Asher Kornbluth, David B. Sachar and The Practice Parameters Committee of the American College of Gastroenterology
Am J Gastroenterol 2010;105:500; doi:10.1038 / ajg.2010.52; published online 23 February 2010
Correction to: Am J Gastroenterol 2010;105:501 – 523; doi:10.1038 / ajg.2009.727
In the Conflict of Interest section of the article, the Financial Support subsection should have stated that “No support was provided for this work.” The publisher regrets any confusion this misstatement may have caused.
The corrected Potential Competing Interests subsection for Dr Kornbluth is as follows: “Asher Kornbluth is a consultant for Salix Pharmaceutical, Shire Pharmaceutical, Proctor and Gamble Pharmaceutical, Centocor, and Prometheus Laboratory and has received research support from Salix Pharmaceutical, Procter and Gamble Pharmaceuticals, and Centocor Inc. He is also on the Speaker’s Bureau of Salix Pharmaceutical, Shire Pharmaceutical, Proctor and Gamble Pharmaceutical, Centocor, Prometheus, and Axcan Pharmaceutical.”
Also in the Conflict of Interest section, Dr Sacher’s Potential Competing Interests statement was not included. It is as follows: “David Sachar serves as expert witness for the plaintiffs in litigation claiming that isotretinoin was a cause of their inflammatory bowel disease. He has no other conflicts of interest to report.”
Asher Kornbluth, MD1, David B. Sachar, MD, MACG1 and The Practice Parameters Committee of the American College of Gastroenterology
1Dr. Henry D. Janowitz Division of Gastroenterology, Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
Guidelines for clinical practice are aimed to indicate preferred approaches to medical problems as established by scientifically valid research. Double-blind placebo controlled studies are preferable, but compassionate-use reports and expert review articles are used in a thorough review of the literature conducted through Medline with the National Library of Medicine. When only data that will not withstand objective scrutiny are available, a recommendation is identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject regardless of specialty training or interests and are aimed to indicate the preferable but not necessarily the only acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standards of care, which are inflexible and rarely violated. Given the wide range of specifics in any health-care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision. Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the board of trustees. Each has been intensely reviewed and revised by the Committee, other experts in the field, physicians who will use them, and specialists in the science of decision analysis. The recommendations of each guideline are therefore considered valid at the time of composition based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at a time established and indicated at publication to assure continued validity. The recommendations made are based on the level of evidence found. Grade A recommendations imply that there is consistent level 1 evidence (randomized controlled trials), grade B indicates that the evidence would be level 2 or 3, which are cohort studies or case–control studies. Grade C recommendations are based on level 4 studies, meaning case series or poor-quality cohort studies, and grade D recommendations are based on level 5 evidence, meaning expert opinion.
Am J Gastroenterol 2010; 105:501–523; doi: 10.1038/ajg.2009.727; published online 12 January 2010
Received 2 February 2009; accepted 19 February 2009.
Correspondence: Asher Kornbluth, MD, The Dr. Henry D. Janowitz Division of Gastroenterology, Samuel Bronfman Department of Medicine, Mount Sinai Medical Center, 1751 York Avenue, New York, New York 10128, USA. E-mail: firstname.lastname@example.org
Ulcerative colitis (UC) is a chronic disease characterized by diffuse mucosal inflammation limited to the colon. It involves the rectum in about 95% of cases and may extend proximally in a symmetrical, circumferential, and uninterrupted pattern to involve parts or all of the large intestine. The hallmark clinical symptom is bloody diarrhea often with prominent symptoms of rectal urgency and tenesmus. The clinical course is marked by exacerbations and remissions, which may occur spontaneously or in response to treatment changes or intercurrent illnesses (1, 2). UC affects approximately 500,000 individuals in the United States with an incidence of 8–12 per 100,000 population per year; the incidence has remained relatively constant over the last five decades (3–8).
The disease accounts for a quarter million physician visits annually, 30,000 hospitalizations, and loss of over a million workdays per year (9). The direct medical costs alone exceed four billion dollars annually, comprising estimated hospital costs of over US$960 million (10, 11) and drug costs of $680 million (11).
Recommendations for Diagnosis and Assessment
In a patient presenting with persistent bloody diarrhea, rectal urgency, or tenesmus, stool examinations and sigmoidoscopy or colonoscopy and biopsy should be performed to confirm the presence of colitis and to exclude the presence of infectious and noninfectious etiologies. Characteristic endoscopic and histologic findings with negative evaluation for infectious causes will suggest the diagnosis of UC.
The diagnosis of UC is suspected on clinical grounds and supported by the appropriate findings on proctosigmoidoscopy or colonoscopy, biopsy, and by negative stool examination for infectious causes (12). Inquiries should be made regarding factors that may potentially exacerbate symptoms of UC; e.g., smoking cessation or nonsteroidal anti-inflammatory drug use or possibly isotretinoin (13–16). Infections can also produce clinical findings indistinguishable from idiopathic UC, so microbiologic studies for bacterial infection (including specific assays for Escherichia coli 0157:H7) and parasitic infestation, as well as serologic testing for ameba when clinical suspicion is high, should be performed in each new patient (17), and should be considered in patients in remission or with mild stable symptoms who unexpectedly develop a severe or atypical exacerbation (18, 19). Similarly, patients who have recently been admitted to hospital or treated with antibiotics should have stools examined for Clostridium difficile, although antibiotic-associated diarrhea may be present even with a negative assay for C. difficile toxin. The incidence of C. difficile is increasing in UC (20–23), and in inflammatory bowel disease (IBD) patients it is associated with a more severe course, greater length of hospital stay, higher financial costs, greater likelihood of colectomy, and increased mortality (22, 24). Multiple stool assays may be required for diagnosis because of frequent false-negative results (22, 24, 25).
Proctosigmoidoscopy or colonoscopy will reveal the mucosal changes characteristic of UC, consisting of loss of the typical vascular pattern, granularity, friability, and ulceration (26–28). These changes typically involve the distal rectum, both endoscopically and histologically (29) and proceed proximally in a symmetric, continuous, and circumferential pattern to involve all or part of the colon. However, isolated patchy cecal inflammation is often seen in UC patients with otherwise only distal disease (30). These endoscopic features may not present in a typical manner in UC patients who have already received treatment, in which case-selective healing may have resulted in skip areas and rectal sparing. Because none of these endoscopic findings is specific for UC, histologic findings obtained from biopsies may be helpful in the differential diagnosis (31). Imaging of the small bowel may also be helpful when the diagnosis of Crohn’s disease (CD) is being considered (32, 33).
In the patient with acute onset of bloody diarrhea, the mucosal biopsy may help distinguish UC from infectious colitis. In UC, more commonly than in infectious colitis, the mucosa shows separation, distortion, and atrophy of crypts; chronic inflammatory cells in the lamina propria; preferential homing of neutrophils to the crypt epithelium; increased number of lymphocytes and plasma cells at the crypt bases; “shortfall” of crypts not reaching to the muscularis mucosae; and basal lymphoid aggregates (12, 34–36). Villous mucosal architecture and Paneth cell metaplasia on rectal biopsy are other features favoring the diagnosis of UC (37). Crypt abscesses, on the other hand, are a nonspecific indication of inflammation and do not indicate a particular diagnosis (38). However, a large, bulging, cystic dilation with a small “necklace” of flat or cuboidal cells around the crypt abscess is more common in infectious, or acute self-limited colitis, than it is in UC (12). CD may be suggested by certain histologic findings such as noncaseating granulomas or microscopic focality, but their absence does not rule out the diagnosis. Furthermore, even in UC or in acute self-limited colitis, muciphage (or “cryptolytic”) granulomas may form in response to ruptured crypts and are therefore not pathognomonic for CD (37). “Backwash ileitis” may occur in UC and appears as mild ileal inflammation endoscopically; it is almost always associated with cecal inflammation and has characteristic histologic findings of mild villous atrophy and only scattered crypt abscesses (39).
Other histologic findings that may suggest an infectious etiology include caseating or confluent granulomas in tuberculosis (TB) (or less commonly in schistosomiasis, syphilis, and Chlamydia trachomatis), trophozoites in amebiasis, pseudomembranes in C. difficile colitis (although in UC, most cases of C. difficile infection occur in the absence of pseudomembranes) (22), ova in schistosomiasis, and viral inclusions in herpetic or cytomegaloviral colitis, although the latter appears almost exclusively in immunocompromised patients (see “Recommendations for management of severe colitis”). In the appropriate clinical settings, sigmoidoscopy or colonoscopy and biopsy may also distinguish the various noninfectious colitides from UC. These conditions include ischemia, radiation, collagenous and microscopic colitis, drug-induced colitis, and the solitary rectal ulcer syndrome (38, 40, 41). Segmental colitis associated with diverticulosis, which usually presents with painless hematochezia in patients older than 60, is distinguished from UC by its segmental location in an area of divericula, typically in the sigmoid colon and with rectal sparing (42–44).
Perinuclear antineutrophil cytoplasmic antibodies (pANCA) have been identified in 60–70% of UC patients, but are also found in up to 40% of patients with CD. These pANCA–positive CD patients typically have a clinical phenotype resembling left-sided UC, so pANCA detection alone is of little value in distinguishing between UC and Crohn’s colitis (45). However, reactivity to CBir 1, an anti-flagellin antibody, is preferentially present in pANCA-positive CD patients as compared with pANCA-positive UC patients, 44% vs. 4%, respectively (46). A meta-analysis of 60 studies analyzing performance characteristics of pANCA and anti-saccharomyces cerevisiae antibodies in 3,841 UC patients and 4,019 CD patients found a specificity of 89% pANCA for UC, but a sensitivity of only 59%. For patients with CD, a positive anti-saccharomyces cerevisiae antibodies with a negative ANCA had a specificity of 93% for CD, but again with a sensitivity of only 55% (47). The low sensitivity of pANCA for the diagnosis of UC prevents it from serving as a useful diagnostic tool. However, their specificities may make these assays useful in the occasional patient in whom no other clinical or pathologic features allow a differential diagnosis between UC and Crohn’s colitis (48, 49). Although this distinction is not always crucial, it may have important consequences in terms of counseling, prognosis, and the choice of medical and surgical therapies (50).
Approach to Management
Goals of treatment are induction and maintenance of remission of symptoms to provide an improved quality of life, reduction in need for long-term corticosteroids, and minimization of cancer risk.
After the diagnosis of UC is confirmed, the anatomic extent is assessed endoscopically. The key question to be addressed at this point is whether the inflammation is “distal” (i.e., limited to below the descending colon and hence within reach of topical therapy) or extends proximal to the descending colon, requiring systemic medication. Therefore, a delineation of the proximal margin of inflammation, if not achieved on initial evaluation, is desirable at some point once the patient’s condition permits. From a practical standpoint, the endoscopic extent and clinical severity of an acute attack determine the approach to therapy. Importantly, a flare-up during which distal disease extends proximally is often a severe episode with the need for early aggressive therapy (51). Although therapeutic decisions are rarely based on histologic severity of inflammation, histology may well be taken into account when planning a surveillance regimen (see below). Based on clinical and endoscopic findings, the severity and extent of the disease are characterized. Severity may be classified as mild, moderate, severe, or fulminant (52, 53). Patients with mild disease have less than four stools daily, with or without blood, no systemic signs of toxicity, and a normal erythrocyte sedimentation rate. Moderate disease is characterized by more than four stools daily but with minimal signs of toxicity. Severe disease is manifested by more than six bloody stools daily, and evidence of toxicity as showed by fever, tachycardia, anemia, or an elevated erythrocyte sedimentation rate (52). Patients with fulminant disease may have more than 10 bowel movement daily, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement, and colonic dilation on abdominal plain films (53). Although this classification of mild, moderate, and severe disease is based on the original Truelove–Witts criteria of 1,955 (52), more recent clinical trials, especially with ambulatory patients, have relied more frequently on composite scores based on the number of loose or soft stools, frequency of rectal bleeding, sigmoidoscopic appearance, and a physician global assessment. These scores are variably termed the Mayo Clinic index, Sutherland index, or the UC Disease Activity Index (54, 55). Despite the widespread adoption of these indices in clinical trials, they do not take into account symptoms of abdominal pain, nocturnal bowel movements, urgency, or the dreadful fear of episodes of incontinence, which are often the patients’ greatest concerns. Furthermore, in assessing patients’ own perception of clinical response, the sigmoidoscopic score may not yield additional information beyond the patients’ simple reports of stool frequency and rectal bleeding (56, 57). As a practical therapeutic end point, endoscopic demonstration of mucosal healing is not usually necessary for a patient who achieves clinical remission. Conversely, long-term mucosal healing may reduce the risk of dysplasia (58, 59) and perhaps predicts a better long-term outcome (60, 61). In addition to the evaluation of colitis extent and activity, a global assessment of the patient should include attention to general health concerns, and quality of life issues that may be influenced by colitis activity as well as by extraintestinal manifestations (EIMs) of the disease. Some EIMs are associated with the colitis disease activity, and include the ocular complications of episcleritis, scleritis, and uveitis (which may require urgent consultation), peripheral arthropathies of small and large joints, and dermatologic findings of erythema nodosum and pyoderma gangrenosum. Other EIMs present with a course independent of the colitis activity and include the axial arthropathies, sacroilitis and ankylosing spondylitis, and the chief hepatic EIM associated with UC, primary sclerosing cholangitis (PSC). Although recognition of these EIMs is usually apparent, their management will often require consultation with the appropriate specialist.
Routine vaccination status should be reviewed (62). In patients on immunosuppresants, live vaccines are contraindicated, so if these are required they should be administered at the time of UC diagnosis. However, patients on immunosuppressant drugs can and should be vaccinated routinely for influenza and pneumococcal infection, and for tetanus and meningococcus in the appropriate settings (63–65). Patients being started on infliximab should be screened for hepatitis B before initiating infliximab therapy (63).
Referral-based series (66, 67) have found an increase in abnormal Pap smears in women with IBD, whereas a population-based series found increased risk only in those patients on corticosteroids and immunosuppressants (68). IBD patients have been reported to undergo routine Pap smear testing with suboptimal frequency (69) and should be advised to adhere to guidelines for cervical dysplasia screening (70). Furthermore, current guidelines recommend consideration of administering the human papilloma virus vaccine to all females between the ages of 9 and 26 (71).
Concerns regarding quality of life should be addressed: impairment of function at school, work, or in personal relationships; social and emotional support; financial resources; and adequacy of patient education regarding their disease (13). Anxiety and major depression are more prevalent in patients with IBD than in the general population, and these conditions are more pronounced in patients with greater ongoing disease activity (72, 73). Besides providing indication for specific therapies, these psychiatric diagnoses may also predict the likelihood for medication noncompliance, a frequent contributing factor to poorer clinical outcomes and greater health-care costs (74–76).
Recommendations for Management of Mild-Moderate Distal Colitis
Patients with mild to moderate distal colitis may be treated with oral aminosalicylates, topical mesalamine, or topical steroids (Evidence A). Topical mesalamine agents are superior to topical steroids or oral aminosalicylates (Evidence A). The combination of oral and topical aminosalicylates is more effective than either alone (Evidence A). In patients refractory to oral aminosalicylates or topical corticosteroids, mesalamine enemas or suppositories may still be effective (Evidence A). The unusual patient who is refractory to all of the above agents in maximal doses, or who is systemically ill, may require treatment with oral prednisone in doses up to 40–60 mg per day, or infliximab with an induction regimen of 5 mg/kg at weeks 0, 2, and 6, although the latter two agents have not been studied specifically in patients with distal disease (Evidence C).
The therapeutic plan in these cases is determined largely by the patient’s preferences, because both oral and topical therapies are effective. However, a meta-analysis of controlled trials indicates that topical mesalamine is superior to oral aminosalicylates alone in achieving clinical improvement in patients with mild – moderate distal colitis (77–79). Oral therapy with the aminosalicylates (sulfasalazine, olsalazine, mesalamine, or balsalazide) is beneficial in achieving and maintaining remission (1,80–84). Effective doses of sulfasalazine range between 4 and 6 g a day in four divided doses (85, 86); for mesalamine 2 and 4.8 g per day in three divided doses (54, 87); for balsalazide 6.75 g per day in three divided doses (82, 88, 89); and for olsalazine 1.5–3 g per day in two divided doses (90–93), although efficacy of olsalazine in active UC is not conclusively established, perhaps in part because of a confounding dose-related diarrhea. A newer mesalamine formulated with a multimatrix formulation allows comparable efficacy with once daily dosing in doses of 2.4–4.8 g per day (94, 95). These drugs generally exert their effect within 2–4 weeks (80) and are effective in 40–80% patients (77, 80). Intolerance to the sulfapyridine moiety of sulfasalazine is fairly common and may result in nausea, vomiting, dyspepsia, anorexia, and headache. More severe but less common adverse effects include allergic reactions, pancreatitis, hepatotoxicity, drug-induced connective tissue disease, bone marrow suppression, interstitial nephritis, and hemolytic anemia or megaloblastic anemia. Abnormal sperm counts, motility, and morphology are also related to the sulfapyridine moiety of sulfasalazine and are not seen with the mesalamine preparations. Approximately 80% of patients intolerant to sulfasalazine are able to tolerate olsalazine, mesalamine, and balsalazide (80, 92, 96–98). However, several of the allergic reactions previously thought to be due to the sulfa moiety have occasionally been seen with newer aminosalicylates as well (80).
The occurrence of nephrotoxicity with either sulfasalazine or any of the mesalamine compounds is rare. In a review of 30 series in which serum creatinine or creatinine clearance was measured regularly in 2,671 patients for 3,070 years of follow-up, the mean annual nephrotoxicity rate per patient-year was 0.26% (99). Nephrotoxicity usually presents as interstitial nephritis; it occurs most frequently during the first year of treatment, but can occur unpredictably with a delayed presentation. There is no clear relationship between dose and the risk of nephrotoxicity, raising the possibility that this reaction might be idiosyncratic (100). In addition, patients with active IBD may develop an increase in microalbuminuria in the presence of active disease (101). Furthermore in an epidemiologic study of over 20,000 IBD patients from the UK, there was not an increased incidence of nephrotoxicity in IBD patients taking mesalamine compounds, compared with IBD patients without mesalamine use (102). It is recommended that serum creatinine should be measured before initiating treatment with mesalamine or its prodrugs, and periodically while on treatment. Although it may be reasonable to monitor serum creatinine at 3–6 months intervals during the first year of mesalamine treatment, and then annually thereafter, at present the optimal monitoring schedule of serum creatinine in patients treated with mesalamine remains to be determined, as there is no evidence currently to suggest that the frequency of testing improves patient outcomes (99).
