Emily T. Nguyen

Specialized enteral nutrition therapy in Crohn’s disease patients on maintenance infliximab therapy: a meta-analysis

Objectives: Many patients with Crohn’s disease on infliximab maintenance therapy have recurrent symptoms despite an initial clinical response. Therefore, concomitant therapies have been studied. We conducted a meta-analysis to assess the effect of specialized enteral nutrition therapy with infliximab versus infliximab monotherapy in patients with Crohn’s disease. Methods: A comprehensive search of multiple databases was performed. All studies of adult patients with Crohn’s disease comparing specialized enteral nutrition therapy (elemental or polymeric diet with low-fat or regular diet) with infliximab versus infliximab monotherapy without dietary restrictions were included. Meta-analysis was performed using the Mantel–Haenszel (fixed effect) model with odds ratio (OR) to assess for clinical remission. Results: Four studies (n = 342) met inclusion criteria. Specialized enteral nutrition therapy with infliximab resulted in 109 of 157 (69.4%) patients reaching clinical remission compared with 84 of 185 (45.4%) with infliximab monotherapy [OR 2.73; 95% confidence interval (CI): 1.73–4.31, p < 0.01]. Similarly, 79 of 106 (74.5%) patients receiving enteral nutrition therapy and infliximab remained in clinical remission after one year compared with 62 of 126 (49.2%) patients receiving infliximab monotherapy (OR 2.93; 95% CI: 1.66–5.17, p < 0.01). No publication bias or heterogeneity was noted for either outcome. Conclusions: The use of specialized enteral nutrition therapy in combination with infliximab appears to be more effective at inducing and maintaining clinical remission among patients with Crohn’s disease than infliximab monotherapy.

Apo and calcium-bound crystal structures of cytoskeletal protein alpha-14 giardin (annexin E1) from the intestinal protozoan parasite Giardia lamblia

Alpha-14 giardin (annexin E1), a member of the alpha giardin family of annexins, has been shown to localize to the flagella of the intestinal protozoan parasite Giardia lamblia. Alpha giardins show a common ancestry with the annexins, a family of proteins most of which bind to phospholipids and cellular membranes in a Ca(2+)-dependent manner and are implicated in numerous membrane-related processes including cytoskeletal rearrangements and membrane organization. It has been proposed that alpha-14 giardin may play a significant role during the cytoskeletal rearrangement during differentiation of Giardia. To gain a better understanding of alpha-14 giardins mode of action and its biological role, we have determined the three-dimensional structure of alpha-14 giardin and its phospholipid-binding properties. Here, we report the apo crystal structure of alpha-14 giardin determined in two different crystal forms as well as the Ca(2+)-bound crystal structure of alpha-14 giardin, refined to 1.9, 1.6 and 1.65 A, respectively. Although the overall fold of alpha-14 giardin is similar to that of alpha-11 giardin, multiwavelength anomalous dispersion phasing was required to solve the alpha-14 giardin structure, indicating significant structural differences between these two members of the alpha giardin family. Unlike most annexin structures, which typically possess N-terminal domains, alpha-14 giardin is composed of only a core domain, followed by a C-terminal extension that may serve as a ligand for binding to cytoskeletal protein partners in Giardia. In the Ca(2+)-bound structure we detected five bound calcium ions, one of which is a novel, highly coordinated calcium-binding site not previously observed in annexin structures. This novel high-affinity calcium-binding site is composed of seven protein donor groups, a feature rarely observed in crystal structures. In addition, phospholipid-binding assays suggest that alpha-14 giardin exhibits calcium-dependent binding to phospholipids that coordinate cytoskeletal disassembly/assembly during differentiation of the parasite.

Optimizing the use of anti-tumor necrosis factor in the management of patients with Crohn’s disease:

Since the approval of the first anti-tumor necrosis factor (anti-TNF) therapy in late 1998, the treatment for Crohn’s disease (CD) has been revolutionized. Anti-TNF therapy has been consistently shown in numerous clinical trials to be effective for patients with more aggressive perianal, internal penetrating, and fistulizing CD. However, the loss of clinical remission is frequent and only one-third of patients remain in clinical remission at 1 year. The pharmacokinetics of anti-TNF is highly variable among patients and could be influenced by many factors including serum albumin, gender, body weight, systemic inflammation and route of administration. The main factor impacting anti-TNF pharmacokinetics and efficacy is the development of immunogenicity where antidrug antibodies accelerate anti-TNF drug clearance. In this review paper, we evaluate the role of combination therapy with anti-TNF drugs and immunomodulators, the role of therapeutic drug monitoring, and strategies to recapture loss of clinical response in order to improve both short- and long-term outcomes in CD patients.

