Abstract
Objective:
There is growing evidence of involvement of inflammatory mechanisms in ADHD. Previous studies found significantly higher rates of ADHD among children with FMF. The present study examined the rate of exposure to FMF in children with a later (within a 5-year period) diagnosis of ADHD compared to non-ADHD children.
Methods:
A population-based case-control study of all children (<18 years) registered in Leumit Health Services during 01.01.2006 to 06.30.2021. All cases met ICD-9/10 criteria for ADHD. They were matched by age, sex, and socioeconomic status on a 1:2 rate to randomly selected non-ADHD controls.
Results:
Fifty-six (0.30%) children with ADHD (N = 18,756) were previously diagnosed with FMF compared to 65 of 37,512 controls (0.17%). A significant, independent association existed between a preceding FMF diagnosis and a later ADHD diagnosis [OR = 1.72 (95% CI 1.18–2.51); p = .003].
Conclusions:
The mechanisms underlying the association w between FMF and later ADHD diagnosis merit further elucidation.
Introduction
Familial Mediterranean Fever (FMF) is a hereditary auto-inflammatory disease particularly prevalent among populations originating in the Mediterranean region (Ben-Chetrit & Touitou, 2009). Repeated high Fever, serositis, and pain in the abdomen, chest, and joints often characterize this disease. Acute inflammatory episodes last 1 to 4 days (Ben-Chetrit & Levy, 1998). In 90% of cases, the disease manifests before age 20 years (Tanatar et al., 2021), with approximately 66% of cases manifesting before age 5 years.
FMF most commonly has an autosomal recessive inheritance pattern (Schnappauf et al., 2019). Approximately 80% of cases are caused by mutations in the MEFV gene. This gene, also called TRIM20, is located on the short arm of chromosome 16 and codes for the pyrin protein (Touitou, 2001), a member of the Tripartite motif (TRIM) protein family (Yang et al., 2020). As part of the innate immune system, this protein is a membrane receptor and part of the cytoskeleton directing the inflammatory activity of neutrophils, monocytes, and eosinophils. Pyrin forms part of the inflammasome complex when activated. The inflammasome’s role is to activate a cascade of intracellular processes, which leads to the secretion of pro-inflammatory cytokines, such as IL-1β, increasing body temperature and local inflammatory responses. The various pathological mutations in the MEFV gene lower the threshold for activating the pyrin inflammasome, resulting in an uncontrolled release of IL-1β, which plays a central role in the pathogenesis of FMF attacks (de Torre-Minguela et al., 2017; Rigante et al., 2014).
ADHD is a common neurodevelopmental disorder characterized by developmentally inappropriate inattention, hyperactivity, and/or impulsivity that cause impairment in social, academic, and/or occupational functioning (American Psychiatric Association, 2013). The heritability of ADHD is high (i.e., heritability coefficient ~.75), though polygenic, with many genes conveying small but additive risk. Genome-wide association Studies (GWAS) have identified several ADHD-risk genes (Bonvicini et al., 2016; Demontis et al., 2019; Zayats et al., 2015) that are also integral to the development and function of the innate immune system (Tylee et al., 2018). These include genes regulating immune pathways (e.g., ADGRL3 (LPHN3 utrophin-3) Adhesion G protein-coupled receptor L3; Arcos-Burgos & Muenke, 2010), genes producing more or less inflammatory variants of monocytes, genes coding the Innate Lymphoid Cell Differentiation and Class I major histocompatibility complex (MHC) mediated antigen processing and presentation, and genes within the Tripartite motif protein family (TRIM36). Recent meta-analyses (Chen et al., 2022) combining large ADHD GWAS studies with inflammatory marker GWAS studies find pleiotropy with genes such as beta nerve growth factor (NGF), stem cell factor (SCF), tumor necrosis factor-alpha (TNF-a), and interleukin 7 (IL-7) associating specifically with ADHD but not with other developmental or psychiatric disorders. There is increasing evidence reflecting a combination of innate genetic predisposition (Faraone & Larsson, 2019) and exposure to intervening environmental factors that mediate risk for ADHD, both in the prenatal period and early childhood (Gustafsson et al., 2020; T. C. Nielsen et al., 2021; O’Shea et al., 2014).
