Hypothyroidism and rheumatoid arthritis: Missing a link?

Abstract

Hypothyroidism is one of the most common autoimmune diseases, especially in older women [1]. Moreover, autoimmune thyroiditis has been associated with different genetic polymorphisms, suggesting a genetic predisposition for developing autoimmune hypothyroidism. In general, hypothyroidism has been considered an organ-specific autoimmune disease, whereas other autoimmune diseases have a more systemic pattern, for example rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Traditionally, individuals suffering from one autoimmune disease have a higher susceptibility to another, and therefore, autoimmune diseases have a tendency to cluster within patients and their relatives. Intriguingly, the manifestations of autoimmune disease may differ between patients, although the patients share a common genetic background—a concept known as the kaleidoscope of autoimmunity [2].

In this issue of the Journal of Internal Medicine, Waldenlind et al. [3] presented a nationwide cohort study from Sweden assessing the incidence of hypothyroidism in patients with RA treated with disease-modifying antirheumatic drugs (DMARDs). This cohort study aimed to investigate whether DMARDs, as used in RA, may have a protective effect on the development of autoimmune thyroid disease (AITD). In this study, ∼16000 patients with RA were identified from the nationwide Swedish Rheumatology Quality Register initiated in 1996. These patients with RA were matched with approximately 63,000 controls as comparators, and the incidence of AITD was assessed between January 2006 and January 2019 in both groups. After RA diagnosis, 2.3% of the patients developed AITD—compared to 2.9% in the matched non-RA comparators—showing a lower risk of AITD development in RA. Intriguingly, the lower risk of incident AITD was even more pronounced in patients with RA treated with immunomodulatory agents receiving biological DMARDs (bDMARDs), especially in bDMARD-treated patients with concomitant use of MTX. Subset analyses stratified by sex and seropositivity showed that this lower risk remained for AITD development in patients treated with bDMARDs compared to non-bDMARD-treated patients with RA. Additional analyses for specific age groups revealed that the lower risk for AITD development was even more pronounced in younger age groups. The novel observation that AITD may be influenced by immunomodulating agents such as TNF inhibitors may have several clinical implications.

First, hypothyroidism has long been considered an organ-specific autoimmune disease, and therefore, the treatment of AITD is also organ-specific. Nowadays, AITD is treated with thyroid hormone replacement at the time that thyroid tissue is destroyed by immunological processes and the thyroid gland has lost its endocrine function. However, if AITD is considered a systemic autoimmune disease, treating it in a more systemic way—such as with immunomodulatory agents, as with RA or SLE—may introduce a new treatment modality for organ-specific autoimmune diseases such as AITD. Although the finding in the study by Waldenlind et al. that, as with TNF inhibitors, treatment with bDMARDs decreased AITD development, these results need further replication in other studies for definite conclusions.

Second, patients with RA receiving immunomodulatory agents such as TNF inhibitors seem to be more protected from AITD development. This has clinical relevance, as previous studies have shown that RA is associated with an elevated prevalence of hypothyroidism and, more importantly, patients with RA have an elevated cardiovascular disease (CVD) risk, which is even more pronounced in patients with RA with hypothyroidism [4]. This has not only been acknowledged for traditional cardiovascular risk factors (i.e. hypertension and dyslipidaemia) [5], but also for prevalent and incident CVD ischaemic events in patients with RA with comorbid hypothyroidism [6, 7]. Potentially, the prevention of AITD development may decrease the already amplified CVD risk in patients with hypothyroidism and RA, although this remains to be established.

Some remarks should be made about the intriguing results of the study by Waldenlind et al. Although they seem to be generalizable as the study is nationwide, one of the main limitations is the uncertainty of diagnosis of AITD. The authors stated that AITD diagnosis was based on the first prescription of thyroid hormone substitution, but AITD should be diagnosed by a clinician based on clinical parameters (e.g. blood tests, including thyroid antibodies). Moreover, it is known that hypothyroidism is mostly present in the elderly. Therefore, the outcome of the study may be biased by the fact that age and frailty are major barriers to the initiation of bDMARDs in patients with RA. This might explain why the observed lower risk of AITD development is more pronounced in the younger age groups.

Altogether, the question is raised whether the substitution of organ-specific treatment with more systemic treatment in an earlier phase of a more organ-specific autoimmune disease such as AITD may prevent the tissue destruction of the thyroid gland by blocking the underlying immunological processes. Whether this study reveals another missing link between AITD and RA remains to be seen, but it is clear that it adds a new mirror to the kaleidoscope of autoimmunity.

The author declares no conflict of interest.