Elsevier

Neuroscience & Biobehavioral Reviews

Volume 71, December 2016, Pages 542-562
Neuroscience & Biobehavioral Reviews

Review article
The link between autoimmune diseases and obsessive-compulsive and tic disorders: A systematic review

https://doi.org/10.1016/j.neubiorev.2016.09.025Get rights and content

Highlights

  • We conducted a systematic review of the association between autoimmune diseases and OCD or tic disorders.

  • Rates of OCD or obsessive compulsive symptoms were higher in rheumatic fever patients with Sydenham’s chorea.

  • The literature on other autoimmune diseases was scarce and the findings were inconclusive.

  • The studies were of limited methodological quality.

  • We offer some suggestions for future research.

Abstract

Immunological factors are increasingly recognized as being important in a range of neuropsychiatric disorders. We aimed to summarize the disperse and often conflicting literature on the potential association between autoimmune diseases (ADs) and obsessive-compulsive disorder (OCD) and tic disorders. We searched PubMed, EMBASE, and PsycINFO for original studies evaluating the relationship between ADs and OCD/tic disorders until July, 13th 2016. Seventy-four studies met inclusion criteria. Overall, the studies were of limited methodological quality. Rates of OCD were higher in rheumatic fever patients who were also affected by its neurological manifestation, Sydenham’s chorea. The literature on other ADs was scarce and the findings inconclusive. Few studies examined the association between ADs and tic disorders. A handful of family studies reported elevated rates of ADs in first-degree relatives of individuals with OCD/tic disorders, and vice versa, potentially suggesting shared genetic and/or environmental mechanisms. In conclusion, at present, there is modest evidence for a possible association and familial co-aggregation between ADs and OCD/tic disorders. We offer some suggestions for future research.

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.

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