Ulcerative Colitis: Achkar JP

Achkar JP. · No affiliation provided · Am J Gastroenterol. · Pubmed #18341487 No free full text.

Abstract: The results of recently completed genome-wide association studies have rapidly advanced knowledge of inflammatory bowel disease (IBD) genetics. Several promising associations between IBD and gene variants have been identified with the two best replicated so far being variants in the IL23R and ATG16L1 genes. These findings highlight the importance of the immune system and interactions with intestinal microflora in the pathogenesis of IBD.

Achkar JP, Shen B. · Department of Gastroenterology, The Cleveland Clinic Foundation, A30, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Curr Gastroenterol Rep. · Pubmed #11696286 No free full text.

Abstract: Surgical intervention is often required for patients with inflammatory bowel disease. Total proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice for patients with ulcerative colitis. The main long-term complication of this surgery is pouchitis, with 10-year cumulative incidence rates between 24% and 46%. For patients with Crohn's disease, postoperative recurrence is a significant problem, with clinical recurrence rates as high as 55% at 5 years and 76% at 15 years. Increasing evidence suggests that postoperative medical therapy has the potential to decrease the risk of postoperative Crohn's disease recurrence.

Achkar JP. · Department of Gastroenterology and Hepatology, Cleveland Clinic, OH 44195, USA. · Cleve Clin J Med. · Pubmed #17879519 links to  free full text

Abstract: Aminosalicylates are the first-line therapy for patients with mild to moderate active ulcerative colitis. Treatment should start at dosages of 4.8 g per day of the active 5-aminosalicylate moiety, rather than starting at a lower dosage and increasing if treatment fails. Infliximab has been shown to be effective and is now approved by the US Food and Drug Administration for the treatment of moderately to severely active ulcerative colitis in patients who have had an inadequate response to conventional therapy.

Shen B, Lashner BA, Bennett AE, Remzi FH, Brzezinski A, Achkar JP, Bast J, Bambrick ML, Fazio VW. · Center for Inflammatory Bowel Disease, Departments of Gastroenterology/Hepatology, Anatomic Pathology, and Colorectal Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · Am J Gastroenterol. · Pubmed #15307872 No free full text.

Abstract: BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the treatment of choice in the majority of patients with ulcerative colitis (UC) who require surgery. To ease the construction of the IPAA and improve functional outcome by minimizing sphincter related stretch injury, a stapling technique is being commonly used in the pouch-anal anastomosis. Despite its advantages, the procedure normally leaves a 1-2 cm of anal transitional zone or rectal cuff, which is susceptible to recurrence of residual UC or cuffitis. Cuffitis can cause symptoms mimicking pouchitis. AIM: To conduct an open-labeled trial of topical mesalamine in patients with cuffitis. METHODS: We treated 14 consecutive patients with cuffitis by giving mesalamine suppositories 500 mg b.i.d. (mean 3.2 months, range 1-9 months). The Cuffitis Activity Index (adapted from the Pouchitis Disease Activity Index) scores and improvement in symptoms of bloody bowel movements and arthralgias were measured as primary and secondary outcomes. RESULTS: All patients had surgery for medically refractory UC. There were significant reductions in the total Cuffitis Activity Index scores after the therapy (11.93 +/- 3.17 vs 6.21 +/- 3.19, p < 0.001). Symptom (3.24 +/- 1.28 vs 1.79 +/- 1.31), endoscopy (3.14 +/- 1.29 vs 1.00 +/- 1.52), and histology (4.93 +/- 1.77 vs 3.57 +/- 1.39) scores each were significantly reduced (p < 0.05). Ninety-two percent of patients with bloody bowel movements and 70% of patients with arthralgias improved after the therapy. No systemic or topical adverse effects were reported. CONCLUSION: Topical mesalamine appears well tolerated and effective in treating patients with cuffitis, with improvement in symptom as well as endoscopic and histologic inflammation.

Shen B, Achkar JP, Lashner BA, Ormsby AH, Remzi FH, Brzezinski A, Bevins CL, Bambrick ML, Seidner DL, Fazio VW. · Center for Inflammatory Bowel Disease, Department of Gastroenterology, The Cleveland Clinic Foundation, Ohio 44195, USA. · Inflamm Bowel Dis. · Pubmed #11720319 No free full text.

