Autoimmune thyroiditis in psoriatic disease

Objectives. To assess autoimmune thyroiditis prevalence in subclinical and clinical psoriatic arthritis (PsA). Materials and methods. 45 female adult Egyptian patients with psoriatic disease were classified into 3 equal groups: PsA, subclinical PsA, and psoriasis. A full assessment was done including Health Assessment Questionnaire, Psoriasis Area Severity Index (PASI), Leeds Enthesitis Index (LEI), PsA disease activity score (DAPSA), MAdrid Sonographic Enthesitis Index (MASEI), thyroid hormones (TSH, FT4, and FT3), thyroglobulin and thyroid peroxidase antibodies (Tg and TPO Abs), and thyroid ultrasound. Results . Thyroid abnormalities prevalence was: 33.3% with subclinical hypothyroidism, 80% with positive TPO Ab, and 46.7% with positive Tg Ab in PsA group, 26.7% with subclinical hypothyroidism, 60% with positive TPO Ab, and 33.3% with positive Tg Ab in subclinical PsA group and none in psoriasis group. PsA patients had higher TPO Ab levels compared to psoriasis patients with high statistical significant difference and lower FT3 levels compared to psoriasis patients with statistical significant difference. In subclinical PsA group, MASEI was positively correlated with TPO Ab with high statistical significance and with FT3 and Tg Ab with statistical significance, FT4 was negatively correlated with LEI with high statistical significance, and FT4 was correlated with PASI with statistical significance. In PsA group, TPO Ab was correlated with DAPSA with statistical significance. Conclusions . Autoimmune thyroiditis is more common in PsA than subclinical PsA patients. PsA patients are advised to be tested for TPO and Tg Abs. Musculoskeletal ultrasound is a screening tool to detect enthesitis in psoriasis patients.


INTRODUCTION
Psoriasis is a chronic inflammatory multifactorial immune-mediated skin disease with almost a third of psoriasis patients developing psoriatic arthritis (PsA) [1].PsA is a chronic systemic heterogeneous inflammatory autoimmune disease [2].It has various musculoskeletal presentations such as peripheral arthritis, axial disease, dactylitis, and enthesitis, together Peripheral arthritis is an important feature with diverse presentations [3].One of the hallmarks of PsA is enthesitis, which is thought to be the main lesion that starts the synovial joint inflammation [4].Enthesitis leads to a worse quality of life by causing pain, fatigue, and sleep disturbances, affecting the functional status, and overall impairment [5].It occurs in the axial and peripheral skeleton.It may precede joint symptoms and increase the risk of erosive disease [6].Preclinical PsA definition and differentiation from psoriasis is challenging as PsA is a broad disease with a wide range of manifestations.It can overlap early with features of osteoarthritis or mechanical overuse, especially in old-age psoriasis patients.Early symptoms of PsA in women include arthralgia, heel pain, fatigue, and stiffness.A worsening in pain, stiffness, fatigue, and physical function may anticipate PsA diagnosis [7].This makes diagnosis and assessment a challenge.So, imaging has a major importance in the assessment, diagnosis, and follow-up.US is used to visualize abnormal vascularity, and structural abnormalities in soft tissue and bone [8].US application in patients with psoriasis without musculoskeletal symptoms revealed 30-50% subclinical enthesitis and/or synovitis.Subclinical enthesitis shows higher degrees of power Doppler activity which is a marker of inflammation and angiogenesis [9].

List of abbreviations (in alphabetical order):
Autoimmune thyroid disease (AITD) or Hashimoto's thyroiditis is one of the commonest autoimmune diseases [10].Hashimoto's thyroiditis is considered the most frequent cause of hypothyroidism [11].It is more prevalent in middle-aged females and can deteriorate the quality of life [12].Antibodies are formed against thyroglobulin (Tg) and thyroid peroxidase (TPO) antigens [13].In about 90% of patients, thyroid peroxidase antibody (TPO-Ab) is the most prevalent antibody [14].Antibodies can be positive for a considerable amount of time prior to the onset of thyroid dysfunction indicating the thyroid gland's large functional reserve [15].AITD can present with musculoskeletal manifestations such as fibromyalgia, chronic fatigue, arthropathy without inflammatory synovitis, and undifferentiated inflammatory seronegative arthropathy which can mimic the early phase of PsA [16].AITD is a T-helper 1-mediated immune disease.Its main characteristics are thyroid gland lymphocytic infiltration with the secretion of large amounts of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and chemokines enhancing the autoimmune process [17].AITD and psoriatic disease association is still debatable.Complications and progression of both diseases can be avoided by early diagnosis and treatment [18].More studies are required to evaluate the definite role of thyroid hormones and antibodies in psoriasis and PsA, if thyroid dysfunction has a role in psoriasis chronicity and severity, and to determine the pathogenesis of both diseases' association [14].This study aimed to assess AITD and subclinical and clinical PsA association.

