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A Nationwide Study on the Risk of Autoimmune Diseases in Individuals With a Personal or a Family History of Schizophrenia and Related Psychosis
Michael E. Benros, M.D., Ph.D.; Marianne G. Pedersen, M.Sc.; Helle Rasmussen, M.Sc.; William W. Eaton, Ph.D.; Merete Nordentoft, Dr.Med.Sc.; Preben B. Mortensen, Dr.Med.Sc.
Am J Psychiatry 2014;171:218-226. doi:10.1176/appi.ajp.2013.13010086
View Author and Article Information

The authors report no financial relationships with commercial interests.

Supported by research grants from the Stanley Medical Research Institute, the European Research Council Advanced Grant Project (grant 294838), the Danish Agency for Science, Technology, and Innovation, and NIMH (grant MH 53188 [to Dr. Eaton]), as well as an unrestricted grant from the Lundbeck Foundation Initiative for Integrative Psychiatric Research.

From the National Center for Register-Based Research, Aarhus University, Aarhus, Denmark; Faculty of Health Sciences, Mental Health Center Copenhagen, University of Copenhagen; the Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark; and the Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore.

Address correspondence to Dr. Benros (Benros@ncrr.dk).

Copyright © 2014 by the American Psychiatric Association

Received January 21, 2013; Revised June 11, 2013; Accepted August 01, 2013.

Abstract

Objective  Previous research has found an increased risk of schizophrenia in individuals with autoimmune diseases and smaller but significant associations with a family history of autoimmune diseases. This study investigates, for the first time, the association between schizophrenia and subsequent autoimmune diseases (the reverse temporality) and also considers the effect of infections, a possible risk factor for both schizophrenia and autoimmune diseases.

Method  Danish nationwide registers were linked to establish a cohort of 3.83 million people, identifying 39,364 individuals with schizophrenia-like psychosis and 142,328 individuals with autoimmune disease. Data were analyzed using survival analysis and adjusted for calendar year, age, and sex.

Results  Individuals with schizophrenia had an elevated risk of subsequent autoimmune diseases, with an incidence rate ratio of 1.53 (95% CI=1.46–1.62). Among persons without hospital contacts for infections, the effect of having schizophrenia was smaller, with an increased incidence rate ratio of 1.32 (95% CI=1.22–1.43) for autoimmune diseases. For individuals with schizophrenia as well as hospital contacts for infections, the combined risk of autoimmune diseases was 2.70 (95% CI=2.51–2.89). A family history of schizophrenia slightly increased the overall risk of developing autoimmune diseases (incidence rate ratio=1.06, 95% CI=1.02–1.09). Autoimmune diseases developed subsequently in 3.6% of people with schizophrenia, and 3.1% of people with autoimmune diseases had a family history of schizophrenia.

Conclusions  The increased risk of subsequent autoimmune diseases in individuals with schizophrenia may involve neuropsychiatric manifestations from the undiagnosed autoimmune disease, medical treatment or lifestyle associated with schizophrenia, or common etiological mechanisms, such as infections and shared genetic factors.

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FIGURE 1. Time Since Schizophrenia Diagnosis and Risk of Autoimmune Diseasesa

a The reference group is people without hospital contacts for schizophrenia and infections.

FIGURE 2. Incidence Rate Ratios and Confidence Intervals for Autoimmune Diseases in Persons With Schizophrenia Spectrum Disorders and Infectionsa

a Data indicate a significant multiplicative interaction between schizophrenia and infection on the risk of autoimmune diseases (p=0.004).

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TABLE 1.Incidence Rate Ratios of Autoimmune Diseases According to Time Since First Registration of a Schizophrenia Spectrum Disorder in Denmark (1987–2010)a
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a Incidence rate ratios were adjusted for age and its interaction with sex and calendar year; persons without a history of schizophrenia spectrum diagnoses were chosen as the reference category; bold indicates a significant result.

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b Only estimates building on five or more exposed cases are presented.

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c Estimates should be interpreted with caution, and the following autoimmune diseases were estimated together for completeness: autoimmune hemolytic anemia, pemphigus, pemphigoid, vitiligo, juvenile arthritis, Wegener’s granulomatosis, dermatopolymyositis, myasthenia gravis, and scleroderma.

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TABLE 2.Incidence Rate Ratios of Any Autoimmune Disease According to Time Since First Registration of a Schizophrenia Spectrum Disorder Diagnosis in Denmark (1987–2010)a
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a Relative risks were adjusted for age and its interaction with sex and calendar year; bold indicates a significant result.

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b There was a significant effect of time since the first schizophrenia diagnosis (p=0.003).

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TABLE 3.Incidence Rate Ratios of Autoimmune Diseases According to a History of Schizophrenia Spectrum Disorders in Parents or Siblings Among Persons Born in Denmark With Known Identity of the Mother (1945–2010)a
Table Footer Note

a Relative risks were adjusted for age and its interaction with sex and calendar year; persons with no parent or sibling having a diagnosis of schizophrenia were chosen as a reference category; bold indicates a significant result.

Table Footer Note

b Estimates were also significant when additionally adjusting for a personal history of schizophrenia spectrum disorders.

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