Objective. To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). Methods.Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified from 11 centers in 4 countries. Medical records were abstracted using a standardized instrument, and resulting data were analyzed to characterize concomitant therapies, clinical course, adverse events, and predictors of outcome.Results. Among 46 patients meeting inclusion criteria, anakinra monotherapy was used in 10 patients (22%), while 67% received corticosteroids and 33% received additional DMARDs. Outcomes were evaluated at a median followup interval of 14.5 months. Fever and rash resolved within 1 month in >95% of patients, while C-reactive protein and ferritin normalized within this interval in >80% of patients. Active arthritis persisted at 1 month in 39% of patients, at 3 months in 27%, and at >6 months of followup in 11%. Approximately 60% of patients, including 8 of 10 receiving anakinra monotherapy, attained a complete response without escalation of therapy. Disease characteristics and treatment were similar in partial and complete responders, except that partial responders were markedly younger at onset (median age 5.2 years versus 10.2 years; P ‫؍‬ 0.004).

Allosteric communication underlies ligand-dependent transcriptional responses mediated by nuclear receptors. While studies have elucidated many of the components involved in this process, the energetic architecture within the receptor protein that mediates allostery remains unknown. Using a sequence-based method designed to detect coevolution of amino acids in a protein, termed the statistical coupling analysis (SCA), we identify a network of energetically coupled residues that link the functional surfaces of nuclear receptor ligand binding domains. Functional analysis of these predicted residues demonstrates their participation in an allosteric network that governs the ability of heterodimeric receptors to activate transcription in response to ligand binding by either partner. Interestingly, mutation of a single network residue can discriminate between receptor activation by endocrine, dietary, and synthetic agonists. These results reveal a structural network required for RXR heterodimer allosteric communication and suggest that the specificity of ligand response and permissivity coevolved to enable signal discrimination.

he metabolic syndrome, also known as syndrome x, is characterized by abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, inflammation, and prothrombotic states. 1 Diagnostic of the metabolic syndrome are abnormalities in three or more of the clinical criteria of the Adult Treatment Panel III of the National Cholesterol Education Program, which include the following: a waist circumference of more than 102 cm in men and more than 88 cm in women; a triglyceride level of 150 mg per deciliter or more; a level of high-density lipoprotein (HDL) cholesterol of less than 40 mg per deciliter in men and less than 50 mg per deciliter in women; a blood pressure of 130/85 mm Hg or more; and a fasting glucose level of 110 mg per deciliter or more. 2 The age-adjusted prevalence of this syndrome in the United States from 1988 to 1994 was estimated to be 23.7 percent, and the scope of the public health challenge it poses is likely to increase. 3 The major sequelae are cardiovascular disease and type 2 diabetes mellitus, but the syndrome also increases the risk of polycystic ovary syndrome, fatty liver, cholesterol gallstones, asthma, sleep disturbances, and some forms of cancer. A prospective study of Finnish men reported a connection between the metabolic syndrome and an increased risk of death associated with cardiovascular disease and all-cause mortality 4 -a finding that underscores the severity of this disease.The pathogenesis of the metabolic syndrome is thought to involve a complex interaction of multiple factors, which include obesity and abnormal fat distribution; insulin resistance; hepatic, vascular, and immunologic factors; and lifestyle and genetic contributions. 1 In addition to behavioral therapies that promote weight reduction through exercise and dietary modification, management of the metabolic syndrome includes a combination of medical therapies targeted to reduce specific metabolic risk factors. 5 Statins and fibric acid derivatives (fibrates) are effective first-line treatments for atherogenic dyslipidemia and have been shown to reduce the risk of cardiovascular disease. 2 Combination therapy with a statin and a fibrate prevents the lowering of HDL cholesterol that is observed with the use of a statin alone and can improve abnormal serum lipoprotein profiles. The ability of statins and fibrates to induce severe myopathy, a toxic effect that is more frequent in combination treatment, limits their use in some patients. 6 Metformin and thiazolidinediones improve insulin sensitivity, but it is unknown if they reduce the risk of cardiovascular disease, and there are dose-limiting toxic effects. Experience with medical therapies highlights the potential of restoration of individual metabolic abnormalities in the treatment of the metabolic syndrome. Although numerous treatment options are available, the syndrome and its long-term sequelae often prove refractory to these interventions.Intense interest in the development of drugs with new mechanisms of action for the metabolic syndrome has fo...