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Clinical Advances in Ulcerative Colitis Disclosures Bret A. Lashner, MD Introduction Important advances in clinical research for ulcerative colitis (UC) were presented during this year's meeting of the American College of Gastroenterology (ACG). As always, the most anticipated presentations focused on therapeutic advances. Still, there were important insights made regarding diagnostic considerations and the natural history of disease. Much was learned during these conference proceedings, and the ACG meeting continues to be the premier forum for the exchange of clinical research. Diagnostic Considerations Once the diagnosis of UC is confirmed, concomitant diagnoses that may be present include celiac disease, interstitial cystitis, and viral infections. Association With Celiac Disease Zali and colleagues[1] conducted serologic screening for celiac disease in patients with inflammatory bowel disease (IBD) to assess the seroprevalence of such an association. Among 114 patients with IBD studied in Iran (103 with UC), 9 (7.8%) tested positive for IgA endomysial antibody. None of the 6 patients who had IgA deficiency was seropositive for IgG antigliadin antibody. Due to this finding of a high seroprevalence, the study authors suggest that concomitant celiac disease be ruled out in patients with IBD. Association With Interstitial Cystitis Interstitial cystitis, a chronic debilitating disease, remains a diagnosis of exclusion, with no characteristic tissue pathology. Data from self-reported questionnaires from patients with interstitial cystitis have indicated a prevalence of IBD nearly 100 times greater than that found in the general population. Investigators from the University of Pennsylvania and Temple University (Philadelphia, Pennsylvania) described 40 patients with interstitial cystitis who underwent blood testing for IBD, had confirmatory testing if positive, and had a gastroenterologic evaluation if both studies were positive.[2] Three patients (2 with UC and 1 with Crohn's disease) were diagnosed with IBD during the study period. A new diagnosis of IBD in 7.5% of patients with interstitial cystitis was suggestive of an association between the entities. Role of Viral Infections Feldman and colleagues[3] from the University of Miami, Miami, Florida, emphasized the importance of considering viral infections as an etiology of colitis in patients with UC. Out of a total of 23 colonic biopsy specimens obtained from patients with active IBD, 10 (43.4%) were positive for cytomegalovirus (CMV) DNA and 2 (8.7%) were positive for human herpesvirus-6 DNA. Of 13 specimens taken from controls (ie, individuals without IBD), 0 were positive for CMV and 2 were positive for human herpesvirus-6. In infected patients, this viral DNA was usually detected in both inflamed and noninflamed mucosa. Thus, viral infection should be considered in the differential diagnosis of an IBD patient who flares. Role of Genetics Clinical features of UC may be genetically determined. Forman and colleagues[4] from Lennox Hill Hospital, New York, NY, reported on 37 ethnic minority patients with IBD (36% African American, 36% Hispanic, 28% Asian American) who were compared with a matched group of white patients with IBD. Minority patients with UC had more left-sided disease (P /= 7 mcg/mL, pouchoscopy should be performed to differentiate between the inflammatory conditions of the ileal pouch. Disease Course Colorectal Cancer The most serious complication associated with UC is the development of colorectal cancer (CRC). Chemoprevention strategies have emerged that, when combined with cancer surveillance colonoscopy, could decrease cancer mortality rates to very low levels. Van Staa and associates[8] from the United Kingdom and The Netherlands performed a nested case-control study using 100 patients with IBD with CRC and 6 IBD controls for each case matched for age, sex, and calendar year. Regular users of 5-aminosalicylic acid (5-ASA) had a decreased risk of developing CRC (adjusted odds ratio: 0.54; 95% confidence interval: 0.35-0.86). Duration of regular 5-ASA use demonstrated a dose-response effect (odds ratio for use 2 years: 0.51). This study provides excellent evidence for the chemopreventive effect of 5-ASA. In an attempt to corroborate a chemopreventive effect for ursodeoxycholic acid (UDCA) on CRC risk among patients with UC with primary sclerosing cholangitis (PSC), Ullman and colleagues[9] from the Mount Sinai