Conundrum for Psoriasis and Thyroid Involvement

Strategies concerning thyroid anomalies in patients confirmed with psoriasis, either on clinical level or molecular levels, and their genetic findings remain an open issue. Identification of the exact subgroup of individuals that are candidates to endocrine assessments is also controversial. Our purpose in this work was to overview clinical and pathogenic data concerning psoriasis and thyroid comorbidities from a dual perspective (dermatologic and endocrine). This was a narrative review of English literature between January 2016 and January 2023. We included clinically relevant, original articles with different levels of statistical evidence published on PubMed. We followed four clusters of conditions: thyroid dysfunction, autoimmunity, thyroid cancer, and subacute thyroiditis. A new piece of information in this field was the fact that psoriasis and autoimmune thyroid diseases (ATD) have been shown to be related to the immune-based side effects of modern anticancer drugs—namely, immune checkpoint inhibitors (ICP). Overall, we identified 16 confirmatory studies, but with heterogeneous data. Psoriatic arthritis had a higher risk of positive antithyroperoxidase antibodies (TPOAb) (25%) compared to cutaneous psoriasis or control. There was an increased risk of thyroid dysfunction versus control, and hypothyroidism was the most frequent type of dysfunction (subclinical rather than clinical), among thyroid anomalies correlated with >2-year disease duration, peripheral > axial and polyarticular involvement. With a few exceptions, there was a female predominance. Hormonal imbalance included, most frequently, low thyroxine (T4) and/or triiodothyronine (T3) with normal thyroid stimulating hormone (TSH), followed by high TSH (only one study had higher total T3). The highest ratio of thyroid involvement concerning dermatologic subtypes was 59% for erythrodermic psoriasis. Most studies found no correlation between thyroid anomalies and psoriasis severity. Statistically significant odds ratios were as follows: hypothyroidism: 1.34–1.38; hyperthyroidism: 1.17–1.32 (fewer studies than hypo); ATD: 1.42–2.05; Hashimoto’s thyroiditis (HT): 1.47–2.09; Graves’ disease: 1.26–1.38 (fewer studies than HT). A total of 8 studies had inconsistent or no correlations, while the lowest rate of thyroid involvement was 8% (uncontrolled studies). Other data included 3 studies on patients with ATD looking for psoriasis, as well as 1 study on psoriasis and thyroid cancer. ICP was shown to potentially exacerbate prior ATD and psoriasis or to induce them both de novo (5 studies). At the case report level, data showed subacute thyroiditis due to biological medication (ustekinumab, adalimumab, infliximab). Thyroid involvement in patients with psoriasis thus remained puzzling. We observed significant data that confirmed a higher risk of identifying positive antibodies and/or thyroid dysfunction, especially hypothyroidism, in these subjects. Awareness will be necessary to improve overall outcomes. The exact profile of individuals diagnosed with psoriasis who should be screened by the endocrinology team is still a matter of debate, in terms of dermatological subtype, disease duration, activity, and other synchronous (especially autoimmune) conditions.


Introduction
Psoriasis, a complex chronic autoimmune multisystem disease with skin as its dominant manifestation, affects between 1% and 8% of adults worldwide [1,2]. While genetic predisposition is important, environmental factors, comorbidities and behavioral elements also matter [3]. The disorder has five major subtypes-plaque, inverse, guttate, pustular (PP) and erythrodermic (EP)-with the most frequent being chronic plaque psoriasis. This latter is characterized by erythematous, well-demarcated, indurated plaques with white-silvery thick scales. These can be either asymptomatic or pruritic, and typically involve the extensor surfaces, gluteal, and sacral areas. Additionally, specific sites may impose a higher burden on the quality of life of patients, such as palmo-plantar surfaces, the scalp, facial area, and the nail apparatus [4][5][6]. Psoriatic arthritis (PsA), an inflammatory polymorphic arthritis, occurs in up to 20-30% of individuals diagnosed with psoriasis. The majority of cases are identified after (or concurrently with) psoriasis vulgaris (PV). In about half of patients, PsA progresses to a destructive erosive disease with associated functional impairment [3,[5][6][7]. Modern approaches to the treatment of psoriasis vary from molecular studies (to better understand pathogenic insights) to complex management in association with comorbidities' assessment to seek better outcomes [6,8].
Pathogenic mechanisms involve a dysregulation of the innate and adaptive immune systems, primarily a T helper 1 cell and T helper 17 cell/interleukin-23 (IL)-mediated immune response, which may also involve IFN-γ (interferon), TNF-α (tumor necrosis factor), IL-17A, IL-12, and IL-23 [6,9]. Triggers, such as infections or local trauma, lead stressed keratinocytes to release molecules. These may include fragments of self DNA, self RNA, and antimicrobial peptides such as cathelidicin LL37, which stimulates plasmacytoid dendritic cells [6,10]. These cells, through their secretion of IFN-α, activate myeloid dendritic cells which migrate to lymph nodes and present this still unknown antigen to naïve T lymphocytes [6]. The myeloid dendritic cells promote differentiation to T helper 1, T helper 17 and T helper 22 subsets via IL-12 and IL-23 secretion [6,11,12]. Subsequent inflammatory cascades lead to keratinocyte hyper-proliferation with abnormal keratinization, excessive angiogenesis, induction of endothelial adhesion molecules, and a cellular infiltrate comprised of macrophages, dendritic cells and IL-17 secreting cells. This creates a feedback loop between keratinocytes and the immune cells that sustain and promote psoriasis plaque formation [13,14].
ATD, with an estimated prevalence of 5% in general population, leads to two autoimmune disorders, situated at the end of the same spectrum: (1) chronic autoimmune (lymphocytic) Hashimoto's thyroiditis (HT), with a higher risk for hypothyroidism due (albeit not exclusively) to thyroid blocking antibodies, namely antithyroperoxidase antibodies (TPOAb) and antithyroglobulin antibodies (TgAb), respectively; (2) Graves' disease (GD), or Basedow-Graves' disease, caused by thyroid-stimulating immunoglobulin or thyroid-stimulating hormone (TSH) receptor antibodies (TRAb), the sole human antibody with stimulating effects [20][21][22][23]. ATD is related to a dysregulation of the immune system, with lymphocytic infiltration of the thyroid gland and associated increased production of autoantibodies. The exact pathogenesis remains an open issue, but both environmental factors (infections, withdrawal of glucocorticoid therapy, stress, etc.) and genetic factors (genes associated with human leukocyte antigen (HLA) system, AIRE gene, or encoding genes for selenoproteins, etc.) are potentially involved [24][25][26].

