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.

甲状腺功能减退症是最常见的自身免疫性疾病之一，尤其是老年女性[ 1 ]。此外，自身免疫性甲状腺炎与不同的基因多态性相关，表明存在发生自身免疫性甲状腺功能减退症的遗传倾向。一般来说，甲状腺功能减退症被认为是一种器官特异性自身免疫性疾病，而其他自身免疫性疾病则具有更系统性的模式，例如类风湿性关节炎（RA）和系统性红斑狼疮（SLE）。传统上，患有一种自身免疫性疾病的个体对另一种自身免疫性疾病的易感性较高，因此，自身免疫性疾病倾向于在患者及其亲属中聚集。有趣的是，尽管患者具有共同的遗传背景，但患者之间的自身免疫性疾病的表现可能有所不同——这一概念被称为自身免疫万花筒[ 2 ]。

在本期《内科医学杂志》中，Waldenlind 等人。 [ 3 ] 介绍了瑞典的一项全国性队列研究，评估接受缓解病情抗风湿药物 (DMARD) 治疗的 RA 患者甲状腺功能减退症的发生率。本队列研究旨在调查治疗 RA 时使用的 DMARD 是否可能对自身免疫性甲状腺疾病 (AITD) 的发展具有保护作用。在这项研究中，从 1996 年启动的全国瑞典风湿病质量登记册中确定了约 16,000 名 RA 患者。这些 RA 患者与大约 63,000 名对照者进行匹配作为比较者，并在 2006 年 1 月至 2019 年 1 月期间评估了两类患者的 AITD 发病率组。 RA 诊断后，2.3% 的患者出现 AITD，而匹配的非 RA 对照者中这一比例为 2.9%，表明 RA 出现 AITD 的风险较低。有趣的是，在接受生物 DMARD (bDMARD) 治疗的 RA 患者中，发生 AITD 的风险更低，尤其是在接受 bDMARD 治疗并同时使用 MTX 的患者中。按性别和血清阳性分层的子集分析表明，与未接受 bDMARD 治疗的 RA 患者相比，接受 bDMARD 治疗的患者发生 AITD 的风险仍然较低。对特定年龄组的其他分析表明，在较年轻的年龄组中，患 AITD 的风险更低。 AITD 可能受到 TNF 抑制剂等免疫调节剂影响的新观察结果可能具有多种临床意义。

首先，甲状腺功能减退症长期以来被认为是一种器官特异性自身免疫性疾病，因此，AITD的治疗也具有器官特异性。如今，当甲状腺组织被免疫过程破坏并且甲状腺失去内分泌功能时，AITD 采用甲状腺激素替代治疗。然而，如果 AITD 被认为是一种系统性自身免疫性疾病，那么以更系统性的方式治疗它——例如使用免疫调节剂，如 RA 或 SLE——可能会为 AITD 等器官特异性自身免疫性疾病引入新的治疗方式。尽管 Waldenlind 等人的研究发现。与 TNF 抑制剂一样，bDMARD 治疗可减少 AITD 的发展，这些结果需要在其他研究中进一步复制才能得出明确的结论。

其次，接受 TNF 抑制剂等免疫调节剂治疗的 RA 患者似乎更能免受 AITD 的影响。这具有临床意义，因为之前的研究表明，RA 与甲状腺功能减退症患病率升高有关，更重要的是，RA 患者心血管疾病 (CVD) 风险升高，这在患有甲状腺功能减退症的 RA 患者中更为明显。4 ]。这不仅在传统的心血管危险因素（即高血压和血脂异常）中得到了认可[ 5 ]，而且在患有甲状腺功能减退症的RA患者中普遍存在和偶发的CVD缺血事件也得到了认可[ 6, 7 ]。预防 AITD 的发展可能会降低甲状腺功能减退症和 RA 患者已经放大的 CVD 风险，尽管这一点仍有待确定。

应该对 Waldenlind 等人的研究的有趣结果发表一些评论。尽管由于该研究是全国性的，因此它们似乎具有普遍性，但主要局限性之一是 AITD 诊断的不确定性。作者指出，AITD 的诊断基于甲状腺激素替代的首次处方，但 AITD 应该由临床医生根据临床参数（例如血液检查，包括甲状腺抗体）进行诊断。此外，众所周知，甲状腺功能减退症大多出现在老年人身上。因此，年龄和虚弱是 RA 患者开始使用 bDMARD 的主要障碍，因此该研究的结果可能存在偏差。这或许可以解释为什么观察到的 AITD 发展风险较低在年轻群体中更为明显。

总而言之，有人提出的问题是，在 AITD 等器官特异性自身免疫性疾病的早期阶段，用更系统的治疗替代器官特异性治疗是否可以通过阻断潜在的免疫过程来防止甲状腺组织破坏。这项研究是否揭示了 AITD 和 RA 之间另一个缺失的联系还有待观察，但很明显它为自身免疫的万花筒增添了一面新的镜子。