Appropriateness of initial treatment for severe Crohn's disease: application of EPACT criteria to the EC-IBD European cohort

Background: The appropriateness of use of therapy for severe active luminal Crohn's disease (CD) cases has never been formally assessed. The European panel on the appropriateness of Crohn's disease therapy [EPACT (http://www.epact.ch)] developed appropriateness criteria. We have applied these criteria to the EC-IBD prospectively assembled, uniformly diagnosed European population-based inception cohort of Inflammatory Bowel Disease (IBD) patients diagnosed between 1991 and 1993. Methods: 426 CD patients from 13 European participating centers (10 countries) were included at the time of diagnosis (first flare, naive patients, no maintenance treatment, no steroids). We used the EPACT definition of the severe active luminal CD, agreed upon by the panel experts (acute flare, hospitalized patient, without documented fistula or stenosis and who did not undergo surgery for abscess drainage or a fistulectomy). The various treatments were analyzed to determine the appropriateness of the medical decision, according to the EPACT criteria. Results: 84 (20%) patients met the inclusion criteria. Considering at least one appropriate (A) treatment as appropriate: 60 patients (71%) received an appropriate treatment, 24 patients (29%) an inappropriate treatment (I). Furthermore, in 87% of the cases with one appropriate treatment an additional mostly inappropriate treatment was added or continued. Detailed results are indicated in the table below. Conclusion: In the EC-IBD cohort, the treatment for severe active luminal CD was appropriate for more than 70% of the patients, but frequently an inappropriate treatment was continued or added, thus increasing the risk of adverse reactions, drugs interactions and costs.

Differentiated chemical reactivity of nanoparticles toward DTT

RATIONALE: Induction of oxidative stress and impairment of the antioxidant defense are considered important biological responses following nanoparticle (NP) exposure. The acellular in vitro dithiothreitol (DTT) assay is proposed to measure the oxidative potential of NP. In addition, DTT can be considered as a model compound of sulfur containing antioxidants. The objective of this work is to evaluate the surface reactivity in solution of a NP panel toward DTT. METHOD: The NP panel was composed of four carbonaceous particles, six types of metal oxides and silver with primary size ranged from 7 to 300 nm. Suspensions were prepared in surfactant solution with 30 min sonication. DTT was used as reductant to evaluate the oxidative properties of the different NP. The determination of the NP ability to catalyze electron transfer from DTT to oxygen was carried out as described in Sauvain et al., Nanotoxicology, 2008, 2:3, 121−129. RESULTS: All the carbonaceous NP catalyzed the oxidation of DTT by oxygen following the mass based order: carbon black > diesel exhaust particle > nanotubes > fullerene. A contrasting reactivity was observed for the metallic NP. Except for nickel oxide and metallic silver, which reacted similarly to the carbonaceous NP, all other metal oxides hindered the oxidation of DTT by oxygen, with ZnO being the most effective one. CONCLUSIONS : DTT was stabilized against oxidation in the presence of metal oxide NP in the solution. This suggests that different chemical interactions take place compared with carbonaceous NP. To explain these differences, we hypothesize that DTT could form complexes with the metal oxide surface (or dissolved metal ions), rendering it less susceptible to oxidation. By analogy, such a process could be thought to apply in biological systems with sulfur−containing antioxidants, reducing their buffer capacity. Such NP could thus contribute to oxidative stress by an alternative mechanism.

Appropriateness of therapy for active Crohn's disease: results of a multidisciplinary International Expert Panel (EPACT II)

Introduction: The development of novel therapies and the increasing number of trials testing management strategies for luminal Crohn's disease (CD) have not filled all the gaps in our knowledge. Thus, in clinical practice, many decisions for CD patients need to be taken without high quality evidence. For this reason, a multidisciplinary European expert panel followed the RAND method to develop explicit criteria for the management of individual patients with active, steroid-dependent (ST-D) and steroid-refractory (ST-R) CD. Methods: Twelve international experts convened in Geneva, Switzerland in December 2007, to rate explicit clinical scenarios, corresponding to real daily practice, on a 9-point scale according to the literature evidence and their own expertise. Median ratings were stratified into three categories: appropriate (7-9), uncertain (4-6) and inappropriate (1-3). Results: Overall, panelists rated 296 indications pertaining to mild-to-moderate, severe, ST-D, and ST-R CD. In anti-TNF naïve patients, budesonide and prednisone were found appropriate for mildmoderate CD, and infliximab (IFX) when those had previously failed or had not been tolerated. In patients with prior success with IFX, this drug with or without co-administration of a thiopurine analog was favored. Other anti-TNFs were appropriate in case of intolerance or resistance to IFX. High doses steroids, IFX or adalimumab were appropriate in severe active CD. Among 105 indications for ST-D or ST-R disease, the panel considered appropriate the thiopurine analogs, methotrexate, IFX, adalimumab and surgery for limited resection, depending on the outcome of prior therapies. Anti-TNFs were generally considered appropriate in ST-R. Conclusion: Steroids, including budesonide for mild-to-moderate CD, remain first-line therapies in active luminal CD. Anti-TNFs, in particular IFX with respect to the amount of available evidence, remain second-line for most indications. Thiopurine analogs are preferred to anti-TNFs when steroids are not appropriate, except when anti-TNFs were previously successful. These recommendations are available online (www.epact.ch). A prospective evaluation of these criteria in a large database in Switzerland in underway to validate these criteria.

Appropriate maintenance treatment for Crohn's disease: results of a multidisciplinary international expert panel - EPACT II

Introduction: Biological. therapy has dramatically changed management of Crohn's disease (CD). New data have confirmed the benefit and relative long-term safety of anti-TNF alpha inhibition as part of a regular scheduled administration programme. The EPACT appropriateness criteria for maintenance treatment after medically-induced remission (MIR) or surgically-induced remission (SIR) of CD thus required updating. Methods: A multidisciplinary international expert panel (EPACT II, Geneva, Switzerland) discussed and anonymously rated detailed, explicit clinical indications based on evidence in the literature and personal expertise. Median ratings (on a 9-point scale) were stratified into three assessment categories: appropriate (7-9), uncertain (4-6 and/or disagreement) and inappropriate (1-3). Experts ranked appropriate medication according to their own clinical practice, without any consideration of cost. Results: Three hundred and ninety-two specific indications for maintenance treatment of CD were rated (200 for MIR and 192 for SIR). Azathioprine, methotrexate and/or anti-TNF alpha antibodies were considered appropriate in 42 indications, corresponding to 68% of all appropriate interventions (97% of MIR and 39% of SIR). The remaining appropriate interventions consisted of mesalazine and a "wait-and-see" strategy. Factors that influenced the panel's voting were patient characteristics and outcome of previous treatment. Results favour use of anti-TNF alpha agents after failure of any immunosuppressive therapy, while earlier primary use remains controversial. Conclusion: Detailed explicit appropriateness criteria (EPACT) have been updated for maintenance treatment of CD. New expert recommendations for use of the classic immunosuppressors as well as anti-TNF alpha agents are now freely available online (www.epact.ch). The validity of these criteria should now be tested by prospective evaluation. (C) 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.