1 Introduction

Systemic lupus erythematosus (SLE) is an autoimmune chronic inflammatory disease that may affect any organ or system in the body [1, 2]. Thyroid dysfunction, primarily autoimmune disorders, have been frequently described in patients with rheumatologic autoimmune diseases, such as SLE, Sjögren’s syndrome or rheumatoid arthritis. The prevalence of thyroid dysfunction in SLE varies between 3.8 and 22.2% among different populations and ethnicities. The most common reported thyroid dysfunction in patients with SLE is clinically overt and subclinical hypothyroidism. Several studies evaluating the correlation between thyroid dysfunction and SLE have shown varying and conflicting results [3,4,5]. Some studies evaluating the prevalence of anti-thyroglobulin antibodies (Tg) and anti-thyroid peroxidase antibodies (TPO) have shown high thyroid dysfunction in patients with SLE [6, 7].

The aims of this study were to determine the prevalence and characteristics of thyroid dysfunction among Saudi patients with SLE at King Fahad Medical City.

2 Materials and Methods

This was a retrospective study in which we reviewed a total 151 patients older than 18 years of age who had a confirmed diagnosis of SLE according to the Systemic Lupus International Collaborating Clinics classification criteria [11] and were treated at our rheumatology clinics.

Data on clinical manifestations and laboratory findings at the time of presentation were obtained from the medical records of the outpatient clinics of King Fahad Medical City, Riyadh, Saudi Arabia, between January 2014 and December 2019.

Data obtained from patients’ files included demographic data, sex, age at diagnosis of SLE, history of thyroid diseases and treatment for thyroid disease. Laboratory evaluations included complete blood count, thyroid function test (TFT), anti-nuclear antibody (ANA) detection by indirect immunofluorescence, anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibody detection with a standardized enzyme-linked immunosorbent assay, serum complement (C3 and C4), TPO and Tg.

The Safety of Estrogens in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) was used to determine disease activity in patients with SLE. Thyroid dysfunction was classified into three categories according to TFT: sick euthyroid, hyperthyroidism and hypothyroidism. Hyperthyroidism status was defined by low TSH levels and high values of free thyroxine (T4), free triiodothyronine (T3) or both; or by treatment with carbimazole or propylthiouracil. Hypothyroidism was defined by an elevated TSH concentration and low T4 and/or low T3; or by treatment with thyroxine replacement therapy. Thyroid autoantibodies, TPO and Tg were also assessed in patients with abnormal TFT.

Ethical approval for this study was obtained from the ethics committee at King Fahad Medical City.

2.1 Statistical Analysis

All data were entered and analyzed in SPSS version 22 software (SPSS Inc., Chicago, IL, USA). A two-tailed P-value of 0.05 was considered significant. Demographic and clinical characteristics of the patients are reported as medians (with 25th and 75th percentiles) for continuous variables and counts (with percentages) for categorical variables. Pearson’s chi-squared test was used to compare the distribution of thyroid diseases, and Student’s t-test was used to assess the associations between disease activity and thyroid diseases.

3 Results

A total of 151 adult patients (141 women and 10 men) with SLE were reviewed. The female to male ratio in our study was 14.1:1. The mean age at diagnosis of SLE was 34 ± 10 years. The main clinical manifestations in our cohort consisted of skin rash in 80 (53%), photosensitivity in 69 (46%), mucosal ulcers in 46 (30.5%) and hair loss 45 (29.8%) patients. Other demographic features in our patients are summarized in Table 1. ANA and anti-dsDNA were positive in 92% and 60.7% of patients, respectively. Anti-phospholipid antibodies were detected in 31 patients (27.7%). Twenty-six patients (17.2%) had thyroid dysfunction. Eleven patients (7.3%) had subclinical hypothyroidism, and seven patients (4.6%) had hypothyroidism. Five patients (3.3%) had subclinical hyperthyroidism, and one patient (0.7%) had hyperthyroidism. Two patients (1.3%) had sick euthyroid status (Table 1). Anti-thyroid antibodies, both TPO and Tg, were present in four patients (57.14%) with hypothyroidism. Neither TPO nor Tg was positive in any patients with hyperthyroidism.

Table 1 Thyroid dysfunction in patients with SLE
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A total of 82% of patients had a positive ANA. The mean value of anti-dsDNA was 91 IU/ml. The mean value of C3 was low, at 0.7. Inflammatory markers revealed a high mean erythrocyte sedimentation rate (51) with normal mean C-reactive protein levels (4.4). Most patients had anemia (73.5%), leukopenia (25.8%) or thrombocytopenia (18.5%). The average 24-h urine protein was unremarkable, at 0.224 g/l. Elevated creatinine was found in 10.6% of patients.

Thyroid status and the prevalence of thyroid auto-antibodies are shown in Table 2. Four of seven (57%) patients with hypothyroidism had positive Tg and TPO. One patient with hyperthyroidism tested negative for thyroid auto-antibodies.

