Commentary
Biological Psychiatry
Posttraumatic Stress Disorder and Autoimmune Diseases Michael E. Benros In this issue of Biological Psychiatry, O’Donovan et al. (1) present the most comprehensive study on autoimmune diseases in individuals with posttraumatic stress disorder (PTSD) to date. The authors use a cohort of 666,269 Iraq and Afghanistan veterans ,55 years old enrolled in the Department of Veterans Affairs health care system in the United States. In 30.6% of the veterans, PTSD was diagnosed, and psychiatric disorders other than PTSD were diagnosed in an additional 19.5% of the veterans. In 1.5% (n 5 9743) of the veterans, an autoimmune disease was diagnosed on two or more separate encounters within the Veterans Affairs health care system, with the most common autoimmune disease being thyroiditis, which was diagnosed in 1.0% of the veterans. The other autoimmune diseases included rheumatoid arthritis, inflammatory bowel disorders, multiple sclerosis, and lupus erythematosus. The mean follow-up time was just over 4 years (range, 366–3819 days). The authors noted that PTSD has been associated with several immune alterations, immune-related genes, and abnormalities in the hypothalamic-pituitary-adrenal axis that may increase the risk of autoimmune diseases through inflammation and impaired function of immune cells (1). The study showed that the risk of autoimmune diseases was increased twofold (adjusted relative risk 5 2.00; 95% confidence interval [CI], 1.91–2.09) in individuals with PTSD compared with individuals without psychiatric disorders. Compared with individuals with other psychiatric diagnoses, individuals with PTSD still had a significantly elevated risk of autoimmune diseases of 51% (adjusted relative risk 5 1.51; 95% CI, 1.43–1.59). Thyroiditis primarily accounted for the further increased risk of autoimmune diseases in individuals with PTSD compared with individuals with other psychiatric disorders owing to the frequency of this autoimmune disease. The risk of inflammatory bowel disorders and rheumatoid arthritis was also increased in individuals with PTSD, whereas multiple sclerosis and lupus had a similarly increased risk among individuals with PTSD compared with individuals with other psychiatric disorders. The association of PTSD with comorbid psychiatric disorders is very common, and this was also the case in the present study. However, even after adjustment for the high level of psychiatric comorbidity, the association between PTSD and autoimmune diseases persisted (adjusted relative risk 5 1.36; 95% CI, 1.29– 1.42). In comparison, individuals with comorbid psychiatric disorders were also at a further increased risk of autoimmune diseases than individuals who had just one psychiatric disorder (adjusted relative risk 5 1.22; 95% CI, 1.20–1.25). The association between autoimmune diseases and PTSD has previously been investigated only in smaller studies. A study of Vietnam veterans (N 5 2490) found an increased risk of self-reported autoimmune diseases among veterans with PTSD (2). Another study on male twins who served during the
Vietnam War era (N 5 3143) found that PTSD was associated with an increased risk of physician-diagnosed rheumatoid arthritis, with twins within the highest PTSD symptom quartile having a 3.8 times increased risk of rheumatoid arthritis (3). The present study also shows that 2940 veterans (.4%) received a diagnosis of an autoimmune disease before being diagnosed with a psychiatric disorder within the Veterans Affairs health care system. The results showed that individuals with autoimmune diseases diagnosed after they had become veterans had a lower risk for a subsequent diagnosis of PTSD and other psychiatric disorders compared with veterans without autoimmune diseases (adjusted relative risk 5 .59; 95% CI, .57–.62), which is contrary to many other studies on autoimmune diseases and subsequent risk of psychiatric disorders. Previous nationwide population-based studies with much larger follow-up periods and study populations consistently associated autoimmune diseases with a broad range of psychiatric disorders, including schizophrenia, bipolar disorder, depression, and eating disorders (4–6). This lack of a bidirectional association in the current study could be due to the fact that the PTSD diagnoses were most likely made shortly after entering the Veterans Affairs health care system because one would presume that there is increased focus on PTSD after the veterans had been exposed to warfare. The study population is highly selected, which might influence the observed temporal associations, compared with other population-based studies that have included entire populations. The temporality of the development of PTSD and autoimmune diseases might be difficult to determine, and any suggested causal relationship should be interpreted with caution within a setting of veterans, as is also noted by the authors. Autoimmune diseases might have been present for many years before a diagnosis is reached. Diagnostic bias (e.g., attributing the psychiatric symptoms to the autoimmune disease (maybe correctly) might also affect the observed associations. The main limitation of the study is the short follow-up period and the lack of more detailed investigations of the temporal associations. Other limitations include a potential detection bias because the veterans with psychiatric problems might be more likely to have more medical follow-up evaluations than veterans without psychiatric problems. This is indicated in the study because the group of veterans with psychiatric disorders had a higher number of visits to primary care in the prior year (p , .001) than veterans with no psychiatric disorders, which the authors also controlled for in their study. The authors additionally controlled for this bias using individuals with other psychiatric disorders than PTSD as an additional control group. Nonetheless, the high comorbidity between PTSD with anxiety and depression makes it difficult to disentangle the specificity of the results on PTSD. The risk of autoimmune diseases was only slightly greater in individuals
