Thomas A. Ullman

Intestinal inflammation and cancer.

Patients with ulcerative colitis and Crohns disease are at increased risk for developing colorectal cancer (CRC). Chronic inflammation is believed to promote carcinogenesis. The risk for colon cancer increases with the duration and anatomic extent of colitis and presence of other inflammatory disorders (such as primary sclerosing cholangitis), whereas it decreases when patients take drugs to reduce inflammation (such as mesalamine and steroids). The genetic features that lead to sporadic CRC-chromosome instability, microsatellite instability, and DNA hypermethylation-also occur in colitis-associated CRC. Unlike the normal colonic mucosa, cells of the inflamed colonic mucosa have these genetic alterations before there is any histologic evidence of dysplasia or cancer. The reasons for these differences are not known, but oxidative stress is likely to be involved. Reactive oxygen and nitrogen species produced by inflammatory cells can affect regulation of genes that encode factors that prevent carcinogenesis (such as p53, DNA mismatch repair proteins, and DNA base excision-repair proteins), transcription factors (such as nuclear factor-κB), or signaling proteins (such as cyclooxygenases). Administration of agents that cause colitis in healthy rodents or genetically engineered, cancer-prone mice accelerates development of colorectal tumors. Mice genetically prone to inflammatory bowel disease also develop CRC, especially in the presence of bacterial colonization. Individual components of the innate and adaptive immune response have also been implicated in carcinogenesis. These observations offer compelling support for the role of inflammation in colon carcinogenesis.

Antibiotic Therapy in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

The etiology of inflammatory bowel disease (IBD) is unknown but may relate to an unidentified bacterial pathogen or an immunological reaction to gut microbiota. Antibiotics have therefore been proposed as a therapy for Crohns disease (CD) and ulcerative colitis (UC) to induce remission in active disease to prevent relapse. Current data are conflicting and we therefore conducted a systematic review of randomized controlled trials (RCTs) evaluating antibiotics in IBD. Only parallel group RCTs were considered eligible. Studies with adult patients receiving any dose of therapy for at least 7 days and up to 16 weeks for active disease, or at least 6 months of follow-up for preventing relapse in quiescent disease were analyzed. We included any antibiotics alone or in combination using predefined definitions of remission and relapse. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat methodology. The data were summarized using relative risk (RR) and pooled using a random effects model. For active CD, there were 10 RCTs involving 1,160 patients. There was a statistically significant effect of antibiotics being superior to placebo (RR of active CD not in remission=0.85; 95% confidence interval (CI)=0.73–0.99, P=0.03). There was moderate heterogeneity between results (I2=48%) and a diverse number of antibiotics were tested (anti-tuberculosis therapy, macrolides, fluroquinolones, 5-nitroimidazoles, and rifaximin) either alone or in combination. Rifamycin derivatives either alone or in combination with other antibiotics appeared to have a significant effect at inducing remission in active CD. In perianal CD fistula there were three trials evaluating 123 patients using either ciprofloxacin or metronidazole. There was a statistically significant effect in reducing fistula drainage (RR=0.8; 95% CI=0.66–0.98) with no heterogeneity (I2=0%) and an number needed to treat 5 (95% CI=3–20). For quiescent CD, there were 3 RCTs involving 186 patients treated with different antibiotics combinations (all including antimycobacterials) vs. placebo. There was a statistically significant effect in favor of antibiotics vs. placebo (RR of relapse=0.62; 95% CI=0.46–0.84), with no heterogeneity (I2=0%). In active UC, there were 9 RCTs with 662 patients and there was a statistically significant benefit for antibiotics inducing remission (RR of UC not in remission=0.64; 95% CI=0.43–0.96). There was moderate heterogeneity (I2=69%) and antibiotics used were all different single or combination drugs. Antibiotic therapy may induce remission in active CD and UC, although the diverse number of antibiotics tested means the data are difficult to interpret. This systematic review is a mandate for further trials of antibiotic therapy in IBD.

Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease.

