Review articleThe link between autoimmune diseases and obsessive-compulsive and tic disorders: A systematic review
Introduction
Obsessive-compulsive disorder (OCD) is a relatively common psychiatric disorder with a lifetime prevalence of 2.3% (Ruscio et al., 2010), similar in both genders (American Psychiatric Association, 2013). OCD is defined by recurrent intrusive thoughts or images (obsessions) that create significant distress and drive individuals to perform repetitive behaviors or mental rituals (compulsions) in an attempt to reduce the distress (American Psychiatric Association, 2013). Tic disorders, including Tourette’s Disorder (TD), are childhood-onset, neurodevelopmental movement disorders characterized by persistent motor and/or vocal tics lasting for more than one year (American Psychiatric Association, 2013). The prevalence of chronic tic disorders is estimated to be around 0.3% to 1% of the population and is much more common in boys than in girls (Knight et al., 2012, Scharf et al., 2012).
The etiologies of OCD and tic disorders are currently unknown, but the conditions are thought to be closely related. OCD and tic disorders share phenomenology and co-aggregate in families (Pauls, 2010, Pauls et al., 1995), and this familiality is largely due to substantial shared genetic liability (Davis et al., 2013, Pinto et al., 2016). Moreover, both disorders have alterations in overlapping cortico- striato-thalamic systems (Amat et al., 2006, Lewis and Kim, 2009), further supporting the idea of a shared biological vulnerability.
In addition to genetic factors, autoimmunity might also play a role in the etiology of these disorders (Davison, 2012, Murphy and Husted, 2004, Najjar et al., 2013). However, the involvement of immunological factors demonstrated in classical autoimmune diseases (ADs) in the pathogenesis of OCD/tic disorders has been inconclusive (Teixeira et al., 2014).
Based on the mechanism of rheumatic fever (RF), a well-defined AD, and its major neurological manifestation, Sydenham’s chorea (SC), Swedo and colleagues proposed a link between OCD and OCD-related disorders and autoimmunity (Swedo et al., 1998). Following a group-A beta-hemolytic streptococcal (GAS) infection, a subgroup of children was found to develop the so-called Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), which included obsessive-compulsive symptoms (OCS) or tics, without meeting the criteria for SC (Swedo et al., 1998). The validity of PANDAS as an independent entity has been widely debated and has evolved to a further conceptualization – the Pediatric Acute- onset Neuropsychiatric Syndrome (PANS) – that no longer requires the evidence of infection (Swedo et al., 2012). Although the exact mechanism remains to be elucidated, molecular mimicry in which antibodies initially develop to respond to a GAS infection and cross-react with neural epitopes has been suggested as a possible developing path (Cunningham, 2014, Garvey et al., 1998, Swedo et al., 1998).
In line with this theoretical link, patients with RF or other ADs, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), or antiphospholipid syndrome, have also been suggested to present higher rates of OCD and, to a lesser extent, tic disorders (de Alvarenga et al., 2009, Foroughipour et al., 2012, Slattery et al., 2004, Toren et al., 1994). However, the literature linking ADs and OCD or tic disorders is large, methodologically diverse and difficult to reconcile. It is possible that ADs and OCD/tic disorders share a common genetic vulnerability (Hounie et al., 2008). Although gene-searching efforts in OCD and tic disorders are in their infancy (Mattheisen et al., 2015, Scharf et al., 2013), genes involved in the pathogenesis of several ADs – such as polymorphisms of the tumor necrosis factor-α (TNF-α) – (Gu et al., 2010, Ishizuka et al., 1999, Jimenez-Morales et al., 2009, Nada and Labib, 2011, Popa et al., 2011, Ramasawmy et al., 2007, Song et al., 2014) have been associated with OCD/tic disorders in some studies (Cappi et al., 2012, Keszler et al., 2014, Rao et al., 2015) but not others (Denys et al., 2004).
In this context, we conducted the first systematic review investi-gating whether there is an association between ADs and OCD or tic disorders, either in individuals with ADs and OCD or tic disorders themselves, or in their relatives. Because common ADs tend to coexist in the same individuals and co-aggregate in the same families (Cardenas-Roldan et al., 2013, Cooper et al., 2009, Sardu et al., 2012, Somers et al., 2006), finding an above-chance association between ADs and OCD/tics, would support a possible role of the immune system in the etiology of these disorders. We also aimed to examine whether this association is stronger in specific ADs. Knowing that specific ADs are more frequently associated with these psychiatric symptoms may lead to a better understanding of the role that the immune system plays in these disorders, and also help guiding gene- searching and gene by environment interaction studies. Finally, we suggest some specific research strategies to help the field move forward.
Section snippets
Methods
The review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and protocol outlined by the PRISMA Group (Moher et al., 2009).
