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Elevated Risk for Autoimmune Disorders in Iraq and Afghanistan Veterans with Posttraumatic Stress Disorder

  • Aoife O’Donovan
    Correspondence
    Address correspondence to Aoife O’Donovan, Ph.D., University of California San Francisco, San Francisco Veterans Affairs Medical Center, 4150 Clement Street (116H), San Francisco, CA 94121
    Affiliations
    Department of Psychiatry, University of California, San Francisco, California

    San Francisco Veterans Affairs Medical Center and Northern California Institute for Research and Education, San Francisco, California
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  • Beth E. Cohen
    Affiliations
    Department of Psychiatry, University of California, San Francisco, California

    San Francisco Veterans Affairs Medical Center and Northern California Institute for Research and Education, San Francisco, California
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  • Karen H. Seal
    Affiliations
    Department of Psychiatry, University of California, San Francisco, California

    San Francisco Veterans Affairs Medical Center and Northern California Institute for Research and Education, San Francisco, California
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  • Dan Bertenthal
    Affiliations
    San Francisco Veterans Affairs Medical Center and Northern California Institute for Research and Education, San Francisco, California
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  • Mary Margaretten
    Affiliations
    Department of Psychiatry, University of California, San Francisco, California
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  • Kristen Nishimi
    Affiliations
    Department of Psychiatry, University of California, San Francisco, California

    San Francisco Veterans Affairs Medical Center and Northern California Institute for Research and Education, San Francisco, California
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  • Thomas C. Neylan
    Affiliations
    Department of Psychiatry, University of California, San Francisco, California

    San Francisco Veterans Affairs Medical Center and Northern California Institute for Research and Education, San Francisco, California
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      Abstract

      Background

      Posttraumatic stress disorder (PTSD) is associated with endocrine and immune abnormalities that could increase risk for autoimmune disorders. However, little is known about the risk for autoimmune disorders among individuals with PTSD.

      Methods

      We conducted a retrospective cohort study of 666,269 Iraq and Afghanistan veterans under age 55 who were enrolled in the Department of Veterans Affairs health care system between October 7, 2001, and March 31, 2011. Generalized linear models were used to examine if PTSD, other psychiatric disorders, and military sexual trauma exposure increased risk for autoimmune disorders, including thyroiditis, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and lupus erythematosus, adjusting for age, gender, race, and primary care visits.

      Results

      PTSD was diagnosed in 203,766 veterans (30.6%), and psychiatric disorders other than PTSD were diagnosed in an additional 129,704 veterans (19.5%). Veterans diagnosed with PTSD had significantly higher adjusted relative risk (ARR) for diagnosis with any of the autoimmune disorders alone or in combination compared with veterans with no psychiatric diagnoses (ARR = 2.00; 95% confidence interval, 1.91–2.09) and compared with veterans diagnosed with psychiatric disorders other than PTSD (ARR = 1.51; 95% confidence interval, 1.43–1.59; p < .001). The magnitude of the PTSD-related increase in risk for autoimmune disorders was similar in women and men, and military sexual trauma exposure was independently associated with increased risk in both women and men.

      Conclusions

      Trauma exposure and PTSD may increase risk for autoimmune disorders. Altered immune function, lifestyle factors, or shared etiology may underlie this association.

      Keywords

      Posttraumatic stress disorder (PTSD) is associated with a number of biological abnormalities that could increase risk for autoimmune disorders. First, PTSD appears characterized by lower levels of the immunomodulatory glucocorticoid hormone cortisol and reduced signaling through anti-inflammatory glucocorticoid receptor transcriptional control pathways (
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      ). Second, accumulating evidence links PTSD with increased inflammatory activity, as indexed by elevated levels of proinflammatory cytokines and higher signaling through proinflammatory nuclear factor-κB transcriptional control pathways (
      • O’Donovan A.
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      Transcriptional control of monocyte gene expression in post-traumatic stress disorder.
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      Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells.
      ). Third, investigators have observed altered patterns of gene expression in immune cells (
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      • Ross J.
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      • Pulliam L.
      Suppressed monocyte gene expression profile in men versus women with PTSD.
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      • Sarapas C.
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      • Ising M.
      • et al.
      Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks.
      ) and reduced methylation of immune-related genes (
      • Uddin M.
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      • de Los Santos R.
      • et al.
      Epigenetic and immune function profiles associated with posttraumatic stress disorder.
      ) in patients with PTSD. Finally, emerging evidence suggests that PTSD is associated with accelerated immune cell aging, as indexed by shorter age-adjusted telomere length (
      • Malan S.
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      • Kidd M.
      • Martin L.
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      Investigation of telomere length and psychological stress in rape victims.
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      • Lin J.
      • Wolkowitz O.
      • Cohen B.
      • Maguen S.
      • et al.
      Childhood trauma associated with short leukocyte telomere length in posttraumatic stress disorder.
      ), which has been linked with elevated inflammation in vivo and in vitro (
      • O’Donovan A.
      • Pantell M.S.
      • Puterman E.
      • Dhabhar F.S.
      • Blackburn E.H.
      • Yaffe K.
      • et al.
      Cumulative inflammatory load is associated with short leukocyte telomere length in the Health, Aging and Body Composition Study.
      ,
      • Freund A.
      • Orjalo A.V.
      • Desprez P.Y.
      • Campisi J.
      Inflammatory networks during cellular senescence: Causes and consequences.
      ). This pattern of abnormalities in the hypothalamic-pituitary-adrenal axis, immune system, and telomere maintenance system may increase risk for autoimmune disorders by increasing inflammation and impairing the function of immune cells (
      • Eskandari F.
      • Webster J.I.
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      Neural immune pathways and their connection to inflammatory diseases.
      ,
      • Goronzy J.J.
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      The telomere/telomerase system in autoimmune and systemic immune-mediated diseases.
      ,
      • Costenbader K.H.
      • Prescott J.
      • Zee R.Y.
      • De Vivo I.
      Immunosenescence and rheumatoid arthritis: Does telomere shortening predict impending disease?.
      ). Nonetheless, relatively little is known about the risk for autoimmune disorders associated with PTSD.
      In one previous study, PTSD was associated with higher prevalence of self-reported autoimmune disorders in a sample of 2490 male Vietnam veterans (
      • Boscarino J.A.
      Posttraumatic stress disorder and physical illness: Results from clinical and epidemiologic studies.
      ). In another study, PTSD was associated with increased risk for physician-diagnosed rheumatoid arthritis in a sample of 3143 pairs of male twins (
      • Boscarino J.A.
      • Forsberg C.W.
      • Goldberg J.
      A twin study of the association between PTSD symptoms and rheumatoid arthritis.
      ). However, no prior study has examined if PTSD increases risk for a range of physician-diagnosed autoimmune disorders with definitive diagnostic criteria, and it is not known if the risk for autoimmune disorders is greater in individuals with PTSD compared with those with other psychiatric disorders. Moreover, although the risk for, or severity of, many autoimmune disorders is substantially higher in women compared with men (
      • Kovacs W.J.
      • Olsen N.J.
      Sexual dimorphism of RA manifestations: Genes, hormones and behavior.
      ,
      • van Vollenhoven R.F.
      Sex differences in rheumatoid arthritis: More than meets the eye.
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      • Lapi P.
      • Fiore E.
      • Tonacchera M.
      • Pinchera A.
      Thyroid autoimmunity and female gender.
      ,
      • Casetta I.
      • Riise T.
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      • Economou N.T.
      • De Gennaro R.
      • Fazio P.
      • et al.
      Gender differences in health-related quality of life in multiple sclerosis.
      ,
      • Schwartzman-Morris J.
      • Putterman C.
      Gender differences in the pathogenesis and outcome of lupus and of lupus nephritis.
      ,
      • Saibeni S.
      • Cortinovis I.
      • Beretta L.
      • Tatarella M.
      • Ferraris L.
      • Rondonotti E.
      • et al.
      Gender and disease activity influence health-related quality of life in inflammatory bowel diseases.
      ), no studies have examined the risk for autoimmune disorders in women with PTSD.
      To assess the risk for autoimmune disorders associated with PTSD and other psychiatric disorders, we conducted the present study in a national sample of Iraq and Afghanistan veterans enrolled in the U.S. Department of Veterans Affairs (VA) health care system. Emerging data indicate high rates of PTSD and other psychiatric disorders (
      • Seal K.H.
      • Metzler T.J.
      • Gima K.S.
      • Bertenthal D.
      • Maguen S.
      • Marmar C.R.
      Trends and risk factors for mental health diagnoses among Iraq and Afghanistan veterans using Department of Veterans Affairs health care, 2002-2008.
      ,
      • Seal K.H.
      • Maguen S.
      • Cohen B.
      • Gima K.S.
      • Metzler T.J.
      • Ren L.
      • et al.
      VA mental health services utilization in Iraq and Afghanistan veterans in the first year of receiving new mental health diagnoses.
      ), as well as high rates of military sexual trauma (MST) exposure (
      • Maguen S.
      • Cohen B.
      • Ren L.
      • Bosch J.
      • Kimerling R.
      • Seal K.
      Gender differences in military sexual trauma and mental health diagnoses among Iraq and Afghanistan veterans with posttraumatic stress disorder.
      ) in this population of veterans. In the present study, we assessed risk for autoimmune disorders associated with PTSD, other psychiatric disorders, and MST, focusing our analyses on the most prevalent autoimmune disorders in the United States that have definitive diagnostic criteria or diagnostic tests (i.e., thyroiditis, rheumatoid arthritis, inflammatory bowel disorders, multiple sclerosis, and lupus erythematosus) (
      • Cooper G.S.
      • Stroehla B.C.
      The epidemiology of autoimmune diseases.
      ).

