*3.1.2. Interleukin-2*

314 Thyroid Hormone

months [30,34].

not generally remit on withdrawal of the drug [35].

patients, remain to be elucidated.

prevent further episodes of the condition [46].

thyrotoxic phase and usually occurs in the first few weeks of interferon treatment and is in close temporal relationship with the appearance of thyroid autoantibodies, especially antithyroglobulin (anti-TG) antibodies. Another form of autoimmune thyroid toxicity associated to interferon- is characterized by the development of thyroid antibodies without hypothyroidism. In the setting of interferon therapy, the risk of hypothyroidism is 2.4%– 10% [30-35], with a risk of thyroid autoimmunity onset (including development of thyroid autoantibodies) approaching 20% [36,37]. Hypothyroidism is persistent in the majority of patients [33,38], even though although transient hypothyroidism has also been described [39]. The presence of anti-thyroperoxidase (anti-TPO) antibodies before treatment considerably increases the risk of hypothyroidism [40-42]. Thyroid abnormalities can occur as early as 4 weeks and as late as 23 months after initiating treatment, with a median of 4

Interferon- has also been associated with classical Graves disease and sometimes Graves' ophthalmopathy also develops, however the latter is less common [30]. This condition does

Several evidence supports the hypothesis that thyroid toxicity may likely be related to an autoimmune response to interferon-. Overexpression of MHC class I antigens are associated with activation of cytotoxic T-cells resulting in cellular destruction [43]. It has been reported that interferon- increases MHC class I expression on thyroid tissue from Graves patients, provided that lymphocytes are present in the thyroid tissue [44]. Hence, interferon- might worsen local immune response in subjects who have preexisting subclinical thyroiditis with intrathyroidal lymphocytes [44]. In addition, interferon- can shift the immune response to a Th1-mediated immune response, with increased production of the proinflammatory cytokines interferon-γ and interleukin-2, which may in turn amplify an autoimmune response. Interferon- has been demonstrated to elicit a direct damage on thyroid cells, which may be responsible for the onset of destructive thyroiditis [28,35,42,45]. However, despite accumulating evidence, the precise mechanisms underlying thyroid toxicity associated to interferon, especially in cancer

Levothyroxine (LT4) therapy is indicated as treatment of interferon-induced hypothyroidism and withdrawal of interferon is not generally needed. When destructive thyroiditis is present, treatment with corticosteroids is needed and β-blockers are often useful to control the signs and symptoms of thyrotoxicosis. When interferon causes hyperthyroidism, antithyroid agents such as methimazole or propylthiouracil may be administered, if clinically indicated. In patients with relapsing flares of thyroiditis during prolonged courses of interferon-, ablation with 131I during remission may be offered to

Despite specific recommendations for patients treated with interferon- for oncological diseases are lacking, it appears rational to apply the recommendations available for patients with hepatitis C [47]. In particular, the same serological screening is suggested, including pretreatment TSH and anti-TPO antibodies evaluation, followed by TSH serum Interleukin-2 is a cytokine involved in several mechanisms of immune response, including activation of natural killer cells and antigen-specific T-cells. These properties are used to stimulate tumor cell killing, also in combination with interferon or lymphokine-activated killer cells. Interleukin-2 is approved for the treatment of metastatic melanoma and RCC, although its use has been recently reduced in concomitance with the availability of more effective and better tolerated agents.

Several autoimmune side-effects have been associated to interleukin-2 therapy, including thyroid disease with an incidence of 10%–50% [48-54]. Hypothyroidism usually occurs 4–17 weeks after initiation of treatment [48,49]. It may be reversible following discontinuation of the drug [49,55]. Most patients who developed hypothyroidism showed positive anti-TG or anti-TPO antibodies. In addition to hypothyroidism, thyroiditis and thyrotoxicosis have also been reported at a lesser frequency [55,56]. An early phase of presumably destructive thyrotoxicosis is common, with variable degrees of hyperthyroidism [57].

Evidence suggests that thyroid disease associated to interleukin-2 may be induced by stimulating autoreactive lymphocytes, leading to autoimmune thyroiditis. Patients under treatment with interleukin-2 showed high levels of interferon-γ and tumor necrosis factor-, which may trigger autoimmunity by enhancing the presentation of human leukocyte antigen class II and associated autoantigens by thyrocytes. Also, interleukin-2 may have direct effects on thyrocyte functioning [58,59]. Increase in serum thyroid autoantibodies levels [48,53] and lymphocyte infiltration of the thyroid gland [57] were found in patients treated with interleukin-2, suggesting a cell-mediated autoimmune mechanism. Similarly to interferon, preexisting positivity of thyroid autoantibodies seems to predict an increased risk of developing hypothyroidism during interleukin-2 treatment [49].

Occurrence of hypothyroidism was associated with a favorable response to treatment [48,60], but other studies did not confirm these results [61]. It has been suggested that thyroid dysfunction may develop more often in the responders because they receive longer courses of the treatment [46,62]. Patients with interleukin-2-induced hypothyroidism may be treated with LT4, while thyrotoxicosis only requires symptom control with β-blockers and corticosteroids. Measuring TSH before treatment and then every 2–3 months during treatment with interleukin-2 is advisable [1].