Abstract: Metronidazole is effective for the treatment of acute pouchitis after ileal pouch-anal anastomosis, but it has not been directly compared with other antibiotics. This randomized clinical trial was designed to compare the effectiveness and side effects of ciprofloxacin and metronidazole for treating acute pouchitis. Acute pouchitis was defined as a score of 7 or higher on the 18-point Pouchitis Disease Activity Index (PDAI) and symptom duration of 4 weeks or less. Sixteen patients were randomized to a 2-week course of ciprofloxacin 1,000 mg/d (n = 7) or metronidazole 20 mg/kg/d (n = 9). Clinical symptoms, endoscopic findings, and histologic features were assessed before and after therapy. Both ciprofloxacin and metronidazole produced a significant reduction in the total PDAI score as well as in the symptom, endoscopy, and histology subscores. Ciprofloxacin lowered the PDAI score from 10.1+/-2.3 to 3.3+/-1.7 (p = 0.0001), whereas metronidazole reduced the PDAI score from 9.7+/-2.3 to 5.8+/-1.7 (p = 0.0002). There was a significantly greater reduction in the ciprofloxacin group than in the metronidazole group in terms of the total PDAI (6.9+/-1.2 versus 3.8+/-1.7; p = 0.002), symptom score (2.4+/-0.9 versus 1.3+/-0.9; p = 0.03), and endoscopic score (3.6+/-1.3 versus 1.9+/-1.5; p = 0.03). None of patients in the ciprofloxacin group experienced adverse effects, whereas three patients in the metronidazole group (33%) developed vomiting, dysgeusia, or transient peripheral neuropathy. Both ciprofloxacin and metronidazole are effective in treating acute pouchitis with significant reduction of the PDAI scores. Ciprofloxacin produces a greater reduction in the PDAI and a greater improvement in symptom and endoscopy scores, and is better tolerated than metronidazole. Ciprofloxacin should be considered as one of the first-line therapies for acute pouchitis.

Shen B, Achkar JP, Lashner BA, Ormsby AH, Remzi FH, Bevins CL, Brzezinski A, Petras RE, Fazio VW. · Department of Gastroenterology, Center for Inflammatory Bowel Disease, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. · Gastroenterology. · Pubmed #11487535 No free full text.

Abstract: BACKGROUND & AIMS: Pouchitis often is diagnosed based on symptoms alone. In this study, we evaluate whether symptoms correlate with endoscopic and histologic findings in patients with ulcerative colitis and an ileal pouch-anal anastomosis. METHODS: Symptoms, endoscopy, and histology were assessed in 46 patients using Pouchitis Disease Activity Index (PDAI). Patients were classified as either having pouchitis (PDAI score > or =7; N = 22) or as not having pouchitis (PDAI score <7; N = 24). RESULTS: Patients with pouchitis had significantly higher mean total PDAI scores, symptom scores, endoscopy scores, and histology scores. There was a similar magnitude of contribution of each component score to the total PDAI for the pouchitis group. Of note, 25% of patients with symptoms suggestive of pouchitis did not meet the PDAI diagnostic criteria for pouchitis. In both groups, the correlation coefficients between symptom, endoscopy, and histology scores were near zero (range, -0.26 to 0.20; P > 0.05). CONCLUSIONS: The symptom, endoscopy, and histology scores each contribute to the PDAI and appear to be independent of each other. Symptoms alone do not reliably diagnose pouchitis.

Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH. · No affiliation provided · Nat Genet. · Pubmed #19471306 No free full text.

This publication has no abstract.

Festen EA, Goyette P, Scott R, Annese V, Zhernakova A, Lian J, Lefèbvre C, Brant SR, Cho JH, Silverberg MS, Taylor KD, de Jong DJ, Stokkers PC, Mcgovern D, Palmieri O, Achkar JP, Xavier RJ, Daly MJ, Duerr RH, Wijmenga C, Weersma RK, Rioux JD. · Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. · Gut. · Pubmed #19201773 No free full text.

Abstract: OBJECTIVES: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that interleukin 2 (IL2) and IL21 play in the immune response also make them attractive candidates for IBD. The objective of this study was to test for association between the IL2/IL21 locus and the IBDs. METHODS: The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated with coeliac disease were genotyped in 1590 subjects with IBD and 929 controls from The Netherlands, and then replicated in a North American cohort (2387 cases and 1266 controls) and an Italian cohort (805 cases and 421 controls), yielding a total of 4782 cases (3194 UC, 1588 CD) and 2616 controls. Allelic association testing and a pooled analysis using a Cochran-Mantel-Haenszel test were performed. RESULTS: All four SNPs were strongly associated with UC in all three cohorts and reached genome-wide significance in the pooled analysis (rs13151961 p = 1.35 x 10(-10), rs13119723 p = 8.60 x 10(-8), rs6840978 p = 3.0 7x 10(-8), rs6822844 p = 2.77 x 10(-9)). A moderate association with CD was also found in the pooled analysis (p value range 0.0016-9.86 x 10(-5)). CONCLUSIONS: A strong association for the IL2/IL21 locus with UC was found, which also confirms it as a general susceptibility locus for inflammatory disease.

Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH. · Mount Sinai Hospital Inflammatory Bowel Disease Group, University of Toronto, 600 University Avenue, Toronto, ON M5G1X5, Canada. · Nat Genet. · Pubmed #19122664 links to  free full text

Abstract: Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29).

Melton GB, Fazio VW, Kiran RP, He J, Lavery IC, Shen B, Achkar JP, Church JM, Remzi FH. · Digestive Disease Institute, Department of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · Ann Surg. · Pubmed #18936574 No free full text.