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http://dx.doi.org/10.1016/j.biopsych.2014.12.006 ISSN: 0006-3223
Biological Psychiatry
Commentary
with PTSD than it was in other individuals with comorbid psychiatric disorders. The study is an observational study, and if screening for autoimmune diseases instead had been carried out in the individuals with PTSD, and vice versa, the associations might have been stronger. The proposed etiologic factors for the development of autoimmune diseases are multifactorial and include genetics, immunologic factors, environmental exposures such as infections, and hormonal factors. Many studies have observed associations between psychological stress and poor outcome in individuals with autoimmune diseases with flare-ups of symptoms and autoimmune disease activity during periods of psychological stress. Psychological stress might affect the immune system and through immune-related mechanisms be responsible for increased autoimmune disease activity or worsening of symptoms during periods of psychological stress. However, a study in veterans with rheumatoid arthritis found no association between PTSD and clinical rheumatoid arthritis disease activity; the only association was with self-reported symptoms (7). Whether psychological stress can induce autoimmune diseases is still debatable; animal studies have suggested this association but have been nonconclusive (8). Animal and human studies have more convincingly shown that brainreactive antibodies and immune responses can induce a broad range of psychiatric symptoms (9,10). Nevertheless, there is clearly a bidirectional interplay between the central nervous system and the immune system. However, whether the psychological stress associated with PTSD increases the risk of autoimmune diseases through dysregulation of the immune system secondary to prolonged psychological stress affecting the neuroendocrine pathways is still an open question. However, the authors also associated the occurrence of military sexual trauma with an increased risk of autoimmune diseases independent of PTSD. Common etiologic factors might also account for the development of both PTSD and autoimmune diseases, and individuals with elevated stress levels might be more prone to the effects of infections, for instance, which could increase the risk of PTSD and autoimmune diseases. The article by O’Donovan et al. extends the current knowledge on the associations between autoimmune diseases and psychiatric disorders, which now include schizophrenia, bipolar disorder, depression, eating disorders, and PTSD. As the authors note, PTSD may increase the risk of developing autoimmune diseases, but prospective longitudinal cohort studies are needed to assess causality and evaluate whether successful treatment of PTSD reduces the risk of autoimmune diseases. Large-scale studies using registers with long followup periods on the association between autoimmune diseases and PTSD would be helpful, particularly by adding important information about the possible bidirectional association that has been shown to exist between autoimmune diseases and other psychiatric disorders in less selected cohorts. Such studies could be conducted using the Scandinavian register or other registers that would provide information on autoimmune disease status before the individuals become veterans, giving a longer follow-up period than in the present study before the PTSD diagnosis is made. Randomized animal models of PTSD equivalent phenotypes, and whether they are more prone to autoimmune diseases, could also add important information, strengthening the authors’ hypothesis.
Mounting evidence suggests a link between psychiatric disorders and physical health, particularly relating to disorders associated with dysfunction of the immune system. The associations between autoimmune diseases and psychiatric disorders have been studied for more than 50 years but have primarily focused on psychosis. Within the last decade, research has intensified and broadened to include other psychiatric disorders because many psychiatric disorders have been associated with immune alterations and genetic markers of the immune system; this has given momentum to immunerelated theories as a potential contributing factor to psychiatric disorders. Focus has increased on the excess occurrence of somatic diseases and the increased mortality among individuals with psychiatric disorders, highlighting the importance of identifying and treating physical diseases in individuals with psychiatric disorders, which cannot be stressed enough.
Acknowledgments and Disclosures The author reports no biomedical financial interests or potential conflicts of interest.
