The skin is located at the boundary between the body and the external environment and is the first line of defense against pathogen invasion (1). Local keratinocytes and skin-resident immune cells initiate innate immune mechanisms when the epidermal barrier is disrupted by intrinsic or extrinsic factors, to clear the infection, promote wound healing, and activate adaptive immunity (2). However, once the skin immune homeostasis is dysregulated, excessive release of cytokines and chemokines forms an inflammatory cascade, causing uncontrolled activation of T cells, the humoral immune system or innate immunity, resulting in inflammatory or autoimmune skin diseases (3).

Autoimmune thyroid disease (AITD) manifests as an organ-specific autoimmune disorder triggered by a T cell attack on the thyroid due to an imbalance in immune system homeostasis. The invasion of lymphocytes into the thyroid, mainly infiltration of activated T cells, leads to gradual replacement of thyroid tissue, which impairs thyroid hormone synthesis (4). In addition, recruited helper T lymphocytes 1 (Th1) produce IFN-γ and TNF-α and then thyroid cells respond and secrete CXCL10, promoting infiltration of more lymphocytes, thereby creating a positive feedback loop that triggers and amplifies the autoimmune process (5). In the early stage of AITD, the prevalent immune response is Th1 immune response, which changes to Th2 immune response in the late stage (6). The prevailing clinical hallmarks of AITD are hyperthyroidism and hypothyroidism (7, 8). In addition, toxic compounds in tobacco smoke, such as nicotine, thiocyanate and benzopyrene, can exert pro- and anti-thyroid effects by affecting iodine uptake and organification or modulating the sympathetic nervous system activity (9), which subsequently cause AITD.

Previous epidemiological findings revealed that AITD was reported to have a higher prevalence among inflammatory (dermatitis, urticaria, etc.) or autoimmune skin diseases ((systemic lupus erythematosus (SLE), vitiligo, pemphigus, systemic sclerosis (SSc), etc.) patients compared to the general population (10), indicating that common underlying pathophysiological mechanisms may exist in the skin-thyroid axis. However, due to the limitations of observational studies, only the high comorbidity rate of these two diseases can be concluded, and a causal effect of inflammatory or autoimmune skin diseases on AITD has not been fully elucidated.

Mendelian Randomization (MR) represents a novel epidemiological research design that employs genetic variants (single-nucleotide polymorphisms (SNPs)) as instrumental variables (IVs) to infer the causal relationship between the outcome and exposure (11). The use of MR can minimize the interference of unmeasured confounding factors and reverse causation bias owing to the random distribution of genetic variants at conception. MR analysis can save considerable human resources, time and costs compared with conventional observational studies and randomized controlled trials (RCTs). Multivariate MR (MVMR) serves an extension of MR designed to evaluate the causal effects of two or more exposures on the outcome (12).

Therefore, the aim of this study was to estimate the causal association between inflammatory or autoimmune skin diseases and thyroid dysfunction using a two-sample MR framework to provide theoretical support for clinical decision-making. We also performed MVMR to evaluate the mediating effect of smoking on the relationship between inflammatory or autoimmune skin diseases and thyroid dysfunction.

This study offers valuable insights into the causal relationships between common inflammatory or autoimmune skin conditions and thyroid dysfunction through UVMR and MVMR analyses. The findings revealed positive causal effects of AD, SLE, SD, and psoriasis vulgaris and negative causal effects of BP on hypothyroidism risk. The positive association between AD, SLE, and SD and hypothyroidism was observed even after adjusting for smoking, indicating the robustness and reliability of the results.

Thyroid diseases elicit various dermatologic manifestations, so we mainly focused on investigating the causal effects of inflammatory or autoimmune skin diseases on thyroid conditions (10). The findings suggested that genetic predisposition to AD was linked to an elevated risk of hypothyroidism, consistent with findings from a recent National Health and Nutrition Examination Survey comprising 10,060 American participants (21). The potential association between AD and thyroid disorders may be attributed to the dysregulation of intestinal γδ T cells caused by childhood food allergies in patients with AD (22). This dysregulation of intestinal γδ T cells may lead to the suppression of regulatory T (Treg) cells through the IL-23 inflammatory cytokine pathway, resulting in development of autoimmune disorders in AD and thyroid conditions (23). Furthermore, according to the latest study by Ma EZ et al., enriched metabolites in patients with AD involved in the synthesis of thyroid hormones, which can modulate immune pathways, so AD and thyroid diseases may have common immune-metabolomics pathways (24).

