Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases

CARD15 is a major susceptibility gene for a frequent multifactorial chronic inflammatory bowel disorder, Crohn disease (CD). By using NF-kappaB activation assays, the cytosolic CARD15 was shown to efficiently detect bacterial peptidoglycan (PGN), reminiscent of the PGN recognition protein surveillance mechanism in Drosophila. The 3 CD-associated variants and 13 additional variants carried by CD patients demonstrated impaired PGN-dependent response revealing null, hypomorphic, or dominant-negative properties. Quantitative parametrization of this response, computed from the patients' CARD15 genotypes, was predictive of several variable CD manifestations. In contrast, CARD15 alleles associated with Blau's syndrome promoted PGN-independent NF-kappaB activation, an observation that accounts for the minimal microbial input in the etiology of this dominant, monogenic inflammatory disorder affecting solely aseptic sites.     

Current status of bosentan for treatment of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a debilitating disease associated with significant morbidity and a high mortality if left untreated. Over the past 5 years, there have been significant advances with regard to the understanding of the pathogenesis, diagnosis and classification of PAH. The availability of newer drugs has resulted in a radical change in the management of this disease with significant improvement in both the quality of life and mortality. One of the recent drugs is an orally active dual endothelin receptor antagonist, bosentan; this drug has shown to improve the exercise capacity and survival in patients with PAH. This review article discusses the pharmacology of bosentan and summarises the current available evidence for the safety and efficacy of bosentan for the treatment of PAH.     

Inefficacy of infliximab in primary Sjögren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren's Syndrome (TRIPSS)

OBJECTIVE: There is no effective treatment for patients with primary Sj?gren's syndrome (SS). Since tumor necrosis factor alpha (TNF alpha) could be a key element in the pathogenesis of primary SS, we conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of infliximab in primary SS. METHODS: A total of 103 patients with primary SS were randomly assigned to receive infliximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6 and were followed up for 22 weeks. All patients fulfilled the new American-European Consensus Group criteria for SS and had active disease as assessed by values >50 mm on 2 of 3 visual analog scales (VAS) (0-100 mm) that evaluated joint pain, fatigue, and buccal, ocular, skin, vaginal, or bronchial dryness. A favorable overall response was defined as the patient having > or =30% improvement between weeks 0 and 10 in the values on 2 of the 3 VAS. Secondary end points were values on each VAS separately, the number of tender and swollen joints, the basal salivary flow rate, results of the Schirmer test for lacrimal gland function, the focus score on labial salivary gland biopsy, the level of C-reactive protein, and the erythrocyte sedimentation rate evaluated at weeks 0, 10, and 22, as well as quality of life evaluated by use of the generic Short Form 36 questionnaire administered at weeks 0, 10, and 22. RESULTS: At week 10, 26.5% of patients receiving placebo and 27.8% of patients treated with infliximab had a favorable overall response (P = 0.89), and at week 22, 20.4% of the placebo group and 16.7% of the infliximab group had a favorable response (P = 0.62). In addition, the 2 groups did not differ in any of the secondary end points over the 22 weeks of the trial. Severe adverse events reported in the infliximab group did not differ from those observed in previous studies. CONCLUSION: This randomized, double-blind, placebo-controlled study of an anti-TNF agent did not show any evidence of efficacy of infliximab in primary SS.     

High incidence of recurrent in stent thrombosis after successful treatment of a first in stent thrombosis

Objectives: We attempted to investigate incidence and predictors of recurrent in stent thrombosis (IST) after successful treatment of a first IST. Background: The occurrence of recurrent IST after successful treatment of a first IST may be a decisive factor for patient clinical outcome. However, incidence and predictors of recurrent IST are currently poorly described in the literature. Methods: Between 2003 and 2005, 2,190 patients underwent a percutaneous coronary intervention in our center. During a median follow‐up of 19.4 months, 49 patients (2.24%) presented a first definite IST. Patients presenting with a first IST were followed during an additional median period of 40 months. Their baseline characteristics were listed and cardiovascular events especially recurrent IST as defined by the Academic Research Consortium definition were systematically indexed. Results: Altogether 39 (80%) patients were successfully treated with an effective reperfusion after percutaneous coronary intervention. Fourteen (36%) patients presented a recurrent IST and three presented multiple recurrent IST. The median occurrence time of recurrent IST was 5 days, range between 1 and 11 days. Multivariate analysis identified history of neoplasia (HR = 11.53, 95% CI 2.32–57.37, P = 0.003), residual diameter stenosis (HR = 1.15, 95% CI 1.02–1.29, P = 0.02), and residual dissection after treatment (HR = 8.78, 95% CI 1.85–41.62, P = 0.006), as independent predictors of recurrent IST. Conclusion: Recurrent IST is a frequent and early event after successful treatment of a first IST. Our results suggest that mechanical factors like residual dissection and residual diameter stenosis should be carefully tracked down. In addition, patients with multiple recurrent IST and the early time course of recurrent IST also suggest a potential role of inadequate antiplatelet therapy. © 2008 Wiley‐Liss, Inc.     

TNFα blockade for inflammatory rheumatic diseases is associated with a significant gain in android fat mass and has varying effects on adipokines: a 2-year prospective study

Purpose

To evaluate the long-term consequences of TNFα inhibitors on body composition and fat distribution, as well as changes in serum adipokines in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS).

Methods

Eight patients with RA and twelve with AS requiring a TNFα inhibitor were prospectively followed for 2 years. Body composition was evaluated by dual X-ray absorptiometry and included measurements of total fat mass, lean mass, fat in the gynoid and android regions, and visceral fat. Serum leptin, total and high molecular weight (HMW) adiponectin, resistin, and ghrelin were also assessed.

Results

There was a significant gain in body mass index (p = 0.05) and a tendency for weight (p = 0.07), android fat (p = 0.07), and visceral fat (p = 0.059) increase in patients with RA, while in AS, total fat mass significantly increased (p = 0.02) with a parallel weight gain (p = 0.07). When examining the whole population of patients, we observed after 2 years a significant increase in body weight (+1.9 %; p = 0.003), body mass index (+2.5 %; p = 0.004), total fat mass (+11.1 %; p = 0.007), and fat in the android region (+18.3 %; p = 0.02). There was a substantial, albeit nonsignificant gain in visceral fat (+24.3 %; p = 0.088). Lean mass and gynoid fat were not modified. No major changes were observed for serum leptin, total adiponectin, and ghrelin, while HMW adiponectin and the HMW/total adiponectin ratio tended to decrease (?15.2 %, p = 0.057 and ?9.3 %, p = 0.067, respectively). Resistin decreased significantly (?22.4 %, p = 0.01).

Conclusions

Long-term TNFα inhibition in RA and AS is associated with a significant gain in fat mass, with a shift to the android (visceral) region. This fat redistribution raises questions about its influence on the cardiovascular profile of patients receiving these treatments.