An alternative to oral aminosalicylates is topical therapy with either mesalamine suppositories or enemas, or hydrocortisone foam or enemas. Mesalamine suppositories in a dose of 500 mg twice daily or 1,000 mg once daily are effective in the treatment of proctitis (103), and maintenance of remission (104), whereas mesalamine enemas in doses of 1–4 g may be able to reach as proximal as the splenic flexure and are effective in inducing (105, 106) and maintaining (107–109) remission in distal colitis. Topical corticosteroids, available in the United States as a 100 mg hydrocortisone enema, or as a 10% hydrocortisone foam, are effective in acute therapy of distal colitis (110–112) but have not proven effective in maintaining remission (77). Foam is often better tolerated by patients who have difficulty retaining enemas. Mesalamine enemas in a dose of 4 g have been more successful than corticosteroid enemas in inducing remission in two double-blind controlled studies (113–115). One-gram mesalamine enemas may prove as effective as the standard 4 g formulation for induction of remission in patients with left-sided colitis (77). Budesonide, a second-generation corticosteroid that undergoes first-pass hepatic metabolism, has also been evaluated; the optimal budesonide enema dose, 2 mg, not yet available in the United States, seems to be at least as effective as the standard hydrocortisone preparation with fewer side effects (116, 117). Advantages of topical therapy include a generally quicker response time and a less frequent dosing schedule than oral therapy, as well as less systemic absorption. The choice of topical vehicle is also guided by patient preference as well as by the proximal extent of disease. Suppositories have been showed to reach approximately 10 cm, hydrocortisone foam to approximately 15 – 20 cm, and enemas as far as the splenic flexure (118–122), although of course in individual patients the actual proximal extent of distribution may vary.
Some patients may achieve maximum benefit from combination of oral and topical therapy; a combination of oral mesalamine 2.4 and 4 g per day mesalamine enema was more effective in achieving clinical improvement, as well as an earlier response, than either agent alone (123).
Recommendations for Maintenance of Remission in Distal Disease
Mesalamine suppositories are effective in the maintenance of remission in patients with proctitis, whereas mesalamine enemas are effective in patients with distal colitis when dosed even as infrequently as every third night (Evidence A). Sulfasalazine, mesalamine compounds, and balsalazide are also effective in maintaining remission; the combination of oral and topical mesalamine is more effective than either one alone (Evidence A). Topical corticosteroids including budesonide, however, have not proven effective for maintaining remission in distal colitis (Evidence A). When all of these measures fail to maintain remission in distal disease, thiopurines (6-mercaptopurine (6-MP) or azathioprine) and infliximab (Evidence A), but not corticosteroids, may prove effective (Evidence B).
Mesalamine suppositories in doses of 500 mg daily or twice daily are effective in maintaining remission with an apparent dose–response relationship; only 10% of patients treated with 500 mg twice daily relapsed at 1 year, compared with a relapse rate of 36% with once daily dosing (124, 125). Mesalamine enemas in doses of 2–4 g maintained remission when administered daily (78% effective), every other day (72% effective), or even as infrequently as every third day (65% effective) (77, 78). Sulfasalazine in a dose of 2 g per day, olsalazine 1 g per day, Eudragit-S-coated mesalamine 3.2 g per day, balsalazide 3–6 g per day (126, 127), and granulated extended release mesalamine capsules 1.5 g per day (128) were all effective in maintaining remission in distal disease. The combination of oral mesalamine 1.6 g per day and mesalamine enema 4 g twice weekly was more effective than the oral mesalamine alone (129). Topical corticosteroids, whether hydrocortisone or budesonide, have not proven effective for maintaining remission in distal colitis (77, 78, 130).
The indications for the use of thiopurines and infliximab are identical to those described in the section on maintenance in extensive colitis although they have not been studied in trials limited to patients with distal disease (79).
Recommendations for Management of Mild-Moderate Extensive Colitis: Active Disease
Patients with mild to moderate extensive colitis should begin therapy with oral sulfasalazine in daily doses titrated up to 4–6 g per day, or an alternate aminosalicylate in doses up to 4.8 g per day of the active 5-aminosalicylate acid (5-ASA) moiety (Evidence A). Oral steroids are generally reserved for patients who are refractory to oral aminosalicylates in combination with topical therapy, or for patients whose symptoms are so troubling as to demand rapid improvement (Evidence B). 6-MP and azathioprine are effective for patients who do not respond to oral steroids, and continue to have moderate disease, and are not so acutely ill as to require intravenous therapy (Evidence A). Infliximab is an effective treatment for patients who are steroid refractory or steroid dependent despite adequate doses of a thiopurine, or who are intolerant of these medications. The infliximab induction dose is 5 mg/kg intravenously at weeks 0, 2, and 6 weeks (Evidence A). Infliximab is contraindicated in patients with active infection, untreated latent TB, preexisting demyelinating disorder or optic neuritis, moderate to severe congestive heart failure, or current or recent malignancies.
When inflammation extends proximal to the reach of topical therapy (i.e., descending colon), oral therapy is required, either solely or in combination with topical therapy. For clinically mild to moderate but anatomically extensive disease, the first-line therapy traditionally has been sulfasalazine. Responses are dose related, with up to 80% of patients who receive daily doses of 4–6 g manifesting complete clinical remission or significant clinical improvement within 4 weeks (85, 86) and approximately half achieving sigmoidoscopic remission (85). However, the benefits of greater efficacy with the higher dose are somewhat offset by an increase in side effects. The strongest advantage of sulfasalazine compared with the “newer” aminosalicylates is its considerably lower cost. However, the most recent Cochrane Systematic Review found a trend in favor of a slight benefit for the newer 5-ASA preparations over sulfasalazine in the induction of global/clinical and endoscopic improvement including remission, when equivalent amounts of the active 5-ASA moiety were compared. There was a modest dose–response relationship of mesalamine when compared to placebo; the trend was significant in terms of global/clinical improvement or remission. This trend was only marginally significant when the rate of complete global/clinical remission was evaluated (80).
If these higher doses of sulfasalazine are not well tolerated, or if there is concern regarding potential sulfonamide toxicity, then one of the other nonsulfonamide 5-ASA-containing compounds should be used at doses of at least 2 g per day, titrating up to 4.8 g per day of the active 5-ASA moiety (54).
The “newer” aminosalicylates—balsalazide (82, 88, 89), olsalazine (90–93), Eudragit-S-coated, pH-dependent mesalamine (54, 87), ethylcellulose-coated mesalamine (131), and multimatrix-release mesalamine (83, 132)—are all superior to placebo and equivalent to sulfasalazine in acute therapy (80). As with sulfasalazine, therapeutic benefit requires a threshold dose, with daily doses less than 2 g being ineffective (54, 80, 87, 133). Two dose-ranging studies of Eudragit-S-coated pH-dependent release mesalamine show a dose–response relationship, comparing 2.4 g daily with 4.8 g daily, with a greater clinical response to the higher dose seen in patients with moderate but not mild disease. No differences were seen, however, in complete remission rates between the two dosages (134, 135). Similarly, there were no significant differences in clinical responses or remissions in patients with mild or moderate disease when treated with multimatrix-mesalamine with 2.4 g daily compared to 4.8 g daily (83, 132). The combination of oral mesalamine and topical mesalamine was more successful than oral mesalamine alone in achieving clinical remission at 8 (but not 4) weeks (136).
A Cochrane systematic review of transdermal nicotine in active UC identified five relevant studies (137). Nicotine was more effective than placebo in achieving remission and improvement. However, comparative trials to mesalamine did not show any clinical advantage for nicotine. At present therefore, the place of nicotine in the therapy of UC remains limited.
Oral prednisone shows a dose–response effect between 20 and 60 mg per day (52, 138, 139), with 60 mg per day modestly more effective than 40 mg per day but at the expense of greater side effects (139). No randomized trials have studied steroid taper schedules; most recommendations (140) have advised 40–60 mg per day until significant clinical improvement occurs and then a dose taper of 5–10 mg weekly until a daily dose of 20 mg is reached. At this point tapering generally proceeds at 2.5 mg per week. The frequency and severity of steroid toxicity are substantial and may involve many metabolic activities in virtually every organ system. These adverse effects include cushingoid features, emotional and psychiatric disturbances, infections, glaucoma, and cataracts. Annual ophthalmologic examinations for patients on chronic steroids are recommended (140). Additional steroid-induced complications include gastroduodenal mucosal injury, skin striae, impaired wound healing, and metabolic bone disease. The latter can present insidiously with osteopenia and osteoporosis, or with the more dramatic bone fracture or unpredictable osteonecrosis. When osteonecrosis occurs, it is almost always after high cumulative doses of steroids. This complication is not prevented by calcium and vitamin D supplementation and is not detected by dual energy X-ray absorptiometry scanning. The diagnosis is generally not suspected until a patient complains of specific joint pain, and it is then established by magnetic resonance imaging. The distribution of affected joints in IBD is similar to other conditions associated with osteonecrosis, with the hips being the most frequently involved (141).
Steroid-induced metabolic disturbances include hyperglycemia, sodium and fluid retention, hypokalemia, metabolic alkalosis, hyperlipidemia, and accelerated atherogenesis. Patients on chronic steroids are at risk of adrenal insufficiency if steroids are discontinued or tapered too rapidly, and therefore require steroid replacement at periods of increased stress, such as surgery (142).
Dual-energy X-ray absorptiometry bone testing should be considered in IBD patients with risk factors for osteoporosis such as smoking, low body mass, sedentary lifestyle, hypogonadism, family history, and nutritional deficiencies (143, 144). IBD patients at greatest risk for fracture are over age 60 and all these subjects should be considered for dual-energy X-ray absorptiometry testing. Patients using corticosteroids beyond 3 months consecutively or who are recurrent users should likewise be considered for dual-energy X-ray absorptiometry testing and even prevention with bisphosphonate therapy (143, 145, 146). Prospective implementation of these guidelines in IBD patients identified 44% of IBD patients with osteopenia and 12% with osteoporosis (147). Calcium supplementation 1,000–1,500 mg per day and vitamin D 800 U per day should be considered as well as estrogen replacement in the postmenopausal woman (148). In non-IBD populations, controlled trials have shown efficacy for alendronate (149), risedronate (150), etidronate (151), and teriparatide (152) in the prevention of glucocorticoid-induced osteoporosis. In IBD patients, clodronate (not yet available in the United States) has shown efficacy in preventing glucocorticoid-induced bone loss (153).
Modifiable risk factors, such as cigarette smoking, alcohol use, and a sedentary lifestyle, should be addressed. It is advisable to prescribe a bisphosphonate for IBD patients at a T score below − 2.5. For patients on long-term corticosteroids, or with other important risk factors such as previous fractures, it may be reasonable to prescribe a bisphosphonate at T scores below − 1.0 (146). However, referral to a specialist should be considered in view of the multiple variables to be assessed in patients with different risk factors, the choices of treatments available, and their potential adverse effects.
The use of steroids in IBD increases the risk of opportunistic infections about threefold: the risk is dose related and more common in those over the age of 50 (154). The risk for opportunistic infections is synergistically increased when steroids are used concomitantly with either the thiopurines or infliximab (154).
Infliximab, an intravenously administered monoclonal antibody to tumor necrosis factor-α, is effective in inducing response and remission and improving quality of life in patients with moderate to severe UC. The two largest randomized controlled trials of infliximab in UC, ACT 1 and ACT 2, studied 728 patients. In ACT 1, patients were enrolled if they had failed corticosteroids and/or thiopurines within the previous 18 months; whereas in ACT 2, patients could be enrolled if they had failed aminosalicylates without having failed previous corticosteroids and/or thiopurines (155).
Doses of 5 vs. 10 mg/ kg vs. placebo were studied for induction (and maintenance, see below) of response and remission, and were infused at weeks 0, 2, and 6 and then every 8 weeks through week 46 in ACT 1, and through week 22 in ACT 2. Both infliximab doses were more effective than placebo in inducing and maintaining response and remission. There was no difference in efficacy between the two doses. All of the patients in these trials were outpatients (for results of infliximab in severe UC, see below). Patients who fail to respond after the initial two doses are very unlikely to respond to a third dose. For patients who initially respond, but then begin to lose their response after a number of infusions, increasing the dose to 10 mg/kg, or shortening the interval between doses, may improve the likelihood of success (although this strategy was not studied in a controlled manner in the ACT 1 and 2 studies). Patients who do not respond to a dose as high as 10 mg/ kg as oft en as every 4 weeks should not be continued on the drug (156).
At present it is unknown whether the concomitant administration of a thiopurine enhances the efficacy of infliximab in UC. In CD, for which infliximab was approved by the US Food and Drug Administration 8 years earlier than for UC, concomitant use of thiopurines reduced the formation of antibodies to infliximab. In CD, regular dosing at 8-week (or shorter) intervals, as opposed to episodic dosing does, reduces the incidence of antibodies to infliximab, and has been associated with higher likelihood of response (157), and a lower incidence of infusion reactions (157, 158).
The infliximab infusion is administered over a 2 h period in a monitored setting, with personnel trained to treat severe infusion reactions (see next paragraph). Besides infusion reactions, the most common or troubling adverse effects of infliximab include autoimmunity and increased risks of infection, lymphoma, and possibly other malignancies; these concerns are described in more detail below. Other rare but serious adverse effects of infliximab include hepatotoxicity, development or exacerbation of multiple sclerosis or optic neuritis, and worsening of congestive heart failure in patients with preexisting cardiac disease (159).
As described above, the incidence of infusion reactions is decreased by regular 8-week dosing intervals and concomitant immunosuppressive treatment. In the ACT 1 and 2 studies, these reactions occurred in approximately 10% of patients, and were more frequent in patients with antibodies to infliximab (155). Even though adverse reactions to infliximab after a treatment hiatus are the exception rather than the rule, premedication with a corticosteroid and an antihistamine may still be prudent. Similarly, patients with previous mild–moderate infusion reactions should be premedicated with corticosteroids and an antihistamine (160). Most infusion reactions are mild–moderate and consist of flushing, headaches, dizziness, chest pain, cough, dyspnea, fevers, chills, and pruritus. For mild–moderate infusion reactions, slowing the infusion rate, or temporarily halting the infusion often relieves the reaction. Delayed hypersensitivity-like or serum sickness-like reactions occur in 1–2% of patients with CD (161, 162), most commonly in patients who have had a long hiatus between infusions. The clinical presentations may include myalgias, arthralgias, fevers, or rashes similar to the symptoms of a serum sickness-like disorder. These symptoms generally respond to a brief course of corticosteroids. Autoantibodies may occur in response to infliximab use. In the ACT 1 and 2 studies, antinuclear antibodies and anti-double-stranded DNA antibodies occurred in approximately 30% and 10% patients, respectively. Fortunately, the development of a lupus-like illness occurs in fewer than 1% of patients (163).
Infliximab increases the risk of infection of intracellular pathogens, most notably TB (164–167). Furthermore, extrapulmonary involvement may occur in more than 50% of cases, and disseminated disease in approximately one-third of patients. A detailed history should be taken with attention to potential risk factors for TB, and a careful physical examination for any evidence of pulmonary or extrapulmonary evidence of TB. Patients should be screened for latent TB with a skin test of standard purified protein derivative, and chest radiograph. Interpretation of the purified protein derivative may be confounded either because of previous vaccination with BCG or because many patients may have anergy due to concomitant immunosuppressive treatment. In these patients, especially those at high risk of latent TB, testing with QuantiFERON (Cellestis International, Melbourne, Victoria, Australia), a more sensitive and specific TB assay, should be considered (156). Patients with evidence of latent TB should be treated according to the recommendations of the American Thoracic Society (168, 169).
Patients treated with infliximab are also at increased risk for other opportunistic infections that require macrophages for intracellular killing. Serious infection occurred in approximately 3% of infliximab-treated patients in the ACT 1 and 2 trials. Additional information regarding risk of infection is available from the Therapy, Resource, Evaluation, and Assessment Tool registry, an ongoing observational infliximab safety registry in patients with CD, which contains approximately 6,000 patients with 16,000 years of patient follow-up, half of whom are treated with infliximab, and compared with an uncontrolled group treated without infliximab (170). Multivariate analysis of this registry indicates that increased rate of serious infection was not associated with infliximab use, but was associated with steroid use, narcotic use, and more severe disease activity. However, a meta-analysis of randomized controlled trials of antitumor necrosis factor treatment in rheumatoid arthritis found a twofold increased risk of serious infection, compared with rheumatoid arthritis patients treated with placebo (171). Furthermore, a case–control series from the Mayo Clinic found that IBD patients treated with infliximab had a significantly increased risk for opportunistic infections, especially when used in conjunction with either steroids or thiopurines or both (154). Similarly, analysis of post-marketing adverse event reported to the Food and Drug Administration indicated that serious infections occurred three times more often than expected (167, 172–174). Use of infliximab is also associated with reactivation of hepatitis B infection, so screening for hepatitis B should be undertaken before initiation with infliximab therapy (175) and vaccination should be considered in those patients at risk for hepatitis B infection (63).
The risk of malignancy in IBD patients treated with tumor necrosis factor-inhibitors remains unclear. An analysis of the Therapy, Resource, Evaluation, and Assessment Tool registry has not found an increased risk of malignancy, though the mean follow-up to date is only 2 years (170). However, multiple analyses indicate an increased risk of lymphoma (176). In rheumatoid arthritis, a meta-analysis found 10 patients with lymphoma in 3,500 infliximab-treated patients, compared to none in 1,500 control patients (171). Review of the Food and Drug Administration adverse event registry found that lymphomas were reported seven times more likely than would have been expected (172). Furthermore, a cluster of cases of a rare, particularly aggressive lymphoma, hepatosplenic T-cell lymphoma, has been reported in CD patients treated with concomitant azathioprine and infliximab (177–179). This particular lymphoma has only rarely been reported and some cases were associated with azathioprine monotherapy (180). It usually presents in younger male patients and has an almost universally fatal outcome.
Patients with decompensated heart failure should not be treated with infliximab because of the risk of further decline in cardiac function (181, 182). Rare reports of the development of optic neuritis and multiple sclerosis have led to the recommendation that infliximab is relatively contraindicated in patients with a history of these disorders (156).