This study showed that SLE was associated with a higher risk of hypothyroidism, aligning with the findings from previous observational and MR studies (25, 26). Increasing data demonstrated that the biological relationship between SLE and thyroid diseases should be established. Firstly, studies reported a higher level of thyroid autoantibodies, including thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb), in patients with SLE compared with healthy controls (27). Another study showed that SLE patients with anti-Smith antibodies were more likely to develop mild hypothyroidism (28). The above evidence confirmed that SLE and AITD, systemic and organ-specific autoimmune diseases, can be immunologically associated through autoantibodies. Secondly, the imbalance between proinflammatory mediators mediated by similar Th1 immune response in SLE and AITD may be the immunopathogenic basis of the link between these two diseases (29). Thirdly, patients with SLE have an increased susceptibility of developing AITD due to shared genetic mutations, such as the R620W polymorphism of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene (30).

The present results showed a suggestive association between SD and higher risk of hypothyroidism. One possible explanation of this association is the bystander activation theory, linking infections to the onset of autoimmune diseases (31). We hypothesized that after Malassezia colonization which acted as the main causative pathogen of SD, interacted with the skin surface through the release of free fatty acids and lipid peroxides, further impairing the skin barrier and activating inflammatory responses (32). This inflammatory background may lead to the activation of thyroid cells in SD patients infected with Malassezia, which resulted in secretion of pro-inflammatory cytokines and chemokines and recruitment of abundant autoreactive lymphocytes to infiltrate the thyroid gland, ultimately initiating and promoting the autoimmune process.

Two large observational cohort studies previously provided inconsistent findings on the susceptibility of patients with psoriasis to thyroid diseases. The results from one study indicated that the risk of thyroid disease was increased in patients with psoriasis (33), whereas the other study reported no significant difference in thyroid disease risk between psoriasis patients and healthy controls (34). Notably, our MR study based on genetic data revealed that psoriasis vulgaris rather than psoriasis potentially increased the risk of hypothyroidism, so the connection between different subtypes of psoriasis and the risk of thyroid dysfunction should be explored further. Scholars are currently investigating the pathogenic pathways implicated in the relationship between psoriasis and thyroid diseases, including the overlap of Th1 immune response with IL-23/Th17 axis (35), shared genetic susceptibility loci (Psoriasis susceptibility 1 candidate 1 (PSORS1C1) gene (36), and Tumor necrosis factor α-induced protein 3 (TNFAIP3) gene) (37), the miRNAome of psoriatic skin functionally enriching in thyroid hormone signaling (38), recognition of thyroid antigens by autoantibodies in patients with psoriasis (39), and vitamin D and omega-3 fatty acid deficiencies (40).

Previous controlled studies found that the association of BP with thyroid disorders is surrounded by a large inconclusiveness (41, 42). Although our results revealed that BP had a slight protective causal effect on hypothyroidism, the results need to be interpreted with caution because of few BP cases patients among the study participants and the unknown severity of BP. In addition, the presence of autoimmune comorbidities might exaggerate the causal impact of BP on the risk of thyroid dysfunction in cross-sectional studies.

Remarkably, previous studies reported that the high prevalence rates of thyroid diseases in patients with vitiligo, especially hypothyroidism (43). This phenomenon may be due to the IFN-γ/TNF-α-CXCL9/10 pathway played a central role in mediating the overlapping autoimmune imbalances in vitiligo and thyroid diseases (44). CXCR3, which is highly expressed on CD4⁺ T cells and effector CD8⁺ T cells, is the common receptor for CXCL9 and CXCL10. Therefore, pathogenic T cells were subsequently recruited and activated, secreting autoantibodies and pro-inflammatory cytokines to attack the skin and thyroid (45). However, a correlation was not observed between vitiligo and thyroid diseases in our study. This might be because the analysis could not be stratified for demographic characteristics or disease subtypes due to the lack of individual data in the GWAS database the analysis, even though vitiligo patients with positive serology or skin involvement exceeding 5% of body surface area were known to be more likely to develop thyroid disorders (46). Furthermore, only the serum levels of thyroid antibodies were abnormally elevated in many patients with vitiligo, but such GWAS databases have not yet been published for further exploration.

Our study showed no significant association of thyroid diseases with AA, which is consistent with the meta-analysis recently published by Kinoshita-Ise M et al (28). However, it is important to note that we cannot conclude based on the current results that hyperthyroidism or hypothyroidism are unrelated to AA. First of all, given that human leukocyte antigen (HLA) polymorphisms may act as main risk factors in the development of AA (47), plus HLA class II haplotypes susceptible or resistant to AA and thyroid autoimmunity (48). Therefore, the non-HLA loci shared by AA and thyroid dysfunction, also known as genetic susceptibility, may be the basis for the comorbidity of the two diseases. In addition to genetic factors, sharing epigenetic, immunological, drug, and environmental factors have been proposed as possible contributors to this association (49). Second and the most importantly, in our study, a clear distinction between overt and subclinical thyroid diseases was not made, which may obscure the relationship between AA and thyroid dysfunction. Truly, most previous controlled studies have only demonstrated that the levels of free triiodothyronine, free thyroxine, thyrotropin, TPOAb and TGAb were prone to abnormalities in patients with AA, especially severe AA (28, 50). In conclusion, although our analyses have not yet found a causal relationship between AA and thyroid diseases, the potential risk of patients with AA suffering from thyroid disorders in the future should be emphasized.