      Methods and Materials

      Study Population

      The Department of Veterans Affairs 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 health care system. We identified 738,785 male and female Iraq and Afghanistan veterans in the OEF/OIF/OND Roster who first received VA health care from October 7, 2001, to March 31, 2011. We excluded veterans without at least 1 year of follow-up within the VA and the study end date was therefore March 31, 2012. Veterans aged over 55 years (1.6%) were excluded from our analyses because our goal was to assess the risk for autoimmune disorders in a more homogenous group of veterans without confounds associated with older age. Veterans who remain in the military later in life—making them older than 55 during their first VA appointment following service in OEF/OIF/OND—may also differ from the general population of veterans because military service personnel are usually eligible for retirement after 20 years of service. Veterans who already had a diagnosis of one of the target autoimmune disorders before receiving a psychiatric diagnosis were excluded to avoid any confounding of psychiatric diagnoses with autoimmune disorder-related symptoms or distress. Finally, to exclude potential inaccurate or rule-out diagnoses, we excluded veterans who had received an autoimmune disorder diagnosis at only one appointment. See Figure 1 for a more complete description of exclusions. After exclusions, our study population included 666,269 veterans. The study was approved by the Committees on Human Research at the University of California, San Francisco, and the San Francisco VA Medical Center.
      Figure thumbnail gr1
      Figure 1Flow chart detailing exclusion criteria applied to identify study population.

      Data Sources

      We used the VA OEF/OIF/OND Roster to obtain basic demographic and military service information for Iraq and Afghanistan veterans (
      • Seal K.H.
      • Bertenthal D.
      • Miner C.R.
      • Sen S.
      • Marmar C.
      Bringing the war back home: Mental health disorders among 103,788 US veterans returning from Iraq and Afghanistan seen at Department of Veterans Affairs facilities.
      ) and the VA electronic medical record database, the National Patient Care Database (NPCD), to obtain information on VA clinical visits and clinical diagnoses based on ICD-9-CM codes.

