Reproductive and lifestyle risk factors for sarcoidosis

Abstract: Sarcoidosis is a systemic inflammatory condition with an unknown origin, characterized by the formation of granulomatous lesions primarily in the lungs and lymphatic system. Despite over a century since it was first described, our understanding of its etiology remains limited. Sarcoidosis incidence peaks in males in mid-thirties (30-50 years old) and in women in midfifties (50-60 years old; around the time when menopause starts). This delayed onset in women could be due to exposure to endogenous hormones (i.e. hormones produced within the body), mainly estrogens, suggesting that reproductive and hormonal factors (events associated with changes in levels of estrogens in the blood that occur throughout a woman's life) play a role in disease development. Current research also indicates that lifestyle factors trigger granulomatous inflammation in genetically predisposed people. In this doctoral thesis four individual studies are included. Two of them dealt with reproductive risk factors for sarcoidosis such as age at menarche, pregnancy, menopause (serving as indicators of endogenous hormones) and the use of exogenous hormones (i.e. hormones not produced within the body) such as oral contraceptives and menopausal hormone therapy. The remaining two studies investigated lifestyle risk factors for sarcoidosis, namely cigarette smoking, snus (smokeless tobacco product), obesity, physical activity and alcohol consumption. Study I was a nested case-control study in which we examined whether reproductive and hormonal factors are associated with risk of developing sarcoidosis in women using a population-based cohort in Northern Sweden with questionnaires and health exams completed before sarcoidosis diagnosis. We found that serval indicators of exposure to endogenous hormones (e.g. later age at menopause, earlier age at menarche, earlier age at pregnancy) may contribute to reduction of sarcoidosis risk. On the other hand, exogenous hormones, especially menopausal hormone therapy, were associated with an increased risk. Similarly to Study I, in Study II we conducted a nested case-control study and investigated whether lifestyle risk factors are associated with risk of developing sarcoidosis using prospectively collected data from a population-based cohort in Northern Sweden. We found that current smoking was associated with a 52% lower sarcoidosis risk and former smoking with 33% higher risk. This pattern with current smoking could not be explained away by early signs or symptoms of the disease before diagnosis (so-called preclinical phase) causing symptomatic individuals to stop smoking or report being non-smokers. Snus use, however, was not associated with sarcoidosis. We also showed that there was a 34% increased risk of sarcoidosis associated with being obese but not with being overweight. Moreover, high physically activity was associated with higher risk of sarcoidosis which could be explained by preclinical sarcoidosis, where extensive exercise might worsen the symptoms of undiagnosed sarcoidosis, making it more likely for individuals to seek medical care and receive a diagnosis. No association was found with alcohol consumption. In Study III, using high-quality and prospectively collected data from population-based registers in Sweden, we examined whether menopausal hormone therapy is associated with the risk of developing sarcoidosis in women and whether this risk varied by treatment type, route of administration and duration of use. In this nested case-control study, we found a 25% increased risk of sarcoidosis associated with a history of menopausal hormone therapy use, with women receiving systemic estrogen having the highest risk. We also found a stronger association between short-term use (<12 months) of menopausal hormone therapy and sarcoidosis than for long-term use. An important finding given that menopausal hormone therapy is typically prescribed during a shorter period (12 months in Sweden). In Study IV, we performed a systematic review and meta-analysis to summarize the existing literature and estimate the relative risk of sarcoidosis associated with smoking. We found that current smoking was associated with a 39% lower sarcoidosis risk; even when we included studies with data on smoking status collected years before sarcoidosis diagnosis, for which preclinical sarcoidosis is unlikely to explain the pattern. Ever smoking was associated with a small decreased risk of sarcoidosis (13%), while former smoking did not seem to be associated with sarcoidosis. Overall, findings from studies on reproductive risk factors in this thesis suggest that indicators of endogenous hormones, specifically later age at menopause, earlier age at menarche and earlier age at first pregnancy may contribute to a decrease in sarcoidosis risk. However, this beneficial effect does not seem to extend to exogenous hormones such as menopausal hormone therapy. Studies on lifestyle risk factors in this thesis showed that current smoking is associated with a reduced sarcoidosis risk. Obesity and being physically active separately increases the risk of sarcoidosis. Alcohol consumption does not seem to be related to sarcoidosis risk. These findings deepen our understanding of long-suspected (e.g. smoking and obesity) and novel (e.g. hormonal factors, alcohol consumption and physical activity) risk factors for sarcoidosis. However, our quest to examine and detect causal exposures for this enigmatic disease should continue by using actual measurements of levels of estrogen or nicotine, rather than relying on indicators. Future epidemiological studies on risk factors for sarcoidosis should take into account the issue of reverse causation bias due to the long preclinical phase in some sarcoidosis patients. Moreover, since sarcoidosis also has a genetic component, future studies should consider genetics by investigating possible gene-environment interactions.

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