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Is the IFN‐alpha‐related thyroid autoimmunity an immunologically heterogeneous disease?

Dear Sir, Over the last years, many studies have aimed to investigate the relationship between the appearance of autoimmune phenomena in the course of interferon-alpha (IFN-a) treatment and the therapeutic response of the underlying viral or neoplastic disease [1–5]. We read with great interest the paper by Dalgrad et al. which demonstrated that, in patients treated with IFN-a plus ribavirin for HCV-related chronic hepatitis, the response to the antiviral treatment was not correlated to the appearance of thyroid dysfunction [5]. This result was in accordance with previous studies [1, 2, 4], but in disagreement with others demonstrating that the IFN-induced thyroid disease occurred more frequently in patients with a sustained response to the cytokine treatment [3]. The authors considered the different duration of the cytokine treatment as a possible factor explaining this discrepancy. We think that immunological and genetic aspects should also be considered in this context. The type 1 immune response plays a critical role in the resolution of viral infection, as well as in the development of many autoimmune diseases [6–8]. In thyroid autoimmune disease, however, the T helper (Th)1 and Th2 responses coexist in the same patients, although with different reciprocal intensity in relationship with the clinical expression of the disease process [9]. The type 1 response seems to be dominant in the course of hypothyroidism occurring in patients with Hashimoto’s thyroiditis and in the course of silent thyroiditis, whereas the type 2 response has been correlated mainly with the appearance of hyperthyroidism in the cases affected by Graves’ disease [10–13]. In particular, the thyroid-destructive process in Hashimoto’s thyroiditis seems to be induced mainly by cell-mediated immunity, as demonstrated by the increase of serum Th1 cytokines in this condition [13]. However, Graves’ thyrotoxicosis is induced by the thyroidstimulating autoantibodies to thyrotropin receptor, the production of which is likely to depend on Th2 cell function [12]. The same mechanisms should be considered for the IFN-related thyroid autoimmunity. In this view, the patients who develop Graves’type thyrotoxicosis in the course of treatment with IFN-a should be considered immunologically different to those showing hypothyroidism or transient thyrotoxicosis by a destructive process in the thyroid gland [14, 15]. The fact that in the various studies the different clinical pictures of the IFN-related thyroid autoimmunity were not considered separately could explain the controversial data of literature about the correlation between the response to the antiviral treatment and the appearance of thyroid disease. Unfortunately, such differentiation is not always possible because different expressions of the thyroid disease can occur in the same patient, suggesting a possible evolution of the immunological process throughout the IFN treatment [16]. However, a probable correlation between the remission of chronic hepatitis and the appearance of thyroid disease should be considered only for those patients with a Th1-mediated destructive process in the thyroid gland, mainly when the antiviral treatment is performed with IFN-a plus ribavirin [17]. Nevertheless, it does not mean that the two events are constantly correlated. In fact, most of the patients with sustained response to antiviral treatment show neither thyroid autoimmunity nor thyroid dysfunction [17]. This apparent paradox is easily explained by the fact that whilst the response to the antiviral treatment is related to both host and viral factors [18, 19], the genetic background seems to play a predominant role in determining the occurrence of the IFN-related thyroid autoimmunity [20]. In this view, the IFN-a plus ribavirin treatment can trigger a Th1-mediated cytotoxic process in the thyroid gland Journal of Internal Medicine 2002; 252: 377–378