title: Thyroxin substitution and the risk of developing rheumatoid arthritis; results from the Swedish population-based EIRA study.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, , Stockholm, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Bengtsson
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Henrik
authors.initials: H
authors.lastname: Källberg
authors.forename: Saedis
authors.initials: S
authors.lastname: Saevarsdottir
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics; D020249:Hormone Replacement Therapy / Q000009:adverse effects* / Q000706:statistics & numerical data; D006801:Humans; D007037:Hypothyroidism / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010456:Peptides, Cyclic / Q000276:immunology; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology; D013548:Sweden / Q000453:epidemiology; D013974:Thyroxine / Q000008:administration & dosage / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D013974:Thyroxine
keywords: Autoimmune Diseases; Epidemiology; Gene Polymorphism; Rheumatoid Arthritis; Smoking