INTRODUCTION

Autoimmune thyroid disease (AITD), including hypothyroidism and hyperthyroidism of autoimmune origin, is the most common autoimmune disease in the general population, with a prevalence of approximately 5%.¹ The prevalence of AITD is increased in patients with rheumatoid arthritis (RA), making AITD one of the most common co-morbid conditions in RA.^{2– 9} The underlying pathogenic mechanisms of the co-occurrence between AITD and RA are not well understood, but polymorphisms in genes involved in the regulation of T-cell response may play a key role.¹

In contrast to the well-established increased occurrence of RA in patients with AITD^{10– 12} and increased occurrence of AITD in patients with RA,^{12 13} considerably less is known about the impact of AITD on the phenotypic presentation of RA, and on its impact on response to anti-rheumatic therapies. Previous findings indicate an association between hypothyroidism and higher macrophage inflammatory response with release of pro-inflammatory cytokines (interleukin-1 (IL-1), IL-6 and tumour necrosis factor-α).^{14 15} Hypothyroidism may cause symptoms such as fatigue, myalgia and arthralgia that may also occur in RA.¹⁶ One study, of 52 prevalent RA patients, reported a correlation between hypothyroidism and higher disease activity.¹⁷ Another study, based on 439 prevalent RA patients from a Danish registry and based on 28-joint Disease Activity Score-C reactive protein (DAS28-CRP) scores reported, somewhat contradictory, no significant difference in RA disease activity at diagnosis but a reduced chance of response to anti-rheumatic drugs at 4 months from treatment initiation.¹⁸ These findings call for a more detailed assessment of how AITD impacts the presentation and evolution of RA disease activity, as measured by different types of metrics, and also of how AITD affects the observed RA treatment response.

The objectives of this study were therefore to investigate, in a study population large enough to allow for assessments of differences across subgroups of patients, whether and how concomitant AITD impacts patient-related and physician-related measures of disease activity, at the time of RA diagnosis and at 3-month and 6-month follow-up visits, and also how AITD affects the response to first-line treatment with methotrexate. In addition to overall effects, we investigated variations in RA disease presentation and treatment response across subsets as defined by RA serological status, sex and age.

RESULTS

Among the 9 004 RA patients who were included in the study, the prevalence of AITD was 11% (n=1 003) (table 1). As expected, the proportion of women was higher in patients with AITD compared with those without (88% vs 65%), while the mean±SD age did not differ substantially between the groups (68±14 vs 65±15 years).

AITD and change in RA disease activity between baseline and 3/6 months

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Figure 1

Change in DAS28 components (mean) between 0 and 3 months, and EULAR DAS28-ESR response at 3 months. DAS28-ESR, 28-joint Disease Activity Score-erythrocyte sedimentation rate.

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Table 4

Changes in DAS28 parameters from baseline to 3-month and 6-month follow-up visit, among RA patients in the Swedish Rheumatology Quality Register (SRQ)

Comparing baseline and 3 months, patients with (vs without) AITD had a more pronounced decrease in patients global (−28 vs −24), whereas the decrease in pain, HAQ and other DAS28 components was similar (table 4). The change in DAS28 components is displayed in figure 1. Comparing baseline and 6 months, there were only small numerical differences, for all parameters under study (table 4). When adjusting also for the baseline value of the parameter under study, the difference in delta patients global for those with versus without AITD disappeared, but for all other parameters, the pattern of small differences remained (online appendix table II).

In analyses stratified by age at RA diagnosis, the ten or so percent of all patients who were below 45 years of age displayed a somewhat different pattern, with AITD linked to a slightly lower disease activity at baseline, though none of these differences reaches statistical significance (online appendix tables III and IV).

DISCUSSION

Our results from this large study on the impact of AITD on RA disease presentation and response, indicate that AITD affects disease presentation at RA diagnosis, primarily through patient-reported but not objective measures. Taking this difference into account, AITD did not seem to affect the chance of receiving a good treatment response. These findings underscore the need for a systematic evaluation of not only composite measures such as DAS28 levels but also of its individual components and additional parameters. In contrast to this overall pattern, we noted a somewhat different pattern of disease activity and a stronger negative effect on treatment response, in patients with AITD and below 45 years of age. These latter results extend previous findings of a stronger link between AITD and RA among younger patients (the OR for hypothyroidism in RA patients, 18–44 years of age: 2.12, OR among 45–69 years: 1.42, and OR 70+ years: 1.37).⁹

In light of the age and sex distributions in our study population, the prevalence of AITD of approximately 11% is in line with previous results.^{6 13 26}

One prior study, with a different design, has addressed the question whether thyroid dysfunction relates to disease activity in RA.¹⁷ However, this was a cross-sectional study in established RA using levels of thyroid-stimulating hormone (TSH >4.2 µIU/mL) as the exposure, which was present in 38% of the 52 prevalent RA patients. They found higher disease activity parameters (DAS28 and ESR) in patients with elevated TSH.