Aim
Our purpose was to overview clinical and pathogenic insights concerning psoriasis and thyroid comorbidities from a dual perspective (dermatologic and endocrine).

Methods
This was a narrative review of literature published in English between January 2016 and January 2023. We included clinically relevant, original studies in humans, with different levels of statistical evidence, starting from two keywords used in PubMed research: "psoriasis" and "thyroid". We identified 177 full-length papers and manually searched each of them in order to serve our purpose (Figure 1). immune system, with lymphocytic infiltration of the thyroid gland and associated increased production of autoantibodies. The exact pathogenesis remains an open issue, but both environmental factors (infections, withdrawal of glucocorticoid therapy, stress, etc.) and genetic factors (genes associated with human leukocyte antigen (HLA) system, AIRE gene, or encoding genes for selenoproteins, etc.) are potentially involved [24][25][26].

Aim
Our purpose was to overview clinical and pathogenic insights concerning psoriasis and thyroid comorbidities from a dual perspective (dermatologic and endocrine).

Methods
This was a narrative review of literature published in English between January 2016 and January 2023. We included clinically relevant, original studies in humans, with different levels of statistical evidence, starting from two keywords used in PubMed research: "psoriasis" and "thyroid". We identified 177 full-length papers and manually searched each of them in order to serve our purpose. (Figure 1)