Randomized controlled trials with a relatively small number of enrolled patients (183, 184) as well as uncontrolled trials (185, 186) of azathioprine in doses up to 1.5–2.5 mg/kg per day have shown its effectiveness in patients who do not respond to, or cannot be weaned from steroids (187). Their primary benefit is in the steroid-sparing effect, rather than as an agent to be used as monotherapy to induce remission. Its use in this setting is somewhat limited by its slow onset of action; up to 3–6 months of treatment may be necessary to appreciate an optimal effect (188, 189). However, its long-term use results in steroid sparing (190), fewer admissions to hospital, and fewer operations (191). In a prospective 2-year trial, the addition of olsalazine did not enhance the efficacy of azathioprine (192).
Azathioprine and 6-MP toxicities include bone marrow suppression, particularly leukopenia, which is usually dose dependent. Leukopenia most often occurs within the first weeks to months of use, so complete blood counts should be measured more frequently during this period, though late bone marrow suppression may occur (193). The risk of opportunistic infections is increased approximately threefold, and there is a further synergistic risk when thiopurines are used concomitantly with either steroids or infliximab (154). There is a greater tendency for serious infections in patients with lower absolute lymphocyte counts or leukopenia (154). The frequency of liver abnormalities varies between 2% and 17% of patients and depends largely on the definitions of liver abnormalities reported (194). The liver test abnormalities are usually reversible and generally occur soon after the initiation of thiopurine treatment. Although the thiopurine metabolite 6-methylmercaptopurine (6-MMP) has been associated with elevated transaminases (195), the sensitivity and specificity of 6MMP for hepatotoxicity are poor (196). Allergic reactions occur in approximately 2–5% of patients and usually present as some combination of fever, rash, myalgias, or arthralgias. Pancreatitis occurs as a hypersensitivity reaction in approximately 2% of patients (197), and will invariably reoccur if treatment with the alternative thiopurine is attempted. Conversely, patients with gastrointestinal intolerance to azathioprine not related to pancreatitis may tolerate 6-MP (198, 199). Long-term use of thiopurines has not been associated with increased risk of solid tumors (200–202).
6-Mercaptopurine, after it is generated from its prodrug, azathioprine, is metabolized by thiopurine methyltransferase (TPMT), an enzyme that exhibits variation as a result of a genetic polymorphism of its alleles and that can be measured by commercial laboratories. Approximately 0.3% (1 in 300) of the general population has low to absent enzyme activity, 11% have intermediate, and 89% have normal to high levels of activity (203). However, only about a quarter of cases of leukopenia in practice are associated with one of these genetic polymorphisms (204). Although TPMT testing cannot substitute for complete blood count monitoring in patients being started on thiopurines, TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Because the phenotype assay reports a quantitative level of the TPMT enzyme activity, it is preferred to the genotype assay. A TPMT assay is therefore recommended by many authorities before initiating thiopurine therapy, to identify the rare patient who is at risk of developing severe myelotoxicity (140).
A meta-analysis of the association between levels of the thiopurine metabolite 6-thioguanine nucleotide (6-TGN) and clinical remission rates (mostly in patients with CD) strongly suggested that higher levels of 6-TGN are associated with clinical remission rates (205). In addition, a retrospective study found that a subset of patients with 6-TGN levels of less than 235 pmol per 8×108 erythrocytes but with high 6-MMP levels may remain refractory to dose escalations of 6-MP/AZA, as they may preferentially metabolize 6-MP/AZA to 6-MMP and thus achieve suboptimal 6-TGN levels (206). Given the conflicting data, the retrospective nature of these studies, and the limited positive and negative predictive values for these particular uses, the utility of measuring metabolite levels needs prospective controlled evaluation before their routine use can be recommended as providing much incremental benefit to the traditional routine of monitoring the complete blood count, liver tests, and clinical response. However, these metabolite markers can be of value in assessing whether a patient is noncompliant or preferentially metabolizes the drug to 6-MMP instead of 6-TGN (206). Leukopenia was observed in only 8% of responders, indicating that it is not a necessary condition for effective dosing (195), though it may still be useful as an indication that maximal dosage has been achieved before abandoning the drug as a failure.
Methotrexate has not been proven to be effective in UC when administered in a weekly dose of 12.5 mg per day (207); neither higher doses nor administration by a parenteral route has been studied in controlled trials.
Recommendations for Mild-Moderate Extensive Colitis: Maintenance of Remission
Once the acute attack is controlled, a maintenance regimen is usually required, especially in patients with extensive or relapsing disease. Sulfasalazine, olsalazine, mesalamine, and balsalazide are all effective in reducing relapses (Evidence A). Patients should not be treated chronically with steroids. Azathioprine or 6-MP may be useful as steroid-sparing agents for steroid-dependent patients and for maintenance of remission not adequately sustained by aminosalicylates, and occasionally for patients who are steroid dependent but not acutely ill (Evidence A). Infliximab is effective in maintaining improvement and remission in the patients responding to the infliximab induction regimen (Evidence A).
Sulfasalazine reduces relapse rates in UC in a dose-related manner, with benefits showed at 2–4 g per day (85, 208, 209). Although the 4 g per day regimen is the most effective in preventing relapse, up to one quarter of patients cannot tolerate the side effects at this dose, which limits its overall utility (208). The newer aminosalicylate preparations—including olsalazine (210, 211), mesalamine (212–218), balsalazide (98), granulated extended release mesalamine capsules (128), and multimatrix-mesalamine (though the latter has not yet been studied in a placebo-controlled trial) (95, 219) have relapse-prevention properties virtually the same as, but not greater than, those of equivalent doses of sulfasalazine (80, 220). Because of the well-documented efficacy of sulfasalazine in the prevention of relapse, most (212, 214–218, 221–225 ) but not all (226) 5-ASA relapse-prevention trials have used sulfasalazine as the control. As with sulfasalazine, most (225, 227, 228) but not all (229, 230) comparison studies of mesalamine have shown increased efficacy with higher doses up to 4 g per day of 5-ASA. However, unlike sulfasalazine, larger doses of 5-ASA in the newer preparations are generally well tolerated, lending these analogues an advantage over sulfasalazine for the prevention of relapse. However, the cost of sulfasalazine, especially when considered for long-term use, is considerably lower. Although the maximum length of remission-maintenance benefit has not been established, most experts recommend permanent maintenance; however, the patient with a mild first episode, or with very infrequent mild relapses that are easily controlled, may opt for being followed without long-term medical maintenance therapy.
The immunomodulators, azathioprine and 6-MP, have been studied for the prevention of relapse prevention. Azathioprine has been found effective in maintaining remission in controlled and uncontrolled drug withdrawal studies (231, 232) and in a meta-analysis of seven placebo-controlled maintenance trials (233). Retrospective studies have shown the value of 6-MP and azathioprine in maintaining long-term remission (200, 234), and it is generally well tolerated during long-term use (197, 200, 201, 234). As with induction of remission in UC, there have been no studies comparing 6-MP with azathioprine. A systematic review (235) and meta-analysis (236) concluded that azathioprine is a modestly effective (236) maintenance therapy for patients who have failed or cannot tolerate mesalamine or sulfasalazine, and for patients who require repeated courses of steroids and this benefit should be considered in the context of the potential for adverse events from the thiopurines (235). Similarly, uncontrolled retrospective data from 105 patients treated with continued long-term 6-MP (234), from 351 patients treated with long-term azathioprine (200) in the United States, and from 298 patients treated with azathioprine in multiple centers in Europe (186) appear to confirm the efficacy of these agents continued long-term in maintaining remissions of UC (237).
The risk-benefit ratio of indefinite azathioprine or 6-MP use for the maintenance of remission, especially when compared with colectomy, is not known. However, experience with the thiopurines over the last four decades indicates that there is not an increased risk of the development of solid tumors (as discussed above) (201) or overall mortality (200, 238). Conversely, a recent meta-analysis of six cohort studies calculated a fourfold increased risk of lymphoma among IBD patients treated with thiopurines, but it remains unclear whether this risk was due to the medications themselves or due to the underlying disease (176, 180, 239).
In the double-blind, placebo-controlled ACT 1 and ACT 2 studies (155), infliximab administered every 8 weeks was effective in maintaining response and remission at week 30 (53% and 32%, respectively), and week 54 (45% and 42%, respectively) in those patients with an initial response or remission at week 8 (after three infusions of 5 or 10 mg/kg at weeks 0, 2, and 6). There was no benefit to initial treatment with the higher dose. Although not studied in a controlled manner in these trials, some patients with an initial response to 5 mg/kg in whom the benefit is attenuated after multiple doses may benefit from dose escalation, or shortening dosing intervals, or both. Similar response and remission rates were seen whether patients had been steroid refractory or steroid naive. However, the success rate in maintaining a steroid-free remission at week 54 was only 21%. These studies did not prospectively address whether concomitant thiopurine therapy would inflence clinical success rates.
Recommendations for Management of Severe Colitis
The patient with severe colitis refractory to maximal oral treatment with prednisone, oral aminosalicylate drugs, and topical medications may be treated with infliximab 5 mg/kg if urgent hospitalization is not necessary (Evidence A). The patient who presents with toxicity should be admitted to hospital for a course of intravenous steroids (Evidence C). Failure to show significant improvement within 3–5 days is an indication for either colectomy (Evidence B) or treatment with intravenous cyclosporine (CSA; Evidence A) in the patient with severe colitis. Long-term remission in these patients is significantly enhanced with the addition of maintenance 6-MP (Evidence B). Infliximab may also be effective in avoiding colectomy in patients failing intravenous steroids but its long-term efficacy is unknown in this setting (Evidence A).
Infliximab 5 mg/kg is indicated for the patient who may not require immediate hospitalization but who continues to have severe symptoms despite optimal doses of oral steroids (40–60 mg daily of prednisone), oral aminosalicylates (4–6 g sulfasalazine, 4.8 g mesalamine or 6.75 g balsalazide), and topical medications (155). The mainstay of therapy for those patients requiring hospitalization at this point is an intravenous steroid in a daily dose equivalent to 300 mg hydrocortisone or 60 mg methylprednisolone if the patient has received steroids in the previous month. There is no benefit to treatment with a much higher daily dose of steroids, which exposes the patient to a higher potential rate of side effects (240).
In the absence of any proven infection, controlled trials of antibiotics have showed no therapeutic benefit from the use of oral vancomycin (241), intravenous metronidazole (242), or ciprofloxacin (243), when added to intravenous steroids. However, protocols outlining treatment regimens for severe colitis generally include broad-spectrum antibiotics for patients with signs of toxicity, or with worsening symptoms despite maximal medical therapy (244–246).
Controlled studies of the impact of total parenteral nutrition show no benefit from this maneuver as a primary therapy for UC (247, 248). In fact, it may even be detrimental by depriving the colonic enterocytes of the short-chain fatty acids vital to their metabolism and repair (249). However, total parenteral nutrition may be useful as a nutritional adjunct in patients with significant nutritional depletion (250).
There are no studies to show that an oral aminosalicylate is of clinical benefit in this setting, so it is generally withheld if the patient is nil per os, but it may be continued if the patient is eating and has been tolerating this drug. Likewise, no controlled studies have confirmed any incremental benefit of topical medications in this setting, but they are still often prescribed if they can be retained and tolerated. Because the failure rate of medical therapy with intravenous steroids in patients admitted to hospital for severe colitis is approximately 20–40% (251), these patients should be followed closely in conjunction with a surgeon experienced in the management of patients with IBD.
Superimposed infection with enteric pathogens and C. difficile should be ruled out. The incidence of C. difficile in hospitalized patients with UC is rising dramatically. This infection results in higher costs, longer length of stay, and increased morbidity and mortality (20–22, 24, 252), and it is more refractory to treatment in patients on immunosuppressive drugs (253). A recent prospective study of hospitalized patients (without IBD) showed a high failure rate with metronidazole treatment for C. difficile in patients who had been recently treated with cephalosporins, in those who were positive for C. difficile on admission, and in those transferred from another hospital. In such cases, therefore, vancomycin should be considered as the preferred initial antibiotic (254).
Cytomegalovirus superinfection may also occur in the setting of severe colitis and should therefore be considered in any patient who is not responding to maximal immunosuppressive therapy. Cytomegalovirus superinfection can be diagnosed with sigmoidoscopic biopsy and viral culture; treatment with gancyclovir may lead to clinical improvement (255, 256). The frequency with which cytomegalovirus has been reported in the setting of severe colitis depends in large part on the sensitivity of the method chosen to detect cytomegalovirus (19, 257–259).
Patients may present with a megacolon with or without toxicity. The absolute dimension to define a “megacolon” has been variably defined and may be considered as total or segmental nonobstructive dilation to >=6 cm. Hypokalemia or hypomagnesemia, which can exacerbate dilation, should be aggressively corrected (260, 261). In patients with either toxic signs (fever, leukocytosis, or worsening symptoms) or megacolon, medications with anticholinergic or narcotic properties should be avoided for possibility of worsening colonic atony or dilatation, as increased colonic and small intestinal gas is a predictor of a poor outcome to medical therapy (262–265).
Enhanced vigilance must be maintained for an additional, potentially lethal complication; namely, venous thromboembolism, which occurs approximately twice as frequently in hospitalized UC patients compared with hospitalized controls. Although heparin no longer warrants consideration as primary therapy for UC (266), it has an important role in prophylaxis against thromboembolism in patients admitted to hospital with severe colitis ( 267 ). For the patient with a series of thrombotic or embolic events during a course of severe colitis, emergent colectomy may be lifesaving in preventing additional, potentially fatal thrombi.
Patients with severe colitis who do not improve significantly after 3–5 days (268, 269) of maximal medical therapy are unlikely to benefit from prolongation of this medical treatment (246, 270) and should either be referred for surgery (see below) or considered for treatment with intravenous CSA or perhaps infliximab. In one placebo-controlled double-blind trial, 82% of patients with steroid-refractory severe colitis treated with intravenous CSA with a dose of 4 mg/kg per day experienced improvement and were able to avoid colectomy in the acute stage (271). These results in the acute phase are consistent with multiple open-label series (272–274). Additional randomized controlled trials showed similar efficacy with an intravenous CSA dose of 2 mg/ kg per day (275), and CSA 2 mg/kg per day was as effective as hydrocortisone intravenously (276). Predictive factors for failure to respond to CSA include persistent fevers, tachycardia, elevated C-reactive protein, hypoalbuminemia, and deep colonic ulcerations (277, 278).
Patients with fulminant colitis are treated similarly but decisions regarding surgery vs. CSA or infliximab should be taken within a few days of initiating intravenous steroid therapy (279). No randomized controlled trials have been performed studying the addition of azathioprine or 6-MP to CSA. Retrospective series with long-term follow-up of up to 14 years (274, 280) indicate a significantly higher long-term success rate when azathioprine or 6-MP was used during the oral CSA phase (272, 275, 276, 280, 281) although the ideal dose or time to add 6-MP or azathioprine has not been studied. However, even in those patients in whom CSA is effective in combination with a thiopurine, the long-term success rate in avoiding relapse and colectomy is substantially lower in those patients who had already been treated (ineffectively) before initiating cyclosporin use. In the largest series to date, 83% of 113 patients had an initial response to CSA and avoided colectomy during the hospital stay. However, during continued follow-up, 54% of the initial patients initially responding to CSA required a future colectomy with the mean time to colectomy at 5 years. The rate of colectomy in those already on azathioprine compared with those starting azathioprine concurrently with CSA was 59% vs. 31%, respectively. Life-table analysis showed that although only 33% of patients required colectomy at 1 year, 88% required colectomy at 7 years (274).
Significant toxicity may occur with CSA use in UC. Severe adverse events include nephrotoxicity, infection, and seizures (particularly in patients with associated hypocholesterolemia or hypomagnesemia). More common but less severe side effects include paresthesias, hypertension, hypertrichosis, headache, abnormal liver function tests, hyperkalemia, and gingival hyperplasia (282). During intervals of triple immunosuppression with steroids, CSA, and a thiopurine, many experts treat patients with prophylaxis against Pneumocystis jiroveci (carinii), such as trimethoprim/sulfamethoxazole or dapsone. Most authors have found that CSA does not increase the rate of postoperative complications in patients undergoing proctocolectomy (281, 283), in contrast to the preoperative use of corticosteroids in patients with IBD that substantially increases the risk of postoperative infections (284).
Tacrolimus, like CSA, is a calcineurin inhibitor, and has been studied in a single randomized controlled trial (285) as well as in several open-label series (286–288). In a 2-week placebo-controlled trial in moderate–severe UC, patients treated with tacrolimus doses targeted to trough levels of 5–15 ng/ml were more likely than placebo-treated patients to achieve clinical response, though not remission (285). However, at present the available data for tacrolimus are insufficient to guide optimal dosing, duration of acute and maintenance treatment, or follow-up intervals. Furthermore, the need for concomitant thiopurine therapy and benefits in achieving long-term, steroid-free remission and avoiding colectomy are not well defined for tacrolimus (289).
There are limited controlled trial data regarding the role of infliximab in patients with severe or fulminant UC refractory to intravenous steroids. In one double-blind series of 45 patients, patients with either fulminant colitis at day 3, or severe colitis at days 6–8, despite continued intravenous steroids, were randomized to either a single dose of infliximab 5 mg/kg or placebo (290). At day 90, 29% of infliximab-treated patients had undergone colectomy, compared to 67% of placebo-treated patients. In patients with fulminant colitis, 47% of infliximab-treated patients underwent colectomy, compared to 69% of placebo-treated patients. In a smaller randomized controlled trial of patients failing intravenous steroids, four of eight patients treated with infliximab responded clinically 2 weeks after a single dose of infliximab, whereas none of three placebo-treated patients responded (291). Comparable results were achieved in open-label series (292) in the short term but at 5 years approximately half of infliximab-treated patients required colectomy (293–295).
There are no controlled or uncontrolled trials directly comparing CSA to infliximab in patients with severe steroid-refractory UC. However, in a series of 19 patients who failed one therapy, and were then treated with the alternative drug within 30 days, only approximately 30% of patients had avoided colectomy and remained in a steroid-free remission at 12 months; 2 patients developed septicemia, and 1 died during the 30-day interval of receiving both the drugs (296). There is conflicting evidence as to whether infliximab increases the risk of postoperative complications. Most (297–300), but not all (301) series found no increased risk of postoperative complications after infliximab treatment: in the latter series, although there was no increased risk of overall surgical morbidity in patients treated with perioperative infliximab, a multivariate analysis found that these patients did have a higher incidence of postoperative infectious complications albeit without correction for concomitant medications or immediate preoperative duration or severity of the attack (301).