While associations between ADHD and inflammatory processes or somatic illnesses among youth have not always been clearly or easily established (Reed et al., 2023), recent work has shown a greater prevalence of early childhood illnesses among youth with ADHD, suggesting an immunological vulnerability (Merzon et al., 2023). Several studies have also reported disturbed neuroimmunological processes in ADHD, including the involvement of pro-inflammatory cytokines (Donfrancesco et al., 2021). Moreover, several studies have also shown clear co-traveling of ADHD with auto-inflammatory and autoimmune disorders such as Lupus SLE and Rheumatoid Arthritis in Northern European populations (Hegvik et al., 2018, 2022; Lee et al., 2023; Li et al., 2019; P. R. Nielsen et al., 2017). Two studies recently reported that children with FMF had a greater prevalence of ADHD (Durcan et al., 2022; Lavi et al., 2022). The two previous studies focused on the frequency of ADHD in the FMF population, looking for the specific characteristics of ADHD in FMF patients. We studied the contrary direction, namely the frequency of FMF, an inflammatory disorder, in ADHD patients. Our focus was the contribution of an inflammatory process to the development of the pathogenesis of ADHD.
Given the above, the possible association with ADHD is interesting from genetic and inflammatory perspectives. Moreover, it could have significant clinical, scientific, and public health relevance. The present study aimed to examine the rate of FMF diagnosis among youth with and without ADHD. Furthermore, the association was examined temporally to establish the presence of FMF, according to ICD-9 code 277.30, during the 5 years before the youth was diagnosed with ADHD.
Methods
Study Design
This was a population-based case-control study of 56,268 children under 18 years belonging to the “Leumit” Health Maintenance Organization (HMO). The information was collected from the HMO database. LHS maintains a comprehensive computerized database regularly updated with demographic information, medical visits, laboratory tests, hospitalizations, and medication prescriptions, for almost three-quarters of a million people, dating back to 1998. The database includes records of refilled and purchased prescriptions per patient. Diagnoses are recorded or updated during each physician visit according to the ICD-9 for somatic diagnoses and the ICD-10 for psychiatric diagnoses.
The population of Leumit HMO is similar to the other HMO populations. Thus, the conclusions of the study can be generalized to the general Israeli population.
Study Population and Definitions
Study Population
This study’s participants were individuals under 18 (56,268) enrolled with Leumit Health Services (LHS) from January 1, 2006 to June 30, 2021. Subjects with underlying oncological disorders or a primary or secondary immune deficiency were excluded from the study due to their increased sensitivity to inflammatory diseases.
Definitions
Cases in this study were defined as individuals with a confirmed diagnosis of ADHD based on the criteria set by the Israeli Ministry of Health, which adheres to international guidelines (Faraone et al., 2021). The diagnosis must be made by a senior physician who specializes in ADHD, such as child or adult psychiatrists, child or adult neurologists, or pediatricians and family physicians with certified ADHD training. The diagnosis is established using the criteria outlined in the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM-4 or 5, depending on the year of diagnosis; American Psychiatric Association, 2013).
Controls were selected in a 2:1 matching ratio, randomly chosen from the study population. To be eligible as controls, individuals had no diagnoses of ADHD before the reference date when the matched case was diagnosed with ADHD. In addition, controls were matched individually to cases based on age at diagnosis of ADHD, sex, sectors such as secular Jews, religious, ultra-orthodox, and Arabs, and socioeconomic status (SES).
FMF diagnosis was established according to Tel HaShomer clinical criteria (Bashardoust, 2015). In most cases, there was also genetic evidence for FMF (characteristic MEFV gene mutations)
SES was determined based on the child’s home address, utilizing the Israeli Central Bureau of Statistics classification, including 20 subgroups. Classifications one to three were considered very low SES, 4 to 6—low, 7 to 9—medium, and 10 to 20 were considered medium-high SES.
The study protocol was approved by the Ethics Committee Review Board of Shamir Medical Center and the Research Committee of LHS (approval number: LEU-0005-22).
Statistical Analysis
Statistical analysis was performed using R-statistic software. Assumptions were two-sided with an α of less than .05. Sociodemographic characteristics between the ADHD and non-ADHD control groups were compared using t-tests and Fisher exact χ2 tests for continuous and categorical variables based on the normal distribution and variable characteristics. The probability of having been diagnosed with Familial Mediterranean Fever (FMF) was compared using logistic regression analysis, and the odds ratio (OR) and 95% confidence interval (CI) were calculated. The study sample was sufficient to detect a statistically significant difference (p < .05) between the groups with a power of 0.80.
Results
The ADHD case group included 18,756 subjects under 18 years (mean = 8.38, SD = 2.71), and the control group included 37,512 based on the 1:2 matching ratio, respectively. The sociodemographic characteristics of the study groups are shown in Table 1. The demographic features, including mean age, sex, sector, and SES levels, were very similar or identical across the two groups, indicating successful matching of subjects.
Sociodemographic Characteristics of the Study Population.
Note. SES = socioeconomic status.
Out of 18,756 children with ADHD, 56 (0.30%) were diagnosed with FMF compared to 65 (0.17%) of 37,512 controls [OR = 1.73, 95%CI (1.18,2.51), p = 0.003] (Table 2).
Diagnoses of FMF in Children With ADHD and Non-ADHD Controls.
