Predicting Outcomes After Restorative Proctocolectomy for Ulcerative Colitis

Abstract

An estimated 1 million Americans have ulcerative colitis (UC) and Crohn's disease (CD). The majority of CD patients will require at least one surgery during the course of their disease, and 30%–40% of UC patients also will require surgery. Abdominal proctocolectomy with ileoanal pouch–anal anastomosis (IPAA) has become the surgery of choice for the majority of patients with UC.1Fleshner P.R. Vasiliauskas E.A. Kam L.Y. et al.High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis.Gut. 2001; 49: 671-677Crossref PubMed Scopus (202) Google Scholar, 2Melmed G.Y. Fleshner P.R. Bardakcioglu O. et al.Family history and serology predict Crohn's disease after ileal pouch-anal anastomosis for ulcerative colitis.Dis Colon Rectum. 2008; 51: 100-108Crossref PubMed Scopus (97) Google Scholar, 3Sheikh S. Uno J. Matsuoka K. et al.Abnormal mucosal immune response to altered bacterial flora following restorative proctocolectomy in patients with ulcerative colitis: serologic measures, immunogenetics, and clinical correlations.Clin Immunol. 2008; 127: 270-279Crossref PubMed Scopus (6) Google Scholar Although surgical management of UC provides satisfactory outcomes in most patients, it can be associated with a variety of surgical complications with significant morbidity. Acute and chronic pouchitis (CP), cuffitis, Crohn's disease–like phenotype (CDL) of the pouch, bowel obstruction caused by adhesions, and irritable pouch syndrome are some of the most common postsurgical complications after an IPAA.3Sheikh S. Uno J. Matsuoka K. et al.Abnormal mucosal immune response to altered bacterial flora following restorative proctocolectomy in patients with ulcerative colitis: serologic measures, immunogenetics, and clinical correlations.Clin Immunol. 2008; 127: 270-279Crossref PubMed Scopus (6) Google Scholar Among these complications, CDL of the pouch is the most serious one that might often be associated with a higher risk of pouch loss.4Shen B. Remzi F.H. Brzezinski A. et al.Risk factors for pouch failure in patients with different phenotypes of Crohn's disease of the pouch.Inflamm Bowel Dis. 2008; 14: 942-948Crossref PubMed Scopus (50) Google Scholar Approximately 8%–10% of patients operated on for UC with an IPAA will have pouch failure, which requires removal of the pouch and conversion to a permanent ileostomy.2Melmed G.Y. Fleshner P.R. Bardakcioglu O. et al.Family history and serology predict Crohn's disease after ileal pouch-anal anastomosis for ulcerative colitis.Dis Colon Rectum. 2008; 51: 100-108Crossref PubMed Scopus (97) Google Scholar, 4Shen B. Remzi F.H. Brzezinski A. et al.Risk factors for pouch failure in patients with different phenotypes of Crohn's disease of the pouch.Inflamm Bowel Dis. 2008; 14: 942-948Crossref PubMed Scopus (50) Google Scholar Identifying clinical, genetic, or immunologic factors that might predict inflammatory complications after IPAA is of major clinical importance for risk stratification, patient education, and therapeutic intervention to prevent disease expression. The intestinal microflora play a critical role in inflammatory bowel disease (IBD) pathogenesis as exemplified by several studies in animal models of colitis and in human disease.5Sartor R.B. Microbial influences in inflammatory bowel diseases.Gastroenterology. 2008; 134: 577-594Abstract Full Text Full Text PDF PubMed Scopus (1396) Google Scholar Several serum immune markers have been well-characterized in patients with IBD.3Sheikh S. Uno J. Matsuoka K. et al.Abnormal mucosal immune response to altered bacterial flora following restorative proctocolectomy in patients with ulcerative colitis: serologic measures, immunogenetics, and clinical correlations.Clin Immunol. 2008; 127: 270-279Crossref PubMed Scopus (6) Google Scholar These are antibodies that are directed against components of the enteric microflora in most instances. Atypical perinuclear antineutrophil cytoplasmic antibodies (pANCAs), anti-Saccharomyces cerevisiae antibody (ASCA), outer membrane porin C (Omp C), I2 antibody, and anti-CBir1 flagellin, the most extensively studied serologic markers, have been used to classify UC and CD into more homogeneous groups with certain phenotypic characteristics to identify common antigenic triggers and are linked to specific defects in mucosal immune regulation.6Papadakis K.A. Targan S.R. Serologic testing in inflammatory bowel disease: its value in indeterminate colitis.Curr Gastroenterol Rep. 1999; 1: 482-485Crossref PubMed Scopus (18) Google Scholar pANCA is detected in the serum of most patients with UC and a small percentage of patients with UC-like CD, and their level is not influenced by disease distribution or activity and remains stable after colectomy.7Saxon A. Shanahan F. Landers C. et al.A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease.J Allergy Clin Immunol. 