BACKGROUND & AIMS Some women with inflammatory bowel disease require therapy with tumor necrosis factor (TNF) antagonists during pregnancy. It is not clear whether these drugs are transferred to the fetus via the placenta and then cleared, or whether structurally different TNF antagonists have different rates of transfer. METHODS We studied 31 pregnant women with inflammatory bowel disease receiving infliximab (IFX, n = 11), adalimumab (ADA, n = 10), or certolizumab (CZP, n = 10). Serum concentrations of the drugs were measured at birth in the mother, infant, and in cord blood, and then monthly in the infant until the drugs were undetectable. Drug concentrations in the cord and the infant at birth were compared with those of the mother. RESULTS Concentrations of IFX and ADA, but not CZP, were higher in infants at birth and their cords than in their mothers. The levels of CZP in infants and their cords were less than 2 μg/mL. The median level of IFX in the cord was 160% that of the mother, the median level of ADA in the cord was 153% that of the mother, and the median level of CZP in the cord was 3.9% that of the mother. IFX and ADA could be detected in the infants for as long as 6 months. No congenital anomalies or serious complications were reported. CONCLUSIONS The TNF antagonists IFX and ADA are transferred across the placenta and can be detected in infants at birth; the drugs were detected in infants up to 6 months after birth. CZP has the lowest level of placental transfer, based on levels measured in cords and infants at birth, of the drugs tested.

Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial.

OBJECTIVES:Patients with extensive, longstanding chronic ulcerative or Crohns colitis face greater risks of developing colorectal cancer. Current standard surveillance relies on detecting dysplasia using random sampling at colonoscopy but may fail to detect dysplasia in many patients. Dye spraying techniques have been reported to aid in detecting otherwise subtle mucosal abnormalities in the setting of colitis. We prospectively compared dye-spray technique using methylene blue to standard colonoscopic surveillance in detecting dysplasia.METHODS:One hundred fifteen patients were referred to the Chromoendoscopy Study Group and prospectively screened for the study. One hundred two (64 M, 38 F) (79 UC 23 CC) patients meeting the inclusion criteria were enrolled. Following a standard bowel preparation, each patient was examined using standard office endoscopic equipment by three methods: (a) standard surveillance colonoscopy with four random biopsies every 10 cm (for a total of at least 32 samples); (b) a targeted biopsy protocol; and finally (c) methylene blue (0.01%) dye spray was segmentally applied throughout the colon and any pit-pattern abnormality or lesion rendered visible by the dye spray was targeted and biopsied. Each patient had a single examination, which included two passes of the colonoscope. Specimens were reviewed in a blinded fashion by a single gastrointestinal pathologist. The three methods were then compared with each patient serving as his or her own control.RESULTS:Targeted biopsies with dye spray revealed significantly more dysplasia (16 patients with low grade and 1 patient with high grade) than random biopsies (3 patients with low-grade dysplasia) (P = 0.001) and more than targeted nondye spray (8 patients with low-grade and 1 patient with high-grade dysplasia) (P = 0.057). Targeted biopsies with and without dye spray detected dysplasia in 20 patients compared with 3 using Method (a) (P = 0.0002, two-tailed exact McNemars Test). There were no adverse events.CONCLUSIONS:Colonoscopic surveillance of chronic colitis patients using methylene blue dye-spray targeted biopsies results in improved dysplasia yield compared to conventional random and targeted biopsy methods. Accordingly, this technique warrants incorporation into clinical practice in this setting and consideration as a standard of care for these patients. The value of multiple random biopsies as a surveillance technique should be revisited.

An evidence-based systematic review on medical therapies for inflammatory bowel disease.

Crohn ’ s disease (CD) and ulcerative colitis (UC) are chronic infl ammatory disorders of the gastrointestinal tract. Collectively they are termed infl ammatory bowel disease (IBD) and it is estimated that 1.5 million Americans ( 1 ) suff er from UC and CD. Th eir etiologies are unknown, although both are thought to arise from a disordered immune response to the gut contents in genetically predisposed individuals ( 1 ). Th e characteristics of the infl ammatory response are diff erent, with CD typically causing transmural infl ammation and occasionally associated with granulomas, whereas in UC the infl ammation is usually confi ned to the mucosa. Both UC and CD exhibit a relapsing and remitting course and there is a signifi cant, oft en dramatic, reduction in quality of life during exacerbations of the disease ( 2 ). Th is has an impact on psychological health, with active IBD patients experiencing greater levels of distress and feelings of lack of sense of self-control compared with the normal population and patients with inactive IBD ( 3,4 ).

