Increased risk of papillary thyroid cancer in systemic sclerosis associated with autoimmune thyroiditis.

OBJECTIVES: Patients with SSc have an increased risk of malignancy compared with the general population. Before now, no study has evaluated the risk of thyroid cancer (TC) in SSc patients. The aim of the study was to evaluate the prevalence of TC in SSc patients. METHODS: We studied the prevalence of TC in 327 unselected SSc patients in comparison with two population-based, gender- and age-matched control groups (654 subjects from an iodine-deficient area and 654 subjects from an iodine-sufficient area). Thyroid status was assessed by measurement of circulating thyroid hormones and autoantibodies, thyroid ultrasonography and fine-needle aspiration cytology (when necessary). RESULTS: Circulating thyroid-stimulating hormone, anti-thyroglobulin and anti-thyroperoxidase antibody levels, and the prevalence of hypothyroidism were significantly higher in SSc patients (P < 0.01, for all). Six patients with papillary TC (PTC) were detected among SSc patients, whereas only one case was observed in each of controls 1 and 2 (P = 0.007, for both). In SSc all patients with TC had evidence of thyroid autoimmunity vs 40% of the other SSc patients (P = 0.001). CONCLUSION: These data suggest a high prevalence of papillary TC in SSc patients, in particular in the presence of thyroid autoimmunity; careful thyroid monitoring would be opportune during the follow-up of these patients.

CXCR3, CXCR5, CXCR6, and CXCR7 in Diabetes.

Many studies have suggested that CXCR3, CXCR5, CXCR6 and CXCR7 chemokine receptors are determinant in type 1 diabetes (T1D), expecially in autoimmunity and ß-cell destruction. In particular circulating CXCL10 level (the ligand of CXCR3) is high in T1D patients, and this suggests that CXCL10 may be a candidate for a predictive marker of T1D. Blocking the CXCL10/CXCR3 axis in newly onset of diabetes seems to be a potential strategy for the therapy of T1D. Attempts have been done in modulating or blocking CXCR5, CXCR6 and CXCR7 chemokine receptors in experimental settings of T1D. More researches are necessary to evaluate the interplay among cytokines, chemokines and the pathogenesis and therapy of T1D.

Autoimmune thyroid disorders.

Autoimmune thyroid diseases (AITD) result from a dysregulation of the immune system leading to an immune attack on the thyroid. AITD are T cell-mediated organ-specific autoimmune disorders. The prevalence of AITD is estimated to be 5%; however, the prevalence of antithyroid antibodies may be even higher. The AITD comprise two main clinical presentations: Graves' disease (GD) and Hashimoto's thyroiditis (HT), both characterized by lymphocytic infiltration of the thyroid parenchyma. The clinical hallmarks of GD and HT are thyrotoxicosis and hypothyroidism, respectively. The mechanisms that trigger the autoimmune attack to the thyroid are still under investigation. Epidemiological data suggest an interaction among genetic susceptibility and environmental triggers as the key factor leading to the breakdown of tolerance and the development of disease. Recent studies have shown the importance of cytokines and chemokines in the pathogenesis of AT and GD. In thyroid tissue, recruited T helper 1 (Th1) lymphocytes may be responsible for enhanced IFN-γ and TNF-α production, which in turn stimulates CXCL10 (the prototype of the IFN-γ-inducible Th1 chemokines) secretion from the thyroid cells, therefore creating an amplification feedback loop, initiating and perpetuating the autoimmune process. Associations exist between AITD and other organ specific (polyglandular autoimmune syndromes), or systemic autoimmune disorders (Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, cryoglobulinemia, sarcoidosis, psoriatic arthritis). Moreover, several studies have shown an association of AITD and papillary thyroid cancer. These data suggest that AITD patients should be accurately monitored for thyroid dysfunctions, the appearance of thyroid nodules, and other autoimmune disorders.

Hepatitis C virus infection and type 1 and type 2 diabetes mellitus.

Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients.

Modulatory effects of peroxisome proliferator-activated receptor-γ on CXCR3 chemokines.