Abstract: OBJECTIVE: To assess long-term outcomes after ileal pouch-anal anastomosis (IPAA) in Crohn's disease (CD). SUMMARY BACKGROUND DATA: Although considered the procedure of choice in ulcerative colitis, performance of ileal pouch-anal anastomosis (IPAA) is controversial in CD. METHODS: CD patients were identified from a prospectively maintained IPAA database. Time-to-diagnosis and pouch retention rates were analyzed using Kaplan-Meier curves. Demographic, clinical, and pathologic factors associated with pouch retention were evaluated with log-rank test and Cox proportional hazards model. RESULTS: Two hundred and four CD patients (108 female, median age 33 years, and median follow-up 7.4 years) with primary IPAA were included. CD diagnosis was before IPAA (intentional) in 20(10%), from postoperative histopathology (incidental) in 97(47%) or made in a delayed fashion at median 36 months after IPAA in 87(43%). Overall 10-year pouch retention was 71%. On multivariate analysis, pouch loss was associated with delayed diagnosis (P = 0.03, hazard ratio [HR] 2.6 (95% confidence interval [CI] 1.1-6.5)), pouch-vaginal fistula (P = 0.01, HR 2.8 (95% CI 1.3-6.4)), and pelvic sepsis (P = 0.0001, HR 9.7(95% CI 3.4-27.3)). Patients with retained IPAA at follow-up had near-perfect/perfect continence (72%), rare/no urgency (68%) with median daily bowel movements 7 (range 2-20). Median overall quality of life, quality of health, level of energy, and happiness with surgery were 9, 9, 8, and 10 of 10, respectively. CONCLUSIONS: For CD patients with IPAA, when the diagnosis is established preoperatively or immediately following surgery, pouch loss rates are low and functional results are favorable. Outcomes in patients with delayed diagnosis are worse but half retain their pouch at 10 years with good functional outcomes.

Dassopoulos T, Nguyen GC, Bitton A, Bromfield GP, Schumm LP, Wu Y, Elkadri A, Regueiro M, Siemanowski B, Torres EA, Gregory FJ, Kane SV, Harrell LE, Franchimont D, Achkar JP, Griffiths A, Brant SR, Rioux JD, Taylor KD, Duerr RH, Silverberg MS, Cho JH, Steinhart AH. · Johns Hopkins University Meyerhoff Inflammatory Bowel Disease Center, Baltimore MD, USA. · Inflamm Bowel Dis. · Pubmed #17427244 links to  free full text

Abstract: BACKGROUND: The NIDDK IBD Genetics Consortium (IBDGC) collects DNA and phenotypic data from inflammatory bowel disease (IBD) subjects to provide a resource for genetic studies. No previous studies have been performed on the reliability and validity of phenotypic determinations in either Crohn's disease (CD) or ulcerative colitis (UC) using primary records. Our aim was to determine the reliability and validity of these phenotypic assessments. METHODS: The de-identified records of 30 IBD patients were reviewed by 2 phenotypers per center using a standard protocol for phenotypic assessment. Each phenotyper evaluated 10 charts on 2 occasions 5 months apart. Reliability was expressed as the kappa (kappa) statistic. Performance characteristics were determined by comparison to a consensus-derived "gold standard" and by generation of receiver operating characteristic (ROC) curves. RESULTS: Agreement for diagnosis was excellent (kappa = 0.82; 95% confidence interval [CI]: 0.71-0.92). Agreement for CD location was good for jejunal, ileal, colorectal, and perianal disease with kappa between 0.60 and 0.74 but was fair for esophagogastroduodenal (kappa = 0.36). Agreement for UC extent (kappa = 0.67; 95% CI: 0.48-0.85), and CD behavior (kappa = 0.67; 95% CI: 0.49-0.83) were very good. Area under the ROC curves was greater than 0.84 for diagnosis, CD behavior, UC extent, and ileal and colonic CD location. CONCLUSIONS: IBD phenotype classification using a standard protocol exhibited very good to excellent inter- and intrarater agreement and validity. This study highlights the importance of standard protocols in generating reliable and valid phenotypic assessments. The data will facilitate estimates of phenotyping misclassification rates that should be considered when making inferences from IBD genotype-phenotype studies.

Achkar JP, Dassopoulos T, Silverberg MS, Tuvlin JA, Duerr RH, Brant SR, Siminovitch K, Reddy D, Datta LW, Bayless TM, Zhang L, Barmada MM, Rioux JD, Steinhart AH, McLeod RS, Griffiths AM, Cohen Z, Yang H, Bromfield GP, Schumm P, Hanauer SB, Cho JH, Nicolae DL. · Center for Inflammatory Bowel Disease, Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH, USA. · Am J Gastroenterol. · Pubmed #16542294 No free full text.

Abstract: OBJECTIVES: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci. METHODS: This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis. RESULTS: We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p < 0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. CONCLUSIONS: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.

