Tumor necrosis factor α (TNFα) is central to the pathogenesis of Crohn’s disease. Infliximab, a chimeric antibody directed against TNFα, has been shown to be an effective treatment of moderate to severe Crohn’s disease. These authors report a Phase II, randomized, double-blind, placebo-controlled, dose-response study of certolizumab pegol (CDP870), a PEGylated Fab′ fragment of a humanized anti-TNFα monoclonal antibody administered by subcutaneous injection, for the treatment of moderate to severe Crohn’s disease. Two-hundred ninety-two patients were enrolled in the study and initially stratified according to whether they were receiving concomitant therapy with steroids, immunosuppressants, or long-term anti-infectives. Subjects were then randomized to receive certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary endpoint was clinical response, defined as a decrease in CDAI of ≥100 points, at 12 weeks. The study by Schreiber et al was powered to detect a true difference between treatment groups of 23%, assuming a placebo response rate of 12%. Certolizumab showed a rapid response with all doses, demonstrating a significant benefit over placebo at week 2. Certolizumab 400 mg showed the greatest efficacy of the 3 doses at all time points, but did not reach a statistical benefit over placebo at week 12 (certolizumab 400 mg 44.4% vs placebo 35.6%; P = .278). The greatest difference in clinical response was observed at week 10 (certolizumab 400 mg 52.8% vs placebo 30.1%; P = .006). Post-hoc analysis was performed and a significant difference in clinical response at week 12 was observed when comparing patients with a baseline CRP ≥10 mg/L in the placebo and certolizumab 400-mg groups, (certolizumab 400 mg 53.1% vs 17.9%; P = .005). A higher than expected placebo-response rate was observed in this clinical trial. A lower placebo response rate was seen in patients with an elevated baseline CRP, possibly explaining the significant difference seen in the post-hoc analysis (Figure 1). There were no significant differences in adverse events among groups (Figure 2).Figure 2Clinical response rates (decrease in CDAI score ≥100 points or remission [CDAI score, ≤150 points]) to certolizumab 100, 200, and 400 mg and placebo at week 12 according to mean baseline CRP concentrations. *P ≤ .05, **P ≤ .01 compared with placebo.View Large Image Figure ViewerDownload (PPT) Certolizumab 400 mg is well tolerated and may be an effective treatment in moderate to severe Crohn’s disease. A significant difference in clinical response at week 12 was not observed in this trial, although the higher than expected placebo response rate may account for the failure of this treatment to reach its primary endpoint. Phase III clinical trials are ongoing. Endoscopic treatment of high-risk ulcers with active bleeding or nonbleeding visible vessels is widely accepted because of the high risk of recurrent bleeding. Reported re-bleeding rates of ulcers with adherent clots vary greatly and therefore the recommended management of these lesions is less clear. Kahi et al set out to compare the effectiveness of endoscopic and medical therapy versus medical therapy alone in patients with bleeding peptic ulcers with an adherent clot. A literature search was performed and 50 references were obtained. Six studies met the pre-specified inclusion criteria for the analysis. Two of these studies were in abstract form, whereas the other 4 trials were full-length articles. The original data from these 4 trials were obtained and used for a “patient-level analysis.” All 6 studies were included in the traditional meta-analysis. The authors chose to use a random effects model before pooling data to adjust for variability among the trials. The outcomes for this analysis included the re-bleeding rate, need for surgical intervention, length of hospital stay, transfusion requirement, and mortality. The re-bleeding rate in the patient-level analysis for the endoscopically treated group was 8.2% (5 of 61) compared with 24.7% (21 of 85) in the medically treated group (pooled RR = 0.35; 95% CI [−.0.22–0.69]; NNT = 6.2). There were no significant differences between endoscopic and medical treatment for the other outcomes (Table 1). There was significant variability amongst the trial results in the meta-analysis with a heterogeneity P value = .017. Again, the re-bleeding rate was lower in the endoscopically treated group than in the medically treated group in the meta-analysis with a pooled RR for re-bleeding of 0.35 (95% CI [0.14–0.83]; NNT = 6.3). The meta-analysis also suggested that endoscopic therapy reduced the need for surgical intervention compared with medical therapy alone with a pooled RR of 0.43 (95% CI [0.19–0.98]; NNT = 13.3). There was no significant difference between