Predicting Responders to Reslizumab after 16 Weeks of Treatment Using an Algorithm Derived from Clinical Studies of Patients with Severe Eosinophilic Asthma.

RATIONALE: Reslizumab is a humanized anti-IL-5 monoclonal antibody used as add-on maintenance treatment for patients with uncontrolled eosinophilic asthma. OBJECTIVES: To predict response and nonresponse to intravenous reslizumab at 52 weeks with an algorithm we developed based on clinical indicators from pivotal clinical trials. METHODS: Patients aged 18 years and older who met Global Initiative for Asthma 4 or 5 criteria and received intravenous reslizumab (n = 321) in two trials ( www.clinicaltrials.gov identifiers, NCT01287039 and NCT01285323) were selected as the data source. A mathematical model was constructed that was based on change from baseline to 16 weeks in Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores and FEV1, and number of clinical asthma exacerbations during the year before enrollment and in the first 16 weeks of treatment, and these measures were evaluated for their ability to predict the outcome at 52 weeks: responder, nonresponder, or indeterminate. MEASUREMENTS AND MAIN RESULTS: The algorithm predicted that 276 patients would be classified as responders; in 248 (89.9%), the prediction was correct. In comparison, 26 patients were predicted to be nonresponders; 50.0% of these predictions were correct. Nineteen patients were classified as indeterminate. The algorithm had 95.4-95.5% sensitivity and 40.6-54.1% specificity. Jackknife and cross-study validation confirmed the robustness of the algorithm. CONCLUSIONS: Our algorithm enabled prediction at 16 weeks of treatment of the response to intravenous reslizumab treatment at 52 weeks, but it was not suitable for predicting nonresponse. A positive score at 16 weeks should encourage continued treatment, and a negative score should prompt close monitoring to determine whether discontinuation is warranted.

In patients with severe asthma with eosinophilia in reslizumab clinical trials, high peripheral blood eosinophil levels are associated with low FEV1 reversibility.

BACKGROUND: A post hoc analysis of two randomized, placebo-controlled, Phase 3 trials of intravenous reslizumab, an anti-interleukin-5 (IL-5) biologic for severe eosinophilic asthma. METHODS: Relationships between baseline blood eosinophil levels (EOS), forced expiratory volume in 1 s (FEV1) reversibility to ß2-agonists and treatment outcomes were assessed. RESULTS: Mean baseline FEV1 reversibility was numerically lower among patients with high (≥ 400 cells/µL) versus low baseline EOS. Reslizumab produced clinically significant improvement in FEV1, exacerbation rates and patient-reported outcomes after 52 weeks, including in patients with high EOS and low FEV1 reversibility (≤ 14%) to ß2-agonists at baseline. CONCLUSIONS: Clinical trial eligibility criteria stipulating minimum FEV1 reversibility to ß2-agonists of ≥ 12% might exclude patients who would benefit from treatment with anti-IL-5 biologics.

Efficacy of Reslizumab Treatment in Exacerbation-Prone Patients with Severe Eosinophilic Asthma.

BACKGROUND: Patients with severe eosinophilic asthma have increased risk of clinical asthma exacerbations (CAEs), impaired lung function, and lower quality of life (QoL) compared with patients with noneosinophilic asthma. The efficacy and safety of intravenous reslizumab have been demonstrated in 2 duplicate, randomized, double-blind, placebo-controlled, phase 3 studies. OBJECTIVE: We present findings from post hoc analyses of the subgroup of patients from the phase 3 studies with severe (Global Initiative for Asthma [GINA] Step 4 or 5) eosinophilic asthma who had ≥2 or ≥3 CAEs in the 12 months before screening. METHODS: Patients aged ≥12 years with severe eosinophilic asthma were randomized (1:1) to reslizumab 3.0 mg/kg or placebo every 4 weeks for 1 year. Outcomes assessed included CAEs, forced expiratory volume in 1 second (FEV1), and Asthma Control Questionnaire 6 (ACQ-6) and Asthma QoL Questionnaire (AQLQ) scores. RESULTS: Of 953 patients randomized, 318 (reslizumab: n = 156; placebo: n = 162) and 164 (reslizumab: n = 72; placebo: n = 92) were GINA 4/5 with ≥2 CAEs in the prior year and ≥3 CAEs in the prior year, respectively. Reslizumab significantly improved CAE rate, time to first CAE, and the proportion of patients who experienced ≥1 CAE versus placebo in both CAE subgroups. Improvements in FEV1, ACQ-6 and AQLQ scores, and systemic corticosteroid burden were also observed with reslizumab versus placebo after 52 weeks of treatment in both CAE subgroups. CONCLUSION: Reslizumab reduced CAE frequency and improved lung function, asthma control, and QoL versus placebo in patients with severe eosinophilic asthma with a high CAE rate before treatment.

Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Modeling of Weight-Based Intravenous Reslizumab Dosing.

Reslizumab 3.0 mg/kg has demonstrated efficacy in clinical studies of patients with eosinophilic asthma and a history of exacerbations. A population pharmacokinetic (PK) model was developed to determine whether 3.0 mg/kg weight-based dosing is appropriate to obtain consistent reslizumab exposures in all patients. PK data in healthy volunteers and patients ≥12 years with moderate to severe asthma, eosinophilic asthma, or nasal polyposis were analyzed from 4 phase 1, 2 phase 2, and 2 phase 3 studies of intravenous (IV) reslizumab (N = 804). Covariates evaluated included age, race, sex, baseline weight, renal and liver function, concomitant medications, and antidrug antibody status. Exposure-response models were developed to characterize key efficacy (blood eosinophil levels, forced expiratory volume in 1 second [FEV1 ], Asthma Control Questionnaire [ACQ-7] scores), and safety end points (muscle disorder adverse events [AEs]). Vial-based dosing was evaluated as an alternative to weight-based dosing. IV reslizumab PK was accurately described by a 2-compartment PK model with 0-order input and first-order elimination. Body weight was the only covariate that significantly influenced PK parameters. However, with weight-based dosing, comparable steady-state exposures were observed across high and low body weights. Greater eosinophil lowering and longer response duration were observed with increasing dose; exposure-related effects on FEV1 and ACQ-7 were also seen, demonstrating the clinical importance of a dosing regimen to optimize reslizumab exposure. The probability of a muscle disorder AE appeared to increase with increasing exposure. Steady-state exposure measures were similar for both dosing regimens, showing vial-based dosing as an alternative method of achieving the benefits of weight-based dosing.

Safety of Reslizumab in Uncontrolled Asthma with Eosinophilia: A Pooled Analysis from 6 Trials.

BACKGROUND: Intravenous reslizumab, a monoclonal IL-5 antibody, is approved for treating severe asthma with eosinophilia. Limited structured information is available on the safety of reslizumab in larger populations. OBJECTIVE: To investigate the safety profile of intravenous reslizumab 3.0 mg/kg by analyzing data from 6 asthma clinical trials: 5 placebo-controlled (duration ≤52 weeks) and 1 open-label extension (up to 2 years of treatment). METHODS: Patients were aged 12 to 75 years with inadequately controlled asthma with eosinophilia. In the placebo-controlled trials, 730 patients received placebo and 1028 received reslizumab 3.0 mg/kg. RESULTS: Adverse events (AEs) and serious AEs occurred in higher percentages of patients in the placebo group (81% and 9%) than in the reslizumab group (67% and 6%). Asthma, nasopharyngitis, and upper respiratory tract infection were the most common AEs with placebo and reslizumab. Three cases of anaphylaxis, related to reslizumab, were successfully managed with standard therapies. No significant difference in the incidence of malignancies was seen when compared with placebo or the general population. Among 756 patients with more than 12 months of reslizumab exposure, the AE rate was lower than in the placebo-controlled trials (367.3 vs 433.9 events/100 patient-years). The incidence of AEs in patients on treatment for more than 12 months was no higher than in patients with shorter treatment durations. CONCLUSIONS: This analysis confirms that treatment with intravenous reslizumab for more than 12 months is well tolerated in patients with asthma, with no evidence of rare safety events that were not detected in individual trials.

Efficacy of Intravenous Reslizumab in Oral Corticosteroid-Dependent Asthma.

