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Clinical and epidemiological research
Extended report
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}ki.se

Abstract

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

https://doi.org/10.1136/annrheumdis-2013-203354

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    Introduction

    Rheumatoid arthritis (RA) and autoimmune thyroid disease (AITD) are among the most common autoimmune diseases, which often seem to co-occur in members of predisposed families.1 Furthermore, AITD and the subset of RA characterised by the presence of anti-citrullinated peptide antibodies (ACPA) share several known risk indicators, including smoking and the PTPN22*R620W risk allele, while different alleles of the HLA-DRB1 locus are associated with these diseases (anticitrullinated peptide antibodies (ACPA)-positive RA: *01, *04 and *10 (shared epitope, SE); AITD: *03).2–6 By contrast, few risk factors have been identified for the ACPA-negative subsets of RA.6

    Hypothyroidism in iodine-repleted areas is usually of autoimmune nature and leads to chronic thyroxin substitution. Hyperthyroidism, which results from autoimmune mechanisms (eg, Graves’ disease), can also lead to thyroxin substitution after therapy that blocks the overproduction of thyroid hormones. Important exceptions to this are side effects of drugs, and surgical removal of the thyroid gland due to cancer.7 There are no internationally accepted classification criteria available for AITD, but if patients reporting a history of thyroid cancer or drugs that are well known to give hypothyroidism are excluded, most patients receiving thyroxin substitution are likely to have an underlying AITD.8

    A higher frequency of AITD, or hypothyroidism, has been observed in prevalent RA patients than in the population,9–12 but no study has, to our knowledge, looked at the association between AITD and the risk of developing RA overall, or at the ACPA-positive/ACPA-negative subgroups separately. By using data from a large population-based case-control study on incident RA cases, we investigated whether thyroxin substitution (excluding non-AITD causes) was associated with an increased risk of ACPA-positive and ACPA-negative RA.6 In addition, we examined potential interaction between thyroxin use and established risk factors, both genetic (PTPN22*R620W (rs2476601 T allele), HLA-DRB1 SE alleles, and the HLA-DRB1 *03 allele) and smoking regarding risk of RA.13–16

    Methods

    Our study is based on EIRA (epidemiological investigation of RA) and comprised the population, aged 18–70 years, living in parts of Sweden during 1996–2006.17 All cases were diagnosed by rheumatologists according to the American College of Rheumatology (ACR) criteria of 1987, and controls were randomly selected from the study base, matched on sex, age and residential area.18 In total, 2097 cases and 2770 controls were identified for our study. Ethical approval was obtained from all relevant ethical committees, and all participants gave written informed consent.

    Data collection

    An extensive questionnaire on environmental exposures, including thyroxin use and smoking, was given to the cases shortly after diagnosis, and sent by post to the controls. Cases and controls were also asked to provide a blood sample. In all, 95% of the cases (1998) and 81% (2252) of the controls answered the questionnaire, and 98% (1964) and 57% (1277) of participating cases and controls donated blood.

    Study participants who reported use of thyroid hormone substitution for at least 3 months were identified. They were all taking thyroxin (levothyroxine, T4), and one of whom also used liothyronin (T3). The thyroxin users also reported which years they had started/stopped treatment. Since we were interested in ever thyroxin use, participants who had ever been treated with thyroxin were classified as thyroxin users. The majority was however current users (89% of the cases, 91% of the controls). No participant reported the use of other thyroid hormone substitutions or medications acting on the thyroid gland without reporting concurrent thyroxin treatment. Thus, all patients receiving treatment blocking the thyroid hormone production replacement due to hyperthyroidism (eg, Graves’ disease) then received thyroxin substitution. Participants who reported a history of thyroid cancer (one case and one control) were excluded from the analyses. Abnormal thyroid function can also be a side effect of treatment with iodine-containing drugs (amiodarone, lithium, interferon-α) and is then usually reversible after discontinuation of the drug. Two cases who were treated with both lithium and thyroxin hormones were excluded from the analyses.

