BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION. ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Objective: Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs. Participants: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public. Evidence: A literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were unavailable or scarce. Consensus Process: The guideline was drafted by committee members and reviewed, revised, and approved by the entire committee during group meetings. Contributing societies reviewed the document and provided approval. Conclusions: Lipodystrophy syndromes are heterogeneous and are diagnosed by clinical phenotype, supplemented by genetic testing in certain forms. Patients with most lipodystrophy syndromes should be screened for diabetes, dyslipidemia, and liver, kidney, and heart disease annually. Diet is essential for the management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic complications in hypoleptinemic patients with generalized lipodystrophy and selected patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated.

Epidemiological data have demonstrated an association between artificial sweetener use and weight gain. Evidence of a causal relationship linking artificial sweetener use to weight gain and other metabolic health effects is limited. However, recent animal studies provide intriguing information that supports an active metabolic role of artificial sweeteners. This systematic review examines the current literature on artificial sweetener consumption in children and its health effects. Eighteen studies were identified. Data from large, epidemiologic studies support the existence of an association between artificially-sweetened beverage consumption and weight gain in children. Randomized controlled trials in children are very limited, and do not clearly demonstrate either beneficial or adverse metabolic effects of artificial sweeteners. Presently, there is no strong clinical evidence for causality regarding artificial sweetener use and metabolic health effects, but it is important to examine possible contributions of these common food additives to the global rise in pediatric obesity and diabetes.

Background: Low-calorie and no-calorie sweeteners (LCSs) have emerged as alternatives to added sugars. Research suggests that consumption among all A

Context: Lipodystrophies are extreme forms of metabolic syndrome. Metreleptin was approved in the United States for generalized lipodystrophy (GLD) but not partial lipodystrophy (PLD). Objective: The objective of the study was to test metreleptin's efficacy in PLD vs GLD and find predictors for treatment response. Design: This was a prospective, single-arm, open-label study since 2000 with continuous enrollment. Current analysis included metreleptin treatment for 6 months or longer as of January 2014. Setting: The study was conducted at the National Institutes of Health (Bethesda, Maryland). Participants: Patients clinically diagnosed with lipodystrophy, leptin less than 8 ng/mL (males) or less than 12 (females), age older than 6 months, and one or more metabolic abnormalities (diabetes, insulin resistance, or hypertriglyceridemia) participated in the study. Intervention: The interventions included sc metreleptin injections (0.06–0.24 mg/kg · d). Main Outcomes and Measures: Changes in glycated hemoglobin A1c (HbA1c) and triglycerides after 6 and 12 months of metreleptin were measured. Results: Baseline metabolic parameters were similar in 55 GLD [HbA1c 8.4% ± 2.3%; triglycerides, geometric mean (25th, 75th percentile), 467 mg/dL (200, 847)] and 31 PLD patients [HbA1c 8.1% ± 2.2%, triglycerides 483 mg/dL (232, 856)] despite different body fat and endogenous leptin. At 12 months, metreleptin decreased HbA1c (to 6.4% ± 1.5%, GLD, P < .001; 7.3% ± 1.6%, PLD, P = .004) and triglycerides [to 180 mg/dL (106, 312), GLD, P < .001; 326 mg/dL (175, 478), PLD, P = .02]. HbA1c and triglyceride changes over time significantly differed between GLD and PLD. In subgroup analyses, metreleptin improved HbA1c and triglycerides in all GLD subgroups except those with baseline triglycerides less than 300 mg/dL and all PLD subgroups except baseline triglycerides less than 500 mg/dL, HbA1c less than 8%, or endogenous leptin greater than 4 ng/mL. Conclusions: In addition to its proven efficacy in GLD, metreleptin is effective in selected PLD patients with severe metabolic derangements or low leptin.