Association of Stress-Related Disorders With Subsequent Autoimmune Disease

Abstract

Psychiatric reactions to life stressors are common in the general population and may result in immune dysfunction. Whether such reactions contribute to the risk of autoimmune disease remains unclear. OBJECTIVE To determine whether there is an association between stress-related disorders and subsequent autoimmune disease. DESIGN, SETTING, AND PARTICIPANTS Population-and sibling-matched retrospective cohort study conducted in Sweden from January 1, 1981, to December 31, 2013. The cohort included 106 464 exposed patients with stress-related disorders, with 1 064 640 matched unexposed persons and 126 652 full siblings of these patients. EXPOSURES Diagnosis of stress-related disorders, ie, posttraumatic stress disorder, acute stress reaction, adjustment disorder, and other stress reactions. MAIN OUTCOMES AND MEASURES Stress-related disorder and autoimmune diseases were identified through the National Patient Register. The Cox model was used to estimate hazard ratios (HRs) with 95% CIs of 41 autoimmune diseases beyond 1 year after the diagnosis of stress-related disorders, controlling for multiple risk factors. RESULTS The median age at diagnosis of stress-related disorders was 41 years (interquartile range, 33-50 years) and 40% of the exposed patients were male. During a mean follow-up of 10 years, the incidence rate of autoimmune diseases was 9.1, 6.0, and 6.5 per 1000 person-years among the exposed, matched unexposed, and sibling cohorts, respectively (absolute rate difference, 3.12 [95% CI, 2.99-3.25] and 2.49 [95% CI, 2.23-2.76] per 1000 person-years compared with the population-and sibling-based reference groups, respectively). Compared with the unexposed population, patients with stress-related disorders were at increased risk of autoimmune disease (HR, 1.36 [95% CI, 1.33-1.40]). The HRs for patients with posttraumatic stress disorder were 1.46 (95% CI, 1.32-1.61) for any and 2.29 (95% CI, 1.72-3.04) for multiple (Ն3) autoimmune diseases. These associations were consistent in the sibling-based comparison. Relative risk elevations were more pronounced among younger patients (HR, 1.48 [95% CI, 1.42-1.55]; 1.41 [95% CI, 1.33-1.48]; 1.31 [95% CI, 1.24-1.37]; and 1.23 [95% CI, 1.17-1.30] for age at Յ33, 34-41, 42-50, and Ն51 years, respectively; P for interaction < .001). Persistent use of selective serotonin reuptake inhibitors during the first year of posttraumatic stress disorder diagnosis was associated with attenuated relative risk of autoimmune disease (HR, 3.64 [95% CI, 2.00-6.62]; 2.65 [95% CI, 1.57-4.45]; and 1.82 [95% CI, 1.09-3.02] for duration Յ179, 180-319, and Ն320 days, respectively; P for trend = .03). CONCLUSIONS AND RELEVANCE In this Swedish cohort, exposure to a stress-related disorder was significantly associated with increased risk of subsequent autoimmune disease, compared with matched unexposed individuals and with full siblings. Further studies are needed to better understand the underlying mechanisms.

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

“…Our subsequent gene set and pathway analyses provide some clues further implicating the immune system. Of note, these genetic results converge with evidence from epidemiologic cohort studies documenting the role of stressrelated disorders such as PTSD in autoimmune diseases, 49 case-control studies showing elevations of immune-related biomarkers in women with PTSD, 50,51 and epigenetic studies pointing to the role of the immune system in PTSD etiology. [52][53][54] Of note, it has been previously suggested that PTSD may be "a systemic disorder rather than one confined to the mind".…”

Genome wide association study of hippocampal subfield volume in PTSD cases and trauma-exposed controls

“…Notably, rs6906714 is also an expression QTL for several genes including PSORS1C1 and PSORS1C2, which are psoriasis susceptibility genes that are expressed in thyroid tissue (Table S2). Genes associated with autoimmune disorders have been previously associated with PTSD(50); the overlap between stress disorders and immune/inflammatory disorders is an ongoing area of research (51). We also observed an interaction of rs6906714 with childhood trauma in the discovery cohort, and of rs6906714 with lifetime PTSD in the replication cohort, which is consistent with neuropsychiatric responses to stress that show increased risk of subsequent autoimmune disease (Figure 2)(51).…”

Inflammation and post‐traumatic stress disorder

“…Although the specific molecular mechanisms by which SSRIs exert such effects are not clear, a variety of mechanisms have been proposed, including those mediated by the serotonin transporter, mediated by NF‐κB, by IL‐10, and via actions on cyclic adenosine monophosphate signaling . Supporting this, a recent large‐scale epidemiological study reported that persistent use of SSRIs during the first year after PTSD diagnosis was associated with attenuated risk of autoimmune disease . Moreover, chronic PTSD patients who received SSRIs showed significant reduction in both clinical symptoms and serum IL‐1β levels .…”

“…In addition to these classic psychobehavioral features, physical morbidities, such as obesity, diabetes, and metabolic syndrome, are common in individuals with PTSD . Moreover, epidemiological studies have found a link between PTSD and an increased risk of serious physical diseases, such as cardiovascular disease and autoimmune disease . As these diseases have an inflammatory component, it is suggested that the immune system is dysregulated in PTSD.…”