Our findings partly corroborate those of Emamifar et al, of 439 RA patients with established RA, who compared disease activity (DAS28-CRP) in RA patients with and without hypothyroidism at treatment initiation. The individual DAS28 components were not evaluated. Treatment response measured as delta DAS28-CRP and DAS28-CRP at 4 months was significantly lower among RA-patients with thyroid disorders.¹⁸ We extend these findings by demonstrating that they are mainly explained by higher patient-related disease activity parameters at baseline. Differences compared with our study include the study design (patients were not defined as early RA, the treatment was not restricted to methotrexate, thyroid dysfunction was based on hospital records) and the statistical approach.

Several susceptibility genes involved in the pathogenesis of both AITD and RA have been identified, including PTPN22 (protein tyrosine phosphatase non-receptor type 22), CTLA4 (cytotoxic T-lymphocyte-associated leucocyte antigen) and the HLA gene complex including HLA-DRB1 (human leucocyte antigen DR B₁).¹ In addition, carriership of different alleles of the HLA-DRB1 locus has been demonstrated to be associated with anti-citrullinated protein antibodies (ACPA)-positivity resulting in a more destructive RA. One hypothesis is that shared susceptibility genes could be one possible explanation to a potential lack of treatment response in the younger (<45 years) subgroup of patients. Individuals, who at young adult age have already developed two autoimmune conditions, potentially have a stronger shared inheritance. Patient-reported parameters such as patient global, VAS pain and HAQ could potentially be increased due to symptoms such as fatigue, arthralgia and myalgia of a concurrent AITD. The different patterns in disease activity over time and the lack of treatment response seen in this limited subgroup of younger patients compared with the whole population need to be further investigated.

Our study has some limitations. We did not have information on the presence of thyroid antibodies or TSH levels. Thyroid antibodies have been reported to be around 12% in the general population while the prevalent of clinically overt AITD has been reported to be lower.²⁷ Taking other defined indications into account, thyroxine prescription has been considered an accurate proxy for capturing clinically overt AITD.^{6 22} Since we aimed to investigate the impact of clinically overt AITD on RA disease activity and treatment response we found this definition of AITD adequate for our study. It cannot be ruled out that some patients may have a non-autoimmune cause for thyroxine treatment but this risk of a potential misclassification must be viewed as having at most marginal effect on our results. The patients in our study were registered as rheumatoid factor (RF) and/or ACPA positive in the SRQ, but we did not have access to additional information on specific auto-antibody profiles or titres. We did not have information about other comorbidities potentially associated with AITD.

Our study also has some strengths. The large sample size, approximately 9 000 included patients compared 52 and 439 in previous studies, allowed us to robustly investigate disease activity and treatment response, also in subgroups. Furthermore, we used prospectively recorded information on prescriptions of thyroxine from the nationwide drug register, irrespective of RA response status, to minimise false-negative comparisons and the risk of bias due to selective recall, which is especially important in such a common condition. We consider that the large population-based sample size and the clinically relevant definition of AITD make our findings generalisable to early RA patients in an international perspective.

Achievement of disease control within 3–6 months after initiation of RA-treatment has been shown to correlate well with long-term outcome.²⁸ Therefore, it is important to identify potential outcome predictors, and common co-morbidities in RA are important candidates, that might capture differences in underlying pathogenic mechanisms, which in turn may relate to clinical disease activity. AITD is of special interest there, since the symptoms of undertreated AITD may overlap with RA symptoms. Based on our results, concomitant AITD only has marginal impact on disease activity and response overall, but RA patients with AITD do have somewhat higher patient reported outcome measures at diagnosis, supporting that measures that may reflect both conditions in a way (patient’s global health, pain and function) can be higher in this subgroup, thereby AITD does have an influence on the phenotypic presentation of RA. In turn, this impacts the treatment response criteria used in clinical practice. The interpretation of treatment response should be seen in this light. Thus, when treating and evaluating early RA patients, those 10% with AITD in particular, it is of importance to pay attention to not only to overall disease activity and response measures such as DAS28 but to unpick its components.