Giusy Elia

The association of other autoimmune diseases in patients with autoimmune thyroiditis: Review of the literature and report of a large series of patients.

We have evaluated prospectively the prevalence of other autoimmune disorders in outpatient clinic in 3069 consecutive patients with diagnosed chronic autoimmune thyroiditis (AT), with respect to two age- and sex-matched control groups: a) a control group of 1023 subjects, extracted from a random sample of the general population without thyroid disorders; b) 1023 patients with non-toxic multinodular goiter extracted from the same random sample of the general population, with similar iodine intake. The results of our study demonstrate a significant increase of the prevalence of autoimmune disorders in AT patients (with respect to both controls), for the following diseases: chronic autoimmune gastritis (CAG), vitiligo (Vit), rheumatoid arthritis, polymialgia rheumatica (Polym), celiac disease, diabetes, sjogren disease, multiple sclerosis, systemic lupus erythematosus, sarcoidosis, alopecia, psoriathic arthritis, systemic sclerosis, and HCV-related cryoglobulinemia. While the statistical analysis reached near the significance for Addisons disease and ulcerative colitis. Interestingly, the association of three autoimmune disorders was observed almost exclusively in AT patients, and the most frequent associations were AT+CAG+Vit and AT+CAG+Polym. We suggest that patients with AT who remain unwell, or who develop new not specific symptoms (despite adequate treatment) should be screened for other autoimmune disorders, avoiding the delay in the diagnosis of these disorders.

Incidence of thyroid disorders in mixed cryoglobulinemia: Results from a longitudinal follow-up.

No study has evaluated the incidence of new cases of thyroid autoimmunity (AT) and dysfunction (TD) in hepatitis C-associated mixed cryoglobulinemia (MC) patients. We aimed to evaluate the incidence of new cases of AT and TD in a wide group of MC patients vs. age- and gender-matched controls from the same geographic area. After exclusion of MC patients with TD at the initial evaluation, the appearance of new cases of TD was evaluated in 112 MC patients and 112 matched controls, with similar iodine intake (median follow-up 67months in MC vs. 78 in controls). A high incidence (P<0.05) of new cases of hypothyroidism, TD, anti-thyroperoxidase antibody (AbTPO) positivity, appearance of a hypoechoic thyroid pattern, and thyroid autoimmunity in MC patients vs. controls was shown. A logistic regression analysis showed that in MC, the appearance of hypothyroidism was related to female gender, a borderline high initial thyroid-stimulating hormone (TSH), AbTPO positivity, a hypoechoic, and small thyroid. In conclusion, we show a high incidence of new cases of AT and TD in MC patients. MC patients at high risk (female gender, a borderline high initial TSH, AbTPO positivity, a hypoechoic, and small thyroid) should have periodically thyroid function follow-up.

Novel Therapies for Thyroid Autoimmune Diseases

ABSTRACT C-X-C chemokine receptor (CXCR)3 and its interferon(IFN)γ-dependent chemokines (CXCL10, CXCL9, CXCL11) are implicated in the immune-pathogenesis of autoimmune thyroiditis (AT), Graves disease (GD) and Graves Ophthalmopathy (GO). In tissue, recruited Th1 lymphocytes produce IFNγ, enhancing the tissue secretion of IFNγ-inducible chemokines, initiating and perpetuating the autoimmune process. Patients with AT (with hypothyroidism), and with GO and GD, particularly in the active phase, have high IFNγ-inducible chemokines. Peroxisome proliferator-activated receptor (PPAR)γ or -α agonists and methimazole exert an immune-modulation on CXCR3 chemokines in AT, GD and GO. Other studies are ongoing to evaluate new molecules acting as antagonists of CXCR3, or blocking CXCL10, in Hashimoto thyroiditis (HT), GD and GO. Recently, novel molecules targeting the various agents involved in the pathogenesis of GO, such as rituximab, have been proposed as an alternative to corticosteroids. However, randomized and controlled studies are needed to generalize these interesting results.

