Colitis bleeding won’t stop

Prednisone Didn’t Clear Colitis — Time for Biologics?

Q1. My son has been diagnosed with colitis and had a nasty flare. He was diagnosed in February, and it was managed through Asacol (mesalamine). However, two weeks ago he was bleeding and going to the bathroom 16 to 17 times a day. A colonoscopy was done and his colon was totally inflamed; it was no longer just the lower part of his colon. He was placed on 40 mg of prednisone and Asacol (12 per day). He has been on this for nine days. He now goes to the bathroom seven times a day, still with some blood. He says he is feeling better, is no longer nauseous and is even working out again. We are supposed to start tapering him off next week but he still is bleeding. He is supposed to start on 35 mg of prednisone and continue to taper. What are your thoughts on this treatment? I am so worried about this. I am also worried as he plays college baseball and plans to play this fall which I feel is foolish. I don’t feel this disease is under control at all! Please help us!

Most patients with severely active ulcerative colitis will respond to prednisone. Those who do not, like your son, will need alternative medications. One alternative is infliximab (Remicade), which is approved for ulcerative colitis treatment and very often helps dramatically. Infliximab is in a class of medications known as biologics and it works by blocking tumor necrosis factor, or TNF, a protein that causes increased inflammation.

Your son will most likely need something like infliximab to induce remission before he is able to play baseball at a competitive level. Prednisone cannot be taken for long periods of time because of serious side effects. So even if this drug eventually helps him, a long-term medication like infliximab should be considered.

Q2. I have heard that Remicade can only be taken for six years. Is this true? If yes, why? If no, are there any limitations on this or any other drug for GI disorders?

No, there is no time limit on the use of Remicade in ulcerative colitis. In general, there are no time limitations on any drug we use for inflammatory bowel disease.

However, the longer you take Remicade, the higher your risk is of developing complications, like opportunistic infections. Other drugs, such as the 5-aminosalicylic acid compounds, are much safer and much less expensive than Remicade. If you can be treated with these medications instead of Remicade, you are better off.

You can find more information on ulcerative colitis treatment in Everyday Health’s Ulcerative Colitis Center, as well as information on planning your colitis treatment strategy, the risks and benefits of colitis drugs, ways to cope with side effects of drugs, and alternative therapies for colitis.

Q3. I have had ulcerative colitis for over 19 years; now I am 34. I’m female. I have tried Asacol (mesalamine), which I am still taking, but I can’t get and stay in remission. I have also tried Colazal (balsalazide), Imuran (azathioprine), Rowasa (mesalamine) and prednisone. Do you have to take any pills with Remicade (infliximab) or just through your IV? I am running out of options. Can it be taken long-term?

All patients with ulcerative colitis should be on a 5-ASA product, like Asacol, and I would recommend that you stay on it.

Remicade need not be given with any additional pills, but many physicians use azathioprine (Imuran) or 6-mercaptopurine (Purinethol) during the first few months of Remicade to diminish your immune system’s response to Remicade. When your body produces antibodies in a mistaken attempt to “fight off” the Remicade, there’s a risk of lower response rate and infusion reactions.

Yes, Remicade can be taken long-term to maintain remission.

Q4. I have a drain in an abscess cavity with a connecting fistula between the cavity and my anal canal. How likely would it be for a fistula to form from the anal canal to the vagina, and what would the symptoms be? Nothing has worked to close the perianal fistula — I’ve tried Remicade, 6-MP, an advancement flap, and plugs.

Fistulas are abnormal communications or passages from the gastrointestinal tract to the skin or other organs, such as the vagina, and they are characteristic of Crohn’s disease. Passage of stool and gas through the vagina or urethra are symptoms you would expect if there were a fistula to the vagina or the bladder from the anal canal.

Surgical drainage of any abscess is an important first step in the management of fistulas, but a combination of medical and surgical therapy usually works best. It seems as though you could benefit from another opinion from experienced physicians, preferably at a major medical center where there are experts in gastrointestinal conditions like Crohn’s and colitis.

Q5. My son (age 17) was diagnosed with ulcerative colitis in December 2004. At that time, he was having diarrhea 10 to 12 times a day. For the past year, he has been on prednisone, which helped. He was finally able to get off it (had trouble with weaning as symptoms came back full force). He is still having somewhat loose and unformed stools about four to five times a day. I feel that he is still not in remission, and I’m wondering what the next step would be to help him. Or will his stools always be this way? Am I expecting too much for him to have formed stools only once a day?

Remission in ulcerative colitis can be maintained with anti-inflammatory medications that do not have steroids in them. The most commonly used medications are ones that have 5-aminosalicylic acid (5-ASA) in them, such as mesalamine (brand names are Asacol, Pentasa, Lialda, Rowasa or Canasa), balsalazide (Colazal) and olsalazine (Dipentum).