Note. FMF = Familial Mediterranean fever.
Discussion
The main finding of this study was a significantly increased rate of a later diagnosis of ADHD in children diagnosed with FMF within 5 years prior to the ADHD diagnosis (OR = 1.73). The increased rate of ADHD in the population previously exposed to FMF indicates a relationship between FMF and ADHD that is consistent with the literature on the association between ADHD and inflammatory disorders more broadly. It is also consistent with previous rheumatology studies that found a higher rate of ADHD in the FMF population (Lavi et al., 2022), which indicates a bidirectional association between the two conditions. A similar association is reported in several extensive population studies in Northern Europe (Hegvik et al., 2022; Lee et al., 2023; Li et al., 2019; P. R. Nielsen et al., 2017) that found higher rates of ADHD co-traveling with specific autoimmune disorders.
The finding that FMF is associated with a later diagnosis of ADHD raises several important questions about the potential mechanisms underlying the relationship. Existing research has associated prenatal exposure to Fever with later development of ADHD (especially of the inattentive presentation) (Gustavson et al., 2019). It is unknown whether this association is due to hyperthermia (a known teratogen) or inflammatory processes occurring at a critical stage and acting on vulnerable circuits. The recurrent inflammatory episodes of FMF may indicate that uncontrolled inflammation plays a significant role in the development of ADHD. This possibility is evidenced by a growing library of genetic risk variants for ADHD, which are also implicated in inflammation-related medical conditions (Tylee et al., 2018). For example, the HTR2A serotonin receptor 2A gene confers risk for ADHD (Bonvicini et al., 2018) and has documented variants associated with Rheumatoid Arthritis and progressive Multiple Sclerosis due to their more significant inhibition of cytokine production and enhanced neuroprotection (Snir et al., 2011)
In FMF, the Pyrin gene is a member of the Tripartite motif protein family (TRIM family; TRIM20), and it triggers the innate immune pathways to initiate a cascade. While TRIM20 is implicated explicitly in FMF, the related gene TRIM36 is implicated in ADHD (Zayats et al., 2015). Both are part of the Major Histocompatibility Complex (MHC), the cluster of genes responsible for the innate immune system’s overall composition and regulation. These genes confer susceptibilities and protections through familial lineage—hence FMF is “Familial,” and the high heritability of ADHD may indeed relate to the multiple MHC genes found to convey risk up or downstream.
Some genes may have more salient up or downstream effects along immune pathways that contribute to the co-traveling of ADHD with inflammatory disorders.
It is unknown whether association mechanisms are primarily related to inhibiting neurodevelopment during critical stages or whether episodes of FMF instigate neurodegeneration. This distinction could have clinical implications for the prevention of ADHD or mitigation of case severity. It is also not known whether the mechanisms of this association are direct or indirect. Such putative direct and indirect mechanisms may include triggering microglial over-pruning of brain synapses or macrophage-related generalized degradation of the vasculature of the blood-brain barrier. A better understanding of such mechanisms can help in targeting preventative therapeutics. Further, it is unknown whether the inflammatory mechanisms are nonspecific or whether there may be mechanisms explicitly associated with the FMF disease process that contribute to the specific developmental processes relevant to ADHD pathophysiology.
Emerging data linking ADHD with inflammatory conditions raise the question of how to use this information best to further our understanding of risk for ADHD pathophysiology and perhaps even treatment. Does inflammation increase ADHD symptoms whenever it occurs, or are there critical periods? Do early-in-life inflammatory processes lead to altered neurodevelopment as an underlying predisposition to ADHD? Does the inflammatory response in certain conditions expose underlying genetic risk so that the adverse consequences of inflammation are seen in individuals otherwise at high risk? Does efficient treatment of inflammatory processes early in life alter the risk for subsequent development of ADHD? It is hoped that ongoing research will answer these and other questions in the years ahead.
Strengths and Limitations
This study has several strengths, including the strict matching between cases and controls. This matching ensured that differences between the two groups were due to the independent association with FMF rather than age, sex, or SES. The design of a population-based nationwide study enhances the generalizability of the finding, at least for Israeli population.
The large sample size also enabled reasonable statistical power. However, there are also several limitations. Due to the study’s observational retrospective nature, ADHD diagnoses were derived from clinical records and did not include a more granular assessment of ADHD symptoms and severity. Moreover, controls were defined as non-ADHD only according to their diagnostic status. Thus, we cannot rule out the possibility that some controls may have had unidentified ADHD (which, it should be said, would work against the finding achieved here). Similarly, unmeasured confounders might account for the observed associations. Additional targeted prospective studies may help to address the latter question.
