Interferon-gamma ELISPOT detecting reactivity of T cells to TSH receptor peptides in Graves' disease.

OBJECTIVE: While thyrotrophin receptor (TSHR) is recognized as the main autoantigen in Graves' disease (GD), the actual antigen specificity of T cells that infiltrate the thyroid and the orbit is unknown. Identifying T cell responses to TSHR peptides has been difficult in the past due to the low frequency of autoreactive T cells and to the diversity of the putative epitopes identified by proliferation assays. METHODS: We used the interferon-gamma ELISPOT assay to identify T cell reactivity to TSHR peptides in patients with GD. Peripheral blood T cells were exposed in vitro to four pools of 10 overlapping TSHR peptides. RESULTS: T cells from 11 of 31 (35%) patients with GD and 1 of 22 (4%) healthy controls reacted to at least one peptide pool (P = 0·009). Mean time since diagnosis was 3·2 years in responder patients and 5·6 years in nonresponders (P = 0·07). In two patients, T cell reactivity was observed shortly after radioiodine treatment and not thereafter. CONCLUSIONS: Our findings demonstrate that the ELISPOT assay is effective to test T cell reactivity in patients with GD and that patients with GD have significantly more interferon-gamma responses towards TSHR peptides than controls. The data suggest that screening for T cell responses in patients with GD might be more efficient in recent-onset disease or after radioiodine treatment.

Effectiveness of pamidronate as treatment of symptomatic osteonecrosis occurring in children treated for acute lymphoblastic leukemia.

BACKGROUND: Osteonecrosis (ON) is a severe complication of acute lymphoblastic leukemia (ALL) treatments. Recent studies suggest that bisphosphonates might reduce pain and loss of motor function in patients with ON. We assessed the effects of pamidronate compared to standard care in patients with symptomatic ON (sON) and studied whether steroids might be continued after diagnosis of ON in some patients. METHODS: We evaluated 17 patients with sON as complication of primary ALL treatment between 2000 and 2008. Fourteen patients were treated with pamidronate. Mobility and pain control were monitored in all patients. Affected joints were classified by magnetic resonance imaging (MRI) at ON diagnosis and after 6-72 months. RESULTS: Out of 220 patients with ALL, 17 (7.7%) patients developed sON. The median age at ALL diagnosis was 11 years (range: 2.7-16.6 years) and sON occurred a median of 13.4 months (range: 2.5-34 months) after ALL diagnosis. Affected joints were hip, knee and ankle. MRI scans showed 7 severe, 4 moderate, and 6 mild ON lesions. Fourteen patients showed improvement in pain (77% of patients) and motor function (59% of patients), even though corticoids were reintroduced in 4 patients. MRI demonstrated improvement, stability or worsening in 6, 3, and 5 cases, respectively. CONCLUSIONS: Pamidronate seems to be effective in the management of pain and motor function recovery in sON. Further studies are needed to provide evidence as to whether bisphosphonates can be recommended for the treatment or the prevention of ON in childhood ALL patients.

Are guidelines for glucocorticoid coverage in adrenal insufficiency currently followed?

OBJECTIVES: To search for evidence of acute adrenal failure linked to inappropriate use of stress management protocols. STUDY DESIGN: Patients followed up for primary adrenal insufficiency (n = 102) or secondary adrenal insufficiency (n = 34) between 1973 and 2007 were included. All hospitalizations, both urgent (n = 157) and elective (n = 90), were examined. We recorded clinical evidence of acute adrenal failure, parental management before admission, and details of glucocorticoid prescription and administration in the hospital setting. RESULTS: For urgent hospitalizations, subgroup and time period did not influence the percentage of patients hospitalized (primary adrenal insufficiency 45%; secondary adrenal insufficiency 38%; P = .55). The use of stress glucocorticoid doses by parents increased significantly after 1997 (P < .05), although still only 47% increased glucocorticoids before hospitalization. Stress doses were more frequently administered on arrival in our emergency department after 1990 (P < .05); patients with signs or symptoms of acute adrenal failure decreased to 27% after 1997 (P < .01). Twenty-four percent of all hospitalizations were marked by suboptimal adherence to glucocorticoid stress protocols, with rare but significant clinical consequences. CONCLUSIONS: In spite of an increased use of glucocorticoid stress dose protocols by parents and physicians, patients remain at risk of morbidity and death from acute adrenal failure. This risk may be minimized with conscientious application of stress protocols, but other patient-specific risk factors may also be implicated.

Monogenic Causes in the Type 1 Diabetes Genetics Consortium Cohort: Low Genetic Risk for Autoimmunity in Case Selection.

HYPOTHESIS: About 1% of patients clinically diagnosed as type 1 diabetes have non-autoimmune monogenic diabetes. The distinction has important therapeutic implications but, given the low prevalence and high cost of testing, selecting patients to test is important. We tested the hypothesis that low genetic risk for type 1 diabetes can substantially contribute to this selection. METHODS: As proof of principle, we examined by exome sequencing families with 2 or more children, recruited by the Type 1 Diabetes Genetics Consortium (T1DGC) and selected for negativity for 2 autoantibodies and absence of risk human leukocyte antigen haplotypes. RESULTS: We examined 46 families that met the criteria. Of the 17 with an affected parent, 7 (41.2%) had actionable monogenic variants. Of 29 families with no affected parent, 14 (48.3%) had such variants, including 5 with recessive pathogenic variants of WFS1 but no report of other features of Wolfram syndrome. Our approach diagnosed 55.8% of the estimated number of monogenic families in the entire T1DGC cohort, by sequencing only 11.1% of the autoantibody-negative ones. CONCLUSIONS: Our findings justify proceeding to large-scale prospective screening studies using markers of autoimmunity, even in the absence of an affected parent. We also confirm that nonsyndromic WFS1 variants are common among cases of monogenic diabetes misdiagnosed as type 1 diabetes.

Rising serum thyroxine levels and chorea in graves' disease.

A 15-year-old girl presented with chorea as a first sign of Graves' hyperthyroidism. Chorea abated with antithyroid drug treatment and reappeared when hyperthyroidism recurred but not when thyrotropin receptor antibodies increased after administration of (131)I. Therefore, chorea in this patient is associated with hyperthyroxinemia and not with autoantibodies.