Patients with fulminant colitis or toxic megacolon should be treated as above; in addition they should be kept nil per os, have a small bowel decompression tube if a small bowel ileus is present, and instructed to rotate frequently into the prone or knee-elbow (302 position to aid in evacuation of bowel gas. Broad-spectrum antibiotics are usually used empirically in these patients. The duration of medical treatment of megacolon is controversial; some experts advocate surgery within 72 h if no significant improvement is noted (303, 304), whereas others take a more watchful stance if no toxic symptoms are present (302). All agree, however, that any clinical, laboratory, or radiologic deterioration on medical therapy mandates immediate colectomy.
Recommendations for Surgery
Absolute indications for surgery are exsanguinating hemorrhage, perforation, and documented or strongly suspected carcinoma (Evidence C). Other indications for surgery are severe colitis with or without toxic megacolon unresponsive to conventional maximal medical therapy, and less severe but medically intractable symptoms or intolerable medication side effects (Evidence C).
There are no prospective randomized trials comparing medical treatment to surgery for any indication in UC, but three situations are absolute indications for surgery because continued medical therapy is doomed to failure and potentially fatal: exsanguinating hemorrhage, frank perforation, and documented or strongly suspected carcinoma; i.e., high-grade dysplasia (HGD) or perhaps low-grade dysplasia (LGD) in flat mucosa (see section “Recommendations for Cancer Surveillance”).
Massive hemorrhage in UC is due to diffuse mucosal ulceration. If the hemorrhage is exsanguinating or even persisting despite maximal medical therapy (see above), it is an indication for emergency surgery. Subtotal colectomy with preservation of the rectum for a future restorative procedure is recommended in this situation (305–307) so long as the small risk of further hemorrhage is appreciated and appropriately monitored. Another indication for emergency surgery is severe colitis or toxic megacolon unresponsive to maximal intravenous medical therapy (see above). It is essential to recognize, however, that perforation can occur without being preceded by megacolon.
Although the clinical scenarios described above provide absolute indications for surgery, the most common indication is persistence of chronic refractory symptoms despite maximal medical therapy, resulting in physical debility, psychosocial dysfunction, or intolerable medication side effects.
Only rarely is surgery necessary to control the EIMs of UC (308, 309). Previously, patients with severe progressive pyoderma gangrenosum, in whom the pyoderma activity paralleled the activity of the colitis, required surgery (310); however, infliximab (311–313) has been found effective in healing pyoderma gangrenosum, and should therefore be tried before resorting to surgery for this indication. By contrast, the course of PSC is independent of the activity of the colitis and is not affected by colectomy (314–317).
Whatever the indication for surgery, patients should be informed of the different options available. These include a total proctocolectomy with permanent ileostomy, or the ileal pouch-anal anastomosis (IPAA) procedure. The patient should be aware of the risks and benefits of these operations within different clinical settings. The option of a total proctocolectomy with a continent ileostomy (Koch pouch) is rarely used because of the frequency of pouch outlet obstruction over time. A subtotal colectomy with an ileorectal anstomosis is rarely advisable as it leaves the potential for disease recurrence and/or cancer risk in the retained rectal segment. IPAA has become the most commonly performed operation for UC, and is performed in 1, 2, or 3 stages, depending on the patient’s clinical status at the time of surgery and the judgment and experience of the surgeon. In general, most series report an improvement in quality of life compared to the patients’ preoperative status (318). Nevertheless, there is increasing recognition of the potential complications following IPAA (319). Besides pouchitis (see below), which may occur in up to 50% of patients during long-term follow-up, a variety of surgical complications may ensue (320). A meta-analysis of 17 series of nearly 1,500 patients undergoing IPAA found that when this surgery was performed without a diverting ileostomy, functional outcomes were similar to those of surgery with proximal diversion but there was an increased risk of anastomotic leak. Notably, 30% of these patients undergoing IPAA required reoperation for postoperative complications including anastomotic leak, pelvic sepsis/abscess, anastomotic stricture, and bowel obstruction; the time intervals during which reoperations for complications were performed were not specified (321). A large database analysis of privately insured UC patients undergoing IPAA found a 20% rate of postoperative complications resulting in an unexpected reoperation. The most frequent early complications (defined as within 30 days of surgery) were abscess (12%), sepsis (8%), and fistula (4%). An additional 11% of IPAA patients required reoperation for complications of abscess and stricture, respectively, between 30 and 180 days after surgery (322). An additional sobering observation was that a 10-year (1995 – 2005) survey of 7,100 patients undergoing surgery for UC found a mortality and morbidity of 2% and 31%, respectively. Furthermore, there were higher mortality rates in hospitals with low-volume experience with IBD patients (323). For patients undergoing colectomy, mortality in hospitals performing low volumes of colectomies was increased twofold compared with high-volume hospitals. Increased mortality was also found in patients who were admitted emergently, aged over 60 years, or insured by Medicaid (324).
In addition to the risks described above, patients should be counseled regarding the effects of the IPAA on fertility and sexual function. A meta-analysis of eight series found a threefold increase in infertility in women after IPAA, compared with women with UC treated medically (though there was no control for the extent of disease severity in patients treated medically) (325). Fecundity among women with UC before surgery is comparable to a control population of women without UC, but is only 20% of fecundity rates of controls after IPAA (326). Approximately 20% of women will have dyspareunia or fecal incontinence during intercourse during a 3-year follow-up after IPAA (320). A meta-analysis of 43 observational studies found a 4% risk of sexual dysfunction in men postoperatively (320). However, most men note improvement in overall sexual quality of life after IPAA, likely due to improvement in general health (327).
Recommendations for the Management of Pouchitis
Patients who develop typical symptoms and signs of pouchitis after the IPAA should be treated with a short course of antibiotics (Evidence A). Controlled trial studies show efficacy for metronidazole in a dose of 400 mg three times daily, or 20 mg/kg daily, or ciprofloxacin 500 mg twice daily (Evidence A). Other etiologies mimicking pouchitis include irritable pouch syndrome, cuffitis, CD of the pouch, and postoperative complications such as anastomotic leak or stricture. Inadequate evidence exists to recommend routine surveillance of the pouch for dysplasia or adenocarcinoma (Evidence C).
Patients who undergo the IPAA procedure may develop an idiopathic inflammation termed “pouchitis,” which typically presents with variable symptoms of increased stool frequency, rectal bleeding, abdominal cramping, rectal urgency, tenesmus, incontinence, fevers, and the appearance of EIMs (328, 329). The diagnosis is suggested based on clinical symptoms but needs to be confirmed with the characteristic endoscopic and histologic features (330, 331). Symptoms do not always correlate with endoscopic and histologic findings (332). Demonstrating the diagnosis with pouchoscopy as opposed to empiric treatment with metronidazole may be the more cost-effective strategy (333). Pouchitis occurs in up to 60% of patients after a mean follow-up of 40 months (334, 335) and occurs more frequently in patients with PSC, preoperative EIMs (336–338), and in patients who had never smoked (339). Chronic pouchitis may be more likely to occur in those patients with early postoperative anastomotic complications (340).
Only rarely does refractory or recurrent pouchitis occur because of the missed diagnosis of CD (341), which may occur more commonly in patients with a family history of CD or preoperative antisaccharomyces cerevisiae antibody seropositivity (342). CD of the pouch should be suspected if a de novo fistula develops 6–12 months after ileostomy takedown in the absence of postoperative leak, abscess, or sepsis. Endoscopically, CD of the pouch shows ulcers and/or strictures in the afferent limb or in other areas of the small bowel, in the absence of nonsteroidal anti-inflammatory drug use. In CD of the pouch, pelvic magnetic resonance imaging may reveal sinus tracts, fistulae, and leaks and abscesses outside the cuff (343). Pouch excision, or revision in expert hands (344), is required as a result of intractable pouch complications in fewer than 5% of patients in most series.
Some patients with episodes of increased stool frequency and cramping, but with normal endoscopic and histologic findings in the pouch may be experiencing “irritable pouch” symptoms and may respond to anticholinergics, antidepressants, and antidiarrheals (343, 345). Other patients may have inflammation limited to a short cuff of retained rectal mucosa (“cuffitis”) and may respond to topical hydrocortisone or mesalamine (346). C. difficile infection should be considered in cases of recurrent or refractory pouchitis, as it may occur in as many as 20% of these patients, who may then benefit from eradication of C. difficile. In patients using chronic nonsteroidal anti-inflammatory drugs, chronic pouchitis may resolve on cessation of the nonsteroidal anti-inflammatory drugs (343).
Controlled drug trials for the treatment of pouchitis are very limited (329, 347–350). Metronidazole in a dose of 400 mg three times daily (349) or 20 mg/kg per day (347) is effective in the treatment of chronic active pouchitis; in clinical practice, metronidazole in a dose of 250 mg three times daily is often used (329, 349). Controlled trials showed at least similar efficacy with ciprofloxacin 500 mg twice daily (347), or with budesonide enema 2 g daily (not available in the United States) (350). Many uncontrolled trials show similar results with metronidazole and other antibiotics (334, 351, 352) as well as with oral and topical mesalamine and steroids. An oral probiotic formulation VSL-3 (containing lactobacilli, bifidobacteria, and Streptococcus salivarius) was effective in the prevention of pouchitis for up to 1 year after surgery (353) and in the prevention of pouchitis relapse (354), although benefit has not been as consistently seen in open-label use in other centers (355).
In a surveillance program of 106 high-risk patients, only 1 patient had multifocal LGD, and no adenocarcinoma was found (356). Nonetheless, adenocarcinoma remains a risk after IPAA as the duration of follow-up increases. A recent review of 26 cases of adenocarcinoma developing after IPAA found that carcinoma can occur after either mucosectomy or stapled anastomosis, even in patients without dysplasia or cancer before colectomy, as well as in patients whose preoperative dysplasia was not located in or near the rectum (360).
Recommendations for Cancer Surveillance
Patients with UC are at increased risk for colorectal cancer (CRC); the degree of risk is related to the duration and anatomic extent of colitis and also to the degree of microscopic inflammation over time (58, 59, 361–368). After 10 years of universal disease, the cancer risk has been widely reported in the range of 0.5–1% per year (361, 363–367). However, a recent nationwide population-based analysis from the Netherlands found that 20% of all UC-related cancers were detected before 8 years of disease had elapsed (369). Even patients with left-sided colitis reach similar levels of cumulative cancer risk after 3–4 decades of disease (361, 363, 370, 371); patients with proctitis or proctosigmoiditis do not appear to be at increased cancer risk. Although some data suggest a later onset of cancer risk in left -sided than in more extensive colitis (361), this evidence is not sufficiently strong to justify different guidelines for surveillance in the two groups (372).
Compared with noncolitis-associated CRC, colitis-associated cancers are more often multiple, broadly infiltrating, anaplastic, and uniformly distributed throughout the colon, and seem to arise from flat mucosa instead of following the usual adenoma–cancer sequence (363). However, lesions that may previously have been interpreted as “flat” may now may be more readily visible with newer, widely available colonoscopes with improved optics, or with the use of chromoendoscopy (described below). Furthermore, colitis-associated CRC often occurs in a much younger patient population than does CRC in the general population (361, 363–367, 369, 371, 372).
Determination of anatomic extent in assessing cancer risk has historically been based on macroscopic rather than histologic inflammation. On the other hand, both macroscopic and microscopic healing may occur, but once extensive colitis is documented, the cancer risk should be assumed to correlate with the greatest previously determined extent. Furthermore, areas of microscopic inflammation, without history of macroscopic inflammation may also harbor the risk of neoplasia proximal to known macroscopic disease (58, 367, 373).
Most groups have found that patients with PSC complicating UC have an increased risk of CRC (362, 374–377). Whether this observation reflects a true biologic phenomenon or a statistical artifact of longer than appreciated colitis duration, it is prudent to start colonoscopic surveillance as soon as the coexisting diagnoses of UC and PSC are established. In addition, ursodeoxycholic acid in daily divided doses of 13–15 mg/kg should be considered, because a prospective randomized, placebo-controlled trial found that this strategy significantly reduced the risk for developing colorectal neoplasia in these patients (378). UC patients with a family history of CRC have a fivefold risk of cancer compared with matched controls (379).
However, the risk of CRC and dysplasia may be reduced with the use of mesalamine. A meta-analysis of six case–control (58, 380–384) and three cohort studies (385–387) that included 334 cases of CRC and 140 cases of dysplasia among 1,932 patients suggested a chemopreventive effect of mesalamine with a 50% risk reduction of CRC and dysplasia (388). Additional series reported since this meta-analysis (362, 389) have not shown the same chemopreventive effect of mesalamine. However comparison of the different series is confounded by failure to control consistently for risk factors including disease duration, family history of CRC, presence of PSC, patient adherence, daily and cumulative mesalamine dose, and degree and duration of colonic inflammation.
The degree of histologic inflammation is an important variable to consider and control risk reduction of dysplasia and CRC in UC. In a case–control series from a surveillance database of 600 patients, Rutter et al. (58) found in a univariate analysis that both increased microscopic and macroscopic inflammation increased CRC and dysplasia risk, whereas in a multivariate analysis microscopic inflammation increased CRC and dysplasia risk fivefold. Similarly, a cohort study from a surveillance database of 400 patients found that an increase in microscopic inflammation increased the risk of CRC threefold (59). Several studies have shown that most dysplasia is visible at colonoscopy: in approximately three quarters of cases of confirmed dysplasia, the endoscopist had noted an abnormality during the procedure (390–392). Endoscopic features that have been predictive of greater likelihood of presence of dysplasia include the presence of pseudopolyps (393, 394) and colonic strictures (393, 395, 396). Although pseudopolyps per se are not premalignant, they indicate a higher degree of previous colonic inflammation. In the presence of countless pseudopolyps, which are too numerous to biopsy or which obscure substantial areas of mucosa, an adequate surveillance examination may be impossible. Patients should be informed of the reduced reliability of colonoscopic surveillance in this situation.
Simply stated, the goals of any cancer surveillance program in UC are to prevent cancer and to save lives. There are no randomized prospective studies comparing different surveillance protocols or, for that matter, even surveillance vs. no surveillance. Nonetheless, at present, the best practical recommendation for patients who are candidates for surgery, based on review of dysplasia surveillance series, calls for annual or biannual colonoscopy. A recent Cochrane analysis concluded that for patients undergoing surveillance, cancers tend to be detected at an earlier stage and hence have a better prognosis. However, lead-time bias could contribute substantially to this apparent benefit. In addition, there appears to be indirect evidence that surveillance is likely to be effective in reducing the risk of death from IBD-associated CRC and that it may be acceptably cost-effective (404).
Examination every second year as opposed to annually would reduce costs, particularly in patients with longer disease duration, but at the expense of reducing likelihood of early cancer detection (405), as in some (365, 406), but not all (367) series annual hazard rates increased with longer disease duration. Whatever schedule might be theoretically most advisable, being both frankly informative and programmatically flexible with patients is important in gaining adherence. The cost of such a surveillance program for each successful detection of precancer or cancer compares favorably with the cost of population-wide screening by flexible sigmoidoscopy for all subjects at average risk for CRC (407–409) as well as with the cost of other widely accepted screening programs such as mammography (410) and Pap smears (411). Patients with long-standing UC may also be offered the option of a prophylactic total proctocolectomy, but patients in remission rarely opt for this approach.
The standardization of “high-grade” and “low-grade” dysplasia published by the Inflammatory Bowel Disease—Dysplasia Morphology Group (IBD-DMG) has been widely adopted and has served to make the diagnosis of dysplasia more stringent and more consistent (412). When colon cancer is identified, the need for surgery is obvious; similarly, the colonoscopic biopsy diagnosis of dysplasia in flat mucosa is often indicative of a concurrent or future cancer. Such findings are an absolute indication for colectomy in patients with HGD (413, 414), and should prompt consideration of colectomy in patients with LGD as well. LGD in a mass lesion (415) that does not resemble a typical sporadic adenoma and cannot be resected endoscopically (see below), or a stricture that is symptomatic or not passable during colonoscopy (393, 395, 396), especially in long-standing disease, is often indicative of coexistent colon cancer; hence, colectomy is advisable. LGD in fl at mucosa (i.e., when no raised lesion is visible endoscopically) may also be an indication for colectomy, as the 5-year predictive value of LGD for either cancer or HGD has been reported as high as 54% (416–418). In fact, a meta-analysis of 20 surveillance series found that among patients with LGD who underwent colectomy within 6 months, 26% of patients had a concurrent cancer, and an additional 12% of patients were found to have HGD. Furthermore, the detection of LGD on surveillance was associated with a 9-fold risk of developing cancer and a 12-fold risk of developing any advanced lesion (cancer or HGD) over a mean of 5.2 years (419). Patients not undergoing colectomy should be counseled regarding these risks, and undergo surveillance at a more frequent surveillance schedule.
A number of series have addressed an approach to management of patients with long-standing UC who are found to have a polypoid or adenomatous mass within a colitic area (420–425). If the lesion is resected in its entirety by colonoscopic polypectomy and if no dysplasia is found in the adjacent flat mucosa or anywhere else in the colon, long-term follow-up has not found an increased risk of cancer in these cases, suggesting that vigilant follow-up surveillance colonoscopy may suffice (420–425). Polyps with a plaque or carpet-like morphology that could not be endoscopically resected in their entirety were excluded from these studies; such cases should be referred for surgery. From a practical perspective, therefore, it matters little whether a mass lesion is called an adenomalike mass, or a dysplasia-associated lesion or mass; the important issue is to determine whether the lesion is completely resectable endoscopically and the rest of the colon is free of dysplasia.
Guidelines for the patient found to have LGD or HGD are discussed above. It is essential to obtain corroborating pathologic review to confirm the unequivocal distinction between definite neoplastic dysplasia and regenerative atypia due to inflammation and repair (426). However, attempts to repeatedly show dysplasia on subsequent examinations before recommending colectomy should not be undertaken without the awareness of the high risk of concomitant or subsequent advanced neoplasia by both patient and physician. Conversely, the patient whose biopsies are interpreted as “indefinite” for dysplasia should have the slides reviewed by an expert gastrointestinal pathologist and should undergo repeat surveillance colonoscopy at a briefer interval (412), because these patients may have an elevated risk of subsequent progression to definite dysplasia (389).
