autoimmune disorders in Iraq and Afghanistan Veterans Posttraumatic stress disorder and female gender associated with increased risk for autoimmune disorders in Iraq and Afghanistan Veterans Kristen Nishimi1,2, Aoife O’Donovan1,2, Beth E. Cohen1,2, Karen Seal1,2, Dan Bertenthal2, Mary Margaretten1, Thomas C. Neylan1,2 1. University of California, San Francisco; 2. San Francisco Veterans Affairs Medical Center and Northern California Institute on Research and Education Methodology: We conducted a retrospective cohort study in order to examine if posttraumatic stress disorder (PTSD) is associated with increased risk for diagnosis with common autoimmune disorders in a large population of US veterans. Sample: 666,269 Iraq and Afghanistan veterans (31% with a diagnosis of PTSD & 20% other psychiatric disorder diagnoses) under age 55 who were enrolled in the Department of Veterans Affairs (VA) healthcare system from October 1, 2005 to March 31, 2011, with at least one year of follow up. Outcome measure: Association of PTSD and other psychiatric disorders with risk for autoimmune disorder diagnoses, adjusting for age, gender, race and primary care visits in generalized linear models. Results: Compared to veterans with no psychiatric diagnoses, those diagnosed with PTSD had significantly higher adjusted relative risk (ARR) for subsequent diagnosis with thyroiditis (ARR = 2.17, 95% CI, 2.06, 2.29), inflammatory bowel disease (ARR = 1.30, 95% CI, 1.16, 1.46), rheumatoid arthritis (ARR = 2.04, 95% CI, 1.70, 2.45), multiple sclerosis (ARR = 2.36, 95% CI, 1.93, 2.89), lupus erythematosus (ARR = 1.85, 95% CI, 1.45, 2.37) and for any of these autoimmune disorders alone or in combination (ARR = 2.00, 95% CI, 1.91, 2.09). Veterans diagnosed with PTSD had significantly higher risk for autoimmune disorder diagnoses than veterans with psychiatric disorders other than PTSD (ARR = 1.51, 95% CI, 1.43, 1.59). Overall risk of autoimmune disorders was significantly higher in females than in males (ARR = 3.03, 95% CI, 2.89, 3.16), but the increase in risk associated with psychiatric disorders was similar in females and males. ABSTRACT Veterans with PTSD and other psychiatric disorders will have higher risk for autoimmune disorders than those with no psychiatric disorders. Veterans with PTSD will have higher risk for autoimmune disorders than veterans with other psychiatric disorders. Risk for autoimmune disorders will be higher in females than in males. HYPOTHESES RESULTS – GENDER DIFFERENCES PTSD-related ARR for autoimmune disorder diagnosis was similar in males and females. MALES: ANY AUTOIMMUNE DISORDER NO PSYCHIATRIC DISORDER OTHER PSYCHIATRIC DISORDERS PTSD FEMALES: ANY AUTOIMMUNE DISORDER 0.50 1.00 1.05 2.00 2.50 adjusted relative risk Percentage with any Autoimmune Disorder diagnosis METHODOLOGY Data Analysis: Generalized Linear Models with Poisson distribution and robust error variance were used to estimate relative risks (RR) for autoimmune diagnoses in veterans with no psychiatric disorders, psychiatric disorders other than PTSD and PTSD with or without other psychiatric disorders. Models were adjusted for potential confounds including age, race, gender and number of primary care visits (ARR). Sample Characteristics: 88% male; 49% white; mean age 31 years (+/- 9) ANY AUTOIMMUNE DISORDER 9,764 received diagnoses (at ≥ 2 visits): Thyroiditis Multiple sclerosis N = 7,013 N = 548 Inflammatory bowel disease Lupus N = 362 N = 1,479 Rheumatoid arthritis N = 598 PSYCHIATRIC HEALTH STATUS MALES FEMALES Females had higher risk for autoimmune disorders than males. Thus, the prevalence of autoimmune disorders was highest in women with PTSD. Percentage of individuals with autoimmune disorder diagnosis MALES FEMALES PTSD is characterized by biological abnormalities that could increase risk for autoimmune disorders, including: HPA axis dysregulation: A large number of studies have shown dysregulation of the hypothalamic pituitary adrenal (HPA) axis in PTSD; particularly showing lower levels of the glucocorticoid hormone cortisol and reduced signaling through anti-inflammatory glucocorticoid receptor transcriptional control pathways.1-4 Increased inflammation: PTSD has been