BACKGROUND: Reslizumab displays efficacy in patients with inadequately controlled eosinophilic asthma; previous reports in oral corticosteroid-dependent asthma are limited. OBJECTIVE: To assess efficacy of reslizumab in oral corticosteroid-dependent patients and benefits on oral corticosteroid burden. METHODS: We report post hoc analyses of pooled data from duplicate, placebo-controlled phase 3 trials. Patients aged 12 to 75 years with inadequately controlled, moderate-to-severe asthma were randomized 1:1 to receive intravenous reslizumab 3.0 mg/kg or placebo every 4 weeks for 52 weeks, stratified by oral corticosteroid use at enrollment and by region. Assessments included efficacy and predictors of clinical asthma exacerbation response in oral corticosteroid-dependent patients, and systemic corticosteroids burden in the overall population. RESULTS: Patients were randomized to reslizumab (n = 477) or placebo (n = 476); 73 (15%) patients in each group were taking oral corticosteroids at baseline. Reslizumab was favored over placebo for all efficacy end points in oral corticosteroid-dependent patients, with numerically greater improvements in oral corticosteroid-dependent patients than the overall population. Having 2 or more versus 1 clinical asthma exacerbation in the previous 12 months was the strongest positive predictor of reduced exacerbation risk with reslizumab (risk reduction, 77.5% vs 15.2%; P ≤ .02). Significantly fewer new systemic corticosteroid prescriptions were issued per patient receiving reslizumab versus placebo (mean ± SD, 0.5 ± 1.07 vs 1.0 ± 1.52; P < .0001). Total and per-patient systemic corticosteroid burdens were lower: 121,135 versus 290,977 mg and 254 versus 611 mg/patient, respectively (both P < .0001). CONCLUSIONS: Oral corticosteroid-dependent patients benefited from reslizumab across asthma efficacy outcome measures. Reslizumab-treated patients required fewer new systemic corticosteroid prescriptions and had a lower systemic corticosteroid burden compared with placebo.

Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma: results from two phase 3, randomised, double-blind, placebo-controlled trials.

BACKGROUND: Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). METHODS: Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per µL or more (including no more than 30% patients with an eosinophil count <400 cells/µL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per µL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2). FINDINGS: Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per µL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies. INTERPRETATION: Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/µL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy. FUNDING: Teva Branded Pharmaceutical Products R&D.

Cost-utility of treatments for pulmonary arterial hypertension: a Markov state-transition decision analysis model.

BACKGROUND AND OBJECTIVE: Clinicians must choose between an increasing number of medications for the treatment of pulmonary arterial hypertension (PAH) with different routes of administration, adverse effects, costs and efficacies. We constructed a decision analysis to help inform treatment choices in PAH. METHODS: We created a Markov-type model to evaluate 1-year treatment with bosentan, treprostinil, epoprostenol, inhaled iloprost, sildenafil, sitaxentan and ambrisentan. Transition probabilities were based on observed transitions between WHO functional classes, adjusted by relative risk of improvement in a 6-minute walk test. Utilities were based on reported values for each functional class, adjusted for burden of treatment administration. Costs were estimated from Medicare and Medicaid reimbursement data. Sensitivity analyses evaluated changes in efficacy, utilities and costs. RESULTS: Treatment with sildenafil was less costly and resulted in a greater gain in quality-adjusted life-years (QALYs) compared with other treatments. Treatment with ambrisentan and bosentan resulted in the same gain in QALYs as sildenafil, but at a higher cost. Sensitivity analyses had minimal impact on these results. CONCLUSIONS: Based on this model, sildenafil is a cost-effective treatment for PAH with a low price and a net increase in QALYs. The results from this analysis are a tool to help guide clinicians in deciding which PAH medications to use; however, the final decisions should be individualized because the effectiveness of therapy, resulting utilities and acceptable costs will differ with each patient.

Effects of Reslizumab on Asthma Outcomes in a Subgroup of Eosinophilic Asthma Patients with Self-Reported Chronic Rhinosinusitis with Nasal Polyps.

