Background/Purpose: Hypothyroidism is usually of autoimmune nature, in areas with sufficient iodine, and leads to chronic substitution treatment with thyroxin. The disease shares some risk factors with ACPA-positive rheumatoid arthritis (RA), i.e. smoking and the PTPN22 risk allele, while different alleles of the HLA-DRB1 locus are associated with these diseases (RA: *01, *04 and *10 (shared epitope, SE); hypothyroidism: *03)^1,2We asked whether thyroxin substitution was associated with RA overall, the ACPA-positive or ACPA-negative subset, and whether an interaction with SE alleles was present.

Methods: Data from the Swedish population-based EIRA (Epidemiological Investigation of Rheumatoid Arthritis) case-control study was analysed. In total, 1947 incident cases and 2246 randomly selected controls (matched on age, sex, residency), aged 18-70 years, participated in the study. Those who started treatment with thyroxin before the year of onset were compared those without treatment. Participants who reported a history of thyroid cancer (1 case and 1 control) were excluded from the analyses. We calculated odds ratios (OR) with 95% confidence intervals (CI) for RA overall and the ACPA-positive and ACPA-negative subsets, by means of unconditional logistic regression models. Adjustments for smoking and PTPN22 only marginally changed the results and were not retained in the final analyses. Interaction was evaluated by calculating the attributable proportion (AP) due to interaction and its 95% confidence interval (CI).

Results: The risk of RA among those with thyroxin substitution was doubled, compared with those without thyroxin substitution (OR=2.0, 95% CI 1.5–2.7). When divided by ACPA status, there were no major differences between these two subsets (ACPA-positive: OR=1.9, 95%CI 1.4–2.7); ACPA-negative: OR=2.2, 95%CI 1.5-3.1). The OR of ACPA-positive RA for the combination of thyroxin substitution and no SE was 1.4 (95% CI 0.7-3.0), compared with neither of these factors. The OR for the combination of no thyroxin substitution and SE was 5.7 (95% CI 4.6-6.9) and for the combination of thyroxin substitution and SE the OR was 12.0 (95% CI 7.1-20.4). Thus a strong interaction between SE and thyroxin substitution was observed (AP=0.5, 95% CI 0.2-0.8).

Conclusion: Thyroxin substitution, reflecting an underlying hypothyroidism, was associated with the risk of developing ACPA-positive and ACPA-negative  RA later in life. Thyroxin substitution also interacted with  the shared epitope in the development of ACPA-positive RA, indicating that in patients with hypothyroidism, the presence of the shared epitope alleles, provides an even higher risk of ACPA-positive RA. Our data suggest overlapping pathways in the development of two common autoimmune diseases.

1. Tomer Y, Huber A: The etiology of autoimmune thyroid disease: a story of genes and environment. Journal of autoimmunity 2009, 32(3-4):231-239.
2. Klareskog L, Catrina AI, Paget S: Rheumatoid arthritis. Lancet 2009, 373(9664):659-672.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-association-between-thyroxin-substitution-and-rheumatoid-arthritis-results-from-the-swedish-eira-study/