treatment groups for the other outcomes.Table 1Results of Patient-Level Analysis and Meta-analysisOutcomeTrial subgroupnPEndoRxPMedRxRR (95% CI)NNTRebleedingAll trials240.13.290.39 (0.22–0.69)6.2Abstracts excluded146.095.250.35 (0.14–0.83)6.3DeathAll trials240.097.0841.11 (0.50–2.49)—Abstracts excluded146.13.062.27 (0.74–6.95)—SurgeryAll trials240.062.140.43 (0.19–0.98)13.3Abstracts excluded146.065.080.82 (0.25–2.65)—EndoRx, endoscopic therapy; MedRx, medical therapy; RR, relative risk; CI, confidence interval; NNT, number needed to treat. Open table in a new tab EndoRx, endoscopic therapy; MedRx, medical therapy; RR, relative risk; CI, confidence interval; NNT, number needed to treat. This meta-analysis suggests endoscopic treatment combined with medical therapy is superior to medical therapy alone in preventing recurrent bleeding from peptic ulcers with adherent clots. The impact of intravenous proton pump inhibitors in this setting is of great interest and warrants future prospective studies. Keratins are epithelial-specific intermediate filament (IF) cytoskeletal proteins that fall into 2 categories, type I and type II, that form non-covalent 1:1 heteropolymers that have tissue-specific expression. Keratin 8 and 18 (K8/K18) heteropolymers, for instance, are found primarily in single-layered epithelia as in the liver, pancreas, and intestine, while K5/K14 and K1/K10 keratins form stratified layers found in basal and suprabasal keratinocytes, respectively. Keratins play important structural and functional roles and mutations in these molecules are associated with a variety of human diseases affecting oral, ocular, esophageal, and liver parenchyma. Mice having mutations of K8/K18 are highly susceptible to liver injury and apoptosis. Similarly, K8 and K18 heterozygous variants found in domains having high mutational frequency were reported in significantly more liver disease patients than in normal blood bank controls. Although these K8/K18 mutations do not affect basal filament organization, they impair normal filament reorganization in transfected cells following exposure to stress, a finding likely to be important to hepatocytes that continuously undergo mitosis and oxidative stress and other cellular functions. In the study by Ku et al, a detailed mutational analysis of the remaining untested coding sequences of K8 and K18 was performed in a cohort of liver disease explants and blood bank controls, specifically looking at mutations present in the remaining 10 exons of K8/K18. Ten novel K8/K18 heterozygous variants were identified in 44 of 467 explants and 11 of 349 controls, including deletion, frameshift truncations, and missense alterations (Table 2). Overall, the frequency of K8/K18 variants was 12.4% in 467 liver disease explants and 3.7% in 349 blood bank controls (P < .0001). The authors predicted that many of the variants affect keratin solubility or phosphorylation, increasing individual susceptibility to end-stage liver disease depending on their genetic background and exposure to other insults such as alcohol or viral infection.Table 2K8/K18 Variants in Human Liver DiseasesKeratinVariantsNo. of variant carriers fromAmino acidNucleotideLiver disease cohort (n = 467)Blood bank controls (n = 349)K8G52VGGC→GTC1NoneY53HTAT→CAT51G61CGGC→TGC61R340HCGT→CAT3010G433SGGC→AGC41R453CCGC→TGC1NoneI465-fsATC→ATCC1NoneI62VaAmino acid substitutions that are considered polymorphisms not associated with liver disease progression because they were found at similar, or higher, incidence in the control cohort as compared with the liver disease explant group.ATC→GTC17L71Lb“Silent” nucleotide mutations that do not result in any amino acid change. The total number of K8/K18 variants shown represents “true” mutations and does not include “silent” mutations or polymorphisms. In addition to the exonic K8/K18 variants, there were frequent polymorphisms in the 5′-untranslated region of K8 at −10 (T/A) and/or −4 (C/T) nucleotides from first amino acid ATG codon.CTG→CTA1NoneL226Lb“Silent” nucleotide mutations that do not result in any amino acid change. The total number of K8/K18 variants shown represents “true” mutations and does not include “silent” mutations or polymorphisms. In addition to the exonic K8/K18 variants, there were frequent polymorphisms in the 5′-untranslated region of K8 at −10 (T/A) and/or −4 (C/T) nucleotides from first amino acid ATG codon.CTA→CTGCommonCommonA318SaAmino acid substitutions that are considered polymorphisms not associated with liver disease progression because they were found at similar, or higher, incidence in the control cohort as compared with the liver disease explant group.GCT→TCT52R301CaAmino acid substitutions that are considered polymorphisms not associated with liver disease progression