Gender differences in multiple sclerosis epidemiology and treatment response.

There is an increasing incidence of multiple sclerosis (MS) in women in Denmark and Danish women's risk of developing MS has more than doubled in 25 years, while it has remained virtually unchanged for men. The explanation for these epidemiological changes should be sought in the environment, as genetics only explain a small part of the MS risk as the changes are too rapid to be explained by gene alterations. The rapid increase of MS incidence likely reflects unidentified changes in the environment and probably gene-environmental interactions. My PhD thesis work was conceived and designed to investigate the relevant exposures in different periods of life that may have contributed to the increasing female to male ratio of cases of multiple sclerosis in Denmark. To study this, we investigated the effect of numerous biological, social, physical and chemical environmental factors available from population-based registries in a case-control approach. Pregnancy may have a biological protective effect against developing MS in women, lasting for about five years. The protective effect is probably due to the modulation of the immune system by pregnancy. Our data on social behaviour changes regarding educational level, income, and relationship stability did not indicate reversed causality as a significant contributor to the lower number of childbirths in the five years before onset. Fewer pregnancies are one possible explanation we found for the increasing incidence of MS in women in our study. The trend towards fewer childbirths in the female population over decades may contribute to the increasing sex ratio and female incidence of MS. Socio-economic status and lifestyle expressed in educational level and the sanitary conditions in youth are not associated with the risk of MS, and cannot contribute to the increasing epidemiological disparity between the genders over the last decades. A greater likelihood to be exposed to common infections did not show any effect on the MS risk neither in puberty nor in adulthood. The apparent protective effect of childbirth does not appear to reflect postnatal child exposure. The only factor that may show association with a higher MS risk in women is working in agriculture but it was based on very small numbers and cannot contribute quantitatively to the incidence of MS in women. Women are generally more prone to autoimmune diseases than men, but significant increased occurrence of some other autoimmune diseases was only found in male MS cases in the period before clinical onset. None of the investigated autoimmune diseases occurred less frequently in MS patients than in control persons. Treatment response to interferon-β, expressed in relapse rate was independently influenced by gender and the presence of NAbs, but it seems that the presence of NAbs does not affect the treatment effect differently in women and men. The results indicate that men's and women's treatment response to interferon-β is similar. Females had a higher frequency of relapses than males. Our study did not reveal only one reason for the incidence increase, but as MS is multifactorial it is presumed that the incidence increase is caused by more than one factor, because women's lifestyle has undergone tremendous changes in the last half century. Our study contributes to clarification of this issue, with the role of pregnancies on the risk of MS. It is accepted that sex hormones have a clear immunologic involvement in the female predominance in MS, but there is no knowledge yet to explain the changes over time.