Confirmatory Data of Association
Positive correlations between psoriasis (including the subgroup with PsA) and ATD and/or thyroid hormonal anomalies were identified in different studies, aiming to address the hormonal imbalance, the autoimmune background, or both. Of note, HT diagnostic is typically sustained based on positive serum antibodies, while associated thyroid functions may be hypothyroidic, thyrotoxic, or normal, depending on disease evolution and applied therapy. GD is usually associated with hyperthyroidism at first diagnosis, but the copresence of HT may induce hypo-or euthyroidism. Additionally, any thyroid dysfunction may be at the clinical or subclinical levels. Moreover, abnormal thyroid hormone levels might not necessarily be related to an autoimmune background [27].  Positive correlations between psoriasis (including the subgroup with PsA) and ATD and/or thyroid hormonal anomalies were identified in different studies, aiming to address the hormonal imbalance, the autoimmune background, or both. Of note, HT diagnostic is typically sustained based on positive serum antibodies, while associated thyroid functions may be hypothyroidic, thyrotoxic, or normal, depending on disease evolution and applied therapy. GD is usually associated with hyperthyroidism at first diagnosis, but the copresence of HT may induce hypo-or euthyroidism. Additionally, any thyroid dysfunction may be at the clinical or subclinical levels. Moreover, abnormal thyroid hormone levels might not necessarily be related to an autoimmune background [27]. Knowing these dynamic aspects, a cross-sectional analysis may not capture the evolutionary aspects and complex inter-relationships between these skin and endocrine disorders.
The most important studies, having confirmatory profiles with regard to thyroid involvement, in patients known with psoriasis, according to our methodology, were as follows. First, a prospective study conducted by Vastarella et al. [28] analyzed the prevalence of HT in subjects confirmed with two types of psoriasis: PsA (N1 = 108) and cutaneous psoriasis (PsC) (N2 = 100). They showed that HT-associated subclinical hypothyroidism was more frequent in the PsA group and the ratio of positive TPOAb was increased in PsA versus PsC (13.9% versus 2%, p = 0.0018, respectively; 25.9 versus 9%, p = 0.018). Additionally, thyroid anomalies were more often found in subjects with PsA with established disease (≥2 years) than early disease (p < 0.05), and in those with peripheral involvement, when compared to axial PsA (85.7% versus 14.3%, p < 0.05). However, in PsC category, psoriasis severity was similar regardless of the copresence of ATD. A greater inflammatory state in patients with PsA, compared to patients without joint involvement, could possibly represent a factor with which to aid in identifying thyroid anomalies [29]. Another factor that could explain the different degrees of prevalence of HT was the female predominance in the PsA group, in contrast to the PsC group (52.7% versus 37%) [28]. Generally, women are prone to any type of ATD, with a 4 to 10 times higher risk than males [30].
In a prospective longitudinal study, Fallahi et al. [31] followed patients with PsA, without evidence of thyroid dysfunction (N = 97) versus control (N = 97), for 92 months. The PsA group developed TPOAb positivity (p < 0.014) and hypothyroidism (p < 0.05) (N = 97) more quickly than controls (N = 97), but this was not true of hyperthyroidism. PsA patients with subclinical hypothyroidism, compared to PsA individuals without any thyroid disorder, had a longer course of disease (18 ± 17 versus 9 ± 9 years; p = 0.005) and exhibited polyarticular involvement (p < 0.05). Logistic regression identified statistically significant risk factors for developing hypothyroidism in the PsA group, as follows: female gender, positive TPOAb, and a small thyroid volume at cervical ultrasound. No association was found between thyroid hormones and/or antibodies levels and PsA-associated disease activity/severity [31].
As previously shown by a Rotterdam study [32], a systematic review of 7 case-control studies and a meta-analysis of 4 studies confirmed a higher risk of ATDs in subjects with psoriasis [33]. The analysis revealed a link between psoriasis and thyroid hormones anomalies, as well (hypothyroidism (OR = 1.34; 95% CI 1.16-1.54)), and hyperthyroidism (OR = 1.17; 95% CI 1.03-1.32) [33].
A retrospective study by Du et al. [34] evaluated the relationship between different types of psoriasis and thyroid anomalies in 469 patients with PP, EP, PsA, and PV, versus 200 psoriasis-free controls (sex-and age-matched subjects). Individuals with EP had decreased levels of free triiodothyronine (T3) or free thyroxine (T4), with normal TSH (χ 2 = 29.816, p < 0.001); patients with PP had decreased fT3 versus non-PP subtypes (p = 0.04); PsA patients had increased levels of TSH (p < 0.05). However, the levels of positive antibodies (TPOAb and TgAb) were similar between the studied subgroups and controls [34]. Another prospective study concerning different types of psoriasis included 63 patients with palmoplantar pustulosis and found a higher prevalence of thyroid disease in these individuals, compared to 34 subjects with PV (31.75% versus 13.51%; p = 0.0421) [35]. Another cross-sectional study on 102 persons suffering from palmoplantar pustulosis showed that comorbidities impacted the quality of life among them, with 16% suffering from ATD [36].
Another retrospective study by Namiki et al. [37] showed a higher rate of thyroid dysfunction in patients with generalized PP (GPP), when compared to PV and PsA (GPP versus PV, p = 0.0037; GPP versus PsA, p = 0.0348), with half of the thyroid anomalies being low T3 or T4 serum levels. The presence of thyroid dysfunction correlated with higher Psoriasis Area and Severity Index (PASI) scores of 21.0 ± 3.2 versus 13.5 ± 1.2 (Shapiro-Wilk test, p < 0.0001; respective Wilcoxon rank sum test, p = 0.0151) and increased C reactive protein (CRP) levels (5.56 ± 2.98 versus 0.73 ± 0.25 mg/dL; Shapiro-Wilk test p < 0.0001; Wilcoxon rank sum test p = 0.0069) [37]. However, the study indicated a higher prevalence of abnormal thyroid hormone profiles in men, as compared to women, which was opposed to most published data [28,30]. While no relationship was established between CRP levels and TSH, a negative correlation was observed between CRP and fT3, respectively, and fT4 (CRP versus TSH, r = -0.0504, p = 0.1777; CRP versus fT3, r = −0.4635, p = 0.0032; CRP versus fT4, r = 0.1242, p = 0.0181) [37].
Zheng et al. [38] published a retrospective study in 2020 on 201 patients with PV, PsA, GPP, and EP, along with 80 controls (individuals with noninflammatory skin conditions). The highest prevalence of thyroid dysfunction was found in the EP group (59.57%), followed by non-EP categories: 42.11% (GPP), 19.05% (PsA), and 18.99% (PV). The EP group was statistically significantly more affected than the PsA group (p < 0.001), but not the GPP group (p = 0.13). It was higher than the control group (p < 0.001) (GPP versus control (p = 0.005)). Two-thirds of the patients with psoriasis exhibited low levels of fT4, with normal TSH as the main abnormal hormonal finding. CRP levels were similar between psoriasispositive subjects displaying thyroid hormone anomalies and those with normal thyroid profiles [38]. It bears mentioning that the general endocrine populations' associations with various thyroid conditions do not typically associate anomalies with serum CRP levels except in subacute (viral) or acute (microbial) thyroiditis. That is why, from a strictly endocrine perspective, assessments of CRP add little value to our understanding of common mechanisms with psoriasis [39].
A meta-analysis from 2022, performed by Zhang et al. [44] and involving 253,313 subjects with psoriasis and 1,376,533 controls, showed an increased prevalence of ATDs in psoriasis group versus control (OR = 1.76, 95% CI 1.35-2.28, p < 0.01). When analyzing the prevalence of a specific ATD, HT was significantly more prevalent in patients with psoriasis than controls (OR = 1.88, 95% CI 1.50-2.35, p < 0.01), but not GD [44].
We identified one study on individuals with psoriasis comparing late onset (after the age of 40) with early onset (before the age of 40) cases (278, respectively, 62 individuals). A higher risk of autoimmune thyroiditis was revealed in first group (adjusted OR = 5.05; 95% CI, 1.62-15.7) [45].
Overall, associations between psoriasis, as a general condition as well as its different subtypes, and thyroid disorders, in terms of abnormal thyroid hormone levels and/or thyroid antibodies, were confirmed by these mentioned studies. The results were heterogenous [40][41][42][43]. The extent of statistical relevance varied with study design, enrolled population, specific endocrine assessments, and dermatologic evaluation (types of psoriasis, disease duration, score of activity/severity, PsA association, etc.). The duration of psoriasis disease increased the risk of detecting thyroid abnormalities. The most frequent associations were observed with HT, not GD, while the most frequent hormonal imbalance seemed to be hypothyrodism (sublinically, rather than clinically, manifested). The severity of psoriasis did not seem to correlate with the presence of thyroid dysfunction and/or autoimmunity in most studies [29,31], though some exceptions were reported [37,46] (Table 1). Abbreviations: aHR = adjusted Hazard Ratio; aOR = adjusted Odds Ratio; ATD = autoimmune thyroid disease; CI = confidence interval; EP = erythrodermic psoriasis; fT3 = free triiodothyronine; fT4 = free thyroxine; HT = Hashimoto's thyroiditis; N = number of patients; OR = odds ratio; PP = pustular psoriasis; GPP = generalized PP; PV = psoriasis vulgaris; PsC = cutaneous psoriasis; PsA = psoriatic arthritis; vs. = versus; years = y; TPOA = antithyroperoxidase antibodies; TgAb = antithyroglobulin antibodies; TSH = Thyroid Stimulating Hormone.