School of Medicine performed a historical cohort study. Among 50 patients with UC and PSC, 32 used UDCA on a regular basis. Cancer or dysplasia was detected in 6 patients (19%) who took UDCA and in 5 patients (28%) who did not. The adjusted odds ratio for the development of cancer or dysplasia in a patient with PSC taking UDCA was 0.64 and was not statistically significant. Thus, the potential chemopreventive effect of UDCA has not been resolved. Disease Activity Quantifying the activity of disease with objective measures could have utility in the noninvasive differentiation of inflammatory (ie, UC) from noninflammatory conditions (ie, IBS associated with IBD). Lactoferrin is an iron-binding glycoprotein that is stored in neutrophils and which can be detected in the stool of patients with active IBD. Walker and colleagues[10] from the Mayo Clinic, Rochester, Minnesota, collected serial stool samples every 2-4 weeks from 20 patients with IBD. Increased levels of fecal lactoferrin were detected in all patients with chronically active disease as well as in patients who had IBD flares. All 3 patients with elevated fecal lactoferrin levels who were in a steroid-induced clinical remission went on to flare clinically when the steroids were tapered. Serial lactoferrin measurements may thus be a noninvasive method for monitoring disease activity and response to therapy. Smedley and colleagues[11] from the Mount Sinai School of Medicine reported that among 17 patients with UC, fecal lactoferrin measurement (with a cut-off point of 15 mcg/g) had a sensitivity of 73% and a specificity of 100% for differentiating active disease from remission. Platelet count and C-reactive protein were also able to differentiate active from inactive disease, but erythrocyte sedimentation rate had no such discriminating ability. Extraintestinal Manifestations Individuals with IBD appear to have an increased risk for low bone mineral density. Comerford and colleagues[12] from the University of Virginia, Charlottesville, reported that among 24 patients with UC recruited from a large heterogeneous database who underwent dual-energy x-ray absorptiometry (DEXA) scanning, osteopenia of the hip was found in 29% and osteoporosis of the hip in 8%. These rates are much lower than what is seen in Crohn's disease, where osteopenia of the hip was found in 48% of cases. Low bone mineral density was associated with a low body mass index, advanced age, African-American ethnicity, and active disease. There were no significant associations with lifetime steroid use, sex, disease duration, and history of surgical resections. Basu and colleagues[13] from the Cleveland Clinic in Florida reported that among 46 patients with pancolitis who had surgery, 58% of all extraintestinal manifestations improved, compared with only 14% among 22 patients with pancolitis who were treated medically (P < .02). Arthralgias and arthritis were the most likely extraintestinal manifestations to improve, but improvement following surgery was seen with erythema nodosum, pyoderma gangrenosum, uveitis, aphthous oral ulceration, venous thromboembolism, and ankylosing spondylitis. Therapeutic Advances Exciting advances have been made in the treatment of UC, involving both new drugs and alternative uses of approved drugs. Novel Treatment Options TNF, interferon-gamma, IL-2, IL-12 inhibition. RDP-58* is an antiinflammatory decapeptide that interferes with cell signaling and inhibits production of tumor necrosis factor (TNF), interferon-gamma, interleukin (IL)-2, and IL-12. Systemic absorption of RDP-58 is very low. Travis and colleagues[14] reported the results of parallel randomized clinical trials that were conducted in the United Kingdom and at multiple centers throughout Europe. One hundred twenty-seven patients (34 in the United Kingdom, 93 in Europe) with mildly to moderately active UC were randomized to receive an oral solution of RDP-58 (at 100 mg, 200 mg, or 300 mg) or placebo daily for 28 days, with concomitant medications held stable. Clinical remission rates were 72% for the 300-mg dose of RDP-58, 70% for the 200-mg dose, 29% for the 100-mg dose, and 40% for placebo (P < .001). Histology scores were significantly better for the 300-mg and 200-mg RDP-58 groups compared with the 100-mg RDP-58 and placebo groups. There were no differences in adverse effects among any of the treatment groups compared with placebo. RDP-58 may be an exciting advance in the treatment of UC due to its effectiveness, novel mechanism