BACKGROUND: An estimated 7% of patients with asthma have chronic rhinosinusitis with nasal polyps (CRSwNP), and more than 80% have at least some radiographic evidence of sinonasal inflammation. Aspirin sensitivity is strongly associated with elevated blood eosinophil levels and increased asthma severity. Intravenous (IV) reslizumab has been shown to improve asthma control in patients with nasal polyps. OBJECTIVE: These post hoc analyses of pooled data from 2 BREATH phase 3 clinical trials, studies 1 and 2 (NCT01287039 and NCT01285323), examined asthma-related outcomes in patients with comorbid, self-reported CRSwNP with and without aspirin sensitivity. METHODS: Patients aged 12-75 years with elevated blood eosinophils (≥400 cells/µL) and inadequately controlled asthma were randomized to receive placebo or reslizumab (3 mg/kg IV) every 4 weeks for 52 weeks. Patients continued their background asthma maintenance therapy during the study. Information regarding the presence of CRSwNP was obtained through patient-reported medical history. RESULTS: Add-on reslizumab treatment reduced the frequency of clinical asthma exacerbations by 83% versus placebo among patients with CRSwNP. Among patients with and without aspirin sensitivity, reductions of 79% and 84%, respectively, were observed. Patients with CRSwNP (with and without aspirin sensitivity) treated with reslizumab add-on therapy also had significant improvements in lung function, as measured by forced expiratory volume in 1 second, compared with placebo. Among patients with CRSwNP, reslizumab was also associated with improvements in patient-reported asthma control and asthma quality of life. CONCLUSIONS: Patients with eosinophilic asthma and self-reported CRSwNP, with and without aspirin sensitivity, are highly responsive to treatment with reslizumab for asthma-related outcomes. These findings suggest that prospective investigation of reslizumab in this patient population is warranted.

Long-term Safety and Efficacy of Reslizumab in Patients with Eosinophilic Asthma.

BACKGROUND: In placebo-controlled trials, reslizumab, an anti-IL-5 monoclonal antibody, significantly reduced asthma exacerbations and improved lung function and asthma control in patients with eosinophilic asthma. OBJECTIVE: This open-label extension study evaluated safety and efficacy of reslizumab for up to 24 months. METHODS: After participation in 1 of 3 placebo-controlled, phase III trials in moderate-to-severe eosinophilic asthma, patients received reslizumab 3.0 mg/kg intravenously every 4 weeks for up to 24 months. Adverse events (AEs), lung function, and patient-reported asthma control were evaluated. RESULTS: In the open-label extension, 1,051 patients received ≥1 reslizumab dose (480 reslizumab-naïve, 571 reslizumab-experienced); median (range) exposure was 319 (36-840) and 343 (36-863) days in reslizumab-naïve and reslizumab-experienced patients, respectively. Continuous exposure, including during the placebo-controlled studies, was ≥12 months for 740 patients and ≥24 months for 249 patients. The most common AEs were worsening of asthma and nasopharyngitis. Serious AEs affected 78 of 1,051 (7%) patients; 18 of 1,051 (2%) discontinued treatment because of AEs; and there were 3 deaths (all non-treatment-related). Fifteen adult patients (15 of 1,023; 1%) had malignancies of diverse tissue types. Reslizumab-experienced patients maintained improved lung function and asthma control; reslizumab-naïve patients had improvements in these measures throughout open-label treatment. Blood eosinophil counts appeared to be returning to baseline after reslizumab discontinuation. CONCLUSIONS: In patients with moderate-to-severe eosinophilic asthma, intravenous reslizumab 3.0 mg/kg displays favorable long-term safety and sustained long-term efficacy. Initial improvements in lung function and asthma control were maintained for up to 2 years. These findings substantially add to our understanding of the long-term safety and efficacy of anti-IL-5 strategies.

Ghrelin is independently associated with anti-mullerian hormone levels in obese but not non-obese women with polycystic ovary syndrome.

Ghrelin is an endogenous appetite stimulant that may have a role in ovarian function. Women with polycystic ovary syndrome have anovulation and frequently weight management issues; however the associations between ghrelin and hormonal markers in polycystic ovary syndrome have not been well studied. In order to characterize the association between total ghrelin levels and ovarian function and the possible modification of this relationship by obesity, we examined total ghrelin levels and anti-mullerian hormone, total testosterone, and insulin in obese and non-obese women with and without polycystic ovary syndrome. Total ghrelin levels were lower in obese women with polycystic ovary syndrome (n = 45) compared to obese controls (n = 33) (p = 0.005), but similar in non-obese women with polycystic ovary syndrome (n = 20) compared to non-obese controls (n = 21) (p = NS). In the obese polycystic ovary syndrome group, anti-mullerian hormone was associated with ghrelin levels independent of age, insulin, and total testosterone (p = 0.008). There was no association between total ghrelin and anti-mullerian hormone levels in non-obese women with polycystic ovary syndrome, non-obese controls, or obese controls (p = NS). Our results provide evidence for a potential relationship between ghrelin and ovarian function in obese women with polycystic ovary syndrome that was not observed in non-obese women with polycystic ovary syndrome or controls.

Phase 3 Study of Reslizumab in Patients With Poorly Controlled Asthma: Effects Across a Broad Range of Eosinophil Counts.

