Manreet Kaur

Clinical, serologic, and genetic factors associated with pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease patients

Background:Pyoderma gangrenosum (PG) and erythema nodosum (EN) are the most common cutaneous manifestations of inflammatory bowel disease (IBD) but little is known regarding their etiopathogenesis. Methods:We performed a case–control study comparing characteristics between IBD patients with a documented episode of PG (PG+) and/or EN (EN+) with those without PG (PG−) and EN (EN−). Data on clinical features were obtained by chart review. IBD-related serology was determined using enzyme-linked immunosorbent assay and genome-wide data generated using Illumina technology. Standard statistical tests for association were used. Results:We identified a total of 92 cases of PG and 103 cases of EN with genetic and clinical characteristics, of which 64 PG and 55 EN cases were available for serological analyses. Fewer male subjects were identified in the PG(+) (odds ratio 0.6, P = 0.009) and EN(+) groups (odds ratio 0.31, P = 0 < 0.0001). Colonic disease, previous IBD-related surgery, and noncutaneous extra-intestinal manifestations were more common among both PG(+) and EN(+) patients compared with controls. PG(+) was associated with anti-nuclear cytoplasmic antibody seropositivity (P = 0.03) and higher anti-nuclear cytoplasmic antibody level (P = 0.02) in Crohns disease. Genetic associations with PG included known IBD loci (IL8RA [P = 0.00003] and PRDM1 [0.03]) as well as with USP15 (4.8 × 10−6) and TIMP3 (5.6 ×10−7). Genetic associations with EN included known IBD susceptibility genes (PTGER4 [P = 8.8 × 10−4], ITGAL [0.03]) as well as SOCS5 (9.64 × 10−6), CD207 (3.14 × 10−6), ITGB3 (7.56 × 10−6), and rs6828740 (4q26) (P < 5.0 × 10−8). Multivariable models using clinical, serologic, and genetic parameters predicted PG (area under the curve = 0.8) and EN (area under the curve = 0.97). Conclusion:Cutaneous manifestations in IBD are associated with distinctive genetic characteristics and with the similar clinical characteristics, including the development of other extra-intestinal manifestations suggesting shared and distinct etiologies.

Surgical Outcome of Ileal Pouch—Anal Anastomosis When Used Intentionally for Well-Defined Crohn's Disease

Background:Crohns disease (CD) is considered a contraindication to ileal pouch—anal anastomosis (IPAA). In this study, we compare outcomes of CD and ulcerative colitis (UC) patients undergoing IPAA. Methods:Patients were considered to have CD before surgery based on a history of small bowel disease, perianal disease, noncrypt-associated granuloma, or pretreatment skip colonic lesions. Patients were prospectively assessed for pouchitis or CD. Postoperative CD (pouch inflammation into the afferent limb or pouch fistula) or pouch failure (need for permanent diversion) were assessed. Preoperative serum was assayed for IBD-associated antibodies using enzyme-linked immunosorbent assay (ELISA). Results:Seventeen patients with preoperative CD were identified. Seven (41%) patients developed postoperative recurrent CD in the afferent limb (n = 3) or pouch fistulizing disease (n = 4). One patient (6%) required pouch excision. The incidence of postoperative CD was higher (P = 0.002) in preoperative CD patients (41%) than UC patients (11%). There was no significant difference in pouchitis or pouch failure. There was also no significant difference in any preoperative clinical feature between patients with or without postoperative CD. Afferent limb inflammation developed in three (50%) of the six patients with pANCA+/OmpC− expression compared to none of the 11 patients without this serologic profile (P = 0.03). Conclusions:Although the intentional use of IPAA in CD has a higher incidence of postoperative disease vs. UC patients, there was no significant difference in pouch failure. Demographics, clinical features, and serologic factors do not predict outcome of CD patients undergoing IPAA. IBD serology may identify the phenotype manifestation of postoperative recurrent CD.