of action, oral delivery, and low toxicity. Humanized alpha4beta7 antibody. MLN-02* is a humanized monoclonal antibody to alpha4beta7 integrin. Its ligand, MadCaM, is expressed on intestinal vascular endothelium and selectively blocks recruitment of lymphocytes to the intestine. Feagan and colleagues[15] presented results of a Canadian cooperative randomized clinical trial in which 181 patients with moderately active UC were given 1 of 2 doses of MLN-02 (0.5 mg/kg or 2.0 mg/kg) or placebo on days 1 and 29. Day 43 remission rates were 33% for the 0.5-mg/kg dose, 34% for the 2.0-mg/kg dose, and 15% for placebo (P < .03). Day 43 response rates were 66% for the 0.5-mg/kg dose, 57% for the 2.0-mg/kg dose, and 33% for placebo (P < .001). Overall, there was little difference in serious adverse effects, which were mostly related to the underlying UC. Adverse events occurred in 8% of patients receiving MLN-02 and in 5% of patients receiving placebo, but 1 patient developed angioedema following MLN-02 infusion. MLN-02 thus appears to be a promising, safe, and effective therapy for UC. ICAM-1 antisense inhibition. ISIS-2302* is an antisense oligonucleotide inhibitor of intercellular adhesion molecule 1 (ICAM-1). ICAM-1 plays a key role in the trafficking and activation of leukocytes, and its expression is upregulated in inflamed mucosa in Crohn's disease. Miner and colleagues[16] from the Oklahoma Foundation for Digestive Research, Oklahoma City, presented results of a study involving 12 patients with chronic pouchitis who were given 240-mg ISIS-2302 enemas nightly for 6 weeks. Mean PDAI fell from 11.4 to 6.8 (P < .01) after 6 weeks of treatment; 3 patients did not respond to therapy. Therefore, ISIS-2302 enemas may offer an acceptable alternative for patients whose pouchitis is difficult to treat with antibiotics. Novel Applications of Treatment Mesalamine and infliximab. Both mesalamine and infliximab are pharmacologic agents that may have new uses in the setting of UC. Cuffitis is a rarely occurring and difficult-to-treat complication of surgery for UC. The underlying pathogenesis of this entity is likely the recurrence of UC in the 1-2 cm of retained rectal cuff. Shen and colleagues[17] from the Cleveland Clinic presented a series of 10 patients with cuffitis who were given 500 mg of mesalamine suppositories twice daily in an open-label fashion. After a mean of 3.5 months of therapy, the mean PDAI symptom and endoscopy component scores were significantly decreased. No adverse effects were noted. Although not approved for treatment of patients with UC, infliximab* (monoclonal antibody to TNF-alpha) has demonstrated efficacy in some case series. Kiafar and colleagues[18] from the Hayden VA Medical Center, Phoenix, Arizona, presented data on 12 patients with steroid-refractory UC who received multiple infusions of infliximab. Ten of 12 patients (83%) responded to treatment. The mean duration of response was 10 weeks. One patient contracted herpes zoster. Immunosuppressive therapy. Loftus and coworkers[19] from the Mayo Clinic reported on the toxicity (safety profile) of 94 incident cases of IBD (23 with UC) that were treated with immunosuppressive therapy (azathioprine* or 6-mercaptopurine*). Thirty-five patients (37%) had an adverse event, and 23 (24%) discontinued therapy due to an adverse event. The most common adverse effects were nausea, leukopenia, abdominal pain, and arthralgia. Two patients developed pancreatitis and 1 developed Hodgkin's lymphoma. Physicians should therefore be aware of these adverse effects when prescribing immunosuppressive medications in patients with IBD. Antibiotic therapy. Is cyclosporine a surgery-sparing option? The long-term follow-up of 42 steroid-refractory patients with UC who were administered cyclosporine* prior to 1996 at the University of Chicago was presented by Chung and colleagues.[20] The short-term response rate was 86% and the long-term response rate (median 6.7 years) was 43%. Azathioprine or 6-mercaptopurine maintenance therapy was associated with improved colectomy-free survival (54% vs 17% in patients who did not receive maintenance therapy; P < .05). If immunosuppression maintenance therapy is administered, long-term success following cyclosporine therapy for severely active UC exceeds 50%. Concluding Remarks As demonstrated by the clinically strong studies presented during this year's meeting proceedings, advances in our understanding of the disease course, pathogenesis, and therapeutic options for UC have been substantial. It is evident that the ongoing elucidation of this inflammatory bowel disease will offer the clinician new insights into the care and follow-up of these patients. * The United States Food and Drug Administration has not approved this medication for this use. References Zali MR, Aghazadeh R, Bahari A, et al. Seroprevalence of celiac disease in IBD. Am J Gastroenterol. 