Article Information From the Mental Health Centre Copenhagen, University of Copenhagen, Faculty of Health Sciences, Copenhagen; and National Centre for Registerbased Research, Aarhus University, Aarhus, Denmark. Address correspondence to Michael Eriksen Benros, M.D., Ph.D., Mental Health Centre Copenhagen, Copenhagen University Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark; E-mail: Benros@ dadlnet.dk Received Nov 3, 2014; revised Dec 8, 2014; accepted Dec 10, 2014.
References 1.
2.
3.
4.
5.
6.
7.
8. 9.
10.
OʼDonovan A, Cohen BE, Seal KH, Bertenthal D, Margaretten M, Nishimi K, Neylan TC (2015): Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry 77:365–374. Boscarino JA (2004): Posttraumatic stress disorder and physical illness: Results from clinical and epidemiologic studies. Ann N Y Acad Sci 1032:141–153. Boscarino JA, Forsberg CW, Goldberg J (2010): A twin study of the association between PTSD symptoms and rheumatoid arthritis. Psychosom Med 72:481–486. Benros ME, Eaton WW, Mortensen PB (2014): The epidemiologic evidence linking autoimmune diseases and psychosis. Biol Psychiatry 75:300–306. Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, Mortensen PB (2013): Autoimmune diseases and severe infections as risk factors for mood disorders: A nationwide study. JAMA Psychiatry 70:812–820. Raevuori A, Haukka J, Vaarala O, Suvisaari JM, Gissler M, Grainger M, et al. (2014): The increased risk for autoimmune diseases in patients with eating disorders. PLoS One 9:e104845. Mikuls TR, Padala PR, Sayles HR, Yu F, Michaud K, Caplan L, et al. (2013): Prospective study of posttraumatic stress disorder and disease activity outcomes in US veterans with rheumatoid arthritis. Arthritis Care Res 65:227–234. Stojanovich L (2010): Stress and autoimmunity. Autoimmun Rev 9: A271–A276. Dantzer R, OʼConnor JC, Freund GG, Johnson RW, Kelley KW (2008): From inflammation to sickness and depression: When the immune system subjugates the brain.. Nat Rev Neurosci 9:46–56. Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT (2009): Losing your nerves? Maybe itʼs the antibodies. Nat Rev Immunol 9: 449–456.
Biological Psychiatry February 15, 2015; 77:312–313 www.sobp.org/journal
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Biological Psychiatry
Posttraumatic Stress Disorder and Autoimmune Diseases Michael E. Benros In this issue of Biological Psychiatry, O’Donovan et al. (1) present the most comprehensive study on autoimmune diseases in individuals with posttraumatic stress disorder (PTSD) to date. The authors use a cohort of 666,269 Iraq and Afghanistan veterans ,55 years old enrolled in the Department of Veterans Affairs health care system in the United States. In 30.6% of the veterans, PTSD was diagnosed, and psychiatric disorders other than PTSD were diagnosed in an additional 19.5% of the veterans. In 1.5% (n 5 9743) of the veterans, an autoimmune disease was diagnosed on two or more separate encounters within the Veterans Affairs health care system, with the most common autoimmune disease being thyroiditis, which was diagnosed in 1.0% of the veterans. The other autoimmune diseases included rheumatoid arthritis, inflammatory bowel disorders, multiple sclerosis, and lupus erythematosus. The mean follow-up time was just over 4 years (range, 366–3819 days). The authors noted that PTSD has been associated with several immune alterations, immune-related genes, and abnormalities in the hypothalamic-pituitary-adrenal axis that may increase the risk of autoimmune diseases through inflammation and impaired function of immune cells (1). The study showed that the risk of autoimmune diseases was increased twofold (adjusted relative risk 5 2.00; 95% confidence interval [CI], 1.91–2.09) in individuals with PTSD compared with individuals without psychiatric disorders. Compared with individuals with other psychiatric diagnoses, individuals with PTSD still had a significantly elevated risk of autoimmune diseases of 51% (adjusted relative risk 5 1.51; 95% CI, 1.43–1.59). Thyroiditis primarily accounted for the further increased risk of autoimmune diseases in individuals with PTSD compared with individuals with other psychiatric disorders owing to the frequency of this autoimmune disease. The risk of inflammatory bowel disorders and rheumatoid arthritis was also increased in individuals with PTSD, whereas multiple sclerosis and lupus had a similarly increased risk among individuals with PTSD compared with individuals with other psychiatric disorders. The association of PTSD with comorbid psychiatric disorders is very common, and this was also the case in the present study. However, even after adjustment for the high level of psychiatric comorbidity, the association between PTSD and autoimmune diseases persisted (adjusted relative risk 5 1.36; 95% CI, 1.29– 1.42). In comparison, individuals with comorbid psychiatric disorders were also at a further increased risk of autoimmune diseases than individuals who had just one psychiatric disorder (adjusted relative risk 5 1.22; 95% CI, 1.20–1.25). The association between autoimmune diseases and PTSD has previously been investigated only in smaller studies. A study of Vietnam veterans (N 5 2490) found an increased risk of self-reported autoimmune diseases among veterans with PTSD (2). Another study on male twins who served during the