Effect of α4β7 blockade on intestinal lymphocyte subsets and lymphoid tissue development

Background: Blockade of the integrin &agr;4&bgr;7 has promise as a therapy for inflammatory bowel disease. &agr;4&bgr;7 plays diverse roles in the intestinal immune system, including lymphocyte homing and lymphoid tissue formation; however, the effects of &agr;4&bgr;7 blockade on these processes during inflammation and their relationship to the efficacy of &agr;4&bgr;7 blockade and its potential untoward effects are largely unknown. Methods: &agr;4&bgr;7 function was inhibited by genetic manipulation or antibody blockade. The effects of these manipulations on lymphoid tissues and the presence of lymphocyte subpopulations in the murine small intestine and colon were evaluated in the unchallenged state, during the acute injury dextran sodium sulfate model, and during the splenocyte transfer chronic inflammation model. Results: &agr;4&bgr;7 inhibition resulted in a decrease in the B‐lymphocyte population in the diffuse lamina propria and a decrease in the number of lymphoid aggregates in the uninflamed intestine and in the acute injury model. &agr;4&bgr;7 blockade did not reduce the Foxp3− T‐lymphocyte population but did decrease the Foxp3+ T‐lymphocyte population located selectively within the lymphoid aggregates in the uninflamed intestine and in the acute injury model. In contrast, &agr;4&bgr;7 blockade reduced the intestinal T‐lymphocyte population and decreased the production of inflammatory cytokines in the T‐lymphocyte mediated chronic inflammation model. Conclusions: These findings demonstrate differential use of &agr;4&bgr;7 by B‐lymphocytes, Foxp3− T‐lymphocytes, and Foxp3+ T‐lymphocytes to home to the gut, and suggest that &agr;4&bgr;7 blockade may serve as a targeted therapy that selectively inhibits the accumulation of pathogenic T‐lymphocyte populations in the chronically inflamed intestine. Inflamm Bowel Dis 2010

Antibiotics for Treatment of Clostridium difficile Infection in Hospitalized Patients with Inflammatory Bowel Disease

ABSTRACT Patients with inflammatory bowel disease (IBD), namely ulcerative colitis (UC) and Crohns disease (CD), have worse outcomes with Clostridium difficile infection (CDI), including increased readmissions, colectomy, and death. Oral vancomycin is recommended for the treatment of severe CDI, while metronidazole is the standard of care for nonsevere infection. We aimed to assess treatment outcomes of CDI in IBD. We conducted a retrospective observational study of inpatients with CDI and IBD from January 2006 through December 2010. CDI severity was assessed using published criteria. Outcomes included readmission for CDI within 30 days and 12 weeks, length of stay, colectomy, and death. A total of 114 patients met inclusion criteria (UC, 62; CD, 52). Thirty-day readmissions were more common among UC than CD patients (24.2% versus 9.6%; P = 0.04). Same-admission colectomy occurred in 27.4% of UC patients and 0% of CD patients (P < 0.01). Severe CDI was more common among UC than CD patients (32.2% versus 19.4%; P = 0.12) but not statistically significant. Two patients died from CDI-associated complications (UC, 1; CD, 1). Patients with UC and nonsevere CDI had fewer readmissions and shorter lengths of stay when treated with a vancomycin-containing regimen compared to those treated with metronidazole (30-day readmissions, 31.0% versus 0% [P = 0.04]; length of stay, 13.62 days versus 6.38 days [P = 0.02]). Patients with UC and nonsevere CDI have fewer readmissions and shorter lengths of stay when treated with a vancomycin-containing regimen relative to those treated with metronidazole alone. Patients with ulcerative colitis and CDI should be treated with vancomycin.

