Calcium-Sensing Receptor Autoantibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1: Epitopes, Specificity, Functional Affinity, IgG Subclass, and Effects on Receptor Activity.

A major manifestation of autoimmune polyendocrine syndrome type 1 (APS1) is hypoparathyroidism, which is suggested to result from aberrant immune responses against the parathyroid glands. The calcium-sensing receptor (CaSR), which plays a pivotal role in maintaining calcium homeostasis by sensing blood calcium levels and regulating release of parathyroid hormone (PTH), is an autoantibody target in APS1. In this study, the aim was to characterize the binding sites, specificity, functional affinity, IgG subclass, and functional effects of CaSR autoantibodies using phage-display technology, ELISA, and bioassays. The results indicated that CaSR autoantibody binding sites were at aa 41-69, 114-126, 171-195, and 260-340 in the extracellular domain of the receptor. Autoantibodies against CaSR epitopes 41-69, 171-195, and 260-340 were exclusively of the IgG1 subclass. Autoantibody responses against CaSR epitope 114-126 were predominantly of the IgG1 with a minority of the IgG3 subclass. Only autoantibodies recognizing CaSR epitopes 114-126 and 171-195 affected receptor activity; inositol-phosphate accumulation was increased significantly in HEK293-CaSR cells, and PTH secretion from PTH-C1 cells was reduced significantly when either were incubated with purified Ab and Ca2+ compared with Ca2+ alone. In conclusion, although the majority of APS1 patients do not have CaSR-stimulating autoantibodies, the hypoparathyroid state in a small minority of patients is the result of functional suppression of the parathyroid glands.

Autoantibodies against the calcium-sensing receptor and cytokines in autoimmune polyglandular syndromes types 2, 3 and 4.

OBJECTIVE: The frequency of autoimmunity against the parathyroid glands in patients with polyglandular autoimmunity that is not due to autoimmune polyendocrine syndrome type 1 (APS1) is unclear. To investigate this, this study aimed to determine the prevalence of autoantibodies against parathyroid autoantigens, calcium-sensing receptor (CaSR) and NACHT leucine-rich-repeat protein 5 (NALP5), in a large group of patients with non-APS1 polyendocrine autoimmunity. Possible occult APS1 was investigated by cytokine autoantibody measurement and AIRE gene analysis. DESIGN, SUBJECTS AND MEASUREMENTS: Subjects were 178 patients with APS2, 3 or 4, and 80 healthy blood donors. Autoantibodies against the CaSR, NALP5 and cytokines were measured by immunoprecipitation, radioligand binding assays or ELISA, respectively. RESULTS: Four patient samples (2.2%), but none of the controls, were positive for CaSR autoantibodies. NALP5 autoantibodies were not detected in any participant. Eleven patients (6.2%) had cytokine autoantibodies, but none of the control samples was positive. None of the patients with cytokine autoantibodies had any known or novel mutations in the AIRE gene. CONCLUSIONS: The low prevalence of CaSR autoantibodies indicate a very low level of subclinical parathyroid autoimmunity in APS types 2, 3 and 4. In addition, autoantibodies against cytokines constitute an uncommon feature of non-APS1 polyglandular autoimmunity.

Cost-effectiveness of sibutramine in the LOSE Weight Study: evaluating the role of pharmacologic weight-loss therapy within a weight management program.

