Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events

<p>Abstract</p> <p>Background</p> <p>Spontaneous reporting systems for adverse drug reactions (ADRs) are handicapped by under-reporting and limited detail on individual cases. We report an investigation from a local surveillance for serious adverse drug reactions associated with disease modifying anti-rheumatic drugs that was triggered by the occurrence of liver failure in two of our patients.</p> <p>Methods</p> <p>Serious ADR reports have been solicited from local clinicians by regular postcards over the past seven years. Patients', who had hepatotoxicity on sulfasalazine and met a definition of a serious ADR, were identified. Two clinicians reviewed structured case reports and assessed causality by consensus and by using a causality assessment instrument. The likely frequency of hepatotoxicity with sulfasalazine was estimated by making a series of conservative assumptions.</p> <p>Results</p> <p>Ten cases were identified: eight occurred during surveillance. Eight patients were hospitalised, two in hepatic failure – one died after a liver transplant. All but one event occurred within 6 weeks of treatment. Seven patients had a skin rash, three eosinophilia and one interstitial nephritis. Five patients were of Black British of African or Caribbean descent. Liver enzymes showed a hepatocellular pattern in four cases and a mixed pattern in six. Drug-related hepatotoxicity was judged probable or highly probable in 8 patients. The likely frequency of serious hepatotoxicity with sulfasalazine was estimated at 0.4% of treated patients.</p> <p>Conclusion</p> <p>Serious hepatotoxicity associated with sulfasalazine appears to be under-appreciated and intensive monitoring and vigilance in the first 6 weeks of treatment is especially important.</p

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Dual antiplatelet therapy duration after coronary stenting in clinical practice: results of an EAPCI survey

Aims: Our aim was to report on a survey initiated by the EuropeanAssociation of Percutaneous Cardiovascular Interventions (EAPCI) concerning opinion on the evidence relating to dual antiplatelet therapy (DAPT) duration after coronary stenting.Methods and results: Results from three randomised clinical trials were scheduled to be presented at the American Heart Association Scientific Sessions 2014 (ARIA 2014). A web-based survey was distributed to all individuals registered in the EuroIntervention mailing list (n=15,200) both before and after ARIA 2014. A total of 1,134 physicians responded to the first (i.e., before AHA 2014) and 542 to the second (i.e., after ARIA 2014) survey. The majority of respondents interpreted trial results consistent with a substantial equipoise regarding the benefits and risks of an extended versus a standard DAPT strategy. Two respondents out of ten believed extended DAFT should be implemented in selected patients. After ARIA 2014, 46.1% of participants expressed uncertainty about the available evidence on DAFT duration, and 40.0% the need for clinical guidance.Conclusions: This EAPCI survey highlights considerable uncertainty within the medical community with regard to the optimal duration of DAFT after coronary stenting in the light of recent reported trial results. Updated recommendations for practising physicians to guide treatment decisions in routine clinical practice should be provided by international societies