Perianal Crohnʼs Disease is Associated with Distal Colonic Disease, Stricturing Disease Behavior, IBD-Associated Serologies and Genetic Variation in the JAK-STAT Pathway

Background:Perianal Crohns Disease (pCD) is a particularly severe phenotype associated with poor quality of life with a reported prevalence of 12%–40%. Previous studies investigating the etiology of pCD have been limited in the numbers of subjects and the intensity of genotyping. The aim of this study was to identify clinical, serological, and genetic factors associated with pCD. Methods:We performed a case–control study comparing patients with (pCD+) and without perianal (pCD−) involvement in CD; defined as the presence of perianal abscesses or fistulae. Data on demographics and clinical features were obtained by chart review. Inflammatory bowel disease-related serology was determined by enzyme-linked immunosorbent assay. Genetic data were generated using Illumina genotyping platforms. Results:We included 1721 patients with CD of which 524 (30.4%) were pCD+ and 1197 were pPCD−. pCD was associated with distal colonic disease (Odds ratio 5.54 [3.23–9.52], P < 0.001), stricturing disease behavior (1.44 [1.14–1.81], P = 0.002) and family history of inflammatory bowel disease (4.98 [3.30–7.46], P < 0.001). pCD was associated with higher anti-sacharomyces cerevisae antibodies IgA (P < 0.001) and OmpC (P = 0.008) antibody levels. pCD was associated with known inflammatory bowel disease loci, including KIF3B, CRTC3, TRAF3IP2, JAZF1, NRIP1, MST1, FUT2, and PTGER (all P < 0.05). We also identified genetic association with genes involved in autophagy (DAPK1, P = 5.11 × 10−5), TNF alpha pathways (NUCB2, P = 8.68 × 10−5; DAPK1), IFNg pathways (DAPK1; NDFIP2, P = 8.74 × 10−5), and extracellular matrix and scaffolding proteins (USH1C, P = 8.68 × 10−5; NDFIP2; TMC07, P = 8.87 × 10−5). Pathway analyses implicated the JAK-Stat pathway (pc = 3.72 × 10−5). Conclusion:We have identified associations between pCD, more distal colonic inflammation, Crohns disease-associated serologies, and genetic variation in the JAK-Stat pathway.

Combined Immunosuppression Impairs Immunogenicity to Tetanus and Pertussis Vaccination Among Patients with Inflammatory Bowel Disease

Background:Pertussis epidemics have recently emerged across the United States, prompting broad public health recommendations for adult Tdap vaccination (tetanus, diphtheria, acellular pertussis). The impact of immunosuppressive regimens for inflammatory bowel disease (IBD) on vaccine responses to the Tdap vaccine is not known. Methods:We performed a prospective controlled trial between April 2011 and March 2012. Adults with IBD were consecutively stratified based on therapeutic regimen into one of 5 groups: A: no IBD therapy or 5-aminosalicylates alone; B: maintenance biologic monotherapy; C: maintenance immunomodulator monotherapy; D: combined biologic and immunomodulator therapy; and E: healthy age-matched controls. Subjects received Tdap, and serum antibody levels against tetanus toxoid, pertussis toxoid, and filamentous hemagglutinin (FHA) were drawn just before and approximately 4 weeks after vaccination. The primary outcome was the booster response rate to each antigen. Secondary outcomes included the differences in pregeometric and postgeometric mean titers. Results:A total of 98 subjects enrolled, and 84 completed the study. Tetanus response rates were 55%, 56%, 40%, 27%, and 63% across groups A to E, respectively. Group D rates were lower than those of group B (P = 0.02). Postvaccination pertussis toxoid responses were 59%, 72%, 47%, 45%, and 75%, while FHA responses were 86%, 72%, 80%, 64%, and 75% across groups A to E, respectively. Prevaccination and postvaccination geometric mean titer differences for FHA were lower in group D than those in group A (P = 0.05). Conclusions:Antibody responses to tetanus and pertussis vaccination may be affected by therapeutic drug regimen. Patients with IBD should optimally receive Tdap before starting immunomodulators, particularly when used in combination with anti–tumor necrosis factor alpha agents.

Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease A Descriptive Cohort Study

Background Pyoderma gangrenosum (PG) is a severe extraintestinal manifestation of inflammatory bowel disease (IBD). Objective To better characterize PG features and management among an IBD cohort. Methods Subjects with PG were identified using a large database at a tertiary center. Patient demographics and clinical characteristics were summarized using descriptive statistics. Results Eighty patients with an episode(s) of PG were identified, yielding an overall prevalence of 1.9%. Overall, 93% of patients with PG had some degree of colonic inflammation. Thirty-one (39%) patients required hospitalization for PG. Underlying bowel disease was active at the time of PG episode(s) in 52 (65%) patients. The PG location was variable, with the lower extremity being the most common. Most patients (71.3%) required multiple therapies to achieve PG healing. Conclusions We describe one of the largest case series of PG among patients with IBD. The variety of treatment strategies used highlights the lack of clear guidelines in managing this complex group of patients.