We acknowledge the invaluable assistance of Seamus J Murphy in the preparation of this paper, particularly his help in assembling, collating, and editing the extensive bibliography.
Conflict of Interest
Specific author contributions: Primary research and analysis, authorship, and final editing of the paper: Asher Kornbluth.
Financial support: This work was supported by Salix Pharmaceutical, Proctor and Gamble Pharmaceutical, and Centocor Inc.
Potential competing interests: Asher Kornbluth is a consultant for Salix Pharmaceutical, Shire Pharmaceutical, Proctor and Gamble Pharmaceutical, Centocor, and Prometheus Laboratory. He is also on the Speaker’s Bureau of Salix Pharmaceutical, Shire Pharmaceutical, Proctor and Gamble Pharmaceutical, Centocor, Prometheus, and Axcan Pharmaceutical.
- 1. Kornbluth AA, Salomon P, Sacks HS et al. Meta-analysis of the effectiveness of current drug therapy of ulcerative colitis. J Clin Gastroenterol 1993;16:215–8.
- 2. Meyers S, Janowitz HD. The “natural history” of ulcerative colitis: an analysis of the placebo response. J Clin Gastroenterol 1989;11:33–7.
- 3. Loftus EV Jr, Silverstein MD, Sandborn WJ et al. Ulcerative colitis in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gut 2000;46:336–43.
- 4. Intestinal diseases. In: The Burden of Gastrointestinal Disease. American Gastroenterology Association: Bethesda, MD, 2001, pp. 30–5.
- 5. Kappelman MD, Rifas-Shiman SL, Kleinman K et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol 2007; 5: 1424–9.
- 6. Loftus CG, Loftus EV Jr, Harmsen WS et al. Update on the incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota, 1940–2000. Inflamm Bowel Dis 2007;13:254–61.
- 7. Herrinton LJ, Liu L, Lewis JD et al. Incidence and prevalence of inflammatory bowel disease in a Northern California managed care organization, 1996–2002. Am J Gastroenterol 2008;103:1998–2006.
- 8. Herrinton LJ, Liu L, Lafata JE et al. Estimation of the period prevalence of inflammatory bowel disease among nine health plans using computerized diagnoses and outpatient pharmacy dispensings. Inflamm Bowel Dis 2007;13:451–61.
- 9. Sonnenberg A, Chang J. Time trends of physician visits for Crohn’s disease and ulcerative colitis in the United States, 1960 – 2006. Inflamm Bowel Dis 2008;14:249–52.
- 10. Nguyen GC, Tuskey A, Dassopoulos T et al. Rising hospitalization rates for inflammatory bowel disease in the United States between 1998 and 2004. Inflamm Bowel Dis 2007;13:1529–35.
- 11. Kappelman MD, Rifas-Shiman SL, Porter C et al. Direct health care costs of Crohn’s disease and ulcerative colitis in US children and adults. Gastroenterology 2008;135:1907–13.
- 12. Sachar DB. What is the role for endoscopy in inflammatory bowel disease? Am J Gastroenterol 2007;102(S1):S29–31.
- 13. Tremaine WJ, Sandborn WJ, Loftus EV et al. A prospective cohort study of practice guidelines in inflammatory bowel disease. Am J Gastroenterol 2001;96:2401–6.
- 14. Reddy D, Siegel CA, Sands BE et al. Possible association between isotretinoin and inflammatory bowel disease. Am J Gastroenterol 2006;101:1569–73.
- 15. Shale M, Kaplan GG, Panaccione R et al. Isotretinoin and intestinal inflammation: what gastroenterologists need to know. Gut 2009;58:737–41.
- 16. Bernstein CN, Nugent Z, Longobardi T et al. Isotretinoin is not associated with inflammatory bowel disease: a population-based case–control study. Am J Gastroenterol 2009;104:2774–8.
- 17. Rahier JF, Yazdanpanah Y, Colombel JF et al. The European (ECCO) consensus on infection in IBD: what does it change for the clinician? Gut 2009;58:1313–5.
- 18. Thielman NM, Guerrant RL. Clinical practice. Acute infectious diarrhea. N Engl J Med 2004;350:38–47.
- 19. Irving PM, Gibson PR. Infections and IBD. Nat Clin Pract Gastroenterol Hepatol 2008;5:18–27.
- 20. Issa M, Vijayapal A, Graham MB et al. Impact of Clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol 2007;5:345–51.
- 21. Rodemann JF, Dubberke ER, Reske KA et al. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol 2007;5:339–44.
- 22. Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease. Gut 2008;57:205–10.
- 23. Clayton EM, Rea MC, Shanahan F et al. The vexed relationship between Clostridium difficile and inflammatory bowel disease: an assessment of carriage in an outpatient setting among patients in remission. Am J Gastroenterol 2009;104:1162–9.
- 24. Nguyen GC, Kaplan GG, Harris ML et al. A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients. Am J Gastroenterol 2008;103:1443–50.
- 25. Jodorkovsky D, Young Y, Abreu MT. Clinical outcomes of patients with ulcerative colitis and co-existing Clostridium difficile infection. Dig Dis Sci ; 3 March 2009 e-pub ahead of print.
- 26. Simpson P, Papadakis KA. Endoscopic evaluation of patients with inflammatory bowel disease. Inflamm Bowel Dis 2008;14:1287–97.
- 27. Leighton JA, Shen B, Baron TH et al. ASGE guideline: endoscopy in the diagnosis and treatment of inflammatory bowel disease. Gastrointest Endosc 2006;63:558–65.
- 28. Fefferman DS, Farrell RJ. Endoscopy in inflammatory bowel disease: indications, surveillance, and use in clinical practice. Clin Gastroenterol Hepatol 2005;3:11–24.
- 29. Robert ME, Skacel M, Ullman T et al. Patterns of colonic involvement at initial presentation in ulcerative colitis: a retrospective study of 46 newly diagnosed cases. Am J Clin Pathol 2004;122:94–9.
- 30. D’Haens G, Geboes K, Peeters M et al. Patchy cecal inflammation associated with distal ulcerative colitis: a prospective endoscopic study. Am JGastroenterol 1997;92:1275–9.
- 31. Yantiss RK, Odze RD. Diagnostic difficulties in inflammatory bowel disease pathology. Histopathology 2006;48:116–32.
- 32. Kornbluth A, Legnani P, Lewis BS. Video capsule endoscopy in inflammatory bowel disease: past, present, and future. Inflamm Bowel Dis 2004;10:278–85.
- 33. Bruining DH, Loftus EV. Current and future diagnostic approaches: from serologies to imaging. Curr Gastroenterol Rep 2007;9:489–96.
- 34. Jenkins D, Balsitis M, Gallivan S et al. Guidelines for the initial biopsy diagnosis of suspected chronic idiopathic inflammatory bowel disease. The British Society of Gastroenterology initiative. J Clin Pathol 1997;50:93–105.
- 35. Nostrant TT, Kumar NB, Appelman HD. Histopathology differentiates acute self-limited colitis from ulcerative colitis. Gastroenterology 1987;92:318–28.
- 36. Surawicz CM, Belic L. Rectal biopsy helps to distinguish acute self-limited colitis from idiopathic inflammatory bowel disease. Gastroenterology 1984;86:104–13.
- 37. Dundas SA, Dutton J, Skipworth P. Reliability of rectal biopsy in distinguishing between chronic inflammatory bowel disease and acute self-limiting colitis. Histopathology 1997;31:60–6.
- 38. Surawicz CM. Differential diagnosis of colitis. In: Targan SR, Shanahan F (eds). Inflammatory Bowel Disease: From Bench to Bedside. Williams and Wilkins: Baltimore, MD, 1994, pp. 409–28.
- 39. Haskell H, Andrews CW Jr, Reddy SI et al. Pathologic features and clinical significance of “backwash” ileitis in ulcerative colitis. Am J Surg Pathol 2005;29:1472–81.
- 40. Nielsen OH, Vainer B, Rask-Madsen J. Non-IBD and noninfectious colitis. Nat Clin Pract Gastroenterol Hepatol 2008;5:28–39.
- 41. Abreu MT, Harpaz N. Diagnosis of colitis: making the initial diagnosis. Clin Gastroenterol Hepatol 2007;5:295–301.
- 42. Sultan K, Fields S, Panagopoulos G et al. The nature of inflammatory bowel disease in patients with coexistent colonic diverticulosis. J Clin Gastroenterol 2006;40:317–21.
- 43. Lamps LW, Knapple WL. Diverticular disease-associated segmental colitis. Clin Gastroenterol Hepatol 2007;5:27–31.
- 44. Harpaz N, Sachar DB. Segmental colitis associated with diverticular disease and other IBD look-alikes. J Clin Gastroenterol 2006;40(Suppl 3):S132–5.
- 45. Vasiliauskas EA, Plevy SE, Landers CJ et al. Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn’s disease define a clinical subgroup. Gastroenterology 1996;110:1810–9.
- 46. Targan SR, Landers CJ, Yang H et al. Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn’s disease. Gastroenterology 2005;128:2020–8.
- 47. Reese GE, Constantinides VA, Simillis C et al. Diagnostic precision of anti-saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Am J Gastroenterol 2006;101:2410–22.
- 48. Papp M, Norman GL, Altorjay I et al. Utility of serological markers in inflammatory bowel diseases: gadget or magic? World J Gastroenterol 2007;13:2028–36.
- 49. Anand V, Russell AS, Tsuyuki R et al. Perinuclear antineutrophil cytoplasmic autoantibodies and anti-saccharomyces cerevisiae antibodies as serological markers are not specific in the identification of Crohn’s disease and ulcerative colitis. Can J Gastroenterol 2008;22:33–6.
- 50. Legnani PE, Kornbluth A. Difficult differential diagnoses in IBD: ileitis and indeterminate colitis. Semin Gastrointest Dis 2001;12:211–22.
- 51. Etchevers MJ, Aceituno M, Garcia-Bosch O et al. Risk factors and characteristics of extent progression in ulcerative colitis. Inflamm Bowel Dis 2009;15:1320–5.
- 52. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2:1041–8.
- 53. Hanauer SB. Inflammatory bowel disease. N Engl J Med 1996;334:841–8.
- 54. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317:1625–9.
- 55. D ’ Haens G, Sandborn WJ, Feagan BG et al. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007;132:763–86.
- 56. Higgins PD, Schwartz M, Mapili J et al. Is endoscopy necessary for the measurement of disease activity in ulcerative colitis? Am J Gastroenterol 2005;100:355–61.
- 57. Lewis JD, Chuai S, Nessel L et al. Use of the noninvasive components of the mayo score to assess clinical response in ulcerative colitis. Inflamm Bowel Dis 2008;14:1660–6.
- 58. Rutter M, Saunders B, Wilkinson K et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004;126:451–9.
- 59. Gupta RB, Harpaz N, Itzkowitz S et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 2007;133:1099–105; quiz 1340–1341.
- 60. Froslie KF, Jahnsen J, Moum BA et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412–22.
- 61. Lichtenstein GR, Rutgeerts P. Importance of mucosal healing in ulcerative colitis. Inflamm Bowel Dis; 27 July 2009 e-pub ahead of print.
- 62. Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, 2009. Ann Intern Med 2009;150:40–4.
- 63. Melmed GY. Vaccination strategies for patients with inflammatory bowel disease on immunomodulators and biologics. Inflamm Bowel Dis 2009;15:1410–6.
- 64. Moscandrew M, Mahadevan U, Kane S. General health maintenance in IBD. Inflamm Bowel Dis 2009;15:1399–409.
- 65. Sands BE, Cuffaric, Katz J et al. Guidelines for immunizations in patients with inflammatory bowel disease. Inflamm Bowel Dis 2004;10:677–92.
- 66. Kane S, Khatibi B, Reddy D. Higher incidence of abnormal pap smears in women with inflammatory bowel disease. Am J Gastroenterol 2008;103:631–6.
- 67. Bhatia J, Bratcher J, Korelitz B et al. Abnormalities of uterine cervix in women with inflammatory bowel disease. World J Gastroenterol 2006;12:6167–71.
- 68. Singh H, Demers AA, Nugent Z et al. Risk of cervical abnormalities in women with inflammatory bowel disease: a population-based nested case–control study. Gastroenterology 2009;136:451–8.
- 69. Long MD, Porter CQ, Sandler RS et al. Suboptimal rates of cervical testing among women with inflammatory bowel disease. Clin Gastroenterol Hepatol 2009;7:549–53.
- 70. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin: clinical management guidelines for obstetrician– gynecologists. Number 45, August 2003. Cervical cytology screening (replaces committee opinion 152, March 1995). Obstet Gynecol 2003;102:417–27.
- 71. Markowitz LE, Dunne EF, Saraiya M et al. Quadrivalent human papilloma-virus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(RR-2):1–24.
- 72. Walker JR, Ediger JP, Graff LA et al. The Manitoba IBD cohort study: a population-based study of the prevalence of lifetime and 12-month anxiety and mood disorders. Am J Gastroenterol 2008;103:1989–97.
- 73. Lix LM, Graff LA, Walker JR et al. Longitudinal study of quality of life and psychological functioning for active, fluctuating, and inactive disease patterns in inflammatory bowel disease. Inflamm Bowel Dis 2008;14:1575–84.
- 74. Kane S, Huo D, Aikens J et al. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med 2003;114:39–43.
- 75. Kane S, Shaya F. Medication non-adherence is associated with increased medical health care costs. Dig Dis Sci 2008;53:1020–4.
- 76. Higgins PD, Rubin DT, Kaulback K et al. Systematic review: impact of non-adherence to 5-aminosalicylic acid products on the frequency and cost of ulcerative colitis flares. Aliment Pharmacol Ther 2009;29:247–57.
- 77. Cohen RD, Woseth DM, Thisted RA et al. A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol 2000;95:1263–76.
- 78. Regueiro M, Loftus EV Jr, Steinhart AH et al. Medical management of left-sided ulcerative colitis and ulcerative proctitis: critical evaluation of therapeutic trials. Inflamm Bowel Dis 2006;12:979–94.
- 79. Regueiro M, Loftus EV Jr, Steinhart AH et al. Clinical guidelines for the medical management of left-sided ulcerative colitis and ulcerative proctitis: summary statement. Inflamm Bowel Dis 2006;12:972–8.
- 80. Sutherland L, Macdonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2006: CD000543.
- 81. Sutherland L, Macdonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2006: CD000544.
- 82. Green JR, Lobo AJ, Holdsworth CD et al. Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. The Abacus Investigator Group. Gastroenterology 1998;114:15–22.
- 83. Kamm MA, Sandborn WJ, Gassull M et al. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology 2007;132:66–75; quiz 432–433.
- 84. Lichtenstein GR, Kamm MA, Sandborn WJ et al. MMX mesalazine for the induction of remission of mild-to-moderately active ulcerative colitis: efficacy and tolerability in specific patient subpopulations. Aliment Pharmacol Ther 2008;27:1094–102.
- 85. Baron JH, Connell AM, Lennard-Jones JE et al. Sulphasalazine and salicylazosulphadimidine in ulcerative colitis. Lancet 1962;1:1094–6.
- 86. DIick AP, Grayson MJ, Carpenter RG et al. Controlled trial of sulphasalazine in the treatment of ulcerative colitis. Gut 1964;5:437–42.
- 87. Sninsky CA, Cort DH, Shanahan F et al. Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis. A multicenter study. Ann Intern Med 1991;115:350–5.
- 88. Levine DS, Riff DS, Pruitt R et al. A randomized, double blind, dose – response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis. Am J Gastroenterol 2002;97:1398–407.
- 89. Pruitt R, Hanson J, Safdi M et al. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis. Am J Gastroenterol 2002;97:3078–86.
- 90. Zinberg J, Molinas S, Das KM. Double-blind placebo-controlled study of olsalazine in the treatment of ulcerative colitis. Am J Gastroenterol 1990;85:562–6.
- 91. Rao SS, Dundas SA, Holdsworth CD et al. Olsalazine or sulphasalazine in first attacks of ulcerative colitis? A double blind study. Gut 1989;30:675–9.
- 92. Meyers S, Sachar DB, Present DH et al. Olsalazine sodium in the treatment of ulcerative colitis among patients intolerant of sulfasalazine. A prospective, randomized, placebo-controlled, double-blind, dose-ranging clinical trial. Gastroenterology 1987;93:1255–62.
- 93. Feurle GE, Theuer D, Velasco S et al. Olsalazine vs. placebo in the treatment of mild to moderate ulcerative colitis: a randomised double blind trial. Gut 1989;30:1354–61.
- 94. Kamm MA, Lichtenstein GR, Sandborn WJ et al. Effect of extended MMX mesalamine therapy for acute, mild-to-moderate ulcerative colitis. Inflamm Bowel Dis 2009;15:1–8.
- 95. Kamm MA, Lichtenstein GR, Sandborn WJ et al. Randomised trial of once- or twice-daily MMX mesalazine for maintenance of remission in ulcerative colitis. Gut 2008;57:893–902.
- 96. Rao SS, Cann PA, Holdsworth CD. Clinical experience of the tolerance of mesalazine and olsalazine in patients intolerant of sulphasalazine. Scand J Gastroenterol 1987;22:332–6.
- 97. Giaffer MH, O ’ Brien CJ, Holdsworth CD. Clinical tolerance to three 5-aminosalicylic acid releasing preparations in patients with infl ammatory bowel disease intolerant or allergic to sulphasalazine. Aliment Pharmacol Ther 1992;6:51–9.
- 98. Green JR, Mansfield JC, Gibson JA et al. A double-blind comparison of balsalazide, 6.75 g daily, and sulfasalazine, 3 g daily, in patients with newly diagnosed or relapsed active ulcerative colitis. Aliment Pharmacol Ther 2002;16:61–8.
- 99. Gisbert JP, Gonzalez-Lama Y, Mate J. 5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 2007;13:629–38.
- 100. de Jong DJ, Tielen J, Habraken CM et al. 5-Aminosalicylates and effects on renal function in patients with Crohn’s disease. Inflamm Bowel Dis 2005;11:972–6.
- 101. Mahmud N, Stinson J, O’Connell MA et al. Microalbuminuria in inflammatory bowel disease. Gut 1994;35:1599–604.
- 102. Van Staa TP, Travis S, Leufk ens HG et al. 5-Aminosalicylic acids and the risk of renal disease: a large British epidemiologic study. Gastroenterology 2004;126:1733–9.