MATERIALS AND METHODS
Forty-five female Egyptian patients ≥18 years-old diagnosed with psoriatic disease were included in this comparative cross-sectional study.The patients were classified into 3 equal groups.The PsA group included patients classified in accordance to CASPAR criteria (ClASsification criteria for Psoriatic ARthritis) [19].The subclinical PsA and psoriasis groups included patients classified by MAdrid Sonographic Enthesitis Index (MASEI) [20].Informed consent from the ethical committee was obtained from each patient.Patients were excluded from participating in the study in case of other rheumatological diseases, known non-autoimmune thyroid disease or thyroidectomy, systemic diseases other than diabetes mellitus and hypertension, malignancy, and previous radiotherapy on the neck or mediastinum, drugs that interfere with thyroid function such as amiodarone, lithium, and highdose steroids, and pregnant females.
The detailed medical history of every patient was reviewed, paying particular attention to the health assessment questionnaire (HAQ) [21] by El Meidany et al., 2003 [22], Arabic translated form, thorough clinical examination with focus on assessment of psoriasis disease activity using Psoriasis Area Severity Index (PASI) [23], enthesitis clinical evaluation using Leeds Enthesitis Index (LEI) [24], PsA disease activity using disease activity score for psoriatic ar th ritis (DAPSA) [25], and laboratory tests entailed complete blood count (CBC), Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum uric acid level, glycated hemoglobin, thyroid profile including thyroid hormones; thyroid stimulating hormone (TSH), free thyroxine (FT4), and free tri-iodothyronine (FT3), thyroid peroxidase antibody (TPO-Ab), and thyroglobulin antibody (Tg-Ab).Thyroid US was performed with the patient's neck extended in the supine position to assess the thyroid gland's volume, echogenicity, nodules, and vascularity.The evaluation of enthesitis for MASEI was done using a high-resolution US with a linear transducer of 10-12 MHz (LOGIQ 5 pro series, GE medical systems, Germany), total score is 136 with a cut-off value of ≥18.

RESULTS
The demographic data of all patients are presented (Table 1).Patients in the PsA group had higher HAQ scores with a high statistical significant difference in comparison to those in the subclinical PsA and psoriasis groups.Patients in the PsA group had higher LEI when compared to those in the subclinical PsA group with a statistical significant difference and to those in the psoriasis group with a high statistical significant difference.Subclinical PsA patients had higher LEI compared to those with psoriasis with a statistical significant difference.
The subclinical PsA group had psoriasis patients with MASEI ≥18, either with musculoskeletal complaints not fulfilling the entry criterion of CASPAR classification criteria or without musculo skeletal complaints.The psoriasis group had psoriasis patients without musculoskeletal complaints with MASEI <18 (Figure 1).In all psoriatic disease patients, 20% had subclinical hypothyroidism, 46.67% had TPO-Ab positivity, and 26.67% had Tg-Ab positivity.These percentages were elevated in the PsA group in contrast to the subclinical PsA group.In the PsA group, 33.3% had subclinical hypothyroidism, 80% had TPO-Ab positivity, and 46.7% had Tg-Ab positivity.In the subclinical PsA group, 26.7% had subclinical hypothyroidism, 60% had TPO-Ab positivity, and 33.3% had Tg-Ab positivity.While in the psoriasis group, 100% of patients were within the normal range of serum levels of thyroid hormones with negative thyroid antibodies.PsA patients had higher TPO-Ab levels compared to psoriasis patients with a high statistical significant difference and subclinical PsA patients had higher TPO-Ab levels compared to psoriasis patients with a statistical significant difference.PsA patients had lower FT3 levels compared to psoriasis patients with a statistical significant difference.Features of thyroiditis in the US were present in 26.7% of the PsA patients and 20% of the subclinical PsA patients with none (0%) of the psoriasis patients.Sonographic thyroiditis features included non-homogenous coarse echopattern, multiple fibrous strands, multiple small nodules, and increased vascularity.There was no change in the thyroid gland volume in thyroiditis patients.No sta-FIGURE 1. Triceps tendon thickening 5.2mm (>4.3mm), hypoechogenicity, and enthesophyte tistical significant difference was detected regarding thyroid US features comparing the 3 groups (Table 2, Figure 2).The correlations of the thyroid profile with other parameters in the 3 groups are demonstrated in (Tables 3-6).