An increasing body of evidence shows the importance of the chemokine (C-X-C motif) receptor (CXCR)3 and cognate chemokines (C-X-C motif) ligand (CXCL)9, CXCL10 and CXCL11 in the T helper 1 immune response, and in inflammatory diseases such as bowel inflammatory disorders, allograft rejection, thyroid autoimmune disorders, vascular and renal inflammation, and others. Peroxisome proliferator-activated receptor (PPAR)-γ agonists show a strong inhibitory effect on the expression and production of CXCR3 chemokines in vitro, in various kinds of cells, such as denditric cells, monocytes, macrophages, endothelial and vascular smooth muscle cells, intestinal cells, thyrocytes, fibroblasts, preadypocytes and mesangial cells, and in vivo in animal models. As rosiglitazone has recently been linked to a higher risk of heart failure, stroke, and all-cause mortality in old patients, it has been interrupted from the European market. On the contrary, the safety profile of pioglitazone seems favorable. However, further studies are ongoing to explore the use of new PPAR-γ agonists in the treatment of the above mentioned inflammatory disorders, and many interesting patents have been recently applied.

Thyroid dysfunctions induced by tyrosine kinase inhibitors.

INTRODUCTION: Recently, tyrosine kinase inhibitors (TKIs) have emerged as a new class of anticancer therapy. Although generally considered less toxic than cytotoxic chemotherapy, TKIs do cause significant side effects including fatigue and hypertension. In addition, thyroid dysfunction is a well-known adverse effect of TKI. AREAS COVERED: This review provides a comprehensive assessment of TKI-induced thyroid dysfunctions by sunitinib, sorafenib, pazopanib, imatinib, dasatinib, nilotinib, vandetanib, axitinib, motesanib and tivozanib. Furthermore, the potential mechanisms that result in this toxicity, the clinical impact of thyroid dysfunction in these patients and the controversies regarding treatment with thyroid hormone (TH) therapy are evaluated. EXPERT OPINION: Detection of TKI-induced thyroid dysfunction requires routine monitoring of thyroid function and may necessitate treatment. Potential benefits in developing thyroid dysfunction and potential harm in treating it necessitate controlled studies. Finally, if treatment is pursued, appropriate dosing and timing of TH replacement will require prospective clinical evaluation.

Variable modulation by cytokines and thiazolidinediones of the prototype Th1 chemokine CXCL10 in anaplastic thyroid cancer.

Until now, no data are present in literature about the prototype Th1 chemokine (C-X-C motif) ligand 10 (CXCL10) in anaplastic thyroid cancer (ATC). This study aimed to test in "primary human ATC cells" (ANA) vs "normal thyroid follicular cells" (TFC): (a) CXCL10 secretion basally and after interferon (IFN)-γ and/or tumor necrosis factor (TNF)-α stimulation; (b) peroxisome proliferator-activated receptor (PPAR)-γ activation by thiazolidinediones, rosiglitazone or pioglitazone, on CXCL10 secretion, on proliferation and apoptosis in ANA. We demonstrate that: (a) ANA, but not TFC, produced basally CXCL10, and did so in half of cases; (b) IFN-γ stimulated dose-dependently CXCL10, in ANA and TFC; (c) TNF-α did not induce CXCL10 secretion, in ANA and TFC; (d) IFN-γ+TNF-α induced a synergistic but variable release of CXCL10 in the different ANA preparations, while it was more reproducible in TFC; (e) rosiglitazone action on CXCL10 in ANA was inhibitory in 2/6, stimulatory in 1/6 and nil in 3/6, whereas it was inhibitory in TFC; (f) rosiglitazone inhibition of proliferation in ANA was not associated with the effect on CXCL10; (g) nuclear factor-κB and ERK1/2 were basally activated in ANA, increased by IFN-γ+TNF-α, and rosiglitazone inhibited that activation. On the whole, the present data first show that ANA cells are able to produce CXCL10, basally and under the influence of cytokines. However, the pattern of modulation by IFN-γ, TNF-α or thiazolidinediones is extremely variable, suggesting that the intracellular pathways involved in the chemokine modulation in ATC have different types of deregulation.

Systemic sclerosis fibroblasts show specific alterations of interferon-γ and tumor necrosis factor-α-induced modulation of interleukin 6 and chemokine ligand 2.

