Tocilizumab, a monoclonal antibody targeting the IL-6 receptor, has recently been added to the therapeutic armamentarium against rheumatoid arthritis (RA). Despite its overall safety, concerns have been raised regarding diverticular perforation in patients receiving the drug. The aim of our research was to document the incidence of diverticular disease in RA patients treated in the pre-disease-modifying anti-rheumatic drug (DMARD) era, following treatment with conventional DMARDs, and subsequent to tocilizumab therapy. We performed a systematic literature review in MEDLINE, EMBASE, Conference Proceedings Citation Index-Science, Cochrane Central Register of Controlled Trials and Current Controlled Trials up to Nov. 2010. The publication titles and abstracts were independently assessed by two reviewers for relevance and quality, and the review was conducted following guidelines from the Centre for Reviews and Dissemination. In the pre-DMARD period of RA management, where patients were largely treated with NSAIDs and corticosteroids, gastrointestinal (GI) complications were a substantial cause of mortality with diverticulitis and colonic ulcers accounting for almost a third of GI-related deaths. In contrast, our search did not reveal any evidence of diverticular perforation in patients treated with conventional DMARDs. Eighteen cases of lower GI perforation (16 of whom had diverticulitis) have been documented in recent conference proceedings following tocilizumab treatment in clinical trials, with a lower GI perforation rate of 1.9 per 1,000 patient years (PY). This lies between the reported rate of GI perforations for corticosteroids and anti-TNF-α agents in the United Health Care database, with rates of 3.9 per 1,000 PY (95% CI 3.1-4.8) and 1.3 per 1,000 PY (95% CI 0.8-1.9), respectively. The majority of these patients were concurrently prescribed NSAIDs and/or long-term corticosteroids. Traditional DMARD therapy for RA appears not only to have modified the risk of lower GI perforation but prevented it. The risk of diverticular perforation may be slightly higher in patients treated with tocilizumab compared with conventional DMARDs or anti-TNF agents, but lower than that for corticosteroids. The mechanism of action of IL-6 antagonism in the pathophysiology of diverticular perforation has yet to be elucidated.

No abstract

The CFTR gene is unique within the ATP-binding cassette (ABC) protein family, predominantly of transporters, by coding a chloride channel. The gating mechanism of ABC proteins has been characterized by the ATP Switch model in terms cycles of dimer formation and dissociation linked to ATP binding and hydrolysis, respectively. It would be of interest to assess the extent that Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a functional channel, fits the ATP Switch model for ABC transporters. Additional transporter mechanisms, namely those of Pgp and HlyB, are discussed for perspective. Literature search of databases selected key references in comparing and contrasting the gating mechanism. CFTR is a functional chloride channel facilitating transmembrane anion flow down electrochemical gradients. A dysfunctional CFTR protein results in cystic fibrosis, a fatal pleiotropic disease currently managed symptomatically. Understanding the gating mechanism will help target drug development aimed at alleviating and curing the disease.

No abstract