Shen B, Fazio VW, Remzi FH, Brzezinski A, Bennett AE, Lopez R, Hammel JP, Achkar JP, Bevins CL, Lavery IC, Strong SA, Delaney CP, Liu W, Bambrick ML, Sherman KK, Lashner BA. · Department of Gastroenterology/Hepatology, Center for Inflammatory Bowel Disease, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · Clin Gastroenterol Hepatol. · Pubmed #16431309 No free full text.

Abstract: BACKGROUND & AIMS: Although pouchitis is considered the most common adverse sequela of ileal pouch-anal anastomosis (IPAA), inflammatory and noninflammatory conditions other than pouchitis are increasingly being recognized. The risk factors for these non-pouchitis conditions, including Crohn's disease (CD) of the pouch, cuffitis, and irritable pouch syndrome (IPS), have not been studied. The aim of this study was to assess risk factors for inflammatory and noninflammatory diseases of IPAA in a tertiary care setting. METHODS: The study consisted of 240 consecutive patients who were classified as having healthy pouches (N = 49), pouchitis (N = 61), CD of the pouch (N = 39), cuffitis (N = 41), or IPS (N =50). Demographic and clinical features were assessed to determine risk factors for each of these conditions by using logistic regression analysis. RESULTS: Risk factors remaining in the final logistic regression models were for pouchitis: IPAA indication for dysplasia (odds ratio [OR], 3.89; 95% confidence interval [CI], 1.69-8.98), never having smoked (OR, 5.09; 95% CI, 1.01-25.69), no use of anti-anxiety agents (OR, 5.19; 95% CI, 1.45-18.59), or use of NSAIDs (OR, 3.24; 95% CI, 1.71-6.13); for CD of the pouch: a long duration of IPAA (OR, 1.20; 95% CI, 1.12-1.30) and current smoking (OR, 4.77; 95% CI, 1.39-16.25); for cuffitis: arthralgias (OR, 4.13; 95% CI, 1.91-8.94) and younger age (OR, 1.16; 95% CI, 1.01-1.33); and for IPS: use of antidepressants (OR, 4.17, 95% CI, 1.95-8.92) or anti-anxiety agents (OR, 3.21; 95% CI, 1.34-7.47). CONCLUSIONS: The majority of risk factors for the 4 inflammatory and noninflammatory conditions of IPAA are different, suggesting that each of these diseases has a different etiology and pathogenesis. The identification and modification of these risk factors might help patients and clinicians to make a preoperative decision for IPAA, reduce IPAA-related morbidity, and improve response to treatment.

Kiran RP, O'Brien-Ermlich B, Achkar JP, Fazio VW, Delaney CP. · Department of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · Dis Colon Rectum. · Pubmed #15868233 No free full text.

Abstract: PURPOSE: This study was designed to evaluate the presentation, management, and outcome of peristomal pyoderma gangrenosum at a specialist colorectal unit and develop a strategy for therapy. METHODS: Patients with peristomal pyoderma gangrenosum were identified from a prospectively accrued Institutional Review Board-approved stoma database. Data were collected regarding demographics, disease status, history of illness, time to healing, and treatments used from the database and by chart review. RESULTS: Sixteen patients presented between 1997 and 2002 with peristomal ulceration consistent with a diagnosis of peristomal pyoderma gangrenosum. Diagnosis was predominantly clinically based on a classic presentation of painful, undermined peristomal ulceration. The underlying diagnosis was Crohn's disease in 11 patients, ulcerative colitis in 3, indeterminate colitis in 1, and posterior urethral valves in 1. At the time of development of peristomal pyoderma gangrenosum, the underlying disease was active in 69 percent of patients. Stoma care, ulcer debridement with unroofing of undermined edges, and intralesional corticosteroid injection was associated with a 40 percent complete response rate and further 40 percent partial response rate. Of five patients who received infliximab, four (80 percent) responded to therapy. Complete response after all forms of therapy, including stoma relocation in seven patients, was 87 percent. CONCLUSIONS: Local wound management and enterostomal therapy are extremely important for patients with peristomal pyoderma gangrenosum. Infliximab may provide a useful option for those failing other forms of medical therapy. Relocation of the stoma is reserved for persistent ulceration failing other therapies, because peristomal pyoderma gangrenosum may recur at the new stoma site.

Shen B, Fazio VW, Remzi FH, Delaney CP, Bennett AE, Achkar JP, Brzezinski A, Khandwala F, Liu W, Bambrick ML, Bast J, Lashner B. · Center for Inflammatory Bowel Disease, Departments of Gastroenterology/Hepatology, The Cleveland Clinic Foundation, Cleveland, Ohio. · Am J Gastroenterol. · Pubmed #15654787 No free full text.