OBJECTIVE: We evaluated the effect of interferon-γ (IFN-γ) and/or tumor necrosis factor-α (TNF-α) on the secretion of prototype proinflammatory cytokine interleukin 6 (IL-6), compared to T-helper 1 [Th1; chemokine (C-X-C motif) ligand 10 (CXCL10)] or Th2 [chemokine (C-C motif) ligand 2 (CCL2)] chemokines, in primary cultured fibroblasts from patients with systemic sclerosis (SSc) at an early stage of the disease. METHODS: Fibroblast cultures from 5 SSc patients (disease duration < 2 yrs) and 5 healthy controls were evaluated for the production of IL-6, CXCL10, and CCL2 at the basal level and after stimulation with IFN-γ and/or TNF-α. RESULTS: SSc fibroblasts basally produced higher levels of IL-6 than controls, while no difference was observed about CCL2 and CXCL10. TNF-α was able to dose-dependently induce IL-6 and CCL2 secretion in SSc, but not in control fibroblasts. By stimulation with increasing doses of IFN-γ, SSc fibroblasts were induced to secrete CCL2 and CXCL10, while no effect was observed on IL-6. The combination of IFN-γ and TNF-α induced a strong secretion of IL-6 and CCL2 in SSc fibroblasts but not in controls. In contrast, the synergistic effect of IFN-γ and TNF-α on CXCL10 secretion was similar in SSc fibroblasts and in controls. CONCLUSION: SSc fibroblasts participate in the self-perpetuation of inflammation by releasing IL-6, CXCL10, and CCL2 under the influence of IFN-γ and/or TNF-α. SSc fibroblasts are more active than controls in the secretion of IL-6 at baseline, and in the production of IL-6 and CCL2 under the combined IFN-γ/TNF-α stimulation.

CLM94, a novel cyclic amide with anti-VEGFR-2 and antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo.

CONTEXT AND OBJECTIVE: We have studied the antitumor activity of a novel cyclic amide, CLM94, with anti-vascular endothelial growth factor (VEGF) receptor-2 and antiangiogenic activity in primary anaplastic thyroid cancer (ATC) cells in vitro and in vivo. DESIGN AND MAIN OUTCOME MEASURES: CLM94 was tested: 1) in two human cell lines (HMVEC-d, dermal microvascular endothelial cells; and 8305C, undifferentiated thyroid cancer) at 0.001-100 µm; 2) in ATC cells at the concentrations of 10, 30, and 50 µm; and 3) in an ATC cell line (AF) in CD nu/nu mice. RESULTS: CLM94 significantly inhibited VEGF receptor-2 and epidermal growth factor receptor phosphorylation in HMVEC-d and proliferation in HMVEC-d and 8305C cells. A significant reduction of proliferation with CLM94 in ATC cells (P < 0.01, ANOVA) and a slight but significant reduction of proliferation with CLM94 30 and 50 µm in normal thyroid follicular cells (P < 0.01, ANOVA) were shown. CLM94 increased the percentage of apoptotic ATC cells dose-dependently (P < 0.001, ANOVA) and inhibited migration (P < 0.01) and invasion (P < 0.001). AF cell line was injected sc in CD nu/nu mice, and tumor masses became detectable 25 d afterward. CLM94 (40 mg/kg · d) significantly inhibited tumor growth (starting 10 d after the beginning of treatment). CLM94 significantly decreased the VEGF-A gene expression in the AF cell line and the VEGF-A protein and microvessel density in AF tumor tissues. CONCLUSIONS: The antitumor and antiangiogenic activity of a new "cyclic amide" compound, CLM94, is very promising in ATC, opening the way to a future clinical evaluation.

Increase of circulating CXCL9 and CXCL11 associated with euthyroid or subclinically hypothyroid autoimmune thyroiditis.

CONTEXT: Recently, CXCL9 and CXCL11 have been shown to be involved in autoimmune thyroid disorders; however, no data are present about CXCL9 and CXCL11 circulating levels in thyroid autoimmunity. OBJECTIVE: Our objective was to evaluate circulating CXCL9 and CXCL11 in autoimmune thyroiditis (AIT). DESIGN AND PATIENTS OR OTHER PARTICIPANTS: Serum CXCL9 and CXCL11 have been measured in 141 consecutive patients with newly diagnosed AIT (AIT-p), 70 euthyroid controls, and 35 patients with nontoxic multinodular thyroid. The three groups were similar in gender distribution and age; among the AIT-p, 26% had subclinical hypothyroidism. RESULTS: Serum CXCL9 and CXCL11 levels were significantly (P < 0.0001 for both) higher in AIT-p (143 ± 164 and 121 ± 63 pg/ml, respectively) than in controls (68 ± 37 and 65 ± 19 pg/ml, respectively) or patients with multinodular thyroid (87 ± 43 and 71 ± 20 pg/ml, respectively). Among AIT-p, CXCL9 and CXCL11 levels were significantly higher in patients older than 50 yr or those with a hypoechoic ultrasonographic pattern or with hypothyroidism. In a multiple linear regression model including age, thyroid volume, hypoechogenicity, hypervascularity, TSH, anti-thyroglobulin, and anti-thyroid peroxidase, only age and TSH were significantly (P < 0.05) related to serum CXCL9 or CXCL11 levels. In a multiple linear regression model of CXCL9 vs. age, TSH, and CXCL11, TSH (P = 0.032) and CXCL11 (P = 0.001) were significantly and independently related to CXCL9. CONCLUSIONS: We first show that circulating CXCL9 and CXCL11 are increased in patients with thyroiditis and hypothyroidism and are related to each other. These results underline the importance of a Th1 immune attack in the initiation of AIT.