Ulcerative colitis: steroid-refractory ulcerative colitis-ciclosporin or infliximab?

Ciclosporin and infliximab are used as rescue therapies for the treatment of severe steroid-refractory ulcerative colitis. Now, an open-label, head-to-head randomized controlled trial has demonstrated that these drugs are well-tolerated and have equivalent efficacy in inducing short-term clinical response, mucosal healing and decreasing colectomy rates at 3 months.

Su1116 Small Bowel Ultrasound Accurately Predicts Post-Operative Endoscopic Recurrence in Crohn's Disease

Background & Aim: Recently, mucosal healing assessed by endoscopic findings appears to predict long-term remission in patients with ulcerative colitis (UC), although there is no agreement on clinical, endoscopic or histological scoring system. In most of clinical trial, endoscopic score of Mayo 0 or 1 is defined as mucosal healing in UC patients. However, assessment of endoscopic score of Mayo 0 or 1 is quite different depending on endoscopists. Therefore, to develop the objectively quantitative scoring system that will help to improve patient outcome is required. Emerging endoscopic imaging modalities, including both, vital and virtual chromoendoscopy and magnification endoscopy, enabled endoscopists to visualize and interpret mucosal details. Among them, i-scan is the newly developed imageenhanced endoscopic technology from HOYA/PENTAX (Tokyo, Japan). i-scan TE-c is one of digital transmission method among HOYA/PENTAX EPK-i system in conjunction with EC38-i10M. The aim of study is to assess the significance of new endoscopic imaging system with i-scan TE-c for quantitative evaluation of colonic inflammation in patients with UC. Method: From January 2011 to Aug 2012, a total of 76 UC patients with endoscopic score of Mayo 0 or 1 by standard white light endoscopy were reassessed by i-scan TE-c. We performed white light (WL) colonoscopy in conjunction with i-scan TE-c in UC patients with endoscopic score of Mayo 0 or 1, and the difference of the tone of color between normal and inflamed colonic mucosa was given with a numeric conversion. The intensity and width of inflammatory lesion identified by modified color phase and saturation was given with a numeric conversion and visualized. Results: In 29 of 76 UC patients, endoscopic score of Mayo was estimated as 0. In the remaining 47 patients, that was estimated as 1. The mean i-scan TE-c score of UC patients with endoscopic score of Mayo 0 and with Mayo 1 was 576.1±437.3 and 1172.7±668.6, respectively. A significant difference of i-scan TE-c score was observed between UC patients with endoscopic score of Mayo 0 and those with Mayo 1 (p,0.001). There was a considerable variation in i-scan TE-c score of UC patients with endoscopic score of Mayo 1 by WL colonoscopy, suggesting that UC patients diagnosed with endoscopic score of Mayo 1 had intestinal inflammation with objectively varying degrees. Conclusion: In UC patients with endoscopic score of Mayo 0 or 1, this new imaging system with i-scan TE-c can make the inflammatory lesion visualized more clearly in comparison with WL colonoscopy, and their intensity and width digitized. Application with this new system is easy and useful for objective and quantitative evaluation of colonic inflammation in UC patients with endoscopic score of Mayo 0 or 1. Further clinical trial with a new imaging system will be required for clinically quiescent UC patients.

Mo1695 Clinical, Serologic, and Genetic Associations Among Patients With Both Inflammatory Bowel Disease and Ankylosing Spondylitis

G A A b st ra ct s between ileitis at the time of TPC with IPAA and pouchitis. We did find a marked difference in ileitis and pouchitis between UC and FAP groups. For this reason, and in an effort to reduce pouch complications following surgery, further studies should be designed to mechanistically investigate the ileitis in UC patients as well as to prospectively examine the ileitis-pouchitis relationship.