Study selection
A total of 2584 studies were retrieved from the search. Among these, 734 duplicates were identified and removed. The remaining 1856 studies were analyzed for inclusion. Six additional publications were identified through other sources. The full texts of 104 studies considered relevant were assessed for eligibility. Of these, 74 met inclusion criteria and were included in the systematic review. The PRISMA flowchart is shown in Fig. 1.
Study characteristics
Of the 74 eligible studies, 62 reported on the association
Discussion
In an attempt to summarize a large and disperse literature, we conducted the first systematic review of the potential link between ADs and OCD/tic disorders. The results suggested associations between some ADs, particularly RF co- occurring with SC, and OCD/OCS. For tic disorders, the reported association with ADs is largely anecdotal and mainly limited to RF. There is some preliminary evidence that ADs and OCD/OCS and tic disorders may co-aggregate in families, suggesting possible genetic
Conclusion
A positive association between some ADs and OCD/tic disorders appears to exist. However, most of the reviewed studies had methodological limitations that preclude firm conclusions at this stage. A number of possible research designs are available to help confirm or refute these associations and to elucidate their mechanisms.
Financial relationship disclosures
Ms. Ana Pérez-Vigil was supported by a grant from the Alicia Koplowitz Foundation. Dr. Fernández de la Cruz was supported by grants from the David and Astrid Hagelén Foundation and the Swedish Research Council for Health, Working Life and Welfare (FORTE grant number 2015- 00569). Mr. Brander was supported by a scholarship from KID-funding (Karolinska Institutet PhD stipend). Dr. Isomura, Dr. Gromark, and Prof. Mataix-Cols have nothing to disclose. Funders had no role in study design, data
Acknowledgements
We thank Klas Moberg and Carl Gornitzki from the Karolinska Institutet Library, who advised and assisted with the bibliometric search. We also thank Eva Hesselmark, who provided constructive comments that enable us to improve the manuscript.
References (139)
Obsessive-compulsive symptoms among patients with Sydenham chorea
Biol. Psychiatry
(2005)Mood and anxiety disorders in systemic sclerosis patients
Presse Med.
(2011)Obsessive-compulsive symptoms in childhood inflammatory bowel disease and cystic fibrosis
J. Am. Acad. Child Psychiatry
(1989)Lifetime prevalence of psychiatric disorders in patients with alopecia areata
Compr. Psychiatry
(1991)- et al.
The epidemiology of autoimmune diseases
Autoimm Rev.
(2003) Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases
J. Autoimmun.
(2009)Higher prevalence of obsessive-compulsive spectrum disorders in rheumatic fever
Gen. Hosp. Psychiatry
(2009)Psychiatric disorders in patients with multiple sclerosis
Comp. Psychiatry
(2015)Decreased TNF-alpha and NK activity in obsessive-compulsive disorder
Psychoneuroendocrinology
(2004)Personality structure disturbances and psychiatric manifestations in primary Sjögren's syndrome
J. Autoimmun.
(1989)
Detection of antibodies against the N-methyl-d-aspartate receptor in a sub-group of patients diagnosed with Tourette's syndrome
J. Neuroimmunol.
Anxiety and depressive disorders in an adult insulin-dependent diabetic mellitus (IDDM) population: relationships with glycaemic control and somatic complications
Eur. Psychiatry
The prevalence of depression and anxiety disorders in patients with euthyroid Hashimoto's thyroiditis: a comparative study
Gen. Hosp. Psychiatry
Tumor necrosis factor alpha (TNF-alpha) polymorphisms in Chinese patients with Graves' disease
Clin. Biochem.
Obsessional-compulsive complaints
Behav. Res. Ther.
Obsessive-compulsive spectrum disorders and rheumatic fever: a family study
Biol. Psychiatry
TNF-alpha polymorphisms are associated with obsessive-compulsive disorder
Neurosci. Lett.
Tumor necrosis factor alpha signaling pathway and apoptosis in pancreatic beta cells
Metab. Clin. Exp.
Epidemiology and estimated population burden of selected autoimmune diseases in the United States
Clin. Immunol. Immunopathol.
Tumor necrosis factor-alpha is a common genetic risk factor for asthma, juvenile rheumatoid arthritis, and systemic lupus erythematosus in a Mexican pediatric population
Hum. Immunol.
Prevalence of tic disorders: a systematic review and meta-analysis
Pediatr. Neurol.
Thyroid peroxidase antibody positivity is associated with symptomatic distress in patients with Hashimoto's thyroiditis
Brain Behav. Immunol.