Abstract: BACKGROUND AND AIMS: Ileal pouch-anal anastomosis (IPAA) improves quality of life (QOL) for ulcerative colitis patients who require surgery. Crohn's disease (CD) of the pouch, pouchitis, cuffitis, and irritable pouch syndrome (IPS) have an adverse impact on physical and psychological well-being, which can compromise the gain in QOL after the surgery. Their clinical, endoscopic, and histologic features have not been fully characterized. The aim of this study was to compare demographic, clinical, endoscopic, and histologic features between CD of the pouch, pouchitis, cuffitis, IPS, and normal pouches. METHODS We enrolled 124 patients: normal pouches (N = 26), CD of the pouch (N = 23), pouchitis (N = 22), cuffitis (N = 21), and IPS (N = 32). Symptomatology, endoscopy, histology, and the Cleveland Global QOL and the Irritable Bowel Syndrome-QOL scores were compared among the groups. RESULTS: Univariate analysis of demographic and clinical data showed a possible association between NSAID use and pouchitis, extraintestinal manifestation and cuffitis, and antidepressant use and IPS. There were no differences in the Pouchitis Disease Activity Index symptom scores between the disease groups, with an exception of bleeding, which occurred almost exclusively in cuffitis. Endoscopy was useful in discriminating between CD of the pouch, pouchitis, cuffitis, and normal pouches or IPS. Patients with diseased IPAA had worse QOL scores. CONCLUSIONS: Symptoms largely overlapped among the disease groups of IPAA. Endoscopy is valuable for diagnosis. Inflammatory or noninflammatory sequelae of IPAA adversely affected patients' QOL.

Achkar JP, Al-Haddad M, Lashner B, Remzi FH, Brzezinski A, Shen B, Khandwala F, Fazio V. · Department of Gastroenterology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk A30, Cleveland, Ohio 44195, USA. · Clin Gastroenterol Hepatol. · Pubmed #15645406 No free full text.

Abstract: BACKGROUND & AIMS: Pouchitis is the most common complication of ileal pouch anal anastomosis in patients with ulcerative colitis. In some cases the inflammation becomes chronic and requires long-term medical therapy. The clinical course and medical therapy are different between acute pouchitis and chronic pouchitis. The aim of this study was to determine if there are predictors of risk for acute vs. chronic pouchitis. METHODS: Patients with acute pouchitis (N = 40) and patients with chronic pouchitis (N = 40) were matched with a control group who never had pouchitis (N = 40). Data were collected for multiple pre-, peri-, and postoperative factors and follow-up telephone calls were performed. Case-control univariable analyses and multivariate logistic regression were used to measure the association between covariates and pouchitis. Results: Multivariate logistic regression showed that extensive colonic disease (odds ratio [OR], 2.99; P = .045 for acute pouchitis; and OR, 4.61; P = .010 for chronic pouchitis) and extraintestinal manifestations (OR, 2.88; P = .037 for acute pouchitis; and OR, 2.69; P = .047 for chronic pouchitis) were associated with both acute and chronic pouchitis. Postoperative nonsteroidal anti-inflammatory drug (NSAID) use was associated with chronic pouchitis, but less so with acute pouchitis. Patients with fulminant colitis as an indication for surgery had a decreased risk for developing chronic pouchitis (OR, 0.22; P = .036), but no such association was seen for acute pouchitis. CONCLUSIONS: Extensive colonic disease and preoperative extraintestinal manifestations are associated with increased risk for both acute and chronic pouchitis. Fulminant colitis leading to colectomy is protective from development of chronic pouchitis. Postoperative use of NSAIDS is a risk factor for chronic pouchitis and possibly for acute pouchitis, and thus should be discouraged for patients who undergo ileal pouch anal anastomosis.

Shen B, Fazio VW, Remzi FH, Delaney CP, Achkar JP, Bennett A, Khandwala F, Brzezinski A, Doumit J, Liu W, Lashner BA. · Department of Gastroenterology/Hepatology, Center for Inflammatory Bowel Disease, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · Am J Gastroenterol. · Pubmed #15571580 No free full text.

Abstract: BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice in patients with ulcerative colitis. Strictures can occur at the inlet and outlet of the pouch. Endoscopic balloon dilation has been successfully used in patients with Crohn's strictures at the small intestine and colon. There are no published trials on endoscopic balloon therapy of ileal pouch strictures. AIM: To evaluate outpatient endoscopic balloon dilation of strictures in ileal pouches. METHODS: Patients underwent nonfluoroscopy-guided, nonsedated, outpatient endoscopic dilations with an 8.6-mm upper endoscope and through-the-scope balloons (size: 11-18 mm). Pre- and posttreatment Pouchitis Disease Activity Index symptom scores (range: 0-6), endoscopic stricture scores based on resistance in passing the endoscope (range: 0-4), and Cleveland Global Quality of Life were compared. RESULTS: Nineteen patients with pouch strictures who had concurrent Crohn's disease of the pouch (n = 11), cuffitis (n = 5), and pouchitis (n = 3), including 14 inlet and 14 outlet strictures, were enrolled. The mean number of strictures for each patient was 1.61 +/- 0.78. All strictures were successfully dilated with the through-the-scope balloon, with a mean of 1.74 +/- 1.19 (range: 1-5) sessions for each patient. Nine patients had a second endoscopy at 8 wk and five patients had a third pouch endoscopy at 16 wk after the initial endoscopic dilation. Endoscopic stricture scores immediately (0.30 +/- 0.47), 8 wk (0.40 +/- 0.51), and 16 wk (0.44 +/- 0.76) after the dilation were significantly improved compared to the predilation stricture scores (2.67 +/- 0.78). The symptom scores and quality-of-life (QOL) scores improved at week 8 and 16 following dilation, with a mean follow-up of 6.10 +/- 5.83 months (2-25 months). No complications were experienced with the procedure. One patient with CD who failed endoscopic and medical therapy underwent pouch resection. CONCLUSION: In conjunction with medical therapy, outpatient endoscopic balloon dilation appears safe and effective in treating pouch inlet and outlet strictures, by relieving symptoms, restoring pouch patency, and improving QOL in the majority of patients.