SCENIC International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease

Patients with ulcerative colitis or Crohn’s colitis have an increased risk of colorectal cancer (CRC). Most cases are believed to arise from dysplasia, and surveillance colonoscopy therefore is recommended to detect dysplasia. Detection of dysplasia traditionally has relied on both examination of the mucosa with targeted biopsies of visible lesions and extensive random biopsies to identify invisible dysplasia. Current U.S. guidelines recommend obtaining at least 32 random biopsy specimens from all segments of the colon as the foundation of endoscopic surveillance. However, much of the evidence that provides a basis for these recommendations is from older literature, when most dysplasia was diagnosed on random biopsies of colon mucosa. With the advent of video endoscopy and newer endoscopic technologies, investigators now report that most dysplasia discovered in patients with inflammatory bowel disease (IBD) is visible. Such a paradigm shift may have important implications for the surveillance and management of dysplasia. The evolving evidence regarding newer endoscopic methods to detect dysplasia has resulted in variation among guideline recommendations from organizations around the world. We therefore sought to develop unifying consensus recommendations addressing 2 issues: (1) How should surveillance colonoscopy for detection of dysplasia be performed? (2) How should dysplasia identified at colonoscopy be managed?

Efficacy of Immunosuppressive Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

OBJECTIVES:There remains controversy regarding the efficacy of thiopurine analogs (azathioprine (AZA) and 6-mercaptopurine (6-MP)), methotrexate (MTX), and cyclosporine for the treatment of inflammatory bowel disease (IBD). We performed an updated systematic review of the literature to clarify the efficacy of immunosuppressive therapy at inducing remission and preventing relapse in ulcerative colitis (UC) and Crohns disease (CD).METHODS:Only parallel group randomized controlled trials (RCTs) were considered eligible. Studies with adult IBD patients receiving immunosuppressive therapy compared with placebo for at least 14 days and up to 17 weeks for active disease, or at least 6 months in quiescent disease were analyzed. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat analysis. The data were summarized using relative risk (RR) and pooled using a random effects model.RESULTS:Data on MTX and cyclosporine in IBD were limited although there were some data to support the use of intramuscular MTX in CD but not UC. There were five trials of AZA/6-MP in 380 active CD patients and there was no significant effect of therapy inducing remission (RR=0.87; 95% confidence interval (CI)=0.71–1.06). In quiescent CD, there were two trials involving 198 patients with no significant benefit of active therapy preventing relapse compared with placebo (RR=0.64; 95% CI=0.34–1.23). There were, however, three additional AZA withdrawal trials in 163 patients that indicated continuing medication did prevent relapse (RR=0.39; 95% CI=0.21–0.74). There were two AZA RCTs in 130 active UC patients that suggested a trend for benefit of therapy, but this did not reach statistical significance (RR=0.85; 95% CI=0.71–1.01). In quiescent UC, there were three trials involving 127 patients and there was a statistically significant benefit of AZA preventing relapse (RR=0.60; 95% CI=0.37–0.95).CONCLUSIONS:Most evidence relates to AZA/6-MP where there is no statistically significant benefit at inducing remission in active CD and UC. Thiopurine analogs may prevent relapse in quiescent UC and CD. However, there is a paucity of data for immunosuppressive therapy in IBD and more research is needed.

