Autoimmune Disease Linked to ADHD

Nancy A. Melville

March 20, 2017

UPDATED March 21, 2017 // A history of autoimmune disease, either personal or maternal, is linked to an increased risk for attention-deficit/hyperactivity disorder (ADHD) in children, with type 1 diabetes showing a particularly strong association, new research shows.

"In this nationwide study, autoimmune disease in the individual and a maternal history of autoimmune disease were associated with an increased risk of ADHD," the authors, led by Soren Dalsgaard, MD, PhD, with Aarhus University, Denmark, write.

The study was published in the Journal of the American Academy of Child and Adolescent Psychiatry.

Maternal Disease Affects Fetal Development

The study included patients with medical and psychiatric diagnoses from a birth cohort of 983,680 children in Danish national registries born from 1990 to 2007. Participants were followed from 1995 through 2012.

Among the children, 23,645 individuals were identified as having ADHD.

Overall, individuals with autoimmune disease showed an increased subsequent risk for ADHD, with an incidence risk ratio (IRR) of 1.24 (95% confidence interval [CI], 1.10 - 1.40; P < .05).

An increased risk was also associated with having a mother with any autoimmune disease (IRR, 1.12; 95% CI, 1.06 - 1.19; P < .05). The risk was not significant with regard to overall parental autoimmune disease.

In an exploratory analysis involving 30 selected autoimmune disorders, including thyroiditis, diabetes, and inflammatory bowel disease, the authors found a significant link only between type 1 diabetes and an increased risk for ADHD (IRR, 1.31; 95% CI, 1.03 - 1.63; P < .05).

A personal history of autoimmune thyroiditis or arthritis juvenilis was each significantly associated with an increased risk for ADHD in unadjusted analysis (IRR, 2.33 and 1.32, respectively). However, the associations became nonsignificant for each after adjusting for factors that included age and sex.

"Autoimmune thyroiditis and arthristis juvenilis were associated with higher risk of ADHD than type 1 diabetes in the unadjusted model, but lost significance in the full adjusted model probably due to fewer cases. However, autoimmune thyroiditis were still associated with a 2.14-fold increased risk of ADHD in the full adjusted model but just below the significance level," study coauthor Michael Eriksen Benros, MD, PhD, told Medscape Medical News.

In terms of maternal autoimmune disease, thyrotoxicosis, type 1 diabetes, autoimmune hepatitis, psoriasis, and ankylosing spondylitis were each associated with ADHD in offspring (IRR, 1.17 - 1.99; P < .05 for each). However, thyrotoxicosis lost significance in the fully adjusted model.

Although the overall paternal history of autoimmune disease was not linked to an ADHD risk, type 1 diabetes in the father did have a significant association (IRR, 1.21; 95% CI, 1.07 - 1.37), as did autoimmune hepatitis (IRR, 1.74; 95% CI, 1.07 - 2.64) and ankylosing spondylitis (IRR, 1.33; 95% CI, 1.00 - 1.72; P < .05 for each).

The findings on type 1 diabetes are consistent with those from a previous Swedish population-based study in 2015, which showed childhood or adolescent type 1 diabetes to be associated with a 1.5-fold increased risk for ADHD.

In other studies, type 1 diabetes has been linked to cognitive and motor dysfunctions associated with impaired brain development, as well as autism, schizophrenia, and depression. The authors speculate that the association with ADHD and maternal and paternal history points to a common genetic factor.

In particular, previous studies have shown links between ADHD and major histocompatibility complex (MHC) genes, which have also been associated with autoimmune diseases.

"Some MHC genes, specifically HLA-DR4, HLA-DRB1, and the complement C4B gene, are important risk factors for several autoimmune diseases, including juvenile arthritis, autoimmune hepatitis, and type 1 diabetes, and these genes also might be linked to ADHD," the authors write.

Maternal disease in general can present a broad range of possible risks for ADHD, they add.

"Maternal disease can affect fetal development through common genetic factors, through environmental factors, or directly through an altered fetal immune response leading to ADHD in offspring," the investigators add.

They note, however, that a variety of factors other than genetic predisposition are also linked to the development of autoimmune diseases, including environmental factors such as smoking, drug use, and infections. Likewise, ADHD has a multitude of potential associated causes.

"The etiology of ADHD is multifactorial, and the found associations work in a complex interplay with genetic and environmental factors," said Dr Benros.

Limitations of the study include the fact that the exploratory analyses of individual autoimmune diseases were not corrected for multiple testing, leaving the possibility that some associations were statistically significant only by chance, the authors note.

They add that with the oldest members of the cohort being only 30 years old, there is a risk autoimmune disease might develop in some individuals after the end of the study period, and therefore the association with ADHD could be underestimated.

"Clinicians treating individuals with autoimmune disorders need to be aware of the increased risk of ADHD and other mental disorders in individuals with autoimmune disorders and include these potential comorbidities in the treatment management," Dr Benros said.

He added that his team is conducting ongoing research on the complex relationships between ADHD and autoimmune disease.

"We are proceeding with other studies investigating the associations with other immune-related disorders, such as infections, with the risk of developing ADHD to further explore the immune hypothesis proposed as potential etiological contributing causes to subgroups with ADHD."

Important Insights

In an accompanying editorial, Kyle Williams, MD, PhD, director of the Pediatric Neuropsychiatry and Immunology Program, Massachusetts General Hospital and Harvard Medical School, Boston, said the study provides important insights regarding the role of autoimmune disorders in ADHD.

"This study, the largest of its kind to date, provides important direction for future investigations," Dr Williams write.

"By identifying specific autoimmune disorders associated with ADHD in the children and their mothers, future longitudinal studies will be well positioned to study the environmental and genetic factors that may underlie this association."

Dr Williams added that the research into autoimmune disease offers important pieces of the puzzle of mental illness in children.

"We may not be far removed from the recognition that the clinical heterogeneity observed in some childhood psychiatric disorders may be, in part, the result of subtypes with predominantly immune-mediated etiologies," he said.

"To that end, the [current] study provides further evidence that this path is worth pursuing."

Mani Pavuluri, MD, PhD, a distinguished fellow of the American Academy of Child and Adolescent Psychiatry and Berger-Colbeth Chair in Child Psychiatry at the University of Illinois at Chicago, further commented that the association of type 1 diabetes with ADHD can be significant regardless of a parental history of the disease.

"Diabetes as a stand-alone diagnosis in youth without parental history can lead to ADHD-like symptoms, with fluctuating glucose levels and CNS vulnerability throughout developmental years, beyond genetic and epigenetic factors," she told Medscape Medical News.

In addition, ADHD and autoimmune disorders share common effects on cytokines, Dr Pavuluri added.

"Epigenetic changes common to many autoimmune disorders and/or ADHD can result from trauma and stress, with underlying inflammatory changes in the cytokines."

Dr Pavuluri echoed the assessment that more needs to be understood to put the findings into proper context.

"As the field is beginning to focus on autoimmune disease prevalence and correlations in ADHD, [the findings] open up a pathway with curiosity to learn more," she said.

"Until we obtain a more advanced model of underlying neurobiology with missing pieces of cellular mechanisms involving inflammatory biomarkers, these findings cannot be put in perspective. So, while [the findings are] not a surprise, the study offers strong leads for future investigation."

The study received funding from the Lundbeck Foundation. The study authors have disclosed no relevant financial relationships. Dr Williams has received research support from the PANDAS Network. Dr Pavuluri is the cofounder of Medcircle, Inc.

J Am Acad Child Adolesc Psychiatry. 2017;56:234-240, 185-186. Abstract, Editorial


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