Outcomes of initial medical compared with surgical strategies in the management of intra-abdominal abscesses in patients with Crohn’s disease: a meta-analysis

Background Several studies have also evaluated the efficacy of initial medical management compared with initial surgical management strategies with regard to abscess resolution with variable results. Objective The aim of this study is to evaluate the efficacy of initial medical management compared with surgical management of Crohn’s disease (CD)-related intra-abdominal abscesses. Data sources A comprehensive search of multiple databases (MEDLINE/PubMed, Cochrane databases, CINAHL, Scopus, and Google Scholar) was performed in August 2014. Study selection All studies on adults comparing initial surgical versus medical approaches to treat CD-related abscesses were included. Main outcomes measured The durability of abscess resolution and rate of stoma creation between the groups undergoing initial surgical versus medical approaches were compared. Results The pooled analysis of the nine studies including a total 603 patients showed an overall rate of abscess resolution were 56.6% in the medical group compared with 80.7% in the surgical group. There was over three-fold higher chance of achieving abscess resolution when an initial surgical strategy was used at the time of abscess diagnosis compared with the medical strategy (odds ratio 3.44, 95% confidence interval: 1.80, 6.58, P<0.001). The number needed to treat using the initial surgical approach to prevent a recurrent abscess was four patients. Limitations All included studies were retrospective case series with potential clinical confounders not fully accounted in the analysis. Conclusion Initial surgical management appears to be superior to medical management in patients with CD-related intra-abdominal abscesses. Though all the included studies in this meta-analysis were retrospective, this meta-analysis is likely the strongest level of evidence with regard to the management of CD-related abscesses, given that a randomized-control trial may not be feasible given the low rate of abscess development in CD.

Does exposure to isotretinoin increase the risk for the development of inflammatory bowel disease? A meta-analysis.

Background Isotretinoin is a treatment option for severe nodulocystic acne. However, its use has inconsistently been associated with the development of inflammatory bowel disease (IBD). This meta-analysis aims to elucidate the association between isotretinoin exposure and the risk for IBD. Methods A comprehensive search of PubMed/MEDLINE, CINAHL, the Cochrane database, and Google Scholar was performed (July 2015). All studies on the development of IBD in patients with or without prior exposure to isotretinoin, along with control participants, were included. Meta-analysis was carried out using the Mantel–Haenszel random effect model to assess the risk for IBD in the context of prior isotretinoin exposure. Results In a pooled analysis of six research studies, there was no increased risk of developing IBD in patients exposed to isotretinoin compared with patients not exposed to isotretinoin [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.82, 1.42, P=0.59]. Furthermore, there was no increased risk of developing Crohn’s disease (OR 0.98, 95% CI 0.62, 1.55, P=0.93, I2=62%) or ulcerative colitis (OR 1.14, 95% CI 0.79, 1.63, P=0.49, I2=44%) in patients exposed to isotretinoin compared with those not exposed to the medication. Conclusion Isotretinoin exposure is not associated with an increased risk of developing both ulcerative colitis and Crohn’s disease.

Antitumor necrosis factor α is more effective than conventional medical therapy for the prevention of postoperative recurrence of Crohn's disease: a meta-analysis.

Background There have seen several studies evaluating the efficacy of anti-tumor necrosis factor &agr; (anti-TNF&agr;) compared with conventional therapy (i.e. immunomodulators, mesalamine, or placebo) at preventing postoperative Crohn’s disease (CD) recurrence. The results of these studies have been variable and the magnitude by which anti-TNF&agr; therapy alters the natural history of CD in the postoperative setting has not yet been fully defined. Methods A comprehensive search of PubMed/MEDLINE, Scopus, CINAHL, and Cochrane databases was performed (May 2014). All studies on adult patients with CD that compared anti-TNF&agr; therapy versus conventional therapy or placebo to prevent CD recurrence were included. Meta-analysis was performed using the Mantel–Haenszel (fixed effects) model with odds ratio (OR) to assess for clinical remission. Results In the pooled analysis, there was a higher frequency of achieving clinical remission beyond 1 year from time of surgery among patients receiving anti-TNF&agr; therapy compared with conventional therapy [OR 6.41; 95% confidence interval (CI) 2.88–14.27]. There was also a significantly higher rate of achieving both endoscopic (OR 26.44; 95% CI 10.48–66.68) and histologic remission (OR 9.80; 95% CI 2.54–37.81) in the anti-TNF&agr; therapy group compared with the conventional therapy group. Conclusion Anti-TNF&agr; therapy is more effective at preventing clinical, endoscopic, and histologic recurrence of CD beyond 1 year from time of surgery compared with conventional therapy.

pANCA positivity predicts lower clinical response to infliximab therapy among patients with IBD.

