Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.

Atopic dermatitis in adults: An Australian management consensus.

BACKGROUND/OBJECTIVES: Atopic dermatitis (AD) has significant negative impact on health-related quality of life, mood, sleep, work productivity and everyday activities. Research into the use of new drugs in the management of AD continues to develop, and international updates and recommendations have been published. However, questions remain in the Australian setting. This consensus aims to provide evidence-based insights and practical advice on the management of adult AD in Australia. METHODS: A panel (five dermatologists and one clinical immunologist) met to review the literature, critically examine clinical questions of relevance to Australian healthcare practitioners and develop a series of recommendation statements. A consensus panel, comprising the initial panel plus nine additional members, used a 2-round Delphi voting process to determine a set of final guidance statements. CONSENSUS: ≥75% agreement in the range 7-9. RESULTS: Round 1 voting comprised 66 guidance statements. Of these, consensus was reached on 26, which were retained, and five were removed. The remainder (35) were modified and one new guidance statement was added for inclusion in round 2 voting. After round 2, consensus was reached on 35, which were retained, and one was removed (considered redundant). The 61 guidance statements upon which consensus was reached were then used to support a series of core consensus recommendations and a management flow chart. CONCLUSIONS: Expert consensus recommendations providing practical guidance of clinical relevance to specialists and primary care physicians in Australia have been developed. Dissemination of this guidance and evaluation of its impact on patient outcomes remain to be undertaken.

Muckle-Wells cryopyrinopathy: complex phenotyping and response to therapy in a new multiplex kindred.

Muckle-Wells syndrome (MWS) is a member of the cryopyrin-associated periodic syndrome family of auto-inflammatory diseases, originally described as a triad of urticaria, sensorineural deafness and amyloidosis. IL-1 blockade is a proven therapy for MWS. The clinical, laboratory and genotypic characteristics of a novel kindred of five individuals with Muckle-Wells syndrome are described. Response to IL-1 blockade therapy in the proband was evaluated. All five affected family members experienced symptoms of multi-organ inflammation. Lead time between symptom onset and diagnosis was approximately 30 years in the proband. Fever was not a universal feature in all affected family members. Anti-IL-1 therapy in the proband resulted in improvements in patient-reported symptoms, inflammatory markers, auditory acuity and reversal of her infertility. Muckle-Wells syndrome is a rare, multisystem, auto-inflammatory syndrome. Delay in diagnosis prevents effective treatment. We propose reversal of infertility to be among the potential benefits of IL-1 inhibition in this disease.

Pentoxifylline-induced drug rash with eosinophilia and systemic symptoms (DRESS) in a patient with caffeine intolerance.

BACKGROUND: Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe drug reaction characterised by rash, eosinophilia and systemic involvement. MAIN OBSERVATIONS: We report a case of DRESS induced by pentoxifylline used for the treatment of severe alcoholic hepatitis, in a patient with longstanding caffeine intolerance. A history of intolerance to caffeine and other methylxanthines is listed as a contraindication to the use of pentoxifylline, yet this precaution is not mentioned in alcoholic hepatitis treatment guidelines. CONCLUSIONS: Prescribers should always seek a history of intolerance to caffeine and related compounds prior to use of pentoxifylline, as severe life threatening reactions can occur.

Age and gender variations in the management of ischaemic stroke in China.

BACKGROUND: Stroke is a major health issue in China. AIMS: We aimed to describe the management of patients admitted to hospitals in China with acute ischaemic stroke, and to determine whether there were any differences by age and gender. METHODS: Using a multicentre prospective hospital register across all eight major economic (geographic) regions in China, data on the socioeconomic characteristics, medical history, clinical features, and in-hospital investigations, management, and outcomes were collected on consecutive patients with acute stroke due to cerebral ischaemia during a 5-month period in 2006. RESULTS: Overall, traditional Chinese medicine and neuroprotectant use were remarkably high, with nearly 80% of patients receiving the former and >70% receiving the latter in hospital. Length of hospital stay was also long (median duration 16-days). Multivariate analyses revealed no clinically important differences in management between the genders. For the age-specific analyses, there were significant trends of decreasing use of thrombolysis (P=0·04), warfarin (P=0·01), corticosteroids (P=0·03), and lipid-lowering therapy (P=0·001); however, more assisted feeding (P=0·004) and rising rates of disability and in-hospital complications occurred with increasing age. CONCLUSIONS: New information is provided regarding the current state of ischaemic stroke management in China. Notably, there is high use of traditional Chinese medicine and neuroprotectants and long lengths of hospital stay. Similar to many other countries, differences in stroke care and management by age and gender also exist to a small extent in China.