George M. Bright

Autoimmunity in congenital rubella syndrome

Two hundred one deaf adolescents with congenital rubella syndrome and 83 age-matched deaf control subjects were evaluated for the presence of organ-specific antibodies directed against thyroid microsomes, thyroglobulin, pancreatic islets, adrenal cortex, and gastric parietal cells. Positive thyroid microsomal or thyroglobulin antibodies were found in 23.3% (47/201) of the rubella group and in 12.0% (10/83) of control subjects. Nine of 46 (19.6%) in the rubella group and two of nine (22.2%) control subjects with thyroid autoimmunity had thyroid gland dysfunction as indicated by elevated serum TSH concentrations. Neither islet cell nor adrenal cortical antibodies were detected in any subject tested; parietal cell antibodies were detected in 5.5% (8/146) of those in the rubella group and 8.8% (6/68) of control subjects tested, but occurred most frequently in subjects with thyroid autoimmunity (6/36, 16.7% vs 8/178, 4.5%; P less than 0.05). It is recommended that all patients with congenital rubella syndrome be screened for thyroid autoimmunity and that those with positive antibody titers be evaluated for the presence of thyroid dysfunction.

Failure of Cortisol Blockade to Inhibit Early Morning Increases in Basal Insulin Requirements in Fasting Insulin-dependent Diabetics

SUMMARY Overnight basal insulin requirements to maintain euglycemia were determined in five insulin-dependent diabetic subjects using a closed-loop insulin infusion system. A significant increase in hourly insulin requirements occurred between 0600 h and 0900 h as compared with 0100 h–0600 h. Although the increased insulin requirement was coincident with only the physiologic diurnal increase in plasma cortisol, the oral administration of the 11-beta hydroxylase inhibitor, metyrapone, decreased only the total overnight (0100 h–0900 h) basal insulin requirement, but not the early morning (0600 h-0900 h) rise in insulin required to maintain euglycemia. It would appear that although cortisol is an important counterregulatory factor, its diurnal elevation cannot account for the increase in early morning basal insulin requirements to maintain euglycemia in insulin-dependent diabetics.

A Long-Acting Human Growth Hormone With Delayed Clearance (VRS-317): Results of a Double-Blind, Placebo-Controlled, Single Ascending Dose Study in Growth Hormone–Deficient Adults

Background: Administration of daily recombinant human GH (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes. Objectives: This study assessed the safety and tolerability and the potential for achieving IGF-I levels within the target range in adults with GH deficiency after a single dose of the long-acting rhGH analog, VRS-317. Design: This was a randomized, double-blind, placebo-controlled, single ascending dose study. Patients: Fifty adults with growth hormone deficiency (mean age, 45 years) were studied in 5 treatment groups of 10 subjects each (8 active drug and 2 placebo). Setting: The study was conducted in 17 adult endocrinology centers in North America and Europe. Main Outcome Measures: Adverse events, laboratory safety assessments, and VRS-317 pharmacokinetics and pharmacodynamics (IGF-I and IGF binding protein-3) were analyzed. Results: At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40, and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3–5.0 μg/kg over 30 d) safely increased the amplitude and duration of IGF-I responses in a dose-dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between −1.5 and 1.5 SD values for a mean of 3 weeks. No unexpected or serious adverse events were observed. Conclusions: The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing.

Quantitative Assay for Human Cytoplasmic Islet Cell Antibodies

An assay for human islet cell antibodies (ICAs) in serum yielding numerical values and amenable to statistical evaluation has been developed utilizing fluorescence spectrophotomicroscopy (FSPM). The results of the blinded trials by FSPM were compared with those by standard indirect immunofluorescence (IFL). No false-positive or false-negative readings were obtained in 258 observations when the results by FSPM were compared with those by IFL. The intraand interassay variabilities encountered were not enough to misclassify a specimen. The presence of anti-thyroid, anti-adrenal, or anti-nuclear antibodies did not produce false-positive readings. Twenty-eight additional specimens from diabetic children were also analyzed via three blood group type O pancreases. There was complete agreement concerning the presence or absence of ICA between IFL and FSPM analyses. Analysis of the three pancreases yielded different numbers of results positive for ICA (14/28 vs. 22/28 vs. 15/28, P = .008) in both assays. Thus, selection of pancreatic substrate may influence the outcome of assays for ICA. A matrix of fluorescent microspheres has been devised that allows calibration of the FSPM system. Now, reproducible and comparable readings for ICA values can be obtained from the various reporting laboratories. Should an international reference serum for ICA become available, the remaining problem in the ICA assay, that of substrate (pancreas) variability, should be resolved.

A Randomized Safety and Efficacy Study of Somavaratan (VRS-317), a Long-Acting rhGH, in Pediatric Growth Hormone Deficiency

CONTEXT Somavaratan (VRS-317) is a long-acting form of recombinant human GH under development for children and adults with GH deficiency (GHD). OBJECTIVES To determine the optimal somavaratan dose regimen to normalize IGF-1 in pediatric GHD and to evaluate safety and efficacy of somavaratan over 6 months. DESIGN Open-label, multicenter, single ascending dose study followed by 6-month randomized comparison of 3 dosing regimens. SETTING Twenty-five United States pediatric endocrinology centers. PATIENTS Naive-to-treatment, prepubertal children with GHD (n = 68). INTERVENTION(S) Patients received single sc doses of somavaratan (0.8, 1.2, 1.8, 2.7, 4.0, or 6.0 mg/kg) during the 30-day dose-finding phase, then were randomized to somavaratan 1.15 mg/kg weekly, 2.5 mg/kg twice monthly, or 5.0 mg/kg monthly for 6 months. MAIN OUTCOME MEASURES Safety, pharmacokinetics, pharmacodynamics, 6-month height velocity (HV). RESULTS Somavaratan pharmacokinetics was linearly proportional to dose; dose-dependent increases in the magnitude and duration of IGF-1 responses enabled weekly, twice-monthly or monthly dosing. A single dose of somavaratan sustained IGF-1 responses for up to 1 month. No somavaratan or IGF-1 accumulation occurred with repeat dosing. Mean annualized HVs for somavaratan administered monthly, twice monthly, or weekly (7.86 ± 2.5, 8.61 ± 2.7, and 7.58 ± 2.5 cm/y, respectively) were similar between groups. Adverse events were mostly mild and transient. CONCLUSIONS Somavaratan demonstrated clinically meaningful improvements in HV and IGF-1 in prepubertal children with GHD, with no significant differences between monthly, twice-monthly, or weekly dosing.