The presence of autoimmune thyroiditis in mixed cryoglobulinemia patients is associated with high levels of circulating interleukin-6, but not of tumor necrosis factor-alpha.

OBJECTIVES: To our knowledge, no study has evaluated serum levels of interleukin-6 (IL-6), together with tumour necrosis factor-alpha (TNF-α), in a large series of patients with 'mixed cryoglobulinemia and HCV chronic infection' (MC+HCV) in relation to the presence of autoimmune thyroiditis (AT). The aims of the study were to evaluate serum levels of IL-6 in MC+HCV patients and to correlate this parameter with the presence of AT and with circulating levels of TNF-α. METHODS: Serum IL-6 and TNF-α were assayed in 41 MC+HCV patients, in 41 MC+HCV patients with autoimmune thyroiditis (MC+AT), in 41 sex- and age-matched controls, and 20 AT patients. RESULTS: MC+HCV patients showed significantly (p<0.01; Mann-Whitney U-test) higher IL-6 (median 8.1ng/l, range 0.7-651) serum levels than controls (median 0.6ng/l, range 0.5-41), or AT (median 2.8ng/l, range 0.5-67). MC+AT showed significantly (p<0.01; Mann-Whitney U-test) higher mean IL-6 (median 15.8ng/l, range 0.5-781) than controls, AT and MC+HCV. Serum TNF-α levels were significantly higher in MC+HCV (median 9.9ng/l, range 1.5-283) or MC+AT (median 11.2ng/l, range 1.6-412) than in controls (median 1.0ng/l, range 0.6-6.4), or AT (median 1.7ng/l, range 0.6-11.8) (p<0.01, for each comparison). CONCLUSIONS: Our study demonstrates significantly higher serum levels of IL-6 and TNF-α in patients with MC+HCV and MC+AT compared to healthy controls. Furthermore, the study first shows a significant increase in circulating IL-6 observed in MC+AT patients with respect to MC+HCV. Future studies in larger patients' series will be needed to evaluate the relevance of serum IL-6 and TNF-α determination as clinico-prognostic markers of MC+HCV patients and its usefulness in the therapeutic approach to these patients.

Interleukin-1ß, C-x-C motif ligand 10, and interferon-gamma serum levels in mixed cryoglobulinemia with or without autoimmune thyroiditis.

The aim of this study was to evaluate serum levels of interleukin-1ß (IL-1ß), chemokine (C-X-C motif) ligand 10 (CXCL10), and interferon-gamma (IFN-γ) in a series of patients with "mixed cryoglobulinemia and hepatitis C virus chronic infection" (MC + HCV) in the presence or absence of autoimmune thyroiditis (AT) and to relate them to the clinical phenotype of these patients. Serum IL-1ß, IFN-γ, and CXCL10 were assayed in 30 patients with MC + HCV without AT, in 30 patients with MC + HCV and AT, and in 30 sex- and age-matched controls. Cryoglobulinemic patients showed significantly higher mean IL-1ß and CXCL10 levels than controls (P < 0.01). Moreover, CXCL10 was significantly increased in patients with AT patients with respect to those without AT (P < 0.01). Serum IFN-γ levels were not significantly higher in MC + HCV patients than in controls. In conclusion, our study demonstrates significantly high serum levels of IL-1ß in patients with MC + HCV with and without AT compared with healthy controls. Further, significantly high serum levels of CXCL10 in patients with MC + HCV compared with healthy controls were confirmed, overall in the presence of AT. Moreover, a pathophysiological association between high circulating levels of IL-1ß and CXCL10 has been suggested. A possible therapeutic role of the anti-IL-1 receptor antagonist (Anakirna) in MC remains to be evaluated.