Barmada MM, Brant SR, Nicolae DL, Achkar JP, Panhuysen CI, Bayless TM, Cho JH, Duerr RH. · Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pennsylvania 15261, USA. · Inflamm Bowel Dis. · Pubmed #15472510 No free full text.

Abstract: We report genome-wide linkage results using model-free linkage analysis (Allegro) of 358 autosomal microsatellites in 260 new inflammatory bowel disease-affected relative pairs from 139 Caucasian families, including 108 Crohn's disease-affected relative pairs and 72 ulcerative colitis-affected relative pairs. Our results provide confirmatory evidence for linkage between the IBD2 locus and the inflammatory bowel disease phenotype (lod = 2.12 at GATA91H06) and ulcerative colitis phenotype (lod = 1.44 at GATA91H06), but not the Crohn's disease phenotype. We also find confirmatory evidence for linkage between the IBD3 locus and Crohn's disease (lod = 2.26 at D6S2439) but not ulcerative colitis or inflammatory bowel disease. We find nominal evidence for linkage of inflammatory bowel disease to loci on chromosome 6q (lod = 2.21 between D6S2436/D6S305), 8q (lod = 1.57 between D8S1113/D8S1136), 15q (lod = 2.02 between D15S652/D15S816), and 22 (lod = 1.50 at D22S689); of Crohn's disease to loci on chromosome 5q approximately 50 centiMorgans centromeric from IBD5 (lod = 1.69 at D5S1501) and 15q (lod = 1.82 at D15S652); and of ulcerative colitis to a locus on chromosome 2q (lod = 2.19 between D2S1776/D2S1391). The inflammatory bowel disease linkage peak on chromosome 6q is located in the same general region that showed nominal evidence for linkage to IBD in a Belgian genome scan, and the ulcerative colitis linkage peak on chromosome 2q is located in the same general region that showed nominal evidence for linkage to the inflammatory bowel disease, Crohn's disease, or ulcerative colitis phenotypes in four other European/North American genome scans.

Wolf JM, Achkar JP, Lashner BA, Delaney CP, Petras RE, Goldblum JR, Connor JT, Remzi FH, Fazio VW. · Department of Gastroenterology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Gastroenterology. · Pubmed #15188163 No free full text.

Abstract: BACKGROUND & AIMS: Some patients who undergo ileal pouch-anal anastomosis (IPAA) surgery for ulcerative colitis (UC) or indeterminate colitis are subsequently diagnosed with Crohn's disease (CD). Making the diagnosis of CD in patients with IPAA can be difficult, but it is important for prognostic and therapeutic purposes. The aim of this study was to identify diagnostic features of CD in patients with IPAA. METHODS: We evaluated 87 patients who had undergone IPAA for inflammatory bowel disease. Patients were classified as having UC (n = 28), CD (n = 27), or indeterminate colitis (n = 32) based on review of the original colectomy pathology and the postoperative clinical course. Each patient underwent a pouch endoscopy with biopsies of the pouch and afferent limb. Both the endoscopist and pathologist were blinded to the patient's diagnosis. RESULTS: Afferent limb ulcers (ALUs) were seen on endoscopy in 12 of 27 patients with CD (45%) and 4 of 28 patients with UC (14%) (P = 0.019). After excluding patients who had taken nonsteroidal anti-inflammatory drugs (NSAIDs) within the past month, ALUs were found in 7 of 18 patients with CD (39%) and 0 of 17 patients with UC (P = 0.010). Controlling for NSAID use and smoking, the odds ratio for ALUs indicating CD was 4.67 (P = 0.03). In the UC population, ALUs were seen in 4 of 11 patients (36%) who had taken NSAIDs in the past month and 0 of 17 patients who had not taken NSAIDs (P = 0.016). CONCLUSIONS: ALUs seen on endoscopy are suggestive of CD in patients with inflammatory bowel disease who are not taking NSAIDs.

Barmada MM, Brant SR, Nicolae DL, Achkar JP, Panhuysen CI, Bayless TM, Cho JH, Duerr RH. · Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Inflamm Bowel Dis. · Pubmed #15058521 No free full text.

Abstract: We report the results of a new genome scan in 260 IBD-affected relative pairs from 139 families that we have recruited since our previous IBD genome scans were performed. The goal of our study was to determine whether we could extend the linkage evidence in any of the more than 20 regions with nominal evidence for linkage to IBD in previous individual genome scans in order to prioritize regions for further study.