Vietnam War era (N 5 3143) found that PTSD was associated with an increased risk of physician-diagnosed rheumatoid arthritis, with twins within the highest PTSD symptom quartile having a 3.8 times increased risk of rheumatoid arthritis (3). The present study also shows that 2940 veterans (.4%) received a diagnosis of an autoimmune disease before being diagnosed with a psychiatric disorder within the Veterans Affairs health care system. The results showed that individuals with autoimmune diseases diagnosed after they had become veterans had a lower risk for a subsequent diagnosis of PTSD and other psychiatric disorders compared with veterans without autoimmune diseases (adjusted relative risk 5 .59; 95% CI, .57–.62), which is contrary to many other studies on autoimmune diseases and subsequent risk of psychiatric disorders. Previous nationwide population-based studies with much larger follow-up periods and study populations consistently associated autoimmune diseases with a broad range of psychiatric disorders, including schizophrenia, bipolar disorder, depression, and eating disorders (4–6). This lack of a bidirectional association in the current study could be due to the fact that the PTSD diagnoses were most likely made shortly after entering the Veterans Affairs health care system because one would presume that there is increased focus on PTSD after the veterans had been exposed to warfare. The study population is highly selected, which might influence the observed temporal associations, compared with other population-based studies that have included entire populations. The temporality of the development of PTSD and autoimmune diseases might be difficult to determine, and any suggested causal relationship should be interpreted with caution within a setting of veterans, as is also noted by the authors. Autoimmune diseases might have been present for many years before a diagnosis is reached. Diagnostic bias (e.g., attributing the psychiatric symptoms to the autoimmune disease (maybe correctly) might also affect the observed associations. The main limitation of the study is the short follow-up period and the lack of more detailed investigations of the temporal associations. Other limitations include a potential detection bias because the veterans with psychiatric problems might be more likely to have more medical follow-up evaluations than veterans without psychiatric problems. This is indicated in the study because the group of veterans with psychiatric disorders had a higher number of visits to primary care in the prior year (p , .001) than veterans with no psychiatric disorders, which the authors also controlled for in their study. The authors additionally controlled for this bias using individuals with other psychiatric disorders than PTSD as an additional control group. Nonetheless, the high comorbidity between PTSD with anxiety and depression makes it difficult to disentangle the specificity of the results on PTSD. The risk of autoimmune diseases was only slightly greater in individuals
SEE COMPANION ARTICLE ON PAGE 365 & 2015 Society of Biological Psychiatry Biological Psychiatry February 15, 2015; 77:312–313 www.sobp.org/journal
312
http://dx.doi.org/10.1016/j.biopsych.2014.12.006 ISSN: 0006-3223
Biological Psychiatry
Commentary
with PTSD than it was in other individuals with comorbid psychiatric disorders. The study is an observational study, and if screening for autoimmune diseases instead had been carried out in the individuals with PTSD, and vice versa, the associations might have been stronger. The proposed etiologic factors for the development of autoimmune diseases are multifactorial and include genetics, immunologic factors, environmental exposures such as infections, and hormonal factors. Many studies have observed associations between psychological stress and poor outcome in individuals with autoimmune diseases with flare-ups of symptoms and autoimmune disease activity during periods of psychological stress. Psychological stress might affect the immune system and through immune-related mechanisms be responsible for increased autoimmune disease activity or worsening of symptoms during periods of psychological stress. However, a study in veterans with rheumatoid arthritis found no association between PTSD and clinical rheumatoid arthritis disease activity; the only association was with self-reported symptoms (7). Whether psychological stress can induce autoimmune diseases is still debatable; animal studies have suggested this association but have been nonconclusive (8). Animal and human studies have more convincingly shown that brainreactive antibodies and immune responses can induce a broad range of psychiatric symptoms (9,10). Nevertheless, there is clearly a bidirectional interplay between the central nervous system and the immune system. However, whether the psychological stress associated with PTSD increases