      Sociodemographic and Clinical Information

      The OEF/OIF/OND Roster was used to identify sociodemographic information including age, gender, and race, as well as military service information including military rank, component type, service branch, and multiple deployments. The VA NPCD was used to obtain clinical information including clinical diagnoses based on ICD-9-CM and number of primary care visits. We also used the VA NPCD to assess the presence of MST-related clinical encounters, and we used the presence of these encounters as an index of MST. Basic sociodemographic, military service, and clinical information for our full sample is provided in Table 1 and stratified by gender in Table S1 in Supplement 1.
      Table 1Sample Characteristics
      NumberNo Psychiatric Disorder n (%)Other Psychiatric Disorders n (%)PTSD n (%)
      Characteristic666,269332,799 (49.9)129,704 (19.5)203,766 (30.6)p Value
      Sex
       Female79,35640,141 (12.1)19,310 (14.9)19,905 (9.8)<.001
       Male586,913292,658 (87.9)110,394 (85.1)183,861 (90.2)<.001
      Age: Mean (SD)
      Age refers to age at initial VA appointment.
      31.2 (8.7)32.2 (9.0)30.8 (8.5)30.0 (8.0)<.001
      Age Group
      Age refers to age at initial VA appointment.
       18–24186,73684,076 (25.3)37,847 (29.2)64,813 (31.8)<.001
       25–34263,743124,286 (37.3)53,353 (41.1)86,104 (42.3)<.001
       35–44149,10484,056 (25.3)26,502 (20.4)38,546 (18.9)<.001
       45–5466,68640,381 (12.1)12,002 (9.3)14,303 (7.0)<.001
      Race/Ethnicity
       White326,101158,349 (47.6)64,941 (50.1)102,811 (50.5)<.001
       Non-White340,168174,450 (52.4)64,763 (49.9)100,955 (49.5)<.001
      Marital Status
       Married293,775153,482 (46.1)52,881 (40.8)87,412 (42.9)<.001
       Never married341,868164,598 (49.5)70,483 (54.4)106,787 (52.4)<.001
       Divorced/widowed/other30,21114,494 (4.4)6249 (4.8)9468 (4.6)<.001
      Military Rank
       Enlisted610,646292,609 (87.9)122,056 (94.1)195,981 (96.2)<.001
       Other55,62340,190 (12.1)7648 (5.9)7785 (3.8)<.001
      Active Duty or Reserve
       Active duty371,342184,043 (55.3)70,365 (54.3)116,934 (57.4)<.001
       Reserve/National Guard294,927148,756 (44.7)59,339 (45.7)86,832 (42.6)<.001
      Military Branch
       Army407,870182,187 (54.7)78,166 (60.3)147,517 (72.4)<.001
       Air Force79,18455,187 (16.6)14,489 (11.2)9508 (4.7)<.001
       Marines91,92841,746 (12.5)15,981 (12.3)34,201 (16.8)<.001
       Navy87,28753,679 (16.1)21,068 (16.2)12,540 (6.2)<.001
      Multiple Deployments265,833132,555 (39.9)48,242 (37.2)85,036 (41.8)<.001
      Urban370,146180,437 (62.0)75,026 (62.8)114,683 (60.0)<.001
      Primary Care Visits: Mean (SD)
      Visits refer to mean annual number of primary care or mental health visits.
      1.6 (2.0)1.1 (1.4)2.0 (2.2)2.3 (2.4)<.001
      Mental Health Visits: Mean (SD)
      Visits refer to mean annual number of primary care or mental health visits.
      2.5 (9.4)0.1 (.6)2.4 (7.7)6.7 (15.0)<.001
      Military Sexual Trauma
      Military sexual trauma exposure is based on VA clinical encounters coded for military sexual trauma.
      13,6501548 (.5)3187 (2.5)8915 (4.4)<.001
      Psychiatric Diagnoses
       PTSD203,766203,766 (100.0)<.001
       Depression184,10957,313 (44.2)126,796 (62.2)<.001
       Anxiety disorder123,81944,632 (34.4)79,187 (38.9)<.001
       Adjustment disorder110,62647,516 (36.6)63,110 (31.0)<.001
       Psychosis95702377 (1.8)7193 (3.5)<.001
       Alcohol use disorder86,08225,913 (20.0)60,169 (29.5)<.001
       Substance use disorder41,37010,382 (8.0)30,988 (15.2)<.001
      Comorbid Psychiatric Disorders: Mean (SD)
      Refers to number of psychiatric diagnoses excluding PTSD. Total column reflects 333,470 patients with one or more psychiatric diagnoses.
      1.7 (1.2)1.5 (1.0)1.8 (1.3)<.001
      PTSD, posttraumatic stress disorder; VA, U.S. Department of Veterans Affairs.
      a Age refers to age at initial VA appointment.
      b Visits refer to mean annual number of primary care or mental health visits.
      c Military sexual trauma exposure is based on VA clinical encounters coded for military sexual trauma.
      d Refers to number of psychiatric diagnoses excluding PTSD. Total column reflects 333,470 patients with one or more psychiatric diagnoses.

      Psychiatric Disorders

      Based on psychiatric diagnoses received within the VA system, we classified patients into three groups: 1) veterans with PTSD alone or combined with other psychiatric disorders; 2) veterans with psychiatric disorders other than PTSD; and 3) veterans with no psychiatric disorders. Psychiatric diagnoses were identified by ICD-9-CM codes from the VA NPCD database and the codes used were as described previously (
      • Seal K.H.
      • Bertenthal D.
      • Miner C.R.
      • Sen S.
      • Marmar C.
      Bringing the war back home: Mental health disorders among 103,788 US veterans returning from Iraq and Afghanistan seen at Department of Veterans Affairs facilities.
      ).

      Autoimmune Disorders

      We identified the most prevalent autoimmune disorders that have definitive diagnostic criteria and/or diagnostic tests based on epidemiologic data and clinical diagnostic criteria (
      • Cooper G.S.
      • Stroehla B.C.
      The epidemiology of autoimmune diseases.
      ). These disorders included thyroiditis, rheumatoid arthritis, inflammatory bowel disorders, multiple sclerosis, and lupus erythematosus. The VA NPCD was then used to obtain information on diagnoses of these autoimmune disorders in our population, based on ICD-9-CM codes (Table S2 in Supplement 1).

      Covariates

      The VA OEF/OIF/OND Roster was used to ascertain age, gender, and race, and the NPCD was used to ascertain number of primary care visits. Due to the frequent misclassification of race/ethnicity in administrative data (
      • Kressin N.R.
      • Chang B.H.
      • Hendricks A.
      • Kazis L.E.
      Agreement between administrative data and patients’ self-reports of race/ethnicity.
      ,
      • Jia H.
      • Zheng Y.E.
      • Cowper D.C.
      • Stansbury J.P.
      • Wu S.S.
      • Vogel W.B.
      • et al.
      Race/ethnicity: Who is counting what?.
      ), we adjusted only for White versus non-White in our models. Because greater health care utilization in patients with psychiatric disorders produces a potential ascertainment bias, we adjusted for the number of primary care visits in the year before the autoimmune disorder diagnosis for each patient diagnosed with an autoimmune disorder. For veterans without an autoimmune disorder diagnosis, we adjusted for the number of primary care visits in the year before their most recent VA encounter.