Other possibilities for steroid-free maintenance include 6-mercaptopurine, Imuran (azathioprine), methotrexate and Remicade (infliximab). With the right combination of medications, your son could have fewer bowel movements daily.

Learn more in the Everyday Health Ulcerative Colitis Center.

PMC

AT WHAT POINT SHOULD WE DEFINE RESISTANCE TO STEROIDS: 3, 7 OR 21 DAYS AFTER INITIATION?

The colectomy rate in severe UC (30%-35%), as well as percentages of remission and response, have remained unchanged since the introduction of corticosteroids in UC treatment, and similar results have been reported in both clinical trials and in the clinical setting. The classic limit of 7-10 d for establishing the criteria of steroid resistance was based on the results of historical series showing that the median time of remission was 7.5 d and that prolonged administration beyond 10 d did not increase the percentage of remission.

However, some authors have argued in favor of a more conservative approach since a group of “slow responders” have been identified. These patients showed a partial response within 10 d of admission, defined as a decrease in stool frequency, with little or no blood. In the largest retrospective series of a single experienced hospital (149 episodes in 115 patients), 19% fulfilling this criteria entered into remission within the first 21 d of treatment. More importantly, the long-term follow-up of these “slow-responders” showed that none of them required colectomy within a median follow-up period of 49 mo. These data are in contrast with the high colectomy rate of corticoesteroid refractory patients one year after ciclosporin-induced remission when azathioprine is not administered to maintain it.

In contrast with this point of view, a more resolute approach is based on the results of several studies which have identified factors predictive of treatment failure soon after corticosteroid initiation. The study of Travis et al was a pioneer in this area, demonstrating a prospective day-by-day evolution, during the first days after admission, of several inflammatory parameters (C reactive protein (CRP), erythrocyte sedimentation rate (ESR), platelets, etc) and clinical symptoms (bowel movements, blood in stools, pulse rate, etc) in 51 consecutive episodes of severe UC. This study identified a turning point in the disease outcome on the third day of treatment, establishing a critical limit for deciding whether patients are responders or non-responders. Two simple parameters (stool frequency of > 8 per day or 3-8 bowel movements per day and CRP > 45 mg/dL on the third day of therapy) have a positive predictive value (PPV) of 85% for colectomy. Similar results (decreased CRP and Montreal classification of UC activity as independent predictive factors for response on the 3rd day of treatment) have been obtained in a recent validated prospective study published as an abstract form. Two additional studies retrospectively analyzed clinical and biochemical data at 1, 3 and 7 d, or within the first 3 d of medical therapy, to obtain predictive models of the likelihood of colectomy. In one of these, a value higher than 8 obtained by the formula stool frequency/d + 0.14 × CRP (mg/dL) calculated on the 3rd day after initiation of treatment had a PPV for colectomy of 72%. This study confirmed that a regression formula including the same simple parameters used in the Travis et al study allows prediction of treatment failure and colectomy in a high percentage of severe UC patients. These results were prospectively validated in the only randomized, placebo-controlled study assessing infliximab as rescue therapy in severe UC, showing that patients fulfilling an index criteria of fulminant colitis (value ≥ 8) in the placebo arm had a PPV for colectomy of 69%. In the other retrospective study, a risk score was proposed to identify patients who are at low, intermediate or high likelihood of not responding to intensive medical treatment, aiding in the early selection of patients for second-line medical therapy or colectomy. Multiple logistic regression analysis identified mean stool frequency (graded from 0 to 4 points) and colonic dilatation (4 points) within the first three days and hypoalbuminemia (1 point) on day 1 of treatment, as significantly predictive of the need for surgery within the hospitalization period. The risk score allowed the stratification of patients into those with low (11%; score 0-1), intermediate (45%; score 2-3) and high risk (85%; score ≥ 4) of not responding to medical therapy. With a cut-off of ≥ 4 points, the sensitivity and specificity in predicting non-response to medical therapy were 85% and 75% respectively.

The results of these studies are in agreement with previous observations showing that complete remission, which takes longer than response, is achieved, in the majority of steroid-sensitive cases, within 7 to 8 d of beginning corticosteroid treatment.

In conclusion, to evaluate steroid resistance, steroids must be intravenously administered, in the hospital setting, at a dose equivalent to 1 mg/kg per body weight of prednisone. The lack of response at day three of steroid treatment, as defined by well-established clinical parameters, suggests a high probability of colectomy and should be used in general as a limit point to define steroid resistance. Whether 3, 7 or 21 d are used as a limit marker for steroid resistance, judicious decisions by physicians, skilled in Inflammatory Bowel Disease management, should prevail. The risks and benefits of any decision have to be carefully weighed, taking into account that the priority in the management of severe UC is to save the patient and, if possible, the colon.

