Objectives Hypothyroidism in iodine-repleted areas is usually of autoimmune nature and leads to chronic thyroxin substitution. It shares some risk factors with anti-citrullinated peptide antibodies (ACPA)-positive rheumatoid arthritis (RA). We asked whether thyroxin substitution associated with risk of ACPA-positive or ACPA-negative RA, and whether interactions with established risk factors were present.

Methods Data from a population-based case-control study with incident RA cases were analysed (1998 adult cases, 2252 controls). Individuals reporting thyroxin substitution were compared with those without thyroxin, by calculating OR with 95% CI, excluding participants reporting non-autoimmune causes for thyroxin substitution (thyroid cancer, iodine-containing drugs). Interaction was evaluated by attributable proportion (AP) with 95% CI.

Results Thyroxin substitution was associated with a twofold risk of both ACPA-positive (OR=1.9, 95% CI 1.4 to 2.6) and ACPA-negative RA (OR=2.1, 95% CI 1.5 to 3.1). For ACPA-positive RA, the risk associated with the combination thyroxin+ HLA-DRB1 shared epitope alleles (SE) was much higher (OR=11.8, 95% CI 6.9 to 20.0) than for thyroxin (OR=1.4, 95% CI 0.7 to 3.0) or SE (OR=5.7, 95% CI 4.6 to 6.9) alone, indicating a strong interaction (AP=0.5, 95% CI 0.2 to 0.8). Thyroxin substitution interacted non-significantly with smoking (AP=0.4, 95% CI 0.0 to 0.7; OR thyroxin+smoking=3.6, thyroxin only=1.5, smoking only=1.8). Thyroxin did not interact with the PTPN22*R620W allele.

Conclusions Thyroxin users had a doubled risk of both ACPA-positive and ACPA-negative RA. The risk of ACPA-positive RA was manifold if they smoked or carried the SE. Furthermore, although joint symptoms can be a manifestation of hypothyroidism, physicians might consider whether it could be an early manifestation of RA.