      Statistical Analyses

      Generalized linear models with Poisson distribution and robust error variance were used to estimate relative risks (RR), adjusted relative risks (ARR), and 95% confidence intervals (CIs). In our primary models, we estimated RR and ARR for any of the autoimmune disorders alone or in combination, as well as risk for each autoimmune disorder separately in veterans with a diagnosis of PTSD compared with 1) veterans without any psychiatric diagnoses; and 2) veterans with psychiatric diagnoses other than PTSD. In follow-up analyses, we stratified by gender and assessed the interaction between gender and psychiatric disorder group. We also used generalized linear models to examine the contribution of common comorbid psychiatric disorders and MST. In follow-up analyses, we assessed risk for autoimmune disorders associated with depressive, anxiety, adjustment, psychotic, and alcohol and substance use disorders with and without PTSD. We did not conduct separate analyses for veterans with PTSD alone without any comorbid psychiatric disorders because the symptoms of PTSD overlap with other common psychiatric disorders (e.g., depression and anxiety). In fact, individuals with severe PTSD who have most or all of the symptoms must by definition also meet criteria for major depression. Nonetheless, there is a lot of variability in the number of comorbid diagnoses received by individuals with PTSD and other psychiatric disorders, and this psychiatric burden may also predict outcomes (
      • Kessler R.C.
      • Berglund P.
      • Demler O.
      • Jin R.
      • Merikangas K.R.
      • Walters E.E.
      Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey replication.
      ). Thus, we computed a psychiatric burden variable based on the sum of depression, anxiety, adjustment, psychotic, alcohol use, and substance use disorders (range 0–6 disorders) to examine the effects of number of comorbidities on risk for autoimmune disorders. Finally, in follow-up analyses testing the reverse of our primary hypothesis, we examined the RR and ARR for diagnosis with PTSD and other psychiatric disorders in veterans with versus without autoimmune disorders, excluding veterans who had a diagnosis of a psychiatric disorder before their autoimmune disorder. Models were adjusted for age, gender, race, and number of primary care visits. Analyses were conducted using SAS software 9.3 (SAS Institute Inc, Cary, North Carolina) and STATA 13.1 (Statacorp, College Station, Texas). All tests of significance were two-sided with an α of p < .05.

      Results

      Sample Characteristics

      Table 1 describes the sample characteristics. PTSD with and without other psychiatric diagnoses was diagnosed in 203,766 veterans (30.6%), and psychiatric disorders other than PTSD were diagnosed in an additional 129,704 veterans (19.5%). Veterans with psychiatric disorders were younger (p < .001), more likely to be male (p < .001) and non-White (p < .001), and had a higher number of visits to primary care in the prior year (p < .001) than veterans with no psychiatric disorders. The median follow-up time from first appointment to the study end date was 1502 days (interquartile range, 913–2186 days) with a minimum of 366 and a maximum of 3819 days.

      Autoimmune Disorders

      Within the sample of 666,269 veterans, 9743 (1.5%) received a diagnosis of an autoimmune diagnosis at two or more separate VA clinical encounters: 6963 (1.0%) with thyroiditis, 1460 (.2%) with inflammatory bowel diseases, 562 (.1%) with rheumatoid arthritis, 535 (.1%) with multiple sclerosis, and 339 (.1%) with lupus erythematosus. Based on previous epidemiologic studies that used a wider age range of participants and balanced samples of male and female subjects, our relatively young and mostly male veteran sample had slightly lower rates of thyroiditis (1% vs. 1.95%) (
      • Jacobson D.L.
      • Gange S.J.
      • Rose N.R.
      • Graham N.M.
      Epidemiology and estimated population burden of selected autoimmune diseases in the United States.
      ), inflammatory bowel diseases (.2% vs. .4%) (
      • Kappelman M.D.
      • Rifas-Shiman S.L.
      • Kleinman K.
      • Ollendorf D.
      • Bousvaros A.
      • Grand R.J.
      • Finkelstein J.A.
      The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States.
      ), and rheumatoid arthritis (.1% vs. .5% to 1%) (
      • Gabriel S.E.
      • Michaud K.
      Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases.
      ) but similar rates of systemic lupus erythematosus (.1% vs. .1%) (
      • Danchenko N.
      • Satia J.A.
      • Anthony M.S.
      Epidemiology of systemic lupus erythematosus: A comparison of worldwide disease burden.
      ) and higher rates of multiple sclerosis (.1% vs. .01%) (

      Olek MJ (2012): Epidemiology and clinical features of multiple sclerosis in adults. In: Up To Date. Available at: http://www.uptodate.com/contents/epidemiology-and-clinical-features-of-multiple-sclerosis-in-adults?source=search_result&search=multiple+sclerois&selectedTitle=2~150. Accessed June 5, 2014.

      ). The median time between first psychiatric diagnosis and first autoimmune disorder diagnosis was 220 days (interquartile range, 6–807 days).