Studies with Inconsistent Correlations between Psoriasis and Thyroid Anomalies
A small case-control study evaluated associations between psoriasis and HT (N = 56 versus 54 controls); similar TSH and fT4 levels were found between the two studied groups. However, higher levels of prevalence of TPOAb and TgAb were observed in the psoriasis group than in the control group. There was also an increased rate of ultrasound findings suggesting ATDs, such as hypo-echogenicity (30.4% versus 9.3%, p = 0.02), high vascularity (35.7% versus 5.6%, p = 0.001), and pseudo-nodularity (16.1% versus 0%, p = 0.002). Severity of disease (PASI score) was not correlated with TPOAb or TgAb positivity [47], as in prior mentioned studies [30,31].
Hansen et al. [48] enrolled a previously-studied population from the Danish General Suburban Population Study [49]. Individuals with psoriasis (N = 1127) were matched (1:5) with healthy controls with regards to gender, age, body mass index, and smoking status. ATD and TPOAb were similar between the groups. Individuals with psoriasis had a higher total T3 (1.69 ± 0.32 versus 1.72 ± 0.33 nmol/L; p = 0.01), but similar levels of TSH and free T4. The exact mechanism behind high total T3 levels, along with normal TSH and total T4, in the studied population was not clearly understood [48]. No correlation was confirmed between psoriasis and thyroid involvement by Lai et al. [50], who analyzed a random population sample of 5560 responders from the U.S. National Health and Nutrition Examination Survey database between 2011 and 2012. Adjusting for confounding factors, such as body mass index, age, gender, smoking habits, and alcohol consumption, yielded results similar to several previous studies [50,51].
Vassilatou et al. [52] examined the prevalence of ATD in subjects with psoriasis (N = 114) in a prospective study (N = 286 age-and body mass index-matched controls, without a history of psoriasis, from areas with sufficient iodine intake). After defining HT as TPOAb and TgAb serum titers over 34 IU/mL and 115 IU/mL, respectively, and evaluating PASI scores, TSH, T3, T4, fT4, and antibody levels were similar between the groups. However, the authors confirmed female predominance by identifying an increased prevalence of HT in females in the control group (14.7% versus 4.9%), but not in the psoriasis groups (10.5% versus 9.6%) [52].
A study focusing on quality of life in patients with psoriasis (N = 74) showed a weak correlation with the presence of thyroid diseases (affecting 6.75% of them) [53]. Another retrospective, observational study showed that patients with plaque psoriasis with thyroid involvement were similar in age, gender, disease severity, and duration to those with normal thyroid profiles. In total, 10% of the entire cohort (N = 290) experienced a thyroid dysfunction (defined as a ≥10% variation in normal thyroid hormone values), while 13.5% of individuals with psoriasis had positive serum TPOAb [54]. Another small study (without a control group) showed that, among 48 patients with palmoplantar pustulosis, 12% had antibody-based thyroiditis [55]. The Mayo Clinic published a retrospective, uncontrolled study on 215 persons with palmoplantar pustulosis, and identified 18 subjects (8%) with thyroid diseases. This was less than expected, according to Olazagasti et al. [56] (Table 2). Thyroid hormones are critical regulators of development. They function at various levels, including the digestive system, cardiac and skeletal muscle, and brain; they also affect energy metabolism and overall homeostasis [57,58]. Skin is involved in thyroid hormone activity, signaling which hormones exert their roles through genomic mechanisms (i.e., by binding nuclear thyroid hormone receptors) as well as non-genomic pathways, involving cellular proteins such as membrane integrin, αvβ3, etc. [57][58][59]. Thyroid hormones are implicated in fetal epidermal differentiation, barrier formation, hair growth, keratinocyte proliferation, and modulation of keratin gene expression [57][58][59]. They induce keratinocyte hyper-proliferation through epidermal growth factor (EGF). Data have shown that antithyroid medications for hyperthyroidism (for example, propylthiouracil) exhibit antiproliferative effects, with beneficial effects on psoriasis plaques [60,61].
T-helper 1 lymphocyte dominant response, observed in psoriasis, determines a proinflammatory milieu, typically comprised of IFN-γ, TNF-α, and chemokines such as CXCL10 (a chemoattractant for neutrophils found in active psoriasis plaques) [64]. ATDs share a Th1 immune-mediated response with IFN-γ and IFN-γ dependent chemokines like chemokine (C-X-C motif) ligand (CXCL)10, involved in the pathogenesis of both GD and HT [5,64,65]. IL-17 of the IL-23/Th17 axis, as seen in psoriasis, plays an important role in ATD, indicating another potential level of connection between the two conditions [42,43,66]. A shift from a Th-1 to a Th-2 immune response through monocyte chemoattractant protein-1 (CCL2) and macrophage-derived chemokine CCL22 has been described in both PsA and GD [58,67,68].