1990; 86: 202-210Abstract Full Text PDF PubMed Scopus (479) Google Scholar, 8Vasiliauskas E.A. Plevy S.E. Landers C.J. et al.Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn's disease define a clinical subgroup.Gastroenterology. 1996; 110: 1810-1819Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar pANCAs are directed against intracellular components of neutrophils, but the real antigenic trigger could be a component of the enteric microflora because absorption of either human or mouse pANCA-positive sera with enteric bacterial antigens greatly reduces or abolishes the specific perinuclear staining of pANCA.9Seibold F. Brandwein S. Simpson S. et al.pANCA represents a cross-reactivity to enteric bacterial antigens.J Clin Immunol. 1998; 18: 153-160Crossref PubMed Scopus (85) Google Scholar ASCAs are present in 50%–60% of patients with CD and in 20%–25% of their healthy relatives.10Standaert-Vitse A. Sendid B. Joossens M. et al.Candida albicans colonization and ASCA in familial Crohn's disease.Am J Gastroenterol. 2009; 104: 1745-1753Crossref PubMed Scopus (141) Google Scholar In pediatric patients, the ASCA antibodies, although highly specific for CD, identify predominantly the subset of children with disease of the ileum and ascending colon who might be at increased risk of surgery.11Zholudev A. Zurakowski D. Young W. et al.Serologic testing with ANCA, ASCA, and anti-OmpC in children and young adults with Crohn's disease and ulcerative colitis: diagnostic value and correlation with disease phenotype.Am J Gastroenterol. 2004; 99: 2235-2241Crossref PubMed Scopus (201) Google Scholar Interestingly, ASCA and pANCA might predict development of IBD years before the disease is clinically diagnosed.12Israeli E. Grotto I. Gilburd B. et al.Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease.Gut. 2005; 54: 1232-1236Crossref PubMed Scopus (249) Google Scholar The CBir1 antigen was identified in a murine model and has a similar pattern of aberrant reactivity in a subset of CD patients.13Targan S.R. Landers C.J. Yang H. et al.Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn's disease.Gastroenterology. 2005; 128: 2020-2028Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar Other antibody reactivities against bacterial peptides and glycans have been recently described and mainly associated with CD: anti-laminaribioside carbohydrate immunoglobulin (Ig) G antibodies (ALCA), anti-chitobioside carbohydrate IgA antibodies (ACCA), and anti-mannobioside carbohydrate IgG antibodies (AMCA).14Ferrante M. Henckaerts L. Joossens M. et al.New serological markers in inflammatory bowel disease are associated with complicated disease behaviour.Gut. 2007; 56: 1394-1403Crossref PubMed Scopus (250) Google Scholar Therefore, serum reactivities to bacterial antigens in IBD patients might represent a surrogate marker for a generalized increased Ig response against intestinal microbiota in CD.15Adams R.J. Heazlewood S.P. Gilshenan K.S. et al.IgG antibodies against common gut bacteria are more diagnostic for Crohn's disease than IgG against mannan or flagellin.Am J Gastroenterol. 2008; 103: 386-396Crossref PubMed Scopus (41) Google Scholar Several studies have emphasized that serum immunoreactivity in IBD patients might be genetically determined and might correlate with complicated disease phenotypes and need for surgery. Certain nuclear factor kappa B haplotypes have been associated with anti-CBir1 and ASCA expression implicating dysregulation of innate immune responses to enhanced seroreactivity to microbial antigens.16Takedatsu H. Taylor K.D. Mei L. et al.Linkage of Crohn's disease-related serological phenotypes: NFKB1 haplotypes are associated with anti-CBir1 and ASCA, and show reduced NF-kappa B activation.Gut. 2009; 58: 60-67Crossref PubMed Scopus (21) Google Scholar Moreover, patients with CD and unaffected relatives carrying variants of the CARD15/NOD2 gene have increased adaptive immune responses to microbial antigens.17Devlin S.M. Yang H. Ippoliti A. et al.NOD2 variants and antibody response to microbial antigens in Crohn's disease patients and their unaffected relatives.Gastroenterology. 2007; 132: 576-586Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar In another study, variants in innate immune receptor genes such as CARD15/NOD2 and TLR4 were found to influence antibody formation against microbial epitopes.18Henckaerts L. Pierik M. Joossens M. et al.Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease.Gut. 2007; 56: 1536-1542Crossref PubMed Scopus (90) Google Scholar ASCA and AMCA antibodies were associated with NOD2/CARD15, in addition to a gene-dosage effect in an Eastern European IBD cohort.19Papp M. Altorjay I. Dotan N. et al.New serological markers for inflammatory bowel disease are associated with earlier age at onset, complicated disease behavior, risk for surgery, and NOD2/CARD15 genotype in a Hungarian IBD cohort.Am J Gastroenterol. 2008; 103: 665-681Crossref PubMed Scopus (120) Google Scholar Defects of innate (CARD15/NOD2 variants) and adaptive (antibodies to microbial antigens) immunity might act synergistically to increase the risk of the fibrostenosis phenotype.20Ippoliti A. Devlin S. Mei L. et al.Combination of innate and adaptive immune alterations increased the likelihood of fibrostenosis in Crohn's disease.Inflamm Bowel Dis. 2010; 16: 1279-1285Crossref PubMed Scopus (27) Google Scholar Both anti-flagellin antibodies and ASCA are also strongly associated with complicated CD phenotypes. ASCA seroreactivity has been associated with higher risk for surgery but not risk of disease recurrence after curative surgery.21Forcione D.G. Rosen M.J. Kisiel J.B. et al.Anti-Saccharomyces cerevisiae antibody (ASCA) positivity is associated with increased risk for early surgery in Crohn's disease.Gut. 2004; 53: 1117-1122Crossref PubMed Scopus (114) Google Scholar, 22Eser A. Papay P. Primas C. et al.The impact of intestinal resection on serum levels of anti-Saccharomyces cerevisiae antibodies (ASCA) in patients with Crohn's disease.Aliment Pharmacol Ther. 2012; 35: 292-299Crossref PubMed Scopus (22) Google Scholar Adult and pediatric CD patients with serum reactivity against multiple microbes have the greatest frequency of strictures, perforations, and small bowel surgery.23Dubinsky M.C. Kugathasan S. Mei L. et al.Increased immune reactivity predicts aggressive complicating Crohn's disease in children.Clin Gastroenterol Hepatol. 2008; 6: 1105-1111Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 24Schoepfer A.M. Schaffer T. Mueller S. et al.Phenotypic associations of Crohn's disease with antibodies to flagellins A4-Fla2 and Fla-X, ASCA, p-ANCA, PAB, and NOD2 mutations in a Swiss cohort.Inflamm Bowel Dis. 2009; 15: 1358-1367Crossref PubMed Scopus (40) Google Scholar Anti-CBir1 serum reactivity in CD patients is independently associated with fibrostenosis phenotype and complicated small intestinal CD. Quantitative, but not qualitative, response to CBir1 is also significantly associated with the CD-associated NOD2 variants.25Papadakis K.A. Yang H. Ippoliti A. et al.Anti-flagellin (CBir1) phenotypic and genetic Crohn's disease associations.Inflamm Bowel Dis. 2007; 13: 524-530Crossref PubMed Scopus (100) Google Scholar Increasing amounts and levels of antibody responses against gASCA, ALCA, ACCA, AMCA, and Omp were associated with more complicated disease behavior and a higher frequency of CD-related abdominal surgery.14Ferrante M. Henckaerts L. Joossens M. et al.New serological markers in inflammatory bowel disease are associated with complicated disease behaviour.Gut. 2007; 56: 1394-1403Crossref PubMed Scopus (250) Google Scholar The study of Tyler et al26Tyler A.D. Milgrom R. Xu W. et al.Antimicrobial antibodies are associated with a Crohn's disease-like phenotype following ileal pouch-anal anastomosis.Clin Gastroenterol Hepatol. 2012; 10: 507-512Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar in this issue of Clinical Gastroenterology and Hepatology elegantly showed an association of antimicrobial antibodies and pouch outcomes in a cohort of UC patients who underwent colectomy with IPAA at Mount Sinai Hospital in Toronto. The authors showed that smoking and the presence of either anti-CBir1 or ASCA IgG was significantly associated with a CDL phenotype because 53.5% and 14% of subjects in the CDL group were positive for anti-CBir1 and ASCA IgG, respectively, compared with 21.4% and 3.8%, respectively, in the “no pouchitis” group and 28.3% and 5%, respectively, in the CP groups (P < .0001 and P = .03, respectively). In addition, the higher the number of positive antibody markers (ASCA IgA and IgG combined, anti-CBir1, anti-OmpC, pANCA), the greater the likelihood of developing a CDL inflammation of the pouch in patients undergoing IPAA. In quartile sum analysis, mean antibody titers for anti-CBir1 were significantly different between outcome groups (P = .001). When comparing the CDL with the no pouchitis group, both smoking and the quartile sum of serum markers were associated with the specific outcome. Several other studies have supported the observations by Tyler et al. Melmed et al2Melmed G.Y. Fleshner P.R. Bardakcioglu O. et al.Family history and serology predict Crohn's disease after ileal pouch-anal anastomosis for ulcerative colitis.Dis Colon Rectum. 