      PTSD and Risk for Autoimmune Disorders

      Veterans diagnosed with PTSD had significantly higher risk for diagnosis with any of the autoimmune disorders alone or in combination and for all of the autoimmune disorders considered individually compared with veterans with no psychiatric disorders (Figure 2, Table 2). Veterans with psychiatric disorders other than PTSD also had significantly higher risk for any of the autoimmune disorders alone or in combination with other autoimmune disorders, as well as for thyroiditis, multiple sclerosis, and lupus erythematosus, compared with veterans with no psychiatric disorders (Figure 2, Table 2).
      Figure thumbnail gr2
      Figure 2Adjusted relative risk for autoimmune disorder diagnoses in veterans without any psychiatric disorder (black circles), with psychiatric disorders other than posttraumatic stress disorder (PTSD) (blue squares), and with PTSD with and without other psychiatric disorders (red triangles) adjusted for age, gender, race, and primary care visits. Dots represent adjusted relative risk and lines represent 95% confidence intervals.
      Table 2Unadjusted and Age-Adjusted Relative Risk for Each Autoimmune Disorder According to Psychiatric Status
      Relative Risk (95% CI)Adjusted
      Relative risk adjusted for age, gender, race, and primary care visits.
      Relative Risk (95% CI)
      Psychiatric StatusNo Psychiatric DisorderOther Psychiatric DisordersPTSDNo Psychiatric DisorderOther Psychiatric DisordersPTSD
      All Veterans
       Any autoimmune disorder1.00 [reference]1.33 (1.26, 1.41)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.81 (1.73, 1.89)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.32 (1.25, 1.39)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.00 (1.91, 2.09)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Thyroiditis1.00 [reference]1.40 (1.31, 1.49)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.92 (1.82, 2.03)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.39 (1.30, 1.48)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.17 (2.06, 2.29)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Inflammatory bowel diseases1.00 [reference].92 (.79, 1.06)1.34 (1.20, 1.50)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference].89 (.77, 1.04)1.30 (1.16, 1.46)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Multiple sclerosis1.00 [reference]2.35 (1.88, 2.93)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.23 (1.83, 2.73)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]2.29 (1.83, 2.86)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.36 (1.93, 2.89)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Rheumatoid arthritis1.00 [reference]1.00 (.78, 1.28)1.70 (1.42, 2.04)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.01 (.79, 1.30)2.04 (1.70, 2.45)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Lupus erythematosus1.00 [reference]1.66 (1.26, 2.19)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.63 (1.28, 2.09)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.57 (1.19, 2.08)
      .001 < p < .05.
      1.85 (1.45, 2.37)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      Female Veterans
       Any autoimmune disorder1.00 [reference]1.26 (1.14, 1.39)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.14 (1.97, 2.33)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.27 (1.14, 1.40)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.09 (1.92, 2.29)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Thyroiditis1.00 [reference]1.20 (1.07, 1.34)
      .001 < p < .05.
      2.10 (1.91, 2.31)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.22 (1.09, 1.37)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.09 (1.89, 2.31)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Inflammatory bowel diseases1.00 [reference]1.31 (.90, 1.93)1.99 (1.42, 2.78)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.28 (.86, 1.92)1.92 (1.34, 2.76)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Multiple sclerosis1.00 [reference]2.63 (1.72, 4.02)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.92 (1.93, 4.41)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]2.68 (1.73, 4.15)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.90 (1.91, 4.40)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Rheumatoid arthritis1.00 [reference]1.22 (.81, 1.81)2.58 (1.86, 3.56)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.20 (.80, 1.80)2.39 (1.72, 3.33)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Lupus erythematosus1.00 [reference]1.37 (.92, 2.06)2.05 (1.43, 2.94)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.34 (.89, 2.02)1.89 (1.30, 2.75)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      Male Veterans
       Any autoimmune disorder1.00 [reference]1.29 (1.21, 1.38)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.79 (1.70, 1.88)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.34 (1.26, 1.44)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.95 (1.85, 2.06)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Thyroiditis1.00 [reference]1.41 (1.30, 1.52)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.97 (1.85, 2.10)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]1.48 (1.37, 1.60)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.22 (2.08, 2.36)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Inflammatory bowel diseases1.00 [reference].87 (.74, 1.02)1.28 (1.13, 1.44)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference].84 (.72, .99)
      .001 < p < .05.
      1.23 (1.09, 1.39)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Multiple sclerosis1.00 [reference]2.14 (1.65, 2.78)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.14 (1.70, 2.70)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference]2.16 (1.65, 2.81)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      2.18 (1.73, 2.76)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Rheumatoid arthritis1.00 [reference].83 (.61, 1.13)1.52 (1.22, 1.88)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.00 [reference].91 (.66, 1.25)1.88 (1.50, 2.43)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
       Lupus erythematosus1.00 [reference]1.69 (1.16, 2.47)
      .001 < p < .05.
      1.57 (1.12, 2.19)
      .001 < p < .05.
      1.00 [reference]1.78 (1.21, 2.62)
      .001 < p < .05.
      1.73 (1.22, 2.45)
      .001 < p < .05.
      CI, confidence interval; PTSD, posttraumatic stress disorder.
      a Relative risk adjusted for age, gender, race, and primary care visits.
      b p ≤ .001 when compared with veterans with no psychiatric disorder.
      c .001 < p < .05.
      In all cases, the effect size for the ARR associated with psychiatric disorders other than PTSD was smaller than that associated with PTSD. Moreover, compared with veterans with other psychiatric disorders, veterans with PTSD had significantly higher risk for diagnosis with any autoimmune disorder alone or in combination (ARR = 1.51, 95% CI, 1.43–1.59; p < .001), as well as for thyroiditis (ARR = 1.56; 95% CI, 1.47–1.66; p < .001), inflammatory bowel disorders (ARR = 1.45; 95% CI, 1.23–1.67; p < .001), and rheumatoid arthritis, (ARR = 2.01; 95% CI, 1.52–2.51; p < .001) but not multiple sclerosis (ARR = 1.03; 95% CI, .82–1.25; p = .63) or lupus erythematosus (ARR = 1.18; 95% CI, .85–1.51; p = .12) individually.
      In follow-up analyses, we examined if the addition of comorbid PTSD was associated with elevated risk for autoimmune disorders in veterans with other specific psychiatric diagnoses including depressive, anxiety, adjustment, psychotic, substance use, and alcohol use disorders. These analyses indicated that in each case, the addition of PTSD conferred significantly higher risk for developing an autoimmune disorder (Table 3). Veterans with PTSD in our sample had a higher number of comorbid psychiatric diagnoses than veterans with other psychiatric disorders (ps < .001) (Table 1 and Table S1 in Supplement 1). Thus, we reran our analyses adjusting for number of comorbid psychiatric disorders (excluding PTSD) and found that PTSD-related increased risk for autoimmune disorders remained significant in analyses adjusted for age, gender, race/ethnicity, and number of primary care visits (ARR = 1.36; 95% CI, 1.29–1.42; p < .001). In the same model, number of comorbidities itself was an independent risk factor for autoimmune disorders (ARR = 1.22; 95% CI, 1.20–1.25; p < .001).
      Table 3Unadjusted and Age-Adjusted Relative Risk for Diagnosis of Any Autoimmune Disorder with Specific Psychiatric Diagnoses without Versus with Comorbid PTSD
      Psychiatric Diagnoses without and with PTSDNumberAutoimmune Disorder Diagnosis Number (%)Relative Risk (95% CI)Adjusted Relative Risk
      Relative risk adjusted for age, gender, race, and primary care visits.
      (95% CI)
      Depression
       Without PTSD57,3131245 (2.2)1.00 [reference]1.00 [reference]
       With PTSD126,7963183 (2.5)1.16 (1.08, 1.23)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.34 (1.25, 1.43)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      Anxiety
       Without PTSD44,632775 (1.7)1.00 [reference]1.00 [reference]
       With PTSD79,1872024 (2.6)1.47 (1.36, 1.60)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.60 (1.47, 1.73)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      Adjustment Disorder
       Without PTSD47,516692 (1.5)1.00 [reference]1.00 [reference]
       With PTSD63,1101520 (2.4)1.65 (1.51, 1.81)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.78 (1.63, 1.95)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      Psychosis
       Without PTSD237776 (3.2)1.00 [reference]1.00 [reference]
       With PTSD7193255 (3.5)1.11 (.86, 1.43)1.16 (.89, 1.51)
      Alcohol Use Disorder
       Without PTSD25,913282 (1.1)1.00 [reference]1.00 [reference]
       With PTSD60,1691157 (1.9)1.77 (1.55, 2.01)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.81 (1.61, 2.11)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      Substance Use Disorder
       Without PTSD10,382126 (1.2)1.00 [reference]1.00 [reference]
       With PTSD30,988660 (2.1)1.75 (1.45, 2.12)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      1.88 (1.54, 2.30)
      p ≤ .001 when compared with veterans with no psychiatric disorder.
      CI, confidence interval; PTSD, posttraumatic stress disorder.
      a Relative risk adjusted for age, gender, race, and primary care visits.
      b p ≤ .001 when compared with veterans with no psychiatric disorder.
      We also reran our analyses for lupus erythematosus, excluding patients with lupus erythematosus (ICD-9 code 695.4) and focusing only on those specifically diagnosed with systemic lupus erythematosus (ICD-9 code 710.0). Results indicated that the pattern of results for the combined lupus erythematosus category was the same as that for systemic lupus erythematosus alone. In fact, the effect size for PTSD-related increased risk was larger for systemic lupus erythematosus alone than for the combination of lupus erythematosus and systemic lupus erythematosus (ARR = 1.65; 95% CI, 1.14–2.40; p = .008).