Objectives Several studies have been performed evaluating the role of perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) to predict early clinical response among patients with inflammatory bowel disease (IBD) who are undergoing infliximab therapy. The results of these studies are variable, however, and the effect of pANCA+ as a predictor of clinical response to infliximab remains largely undefined. The goal of this meta-analysis was to evaluate the role of pANCA in predicting poor responders to infliximab. Methods A comprehensive search of the PubMed/MEDLINE, Scopus, Cumulative Index of Nursing and Allied Health Literature, Google Scholar, and Cochrane databases was performed in June 2014. All of the studies that evaluated pANCA levels in patients with IBD who were undergoing antitumor necrosis factor-&agr; (anti-TNF-&agr;) therapy and their clinical responses were included. A meta-analysis was performed using the Mantel-Haenszel model with odds ratios to assess for clinical remission. Results In the pooled analysis (N = 415), patients who were pANCA negative had nearly a twofold higher response to anti-TNF-&agr; therapy compared with patients who were pANCA+ (odds ratio 1.87; 95% confidence interval 1.02–3.41). Serologic testing for pANCA+ predicting nonresponse to infliximab therapy showed a sensitivity of 25.2%, a specificity of 85.5%, a positive predictive value of 41.1%, and a negative predictive value of 74.0%. Conclusions Being more proactive (ie, early dose escalation or accelerated loading regimen) in patients who are pANCA+ may be necessary to improve clinical response.

Exposure to oral contraceptives increases the risk for development of inflammatory bowel disease: a meta-analysis of case-controlled and cohort studies

Background The oral contraceptive pill (OCP) is a widely used method of contraception. There have been conflicting studies linking the use of OCPs to the development of inflammatory bowel disease (IBD). The intent of this meta-analysis is to better define the association between OCP exposure and the risk for development of IBD. Methods A thorough search of multiple databases, including Scopus, Cochrane, MEDLINE/PubMed, and CINAHL, and abstracts from major gastroenterology meetings was performed (October, 2016). Studies reporting the development of IBD in patients with or without previous exposure to OCP, compared with healthy controls, were included. A meta-analysis was completed using the Mantel–Haenszel model to evaluate the risk of developing IBD in the setting of previous OCP exposure. Results In a complete analysis of 20 studies, there appeared to be over a 30% increased risk for the development of IBD in patients exposed to OCP compared with patients not exposed to OCP [odds ratio (OR): 1.32, 95% confidence interval (CI): 1.17–1.49, P<0.001, I2=14%]. More specifically, there was a 24% higher risk for developing Crohn’s disease (OR: 1.24, 95% CI: 1.09–1.40, P<0.001; I2=38%) and a 30% higher risk for developing ulcerative colitis (OR: 1.30, 95% CI: 1.13–1.49, I2=26%) in patients exposed to OCP compared with those not exposed to the medication. Conclusion The use of OCP is associated with an increased risk for development of Crohn’s disease and ulcerative colitis in the genetically susceptible host. The total duration, dose of OCP exposure, and the risk for development of IBD need to be better characterized.

Expression, purification, crystallization and preliminary X-ray diffraction analysis of α-11 giardin from Giardia lamblia

Alpha-11 Giardin, a protein from the annexin superfamily, is a 35.0 kDa protein from the intestinal protozoan parasite Giardia lamblia which triggers a form of diarrhea called giardiasis. Here, the cloning, expression, purification and the crystallization of alpha-11 giardin under two different conditions and in two different space groups is reported. Crystals from the first condition diffracted to 1.1 A and belong to a primitive orthorhombic space group, while crystals from the second condition, which included calcium in the crystallization solution, diffracted to 2.93 A and belong to a primitive monoclinic space group. Determination of the detailed atomic structure of alpha-11 giardin will provide a better insight into its biological function and might establish whether this class of proteins is a potential drug target against giardiasis.