Recent Pathogenic Landscape
The latest data concern new pathogenic pathways to potentially connect psoriasis to different anomalies at the thyroid level, either through direct links or indirect associations with other conditions, especially those with a higher risk for developing both skin and thyroid diseases of the autoimmune type [69][70][71][72][73][74].
Jiang Y. et al. published a study in 2022 regarding the Psoriasis susceptibility 1 candidate 1 (PSORS1C1) gene, which has been associated with various autoimmune conditions, including rheumatoid arthritis, ankylosing spondylitis, and systemic lupus erythematosus. This case-control study involved 1065 patients (Chinese Han participants) with ATD and 943 healthy controls, and analyzed 4 single nucleotide polymorphisms (SNPs): rs3130983, rs3778638, rs3815087, and rs4959053. They determined that rs3778638 genotypes were statically significant different from ATD and control (p = 0.046), but the rs3778638 genotype was only correlated with GD (p = 0.039), not with HT (p = 0.141) [75]. Tumor necrosis factor α-induced protein 3 (TNFAIP3) gene was recently incriminated in a large spectrum of autoimmune disorders, including ATD and psoriasis [76].
Another common pathogenic mechanism concerns thyroid hormone signaling, potentially involved in the microRNA-ome underlying psoriatic skin [77]. Anomalies of apoptosis affecting keratinocyte proliferation in psoriasis have been described in ATD, as well [78]. Defects of apoptotic pathways might represent a link to metabolic syndrome in PV and hypothyroidism [79].
A recent hypothesis suggested that viral infections in pregnant females could trigger autoimmune conditions early in life, including type 1 diabetes mellitus, HT, and psoriasis [80]. Another clinical circumstance for developing both ATD and psoriasis was found in HIV-positive and hepatitis C-positive patients to whom prolonged survival was recently registered due to advance of antiviral drugs. A higher risk of developing different autoimmune disorders was identified [81,82]. Globally, one-third of adults presenting common variable immunodeficiencies are admitted for autoimmune comorbidities, including psoriasis and thyroiditis of different kinds [83]. Another clinical entity that may be associated with a higher risk of psoriasis and HT is idiopathic retroperitoneal fibrosis, an immune-mediated condition involving a large frame of chemokines (e.g., CXCL12 and CCL11) and cytokines (e.g., IL-6, IL-12, and IL-13) [84]. Another clinical example is primary biliary cholangitis; a study from 2021 (N = 1554 patients with this condition) showed that ATD coexisted in 10.6% of cases, while 1.5% had psoriasis [85].
Moreover, both HT and psoriasis have been listed as autoimmune complications triggered by infection with Helicobacter pylori, in association with positive gastric autoim-munity [86]. Additionally, the prescription of proton pump inhibitors could exacerbate autoimmunity (including HT and psoriasis) under certain circumstances [87].
A multimodal approach was proposed, involving thyroid hormones and vitamin D as players in psoriasis lesions progression [89]. One small study on 30 patients with psoriasis and 30 healthy controls showed a higher serum TSH value in the psoriasis group (p < 0.05), but with intra-normal TSH variations and a negative correlation between serum 25-hydroxyvitamin D and PASI [90]. Another endocrine component of psoriasis and disorders associated with an abnormal thyroid profile, like thyroid eye disease (in GD), potentially involves insulin-like growth factor (IGF) axis [91].
One of the most recent pathogenic factors is represented by COVID-19 infection, which seems to trigger various panel of single or poly-autoimmunity, potentially as part of long COVID-19 syndrome [92][93][94]. We identified a single case to highlight this combination: a previously healthy teenager with negative family history for autoimmunity who developed GD and PV after infection with COVID-19 [95]. Further data are expected to highlight autoimmunity following COVID-19 ( Figure 2  Of note, major histocompatibility complex (MHC) loci have been reported in relation with a myriad of autoimmune disorders, including many at the skin and thyroid levels. Antigen presentation by MHC-II is related to the immune response, including self-tolerance. Anomalies of MHC are connected to triggering autoimmune responses, Of note, major histocompatibility complex (MHC) loci have been reported in relation with a myriad of autoimmune disorders, including many at the skin and thyroid levels. Antigen presentation by MHC-II is related to the immune response, including self-tolerance. Anomalies of MHC are connected to triggering autoimmune responses, involving T cells at many levels, as well as immune recognition, comprising both MHC-I and MHC-II. For instance, genetic susceptibility to PsA includes, among others, MHC-I-associated gene polymorphisms like IL12B, TYK2, etc., while haplotypes such as DR3-DQ2 and DR4-DQ8 are prone to autoimmune thyroiditis [96][97][98][99]. On the other hand, another modern field of common pathogenic interest for many autoimmune diseases, including psoriasis and ATD, bears mentioning: gut microbiota. Anomalies of intestinal metabolites or abnormal interactions between intestinal microorganisms and human host systems might be a cornerstone factor contributing to autoimmune responses [100]. In many skin diseases with autoimmune backgrounds, dual interplays between the immune system, which modulates normal dermatological processes, and intestinal microorganisms (underlying dysbiosis) have been reported [101,102]. Both microbiomes and macrobiomes have been described in terms of their relationships to developing psoriasis [103]. Moreover, Chao1 (which is the index of microflora richness) has been found at increased levels in HT and decreased levels in GD [100,104]. Additionally, T3, by activating its receptor α1 at the intestinal level, represents a contribution to epithelial homeostasis, while metabolite-derived short-chain fatty acids modulate thyroid function [105,106].
With regard to assessing psoriasis in endocrine patients, we identified 3 studies, according to our methodology. Fallahi et al. [117] conducted a prospective study on 3069 individuals with autoimmune thyroiditis and found a higher prevalence of PsA in these patients (p < 0.0180) when compared to controls. However, no statistically significant evidence was attained for the PsC subgroup (p = 0.6237) [117]. Kelada et al. retrospectively studied a population diagnosed with thyroid eye disease (GD-associated autoimmune orbitopathy) between 2011 and 2019 (N = 267). Of these, 13.9% displayed non-thyroid autoimmune comorbidities, associated with a more severe/active eye presentation, and 3% of subjects had psoriasis [118]. Takir et al. [119] examined, in a cross-sectional study, 300 persons with thyroid diseases (N1 = 173 with autoimmune disorders, N2 = 127 with non-autoimmune conditions) versus 100 healthy controls. Psoriasis was identified as statistically significantly more frequent in N1 than N2 (p = 0.001), suggesting that patients under endocrine surveillance were more likely to have psoriasis if their thyroid condition were autoimmune [119] (Table 3).

