Reinduction with Certolizumab Pegol in Patients with Crohn's Disease Experiencing Disease Exacerbation: 7-Year Data from the PRECiSE 4 Study.

BACKGROUND: Patients with Crohn's disease in whom tumor necrosis factor antagonist therapy fails have limited treatment options, and the benefit of reintroducing the same therapy remains unclear. Here, we report results from PRECiSE 4 (NCT00160706), an open-label extension study of certolizumab pegol in patients who withdrew from the placebo-controlled studies PRECiSE 1 or 2. METHODS: Patients eligible for PRECiSE 4 had Crohn's disease exacerbation on placebo or primary or secondary failure to certolizumab pegol in PRECiSE 1 or 2, and received 400 mg certolizumab pegol subcutaneously at weeks 0, 2, and 4 and every 4 weeks thereafter up to 360 weeks. We assessed safety (adverse events) and efficacy (clinical remission) of extended certolizumab pegol therapy. RESULTS: Patients enrolled in PRECiSE 4 (N = 310; mean age, 37 yr; 58% female; 95% white) had a mean Crohn's disease duration of 8.5 years before entering the qualifying studies. At weeks 52, 104, and 156, remission rates were 28.5%, 17.5%, and 12.6% by nonremitter imputation, and 63.8%, 60.0%, and 63.5% by observed cases, with 47.4%, 31.9%, and 23.2% of patients, respectively, remaining on therapy. By study end (7.5 yr), 92.3% of patients discontinued therapy, 49% on account of adverse events. No new safety signals emerged. Incidence rate (new cases)/100 patient-years was 6.11 for serious infections and 1.29 for malignancies. CONCLUSIONS: Certolizumab pegol was effective in many patients who previously discontinued certolizumab pegol for lack or loss of response. Thus, discontinuation of therapy may not always be necessary. Safety was consistent with previous findings.

Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: potential contributors to IBD-associated diarrhea.

BACKGROUND: One of the most common symptoms among patients with inflammatory bowel disease (IBD) is diarrhea, which is thought to be contributed by changes in electrolyte transport associated with intestinal inflammation. This study was designed to test the hypothesis that intestinal Na(+)-related transporters/channels and their regulatory proteins may be downregulated as a potential contributor to IBD-associated diarrhea. METHODS: SDS-PAGE and Western blotting and/or confocal immunomicroscopy were used to examine the expression of Na(+)/H(+)-exchangers 1-3 (NHE1-3), epithelial Na(+) channel (ENaC), Na(+)/K(+)-ATPase, the intracellular Cl(-) channel 5 (ClC-5), and NHE3 regulatory factors (NHERF1,2) in ileal and colonic pinch biopsies from IBD patients and noninflammatory controls, as well as from colonic mucosa of dextran sodium sulfate (DSS)- and TNBS-induced acute murine IBD models. RESULTS: NHE1,3 (but not NHE2), beta-ENaC, Na(+)/K(+)-ATPase-alpha, ClC-5, and NHERF1 were all downregulated in sigmoid mucosal biopsies from most cases of active UC and/or CD compared to controls. NHE3 was also decreased in ileal mucosal biopsies of active CD, as well as in approximately 50% of sigmoid biopsies from inactive UC or CD. Importantly, similar downregulation of NHE1,3, beta-ENaC, and NHERF1,2 was also observed in the mouse colon (but not ileum) of DSS- and TNBS-induced colitis. CONCLUSIONS: IBD-associated diarrhea may be due to a coordinated downregulation of multiple Na(+) transporter and related regulatory proteins, including NHE1,3, Na(+)/K(+)-ATPase, and ENaC, as well as NHERF1,2, and ClC-5, all of which are involved directly or indirectly in intestinal Na(+) absorption.

A meta registration framework for lesion matching.

A variety of pixel and feature based methods have been proposed for registering multiple views of anatomy visible in studies obtained using diagnostic, minimally invasive imaging. A given registration method may outperform another depending on anatomical variations, imaging conditions, and imaging sensor performance, and it is often difficult a priori to determine the best registration method for a particular application. To address this problem, we propose a registration framework that pools the results of multiple registration methods using a decision function for validating registrations. We refer to this as meta registration. We demonstrate that our framework outperforms several individual registration methods on the task of registering multiple views of Crohn's disease lesions sampled from a Capsule Endoscopy (CE) study database. We also report on preliminary work on assessing the quality of registrations obtained, and the possibility of using such assessment in the registration framework.