Psoriasis, Psoriatic Arthritis, and Thyroid Autoimmunity

Psoriasis (PsO) is a chronic relapsing/remitting autoimmune skin disease, associated with an increased risk of other autoimmune disorders. Psoriatic arthritis (PsA) is a chronic inflammatory arthritis occurring approximately in 30% of PsO patients. Sporadic cases of association between PsO and autoimmune thyroid disorders (AITDs) have been reported. However, two different recent studies did not find any association between them. In patients with PsO and PsA, an association with AITD has been shown by most of the studies in adults, but not in the juvenile form. In PsA women and men, thyroid autoimmunity [positive antithyroid peroxidase (AbTPO) antibodies, hypoechoic thyroid pattern] and subclinical hypothyroidism were more prevalent than in the general population. An association has been shown also in patients with PsO, arthritis, and inflammatory bowel disease, who have more frequently AITD. A Th1 immune predominance has been shown in early PsO, and PsA, with high serum CXCL10 (Th1 prototype chemokine), overall in the presence of autoimmune thyroiditis. This Th1 immune predominance might be the immunopathogenetic base of the association of these disorders. A raised incidence of new cases of hypothyroidism, thyroid dysfunction, positive AbTPO, and appearance of a hypoechoic thyroid pattern in PsA patients, especially in women, has been shown recently, suggesting to evaluate AbTPO levels, thyroid function, and thyroid ultrasound, especially in PsA women. Thyroid function follow-up and suitable treatments should be performed regularly in PsA female patients at high risk (thyroid-stimulating hormone within the normal range but at the higher limit, positive AbTPO, hypoechoic, and small thyroid).

of elbows and knees, and also on scalp, palms of hands, and soles of feet. Psoriatic nail dystrophy is usually present in fingernails and toenails and can be an isolated sign. A genetic predisposition is very important in the pathogenesis of PsO; however, environmental factors can activate the disease (1). The skin epidermal layer grows rapidly in PsO (4), determining an abnormal production and an excess of skin cells (5), that are replaced in 3-5 days in PsO (while commonly every 28-30 days) (6). These events are probably induced by the premature keratinocytes maturation, induced by the inflammatory cascade in the dermis (7). The immune competent cells go from dermis to epidermis and release different inflammatory cytokines [interleukin (IL)-1β, interferon (IFN)-γ, tumor necrosis factor-α, chemokine (C-X-C motif) ligand (CXCL)10, IL-6, IL-22] (8). In PsO, DNA can stimulate the dendritic cells, to produce IFN-α. The secretion of such inflammatory cytokines leads to stimulate the proliferation of keratinocytes (8).
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis that has a variable clinical presentation and occurs approximately in 30% of PsO patients (7,9,10). PsA typically affects the joints of the fingers and toes, and it is characterized by a painful inflammation of the joints and surrounding connective tissue. This process results in a sausage-shaped swelling of the fingers and toes called dactylitis (9). PsA can also affect the hips, spine (spondylitis), knees, and sacroiliac joint (sacroiliitis), and any other joint (11). Dermatologic manifestations of PsO appear before the manifestations of arthritis in about 75% of patients (10).
Psoriasis is associated with an increased risk of other autoimmune disorders like ulcerative colitis, Crohn's disease, and autoimmune thyroiditis (AT) too (12).
Here, we review the scientific literature about PsO, PsA, and the possible association with autoimmune thyroid disorders (AITDs).