2008; 51: 100-108Crossref PubMed Scopus (97) Google Scholar reported that patients with UC and indeterminate colitis (IC) with a family history of CD or preoperative ASCA IgA seropositivity are more likely to be diagnosed with CD after IPAA. High-level pANCA before colectomy in patients with UC is significantly associated with the development of CP after IPAA.1Fleshner P.R. Vasiliauskas E.A. Kam L.Y. et al.High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis.Gut. 2001; 49: 671-677Crossref PubMed Scopus (202) Google Scholar Dendrinos et al27Dendrinos K.G. Becker J.M. Stucchi A.F. et al.Anti-Saccharomyces cerevisiae antibodies are associated with the development of postoperative fistulas following ileal pouch-anal anastomosis.J Gastrointest Surg. 2006; 10: 1060-1064Crossref PubMed Scopus (43) Google Scholar reported that patients with UC and IC who were pANCA–/ASCA+ were at increased risk for the development of fistulas postoperatively, compared with patients who were pANCA+/ASCA–, and were also more likely to have their diagnosis changed postoperatively to CD. Both pANCA and anti-CBir1 expression are associated with pouchitis after IPAA.28Fleshner P. Ippoliti A. Dubinsky M. et al.Both preoperative perinuclear antineutrophil cytoplasmic antibody and anti-CBir1 expression in ulcerative colitis patients influence pouchitis development after ileal pouch-anal anastomosis.Clin Gastroenterol Hepatol. 2008; 6: 561-568Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar These studies support the notion that the stronger the adaptive immune response in patients with UC or IC, the higher the likelihood of pouch inflammatory complications after an IPAA. What are some potential clinical implications of the study by Tyler et al26Tyler A.D. Milgrom R. Xu W. et al.Antimicrobial antibodies are associated with a Crohn's disease-like phenotype following ileal pouch-anal anastomosis.Clin Gastroenterol Hepatol. 2012; 10: 507-512Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar? First, we should aim to intensify medical treatment in those patients with UC or even IC with strong adaptive immune response, which are associated with CDL inflammatory pouch complications in an attempt to avoid colectomy. Second, if colectomy cannot be avoided because of medically refractory disease or the development of dysplasia/cancer, these patients would be potential candidates for preventive treatment after IPAA, for instance with the use of probiotics or even immunomodulators; however, future studies are needed to address these questions. From a research point of view, the ileal pouch after surgery for UC could represent an important experimental model system for studying changes in the microbiome of the pouch, its effect on the local immune response in the genetic background of the individual, and how this translates into different inflammatory pouch complications. Finally, when should we test IBD patients in general for serum antibody reactivity? In clinical practice, testing serum antibodies has been mostly useful as an adjunct test to differentiate CD and UC in patients with a clinical diagnosis of IBD and nondiagnostic histology and imaging studies.29Joossens S. Reinisch W. Vermeire S. et al.The value of serologic markers in indeterminate colitis: a prospective follow-up study.Gastroenterology. 2002; 122: 1242-1247Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar The determination of serum markers during early diagnosis to predict disease severity and potential complications could provide researchers and clinicians with a unique tool to intervene early and to optimize treatment or to implement preventative measures to decrease potential progression and complications related to the disease. Future long-term longitudinal studies are needed to better clarify the clinical utility of these markers in the long-term evolution of the disease and whether antibody-based risk stratification improves the clinical outcome of IBD patients.24Schoepfer A.M. Schaffer T. Mueller S. et al.Phenotypic associations of Crohn's disease with antibodies to flagellins A4-Fla2 and Fla-X, ASCA, p-ANCA, PAB, and NOD2 mutations in a Swiss cohort.Inflamm Bowel Dis. 2009; 15: 1358-1367Crossref PubMed Scopus (40) Google Scholar Antimicrobial Antibodies Are Associated With a Crohn's Disease–Like Phenotype After Ileal Pouch–Anal AnastomosisClinical Gastroenterology and HepatologyVol. 10Issue 5PreviewPouchitis and Crohn's disease (CD)-like (CDL) complications of the pouch occur at rates near 50% and 20%, respectively, after colectomy with ileal pouch–anal anastomosis (IPAA) for ulcerative colitis (UC). We investigated whether antimicrobial antibodies are associated with pouch outcome after IPAA. 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