BACKGROUND: IL-5, a mediator of eosinophil activity, is an important potential treatment target in patients with uncontrolled asthma. The efficacy of reslizumab, a humanized anti-human IL-5 monoclonal antibody, has been characterized in patients with blood eosinophils ≥ 400 cells/µL. This study further characterizes the efficacy and safety of reslizumab in patients with poorly-controlled asthma, particularly those with eosinophils < 400 cells/µL. METHODS: Patients were randomly assigned to intravenous reslizumab 3.0 mg/kg or placebo once every 4 weeks for 16 weeks. The primary end point was the change in FEV1 from baseline to week 16. Secondary measures included Asthma Control Questionnaire-7 (ACQ-7) scores, use of short-acting ß-agonists (SABAs), and FVC. RESULTS: Four hundred ninety-two patients received ≥ 1 dose of placebo (n = 97) or reslizumab (n = 395). In the overall population, mean FEV1 change from baseline to week 16 was not significantly different between reslizumab and placebo, and no significant relationship was detected between treatment, baseline blood eosinophils and change in FEV1. In the subgroup of patients with baseline eosinophils < 400 cells/µL, patients treated with reslizumab showed no significant improvement in FEV1 compared with those receiving placebo. In the subgroup with eosinophils ≥ 400 cells/µL, however, treatment with reslizumab was associated with much larger improvements in FEV1, ACQ-7, rescue SABA use, and FVC compared with the placebo group. Reslizumab was well tolerated, with fewer overall adverse events compared with placebo (55% vs 73%). CONCLUSIONS: Reslizumab was well tolerated in patients with inadequately controlled asthma. Clinically meaningful effects on lung function and symptom control were not seen in patients unselected for baseline eosinophils. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01508936; URL: www.clinicaltrials.gov.

Subclinical thyroid dysfunction and hip fracture and bone mineral density in older adults: the cardiovascular health study.

BACKGROUND: Subclinical thyroid dysfunction is common in the elderly, yet its relationship with hip fracture and bone mineral density (BMD) is unclear. OBJECTIVE: We examined the association between endogenous subclinical hyper- and hypothyroidism and hip fracture and BMD in older adults. METHODS: A total of 4936 US individuals 65 years old or older enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of incident hip fracture were performed by thyroid status, over a median follow-up of 12 years. A cross-sectional analysis of thyroid status and BMD was performed in a subset of 1317 participants who had dual-energy x-ray absorptiometry scans. Models were adjusted for risk factors and stratified by sex. RESULTS: No association was found between subclinical hypothyroidism and incident hip fracture compared with euthyroidism, when assessed at a single time point or persisting at two time points, in either women [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.69-1.20 for a single and HR 0.79, 95% CI 0.52-1.21 for two time points] or men (HR 1.27, 95% CI 0.82-1.95 for a single and HR 1.09, 95% CI 0.57-2.10 for two time points). Likewise, no association was found between subclinical hyperthyroidism and incident hip fracture in either sex (HR 1.11, 95% CI 0.55-2.25 in women and HR 1.78, 95% CI 0.56-5.66 in men). No association was found between subclinical thyroid dysfunction and BMD at the lumbar spine, total hip, or femoral neck sites. CONCLUSIONS: Our data suggest no association between subclinical hypothyroidism or subclinical hyperthyroidism and hip fracture risk or BMD in older men and women. Additional data are needed to improve the precision of estimates for subclinical hyperthyroidism and in men.

Subclinical hypothyroidism, weight change, and body composition in the elderly: the Cardiovascular Health Study.

BACKGROUND: Subclinical hypothyroidism is common in the elderly, yet its relationship with weight and body composition is unclear. OBJECTIVE: We examined the relationship between subclinical hypothyroidism and weight change and body composition in older adults. METHODS: A total of 427 subclinically hypothyroid and 2864 euthyroid U.S. individuals ≥65 years old enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of 6-year weight change were performed, compared by thyroid status. A cross-sectional analysis of thyroid status and body composition was performed in a subset of 1276 participants who had dual-energy x-ray absorptiometry scans. Models were risk factor-adjusted and stratified by sex. RESULTS: Overall, participants lost weight during follow-up (-0.38 kg/y in men, -0.37 kg/y in women). Subclinical hypothyroidism, when assessed at a single time point or persisting over 2 years, was not associated with a difference in weight change compared with euthyroidism. Subclinical hypothyroidism was also not associated with differences in lean mass, fat mass, or percent fat compared with euthyroidism. A TSH level 1 mU/L higher within the euthyroid or subclinical hypothyroid range was associated with a 0.51-kg higher baseline weight in women only (P < .001) but not with weight change in either sex. A 1 ng/dL higher free T4 level was associated with lower baseline weight and 0.32 kg/y greater weight loss in women only (P = .003). Baseline weight and weight change did not differ by T3 levels. CONCLUSIONS: Our data do not support a clinically significant impact of subclinical hypothyroidism on weight status in the elderly.