PsO, PsA, AnD AiTD
Few case reports initially reported an association of PsO and Hashimoto's thyroiditis (13,14) (Table 1). A first systematic study by Bianchi et al. (15) evaluated thyroid volume and function and the prevalence of anti-microsome and anti-thyroglobulin antibodies (AbTg) in 42 patients with PsA, versus 52 normal subjects, as controls. The average thyroid volume, measured at ultrasounds, was increased in comparison to controls. Patients with PsA had a raised prevalence of anti-microsome antibodies; thyroid involvement was confined to patients with active disease. These results suggested a significant thyroid involvement in PsA patients. However, the study was basically a retrospective study, and it did not specify the selection criteria of the patients (15).
A second study evaluated the prevalence of thyroid disorders in PsA patients, conducting a complete thyroid work-out in 80 PsA patients, versus control subjects extracted (1:5) from the general population (matched by age and gender), and 112 patients with rheumatoid arthrtitis (RA) (with similar iodine intake). PsA women had significantly more frequently a hypoechoic thyroid pattern, antithyroid peroxidase antibodies (AbTPO), and subclinical hypothyroidism than control women, with a frequency comparable to that in RA patients (hypoechoic thyroid 31, 16, and 36%; positive AbTPO titer 28, 12, and 31%; subclinical hypothyroidism 25, 8, and 12%, respectively). PsA and RA men showed more frequently hypoechoic thyroid pattern and positive AbTPO than control subjects (hypoechoic thyroid 16, 10, and 3%; positive AbTPO titer 14, 5, and 2%, respectively). PsA patients with subclinical hypothyroidism had a longer disease duration (years; 19 ± 15 versus 11 ± 8, p = 0.03) and polyarticular involvement (p ≤ 0.05) than euthyroid PsA patients. Therefore, a significantly higher prevalence of thyroid autoimmunity (positive AbTPO, hypoechoic thyroid pattern) in PsA men and women, and of subclinical hypothyroidism in PsA women, than in the general population were evidenced (12). Conversely, a subsequent study investigated the frequency of rheumatic diseases in 65 patients (56 F, 9 M), suffering from AITD; antinuclear antibody and rheumatoid factor levels were also measured. Various rheumatic disorders were detected in 40 (62%) of patients with AITD: the most frequent were fibromyalgia, osteoarthritis, keratoconjunctivitis sicca, and xerostomia. Autoimmune diseases were detected in 10 patients with AITD, and among them also PsO and PsA (19). A further study (20) evaluated the frequency of AITD in 80 children with juvenile idiopathic arthritis (JIA) (27 oligoarticular, 26 polyarticular, 17 enthesitis-related, 6 systemic, and 4 PsA), versus 81 healthy control subjects, matched by age and gender. AITD were found in four patients in the JIA group (5%). No significant difference between the study and control groups was observed in the frequency of circulating antithyroid antibodies, or AT, suggesting that in JIA there is no association with AITD (20).
A further study evaluated thyroid autoimmunity in 105 patients with PsO (without PsA), versus 96 sex-and agematching controls (with tinea pedis). The levels of free thyroxine (FT4) resulted significantly increased in the PsO group; however, AbTPO and AbTg levels were not significantly different between the two groups. The study showed that the serum FT4 levels can increase in psoriatic patients. However, thyroid-stimulating hormone (TSH), FT4, or FT3 were not reported. Furthermore, an increase of FT4 should be related to TSH decreased levels, however any correlation was reported (16).
The association between PsO and inflammatory bowel disease (IBD) has been previously reported, even if potential associated comorbidities are not clear. A study (21) examined comorbidities in 146 patients diagnosed with both PsO and IBD, in comparison with those diagnosed with PsO-only (146, matched by gender, ethnicity, and age). Patients with both PsO and IBD (versus PsO-only) had significantly higher rates of hepatitis (6.2 versus 0.7%), AT (6.8 versus 2.1%), and diabetes (26.77 versus 11.0%), and 60 (41.1%) were diagnosed with seronegative arthritis, suggesting that patients with both PsO and IBD have more frequently AITD and arthritis (21).
The prevalence of 12 autoimmune diseases was also evaluated in 25,885 people extracted from the general population in Sardinia (22). A high prevalence was observed for RA, ulcerative colitis, Crohn's disease, type 1 diabetes, systemic lupus erythematosus, celiac disease, myasthenia gravis, systemic sclerosis, multiple sclerosis, Sjogren's syndrome, PsO/PsA (939 cases), and AT (2,619 cases). The statistical analysis of the comorbidity of autoimmune diseases shows that the number of people with more than one autoimmune disease was significantly higher than the expected number, both in women and men (22).
Another study (17) evaluated prospectively 114 PsO patients with disease duration of 5-38 years, 30 of them with PsA, in comparison with 286 age-and body mass index-matched subjects. No difference in the prevalence of AT between PsO patients and controls (20.2 versus 19.6%) was present. The prevalence of AT in male and female PsO patients was similar (9.6 and 10.5%, respectively) unlike the increased, as expected, prevalence in female versus male controls (14.7 versus 4.9%). Detected cases with hypothyroidism due to AT were similar in PsO patients and controls (7.9 and 7.0%, respectively). However, the number of patients with PsA was low (23) and not sufficient to a reliable evaluation of AITD in these last patients (17).
Conversely, a subsequent study evaluated prospectively the prevalence of other autoimmune disorders in outpatient clinic in 3,069 consecutive patients with diagnosed chronic AT, with respect to two age-and sex-matched control groups: (a) a control group of 1,023 subjects, extracted from a random sample of the general population without thyroid disorders and (b) 1,023 patients with non-toxic multinodular goiter drawn by the same random sample of the general population, with similar iodine intake. The results of our study demonstrated a significant increase of the prevalence of PsA in AT patients (24).
A more recent study (18) aimed to assess the incidence of new cases of clinical and subclinical thyroid dysfunction (TD) in a broad group of PsA patients versus a control group, matched by age and gender with a similar iodine intake. PsA patients with TD were excluded first, and new cases of thyroid disorders were evaluated in 97 PsA patients and 97 matched controls (median follow-up of 74 months in PsA versus 92 in controls). A raised rate of new cases of hypothyroidism, TD, positive AbTPO, and appearance of a small hypoechoic thyroid pattern in PsA, especially in female gender, compared to controls has been evidenced. Risk factors in female gender for the development of TD were TSH within the normal range but at the higher limit, positive AbTPO, and small thyroid volume (18).
Interferon-γ and Th1 cytokines/chemokines are involved in the pathogenesis of PsO. Activated T cells and HLA-DR keratinocytes have been shown in active plaques (25). It has been shown that CXCL10, the Th1 prototype chemokine, and its receptor (CXCR)3 are present in keratinocytes and in the dermal infiltrate derived from active psoriatic plaques and that effective treatment of active plaques decreased the expression of CXCL10. Elevated circulating CXCL10 has been shown in PsO patients (25)(26)(27)(28). The cellular infiltrate in acute plaques is constituted by 5-8% CD3(−)CD56(+) NK cells, as indicated by immunohistochemical techniques, especially localized in the mid and papillary dermis. NK lymphocyte migration toward CXCL10 is involved in the pathogenesis of PsO (27).
CXCL10 is a determinant chemoattractant for neutrophils, and an elevated infiltration and microabscess formation by neutrophils is a characteristic PsO feature. Different papers have shown a critical pathogenic role of neutrophils in PsO, particularly in the first phases, leading to hypothesize that blocking neutrophil function could have therapeutic effectiveness in this disease (23,29,30).
Also, in PsA patients, high levels of CXCL10 are observed in synovial fluid, and in circulation. Th1 cells immune predominance has been also shown at the beginning of the disease, with a subsequent later decline in long-lasting PsO or PsA, suggesting a shift from Th1 to Th2 immune response in long duration diseases (31)(32)(33).
Serum levels of CXCL10 (the Th1 prototype chemokine) and CCL2 (the Th2 prototype chemokine) were measured in 37 patients with PsA without AT (PsA) and 28 with AT (PsA + AT), and in gender-and age-matched controls. The results of the study demonstrated higher circulating CXCL10 and CCL2 in PsA patients than in control subjects. Furthermore, serum CXCL10 (but not CCL2) levels in PsA patients were significantly higher in the presence of AT (36). These data suggested that a Th1 immune predominace, both in PsA such as in AT, might be the immunopathogenetic base of the association of these diseases.

