between 15 and 44 years old) and multiple sclerosis have led to the suggestion that these diseases may have related etiologies. Previous investigations have not supported this hypothesis, but the negative results could have been caused by methodologic problems. We therefore assessed the risk of developing Hodgkin lymphoma for patients with multiple sclerosis and for their families and the risk of developing multiple sclerosis for patients with Hodgkin lymphoma and for their families. METHODS: We identified 11,790 patients with multiple sclerosis and 19,599 of their first-degree relatives in Danish population-based registers and followed them for the occurrence of Hodgkin lymphoma. Analogously, we identified 4381 patients with Hodgkin lymphoma and 7388 of their first-degree relatives and followed them for the occurrence of multiple sclerosis. The relative risks (RRs) of Hodgkin lymphoma and multiple sclerosis were expressed as standardized incidence ratios (i.e., the ratio between observed and expected numbers of outcomes based on age, sex, and period-specific incidence rates). All statistical tests were two-sided. RESULTS: Overall, six cases of Hodgkin lymphoma were identified in patients with multiple sclerosis (RR for Hodgkin lymphoma = 1.40, 95% confidence interval [CI] = 0.63 to 3.12), two of which occurred in young adults (RR = 1.59, 95% CI = 0.40 to 6.37). The risk of young-adult-onset Hodgkin lymphoma was statistically significantly increased in the first-degree relatives of patients with multiple sclerosis (RR = 1.93, 95% CI = 1.01 to 3.71; n = 9 such lymphomas). Two cases of multiple sclerosis were identified among young adult patients with Hodgkin lymphoma (RR for multiple sclerosis = 0.82, 95% CI = 0.20 to 3.27), and the risk for multiple sclerosis was statistically significantly increased in their first-degree relatives (RR = 2.76, 95% CI = 1.44 to 5.31; n = 9 such multiple sclerosis cases). CONCLUSION: The observed familial clustering of multiple sclerosis and young-adult-onset Hodgkin lymphoma is consistent with the hypothesis that the two conditions share environmental and/or constitutional etiologies.

Trends in survival and cause of death in Danish patients with multiple sclerosis.

The Danish Multiple Sclerosis Registry contains information about all Danish patients in whom multiple sclerosis has been diagnosed since 1948. The purpose of this study was to analyse trends in survival and causes of death of these patients and to compare them with those of the general population. The study comprised all patients with onset in the period 1949-1996. All case records were validated and classified according to standardized diagnostic criteria. Data on emigration and death were obtained by record linkage to official registers. The end of follow-up was 1 January 2000 for emigration and death, and 1 January 1999 for cause-specific deaths. Standardized mortality ratios and excess death rates were calculated for various causes of death and periods after multiple sclerosis onset, and time trends in survival probability were analysed by Cox regression. The study comprised 9881 patients, of whom 4254 had died before end of follow-up. The median survival time from onset was approximately 10 years shorter for multiple sclerosis patients than for the age-matched general population, and multiple sclerosis was associated with an almost threefold increase in the risk for death. According to death certificates, more than half (56.4%) of the patients had died from multiple sclerosis. They also had excess mortality rates from other diseases, except cancer, and from accidents and suicide. The probability for survival improved significantly during the observation period. Thus, the 10-year excess mortality was almost halved in comparison with that in the middle of the 1900s.