Levothyroxine in euthyroid autoimmune thyroiditis and type 1 diabetes: a randomized, controlled trial.

CONTEXT: Patients with type 1 diabetes (T1D) have an increased risk of autoimmune thyroiditis (AIT). OBJECTIVE: Our objective was to determine whether levothyroxine (l-T(4)) treatment prevents the clinical manifestation of AIT in euthyroid subjects with T1D. DESIGN AND SETTING: We conducted a prospective, randomized, open, controlled clinical trial at six tertiary care centers for pediatric endocrinology and diabetes. PATIENTS: Of 611 children and adolescents with T1D, 89 individuals (14.5%) were identified with positive thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), or both. Of these, 30 patients (age, 13.3 +/- 2.1 yr) met the inclusion criteria and were randomized to receive l-T(4) (n = 16 patients) or no treatment (n = 14 patients). INTERVENTION: l-T(4) (1.3 microg/kg daily) was given for 24 months in the treatment group, followed by an additional observation period of 6 months in both groups. MAIN OUTCOME MEASURES: Thyroid gland volume (as determined by ultrasound), serum levels of TSH, thyroid hormones, TPOAb, and TgAb were assessed every 6 months for 30 months. RESULTS: Mean thyroid volume decreased in the treatment group after 24 months (-0.60 sd score) and increased in the observation group (+ 1.11 sd score; P = 0.0218). Serum thyrotropin, free T(4), TPOAb, and TgAb levels were not significantly different in both groups during the entire study period. Hypothyroidism developed in three individuals treated with l-T(4) and in four untreated patients (conversion rate, 9.3% per year). CONCLUSIONS: In this study in euthyroid patients with AIT and T1D, l-T(4) treatment reduced thyroid volume but had no effect on thyroid function and serum autoantibody levels.

Molecular mechanisms of sulfasalazine-induced T-cell apoptosis.

Impaired apoptosis of T-lymphocytes is involved in the development of chronic inflammatory disorders. Previously we have shown that the anti-inflammatory drug sulfasalazine induces apoptosis in a murine T-lymphocyte cell line. The aims of the present study were to expand these observations to human systems and to analyse the molecular basis for sulfasalazine-induced apoptosis. Sulfasalazine induces apoptosis both in Jurkat cells, a human T-leukaemia cell line (ED50 value approximately 1.0 mM), and in primary human peripheral blood T-lymphocytes (ED50 value approximately 0.5 mM). In contrast SW620 colon carcinoma cells or primary human synoviocytes are not affected at these concentrations suggesting a cell type-specific sensitivity to sulfasalazine. Sulfasalazine triggers the mitochondrial accumulation of Bax and induces a collapse of the mitochondrial transmembrane potential (deltapsi(m)). Sulfasalazine causes cytochrome c release from mitochondria and subsequent activation of caspase-3 and downstream substrates. However, the pan-caspase inhibitor Z-VAD.fmk fails to inhibit sulfasalazine-induced apoptosis. Sulfasalazine stimulates mitochondrio-nuclear translocation of the novel apoptogenic factor apoptosis-inducing factor (AIF) and triggers large-scale DNA fragmentation, a characteristic feature of AIF-mediated apoptosis. Sulfasalazine-induced DeltaPsi(m) loss, AIF redistribution, and cell death are fully prevented by overexpression of Bcl-2. In conclusion, our data suggest that sulfasalazine-induced apoptosis of T-lymphocytes is mediated by mitochondrio-nuclear translocation of AIF and occurs in a caspase-independent fashion. Sulfasalazine-induced apoptosis by AIF and subsequent clearance of T-lymphocytes might thus provide the molecular basis for the beneficial therapeutic effects of sulfasalazine in the treatment of chronic inflammatory diseases.