DISCUSSION
Psoriasis is an inflammatory autoimmune chronic disease affecting multiple systems but mainly the skin [26].Synovioentheseal inflammation will occur eventually in up to 30% of patients with psoriasis [27].PsA is a chronic inflammatory autoimmune heterogeneous musculoskeletal disease with various presentations involving peripheral arthritis, axial disease, enthesitis, and dactylitis with negative effects on the quality of life [28].AITD is a common autoimmune disease affecting almost 5% of the population.Hashimoto's thyroiditis is the most common form, with lymphocytic thyroid gland infiltration and antibodies production including TPO and Tg Abs resulting eventually in hypothyroidism [26].[30] who demonstrated an association between psoriatic disease and autoimmune thyroiditis, while disagreed with Vassilatou et al., 2017 [15] and Khan et al., 2017 [31] who found no association between psoriatic disease and autoimmune thyroiditis.Psoriasis patients have twice the chance to develop another autoimmune disease [14].Many theories have been postulated to explain this association.Both diseases are common autoimmune inflammatory diseases that share many characteristics such as a long asymptomatic period before the starting of symptoms, an elevated comorbidity risk most likely metabolic syndrome, and several complications affecting the health and quality of life of patients, as well as many risk factors besides genetic predisposition sharing in both diseases such as dietary, lifestyle, and environmental factors [32].Both diseases are Th-1 cell-mediated immune diseases [30].Thyroid hormones may have a role in psoria- sis pathogenesis by many factors.Skin has receptors for thyroid hormones on which thyroid hormones have hyperproliferative effects through epidermal growth factor that increases epidermal hyperplasia and keratin synthesis.Psoriasis disease severity is demonstrated in some studies to be correlated with TSH level and is improved with antithyroid therapy [32].Compared to psoriasis, PsA patients have a higher risk of hypothyroidism, hyperthyroidism, and AITD.This may be illustrated by the increased systemic inflammation denoted by the elevated levels of IL-6, IL-1 receptor, IL-1 receptor antagonist, soluble IL-2 receptor, vascular endothelial growth factor, high-sensitive CRP, CD16+ proinflammatory monocytes, and osteoprotegerin in patients with PsA in contrast to patients with psoriasis and the general population [14,30].Patients with PsA and AITD had more peripheral polyarticular involvement indicating that thyroid evaluation could be included in PsA patients' assessment, especially females with peripheral polyarticular affection [30].
In the PsA group, a statistical significant negative correlation was detected between TPO-Ab level and the patient's age while in the subclinical PsA group, a statistical significant positive correlation was detected between TPO-Ab level and the patient's age.In the subclinical PsA group, a high statistical significant positive correlation was detected between TPO-Ab level and the psoriasis duration.Vassilatou et al., 2017 [15] and Borges et al., 2018[33], demonstrated that there was no association between AITD and neither psoriatic patient's age, age at disease onset, or psoriatic disease duration.Alidrisi et al., 2019[34], demonstrated a significant correlation between psoriasis onset at age >40 and higher TPO-Ab level (42.1%) while there were no correlations found between the patient's age and the thyroid antibodies.Fallahi et al., 2017 [35], found an increase in thyroid abnormalities in PsA patients with long-standing disease.In the subclinical PsA group, a high statistical significant negative correlation was demonstrated between FT4 and LEI, a high statistical significant positive correlation was demonstrated between TPO-Ab and MASEI, and statistical significant positive correlations between each of FT3 and Tg-Ab and MASEI.Higher MASEI scores as in subclinical PsA are associated with more enthesitis which reflects more inflammation and are associated with more peripheral and radiographic damage.AITD is more frequent in psoriatic disease due to increased inflammation [30].
There were statistical significant correlations between TPO-Ab and DAPSA score and between FT4 and PASI in the PsA group.This agrees with Vastarella et al., 2021 [30], who demonstrated an increased frequency of AITD in PsA with peripheral  [33], showed no association between AITD and severity of psoriatic disease.
A statistical significant positive correlation was detected between TPO-Ab and ESR in the subclinical PsA group and a high statistical significant positive correlation was detected between Tg-Ab and CRP in the psoriasis group.AITD is more prevalent in psoriatic disease due to increased inflammation represented by increased levels of inflammatory mediators such as IL-6, CRP, IL-1 receptor, IL-1 receptor antagonist, and soluble IL-2 receptor [30].
In the PsA group, a high statistical significant positive correlation was found between TSH and serum uric acid.This disagrees with Jat et al., 2019 [36] who demonstrated no significant correlations between thyroid hormones in various thyroid disorders and serum uric acid levels.Helmy, 2020 [37], found a statistical significant negative correlation between TSH and serum uric acid and a statistical significant positive correlation between each of FT4 and FT3 and serum uric acid.The effect of hypothyroidism on purine metabolism results in increasing serum uric acid levels.Hypothyroidism also results in a reduction in renal perfusion and glomerular filtration rate [37].
The study's limitations included the limited number of patients including females only.We recommend future larger-scale longitudinal studies involving both genders.Musculoskeletal ultrasound can be used to screen for subclinical synovitis and enthesitis in psoriasis patients to screen for subclinical PsA.Assessment of psoriatic disease patients by thyroid antibodies and thyroid stimulating hormone is needed to diagnose autoimmune thyroid disease in these patients and to reduce the risk of comorbidities, especially cardiovascular diseases.

CONCLUSION
Musculoskeletal ultrasound is a screening tool to detect enthesitis in psoriasis patients.It also can help in diagnosing psoriasis patients with musculoskeletal complaints not fulfilling the entry criterion for CASPAR criteria whether they have subclinical PsA or fibromyalgia.Autoimmune thyroiditis is increased in psoriatic disease.The percentage of thyroglobulin and thyroid peroxidase antibodies' positivity is higher in PsA patients than in subclinical PsA and higher in subclinical PsA than psoriasis.

TABLE 2 .
Comparing the 3 groups regarding thyroid profile