Thyroid Cancer in Patients with Psoriasis
Patients with psoriasis are at higher risk of some cancers, and some safety concerns arise in relation to thyroid cancer, as well. However, the fact that patients with psoriasis display an increased risk of thyroid malignancy remains controversial [120,121]. As mentioned, one single study identified a higher risk of nontoxic goiter in PsA [40]. Of note, 5% of the general population (depending on age) has a thyroid nodule, while thyroid cancer represents the most frequent endocrine neoplasia, with an age-dependent prevalence of almost 5% of thyroid nodules [122,123].
We identified only one study which examined thyroid cancer in individuals with psoriasis. This was a nested case-control study (Korean National Health Insurance Service-Health Screening Cohort) that included individuals 40 years and older (N = 6822 subjects with thyroid cancer versus 27,288 controls). A previous history of psoriasis was similar between studied groups (OR = 1.02; 95% CI, 0.85-1.22). The subgroup without hypothyroidism had a higher rate of thyroid malignancy associated with psoriasis (overlapweighted OR = 1.29; 95% CI 1.06-1.57, p = 0.012) while those with hypothyroidism showed a low rate (overlap-weighted OR = 0.59; 95% CI 0.37-0.96, p = 0.034); no other correlations were identified [121] (Table 4). Table 4. Studies concerning thyroid cancer and psoriasis [121]. Based on these findings, we concluded that we did not have sufficient data to support an association between thyroid cancer and psoriasis.

Psoriasis and Thyroiditis among Immune Side Effect of Anti-Cancer Drugs
Medication used in psoriasis treatment could contribute to the development of immune and autoimmune events with concomitant anticancer drugs. On the other hand, both ATD and psoriasis have been incidentally reported in oncologic patients who developed immune/autoimmune side effects to modern categories of immune checkpoint inhibitors [124,125]. Pre-existent autoimmune conditions increase the risk of developing immune side effects while being treated with anticancer medication [126]. Several studies have observed exacerbation of psoriasis and ATD in oncologic patients [127][128][129][130][131] (Table 5). Table 5. Studies in oncologic patients affected by psoriasis and ATD due to anticancer drugs (from 2016 to the most recent data) [127][128][129][130][131].

Studied Population
Anti-Cancer Drug Effects The largest study, as of 2016, on ipilimumab treatment for melanoma in patients with preexistent autoimmune conditions, showed that one-third of the subjects suffered an exacerbation of prior comorbidities; one-third of these exacerbations were reversible upon glucocorticoid exposure [131].
Studies published within the last few years confirmed that previous psoriasis or ATD may worsen in response to immune checkpoint blockade. In cases with thyroiditis, glucocorticoid therapy and antithyroid medication for hyperthyroidism or, alternatively, substitution with levothyroxine for hypothyroidism, is required, sometimes for the remainder of a patient's life [129]. A meta-analysis from 2021 on randomized, placebo-controlled studies, including oncologic patients under immune checkpoint inhibitors (N = 5560), showed an incidental rate of thyroiditis (0.86%), and identified one new case with psoriasis [128].