      Gender Differences

      Table S1 in Supplement 1 describes sample characteristics stratified by gender. Women had significantly higher risk for autoimmune disorders overall with 4.6% of women versus 1.7% of men being diagnosed with an autoimmune disorder. In models adjusted for age, race, and primary care visits, women relative to men had more than three times higher risk for any of the autoimmune disorders alone or in combination (ARR = 3.03; 95% CI, 2.89–3.16; p < .001) and significantly elevated risk for thyroiditis (ARR = 3.48; 95% CI, 3.31–3.67; p < .001), rheumatoid arthritis (ARR = 3.94; 95% CI, 3.30–4.69; p < .001), multiple sclerosis (ARR = 2.63; 95% CI, 2.16–3.19; p < .001), and lupus erythematosus (ARR = 6.23; 95% CI, 5.01–7.73; p < .001), but not inflammatory bowel disorders (ARR = 1.04; 95% CI, .89–1.22; p = .59), considered individually.
      Relative risks for autoimmune disorders in PTSD, other psychiatric disorders, and no psychiatric disorder are shown separately for women and men in Table 2. PTSD-related increased risk for autoimmune disorders was similar in both genders, and we did not find evidence of a PTSD by gender interaction. However, due to the increased risk for autoimmune disorders in women overall, the absolute prevalence of autoimmune disorders was highest in women with PTSD (Figure 3).
      Figure thumbnail gr3
      Figure 3Percentage of female and male veterans with any autoimmune disorder. The absolute prevalence of autoimmune disorders was highest in women with posttraumatic stress disorder (PTSD) at 5.4%, followed by women with psychiatric disorders other than PTSD at 3.1% and women with no psychiatric disorders at 2.5%. Men with PTSD had the next highest prevalence at 1.7%, followed by men with psychiatric disorders other than PTSD at 1.2% and finally men with no psychiatric disorders with the lowest prevalence of the autoimmune disorders at .9%.

      Military Sexual Trauma and Autoimmune Disorders

      One factor that differed markedly between women and men was MST, which was much more common in women (13%) than men (.5%). Table 1 shows rates of MST across the sample and Table S1 in Supplement 1 shows MST rates stratified by gender. To examine if MST was contributing to our finding of elevated risk for autoimmune disorders in veterans with PTSD, we compared the risk for autoimmune disorders among veterans with MST without PTSD, veterans with PTSD without MST, veterans with both PTSD and MST combined compared with all other veterans. In the combined sample of male and female subjects, both MST without PTSD (ARR = 1.64; 95% CI, 1.41–1.92; p < .001) and PTSD without MST (ARR = 1.84; 95% CI, 1.75–1.93; p < .001) were significant risk factors for autoimmune disorder diagnoses and the combination of PTSD and MST was associated with even higher risk (ARR = 2.40; 95% CI, 2.17–2.65; p < .001). When we repeated these analyses in the stratified samples of women and men, the pattern of results was similar. The only difference was that in women, the risk for autoimmune disorders with PTSD without MST was higher than risk associated with MST without PTSD (ARR = 1.95 vs. 1.65), whereas in men, the risk for autoimmune disorders associated with MST without PTSD was higher than risk associated with PTSD without MST (ARR = 2.24 vs. 1.80). The combination of MST and PTSD was associated with the highest risk in both women (ARR = 2.57; 95% CI, 2.28–2.89; p < .001) and men (ARR = 2.40; 95% CI, 1.81–3.20; p < .001). Thus, MST was an independent risk factor for autoimmune disorders in our sample, but it did not fully account for our findings of PTSD-related increased risk.

      Autoimmune Disorders and Risk for Psychiatric Disorders

      A total of 2940 veterans received a diagnosis of an autoimmune disorder before being diagnosed with a psychiatric disorder. Surprisingly, veterans with autoimmune disorders had lower risk for subsequent diagnosis with PTSD and other psychiatric disorders compared with those without autoimmune disorders (ARR = .59; 95% CI, .57–.62; p < .001).

