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Thyroxin substitution and the risk of developing rheumatoid arthritis; results from the Swedish population-based EIRA study
  1. Camilla Bengtsson1,
  2. Leonid Padyukov2,
  3. Henrik Källberg1,
  4. Saedis Saevarsdottir1,2
  1. 1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  2. 2Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  1. Correspondence to Dr Camilla Bengtsson, Institute of Environmental Medicine, Karolinska Institutet, Box 210, Stockholm S-171 77, Sweden; camilla.bengtsson{at}


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.

  • Rheumatoid Arthritis
  • Autoimmune Diseases
  • Smoking
  • Gene Polymorphism
  • Epidemiology

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