- 103. Campieri M, De Franchis R, Bianchi Porro G et al. Mesalazine (5-aminosalicylic acid) suppositories in the treatment of ulcerative proctitis or distal proctosigmoiditis. A randomized controlled trial. Scand J Gastroenterol 1990;25:663–8.
- 104. D’Arienzo A, Panarese A, D’Armiento FP et al. 5-Aminosalicylic acid suppositories in the maintenance of remission in idiopathic proctitis or proctosigmoiditis: a double-blind placebo-controlled clinical trial. Am J Gastroenterol 1990;85:1079–82.
- 105. Sutherland LR, Martin F, Greer S et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology 1987;92:1894–8.
- 106. Hanauer SB. Dose-ranging study of mesalamine (PENTASA) enemas in the treatment of acute ulcerative proctosigmoiditis: results of a multicentered placebo-controlled trial. The US PENTASA Enema Study Group. Inflamm Bowel Dis 1998;4:79–83.
- 107. d’Albasio G, Trallori G, Ghetti A et al. Intermittent therapy with high-dose 5-aminosalicylic acid enemas for maintaining remission in ulcerative proctosigmoiditis. Dis Colon Rectum 1990;33:394–7.
- 108. Marshall JK, Irvine EJ. Rectal aminosalicylate therapy for distal ulcerative colitis: a meta-analysis. Aliment Pharmacol Ther 1995;9:293–300.
- 109. Biddle WL, Greenberger NJ, Swan JT et al. 5-Aminosalicylic acid enemas: effective agent in maintaining remission in left-sided ulcerative colitis. Gastroenterology 1988;94:1075–9.
- 110. Sutherland LR. Topical treatment of ulcerative colitis. Med Clin North Am 1990;74:119–31.
- 111. Watkinson G. Treatment of ulcerative colitis with topical hydrocortisone hemisuccinate sodium; a controlled trial employing restricted sequential analysis. Br Med J 1958;2:1077–82.
- 112. Truelove SC, Hambling MH. Treatment of ulcerative colitis with local hydrocortisone hemisuccinate sodium; a report on a controlled therapeutic trial. Br Med J 1958;2:1072–7.
- 113. Campieri M, Lanfranchi GA, Bazzocchi G et al. Treatment of ulcerative colitis with high-dose 5-aminosalicylic acid enemas. Lancet 1981;2:270–1.
- 114. Topical 5-aminosalicylic acid vs. prednisolone in ulcerative proctosigmoiditis. A randomized, double-blind multicenter trial. Danish 5-ASA group. Dig Dis Sci 1987;32:598–602.
- 115. Marshall JK, Irvine EJ. Rectal corticosteroids vs. alternative treatments in ulcerative colitis: a meta-analysis. Gut 1997;40:775–81.
- 116. Hanauer SB, Robinson M, Pruitt R et al. Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-ranging study. US Budesonide Enema Study Group. Gastroenterology 1998; 115:525–32.
- 117. Budesonide enema in distal ulcerative colitis. A randomized dose–response trial with prednisolone enema as positive control. The Danish Budesonide Study Group. Scand J Gastroenterol 1991;26:1225–30.
- 118. Lofberg R, Danielsson A, Suhr O et al. Oral budesonide vs. prednisolone in patients with active extensive and left-sided ulcerative colitis. Gastroenterology 1996;110:1713–8.
- 119. Farthing MJ, Rutland MD, Clark ML. Retrograde spread of hydrocortisone containing foam given intrarectally in ulcerative colitis. Br Med J 1979;2:822–4.
- 120. Jay M, Digenis GA, Foster TS et al. Retrograde spreading of hydrocortisone enema in inflammatory bowel disease. Dig Dis Sci 1986;31:139–44.
- 121. Chapman NJ, Brown ML, Phillips SF et al. Distribution of mesalamine enemas in patients with active distal ulcerative colitis. Mayo Clin Proc 1992;67:245–8.
- 122. Williams CN, Haber G, Aquino JA. Double-blind, placebo-controlled evaluation of 5-ASA suppositories in active distal proctitis and measurement of extent of spread using 99mTc-labeled 5-ASA suppositories. Dig Dis Sci 1987;32(12 Suppl):71S–5S.
- 123. Safdi M, DeMicco M, Sninsky C et al. A double-blind comparison of oral vs. rectal mesalamine vs. combination therapy in the treatment of distal ulcerative colitis. Am J Gastroenterol 1997;92:1867–71.
- 124. Hanauer S, Good LI, Goodman MW et al. Long-term use of mesalamine (Rowasa) suppositories in remission maintenance of ulcerative proctitis. Am J Gastroenterol 2000;95:1749–54.
- 125. d’Albasio G, Paoluzi P, Campieri M et al. Maintenance treatment of ulcerative proctitis with mesalazine suppositories: a double-blind placebo-controlled trial. The Italian IBD Study Group. Am J Gastroenterol 1998;93:799–803.
- 126. Kruis W, Schreiber S, Theuer D et al. Low dose balsalazide (1.5 g twice daily) and mesalazine (0.5 g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3.0 g twice daily) was superior
- 127. Green JR, Gibson JA, Kerr GD et al. Maintenance of remission of ulcerative colitis: a comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator Group. Aliment Pharmacol Ther 1998;12:1207–16.
- 128. Apriso (mesalamine) extended release capsules. Available at: http://www.fda.gov/default.htm.
- 129. d’Albasio G, Pacini F, Camarri E et al. Combined therapy with 5-aminosalicylic acid tablets and enemas for maintaining remission in ulcerative colitis: a randomized double-blind study. Am J Gastroenterol 1997;92:1143–7.
- 130. Lindgren S, Lofberg R, Bergholm L et al. Effect of budesonide enema on remission and relapse rate in distal ulcerative colitis and proctitis. Scand J Gastroenterol 2002;37:705–10.
- 131. Hanauer S, Schwartz J, Robinson M et al. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial. Pentasa Study Group. Am J Gastroenterol 1993;88:1188–97.
- 132. Lichtenstein GR, Kamm MA, Boddu P et al. Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol 2007;5:95–102.
- 133. Willoughby CP, Cowan RE, Gould SR et al. Double-blind comparison of olsalazine and sulphasalazine in active ulcerative colitis. Scand J Gastroenterol Suppl 1988;148:40–4.
- 134. Hanauer SB, Sandborn WJ, Dallaire C et al. Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I Trial. Can J Gastroenterol 2007;21:827–34.
- 135. Hanauer SB, Sandborn WJ, Kornbluth A et al. Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: The ASCEND II Trial. Am J Gastroenterol 2005;100:2478–85.
- 136. Marteau P, Probert CS, Lindgren S et al. Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study. Gut 2005;54:960–5.
- 137. McGrath J, McDonald JW, Macdonald JK. Transdermal nicotine for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2004: CD004722.
- 138. Lennard-Jones JE, Longmore AJ, Newell AC et al. An assessment of prednisone, salazopyrin, and topical hydrocortisone hemisuccinate used as outpatient treatment for ulcerative colitis. Gut 1960;1:217–22.
- 139. Baron JH, Connell AM, Kanaghinis TG et al. Outpatient treatment of ulcerative colitis. Comparison between three doses of oral prednisone. Br Med J 1962;2:441–3.
- 140. Lichtenstein GR, Abreu MT, Cohen R et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130:940–87.
- 141. Klingenstein G, Levy RN, Kornbluth A et al. Infl ammatory bowel disease related osteonecrosis: report of a large series with a review of the literature. Aliment Pharmacol Ther 2005;21:243–9.
- 142. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348:727–34.
- 143. Lichtenstein GR, Sands BE, Pazianas M. Prevention and treatment of osteoporosis in inflammatory bowel disease. Inflamm Bowel Dis 2006;12:797–813.
- 144. Bernstein CN, Leslie WD. Therapy insight: osteoporosis in inflammatory bowel disease—advances and retreats. Nat Clin Pract Gastroenterol Hepatol 2005;2:232–9.
- 145. Bernstein CN. Neoplastic and other complications of infl ammatory bowel disease. Curr Gastroenterol Rep 2000;2:451–9.
- 146. Bernstein CN, Katz S. Guidelines for Osteoporosis and Infl ammatory Bowel Disease: A Guide to Diagnosis and Management for the Gastroenterologist. American College of Gastroenterology, Bethesda, MD, 2003.
- 147. Kornbluth A, Hayes M, Feldman S et al. Do guidelines matter? Implementation of the ACG and AGA osteoporosis screening guidelines in inflammatory bowel disease (IBD) patients who meet the guidelines’ criteria. Am J Gastroenterol 2006;101:1546–50.
- 148. AGA Committee on Osteoporosis in Gastrointestinal Diseases. American Gastroenterological Association medical position statement: guidelines on osteoporosis in gastrointestinal diseases. Gastroenterology 2003;124:791–4.
- 149. Saag KG, Emkey R, Schnitzer TJ et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoidinduced osteoporosis Intervention Study Group. N Engl J Med 1998;339:292–9.
- 150. Cohen S, Levy RM, Keller M et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 1999;42:2309–18.
- 151. Adachi JD, Bensen WG, Brown J et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997;337:382–7.
- 152. Saag KG, Shane E, Boonen S et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007;357:2028–39.
- 153. Abitbol V, Briot K, Roux C et al. A double-blind placebo-controlled study of intravenous clodronate for prevention of steroid-induced bone loss in inflammatory bowel disease. Clin Gastroenterol Hepatol 2007;5:1184–9.
- 154. Toruner M, Loftus EV Jr, Harmsen WS et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008;134:929–36.
- 155. Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76.
- 156. Clark M, Colombel JF, Feagan BC et al. American Gastroenterological Association Consensus Development Conference on the use of biologics in the treatment of inflammatory bowel disease, 21–23 June, 2006. Gastroenterology 2007;133:312–39.
- 157. Baert F, Noman M, Vermeire S et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601–8.
- 158. Rutgeerts P, Feagan BG, Lichtenstein GR et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 2004;126:402–13.
- 159. Lin J, Ziring D, Desai S et al. TNFalpha blockade in human diseases: an overview of efficacy and safety. Clin Immunol 2008;126:13–30.
- 160. Cheifetz A, Smedley M, Martin S et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003;98:1315–24.
- 161. Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9.
- 162. Colombel JF, Loftus EV Jr, Tremaine WJ et al. The safety profile of infliximab in patients with Crohn’s disease: the Mayo Clinic experience in 500 patients. Gastroenterology 2004;126:19–31.
- 163. Vermeire S, Noman M, Van Assche G et al. Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn’s disease: a prospective cohort study. Gastroenterology 2003;125:32–9.
- 164. Keane J, Gershon S, Wise RP et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098–104.
- 165. Fidder HH, Schnitzler F, Ferrante M et al. Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single center cohort study. Gut 2009;58:501–8.
- 166. Keane J. Tumor necrosis factor blockers and reactivation of latent tuberculosis. Clin Infect Dis 2004;39:300–2.
- 167. Garcia-Vidal C, Rodriguez-Fernandez S, Teijon S et al. Risk factors for opportunistic infections in infliximab-treated patients: the importance of screening in prevention. Eur J Clin Microbiol Infect Dis 2009;28:331–7.
- 168. Blumberg HM, Burman WJ, Chaisson RE et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603–62.
- 169. Theis VS, Rhodes JM. Review article: minimizing tuberculosis during antitumour necrosis factor-alpha treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2008;27:19–30.
- 170. Lichtenstein GR, Feagan BG, Cohen RD et al. Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry. Clin Gastroenterol Hepatol 2006;4:621–30.
- 171. Bongartz T, Sutton AJ, Sweeting MJ et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295:2275–85.
- 172. Hansen RA, Gartlehner G, Powell GE et al. Serious adverse events with infliximab: analysis of spontaneously reported adverse events. Clin Gastroenterol Hepatol 2007;5:729–35.
- 173. Doherty SD, Van Voorhees A, Lebwohl MG et al. National Psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis treated with systemic and biologic agents. J Am Acad Dermatol 2008;59:209–17.
- 174. Domm S, Cinatl J, Mrowietz U. The impact of treatment with tumour necrosis factor-alpha antagonists on the course of chronic viral infections: a review of the literature. Br J Dermatol 2008;159:1217–28.
- 175. Shale MJ, Seow CH, Coffin CS et al. Review article: chronic viral infection in the anti-tumour necrosis factor therapy era in inflammatory bowel disease. Aliment Pharmacol Ther 2010;31:20–34.
- 176. Jones JL, Loftus EV Jr. Lymphoma risk in inflammatory bowel disease: is it the disease or its treatment? Inflamm Bowel Dis 2007;13:1299–307.
- 177. Mackey AC, Green L, Liang LC et al. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007;44:265–7.
- 178. Drini M, Prichard PJ, Brown GJ et al. Hepatosplenic T-cell lymphoma following infliximab therapy for Crohn’s disease. Med J Aust 2008;189:464–5.
- 179. Zeidan A, Sham R, Shapiro J et al. Hepatosplenic T-cell lymphoma in a patient with Crohn’s disease who received infliximab therapy. Leuk Lymphoma 2007;48:1410–3.
- 180. Shale M, Kanfer E, Panaccione R et al. Hepatosplenic T cell lymphoma in inflammatory bowel disease. Gut 2008;57:1639–41.
- 181. Chung ES, Packer M, Lo KH et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107:3133–40.
- 182. Kwon HJ, Cote TR, Cuffe MS et al. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003;138:807–11.
- 183. Kirk AP, Lennard-Jones JE. Controlled trial of azathioprine in chronic ulcerative colitis. BMJ (Clin Res Ed) 1982;284:1291–2.
- 184. Rosenberg JL, Wall AJ, Levin B et al. A controlled trial of azathioprine in the management of chronic ulcerative colitis. Gastroenterology 1975;69:96–9.
- 185. Adler DJ, Korelitz BI. The therapeutic efficacy of 6-mercaptopurine in refractory ulcerative colitis. Am J Gastroenterol 1990;85:717–22.
- 186. Holtmann MH, Krummenauer F, Claas C et al. Long-term effectiveness of azathioprine in IBD beyond 4 years: a European multicenter study in 1176 patients. Dig Dis Sci 2006;51:1516–24.
- 187. Ardizzone S, Maconi G, Russo A et al. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut 2006;55:47–53.
- 188. Sandborn WJ. Rational dosing of azathioprine and 6-mercaptopurine. Gut 2001;48:591–2.
- 189. Sands BE. Immunosuppressive drugs in ulcerative colitis: twisting facts to suit theories? Gut 2006;55:437–41.
- 190. Chebli LA, Chaves LD, Pimentel FF et al. Azathioprine maintains long-term steroid-free remission through 3 years in patients with steroid-dependent ulcerative colitis. Inflamm Bowel Dis; 24 August 2009 e-pub ahead of print.
- 191. Gisbert JP, Nino P, Cara C et al. Comparative effectiveness of azathioprine in Crohn’s disease and ulcerative colitis: prospective, long-term, follow-up study of 394 patients. Aliment Pharmacol Ther 2008;28:228–38.
- 192. Mantzaris GJ, Sfakianakis M, Archavlis E et al. A prospective randomized observer-blind 2-year trial of azathioprine monotherapy vs. azathioprine and olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. Am J Gastroenterol 2004;99:1122–8.
- 193. Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol 2008;103:1783–800.
- 194. de Boer NK, van Bodegraven AA, Jharap B et al. Drug insight: pharmacology and toxicity of thiopurine therapy in patients with IBD. Nat Clin Pract Gastroenterol Hepatol 2007;4:686–94.
- 195. Dubinsky MC, Lamothe S, Yang HY et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in infl ammatory bowel disease. Gastroenterology 2000;118:705–13.
- 196. Shaye OA, Yadegari M, Abreu MT et al. Hepatotoxicity of 6-mercaptopurine (6-MP) and azathioprine (AZA) in adult IBD patients. Am J Gastroenterol 2007;102:2488–94.
- 197. Present DH, Meltzer SJ, Krumholz MP et al. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989;111:641–9.
- 198. Domenech E, Nos P, Papo M et al. 6-Nercaptopurine in patients with inflammatory bowel disease and previous digestive intolerance of azathioprine. Scand J Gastroenterol 2005;40:52–5.
- 199. Lees CW, Maan AK, Hansoti B et al. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008;27:220–7.
- 200. Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002;50:485–9.
- 201. Connell WR, Kamm MA, Dickson M et al. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994;343:1249–52.
- 202. Masunaga Y, Ohno K, Ogawa R et al. Meta-analysis of risk of malignancy with immunosuppressive drugs in inflammatory bowel disease. Ann Pharmacother 2007;41:21–8.
- 203. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980;32:651–62.
- 204. Colombel JF, Ferrari N, Debuysere H et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000;118:1025–30.
- 205. Osterman MT, Kundu R, Lichtenstein GR et al. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a metaanalysis. Gastroenterology 2006;130:1047–53.
- 206. Dubinsky MC, Yang H, Hassard PV et al. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 2002;122:904–15.
- 207. Oren R, Arber N, Odes S et al. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Gastroenterology 1996;110:1416–21.
- 208. Azad Khan AK, Howes DT, Piris J et al. Optimum dose of sulphasalazine for maintenance treatment in ulcerative colitis. Gut 1980;21:232–40.
- 209. Dissanayake AS, Truelove SC. A controlled therapeutic trial of long-term maintenance treatment of ulcerative colitis with sulphazalazine (salazopyrin). Gut 1973;14:923–6.
- 210. Sandberg-Gertzen H, Jarnerot G, Kraaz W. Azodisal sodium in the treatment of ulcerative colitis. A study of tolerance and relapse-prevention properties. Gastroenterology 1986;90:1024–30.
- 211. Ireland A, Jewell DP. Olsalazine in patients intolerant of sulphasalazine. Scand J Gastroenterol 1987;22:1038–40.
- 212. Dew MJ, Hughes P, Harries AD et al. Maintenance of remission in ulcerative colitis with oral preparation of 5-aminosalicylic acid. BMJ (Clin Res Ed) 1982;285:1012.
- 213. Dew MJ, Harries AD, Evans N et al. Maintenance of remission in ulcerative colitis with 5-amino salicylic acid in high doses by mouth. BMJ (Clin Res Ed) 1983;287:23–4.
- 214. Gionchetti P, Campieri M, Belluzzi A et al. Pentasa in maintenance treatment of ulcerative colitis. Gastroenterology 1990;98:251.
- 215. Riley SA, Mani V, Goodman MJ et al. Comparison of delayed-release 5-aminosalicylic acid (mesalazine) and sulfasalazine as maintenance treatment for patients with ulcerative colitis. Gastroenterology 1988;94:1383–9.