Executive dysfunction, obsessive-compulsive symptoms, and attention deficit and hyperactivity disorder in systemic lupus erythematosus: evidence for basal ganglia dysfunction
J. Neurol. Sci.
Obsessive-compulsive disorder in children and adolescents: a review of the past 10 years
J. Am. Acad. Child Adolesc. Psychiatry
Psychiatric disorders in persistent and remitted Sydenham's chorea
Parkinsonism Relat. Disord.
Maternal history of autoimmune disease in children presenting with tics and/or obsessive-compulsive disorder
J. Neuroimmunol.
Obsessive-compulsive disorder and rheumatic chorea: is there a connection?
Psychopathology
Obsessive-compulsive symptoms in non-active rheumatic fever
Rev. Bras. Psiquiatr.
Obsessive-compulsive symptoms in heart disease patients with and without history of rheumatic fever
J. Neuropsychiatry Clin. Neurosci.
Increased number of subcortical hyperintensities on MRI in children and adolescents with Tourette's syndrome, obsessive-compulsive disorder, and attention deficit hyperactivity disorder
Am. J. Psychiatry
Diagnostic and Statistical Manual of Mental Disorders: DSM-5
Psychiatric symptoms associated with scleroderma
Psychother. Psychosom.
Obsessive-compulsive and related symptoms in children and adolescents with rheumatic fever with and without chorea: a prospective 6-month study
Am. J. Psychiatry
Obsessive-compulsive symptoms in adults with history of rheumatic fever, Sydenham's chorea and type I diabetes mellitus: preliminary results
Acta Psychiatr. Scand.
Obsessive compulsive disorder in adults with rheumatic heart disease
Acta Neuropsychiatry
Association of family history of autoimmune diseases and autism spectrum disorders
Pediatrics
Prevalence of mood and anxiety disorders in women with systemic lupus erythematosus
Arthrit. Care Res.
Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes
Nat. Genet.
Obsessional scores and subjective general psychiatric complaints of patients with duodenal ulcer or ulcerative colitis
Psychol. Med.
Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study
JAMA Psychiatry
Psychometric evaluation of patients with Behçet's disease
Iran J. Med. Sci.
Maternal psychiatric disorders in pediatric inflammatory bowel disease and cystic fibrosis
Child Psychiatry Hum. Dev.
Association study between functional polymorphisms in the TNF-alpha gene and obsessive-compulsive disorder
Arq. Neuropsiquiatr.
How do autoimmune diseases cluster in families? A systematic review and meta-analysis
BMC Med.
The link between thyroid autoimmunity (antithyroid peroxidase autoantibodies) with anxiety and mood disorders in the community: a field of interest for public health in the future
BMC Psychiatry
An assessment of psychiatric disturbances in graves disease in a medical college in eastern India
Niger. J. Clin. Pract.
Psychiatric comorbidities in patients with alopecia areata in Taiwan: a case-control study
Brit. J. Dermatol.
A short clinical diagnostic self-rating scale for psychoneurotic patients: the Middlesex Hospital Questionnaire (M.H.Q.)
Br. J. Psychiatry
Rheumatic fever, autoimmunity, and molecular mimicry: the streptococcal connection
Int. Rev. Immunol.
Prevalence of psychiatric disorders in patients with mechanicalvalve prostheses with and without rheumatic fever
J. Bras. Psiquiatr.
Cited by (52)
Parental history of psychiatric disorders and risk of type 1 diabetes in the offspring
2023, Diabetes and MetabolismLow-grade inflammation as mediator between diet and behavioral disinhibition: A UK Biobank study
2022, Brain, Behavior, and ImmunityMorbidity and mortality in obsessive-compulsive disorder: A narrative review
2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :The hypothesized molecular mechanisms, evidence, and controversies surrounding this model are covered elsewhere (Cunningham, 2014; Gilbert, 2019). A body of work has focused on the co-occurrence of autoimmune diseases and OCD (see (Pérez-Vigil et al., 2016) for a review). A population-based study in Taiwan compared 63,165 individuals with systemic autoimmune diseases to 315,825 unaffected individuals.
Searching for host immune-microbiome mechanisms in obsessive-compulsive disorder: A narrative literature review and future directions
2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Therefore, reliable biomarkers of disease, predictors of treatment response, and individualized treatments are critically needed for OCD. Immune-mediated mechanisms may be involved in at least some cases of OCD (Gerentes et al., 2019; Lamothe et al., 2018; Marazziti et al., 2018; Pérez-Vigil et al., 2016). Epidemiologic studies suggest that OCD is associated with immunologic comorbidities (Isung et al., 2020; Mataix-Cols et al., 2018; Orlovska et al., 2017; Wang et al., 2019), and genetic studies have implicated immune-related genes in OCD (Cappi et al., 2016, 2012; Den Braber et al., 2016; Hounie et al., 2008; Rodriguez et al., 2017).