Moreover, in this type of study, there is always the issue of specificity of the findings. Families that take their children to doctors might be those more careful with health issues in general increasing, probabilities of detecting associations among diverse medical outcomes. Thus, it would be of interest to assess the associations between the current pediatric ADHD population to previous non-inflammatory conditions in the data set. Unfortunately, such an analysis is beyond the scope of the present study and merits a separate study
Conclusions
The present study, and two previous studies (Lavi et al., 2015, 2022), indicate that ADHD is associated with a higher rate of FMF and vice versa. This bidirectional association supports the involvement of autoimmune and inflammatory pathways in the pathophysiology of ADHD phenotype. The emerging data linking ADHD with inflammatory conditions—at both the clinical and genetic level—represents an important new direction for the ADHD field. Further research on this topic will enhance the understanding of ADHD pathophysiology and hopefully lead to novel therapeutic interventions.
Footnotes
Acknowledgements
This paper is dedicated to Joe Biederman. His vision and creativity re-defined our understanding of ADHD and psychiatry at large. His impact on our work in Israel was tremendous, enabling us to enter 21st-century psychiatry. He drove the understanding that ADHD is a medical condition, and our last two papers focused on the association between ADHD and the inflammatory processes. He was my mentor, and his unique supervision will not be forgotten.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Over the past 3 years Dr. Eugene Merzon received support for continuing medical education programs or advisory boards meetings sponsored by: SK-Pharma, Medison Israel, Teva Israel, AstraZeneca Israel, and Merk Israel. Over the past 3 years Dr. Ariel Israel has No disclosure. Dr. Beth Krone: Over the past 3 years, Dr. Krone has received financial compensation as a scientific consultant to HIPPO T & C and MaxisHealth, makers of digital health technologies for ADHD. Dr. Krone also provides clinical review for Signant Health, a company that provides rater training for clinical trials. Over the past 3 years Ms. Shani Medvejer has no disclosure. Over the past 3 years Ms. . Shira Cohen has no disclosure. Over the past 3 years Dr. Ilan Green has no disclosure. Over the past 3 years Dr. Avivit Golan-Cohen has no disclosure. Over the past 3 years Prof. Shlomo Vinker has no disclosure. Over the past 3 years Prof. Stephen V. Faraone received income, travel expenses, research support, continuing medical education programs, or advisory boards, sponsored by: Aardvark, Aardwolf, Akili, Atentiv, Corium, Genomind, Ironshore, Medice, Noven, Otsuka, Sandoz, Sky Therapeutics, Supernus, Tris, and Vallon. In previous years, he received support from: Alcobra, Arbor, Aveksham, Axsome, CogCubed, Eli Lilly, Enzymotec, Impact, Janssen, KemPharm, Lundbeck/Takeda, Shire/Takeda, McNeil, NeuroLifeSciences, Neurovance, Novartis, Pfizer, Rhodes, Shire, and Sunovion. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health; Oxford University Press: Schizophrenia: The Facts; and Elsevier: ADHD: Non-Pharmacologic Interventions. In addition, he is the program director of www.adhdinadults.com and 
Dr. Faraone is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 965381; NIMH grants U01AR076092-01A1, 1R21MH1264940, R01MH116037, and 1R01NS128535—01; Oregon Health and Science University. Over the past 3 years, Prof. Jeff Newcorn has received financial compensation as a consultant, advisory board member, and lecturer from Shire Pharmaceuticals (the study sponsor and manufacturer of the study drug Vyvanse (Lisdexamfetamine)). Dr. Newcorn also receives financial compensation from other companies which either develop or assess medicines used for the treatment of ADHD. Over the past 3 years Prof. Shai Ashkenazi has no disclosure relevant to this manuscript. Over the past 3 years Prof Abraham Weizman declares honoraria for educational lectures from the following pharmaceutical companies: Pfizer, Novartis, Janssen, Lundbeck, Teva, Unipharm, Dexcel, and Medison. None of these are relevant to the submitted manuscript. Over the past 3 years, Prof. Iris Manor has received financial compensation as a consultant, advisory board member, and lecturer from Madison Ltd. (the distributor of the study drug Vyvance (Lisdexamfetamine) in Israel) and Teva Israel (the manufacturer and the distributor in Israel of the study drug attent (Mixed Amphetamine Salts), and attent XR (Mixed Amphetamine Salts—Extended Release). She was a lecturer for Takeda Ltd. Dr. Manor is a consultant to the startup companies Peri and Vizo, which either develop or assess medicines used to treat ADHD. She also served/serves as a PI (as a part of her position in Geha MHC) in several startups: Nuance Ltd and Mindtension Ltd.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Data Avaliability
The data are stored in Leumit Health Services (LHS) database. It can be reached by applying to Dr. Ariel Israel from LHS upon the regulation of the Israeli Ministry of Health and approval of the research institute of LHS.
Author Biographies
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