      Discussion

      This study of 666,269 Iraq and Afghanistan veterans indicates that PTSD is associated with increased risk for diagnosis with autoimmune disorders. Specifically, our results showed that veterans with PTSD had twice the risk of being diagnosed with an autoimmune disorder compared with those without any psychiatric disorders and 51% increased risk compared with veterans with psychiatric disorders other than PTSD. Veterans with a higher number of comorbid psychiatric diagnoses were also at increased risk for autoimmune disorders, but high levels of comorbidity did not entirely account for the effect of PTSD on risk. Although the magnitude of PTSD-related increased risk was similar in women and men, women overall had almost three times higher risk for diagnosis with an autoimmune disorder. Thus, the absolute prevalence of autoimmune disorders was highest in women with PTSD. MST was independently associated with risk for autoimmune disorders in both women and men.
      Our findings expand upon prior studies in smaller samples that have indicated increased risk for autoimmune disorders in patients with PTSD (
      • Boscarino J.A.
      Posttraumatic stress disorder and physical illness: Results from clinical and epidemiologic studies.
      ,
      • Boscarino J.A.
      • Forsberg C.W.
      • Goldberg J.
      A twin study of the association between PTSD symptoms and rheumatoid arthritis.
      ). Taken together with the two smaller previous studies, our data indicate that PTSD, and not cohort-specific environmental exposures, may increase risk for autoimmune disorders. Our findings also contribute to a growing literature highlighting the increased risk for other chronic physical diseases in veterans with PTSD and other psychiatric disorders (
      • Cohen B.E.
      • Marmar C.
      • Ren L.
      • Bertenthal D.
      • Seal K.H.
      Association of cardiovascular risk factors with mental health diagnoses in Iraq and Afghanistan war veterans using VA health care.
      ,
      • Yaffe K.
      • Vittinghoff E.
      • Lindquist K.
      • Barnes D.
      • Covinsky K.E.
      • Neylan T.
      • et al.
      Posttraumatic stress disorder and risk of dementia among US veterans.
      ,
      • Kubzansky L.D.
      • Koenen K.C.
      • Spiro A.I.
      • Vokonas P.S.
      • Sparrow D.
      Prospective study of posttraumatic stress disorder symptoms and coronary heart disease in the Normative Aging Study.
      ).
      In the present cohort, women had almost threefold higher risk for autoimmune disorders compared with men, which is likely due to sex differences in immunomodulation. Compared with men, women tend to show elevated antibody response to infection, vaccination, and physical trauma, which is thought to confer protection from infectious diseases but greater risk for autoimmune disorders (
      • Fairweather D.
      • Frisancho-Kiss S.
      • Rose N.R.
      Sex differences in autoimmune disease from a pathological perspective.
      ,
      • Fairweather D.
      • Petri M.A.
      • Coronado M.J.
      • Cooper L.T.
      Autoimmune heart disease: Role of sex hormones and autoantibodies in disease pathogenesis.
      ). Moreover, previous studies have shown sex differences in stress-response systems that may lead to differences in biological and health outcomes in women versus men with PTSD (
      • Almli L.M.
      • Mercer K.B.
      • Kerley K.
      • Feng H.
      • Bradley B.
      • Conneely K.N.
      • Ressler K.J.
      ADCYAP1R1 genotype associates with post-traumatic stress symptoms in highly traumatized African-American females.
      ,
      • Ressler K.J.
      • Mercer K.B.
      • Bradley B.
      • Jovanovic T.
      • Mahan A.
      • Kerley K.
      • et al.
      Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.
      ,
      • Inslicht S.S.
      • Metzler T.J.
      • Garcia N.M.
      • Pineles S.L.
      • Milad M.R.
      • Orr S.P.
      • et al.
      Sex differences in fear conditioning in posttraumatic stress disorder.
      ). However, women and men with PTSD in our population had roughly equivalent levels of increased risk for autoimmune disorders than same-sex veterans without PTSD. Thus, our results suggest no interaction between PTSD and gender in risk for autoimmune disorders. Women had much higher levels of MST exposure compared with men and MST was itself a risk factor for autoimmune disorder diagnoses. However, PTSD without MST remained significantly associated with increased risk for autoimmune disorders in both women and men.
      The mechanisms of the observed association between PTSD and autoimmune disorders remain unclear. However, a dysregulated hypothalamic-pituitary-adrenal axis, elevated inflammation, accelerated immune cell aging, and altered immune cell gene expression patterns may play a mechanistic role (
      • Yehuda R.
      • Teicher M.H.
      • Levengood R.A.
      • Trestman R.L.
      • Siever L.J.
      Circadian regulation of basal cortisol levels in posttraumatic stress disorder.
      ,
      • Neylan T.C.
      • Brunet A.
      • Pole N.
      • Best S.R.
      • Metzler T.J.
      • Yehuda R.
      • Marmar C.R.
      PTSD symptoms predict waking salivary cortisol levels in police officers.
      ,
      • Yehuda R.
      • Golier J.A.
      • Kaufman S.
      Circadian rhythm of salivary cortisol in Holocaust survivors with and without PTSD.
      ,
      • O’Donovan A.
      • Sun B.
      • Cole S.
      • Rempel H.
      • Lenoci M.
      • Pulliam L.
      • Neylan T.
      Transcriptional control of monocyte gene expression in post-traumatic stress disorder.
      ,
      • Pace T.W.
      • Wingenfeld K.
      • Schmidt I.
      • Meinlschmidt G.
      • Hellhammer D.H.
      • Heim C.M.
      Increased peripheral NF-kappaB pathway activity in women with childhood abuse-related posttraumatic stress disorder.
      ,
      • Hoge E.A.
      • Brandstetter K.
      • Moshier S.
      • Pollack M.H.
      • Wong K.K.
      • Simon N.M.
      Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder.
      ,
      • Neylan T.C.
      • Sun B.
      • Rempel H.
      • Ross J.
      • Lenoci M.
      • O’Donovan A.
      • Pulliam L.
      Suppressed monocyte gene expression profile in men versus women with PTSD.
      ,
      • Uddin M.
      • Aiello A.E.
      • Wildman D.E.
      • Koenen K.C.
      • Pawelec G.
      • de Los Santos R.
      • et al.
      Epigenetic and immune function profiles associated with posttraumatic stress disorder.
      ,
      • von Kanel R.
      • Hepp U.
      • Kraemer B.
      • Traber R.
      • Keel M.
      • Mica L.
      • Schnyder U.
      Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder.
      ). In addition, increased tobacco use, impaired sleep, poor diet, and substance and alcohol use may contribute to both biological abnormalities and risk for autoimmune disorders observed in individuals with PTSD (
      • Padyukov L.
      • Silva C.
      • Stolt P.
      • Alfredsson L.
      • Klareskog L.
      A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis.
      ,
      • Palma B.D.
      • Gabriel Jr, A.
      • Colugnati F.A.
      • Tufik S.
      Effects of sleep deprivation on the development of autoimmune disease in an experimental model of systemic lupus erythematosus.
      ,
      • Ascherio A.
      • Munger K.L.
      Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors.
      ,
      • Cook R.T.
      Alcohol abuse, alcoholism, and damage to the immune system–a review.
      ). It is also possible that shared genetic and environmental vulnerability factors, including dysregulated glucocorticoid signaling, accelerated immune cell aging, and childhood trauma, may contribute to the development of PTSD as well as autoimmune disorders (
      • Dantzer R.
      • O’Connor J.C.
      • Freund G.G.
      • Johnson R.W.
      • Kelley K.W.
      From inflammation to sickness and depression: When the immune system subjugates the brain.
      ,
      • Pace T.W.
      • Heim C.M.
      A short review on the psychoneuroimmunology of posttraumatic stress disorder: From risk factors to medical comorbidities.
      ,
      • Dube S.R.
      • Fairweather D.
      • Pearson W.S.
      • Felitti V.J.
      • Anda R.F.
      • Croft J.B.
      Cumulative childhood stress and autoimmune diseases in adults.
      ). In fact, prior studies indicate that autoimmune disorders increase risk for subsequent diagnosis with mood disorders and schizophrenia (
      • Benros M.E.
      • Waltoft B.L.
      • Nordentoft M.
      • Ostergaard S.D.
      • Eaton W.W.
      • Krogh J.
      • Mortensen P.B.
      Autoimmune diseases and severe infections as risk factors for mood disorders: A nationwide study.
      ,
      • Benros M.E.
      • Eaton W.W.
      • Mortensen P.B.
      The epidemiologic evidence linking autoimmune diseases and psychosis.
      ). Moreover, the autoimmune disorders that we have included in the present study have distinct, as well as overlapping, etiological mechanisms and the pathway from psychiatric disorders to autoimmune disorders may differ among them.
      Although studies such as the present one indicate that psychiatric disorders and autoimmune disorders co-occur, causal direction is less clear. In our study, we focused on the risk for autoimmune disorders in individuals with PTSD. The hypothesis that trauma exposure and PTSD may increase risk for the development of autoimmune disorders is supported by some nonhuman experimental stress studies (
      • Johnson R.R.
      • Prentice T.W.
      • Bridegam P.
      • Young C.R.
      • Steelman A.J.
      • Welsh T.H.
      • et al.
      Social stress alters the severity and onset of the chronic phase of Theiler’s virus infection.
      ,
      • Welsh C.J.
      • Steelman A.J.
      • Mi W.
      • Young C.R.
      • Storts R.
      • Welsh Jr, T.H.
      • Meagher M.W.
      Neuroimmune interactions in a model of multiple sclerosis.
      ). However, other investigators have proposed that stress may actually protect against the development of specific autoimmune disorders under some circumstances (
      • Dhabhar F.S.
      Effects of stress on immune function: The good, the bad, and the beautiful.
      ).
      Our analyses indicated lower risk for subsequent diagnosis with psychiatric disorders in individuals previously diagnosed with autoimmune disorders, which may be due to diagnostic biases. Autoimmune disorders such as lupus and multiple sclerosis can be accompanied by psychiatric symptoms, including depressive and even psychotic symptoms (
      • Weiss D.B.
      • Dyrud J.
      • House R.M.
      • Beresford T.P.
      Psychiatric manifestations of autoimmune disorders.
      ). In the present study, we relied on physician diagnoses made during routine clinical care as indices of psychiatric and autoimmune disorders, which may bias results. For example, once an autoimmune disorder has been diagnosed, psychiatric symptoms (e.g., fatigue, confusion, sadness, and anxiety) may be attributed to the autoimmune disorder rather than to a de novo psychiatric disorder. Further large-scale prospective research studies in different health care settings will be necessary to clarify this issue.