    For each case, the year when the first symptoms of RA occurred was defined as the index year, and the same index year was used for the corresponding control. Only data on thyroxin use before the index year was analysed in the main analyses. Those starting thyroxin during the index year were analysed separately (16 cases and 5 controls). Smoking was classified into never, and ever (current, past) cigarette smoking.

    Genotyping and antibody assays

    ACPA positivity was determined by the standard anti-cyclic citrullinated peptide (CCP) antibody ELISA (Immunoscan-RA Mark2 ELISA test, Euro-Diagnostica, Malmö, Sweden) and rheumatoid factor status by standard agglutination assays.

    The methods for determining the HLA-DRB1 SE alleles, defined as DRB1*01, DRB1*04 and DRB1*10 in the HLA-DRB1 gene as well as HLA-DRB1*03, and the PTPN22*R620W (1858C/T) polymorphism (rs2476601) have been previously reported.16 ,19 ,20

    Statistical analysis

    We calculated OR with 95% CIs for RA overall and the ACPA-positive and ACPA-negative subsets, associated with thyroxin use, by means of unconditional logistic regression models. Women and men were analysed separately, as well as together. We adjusted for the matching variables (age, gender, residential area). Additional adjustments for formal education (university degree yes/no), body mass index (BMI) (<25, >=25), oral contraceptive use (ever/never) and parity (yes/no) only marginally changed the estimates and were not retained in the final analyses. ORs were interpreted as relative risks as the study was population based and the controls were selected randomly and continuously from the study base.21

    The analysis of a potential interaction, between thyroxin substitution and smoking, HLA-DRB1 SE alleles and PTPN22*R620W was performed only for ACPA-positive disease, since these factors are only associated with the risk of this subset of RA.13–16 Possible interaction between thyroxin substitution and HLA-DRB1*03 was performed for RA overall, as well as ACPA-positive/ACPA-negative RA. Interaction was evaluated by calculating the proportion attributable to interaction (AP) together with its 95% CI. The AP between two interacting factors reflects the joint effect beyond the sum of the independent effects.22 ,23

    All analyses were performed using the Statistical Analysis System (SAS) V.9.2.

    Results

    The RA cases had average symptom duration of 10 months at inclusion, and 63% were ACPA-positive. In total, 124 (6%) of the cases had started treatment with thyroxin substitution before index year, compared with 74 (3%) among the controls. The majority of these were women (113 cases, 71 controls).

    Thyroxin substitution and risk of RA overall, ACPA-positive RA and ACPA-negative RA

    The relative risk of RA among those with thyroxin substitution was twice as high as among those without substitution (table 1). When thyroxin substitution was analysed in relation to the incidence of ACPA-positive and ACPA-negative disease, there were no major differences between these two subsets.

    View this table:
    Table 1

    Relative risk of RA, both overall and of the ACPA-positive and ACPA-negative subsets, associated with thyroxin substitution

    Thyroxin substitution, smoking and risk of ACPA-positive RA

    Thyroxin substitution among never smokers implied a somewhat increased risk of ACPA-positive RA (OR=1.5, 95% CI 0.8 to 2.7), but was related to a greater increased risk in ever smokers (OR=3.6, 95% CI 2.3 to 5.8), compared with those with neither of these factors (table 2). A borderline significant interaction between smoking and thyroxin substitution was observed (AP=0.4, 95% CI 0.0 to 0.7), indicating that the risk increase associated with thyroxin substitution was more pronounced in ever smokers than in never smokers.

    View this table:
    Table 2

    Relative risk of ACPA-positive RA related to different combinations of thyroxin substitution and smoking, HLA-DRB1 SE alleles or the PTPN22*R620W allele

    Thyroxin substitution, HLA-DRB1 SE alleles, and risk of ACPA-positive RA

    As shown in table 2, thyroxin substitution was associated with a small and non-significantly increased risk of ACPA-positive RA in those without SE (OR=1.4, 95% CI 0.7 to 3.0), while the use of thyroxin increased the risk substantially among SE carriers (OR=11.8, 95% CI 6.9 to 20.0), compared with SE non-carriers not using thyroxin. Thus, a strong interaction between SE alleles and thyroxin substitution was observed for the risk of ACPA-positive RA (AP=0.5, 95% CI 0.2 to 0.8), meaning that the risk for this subgroup of RA related to thyroxin use was higher among carriers of SE alleles than non-carriers.

