The Association Between Schizophrenia and Rheumatoid Arthritis: A Nationwide Population-Based Swedish Study on Intraindividual and Familial Risks

Abstract

Numerous studies have reported a reduced risk of rheumatoid arthritis (RA) in schizophrenia. The mechanisms are unknown, but recent genome-wide association studies of schizophrenia have shown strong associations with markers spanning the major histocompatibility complex region, indicating a possible role for adaptive immunity also in schizophrenia. In this population-based cohort study, we assess the associations between RA and schizophrenia and the extent to which any observed associations are specific to RA/schizophrenia. We then extend the assessments per RA subtype and to risks in first-degree relatives. The study population included every individual identified in the Swedish Population Register born in Sweden between 1932 and 1989. The risk for RA in schizophrenia was significantly decreased (hazard ratio [HR] = 0.69, 95% CI = 0.59-0.80), but similar reductions were noted for osteoarthritis (a noninflammatory joint disorder) and ankylosing spondylitis (a non-RA inflammatory disorder). Comparable associations were seen in schizoaffective subjects while no significant associations were observed in bipolar disorder. Overall, first-degree relatives of schizophrenia patients were not at reduced risk of RA, but the risk for seronegative RA was significantly decreased in children and siblings of schizophrenia probands (HR = 0.13, 95% CI = 0.02-0.95 and HR = 0.67, 95% CI = 049-0.92, respectively). In conclusion, our intraindividual analyses suggest that differential misclassification bias is an important factor for the observed inverse association and emphasize the need of optimized care-provision for nonpsychiatric symptoms in schizophrenia patients. Our familial analyses indicted the possibility of an inverse coinheritance of schizophrenia and seronegative RA.

Increased Burden of Psychiatric Disorders in Rheumatoid Arthritis

“…Although the prevalence of anxiety disorders is reportedly increased in RA , we could not identify prior studies reporting the incidence of anxiety disorders. Our findings regarding the increased incidence of bipolar disorder in RA are consistent with 1 previous study which evaluated the association of RA and bipolar disorder . In that study of 2,570 individuals with RA from Taiwan and 2,570 individuals without RA, matched on age, sex, comorbidities, and date of enrollment in the national health insurance plan, RA was associated with a 2‐fold increased incidence of bipolar disorder .…”

“…In that study of 2,570 individuals with RA from Taiwan and 2,570 individuals without RA, matched on age, sex, comorbidities, and date of enrollment in the national health insurance plan, RA was associated with a 2‐fold increased incidence of bipolar disorder . Two other studies failed to showed associations between RA and bipolar disorder . These differences may reflect differences in study design or study populations.…”

HLA genetics in bipolar disorder

“…Additionally, the 8.1 AH conferring susceptibility to BD also confers susceptibility to an atypical form of rheumatoid arthritis characterized by the absence of the pathognomonic anti‐citrullinated protein antibodies . In this context, it is of interest to note that in SZ, RA is a rare medical comorbidity while in BD it is not uncommon . Hence, we predict that BD‐associated RA may be dominated by the above‐mentioned atypical form.…”

Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling

“…The earliest interest connecting autoimmunity and schizophrenia stems from a repeated finding of a low prevalence of rheumatoid arthritis in individuals with schizophrenia, beginning with studies in the 1950’s and including analyses up to the present (Eaton et al, 1992; Oken and Schulzer, 1999; Pilkington, 1955; Sellgren et al, 2014; Trevathan and Tatum, 1953; Vinogradov et al, 1991). The finding was replicated more than a dozen times, and various explanations were offered, such as that neuroleptic medications had a protective effect; or that persons with schizophrenia were less likely to report pain; or that life as an inpatient was less physically active and thereby less prone to raising risk for rheumatoid arthritis.…”