A history of depression is associated with more than double the risk of developing systemic lupus erythematosus (SLE) among women, new research suggests. The study, which included data from almost 200,000 participants in the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II), supports the hypothesis that depression is a causal risk factor for developing SLE, note the investigators. "Screening patients who have depression for a family history of autoimmune disease and considering the possibility that they may be developing an autoimmune disease would be helpful," Andrea L. Roberts, PhD, research scientist, Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, told Medscape Medical News. The findings were published online September 12 in JAMA Psychiatry. Serious Autoimmune Disorder A serious autoimmune disorder, SLE is characterized by widespread organ system involvement and is associated with early death. The incidence of SLE is far higher among women than men. The current analysis included 194,483 mostly white women, aged 28 to 93 years, from the NHS and NHS II. All were followed for 20 years. With information from biennial questionnaires, researchers assessed depression using three indicators: self-reported clinical diagnosis; self-reported use of antidepressants; and the five-item Mental Health Inventory (MHI-5) questionnaire. The latter identifies depressive symptoms; scores less than 60 indicate probable depression. To determine SLE, the investigators used the American College of Rheumatology 1997 classification criteria. During follow-up, 145 cases of SLE occurred. The researchers determined that diet, exercise, and alcohol use were not associated with lupus and so did not consider them in their analyses. They adjusted for age and race in their main analysis, because African Americans are at higher risk for lupus compared with whites. Twofold Risk The analysis showed that depression was associated with a more than twofold increased risk for incident SLE (hazard ratio [HR], 2.67; 95% confidence interval [CI], 1.91 - 3.75; P < .001). The median time from depression to incident SLE was 4.5 years. The researchers then adjusted for body mass index, cigarette smoking, and use of oral contraceptives and postmenopausal hormones. This approach aimed to reduce the chance that depressed women smoked or used hormones more or were heavier and that these factors contributed to the development of lupus, the researchers note. The findings showed that these factors "accounted for only a small amount of the association," said Roberts. To reduce the likelihood that the association occurred because SLE may cause depression, rather than the other way around, the investigators conducted three additional analyses: A "lagged" analysis, which included only women who had depression at least 4 years prior to SLE; An analysis only of data from the first year in which patients were asked about all depression measures: symptoms, diagnosis, and antidepressant use; An analysis of available data from a subsample of 120 women that used the date of the first symptoms rather than the date of diagnosis to indicate SLE onset. These sensitivity analyses "basically affirmed" the robust results, said Roberts. Using a more stringent cutoff for the MHI-5 (score less than 52), the association was still strong (HR for age and race, 2.29; P < .01). These analyses suggest that "perhaps the more depressed you are, the greater your risk" of developing lupus, Roberts said. Strongest Factors The investigators found that the strongest association with SLE was for antidepressant use (HR for age and race, 2.80; P < .001) — possibly because these drugs are prescribed for anxiety and chronic pain, which are often associated with SLE. This was followed by physician diagnosis of depression (HR for age and race, 2.19; P < .01) and symptoms of depression, as shown by an MHI-5 score less than 60 (HR for age and race, 1.70; P < .01). The researchers also assessed use of selective serotonin reuptake inhibitors, tricyclics, and other antidepressants. They found that associations between antidepressant use and SLE were not specific to drug class. This suggests that it was not the drugs but depression itself that is linked to lupus, said Roberts. The association between depression and lupus may be driven by an altered immune function. Past research has linked depression with increased concentrations of interleukin-6 and C-reactive protein, which are biomarkers of systemic inflammation. "Your brain plays a big role in activating your immune system, so the idea that a mood disorder would have an effect on the immune system is not surprising," said Roberts. She noted that a number of studies have shown such a relationship. Because many diseases, including heart disease, are related to inflammatory processes, physicians might want to look more closely into whether a patient has inflammation and "do something to prevent negative health effects" if inflammation is uncovered, Roberts said. "Attractive Hypothesis" For comment, Medscape Medical News reached out to John G. Hanly, MD, professor in the Division of Rheumatology, Dalhousie University, Halifax, Nova Scotia, Canada. Hanly was the lead author of a 2015 study published in Arthritis and Rheumatology that examined the frequency and characteristics of mood disorders in patients with SLE, as well as use of antidepressants and clinical outcomes. Hanly said that the new study is valuable because it includes a large number of patients and offers "an attractive hypothesis" and that its findings are "certainly of interest." However, he said he remains skeptical about the results and would have liked the study to have included a control group of patients with a nonautoimmune rheumatic disease, such as osteoarthritis, which has "a totally different mechanism" than lupus but some of the same symptoms, such as joint pain. Hanly also criticized the use of questionnaires to identify mood disorders. "Even though there was a certain amount of chart review and confirmation of certain things, there wasn't a physician-patient interaction," which is what experts in mood disorders recommend over questionnaires, he said. And although the study authors found a relationship between depression and SLE at the time of the first symptom of the autoimmune disease, it is not clear when lupus began, said Hanly. "Once the diagnosis is made, it has likely been going on for quite some time. We know that the autoantibodies can be there for at least 7 years before the disease develops," he said. Source