COnCLUSiOn
Psoriasis is associated with an increased risk of other autoimmune disorders like ulcerative colitis, Crohn's disease, and celiac disease (37). Sporadic cases of association of PsO and AITD have been reported. However, two different recent studies did not find any association between PsO and AITD.
Psoriatic arthritis is a chronic inflammatory arthritis that occurs approximately in 30% of PsO patients. In patients with PsO and PsA, an association with AITD has been shown by most of the studies in adults, but not in the juvenile form. In PsA women and men, thyroid autoimmunity (positive AbTPO antibodies, hypoechoic thyroid pattern) and subclinical hypothyroidism were more prevalent than in the general population. An association has been shown also in patients with PsO, arthritis, and IBD who have more frequently AITD.
A Th1 immune predominance has been shown in early PsO, and PsA, such as in AT, with high circulating levels of the Th1 prototype chemokine CXCL10 overall in the presence of the association with AT. These data suggest that this Th1 immune predominance might be the immunopathogenetic base of the association of these disorders.
A very recent longitudinal study in PsA patients has shown a raised incidence of new cases of hypothyroidism, TD, positive AbTPO, and appearance of a small and hypoechoic thyroid in PsA, especially in female gender, compared to controls. Risk factors in female gender for the development of TD are TSH within the normal range but at the higher limit, positive AbTPO, and small thyroid volume, suggesting to evaluate AbTPO levels, thyroid function, and thyroid ultrasound, especially in PsA women. Thyroid function follow-up and suitable treatments should be performed regularly in PsA female patients at high risk TSH within the normal range but at the higher limit, positive AbTPO, hypoechoic, and small thyroid.
However, studies in larger number of patients are required to evaluate if routine thyroid screening could be beneficial for PsO patients.

AUTHOR COnTRibUTiOnS
IR, FR, SB, RV, AA, PF, and SMF gave substantial contribution in the conception and design of the work, and in writing the paper; gave the final approval of the version to be published; agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. AA and SB revised it critically for important intellectual content.