Available from: Pat Kendall-Taylor, Apr 18, 2015
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    ABSTRACT: To better understand the pathogenesis of thyroid-associated orbitopathy (TAO) through elucidating the role of thyrotropin receptor (TSHR) and CD40 in the expression of interleukin-8 (IL-8) in peripheral blood fibrocytes. Fibrocytes infiltrate the orbit of patients with TAO, where they differentiate into fibroblasts. Fibrocyte precursors occur with increased frequency in the peripheral blood expressing TSHR and CD40 in TAO patients. We hypothesize that in vitro derived fibrocytes and peripheral blood fibrocyte precursors express proinflammatory chemoattractant molecules including IL-8 initiated by TSHR and CD40 signaling. Since nearly all TAO patients express activating antibodies to TSHR, this is particularly relevant for activation of peripheral blood fibrocytes. TSHR and CD40 expression on peripheral blood fibrocytes was determined by flow cytometry. IL-8 RNA was quantitated by real-time polymerase chain reaction. IL-8 protein production was measured by Luminex and flow cytometry. Thyroid-stimulating hormone and CD40 ligand-stimulated phosphorylation of Akt in peripheral blood fibrocytes was studied by flow cytometry. Both TSHR- and CD40-mediated signaling lead to IL-8 expression in mature fibrocytes. Fibrocyte precursors assayed directly from circulating peripheral blood demonstrate intracellular IL-8 expression with addition of thyroid-stimulating hormone or CD40 ligand. TSHR- and CD40-induced IL-8 production is mediated by Akt phosphorylation. Peripheral blood TSHR(+) and CD40(+) fibrocytes express IL-8 and may promote the recruitment of inflammatory cells, mitogenesis, and tissue remodeling in TAO. TSHR- and CD40-mediated IL-8 signaling is mediated by Akt. Delineating the molecular mechanisms of fibrocyte immune function may provide potential therapeutic targets for TAO.
    Transactions of the American Ophthalmological Society 07/2014; 112:26-37.
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    ABSTRACT: IntroductionGraves’ disease is the most frequent form of hyperthyroidism in iodine sufficient countries [1], and Graves’ orbitopathy (GO) is its most important and common extrathyroidal manifestation [2], affecting about 25 % of patients [3]. Although GO is generally mild and rarely progressive [4], thyroid dysfunction, both hyperthyroidism and hypothyroidism, can influence its course. GO has been reported to improve after correction of hyperthyroidism with antithyroid drug (ATD) treatment [5], or to occur or worsen after a period of uncontrolled hypothyroidism [6]. Accordingly, the European Group on Graves’ Orbitopathy (EUGOGO) Consensus Statement few years ago recommended that restoration and maintenance of euthyroidism are priorities in Graves’ disease patients with GO [7]. How to treat hyperthyroidism when GO is present is, however, a challenging dilemma [8]. Are current modalities for hyperthyroidism [ATDs, radioiodine (RAI), thyroidectomy] per se capable to affect the course of G ...
    Journal of endocrinological investigation 02/2015; 38(4). DOI:10.1007/s40618-015-0257-z · 1.55 Impact Factor
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    ABSTRACT: Safety of intravenous (IV) steroid pulses in patients with Graves' orbitopathy (GO) is still controversial while steroid dose and treatment application have not been finalized. Frequency, severity and characterization of adverse events (AE) were prospectively analyzed. Academic referral orbital center with a joint thyroid-eye clinic. Eighty consecutive and unselected patients with active and severe GO. During an established treatment with IV methylprednisolone (cumulative dose 4.5 g) occurring AE were prospectively coded according to the standardized and recognized medical dictionary for regulatory activities (MedDRA). Outcome and severity of AE were documented. AEs judged as at least possibly related to drug treatment were graded as side effect (SE). AEs matching a seriousness criteria as defined by the ICH guideline E6 (good clinical practice) were graded as serious. A total of 38.75 % (31/80) of the treated GO patients reported at least one AE while 18 patients (22.5 %) reported at least one SE. All SE were within the safety profile of IV methylprednisolone; 31/32 SE (96.87 %) were mild-moderate and reversible and only 1/80 patient (1.25 %) stopped steroid treatment due to exacerbation of her depression. Most AE were accessory symptoms of the underlying disease and a few only were directly related to IV steroids. Most AEs (90.6 %) were graded as mild. Only six patients (7.5 %) were hospitalized, three of them due to a dysthyroid optic neuropathy. Prospective and standardized evaluation with MedDRA and the ICH guideline demonstrated the good pharmacological tolerance and low morbidity of this moderate steroid regimen.
    Journal of endocrinological investigation 01/2015; DOI:10.1007/s40618-014-0227-x · 1.55 Impact Factor