Previous studies documented an elevated risk of developing thyroid diseases in patients with urticaria, pemphigus, and SSc (51–53), but the incidence of thyroid dysfunction in patients with acne and rosacea is controversial (54–57). In the present study, the results did not show a causal relationship between acne, rosacea, urticaria, pemphigus, SSc and LS and either hyperthyroidism or hypothyroidism. Several factors may contribute to the inconsistency between the current MR findings and results from previous observational research. First, observational studies can merely illuminate the co-occurrence of inflammatory or autoimmune skin diseases and thyroid disorders, so they cannot establish the sequence or establish a causal association between the two conditions. The MR analyses in this study were based on genetic predictions and the results revealed that acne, rosacea, urticaria, SSc and LS do not predispose individuals to an elevated risk of thyroid diseases. Secondly, cross-sectional studies often comprise participants with multiple coexisting autoimmune disorders, so it is challenging to eliminate the confounding effects of other comorbid diseases on thyroid disorders. To circumvent this challenge, we identified and excluded the SNPs implicated in concurrent autoimmune diseases, such as rheumatoid arthritis, celiac disease, type 1 diabetes, and pernicious anemia to obtain “pure” causal effect estimates (15). Therefore, the results from the MR analysis indicated a significant reduction in the risk of thyroid disorders among individuals with specific inflammatory or autoimmune skin diseases, and in some instances, no significant association was identified between some skin conditions and thyroid disorders. Thirdly, recent studies revealed that glucocorticoids or immunosuppressants can modulate lymphocyte maturation, proliferation, and antibody formation by B lymphocytes, thereby affecting the prevalence of thyroid diseases (58). Inclusion of study subjects with a history of corticosteroid or immunosuppressant use may result in discordant results between MR studies and observational investigations.

It is worth noting that our results showed that both inflammatory and autoimmune skin diseases are associated with hypothyroidism but not hyperthyroidism. Differences in genetic factors, epigenetic mechanisms, and autoimmune responses between hyperthyroidism and hypothyroidism may partially explain the variation in the causal effect of these factors on hypothyroidism and hyperthyroidism (59). More importantly, hyperthyroidism exhibits apparent symptoms such as irritability, tremors, and weight loss (8), whereas hypothyroidism has subtle manifestations including fatigue, excessive sleep, and depression (7), which may be easily ignored. Therefore, clinicians should recommend that patients with inflammatory or autoimmune skin diseases undergo early and regular thyroid function screening to prevent and treat thyroid conditions that has not yet occurred or already exists.

The present study has several strengths. First, our study stands as the inaugural MR analysis to delve the causal relationship between inflammatory or autoimmune skin diseases and thyroid dysfunction using both UVMR and MVMR methods. Second, we included relatively comprehensive phenotypes of common inflammatory or autoimmune skin diseases in the MR setting. Moreover, the utilization of disparate data sources for exposure and outcome datasets mitigated the likelihood of sample overlap (60). We also performed multiple sensitivity analyses and outlier assessments to minimize the impact of pleiotropy and outliers, increasing the robustness and reliability of the findings. Third, the participants included in the GWAS studies were of European ancestry, which helped reduce population stratification bias.

The MR analyses have some limitations. First, pleiotropy in the MR setting was a major challenge. Thus, we employed the MR-Egger intercept evaluation and MR-PRESSO to detect and exclude the horizontal pleiotropy. The two tests showed limited indications of pleiotropy, indicating that the results were reliable. Second, significant heterogeneity was observed in some of the MR analyses, but our main results presented homogeneity in the direction and magnitude of effect estimates when weighted median, MR-Egger, multiplicative-random-effects IVW, and MR-PRESSO analyses were conducted after excluding any potential outlier SNPs. Third, our results drew upon GWAS data from mainly individuals of European descent. Therefore, the conclusions obtained in this study should be carefully generalized to other races and populations.

The current study provides evidence that AD, SLE, and SD are causally associated with an increased risk of hypothyroidism. The pathophysiologic mechanisms underlying the crosstalk between skin diseases and thyroid dysfunction should be explored in further investigations. The findings from this research provide vital information for clinicians that measures and concerted efforts for follow-up of thyroid function and early intervention of thyroid diseases should be considered in subjects diagnosed with AD, SLE, and SD, particularly patients with other autoimmune comorbidities.