UNLABELLED: the cost-effectiveness of drug therapy when used in conjunction with a weight management program (WMP) for treatment of obesity. The objective was to compare the cost-effectiveness of sibutramine (Meridia) plus a structured WMP versus only a structured WMP in both overweight and obese individuals. The core WMP was a physician-supervised, multidisciplinary program for which each enrollee paid $100 out of pocket. METHODS: A cost-effectiveness analysis was performed based upon the results of a previously published randomized controlled trial conducted within a managed care organization. The target population for this study was obese or overweight persons. The perspective of the study was that of a managed care organization. The intervention consisted of subjects receiving a WMP with or without sibutramine. The primary outcomes of this study were (a) absolute change in body weight and percentage change in body weight over 12 months, (b) change in obesity-related and total medical costs from 12 months prior to enrollment through 12 months after enrollment, and (c) cost-effectiveness in terms of cost per pound of weight loss. All costs were adjusted to 2004 dollars using the respective components of the consumer price index for each medical service or medication. RESULTS: A total of 501 evaluable subjects were enrolled in the study, with 281 receiving sibutramine plus a structured WMP and 220 receiving only the structured WMP. The meanSD weight loss was significantly greater in the sibutramine (13.715.5 pounds, 4.8%) group than in the nondrug group (513.2 pounds, 2.2%) (P < 0.001). The change in obesity-related total cost was a median increase of $408 for the sibutramine group compared with $31 for the nondrug group (P < 0.001). The change in total health care cost was a median $1,279 increase in the sibutramine group compared with $271 for the nondrug group (P < 0.001). Adding sibutramine to the WMP increased the total cost by $44 per additional pound of weight loss (95% confidence interval, 42-46). Sensitivity analyses found that the results were sensitive to the price of sibutramine, whereas varying the cost of clinic visits did not substantially change the results. CONCLUSION: Patients enrolled in a WMP receiving sibutramine had greater weight loss and decrease in body mass index at greater cost than did patients enrolled in the same program who did not receive sibutramine. There were no observed savings in total health care resource utilization or cost in the sibutramine group compared with the nondrug group.

Health services use and health care costs of obese and nonobese individuals.

BACKGROUND: Obesity has clinical and economic consequences. Few studies have compared health care resource utilization between age- and sex-matched obese and nonobese persons. METHODS: We conducted a retrospective study in obese and nonobese individuals matched by age, sex, medical clinic, and selected exclusionary diagnoses. Data collected included hospitalizations, outpatient visits, professional claims, and prescriptions over 1 year. Costs were assigned to medical resources based on market prices using publicly available costs. Comorbid conditions were determined using a chronic disease score (CDS) index. Groups were compared on types and costs of resources consumed. Regression models were used to examine the effect of body mass index (BMI) on costs while controlling for age and chronic diseases. RESULTS: A total of 539 obese and 1225 nonobese persons were examined. Obese patients had more hospitalizations (P<.001), prescription drugs (P<.001), professional claims (P<.001), and outpatient visits (P = .005). Obese patients used more cardiovascular, intranasal allergic rhinitis, asthma, ulcer, diabetes, thyroid, and analgesic drugs. Total costs between groups were different (median of $585.44 for obese and $333.24 for nonobese patients; P<.001). Cost differences were primarily due to medications (P<.001). Predictors of total costs were age, sex, BMI, and CDS. For each unit BMI increase, costs increased 2.3% (P<.001). For each CDS unit increase, costs increased 52.9% (P<.001). CONCLUSION: Over 1 year, health care costs for obese persons are higher than for nonobese persons, primarily because of prescription drugs.

The Long-term Outcomes of Sibutramine Effectiveness on Weight (LOSE Weight) study: evaluating the role of drug therapy within a weight management program in a group-model health maintenance organization.

OBJECTIVE: To assess the benefit of sibutramine hydrochloride monohydrate within a weight management program. STUDY DESIGN: Prospective randomized controlled trial in a health maintenance organization. PATIENTS AND METHODS: Obese patients (n = 588) starting a weight management program were enrolled. Patients were randomly assigned to participate in the program alone or to participate in the program and receive sibutramine for 12 months. Outcome measures were change in weight, body mass index (BMI), percentage body fat, serum lipids, serum glucose, and blood pressure. RESULTS: At baseline, there was a younger age and higher weight, BMI, and waist circumference in the drug group. There was more degenerative joint disease in the nondrug group. The mean weight loss at 6 months was 6.8 kg (95% confidence interval [CI], -7.4 to -6.1 kg) in the drug group vs 3.1 kg (95% CI, -3.8 to -2.4 kg) (P < .001) in the nondrug group. Weight loss was maintained at 12 months. Significant reductions in BMI, body fat, and waist circumference occurred in the drug group. There were no significant changes in laboratory values or blood pressure. Patients taking sibutramine experienced a significant increase in heart rate (1.7 beats/min [95% CI, 0.5-2.9 beats/min] vs -0.4 beats/min [95% CI, -1.5 to 0.8 beats/min]; P <.004). CONCLUSION: In this managed care setting, the effectiveness and safety of sibutramine were similar to those observed in randomized, double-blind clinical efficacy trials.