- 216. Riley SA, Mani V, Goodman MJ et al. Comparison of delayed release 5 aminosalicylic acid (mesalazine) and sulphasalazine in the treatment of mild to moderate ulcerative colitis relapse. Gut 1988;29:669–74.
- 217. Rutgeerts P. Comparative efficacy of coated, oral 5-aminosalicylic acid (Claversal) and sulphasalazine for maintaining remission of ulcerative colitis. International Study Group. Aliment Pharmacol Ther 1989;3:183–91.
- 218. Mulder CJ, Tytgat GN, Weterman IT et al. Double-blind comparison of slow-release 5-aminosalicylate and sulfasalazine in remission maintenance in ulcerative colitis. Gastroenterology 1988;95:1449–53.
- 219. Prantera C, Kohn A, Campieri M et al. Clinical trial: ulcerative colitis maintenance treatment with 5-ASA— a 1-year, randomized multicentre study comparing MMX with Asacol. Aliment Pharmacol Ther 2009;30:908–18.
- 220. Sachar DB. Maintenance therapy in ulcerative colitis and Crohn’s disease. J Clin Gastroenterol 1995;20:117–22.
- 221. Ireland A, Mason CH, Jewell DP. Controlled trial comparing olsalazine and sulphasalazine for the maintenance treatment of ulcerative colitis. Gut 1988;29:835–7.
- 222. Kiilerich S, Ladefoged K, Rannem T et al. Prophylactic effects of olsalazine v sulphasalazine during 12 months maintenance treatment of ulcerative colitis. The Danish Olsalazine Study Group. Gut 1992;33:252–5.
- 223. McIntyre PB, Rodrigues CA, Lennard-Jones JE et al. Balsalazide in the maintenance treatment of patients with ulcerative colitis, a double-blind comparison with sulphasalazine. Aliment Pharmacol Ther 1988;2:237–43.
- 224. Rijk MC, van Lier HJ, van Tongeren JH. Relapse-preventing effect and safety of sulfasalazine and olsalazine in patients with ulcerative colitis in remission: a prospective, double-blind, randomized multicenter study. The Ulcerative Colitis Multicenter Study Group. Am J Gastroenterol 1992;87:438–42.
- 225. Travis SP, Tysk C, de Silva HJ et al. Optimum dose of olsalazine for maintaining remission in ulcerative colitis. Gut 1994;35:1282–6.
- 226. Miner P, Hanauer S, Robinson M et al. Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis. Pentasa UC Maintenance Study Group. Dig Dis Sci 1995;40:296–304.
- 227. Fockens P, Mulder CJ, Tytgat GN et al. Comparison of the efficacy and safety of 1.5 compared with 3.0 g oral slow-release mesalazine (Pentasa) in the maintenance treatment of ulcerative colitis. Dutch Pentasa Study Group. Eur J Gastroenterol Hepatol 1995;7:1025–30.
- 228. Giaffer MH, Holdsworth CD, Lennard-Jones JE et al. Improved maintenance of remission in ulcerative colitis by balsalazide 4 g/day compared with 2 g/day. Aliment Pharmacol Ther 1992;6:479–85.
- 229. Kruis W, Judmaier G, Kayasseh L et al. Double-blind dose-finding study of olsalazine vs. sulphasalazine as maintenance therapy for ulcerative colitis. Eur J Gastroenterol Hepatol 1995;7:391–6.
- 230. Green JR, Swan CH, Rowlinson A et al. Short report: comparison of two doses of balsalazide in maintaining ulcerative colitis in remission over 12 months. Aliment Pharmacol Ther 1992;6:647–52.
- 231. Hawthorne AB, Logan RF, Hawkey CJ et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992;305:20–2.
- 232. Cassinotti A, Actis GC, Duca P et al. Maintenance treatment with azathioprine in ulcerative colitis: outcome and predictive factors after drug withdrawal. Am J Gastroenterol 2009;104:2760–7.
- 233. Gisbert JP, Linares PM, McNicholl AG et al. Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther 2009;30:126–37.
- 234. George J, Present DH, Pou R et al. The long-term outcome of ulcerative colitis treated with 6-mercaptopurine. Am J Gastroenterol 1996;91:1711–4.
- 235. Leung Y, Panaccione R, Hemmelgarn B et al. Exposing the weaknesses: a systematic review of azathioprine efficacy in ulcerative colitis. Dig Dis Sci 2008;53:1455–61.
- 236. Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2007: CD000478.
- 237. Ghosh S, Chaudhary R, Carpani M et al. Is thiopurine therapy in ulcerative colitis as effective as in Crohn’s disease? Gut 2006;55:6–8.
- 238. Lewis JD, Gelfand JM, Troxel AB et al. Immunosuppressant medications and mortality in inflammatory bowel disease. Am J Gastroenterol 2008;103:1428–35; quiz 1436.
- 239. Kandiel A, Fraser AG, Korelitz BI et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005;54:1121–5.
- 240. Rosenberg W, Ireland A, Jewell DP. High-dose methylprednisolone in the treatment of active ulcerative colitis. J Clin Gastroenterol 1990;12:40–1.
- 241. Dickinson RJ, O ’ Connor HJ, Pinder I et al. Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut 1985;26:1380–4.
- 242. Chapman RW, Selby WS, Jewell DP. Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 1986;27:1210–2.
- 243. Mantzaris GJ, Petraki K, Archavlis E et al. A prospective randomized controlled trial of intravenous ciprofloxacin as an adjunct to corticosteroids in acute, severe ulcerative colitis. Scand J Gastroenterol 2001;36:971–4.
- 244. Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1974;1:1067–70.
- 245. Truelove SC, Willoughby CP, Lee EG et al. Further experience in the treatment of severe attacks of ulcerative colitis. Lancet 1978;2:1086–8.
- 246. Jarnerot G, Rolny P, Sandberg-Gertzen H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology 1985;89:1005–13.
- 247. Dickinson RJ, Ashton MG, Axon AT et al. Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 1980;79:1199–204.
- 248. McIntyre PB, Powell-Tuck J, Wood SR et al. Controlled trial of bowel rest in the treatment of severe acute colitis. Gut 1986;27:481–5.
- 249. Roediger WE. The starved colon—diminished mucosal nutrition, diminished absorption, and colitis. Dis Colon Rectum 1990;33:858–62.
- 250. Koretz RL, Lipman TO, Klein S et al. AGA technical review on parenteral nutrition. Gastroenterology 2001;121:970–1001.
- 251. Kornbluth A, Marion JF, Salomon P et al. How effective is current medical therapy for severe ulcerative and Crohn’s colitis? An analytic review of selected trials. J Clin Gastroenterol 1995;20:280–4.
- 252. Freeman HJ. Recent developments on the role of Clostridium difficile in inflammatory bowel disease. World J Gastroenterol 2008;14:2794–6.
- 253. Ben-Horin S, Margalit M, Bossuyt P et al. Combination immunomodulator and antibiotic treatment in patients with inflammatory bowel disease and Clostridium difficile infection. Clin Gastroenterol Hepatol 2009;7:981–7.
- 254. Hu MY, Maroo S, Kyne L et al. A prospective study of risk factors and historical trends in metronidazole failure for Clostridium difficile infection. Clin Gastroenterol Hepatol 2008;6:1354–60.
- 255. Cottone M, Pietrosi G, Martorana G et al. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn’s colitis. Am J Gastroenterol 2001;96:773–5.
- 256. Papadakis KA, Tung JK, Binder SW et al. Outcome of cytomegalovirus infections in patients with inflammatory bowel disease. Am J Gastroenterol 2001;96:2137–42.
- 257. Domenech E, Vega R, Ojanguren I et al. Cytomegalovirus infection in ulcerative colitis: a prospective, comparative study on prevalence and diagnostic strategy. Inflamm Bowel Dis 2008;14:1373–9.
- 258. D’Ovidio V, Vernia P, Gentile G et al. Cytomegalovirus infection in inflammatory bowel disease patients undergoing anti-TNFalpha therapy. J Clin Virol 2008;43:180–3.
- 259. Maher MM, Nassar MI. Acute cytomegalovirus infection is a risk factor in refractory and complicated inflammatory bowel disease. Dig Dis Sci 2009;54:2456–62.
- 260. Gan SI, Beck PL. A new look at toxic megacolon: an update and review of incidence, etiology, pathogenesis, and management. Am J Gastroenterol 2003;98:2363–71.
- 261. Sheth SG, LaMont JT. Toxic megacolon. Lancet 1998;351:509–13.
- 262. Caprilli R, Vernia P, Latella G et al. Early recognition of toxic megacolon. J Clin Gastroenterol 1987;9:160–4.
- 263. Caprilli R, Latella G, Vernia P et al. Multiple organ dysfunction in ulcerative colitis. Am J Gastroenterol 2000;95:1258–62.
- 264. Chew CN, Nolan DJ, Jewell DP. Small bowel gas in severe ulcerative colitis. Gut 1991;32:1535–7.
- 265. Latella G, Vernia P, Viscido A et al. GI distension in severe ulcerative colitis. Am J Gastroenterol 2002;97:1169–75.
- 266. Chande N, McDonald JW, Macdonald JK. Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2008: CD006774.
- 267. Nguyen GC, Sam J. Rising prevalence of venous thromboembolism and its impact on mortality among hospitalized inflammatory bowel disease patients. Am J Gastroenterol 2008;103:2272–80.
- 268. Seo M, Okada M, Yao T et al. An index of disease activity in patients with ulcerative colitis. Am J Gastroenterol 1992;87:971–6.
- 269. Ho GT, Mowat C, Goddard CJ et al. Predicting the outcome of severe ulcerative colitis: development of a novel risk score to aid early selection of patients for second-line medical therapy or surgery. Aliment Pharmacol Ther 2004;19:1079–87.
- 270. Meyers S, Sachar DB, Goldberg JD et al. Corticotropin vs. hydrocortisone in the intravenous treatment of ulcerative colitis. A prospective, randomized, double-blind clinical trial. Gastroenterology 1983;85:351–7.
- 271. Lichtiger S, Present DH, Kornbluth A et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841–5.
- 272. Actis GC, Fadda M, David E et al. Colectomy rate in steroid-refractory colitis initially responsive to cyclosporin: a long-term retrospective cohort study. BMC Gastroenterol 2007;7:13.
- 273. Arts J, D ’ Haens G, Zeegers M et al. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Inflamm Bowel Dis 2004;10:73–8.
- 274. Moskovitz DN, Van Assche G, Maenhout B et al. Incidence of colectomy during long-term follow-up after cyclosporine-induced remission of severe ulcerative colitis. Clin Gastroenterol Hepatol 2006;4:760–5.
- 275. Van Assche G, D’Haens G, Noman M et al. Randomized, double-blind comparison of 4 vs. 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology 2003;125:1025–31.
- 276. D’Haens G, Lemmens L, Geboes K et al. Intravenous cyclosporine vs. intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology 2001;120:1323–9.
- 277. Cacheux W, Seksik P, Lemann M et al. Predictive factors of response to cyclosporine in steroid-refractory ulcerative colitis. Am J Gastroenterol 2008;103:637–42.
- 278. Rowe FA, Walker JH, Karp LC et al. Factors predictive of response to cyclosporin treatment for severe, steroid-resistant ulcerative colitis. Am J Gastroenterol 2000;95:2000–8.
- 279. Sands BE. Fulminant colitis. J Gastrointest Surg 2008;12:2157–9.
- 280. Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol 1999;94:1587–92.
- 281. Campbell S, Travis S, Jewell D. Cyclosporin use in acute ulcerative colitis: a long-term experience. Eur J Gastroenterol Hepatol 2005;17:79–84.
- 282. Sternthal MB, Murphy SJ, George J et al. Adverse events associated with the use of cyclosporine in patients with inflammatory bowel disease. Am J Gastroenterol 2008;103:937–43.
- 283. Hyde GM, Jewell DP, Kettlewell MG et al. Cyclosporin for severe ulcerative colitis does not increase the rate of perioperative complications. Dis Colon Rectum 2001;44:1436–40.
- 284. Aberra FN, Lewis JD, Hass D et al. Corticosteroids and immunomodulators: postoperative infectious complication risk in inflammatory bowel disease patients. Gastroenterology 2003;125:320–7.
- 285. Ogata H, Matsui T, Nakamura M et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 2006;55:1255–62.
- 286. Baumgart DC, Pintoffl JP, Sturm A et al. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease—a long-term follow-up. Am J Gastroenterol 2006;101:1048–56.
- 287. Benson A, Barrett T, Sparberg M et al. Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn’s disease: a single-center experience. Inflamm Bowel Dis 2008;14:7–12.
- 288. Fellermann K, Ludwig D, Stahl M et al. Steroid-unresponsive acute attacks of inflammatory bowel disease: immunomodulation by tacrolimus (FK506). Am J Gastroenterol 1998;93:1860–6.
- 289. Baumgart DC, Macdonald JK, Feagan B. Tacrolimus (FK506) for induction of remission in refractory ulcerative colitis. Cochrane Database Syst Rev 2008: CD007216.
- 290. Jarnerot G, Hertervig E, Friis-Liby I et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005;128:1805–11.
- 291. Sands BE, Tremaine WJ, Sandborn WJ et al. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis 2001;7:83–8.
- 292. Bressler B, Law JK, Al Nahdi Sheraisher N et al. The use of infliximab for treatment of hospitalized patients with acute severe ulcerative colitis. Can J Gastroenterol 2008;22:937–40.
- 293. Kohn A, Daperno M, Armuzzi A et al. Infliximab in severe ulcerative colitis: short-term results of different infusion regimens and long-term follow-up. Aliment Pharmacol Ther 2007;26:747–56.
- 294. Lees CW, Heys D, Ho GT et al. A retrospective analysis of the efficacy and safety of infliximab as rescue therapy in acute severe ulcerative colitis. Aliment Pharmacol Ther 2007;26:411–9.
- 295. Aratari A, Papic, Clemente V et al. Colectomy rate in acute severe ulcerative colitis in the infliximab era. Dig Liver Dis 2008;40:821–6.
- 296. Maser EA, Deconda D, Lichtiger S et al. Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis. Clin Gastroenterol Hepatol 2008;6:1112–6.
- 297. Colombel JF, Loftus EV Jr, Tremaine WJ et al. Early postoperative complications are not increased in patients with Crohn’s disease treated perioperatively with infliximab or immunosuppressive therapy. Am J Gastroenterol 2004;99:878–83.
- 298. Kunitake H, Hodin R, Shellito PC et al. Perioperative treatment with infliximab in patients with Crohn’s disease and ulcerative colitis is not associated with an increased rate of postoperative complications. J Gastrointest Surg 2008;12:1730–6; discussion 1736–7.
- 299. Marchal L, D ’ Haens G, Van Assche G et al. The risk of post-operative complications associated with infliximab therapy for Crohn’s disease: a controlled cohort study. Aliment Pharmacol Ther 2004;19:749–54.
- 300. Schluender SJ, Ippoliti A, Dubinsky M et al. Does infliximab influence surgical morbidity of ileal pouch-anal anastomosis in patients with ulcerative colitis? Dis Colon Rectum 2007;50:1747–53.
- 301. Selvasekar CR, Cima RR, Larson DW et al. Effect of infliximab on short-term complications in patients undergoing operation for chronic ulcerative colitis. J Am Coll Surg 2007;204:956–62; discussion 962–3.
- 302. Present DH, Wolfson D, Gelernt IM et al. Medical decompression of toxic megacolon by “rolling”. A new technique of decompression with favorable long-term follow-up. J Clin Gastroenterol 1988;10:485–90.
- 303. Truelove SC, Marks CG. Toxic megacolon. Part I: pathogenesis, diagnosis and treatment. Clin Gastroenterol 1981;10:107–17.
- 304. Barrie A, Regueiro M. Biologic therapy in the management of extraintestinal manifestations of inflammatory bowel disease. Inflamm Bowel Dis 2007;13:1424–9.
- 305. Alves A, Panis Y, Bouhnik Y et al. Subtotal colectomy for severe acute colitis: a 20-year experience of a tertiary care center with an aggressive and early surgical policy. J Am Coll Surg 2003;197:379–85.
- 306. Berg DF, Bahadursingh AM, Kaminski DL et al. Acute surgical emergencies in inflammatory bowel disease. Am J Surg 2002;184:45–51.
- 307. Hyman NH, Cataldo P, Osler T. Urgent subtotal colectomy for severe inflammatory bowel disease. Dis Colon Rectum 2005;48:70–3.
- 308. Danese S, Semeraro S, Papa A et al. Extraintestinal manifestations in inflammatory bowel disease. World J Gastroenterol 2005;11:7727–39.
- 309. Ardizzone S, Puttini PS, Cassinotti A et al. Extraintestinal manifestations of inflammatory bowel disease. Dig Liver Dis 2008;40(Suppl 2):S253–9.
- 310. Talansky AL, Meyers S, Greenstein AJ et al. Does intestinal resection heal the pyoderma gangrenosum of inflammatory bowel disease? J Clin Gastroenterol 1983;5:207–10.
- 311. Brooklyn TN, Dunnill MG, Shetty A et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut 2006;55:505–9.
- 312. Ermis F, Ozdil S, Akyuz F et al. Pyoderma gangrenosum treated with infliximab in inactive ulcerative colitis. Inflamm Bowel Dis 2008;14:1611–3.
- 313. Friedman S, Marion JF, Scherl E et al. Intravenous cyclosporine in refractory pyoderma gangrenosum complicating inflammatory bowel disease. Inflamm Bowel Dis 2001;7:1–7.
- 314. Broome U, Bergquist A. Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin Liver Dis 2006;26:31–41.
- 315. Silveira MG, Lindor K. Clinical features and management of primary sclerosing cholangitis. World J Gastroenterol 2007;14:3338–49.
- 316. Cangemi JR, Wiesner RH, Beaver SJ et al. Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology 1989;96:790–4.
- 317. Broome U, Olsson R, Loof L et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996;38:610–5.
- 318. Tariverdian M, Leowardic, Hinz U et al. Quality of life aft er restorative proctocolectomy for ulcerative colitis: preoperative status and long-term results. Inflamm Bowel Dis 2007;13:1228–35.
- 319. Bach SP, Mortensen NJ. Revolution and evolution: 30 years of ileoanal pouch surgery. Inflamm Bowel Dis 2006;12:131–45.