2003;98:S238-S239. [Abstract #720] Tudi SR, Jati A, Novi JM, et al. Inflammatory bowel disease and interstitial cystitis: Is there an association? Am J Gastroenterol. 2003;98:S242- S 243. [Abstract #731] Feldman PA, Fregein N, Sable A, et al. A prospective study of the prevalence of cytomegalovirus and human herpes-6 virus in patients with inflammatory bowel disease. Am J Gastroenterol. 2003;98:S251. [Abstract #756] Forman RB, Gordon NM, Panagopoulos G, Korelitz BI. Inflammatory bowel disease: a comparison of demographic and clinical characteristics between Caucasians and ethnic minorities. Am J Gastroenterol. 2003;98:S254- S 255. [Abstract #767] Farhadi A, Banan A, Van de Kar LD, et al. Exaggerated response to physiological stress in patients with IBD: a possible contributing factor in the pathogenesis of IBD. Am J Gastroenterol. 2003;98:S253. [Abstract #762] Shen B, Lashner B, Parsi M, et al. Characterization of irritable pouch syndrome: clinical presentation and quality of life. Am J Gastroenterol. 2003;98:S240- S 241. [Abstract #726] Parsi MA, Lashner BA, Shen B, et al. Fecal lactoferrin distinguishes inflammatory from non-inflammatory causes of symptoms in patients with ileal-pouch anal anastomosis. Am J Gastroenterol. 2003;98:S76- S 77. [Abstract #223] Van Staa TP, Card T, Leufkens HGM, Logan RF. Prior aminosalicylate use and the development of colorectal cancer in IBD: a large British epidemiological study. Am J Gastroenterol. 2003;98:S244- S 245. [Abstract #737] Ullman TA, Croog V, Maratchi L, et al. Ursodeoxycholic acid for chemoprevention in ulcerative colitis and primary sclerosing cholangitis: a retrospective cohort study. Am J Gastroenterol. 2003;98:S258. [Abstract #777] Walker TR, Sandborn WJ, Moone J, et al. Fecal lactoferrin measurements are useful in the interval assessment of patients with active and inactive IBD. Am J Gastroenterol. 2003;98:S246. [Abstract #742] Smedley MV, Bodian C, Boone JH, Present DH. Are laboratory tests effective in assessing disease activity in IBD? Am J Gastroenterol. 2003;98:S258. [Abstract #776] Comerford LW, Bickston SJ, Arseneau K, et al. Low bone mineral density in inflammatory bowel disease -- a study of the prevalence and risk factors. Am J Gastroenterol. 2003;98:S257- S258. [Abstract #775] Basu A, Wexner SD, Weiss EG, et al. Surgery improves extraintestinal manifestations of mucosal ulcerative colitis. Am J Gastroenterol. 2003;98:S260. [Abstract #782] Travis SPL, Yap LM, Hawkey CJ, et al. RDP-58: Novel and effective therapy for ulcerative colitis: results of parallel, prospective, placebo-controlled trials. Am J Gastroenterol. 2003;98:S239. [Abstract #721] Feagan B, Greenberg G, Wild G, et al. A randomized controlled trial of a humanized alpha4beta7 antibody in ulcerative colitis. Am J Gastroenterol. 2003;98:S248- S 249. [Abstract #749] Miner PB, Bane B, Bradley JD, et al. ICAM-1 antisense inhibition by enema improves pouchitis and suggests long-term mucosal healing in patients with chronic unremitting disease. Am J Gastroenterol. 2003;98:S246-S247. [Abstract #743] Shen B, Lashner B, Remzi F, et al. Topical mesalamine is same and effective in treating rectal cuff inflammation (cuffitis) in patients with ulcerative colitis following total proctocolectomy and ileal pouch-anal anastomosis. Am J Gastroenterol. 2003;98:S240. [Abstract #725] Kiafar C, Ramirez FC, Shernoff N, Hayden CT. Anti-tumor necrosis factor therapy for patients with refractory ulcerative colitis. Am J Gastroenterol. 2003;98:S255-S256. [Abstract #770] Loftus CG, Loftus EV, Tremaine WJ, Sandborn WJ. The safety profile of azathioprine/6-mercaptopurine in the treatment of IBD: a population-based study in Olmsted County, MN. Am J Gastroenterol. 2003;98:S242. [Abstract #730] Chung PY, Cohen RD, Kirschner BS, Hanauer SB. Intravenous cyclosporine in ulcerative colitis: long-term follow-up of the University of Chicago experience. Am J Gastroenterol. 2003;98:S255. [Abstract #768] You must read all articles in this activity to prepare for the post test. Copyright © 2003 Medscape.

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