**3.1 Thyroid disease in SLE**

Autoimmune thyroid disease has been observed in patients with systemic lupus erythematosus, such as autoimmune Hashimoto's thyroiditis, hypothyroidism and Graves' disease.

## *3.1.1 Hypothyroidism*

*Lupus - Need to Know*

excess IL-10, disease activity may increase during states of high catecholamine release, such as acute stress. In a prospective study of patients with SLE, disease flares were associated with emotional stress or with the number or severity of daily stressors [41, 42]. Additionally, the effect of acute psychological stress induced differential immune response in SLE patients as compared to controls [43].

**2.2 Estrogens in the pathogenesis of systemic lupus erythematosus**

tion and in vitro fertilization may cause disease flare in SLE [52].

The main pathophysiologic processes of SLE are the loss of self-tolerance and the production of autoantibodies with consequent inflammatory response and organ injury [15]. Estrogens are capable of inducing these alterations in the immune system. Treg cells, immunosuppressive regulatory T cells, play an important role in the maintenance of self-tolerance and the prevention of autoimmunity. SLE

The hypothalamic–pituitary–adrenal axis responds to inflammatory cytokines [44]. It has been demonstrated that inflammatory cytokines, such as IL-1a and IL-1b, IL-6 and TNF-a are powerful activators of the hypothalamic–pituitary–adrenal axis [45, 46]. In SLE patients with central nervous system involvement elevated levels of inflammatory cytokines were observed in the cerebrospinal fluid [47] suggesting an involvement of these inflammatory cytokines in disease pathogenesis.

SLE is a disease affecting primarily female patients in the reproductive age [48]. Evidence exists implicating estrogens in the pathogenesis of SLE [49]. An extensive cross-talk takes place between estrogen and the immune system. Estrogens are a major modulating factor of the immune response [50] (**Figure 3**). Epidemiological evidence implicates estrogens in the pathogenesis of SLE, as during childhood where estrogen secretion is minimal the female: male ratio is 3:1 as opposed to 9:1 in the reproductive age. In the postmenopausal period the ratio is 8:1 [51]. Evidence has shown that women with early menarche, or treated with oral contraceptives or hormone replacement therapy have an increased risk for SLE [52, 53]. The presence of the X chromosome appears also to be important for the pathogenesis of SLE. There appears to be a gene dose effect, as the prevalence of SLE in Klinefelter's syndrome (XXY) is 14-fold that in the general male population, whereas it is decreased in female patients with Turner's syndrome (XO) [54]. Pregnancy, in which the concentration of estrogens is extremely increased can cause a disease flare or even trigger the development of lupus [55, 56]. The puerperium is characterized by an increased risk for disease relapse [57]. Hormonal factors used for ovulation induc-

**66**

**Figure 3.**

*The effect of estrogens on the immune system.*

Hypothyroidism is observed in patients with SLE in a higher rate than in the normal population. In particular, Munoz and Isenberg [14] reported a rate of 5.22% hypothyroidism, i.e. 37 patients, in their cohort of 708 patients with SLE in University College of London Hospital, as compared to 1–2% in the general UK population. In this cohort the onset of hypothyroidism occurred after the onset of SLE oftener. Other reports confirmed a higher than in the general population rate of hypothyroidism in SLE. In particular, Ong and Choy [68] in a Malaysian population of SLE patients observed a prevalence of hypothyroidism of 3.7%. Antonelli et al. [69] reported a prevalence of hypothyroidism of 4.5%. In an earlier report from the University College of London Hospital SLE cohort Pyne and Isenberg [70] reported a prevalence of hypothyroidism of 5.7%.

#### *3.1.2 Hyperthyroidism*

Hyperthyroidism is observed in patients with SLE. In their cohort of 708 patients with SLE Munoz and Isenberg [14] observed a prevalence of hyperthyroidism of 1.41% (10/708 SLE patients), similar to that in the general population [71]. Watad *et al* [72] and Ong *et al* [68] reported a prevalence of hyperthyroidism in SLE patients of 2.59% and 2.6%, respectively. Chan *et al* [73] observed a prevalence of 5.8% of hyperthyroidism in a study of 69 SLE patients. However, only 2.9% had a clinical hyperthyroidism.

#### *3.1.3 Autoimmune Hashimoto's thyroiditis*

Autoimmune Hashimoto's thyroiditis is frequently observed in patients with SLE. The prevalence of Hashimoto's thyroiditis in patients with SLE as opposed to control subjects was investigated in a study [74]. The association of Hashinoto's Hashimoto's thyroiditis and anti-thyroid antibodies to the clinical, serological

profile and disease activity as well as cumulative organ damage in this group was also investigated. In a group of 301 SLE patients and 141 controls TSH levels, T4 levels, antiTg antibodies and antiTPO antibodies were measured by chemiluminescence and immunometric methods. The serological and clinical profile of the patients was reviewed. SLE disease activity was measured using the SLEDAI index. The prevalence of Hashimoto's thyroiditis was 12.6% in SLE as opposed to 5.6% in controls, the difference being statistically significant. A lower prevalence of malar rash and a higher prevalence of anti-Sm was noted in lupus patients with Hashimoto's thyroiditis. No association was noted between Hashimoto's thyroiditis and disease activity of cumulative organ damage. In conclusion, a two-fold increased risk of Hashimoto's thyroiditis was noted in lupus patients. In a study performed in China 63 cases of lupus patients who also had Hashimoto's thyroiditis were studied [75]. Lupus patients were classified in four groups, those in remission, those with low disease activity, those with moderate and those with high disease activity. Free T3 levels were found to be negatively correlated with disease activity. In an effort to find a way to treat effectively Hashimoto's thyroiditis and SLE a group of scientists [76] injected human amniotic epithelial cells in murine models of Hashimoto's thyroiditis and SLE. They observed that levels of antiTg, antiTPO antibodies and TSH levels decreased as well as evidence of tissue destruction within the thyroid decreased. Additionally, the injection of human amniotic epithelial cells induced the disappearance of antidsDNA antibodies and ANA in mice with SLE and improved immunoglobulin profiles. It downregulated the ratio of Th17/Treg cells in both Hashimoto thyroiditis and SLE mice and upregulated the proportion of B10 cells. Human epithelial amniotic cells suppressed the levels of pro-inflammatory cytokines, IL-17A and IFN-γ and enhanced TGF-β in the murine models of Hashimoto's thyroiditis and SLE, thus suggesting a common pathogenic substrate in both diseases.