Systemic Lupus Erythematosus and Thyroid Autoimmunity

Most of the studies present in the literature show a high prevalence, and incidence, of new cases of hypothyroidism and autoimmune thyroiditis (AT) in systemic lupus erythematosus (SLE) patients, overall in female gender. A limited number of cases of Graves’ disease have been also reported in SLE patients, in agreement with the higher prevalence of thyroid autoimmunity. It has been also demonstrated that a Th1 predominance is associated with AT in SLE patients. Furthermore, a higher prevalence of papillary thyroid cancer has been recently reported in SLE, in particular in the presence of thyroid autoimmunity. However, studies in larger number of SLE patients are needed to confirm findings about thyroid cancer. On the whole, data from literature strongly suggest that female SLE patients, with a high risk (a normal but at the higher limit thyroid-stimulating hormone value, positive antithyroid peroxidase antibodies, a hypoechoic pattern, and small thyroid), should undergo periodic thyroid function follow-up, and appropriate treatments when needed. A careful thyroid monitoring would be opportune during the follow-up of these patients.

Autoimmune Thyroid Diseases and Epigenetics

Abstract Genetic mapping has identified several candidate variants in autoimmune conditions; however, thyroid autoimmune diseases cannot be explained by genetic susceptibility alone. In monozygotic twins, the concordance for most autoimmune diseases is only 20%–30%, indicating that epigenetics and environmental factors may also be determinant. Epigenetics refers to inheritable and potentially reversible changes in DNA and chromatin, which regulate gene expression without altering the DNA sequence. Epigenetic regulation includes DNA methylation, histone modification, and noncoding RNA-mediated regulation. Epigenetic mechanisms regulate gene expression levels, and their impairments result in networks of genes that are switched on or off, thus contributing to disease pathogenesis. This chapter describes the contribution of epigenetics to autoimmune thyroid disorders.

Molecular testing in the diagnosis of differentiated thyroid carcinomas

Different genetic mutations and other molecular alterations in papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) can be detected in fine-needle aspiration (FNA) of thyroid nodules, and can be used successfully to ameliorate cancer diagnosis and management of patients with thyroid nodules. The greatest experience has been obtained with the diagnostic use of BRAF mutation that is strongly specific for malignancy when detected using well-validated techniques. The strongest diagnostic result can be obtained testing FNA samples for a panel of mutations that typically involve TERT, BRAF, PAX8/PPARγ, RAS, and RET/PTC. Finding any of these mutations in a thyroid nodule provides strong indication for malignancy and helps to refine clinical management for a significant proportion of patients with indeterminate cytology. The use of molecular markers, as TERT, BRAF, PAX8/PPARγ, RAS, and RET/PTC, may be considered for patients with indeterminate FNA cytology (FNAC) to help guide management. In patients with indeterminate TIR3 FNA, the combination of precise molecular marker expression analysis with molecular mutations evaluations could ameliorate significantly the accuracy of cancer diagnosis. However other prospective studies are needed to identify more accurate molecular markers. Finally, the knowledge of these molecular pathways has permitted the development of new targeted therapies for aggressive TC.

Novel treatment options for anaplastic thyroid cancer

ABSTRACT Introduction: Several genetic alterations have been identified in different molecular pathways ofanaplastic thyroid cancer (ATC) and associated with tumor aggressiveness and progression (BRAF, p53,RAS, EGFR, VEGFR-1, VEGFR-2, etc). New drugs targeting these molecular pathways have beenrecently evaluated in ATC. Areas covered: We review the new targeted therapies of ATC. Interesting results have been reported with molecules targeting different pathways, as: a-BRAF (dabrafenib/trametinib, vemurafenib); b-angiogenesis (sorafenib, combretastatin, vandetanib, sunitinib, lenvatinib, CLM3, etc); c-EGFR (gefitinib); d- PPARγ agonists (rosiglitazone, pioglitazone, efatutazone). In patients with ATC treated with lenvatinib, a median overall survival of 10.6 (3.8–19.8) months was reported. In order to bypass the resistance to the single drug, the capability of targeted drugs to synergize with radiation, or chemotherapy, or other targeted drugs is explored. Expert commentary: New, affordable and individual genomic analysis combined with the opportunity to test these new treatments in primary cell cultures from every ATC patient in vitro, may permit the personalization of therapy. Increasing the therapeutic effectiveness and avoiding the use of ineffective drugs. The identification of new treatments is necessary, to extend life duration guaranteing a good quality of life. To bypass the resistance to asingle drug, the capability of targeted drugs to synergize with radiation, or chemotherapy, or othertargeted drugs is explored. Moreover, new affordable individual genomic analysis and the opportunity totest these novel treatments in primary cell cultures from every ATC patient in vitro, might permit topersonalize the therapy, increasing the therapeutic effectiveness and avoiding the use of ineffectivedrugs.