because they were found at similar, or higher, incidence in the control cohort as compared with the liver disease explant group.CGC→TGCNone1A332Ab“Silent” nucleotide mutations that do not result in any amino acid change. The total number of K8/K18 variants shown represents “true” mutations and does not include “silent” mutations or polymorphisms. In addition to the exonic K8/K18 variants, there were frequent polymorphisms in the 5′-untranslated region of K8 at −10 (T/A) and/or −4 (C/T) nucleotides from first amino acid ATG codon.GCC→GCT51E376Eb“Silent” nucleotide mutations that do not result in any amino acid change. The total number of K8/K18 variants shown represents “true” mutations and does not include “silent” mutations or polymorphisms. In addition to the exonic K8/K18 variants, there were frequent polymorphisms in the 5′-untranslated region of K8 at −10 (T/A) and/or −4 (C/T) nucleotides from first amino acid ATG codon.GAG→GAA2—V460MaAmino acid substitutions that are considered polymorphisms not associated with liver disease progression because they were found at similar, or higher, incidence in the control cohort as compared with the liver disease explant group.GTG→ATGNone1V4791aAmino acid substitutions that are considered polymorphisms not associated with liver disease progression because they were found at similar, or higher, incidence in the control cohort as compared with the liver disease explant group.GTC→ATCNone2K18Δ64–71Deletion2NoneT102AACC→GCC1NoneH127LCAT→CTT2NoneI149VATC→GTC2NoneR260QCGG→CAG1NoneE275GGAG→GGG1NoneQ284RCAG→CGG1NoneT294MACG→ATG1NoneT296IACA→ATA1NoneG339RGGG→AGG1NoneS229TaAmino acid substitutions that are considered polymorphisms not associated with liver disease progression because they were found at similar, or higher, incidence in the control cohort as compared with the liver disease explant group.AGC→ACC24Y330Yb“Silent” nucleotide mutations that do not result in any amino acid change. The total number of K8/K18 variants shown represents “true” mutations and does not include “silent” mutations or polymorphisms. In addition to the exonic K8/K18 variants, there were frequent polymorphisms in the 5′-untranslated region of K8 at −10 (T/A) and/or −4 (C/T) nucleotides from first amino acid ATG codon.TAC→TAT1NoneK848/46713/349K1813/467NoneK8/1858cThree patients had a double mutation (K8 R340H and K18 R260Q, K8 R340H and K18 T102A, or K18 I149V and K18 T294M), which accounts for the total net number of 58 patients with keratin mutations (ie, 61 − 3 = 58)./46713/349NOTE. Single-letter standard abbreviations are used to represent amino acids (numbered excluding the first methionine14–16) and nucleotides. Sequences are categorized such that those with underlined or bold lettering refer to variants that are likely to pose a potential risk for end-stage liver disease (ie, the total of 58 livers with K8/18 variants), according to analysis of the liver explant cohort and the blood bank control group. The underlined letters highlight the 10 new K8/K18 variants in the remaining 10 exons of K8/18 (the bold lettering highlights the previously defined variants14–16). K8 I465-fs represent a frameshift mutation at Ile-465 (ATC→ATCC) that generates a truncated 468 (465IRDT) amino acid protein (instead of 482 in WT K8), whereas K18Δ64–71 generates a 421–amino acid protein (instead of 429).a Amino acid substitutions that are considered polymorphisms not associated with liver disease progression because they were found at similar, or higher, incidence in the control cohort as compared with the liver disease explant group.b “Silent” nucleotide mutations that do not result in any amino acid change. The total number of K8/K18 variants shown represents “true” mutations and does not include “silent” mutations or polymorphisms. In addition to the exonic K8/K18 variants, there were frequent polymorphisms in the 5′-untranslated region of K8 at −10 (T/A) and/or −4 (C/T) nucleotides from first amino acid ATG codon.c Three patients had a double mutation (K8 R340H and K18 R260Q, K8 R340H and K18 T102A, or K18 I149V and K18 T294M), which accounts for the total net number of 58 patients with keratin mutations (ie, 61 − 3 = 58). Open table in a new tab NOTE. Single-letter standard abbreviations are used to represent amino acids (numbered excluding the first methionine14–16) and nucleotides. Sequences are categorized such that those with underlined or bold lettering refer to variants that are likely to pose a potential risk for end-stage liver disease (ie, the total of 58 livers with K8/18 variants), according to analysis of the liver explant cohort and the blood bank control group. The underlined letters highlight the 10 new K8/K18 variants in the remaining 10 exons of K8/18 (the bold lettering highlights the previously