the risk of autoimmune diseases through dysregulation of the immune system secondary to prolonged psychological stress affecting the neuroendocrine pathways is still an open question. However, the authors also associated the occurrence of military sexual trauma with an increased risk of autoimmune diseases independent of PTSD. Common etiologic factors might also account for the development of both PTSD and autoimmune diseases, and individuals with elevated stress levels might be more prone to the effects of infections, for instance, which could increase the risk of PTSD and autoimmune diseases. The article by O’Donovan et al. extends the current knowledge on the associations between autoimmune diseases and psychiatric disorders, which now include schizophrenia, bipolar disorder, depression, eating disorders, and PTSD. As the authors note, PTSD may increase the risk of developing autoimmune diseases, but prospective longitudinal cohort studies are needed to assess causality and evaluate whether successful treatment of PTSD reduces the risk of autoimmune diseases. Large-scale studies using registers with long followup periods on the association between autoimmune diseases and PTSD would be helpful, particularly by adding important information about the possible bidirectional association that has been shown to exist between autoimmune diseases and other psychiatric disorders in less selected cohorts. Such studies could be conducted using the Scandinavian register or other registers that would provide information on autoimmune disease status before the individuals become veterans, giving a longer follow-up period than in the present study before the PTSD diagnosis is made. Randomized animal models of PTSD equivalent phenotypes, and whether they are more prone to autoimmune diseases, could also add important information, strengthening the authors’ hypothesis.
Mounting evidence suggests a link between psychiatric disorders and physical health, particularly relating to disorders associated with dysfunction of the immune system. The associations between autoimmune diseases and psychiatric disorders have been studied for more than 50 years but have primarily focused on psychosis. Within the last decade, research has intensified and broadened to include other psychiatric disorders because many psychiatric disorders have been associated with immune alterations and genetic markers of the immune system; this has given momentum to immunerelated theories as a potential contributing factor to psychiatric disorders. Focus has increased on the excess occurrence of somatic diseases and the increased mortality among individuals with psychiatric disorders, highlighting the importance of identifying and treating physical diseases in individuals with psychiatric disorders, which cannot be stressed enough.
Acknowledgments and Disclosures The author reports no biomedical financial interests or potential conflicts of interest.
Article Information From the Mental Health Centre Copenhagen, University of Copenhagen, Faculty of Health Sciences, Copenhagen; and National Centre for Registerbased Research, Aarhus University, Aarhus, Denmark. Address correspondence to Michael Eriksen Benros, M.D., Ph.D., Mental Health Centre Copenhagen, Copenhagen University Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark; E-mail: Benros@ dadlnet.dk Received Nov 3, 2014; revised Dec 8, 2014; accepted Dec 10, 2014.
References 1.
2.
3.
4.
5.
6.
7.
8. 9.
10.
OʼDonovan A, Cohen BE, Seal KH, Bertenthal D, Margaretten M, Nishimi K, Neylan TC (2015): Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry 77:365–374. Boscarino JA (2004): Posttraumatic stress disorder and physical illness: Results from clinical and epidemiologic studies. Ann N Y Acad Sci 1032:141–153. Boscarino JA, Forsberg CW, Goldberg J (2010): A twin study of the association between PTSD symptoms and rheumatoid arthritis. Psychosom Med 72:481–486. Benros ME, Eaton WW, Mortensen PB (2014): The epidemiologic evidence linking autoimmune diseases and psychosis. Biol Psychiatry 75:300–306. Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, Mortensen PB (2013): Autoimmune diseases and severe infections as risk factors for mood disorders: A nationwide study. JAMA Psychiatry 70:812–820. Raevuori A, Haukka J, Vaarala O, Suvisaari JM, Gissler M, Grainger M, et al. (2014): The increased risk for autoimmune diseases in patients with eating disorders. PLoS One 9:e104845. Mikuls TR, Padala PR, Sayles HR, Yu F, Michaud K, Caplan L, et al. (2013): Prospective study of posttraumatic stress disorder and disease activity outcomes in US veterans with rheumatoid arthritis. Arthritis Care Res 65:227–234. Stojanovich L (2010): Stress and autoimmunity. Autoimmun Rev 9: A271–A276. Dantzer R, OʼConnor JC, Freund GG, Johnson RW, Kelley KW (2008): From inflammation to sickness and depression: When the immune system subjugates the brain.. Nat Rev Neurosci 9:46–56. Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT (2009): Losing your nerves? Maybe itʼs the antibodies. Nat Rev Immunol 9: 449–456.
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