Table 2 Thyroid status and thyroid antibodies (Tg and TPO)
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Fourteen patients (53.8%) had severe flares, and 12 patients (46.2%) had mild to moderate flares. Fourteen patients (53.8%) had anti-dsDNA positivity.

No association was observed between thyroid dysfunction and SLE disease activity, specifically the SELENA-SLEDAI score, anti-dsDNA level, C3 level and 24-h urine protein, with P-values of 0.206, 0.775, 0.729 and 0.366, respectively (Table 3).

Table 3 Association between thyroid dysfunction and SLE disease activity
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4 Discussion

Thyroid dysfunction is fairly common in patients with SLE. Several studies have shown that the prevalence of thyroid disorders is higher among patients with SLE than in the general population, and is associated with SLE activity [3, 8,9,10,11].

Growing evidence indicates a genetic link between SLE and thyroid disorders. Concurrent thyroid disease and SLE tend to be encountered in patients with the R620W polymorphism in the PTPN22 gene encoding a T-cell protein [12]. Moreover, in a study of families with both SLE and thyroid disease, a site on chromosome 5 (5q14.3–15) has been reported to be a susceptibility gene shared by patients with SLE and patients with autoimmune thyroid diseases [13].

Data exploring the prevalence of thyroid dysfunction in patients with SLE in Saudi Arabia are lacking. In this study, 17.2% of patients with SLE had thyroid dysfunction, 7.3% had subclinical hypothyroidism, and 4.6% had hypothyroidism. We found subclinical hyperthyroidism in 3.3%, hyperthyroidism in 0.7% and sick euthyroid in 1.3% of patients. Our findings are in line with those in previous studies, in which the rate of hypothyroidism has been reported to be 3.9–17.4%, and that of hyperthyroidism has been reported to be 0.5–8% in patients with SLE [1,2,3, 5, 9, 13,14,15,16,17,18]. The high variability among studies is probably due to differences in sample size, ethnic groups and study design.

In our study, subclinical hypothyroidism was the most frequent thyroid disorder; this finding is supported by a recent meta-analysis of 10,500 patients with SLE and 44,170 controls, which has reported that subclinical hypothyroidism is more common in patients with SLE than controls (OR = 5.67, 95% CI = 3.50–9.18) [8]. In contrast, other studies have described primary hypothyroidism as a common thyroid dysfunction in patients with lupus (15–19%) [9, 14, 18]. This discrepancy might have been due to a lack of evaluation of subclinical hypothyroidism [9, 16], or to differences in the study design and populations [14].

Regarding anti-thyroid antibodies in lupus patients, autoimmunity is responsible for approximately 80% of primary hypothyroidism pathogenesis [18]. Moreover, ATA levels are associated with certain SLE antibodies, such as anti-dsDNA, RNP and anti-Smith (Sm) antibody [21]. Antonelli et al. have reported anti-thyroid antibodies in more than two-thirds of patients with SLE with hypothyroidism. Moreover, hypothyroidism has been found to be higher in patients with than without SLE [14].

Pan et al. have detected higher levels of Tg and TPO in patients with SLE than controls [20]. Further subgroup analysis by geographic location has indicated that participants with SLE from American and European populations are more likely to be Tg positive, whereas those from Asian and African populations are less likely. Regarding TPO, a positive association has been observed between TPO positivity and SLE in African and European populations, but not in Asian populations or American populations, thus suggesting a possible role of geography-driven differences in genetic backgrounds and living environments [20].

In our cohort, anti-thyroid antibodies were detected in 57% of patients who had hypothyroidism, a value greater than previously reported in some studies [5]. One explanation for this dissimilarity is the low number of patients with hypothyroidism in our study.

With respect to the relationship between thyroid disorders and SLE activity, our data did not show a significant association between thyroid disease and SLE disease activity in terms of SELENA-SLEDAI (P = 0.20), anti-ds-DNA (P = 0.77), C3 levels (P = 0.72) or 24-h urine for protein > 500 mg/day (P = 0.36). Our findings are consistent with those in a previous report by Mader et al. [2], who did not find an association between the SLEDAI score and ATA positivity. By contrast, one study in 167 patients with SLE has reported that patients with SLE with hypothyroidism had a statistically significantly higher Systemic Lupus Activity Measure (SLAM) and SLEDAI score than patients with euthyroid and subclinical hyperthyroidism [21]. This finding is inconsistent with our study outcome and may be explained by differences in the study populations.

Another study in 63 patients with SLE has revealed that Hashimoto's thyroiditis is associated with disease activity [22]. Moreover, Liu et al. have demonstrated a high risk of renal and CNS involvement in patients with SLE with thyroid diseases (3).

Notably, our study has several limitations. First, because it was a retrospective single-center study, selection bias could not be completely avoided. Moreover, the lack of some information regarding demographic data among patients who were diagnosed with thyroid dysfunction, in addition to the lack of a control group, might have influenced the conclusions.

5 Conclusion

Our study suggests that subclinical and overt hypothyroidism is common in patients with SLE, but SLE activity is not associated with thyroid disorders. Physicians should be aware of the possibility of thyroid disorder when treating patients with SLE.