- 320. Hueting WE, Buskens E, van der Tweel I et al. Results and complications after ileal pouch anal anastomosis: a meta-analysis of 43 observational studies comprising 9,317 patients. Dig Surg 2005;22:69–79.
- 321. Weston-Petrides GK, Lovegrove RE, Tilney HS et al. Comparison of outcomes after restorative proctocolectomy with or without defunctioning ileostomy. Arch Surg 2008;143:406–12.
- 322. Loftus EV Jr, Delgado DJ, Friedman HS et al. Colectomy and the incidence of postsurgical complications among ulcerative colitis patients with private health insurance in the United States. Am J Gastroenterol 2008;103:1737–45.
- 323. Ananthakrishnan AN, McGinley EL, Binion DG. Does it matter where you are hospitalized for inflammatory bowel disease? A nationwide analysis of hospital volume. Am J Gastroenterol 2008;103:2789–98.
- 324. Kaplan GG, McCarthy EP, Ayanian JZ et al. Impact of hospital volume on postoperative morbidity and mortality following a colectomy for ulcerative colitis. Gastroenterology 2008;134:680–7.
- 325. Waljee A, Waljee J, Morris AM et al. Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis. Gut 2006;55:1575–80.
- 326. Ording Olsen K, Juul S, Berndtsson I et al. Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample. Gastroenterology 2002;122:15–9.
- 327. Gorgun E, Remzi FH, Montague DK et al. Male sexual function improves after ileal pouch anal anastomosis. Colorectal Dis 2005;7:545–50.
- 328. Mahadevan U, Sandborn WJ. Diagnosis and management of pouchitis. Gastroenterology 2003;124:1636–50.
- 329. Pardi DS, D ’ Haens G, Shen B et al. Clinical guidelines for the management of pouchitis. Inflamm Bowel Dis 2009;15:1424–31.
- 330. Sandborn WJ, Tremaine WJ, Batts KP et al. Pouchitis after ileal pouch-anal anastomosis: a pouchitis disease activity index. Mayo Clin Proc 1994;69:409–15.
- 331. Pardi DS, Shen B. Endoscopy in the management of patients after ileal pouch surgery for ulcerative colitis. Endoscopy 2008;40:529–33.
- 332. Shen B, Achkar JP, Lashner BA et al. Endoscopic and histologic evaluation together with symptom assessment are required to diagnose pouchitis. Gastroenterology 2001;121:261–7.
- 333. Shen B, Shermock KM, Fazio VW et al. A cost-effectiveness analysis of diagnostic strategies for symptomatic patients with ileal pouch-anal anastomosis. Am J Gastroenterol 2003;98:2460–7.
- 334. Hurst RD, Molinari M, Chung TP et al. Prospective study of the incidence, timing and treatment of pouchitis in 104 consecutive patients after restorative proctocolectomy. Arch Surg 1996;131:497–500; discussion 501–2.
- 335. Pardi DS, Sandborn WJ. Systematic review: the management of pouchitis. Aliment Pharmacol Ther 2006;23:1087–96.
- 336. Penna C, Dozois R, Tremaine W et al. Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis. Gut 1996;38:234–9.
- 337. Lohmuller JL, Pemberton JH, Dozois RR et al. Pouchitis and extraintestinal manifestations of inflammatory bowel disease after ileal pouch-anal anastomosis. Ann Surg 1990;211:622–7; discussion 627–9.
- 338. Aisenberg J, Wagreich J, Shim J et al. Perinuclear anti-neutrophil cytoplasmic antibody and refractory pouchitis. A case–control study. Dig Dis Sci 1995;40:1866–72.
- 339. Shen B, Fazio VW, Remzi FH et al. Risk factors for diseases of ileal pouch-anal anastomosis after restorative proctocolectomy for ulcerative colitis. Clin Gastroenterol Hepatol 2006; 4: 81–9; quiz 2–3.
- 340. Hoda KM, Collins JF, Knigge KL et al. Predictors of pouchitis after ileal pouch-anal anastomosis: a retrospective review. Dis Colon Rectum 2008;51:554–60.
- 341. Subramani K, Harpaz N, Bilotta J et al. Refractory pouchitis: does it reflect underlying Crohn’s disease? Gut 1993;34:1539–42.
- 342. Melmed GY, Fleshner PR, Bardakcioglu O et al. Family history and serology predict Crohn’s disease after ileal pouch-anal anastomosis for ulcerative colitis. Dis Colon Rectum 2008;51:100–8.
- 343. Shen B, Remzi FH, Lavery IC et al. A proposed classification of ileal pouch disorders and associated complications after restorative proctocolectomy. Clin Gastroenterol Hepatol 2008;6:145–58; quiz 124.
- 344. McGuire BB, Brannigan AE, O’Connell PR. Ileal pouch-anal anastomosis. Br J Surg 2007;94:812–23.
- 345. Shen B, Achkar JP, Lashner BA et al. Irritable pouch syndrome: a new category of diagnosis for symptomatic patients with ileal pouch-anal anastomosis. Am J Gastroenterol 2002;97:972–7.
- 346. Shen B, Lashner BA, Bennett AE et al. Treatment of rectal cuff inflammation (cuffitis) in patients with ulcerative colitis following restorative proctocolectomy and ileal pouch-anal anastomosis. Am J Gastroenterol 2004;99:1527–31.
- 347. Shen B, Achkar JP, Lashner BA et al. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis. Inflamm Bowel Dis 2001;7:301–5.
- 348. Sandborn W, McLeod R, Jewell D. Pharmacotherapy for inducing and maintaining remission in pouchitis. Cochrane Database Syst Rev 2000: CD001176.
- 349. Madden MV, McIntyre AS, Nicholls RJ. Double-blind crossover trial of metronidazole vs. placebo in chronic unremitting pouchitis. Dig Dis Sci 1994;39:1193–6.
- 350. Sambuelli A, Boerr L, Negreira S et al. Budesonide enema in pouchitis—a double-blind, double-dummy, controlled trial. Aliment Pharmacol Ther 2002;16:27–34.
- 351. Scott AD, Phillips RK. Ileitis and pouchitis after colectomy for ulcerative colitis. Br J Surg 1989;76:668–9.
- 352. Isaacs KL, Sandler RS, Abreu M et al. Rifaximin for the treatment of active pouchitis: a randomized, double-blind, placebo-controlled pilot study. Inflamm Bowel Dis 2007;13:1250–5.
- 353. Gionchetti P, Rizzello F, Venturi A et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119:305–9.
- 354. Gionchetti P, Rizzello F, Helwig U et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology 2003;124:1202–9.
- 355. Shen B, Brzezinski A, Fazio VW et al. Maintenance therapy with a probiotic in antibiotic-dependent pouchitis: experience in clinical practice. Aliment Pharmacol Ther 2005;22:721–8.
- 356. Thompson-Fawcett MW, Marcus V, Redston M et al. Risk of dysplasia in long-term ileal pouches and pouches with chronic pouchitis. Gastroenterology 2001;121:275–81.
- 357. Nilubol N, Scherl E, Bub DS et al. Mucosal dysplasia in ileal pelvic pouches after restorative proctocolectomy. Dis Colon Rectum 2007;50:825–31.
- 358. Sarigol S, Wyllie R, Gramlich T et al. Incidence of dysplasia in pelvic pouches in pediatric patients after ileal pouch-anal anastomosis for ulcerative colitis. J Pediatr Gastroenterol Nutr 1999;28:429–34.
- 359. Das P, Johnson MW, Tekkis PP et al. Risk of dysplasia and adenocarcinoma following restorative proctocolectomy for ulcerative colitis. Colorectal Dis 2007;9:15–27.
- 360. Branco BC, Sachar DB, Heimann T et al. Adenocarcinoma following ileal pouch-anal anastomosis for ulcerative colitis: review of 26 cases. Inflamm Bowel Dis 2009;15:205–9.
- 361. Greenstein AJ, Sachar DB, Smith H et al. Cancer in universal and left-sided ulcerative colitis: factors determining risk. Gastroenterology 1979;77:290–4.
- 362. Jess T, Loftus EV Jr, Velayos FS et al. Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case–control study from Copenhagen County, Denmark and Olmsted County, Minnesota. Am J Gastroenterol 2007;102:829–36.
- 363. Sugita A, Sachar DB, Bodian C et al. Colorectal cancer in ulcerative colitis. Influence of anatomical extent and age at onset on colitis–cancer interval. Gut 1991;32:167–9.
- 364. Sachar DB. Cancer risk in inflammatory bowel disease: myths and metaphors. In: Riddell RH (ed). Dysplasia and Cancer in Colitis. Elsevier: New York, 1991 pp. 5–9.
- 365. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48:526–35.
- 366. Gilat T, Fireman Z, Grossman A et al. Colorectal cancer in patients with ulcerative colitis. A population study in central Israel. Gastroenterology 1988;94:870–7.
- 367. Rutter MD, Saunders BP, Wilkinson KH et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006;130:1030–8.
- 368. Ullman T, Odze R, Farraye FA. Diagnosis and management of dysplasia in patients with ulcerative colitis and Crohn’s disease of the colon. Inflamm Bowel Dis 2009;15:630–8.
- 369. Lutgens MW, Vleggaar FP, Schipper ME et al. High frequency of early colorectal cancer in inflammatory bowel disease. Gut 2008;57:1246–51.
- 370. Greenstein AJ, Sachar DB, Pucillo A et al. Cancer in universal and leftsided ulcerative colitis: clinical and pathologic features. Mt Sinai J Med 1979;46:25–32.
- 371. Gyde SN, Prior P, Allan RN et al. Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres. Gut 1988;29:206–17.
- 372. Itzkowitz SH, Present DH, Crohn’s and Colitis Foundation of America Colon Cancer in IBD Study Group. Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005;11:314–21.
- 373. Mathy C, Schneider K, Chen YY et al. Gross vs. microscopic pancolitis and the occurrence of neoplasia in ulcerative colitis. Inflamm Bowel Dis 2003;9:351–5.
- 374. Shetty K, Rybicki L, Brzezinski A et al. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol 1999;94:1643–9.
- 375. Broome U, Lofberg R, Veress B et al. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology 1995;22:1404–8.
- 376. Nuako KW, Ahlquist DA, Sandborn WJ et al. Primary sclerosing cholangitis and colorectal carcinoma in patients with chronic ulcerative colitis: a case–control study. Cancer 1998;82:822–6.
- 377. Loftus EV Jr, Sandborn WJ, Tremaine WJ et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis. Gastroenterology 1996;110:432–40.
- 378. Pardi DS, Loftus EV Jr, Kremers WK et al. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003;124:889–93.
- 379. Askling J, Dickman PW, Karlen P et al. Family history as a risk factor for colorectal cancer in inflammatory bowel disease. Gastroenterology 2001;120:1356–62.
- 380. Bernstein CN, Blanchard JF, Metge C et al. Does the use of 5-aminosalicylates in inflammatory bowel disease prevent the development of colorectal cancer? Am J Gastroenterol 2003;98:2784–8.
- 381. Eaden J, Abrams K, Ekbom A et al. Colorectal cancer prevention in ulcerative colitis: a case–control study. Aliment Pharmacol Ther 2000;14:145–53.
- 382. Pinczowski D, Ekbom A, Baron J et al. Risk factors for colorectal cancer in patients with ulcerative colitis: a case–control study. Gastroenterology 1994;107:117–20.
- 383. van Staa TP, Card T, Logan RF et al. 5-Aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiological study. Gut 2005;54:1573–8.
- 384. Rubin DT, Djordjjevic A, Huo D. Use of 5-ASA is associated with decreased risk of dysplasia and colon cancer (CRC) in ulcerative colitis. Gastroenterol 2003;124:A279.
- 385. Lashner BA, Provencher KS, Seidner DL et al. The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis. Gastroenterology 1997;112:29–32.
- 386. Lindberg BU, Broome U, Persson B. Proximal colorectal dysplasia or cancer in ulcerative colitis. The impact of primary sclerosing cholangitis and sulfasalazine: results from a 20-year surveillance study. Dis Colon Rectum 2001;44:77–85.
- 387. Moody GA, Jayanthi V, Probert CS et al. Long-term therapy with sulphasalazine protects against colorectal cancer in ulcerative colitis: a retrospective study of colorectal cancer risk and compliance with treatment in Leicestershire. Eur J Gastroenterol Hepatol 1996;8:1179–83.
- 388. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol 2005;100:1345–53.
- 389. Ullman T, Croog V, Harpaz N et al. Progression to colorectal neoplasia in ulcerative colitis: effect of mesalamine. Clin Gastroenterol Hepatol 2008;6:1225–30; quiz 1177.
- 390. Rutter MD, Saunders BP, Wilkinson KH et al. Most dysplasia in ulcerative colitis is visible at colonoscopy. Gastrointest Endosc 2004;60:334–9.
- 391. Rubin DT, Rothe JA, Hetzel JT et al. Are dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis? Gastrointest Endosc 2007;65:998–1004.
- 392. Blonski W, Kundu R, Lewis J et al. Is dysplasia visible during surveillance colonoscopy in patients with ulcerative colitis? Scand J Gastroenterol 2008;43:698–703.
- 393. Rutter MD, Saunders BP, Wilkinson KH et al. Cancer surveillance in long-standing ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 2004;53:1813–6.
- 394. Velayos FS, Loftus EV Jr, Jess T et al. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case–control study. Gastroenterology 2006;130:1941–9.
- 395. Reiser JR, Waye JD, Janowitz HD et al. Adenocarcinoma in strictures of ulcerative colitis without antecedent dysplasia by colonoscopy. Am J Gastroenterol 1994;89:119–22.
- 396. Gumaste V, Sachar DB, Greenstein AJ. Benign and malignant colorectal strictures in ulcerative colitis. Gut 1992;33:938–41.
- 397. Kiesslich R, Galle PR, Neurath MF. Endoscopic surveillance in ulcerative colitis: smart biopsies do it better. Gastroenterology 2007;133:742–5.
- 398. Kiesslich R, Goetz M, Lammersdorf K et al. Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis. Gastroenterology 2007;132:874–82.
- 399. Hurlstone DP, McAlindon ME, Sanders DS et al. Further validation of high-magnification chromoscopic-colonoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2004;126:376–8.
- 400. Hurlstone DP, Sanders DS, Lobo AJ et al. Indigo carmine-assisted high-magnification chromoscopic colonoscopy for the detection and characterisation of intraepithelial neoplasia in ulcerative colitis: a prospective evaluation. Endoscopy 2005;37:1186–92.
- 401. Kiesslich R, Fritsch J, Holtmann M et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003;124:880–8.
- 402. Rutter MD, Saunders BP, Schofield G et al. Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut 2004;53:256–60.
- 403. Marion JF, Waye JD, Present DH et al. Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial. Am J Gastroenterol 2008;103:2342–9.
- 404. Collins PD, Mpofu C, Watson AJ et al. Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease. Cochrane Database Syst Rev 2006: CD000279.
- 405. Connell WR, Lennard-Jones JE, Williams CB et al. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 1994;107:934–44.
- 406. Lashner BA, Silverstein MD, Hanauer SB. Hazard rates for dysplasia and cancer in ulcerative colitis. Results from a surveillance program. Dig Dis Sci 1989;34:1536–41.
- 407. Vemulapalli R, Lance P. Cancer surveillance in ulcerative colitis: more of the same or progress? Gastroenterology 1994;107:1196–9.
- 408. Provenzale D, Wong JB, Onken JE et al. Performing a cost-effectiveness analysis: surveillance of patients with ulcerative colitis. Am J Gastroenterol 1998;93:872–80.
- 409. Miller AB. Implementation of colon cancer screening: techniques, costs, and barriers. Gastroenterol Clin North Am 2008;37:83–95, vi.
- 410. van der Maas PJ, de Koning HJ, van Ineveld BM et al. The cost-effectiveness of breast cancer screening. Int J Cancer 1989;43:1055–60.
- 411. Eddy DM. Screening for cervical cancer. Ann Intern Med 1990;113:214–26.
- 412. Melville DM, Jass JR, Morson BC et al. Observer study of the grading of dysplasia in ulcerative colitis: comparison with clinical outcome. Hum Pathol 1989;20:1008–14.
- 413. Nugent FW, Haggitt RC, Gilpin PA. Cancer surveillance in ulcerative colitis. Gastroenterology 1991;100(5 Part 1):1241–8.
- 414. Rosenstock E, Farmer RG, Petras R et al. Surveillance for colonic carcinoma in ulcerative colitis. Gastroenterology 1985;89:1342–6.
- 415. Blackstone MO, Riddell RH, Rogers BH et al. Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: an indication for colectomy. Gastroenterology 1981;80:366–74.
- 416. Woolrich AJ, DaSilva MD, Korelitz BI. Surveillance in the routine management of ulcerative colitis: the predictive value of low-grade dysplasia. Gastroenterology 1992;103:431–8.
- 417. Ullman TA, Loftus EV Jr, Kakar S et al. The fate of low grade dysplasia in ulcerative colitis. Am J Gastroenterol 2002;97:922–7.
- 418. Ullman T, Croog V, Harpaz N et al. Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003;125:1311–9.
- 419. Thomas T, Abrams KA, Robinson RJ et al. Meta-analysis: cancer risk of low-grade dysplasia in chronic ulcerative colitis. Aliment Pharmacol Ther 2007;25:657–68.
- 420. Engelsgjerd M, Farraye FA, Odze RD. Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis. Gastroenterology 1999;117:1288–94; discussion 1488–91.
- 421. Rubin PH, Friedman S, Harpaz N et al. Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps. Gastroenterology 1999;117:1295–300.
- 422. Bernstein CN. ALMs vs. DALMs in ulcerative colitis: polypectomy or colectomy? Gastroenterology 1999;117:1488–92.
- 423. Blonski W, Kundu R, Furth EF et al. High-grade dysplastic adenoma-like mass lesions are not an indication for colectomy in patients with ulcerative colitis. Scand J Gastroenterol 2008;43:817–20.
- 424. Odze RD, Farraye FA, Hecht JL et al. Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis. Clin Gastroenterol Hepatol 2004;2:534–41.
- 425. Vieth M, Behrens H, Stolte M. Sporadic adenoma in ulcerative colitis: endoscopic resection is an adequate treatment. Gut 2006;55:1151–5.
- 426. Rubin DT, Turner JR. Surveillance of dysplasia in inflammatory bowel disease: the gastroenterologist–pathologist partnership. Clin Gastroenterol Hepatol 2006;4:1309–13.