Clinical review: The human experience with ghrelin administration.

CONTEXT: Ghrelin is an endogenous stimulator of GH and is implicated in a number of physiological processes. Clinical trials have been performed in a variety of patient populations, but there is no comprehensive review of the beneficial and adverse consequences of ghrelin administration to humans. EVIDENCE ACQUISITION: PubMed was utilized, and the reference list of each article was screened. We included 121 published articles in which ghrelin was administered to humans. EVIDENCE SYNTHESIS: Ghrelin has been administered as an infusion or a bolus in a variety of doses to 1850 study participants, including healthy participants and patients with obesity, prior gastrectomy, cancer, pituitary disease, diabetes mellitus, eating disorders, and other conditions. There is strong evidence that ghrelin stimulates appetite and increases circulating GH, ACTH, cortisol, prolactin, and glucose across varied patient populations. There is a paucity of evidence regarding the effects of ghrelin on LH, FSH, TSH, insulin, lipolysis, body composition, cardiac function, pulmonary function, the vasculature, and sleep. Adverse effects occurred in 20% of participants, with a predominance of flushing and gastric rumbles and a mild degree of severity. The few serious adverse events occurred in patients with advanced illness and were not clearly attributable to ghrelin. Route of administration may affect the pattern of adverse effects. CONCLUSIONS: Existing literature supports the short-term safety of ghrelin administration and its efficacy as an appetite stimulant in diverse patient populations. There is some evidence to suggest that ghrelin has wider ranging therapeutic effects, although these areas require further investigation.

Limitations to the 6-minute walk test in interstitial lung disease and pulmonary hypertension in scleroderma.

OBJECTIVE: To determine factors that influence 6-minute walk distance (6MWD) in patients with scleroderma (systemic sclerosis, SSc)-interstitial lung disease (ILD), SSc-pulmonary hypertension (PH), and idiopathic pulmonary fibrosis (IPF). METHODS: We retrospectively evaluated all patients with SSc or IPF who performed a 6-minute walk test (6MWT) at a university hospital between 1999 and 2003. Chi-square, ANOVA, simple linear regression, and backwards elimination multivariable regressions were performed. RESULTS: Forty-eight consecutive IPF patients with 6MWT were compared to 33 patients with SSc-ILD, 13 with SSc-PH, 19 with both SSc-ILD and SSc-PH (SSc-Both), and 15 with SSc without ILD or PH (SSc-Neither). Mean 6MWD did not differ between groups. Limitations to 6MWT trended toward dyspnea in IPF and lower extremity pain in SSc. SSc-Both had dyspnea limitation more than other SSc subgroups (p = 0.017). Percentage predicted forced vital capacity (FVC%) and percentage predicted carbon monoxide diffusing capacity (DLCO%) were more strongly predictive of 6MWD in IPF than in SSc; however, exclusion of SSc subjects with pain limitation improved the predictive value. Significant correlates of 6MWD in multivariable analysis differed between subgroups. CONCLUSION: Pain limitations confound the utility of the 6MWT, particularly in SSc. Pain may cause failure to reach a dyspnea limitation during 6MWT, especially in SSc patients without both ILD and PH. Correlates of 6MWD differ between SSc subgroups and IPF; therefore, the 6MWT distance is not always reflective of the same physiological process. 6MWT interpretation should include consideration of vascular, pulmonary, and musculoskeletal exercise limitations.

The spectrum of scleroderma lung disease.

Pulmonary disease is the most common cause of death in patients with systemic sclerosis. This article discusses the variety of ways the lung is affected in systemic sclerosis. These include pulmonary hypertension, interstitial lung disease and other restrictive disorders, obstructive disease, pleural disease, lung cancer, and aspiration. For each manifestation we outline the current knowledge of etiology, risk factors, diagnosis, treatment, and prognosis. We also discuss the current state of lung transplantation in this population.