defined variants14–16). K8 I465-fs represent a frameshift mutation at Ile-465 (ATC→ATCC) that generates a truncated 468 (465IRDT) amino acid protein (instead of 482 in WT K8), whereas K18Δ64–71 generates a 421–amino acid protein (instead of 429). Interleukin (IL)-22 is part of a cytokine family with limited homology to IL-10 that is primarily expressed by activated Th1-polarized and memory T-lymphocytes. Interestingly, its receptor is not expressed by human immune cells even under stimulated conditions, but by tissues such as skin, liver, lung, kidney, pancreas, small intestine, and colon. Upon receptor stimulation, pancreatitis-associated protein-1 expression in the pancreas is increased and secretion of several acute phase proteins is observed in HepG2 human hepatoma cells. In Colo205 colon cancer cells, IL-22 stimulates IL-10 secretion. However, it remains unclear whether IL-22 plays a role in the proinflammatory process. To examine this possibility, IL-22 expression was determined in active areas of human inflammatory bowel diseases. Although IL-22 was not detectable in normal colonic mucosa, it was expressed by CD4-positive T cells in both ulcerative colitis and Crohn’s disease tissues, albeit much greater in the latter. Interestingly, IL-22 receptor expression co-localized with a marker of SEMFs. To determine the significance of this finding, studies were then performed on nontransformed human colonic subepithelial myofibroblasts (SEMFs) using cDNA microarrays, Northern blots, enzyme-linked immunosorbent assay, and electrophoretic gel mobility shift assays (EMSA). In SEMFs, IL-22 activated NF-κB, AP-1, and MAP-kinase dependent pathways to increase expression of IL-6, IL-8, IL-11, and leukemia inhibitory factor. By microarray, expression of metalloproteinases was also increased. In contrast, IL-22 had no effects on SEMF proliferation and collagen synthesis (Figure 3). These findings therefore implicate a role for T-cell–derived IL-22 in promoting intestinal inflammation through the elaboration of proinflammatory cytokines and matrix-degrading molecules produced through subepithelial myofibroblasts. A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for Treatment of Crohn’s DiseaseGastroenterologyVol. 129Issue 3PreviewBackground & Aims: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab′ fragment of anti–tumor necrosis factor, CDP870) in Crohn’s disease. Methods: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn’s disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn’s Disease Activity Index decrease of ≥ 100 points or remission [Crohn’s Disease Activity Index ≤ 150 points]) in the intent-to-treat population. Full-Text PDF Endoscopic Therapy Versus Medical Therapy for Bleeding Peptic Ulcer With Adherent Clot: A Meta-analysisGastroenterologyVol. 129Issue 3PreviewBackground & Aims: The optimal management of bleeding peptic ulcer with adherent clot is controversial and may include endoscopic therapy or medical therapy. Methods: We searched MEDLINE, BIOSIS, EMBASE, and the Cochrane Library to identify all randomized controlled trials comparing the 2 interventions. Outcomes evaluated in the meta-analysis were recurrent bleeding, need for surgical intervention, length of hospitalization, transfusion requirement, and mortality. Results: Six studies were identified that included 240 patients from the United States, Hong Kong, South Korea, and Spain. Full-Text PDF Keratins as Susceptibility Genes for End-Stage Liver DiseaseGastroenterologyVol. 129Issue 3PreviewBackground & Aims: Keratins 8 and 18 protect the liver from stress. Keratin 8 and 18 variants in 17 of 467 liver disease explants and 2 of 349 blood bank controls were previously reported in 5 analyzed exonic regions. We asked whether mutations were present in the remaining 10 exons of keratins 8 and 18. Methods: Exonic regions were polymerase chain reaction–amplified from genomic DNA, isolated from the above-mentioned 2 cohorts, and analyzed for the presence of mutations. Mutant keratins were also studied biochemically. Full-Text PDF Interleukin-22, a Member of the IL-10 Subfamily, Induces Inflammatory Responses in Colonic Subepithelial MyofibroblastsGastroenterologyVol. 129Issue 3PreviewBackground & Aims: Interleukin (IL)-22, a member of the IL-10 subfamily, is a recently identified T-cell-derived cytokine. We investigated IL-22 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and analyzed its biologic activities in human colonic subepithelial myofibroblasts (SEMFs). Methods: Mucosal IL-22 expression was evaluated by immunohistochemical procedures. The effects of IL-22 on colonic SEMFs were investigated by cDNA microarrays, Northern blots, enzyme-linked immunosorbent assay, and electrophoretic gel mobility shift assays (EMSAs). Full-Text PDF