linked with increased inflammatory activity, indexed by elevated levels of pro-inflammatory cytokines and higher signaling through pro-inflammatory nuclear factor-κB (NF- κ-B) transcriptional control pathways.1-4,6 Females with PTSD are at increased risk for autoimmune disorders: Immune response: Females response to infection, vaccination and trauma is characterized by a T helper (Th)2-predominant type immune response which promotes chronic inflammation.16,17 Disease risk: Females are at higher risk of the autoimmune disorders of interest than males.18-22 THEORETICAL BACKGROUND Veterans with PTSD had significantly higher risk for diagnosis with autoimmune disorders compared to veterans without any psychiatric disorders: Thyroiditis (ARR = 2.17, 95% CI, 2.06, 2.29) Inflammatory bowel disease (ARR = 1.30, 95% CI, 1.16, 1.46) Rheumatoid arthritis (ARR = 2.04, 95% CI, 1.70, 2.45) Multiple sclerosis (ARR = 2.36, 95% CI, 1.93, 2.89) Lupus erythematosus (ARR = 1.85, 95% CI, 1.45, 2.37) Any autoimmune disorder (ARR = 2.00, 95% CI, 1.91, 2.09) Veterans with PTSD had higher risk for diagnosis with autoimmune disorders compared to veterans with other psychiatric disorders (ARR = 1.51, 95% CI, 1,43, 1.59). RESULTS - AUTOIMMUNE DISORDER RISK PTSD and other psychiatric diagnoses were prevalent among Iraq and Afghanistan veterans seeking healthcare from VA Medical Centers. Veterans with psychiatric disorders had increased risk for diagnoses of autoimmune disorders; veterans with PTSD showed the highest risk. Female gender conferred higher risk of autoimmune disorders overall, but the ARR associated with PTSD and other psychiatric disorders was similar in females and males. While mechanisms of PTSD-related increased risk for autoimmune disorders remain unclear, biological abnormalities observed in patients with PTSD (e.g., low cortisol, high inflammation, shorter telomere length) and behavioral correlates of PTSD (smoking, drug use) could contribute to ill health in PTSD. Limitations: This observational study does not shed light on causality in the relationships between psychiatric and autoimmune disorders. Our sample includes only treatment-seeking veterans and may not generalize beyond this population. DISCUSSION STUDY POPULATION Study Population: The VA national Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF) and Operation New Dawn (OND) Roster includes veterans deployed in OEF/OIF/OND who have separated from service and enrolled in the VA healthcare system. This roster provided basic demographic and military service information, and the VA’s electronic medical record database, the National Patient Care Database (NPCD), provided information on VA clinical visits and clinical diagnoses based on (ICD-9-CM) codes. Exclusion: 2,940 veterans who had an autoimmune disorder diagnosis previous to psychiatric diagnosis Also exclude 1 patient with unknown sex   Exclusion: 12,087 veterans with age > 55 years Exclusion: 53,510 veterans with less than one year follow up in the VA healthcare system Full Cohort N = 738,785 Restrict to veterans with autoimmune disorder diagnosis after psychiatric N =670,337 Restrict to veterans with age ≤ 55 years  N = 673,278 Restrict to veterans with one year follow up in the VA healthcare system Final Cohort N = 666,269 Exclude veterans with autoimmune disorder diagnosis coded only at one visit Exclusion: 4,068 veterans with a specific autoimmune disorder diagnosis coded only at one visit N = 685,365 PTSD is associated with increased risk for diagnosis with autoimmune disorders. Given that the absolute prevalence of autoimmune disorders is higher in females, women with PTSD show particularly high levels of autoimmune disorders. Prospective longitudinal cohort studies are needed to assess causality and evaluate whether successful treatment of PTSD reduces risk of autoimmune disorders. CONCLUSION This research was supported by the Mental Illness Research and Education Clinical Center (MIRECC) of the US Veterans Health Administration and a Society in Science – Branco Weiss Fellowship (to AOD). None of the authors have financial interests over the past two years that are relevant to the subject matter of this manuscript. ACKNOWLEDGEMENTS