Cyclosporine and Infliximab as Rescue Therapy for Each Other in Patients With Steroid-Refractory Ulcerative Colitis

BACKGROUND & AIMS In patients with severe corticosteroid-refractory ulcerative colitis, cyclosporine or infliximab may be added in an effort to induce remission. If the patient then fails either of these drugs, it is unknown whether success can be achieved by using the other agent. The aim of this study was to assess outcomes of using cyclosporine after failure of infliximab, and vice versa. METHODS We retrospectively reviewed the charts of 19 patients with corticosteroid-refractory ulcerative colitis who received either infliximab after failed cyclosporine or cyclosporine after failed infliximab. Acute salvage therapy was defined as having received the alternate drug within 4 weeks of discontinuing the first agent. RESULTS Ten patients received infliximab after failing cyclosporine; 9 patients received cyclosporine after failing infliximab. Four patients (40%) in the infliximab-salvage group achieved remission, as did 3 (33%) in the cyclosporine-salvage group. Remission lasted a mean of 10.4 months (range, 4.4-17.03 mo) and 28.5 months (range, 5.0-41.5 mo), respectively. Severe adverse events included one patient who developed sepsis and died after receiving infliximab salvage. One patient who received cyclosporine salvage developed herpetic esophagitis, and another patient who received cyclosporine salvage developed pancreatitis and bacteremia. CONCLUSIONS In patients with severe corticosteroid-refractory ulcerative colitis who fail treatment with either cyclosporine or infliximab, remission rates using acute salvage therapy by crossing over to the other drug occur in approximately one third of patients and have limited duration. Serious adverse events occurred in 16%, including 1 death, suggesting that the risks of acute salvage therapy may outweigh the benefits.

The fate of low grade dysplasia in ulcerative colitis

Abstract OBJECTIVE: The optimal strategy for the management of definite low grade dysplasia (LGD) detected in surveillance in ulcerative colitis (UC) is unknown, because the natural history of LGD has not been well described. METHODS: We reviewed the Mayo Clinic records of patients with UC found to have flat LGD between 1990 and 1993 in whom a nonoperative strategy was pursued for 2 months or more. RESULTS: Eighteen patients with UC and LGD were observed for a median of 32 months. Nine of 18 patients identified with UC and LGD developed advanced neoplastic lesions during follow-up, which were defined as adenocarcinoma, raised dysplasia, or high grade dysplasia. The cumulative incidence of progression to an advanced lesion was 33% at 5 yr (95% CI = 9–56%). Only one patient developed adenocarcinoma, diagnosed 74 months after his initial finding of LGD and 20 months after his last surveillance exam. Besides this patient, adenocarcinoma was not detected in the colectomy specimens of 13 other patients who underwent surgery. Colectomies were performed for dysplasia or cancer in seven patients, active colitis in five patients, and unknown reasons in two patients. Four patients did not have colectomies. CONCLUSIONS: Neoplastic progression in patients with UC and LGD is common. Total proctocolectomy should be offered to all patients with flat LGD. Our study illustrates numerous pitfalls in the practice of surveillance.

5-aminosalicylic acid therapy and the risk of colorectal cancer among patients with inflammatory bowel disease

Background: Patients with inflammatory bowel disease (IBD) affecting the colon are at increased risk of developing colorectal cancer (CRC). Published data are conflicting about whether 5‐aminosalicylic acid (5‐ASA) has chemopreventive properties against IBD‐related carcinogenesis. The objective of this observational study was to determine if an association between 5‐ASA therapy and CRC risk exists in IBD patients. Methods: Adult patients with a new CRC diagnosis (n = 18,440) were identified from 2 large administrative claims databases. For each case, 20 control patients with no record of CRC diagnosis or bowel surgery (n = 368,800) were identified. Results: An IBD diagnosis was associated with a 6‐ to 7‐fold increased risk of CRC (ulcerative colitis, crude odds ratio [OR] = 6.72, 95% CI, 5.79–7.81; Crohns disease, crude OR = 6.60, 95% CI, 5.56–7.82). Among patients with IBD (364 CRC cases, 1172 controls), exposure to 5‐ASA therapy of any dose or duration during the 12 months before CRC diagnosis was not associated with a reduced risk of CRC (OR = 0.97; 95% CI, 0.77–1.23). However, there was a trend toward a decreased risk of CRC with increasing number of mesalamine prescriptions in the previous year, though statistical significance was not achieved (trend P = 0.08). Conclusions: Treating IBD patients with 5‐ASA medications was not found to have a protective effect against colitis‐related CRC when assessed over a short period of exposure.