Subacute Thyroiditis in Patients Treated for Psoriasis
Anti-psoriasis medications, as contributors to thyroid anomalies, include anti-TNF-α drugs; their contributions remain a matter of debate [132]. Subacute thyroiditis, despite being a classically viral condition, has been reported in circumstances involving an abnormal cytokine profile [133]. Biological medications for skin conditions might play a role in triggering flare-ups of colloidal pools filled with thyroid hormones T3 and T4, as seen in thyroiditis-associated thyrotoxicosis [134,135].
For instance, there was a case of a 32-year-old male with confirmed thyrotoxicosis being treated with ustekinumab (monoclonal antibody against IL-12/23). He relapsed twice after reinitiation of the drug [136] Another case (published in 2021) introduced a 71-year-old male patient with PsA who was treated with secukinumab (IL-17A inhibitor), which was later switched to adalimumab (TNF-α inhibitor), while developing subacute thyroiditis. Therapy with prednisolone was necessary. Consecutive treatment with ixekizumab (IL-17A inhibitor) controlled PsA and did not induce a relapse of thyroiditis [137]. Another case of adalimumab-associated subacute thyroiditis was reported in 2017 [138]. Cytomegalovirusinduced subacute thyroiditis was reported in 2016 in a patient with PsA treated with infliximab [139].

Pediatric Population
As mentioned, most of the data included adult patients. However, APS can be associated with HT, especially type 3, and psoriasis has been reported, extremely rarely, in adults and in children [140,141].
Moreover, results from the International Pharma-Child Registry confirmed that both psoriasis and ATD were among the most frequent autoimmune disorders in populations diagnosed with juvenile idiopathic arthritis. Positive familial autoimmune diseases have been determined to be a risk factor for developing this type of arthritis [142]. Concerning the burden of autoimmune comorbidities in 79 individuals diagnosed with juvenile idiopathic arthritis (aged between 0 and 21 years), a rate of 10% (N = 8) was identified with ATD, while approximatively 4% had psoriasis [143]. Cumulative incidence of ATD was 36%, with mean age at diagnosis of 13.2 years. First-degree relatives were more affected by autoimmune comorbidities than second-degree relatives (16.7% versus 11%) [143].

Interventional Considerations
Interventional studies addressing psoriasis and ATD remain an open issue. Some nutraceutical supplements could improve both psoriasis and HT [144]. Among these, vitamin D supplementation and omega 3 fatty acid supplementation could potentially reduce the burden of autoimmune diseases, but only upon exposure to certain doses and only for a limited period of time [145]. It has not been determined whether or not hypo-or hyperthyroidism in subjects with psoriasis improves skin condition. As has been pointed out, individuals with the most severe psoriasis cases may not necessarily be those displaying a pathological profile, with respect to the thyroid gland.
Gluten-free diets have yet to be proven useful in ameliorating psoriasis and ATD, as suggested by some authors. Based on current data, unless celiac disease is co-present, this routine recommendation is not supported [146]. Additionally, vegan and vegetarian habits might trigger phytophotodermatitis; thus, diet could play an important role in modulating thyroid profiles and in psoriasis therapies [147]. The association with celiac disease is not rare; one retrospective study on 749 patients with this digestive condition showed a prevalence of 19.9% for ATD, 14.7% for hypothyroidism, and 2.7% for psoriasis [148]. Additionally, a case-controlled study on 341 individuals with celiac disease showed that 26.6% of them had at least one autoimmune disease (autoimmune thyroiditis, 48%; psoriasis, 17%) [149]. Another case-controlled study on 255 persons with celiac disease (versus 250 controls) showed that 35.2% of them had autoimmune disorders. HT was the most frequent comorbidity (24.3% versus 10%), while the second most prevalent was psoriasis (4.3% versus 1.6%) [150]. Another endocrine condition that can predispose someone to all three mentioned autoimmune diseases is Turner syndrome. In patients suffering from Turner syndrome, lifelong surveillance-including monitoring for autoimmune complications-is necessary [151,152].
Future studies will likely continue the search for an ideal drug to concomitantly target disorders like psoriasis and ATD.