    Thyroxin substitution, PTPN22 alleles, and risk of ACPA-positive RA

    The risk of ACPA-positive RA was similar for thyroxin in non-carriers of the PTPN22*R620W allele (OR=1.6, 95% CI 1.0 to 2.5), as it was for the PTPN22*R620W allele in those not using thyroxin substitution (OR=1.7, 95% CI 1.4 to 2.0; table 2). The combination of PTPN22*R620W allele and thyroxin use, yielded an OR of 3.0 (95% CI 1.5 to 5.8), compared with those without these factors. However, no interaction between the PTPN22 alleles and thyroxin use was found (AP=0.2, 95% CI −0.3 to 0.8).

    Thyroxin substitution, HLA-DRB1*03 alleles, and risk of ACPA-positive/ACPA-negative RA

    We observed no interaction between thyroxin use and the carriage of HLA-DRB1*03 alleles regarding risk of neither ACPA-positive nor ACPA-negative RA. However, since the possibility of carrying HLA-DRB1*03 is dependent on the presence of SE alleles, we made separate analyses for SE carriers and SE non-carriers. In the SE non-carrier group, we found a non-significant indication of interaction between thyroxin use and HLA-DRB1*03 (AP 0.5, (95% CI −0.1 to 1.1), for ACPA-negative (table 3), but not ACPA-positive RA. No indication of a corresponding interaction was found among SE carriers.

    View this table:
    Table 3

    Relative risk of ACPA-negative RA for subjects exposed to different combinations of thyroxin substitution and HLA-DRB1*03 alleles, separately among carriers and non-carriers of the HLA-DRB1 SE alleles

    Discussion

    Our data demonstrates, for the first time, an association between thyroxin substitution (reflecting an autoimmune thyroid disease) and risk of developing RA, which is not dependent of ACPA-status. We also found a striking interaction between thyroxin substitution and the main genetic risk factor, HLA-DRB1 SE alleles, as well as an indication of a similar interaction with smoking, for ACPA-positive RA. However, thyroxin substitution was not found to interact with the PTPN22*R620W allele, which is known to associate with the risk of both ACPA-positive RA and AITD.

    Our results were based on data from a large case-control study with incident RA cases. To minimise the risk of selection bias, that frequently threats the validity of case-controls studies, we used a population-based design where controls were randomly and continuously selected from the same study base as the cases. The high participation proportion among both cases and controls also reduced the risk of such bias.

    Approximately 12% of the general population has been reported to have autoantibodies against the thyroid tissue, while the prevalence of a clinically overt AITD is up to 10 times lower.24 However, in iodine-repleted areas, the diagnosis of hypothyroidism is often, in clinical practice, based on an elevated serum thyrotropin (thyroid stimulating hormone, TSH) concentration alone, so in order to get as good as possible coverage of all AITD cases, thyroxin substitution (except for those with a history of cancer and iodine-containing drugs) could be regarded as the best way to capture the majority of cases with a clinically overt AITD.8 In our study, participants who reported a history of thyroid cancer or the combined use of iodine-containing drugs and thyroxin substitution were excluded from the analyses, and we assumed that thyroxin substitution in the remaining participants, to a large extent, reflected an underlying autoimmunity in the thyroid gland, aggregating both the large group of Hashimotos’ disease and the more rare Graves’ disease (those with secondary hypothyroidism or combination treatment with thyroxin), as well as the spectrum of silent and postpartum thyroiditis, which also are believed to be of autoimmune nature and included as part of AITD.7 However, the lack of information on other thyroid comorbidities than malignancies still may introduce potential misclassification of AITD, which most likely is independent of case or control status, implying a dilution of estimated associations.