Karban AS, Okazaki T, Panhuysen CI, Gallegos T, Potter JJ, Bailey-Wilson JE, Silverberg MS, Duerr RH, Cho JH, Gregersen PK, Wu Y, Achkar JP, Dassopoulos T, Mezey E, Bayless TM, Nouvet FJ, Brant SR. · Johns Hopkins University School of Medicine, 1503 E. Jefferson Street, Room B136, Baltimore, MD 21231, USA. · Hum Mol Genet. · Pubmed #14613970 links to  free full text

Abstract: Nuclear Factor-kappaB (NF-kappaB) is a major transcription regulator of immune response, apoptosis and cell-growth control genes, and is upregulated in inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease. The NFKB1 gene encodes the NF-kappaB p105/p50 isoforms. Genome-wide screens in IBD families show evidence for linkage on chromosome 4q where NFKB1 maps. We sequenced the NFKB1 promoter, exon 1 and all coding exons in 10 IBD probands and two controls, and identified six nucleotide variants, including a common insertion/deletion promoter polymorphism (-94ins/delATTG). Using pedigree-based transmission disequilibrium tests, we observed modest evidence for linkage disequilibrium (LD), independent of linkage, between the -94delATTG allele and UC in 131 out of 235 IBD pedigrees with UC offspring (P=0.047-0.052). This allele was also more frequent in the 156 non-Jewish UC probands from the 235 IBD pedigrees than in 149 non-Jewish controls (P=0.015). The -94delATTG association with UC was replicated in a second set of 258 unrelated, non-Jewish UC cases and 653 new, non-Jewish controls (P=0.021). Nuclear proteins from normal human colon tissue and colonic cell lines, but not ileal tissue, showed significant binding to -94insATTG but not to -94delATTG containing oligonucleotides. NFKB1 promoter/exon 1 luciferase reporter plasmid constructs containing the -94delATTG allele and transfected into either HeLa or HT-29 cell lines showed less promoter activity than comparable constructs containing the -94insATTG allele. Therefore, we have identified the first potentially functional polymorphism of NFKB1 and demonstrated its genetic association with a common human disease, ulcerative colitis.

Brant SR, Panhuysen CI, Nicolae D, Reddy DM, Bonen DK, Karaliukas R, Zhang L, Swanson E, Datta LW, Moran T, Ravenhill G, Duerr RH, Achkar JP, Karban AS, Cho JH. · The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Am J Hum Genet. · Pubmed #14610718 links to  free full text

Abstract: Crohn disease (CD) and ulcerative colitis (UC) are overlapping chronic inflammatory bowel diseases (IBDs). Suggestive evidence for linkage at chromosome 7q has been reported for both CD and UC. Contained within this region is the gene for MDR1 (multidrug resistance), a membrane transport protein for which human polymorphisms have been reported in Ala893Ser/Thr and C3435T that alter pharmacokinetic profiles for a variety of drugs. Because mdr1 knockout mice spontaneously develop colitis, exonic regions were resequenced and tested for IBD association in a large, multicenter North American cohort. Two missense mutations, Asn21Asp and Ala893Ser/Thr, as well as the expression-associated polymorphism C3435T, described elsewhere, were genotyped in the entire cohort. Significant association of Ala893 with IBD was observed by both case-control analysis (P=.002) and the pedigree disequilibrium test (PDT [P=.00020-.00030]) but not for the Asn21Asp or C3435T polymorphisms. Significant association by PDT was observed within the subset with CD (P=.0014-.00090), with similar, nonsignificant trends in a smaller subset with UC. The Ala893Ser/Thr variant is triallelic, and the associated, common allele is Ala893, with undertransmission of the 893Ser (common) and the 893Thr (rare) variants. The Ala893 variant has decreased activity compared with the 893Ser variant; therefore, the association with human IBD is consistent with the murine model of mdr1 deficiency. Taken together, these data support the association of the common Ala893 polymorphism with IBD specifically and, more broadly, provides additional support for its contribution to interindividual pharmacogenetic variation.

Shen B, Achkar JP, Connor JT, Ormsby AH, Remzi FH, Bevins CL, Brzezinski A, Bambrick ML, Fazio VW, Lashner BA. · Center for Inflammatory Bowel Disease, Cleveland, Ohio, USA. · Dis Colon Rectum. · Pubmed #12794576 No free full text.