From Today to Tomorrow
Strategically searching for thyroid anomalies in patients confirmed with psoriasis, either on clinical or molecular levels or using genetic findings, also remains an open issue. The exact subgroup of individuals that should be candidates for strategic endocrine assessments has not been determined. The minimum panel of thyroid assays includes: TSH, freeT4 (perhaps also freeT3), and TPOAb (perhaps also TgAb). We followed 4 clusters of conditions: thyroid dysfunction, autoimmunity, thyroid cancer, and subacute thyroiditis. The fact that psoriasis and ATD are related to the immune-based side effects of modern anticancer drugs, namely immune checkpoint inhibitors, is a new piece of information in this field (Figure 3). TSH, freeT4 (perhaps also freeT3), and TPOAb (perhaps also TgAb). We followed 4 clusters of conditions: thyroid dysfunction, autoimmunity, thyroid cancer, and subacute thyroiditis. The fact that psoriasis and ATD are related to the immune-based side effects of modern anticancer drugs, namely immune checkpoint inhibitors, is a new piece of information in this field ( Figure 3). To our knowledge, this was one the most complex analyses of published studies concerning a dermatological and endocrine dual perspective. Overall, we identified 16 confirmatory studies, but with heterogeneous data. PsA had a higher risk of positive TPOAb (25%) versus PsC or control, as well as an increased risk of thyroid dysfunction versus control. Hypothyroidism was the most frequent type of dysfunction (subclinical rather than clinical). Thyroid anomalies were correlated with >2-year disease duration, peripheral > axial and polyarticular involvement. With a few exceptions, female predominance was observed. Hormonal imbalances included, most frequently, low T4 and/or T3 with normal TSH, followed by high TSH; only one study observed higher total To our knowledge, this was one the most complex analyses of published studies concerning a dermatological and endocrine dual perspective. Overall, we identified 16 confirmatory studies, but with heterogeneous data. PsA had a higher risk of positive TPOAb (25%) versus PsC or control, as well as an increased risk of thyroid dysfunction versus control. Hypothyroidism was the most frequent type of dysfunction (subclinical rather than clinical). Thyroid anomalies were correlated with >2-year disease duration, peripheral > axial and polyarticular involvement. With a few exceptions, female predominance was observed. Hormonal imbalances included, most frequently, low T4 and/or T3 with normal TSH, followed by high TSH; only one study observed higher total T3. The highest ratio of thyroid involvement in dermatologic subtypes was 59% for EP. An analysis of specific psoriasis subtypes and associated thyroid anomalies, according to prior mentioned studies, can be found in Figure 4. . Analysis of specific psoriasis subtypes and thyroid anomalies according to our methodology (please see references in main text above). References [28,29,34,35,37,38] are pointed out in each box. Abbreviations: EP = erythrodermic psoriasis; PsA = psoriatic arthritis; PsC = cutaneous psoriasis; PP = pustular psoriasis; PV = psoriasis vulgaris; GPP = generalized PP; TPOAb= antithyroperoxidase antibodies; TgAb = antithyroglobulin antibodies; HT = Hashimoto's thyroiditis.
Most studies found no correlation between thyroid anomalies and psoriasis severity. Statistically significant ORs for hypothyroidism: 1.34-1.38; hyperthyroidism: 1.17-1.32 (fewer studies than hypothyroidism); ATD: 1.42-2.05; HT: 1.47-2.09; GD: 1.26-1.38 (fewer studies than HT). Additionally, 8 studies had inconsistent or no correlations or weak statistical power concerning associations between thyroid autoimmunity or dysfunction and psoriasis. The lowest rate of thyroid involvement was 8% (uncontrolled studies). Other data included: 3 studies on patients with thyroid autoimmune conditions looking for psoriasis and one study on psoriasis and thyroid cancer. ICP was shown to possibly exacerbate prior ATD and psoriasis or to induce them both de novo (5 studies). At the case report level, studies examined subacute thyroiditis due to biological medication (ustekinumab, adalimumab, infliximab). Further well-designed, longitudinal controlled studies are necessary.

Conclusions
Thyroid involvement in patients with psoriasis remains an open question. However, observed significant data that confirmed a higher risk positive antibodies and/or thyroid dysfunction, especially hypothyroidism, in subjects with psoriasis. Further study, and greater awareness, is necessary to improve overall outcomes for patients. Debate continues concerning the exact profile of individuals, diagnosed with psoriasis, who should undergo endocrinological screening. Uncertainty exists regarding dermatological subtypes, disease duration and activity, and other synchronous (especially autoimmune) Figure 4. Analysis of specific psoriasis subtypes and thyroid anomalies according to our methodology (please see references in main text above). References [28,29,34,35,37,38] are pointed out in each box. Abbreviations: EP = erythrodermic psoriasis; PsA = psoriatic arthritis; PsC = cutaneous psoriasis; PP = pustular psoriasis; PV = psoriasis vulgaris; GPP = generalized PP; TPOAb= antithyroperoxidase antibodies; TgAb = antithyroglobulin antibodies; HT = Hashimoto's thyroiditis.
Most studies found no correlation between thyroid anomalies and psoriasis severity. Statistically significant ORs for hypothyroidism: 1.34-1.38; hyperthyroidism: 1.17-1.32 (fewer studies than hypothyroidism); ATD: 1.42-2.05; HT: 1.47-2.09; GD: 1.26-1.38 (fewer studies than HT). Additionally, 8 studies had inconsistent or no correlations or weak statistical power concerning associations between thyroid autoimmunity or dysfunction and psoriasis. The lowest rate of thyroid involvement was 8% (uncontrolled studies). Other data included: 3 studies on patients with thyroid autoimmune conditions looking for psoriasis and one study on psoriasis and thyroid cancer. ICP was shown to possibly exacerbate prior ATD and psoriasis or to induce them both de novo (5 studies). At the case report level, studies examined subacute thyroiditis due to biological medication (ustekinumab, adalimumab, infliximab). Further well-designed, longitudinal controlled studies are necessary.

Conclusions
Thyroid involvement in patients with psoriasis remains an open question. However, observed significant data that confirmed a higher risk positive antibodies and/or thyroid dysfunction, especially hypothyroidism, in subjects with psoriasis. Further study, and greater awareness, is necessary to improve overall outcomes for patients. Debate continues concerning the exact profile of individuals, diagnosed with psoriasis, who should undergo endocrinological screening. Uncertainty exists regarding dermatological subtypes, disease duration and activity, and other synchronous (especially autoimmune) conditions.

Conflicts of Interest:
The authors declare no conflict of interest.