      Limitations

      The present study benefits from a large sample size comprising most of the population being studied, longitudinal data, physician rather than self-report diagnoses of psychiatric and autoimmune disorders, adjustment for many relevant confounds, and the ability to assess gender differences. However, the study also has several limitations. First, we cannot claim to have shown causal relationships in this retrospective observational study. Moreover, we cannot be confident about temporality because diagnoses were made at the point when VA providers first coded the condition using ICD-9-CM criteria, which may not correspond with emergence of symptoms, and psychiatric and autoimmune disorders may be present for years or even decades before an official diagnosis. Second, the use of codes rather than clinical diagnoses may lead to misclassification errors and our data may be at risk of bias due to underreporting or overreporting of symptoms by veterans seeking VA care (
      • Gold P.B.
      • Frueh B.C.
      Compensation-seeking and extreme exaggeration of psychopathology among combat veterans evaluated for posttraumatic stress disorder.
      ,
      • McNally R.J.
      • Frueh B.C.
      Why are Iraq and Afghanistan war veterans seeking PTSD disability compensation at unprecedented rates?.
      ). Third, veterans with PTSD are known to be at increased risk for other chronic physical diseases, and we did not adjust for the presence of these disorders in our analytic models (
      • Spitzer C.
      • Barnow S.
      • Volzke H.
      • John U.
      • Freyberger H.J.
      • Grabe H.J.
      Trauma, posttraumatic stress disorder, and physical illness: Findings from the general population.
      ,
      • Boscarino J.A.
      A prospective study of PTSD and early-age heart disease mortality among Vietnam veterans: Implications for surveillance and prevention.
      ). Fourth, our focus on Iraq and Afghanistan veterans who have served in conflict relatively recently means that we have a relatively short follow-up time. Later follow-up studies will be necessary to explore if the findings remain consistent over time as veterans age. Fifth, our data on MST may underestimate actual MST in the population because it is based on clinical visits related to MST. However, the rates observed in our sample are similar to those seen in studies that used the VA MST screen (
      • Maguen S.
      • Cohen B.
      • Ren L.
      • Bosch J.
      • Kimerling R.
      • Seal K.
      Gender differences in military sexual trauma and mental health diagnoses among Iraq and Afghanistan veterans with posttraumatic stress disorder.
      ). Our study also lacks information on other traumatic events that may vary by gender, including other war zone trauma exposures. Finally, our study is based on treatment-seeking veterans using the VA health care system. Although the VA is the largest provider of health care to returning veterans, our results may not generalize to Iraq and Afghanistan veterans not enrolled in VA health care, other veterans, or civilians.

      Conclusions

      The present results underline high rates of PTSD and other psychiatric diagnoses in Iraq and Afghanistan veterans and highlight the knock-on effects of trauma exposure and PTSD on physical health. Our results indicate that young veterans diagnosed with PTSD have significantly increased risk for diagnosis with autoimmune disorders with definitive diagnostic criteria. Future prospective longitudinal cohort studies are needed to establish causality, measure endocrine and immune system activity in veterans with PTSD, and evaluate whether timely and successful treatment of PTSD reduces risk of autoimmune disorders. However, lower thresholds for evaluating the presence of autoimmune disorders may be warranted in veterans with PTSD and other psychiatric disorders immediately. Our data underscore the need to identify and treat PTSD and other psychiatric disorders in veterans to enhance not only mental but also physical health.

      Acknowledgments and Disclosures

      We acknowledge support for the present manuscript from The Mental Illness Research, Education and Clinical Centers; Society in Science–The Branco Weiss Fellowship; and the National Institutes of Health, as well as the Department of Veterans Affairs and the NCIRE–The Veterans Health Research Institute. We also thank Ashkan Ahmadian for his excellent assistance with this manuscript.
      Dr. Aoife O’Donovan received salary support from Society in Science–The Branco Weiss Fellowship. Dr. Beth Cohen received salary support through NIH-K23 HL 094765-0 . Mr. Dan Bertenthal received grant salary support through grants to Dr. Karen Seal and The Mental Illness Research, Education and Clinical Centers Program Director Dr. Thomas Neylan. Dr. Mary Margaretten received grant support through NIH-KL2 TR 000143 . All other authors reported no biomedical financial interests or potential conflicts of interest.

      Appendix A. Supplementary materials

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