    RA and hypothyroidism share symptoms including fatigue and joint pain. Close to RA diagnosis, it is likely that the RA cases were under surveillance and, thus, more likely than the controls to receive thyroxin substitution. This was confirmed in a separate analysis where a strong association between thyroxin substitution initiated during the index year and RA was observed (see online supplementary table S1). The index year was the year of RA symptom debut and these observations were not retained in the main analyses. This analysis might also reflect a common pathway leading to two autoimmune conditions at a similar time-point. This is, however, contradicted by the fact that only the start of thyroxin use at least four years before RA diagnosis was associated with an increased risk of both ACPA+ and ACPA− RA (see online supplementary table S1). These analyses indicate no surveillance of pre-RA cases in the years before the index year. Thus, a potential inability to capture untreated hypothyroidism/AITD was probably equal among incident cases and controls, and rather biases our estimates toward a null association.

    Another study, focused on cardiovascular comorbidity, did not find a significantly higher cumulative incidence of hypothyroidism or thyroxin substitution in RA patients with established RA than the non-RA comparators (7.7% vs 6.7%, p=0.2) during 10 years of follow-up.25 Thus, while our findings indicate that thyroxin substitution (AITD) increases the risk of RA, their findings indicate that the incidence of hypothyroidism does not escalate after the RA diagnosis.

    In conclusion, we found that thyroxin substitution is associated with the risk of both ACPA-positive and ACPA-negative RA. For ACPA-positive RA, a strong interaction between thyroxin substitution and the HLA-DRB1 SE alleles, as well as a borderline interaction with smoking, was observed. For clinical practice, our results indicate two important findings. First, patients on thyroxin substitution treatment may have an increased risk of RA, particularly if they are genetically predisposed, that is, those with RA in their family, and should refrain from smoking. Secondly, although joint symptoms can be a manifestation of hypothyroidism, physicians should consider whether it could be an early RA.

    Acknowledgments

    First, we express our sincere gratitude to Professor Lars Alfredsson and Professor Lars Klareskog, the principal investigators and founders of the EIRA study. Furthermore, we want to thank all participating controls and patients with RA, and the following people who recruited patients for EIRA along with their collaborating clinicians and nurses: Ingeli Andreasson, Landvetter; Eva Baecklund, Akademiska Hospital; Ann Bengtsson and Thomas Skogh, Linkoping Hospital; Birgitta Nordmark, Johan Bratt, and Ingiald Hafstrom, Karolinska University Hospital; Kjell Huddenius, Rheumatology Clinic (Stockholm); Shirani Jayawardene, Bollnas Hospital; Ann Knight, Hudiksvall Hospital and Uppsala University Hospital; Ido Leden, Kristianstad Hospital; Goran Lindahl, Danderyd Hospital; Bengt Lindell, Kalmar Hospital; Christine Lindstrom and Gun Sandahl, Sophiahemmet; Bjorn Lofstrom, Katrineholm Hospital; Ingmar Petersson, Spenshult Hospital; Christoffer Schaufelberger, Sahlgrenska University Hospital; Patrik Stolt, Vasteras Hospital; Berit Sverdrup, Eskilstuna Hospital; Olle Svernell, Vastervik Hospital; and Tomas Weitoft, Gavle Hospital. For excellent data collection in EIRA, we thank Marie-Louise Serra and Lena Nise. For helpful discussions about thyroid disease and critical reading of the manuscript, we thank Dr Jan Calissendorff and Sigridur Björnsdottir, endocrinologists at Karolinska.

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    Supplementary materials

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    Footnotes

    • Handling editor Tore K Kvien

    • Contributors CB and SS initiated the study and shared the responsibility for analyses and interpretation of results. In addition, CB was responsible for the statistical analyses and in writing the paper. SS had the responsibility for the clinical perspective and in cowriting the paper. LP was responsible for the HLA-DRB1 and PTPN22 genotyping and interpretation of genetic results. HK was responsible for interpretation of statistical/epidemiological results, and of guidance of the interaction analyses. All authors contributed to the final paper.

    • Funding The study was supported by grants from the Swedish Medical Research Council; from the Swedish Council for Working Life and Social Research; from the 80-year foundation of King Gustaf V; from the Swedish Rheumatism Foundation; from Stockholm County Council; from the insurance company AFA and from the BTCure.

    • Competing interests None.

    • Ethics approval Regionala etikprövningsnämnden (EPN), Stockholm, Sweden.

    • Provenance and peer review Not commissioned; externally peer reviewed.