Abstract: PURPOSE: Pouchitis is the most common complication of ileal pouch-anal anastomosis for ulcerative colitis. Our previous study suggested that symptoms alone are not reliable for the diagnosis of pouchitis. The most commonly used diagnostic instrument is the 18-point pouchitis disease activity index consisting of three principal component scores: symptom, endoscopy, and histology. Despite its popularity, the pouchitis disease activity index has mainly been a research tool because of costs of endoscopy (especially with histology), complexity in calculation, and time delay in determining histology scores. It is not known whether pouch endoscopy without biopsy can reliably diagnose pouchitis in symptomatic patients. The aim of the present study was to determine whether omitting histologic evaluation from the pouchitis disease activity index significantly affects the sensitivity and specificity of diagnostic criteria for pouchitis. METHODS: Ulcerative colitis patients with an ileal pouch-anal anastomosis and symptoms suggestive of pouchitis were evaluated. Patients with chronic refractory pouchitis and Crohn's disease were excluded. Patients with pouchitis disease activity index scores of seven or more were diagnosed as having pouchitis. Different diagnostic criteria were compared on the basis of the pouchitis disease activity index component scores. Nonparametric receiver-operating-characteristic curves were used to measure proposed pouchitis scores' diagnostic accuracy compared with diagnosis from the pouchitis disease activity index. The receiver-operating-characteristic area under the curve measured how much these diagnostic strategies differed from each other. RESULTS: Fifty-eight consecutive symptomatic patients were enrolled; 32 (55 percent) patients were diagnosed with pouchitis. With the use of the pouchitis disease activity index as a criterion standard, the use of only symptom and endoscopy scores (modified pouchitis disease activity index) produced an area under the curve of 0.995. Establishing a cut-point of five or more for diseased patients resulted in a sensitivity equal to 97 percent and specificity equal to 100 percent. CONCLUSIONS: Diagnosis based on the modified pouchitis disease activity index offers similar sensitivity and specificity when compared with the pouchitis disease activity index for patients with acute or acute relapsing pouchitis. Omission of endoscopic biopsy and histology from the standard pouchitis disease activity index would simplify pouchitis diagnostic criteria, reduce the cost of diagnosis, and avoid delay associated with determining histology score, while providing equivalent sensitivity and specificity.

Achkar JP, Barmada MM, Duerr RH. · Department of Gastroenterology, The Cleveland Clinic Foundation, Ohio 44195, USA. · Am J Gastroenterol. · Pubmed #12358254 No free full text.

Abstract: OBJECTIVES: Autoantibodies that bind to the perinuclear region of neutrophils have been suggested to represent subclinical markers of genetic susceptibility and indicators of genetic heterogeneity in ulcerative colitis (UC). However, results from more recent studies have contradicted this statement. To address this discrepancy, we assayed perinuclear neutrophil antibodies in the UC-affected members of 53 families with at least one relative pair affected with UC. METHODS: Perinuclear neutrophil antibodies were detected using an indirect immunofluorescence assay. RESULTS: Perinuclear neutrophil antibodies were present in 53% of the study subjects with ulcerative colitis (UC). In 15 families (28%), all members with UC were positive for perinuclear neutrophil antibodies, whereas in 12 families (23%), none of the UC-affected members were positive. In the remaining 26 families (49%), the results for the UC-affected relatives were discordant. Similar results were found when only sibling pairs were evaluated. Statistical analysis revealed that for all affected relative pairings, observed concordance did not significantly exceed expected concordance. Logistic regression analyses demonstrated that the degree of relationship was not enough to predict concordance for perinuclear neutrophil antibodies, and that these antibodies are not markers of genetic heterogeneity. CONCLUSIONS: Perinuclear neutrophil antibodies are not markers for genetic susceptibility or indicators of genetic heterogeneity in UC.

Duerr RH, Barmada MM, Zhang L, Achkar JP, Cho JH, Hanauer SB, Brant SR, Bayless TM, Baldassano RN, Weeks DE. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Hum Mol Genet. · Pubmed #12354785 links to  free full text

Abstract: Crohn's disease and ulcerative colitis, the two major forms of idiopathic inflammatory bowel disease (IBD), are heritable, complex traits that appear to share some but not all susceptibility loci. We report that transmission/disequilibrium test analysis of a Crohn's disease genome scan dataset has detected an inflammatory bowel disease locus on chromosome 3p26 (nominal P=0.000052 and genome-wide corrected P=0.039 at D3S1297). An allele sharing method shows significant linkage (multipoint lod=3.69) in a larger, independent sample of inflammatory bowel disease-affected sibling pairs. A survey of 16 chromosome 3p26 short tandem repeat polymorphisms in a combined sample of 234 independent nuclear families with 324 IBD-affected sibling pairs shows significant linkage to chromosome 3p26 (multipoint lod=3.78) and significant transmission/disequilibrium test results at two adjacent markers (nominal P values in two different transmission/disequilibrium analysis methods=0.00011 and 0.0011 for the first marker, and 0.00071 and 0.00013 for the second marker). There is highly significant under-transmission of a common allele and modest over-transmission of other alleles at both markers. Families with no transmission to affected individuals of the under-transmitted alleles show significant linkage (multipoint lod=4.50) that is significantly greater in four simulation studies (P=0.0001, 0.0000625, 0.0000625 and 0.0000625, respectively) than the linkage evidence in families with transmission of the under-transmitted alleles (multipoint lod=0.12). Thus, the existence of an inflammatory bowel disease locus on chromosome 3p26 is supported by significant linkage, transmission/disequilibrium and partitioning of linkage evidence.