Current approaches to the management of new-onset ulcerative colitis

Nonadherence to 5-ASAs is particularly high with reported index medication compliance of 57.2% in one study.119 Greater risk of disease relapse has been seen in both nonadherent patients and in adherent patients whose mesalazine formulations were switched.122 Patients on single daily dose MMX mesalamine appear to have the lowest discontinuation risk and highest adherence rate.121 Over 75% of IBD patients are compliant with anti-TNF therapy. Factors predicting nonadherence for IFX or ADA include female sex, smoking, anxiety, moodiness, and treatment-related constraints.123 It has been reported that IBD patients may misperceive the risks and benefits of anti-TNF therapy, namely IFX; as per questionnaire results, a majority of IBD patients would be unwilling to accept treatment-related side effects if the remission rate at 1 year was <75%. Such perceptions appear to be independent of age and duration of disease.124 In one study, highest adherence rates were seen with immunomodulators.125

Medication compliance should be assessed during each patient evaluation, especially in the setting of quiescent disease. Stress and mental health-related disorders like anxiety and depression reflect health-related QOL in IBD patients and may affect compliance so should be addressed in conjunction with medical and/or surgical therapy.126 Development of a patient-administered tool to assist practitioners in evaluating noncompliance would be beneficial in the clinical setting.125 Web-based health care designs may improve patients’ knowledge and QOL in the setting of chronic disease and may encourage adherence through a model of continued care.127

Practitioners should have a heightened sensitivity for the aforementioned patient-centered issues. Individualized therapeutic approaches are required and must take into account extent and severity of inflammatory disease with additional considerations for such factors as medication administration (route, pill burden), financial costs, age, lifestyle, occupation, and fertility/pregnancy status among others. Careful provision of informed consent relating to IBD therapy includes discussion of available therapeutic options, risks associated with lack of or suboptimal treatment and/or noncompliance, and pharmacotherapeutic alternatives such as colectomy. The ability of patients to comprehend and procure information about their chronic disease state is paramount. Shared decision making is an optimal model in such medical treatment encounters and should thus be advocated.128

Conclusion

UC is a chronic inflammatory colonic disease with a relapsing and remitting course. Once the diagnosis is established, new-onset cases should be stratified into mild, moderate, or severe disease categories to guide initial therapy. In general, mild-to-moderate UC can be managed in the outpatient setting with 5-ASAs, mesalamine, and topical corticosteroids (combined topical and rectal therapy ideal) and with oral corticosteroids in unresponsive cases. Oral or IV corticosteroids in the short-term are used for moderate UC with consideration of long-term options such as biologic agents or immunomodulators. Patients with moderate UC, those recalcitrant to IV corticosteroids, or those with disease complications should be considered for a biologic agent or CsA; colectomy is also a rescue option for moderate-to-severe cases. Early surgical involvement is crucial, and colectomy may be life-saving in refractory or fulminant cases. Frequent assessments are needed to determine clinical response with intensification of therapy as needed to achieve disease control. Short-term treatment choices may be influenced by long-term management goals. Several new drugs have shown efficacy and safety for UC. Medication compliance and health-related QOL are important patient-centered issues. Future directions include continued drug development with longer-term safety and efficacy profiling and patient initiatives to encourage continued quality IBD care.

Disclosure

Dr Sunanda Kane is a consultant for AbbVie and Shire. Renée Marchioni Beery reports no conflicts of interest in this work.

Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501–523.

Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007;369(9573):1641–1657.

Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142(1):46–54.

Kappelman MD, Moore KR, Allen JK, Cook SF. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Dig Dis Sci. 2013;58(2):519–525.

Khalili H, Huang ES, Ananthakrishnan AN, et al. Geographical variation and incidence of inflammatory bowel disease among US women. Gut. 2012;61(12):1686–1692.

Munkholm P. Crohn’s disease – occurrence, course and prognosis. An epidemiologic cohort-study. Dan Med Bull. 1997;44(3):287–302.

Samuel S, Ingle SB, Dhillon S, et al. Cumulative incidence and risk factors for hospitalization and surgery in a population-based cohort of ulcerative colitis. Inflamm Bowel Dis. 2013;19(9):1858–1866.

Andres PG, Friedman LS. Epidemiology and the natural course of inflammatory bowel disease. Gastroenterol Clin North Am. 1999;28(2):255–281,vii.

Bernstein CN, Ng SC, Lakatos PL, et al. A review of mortality and surgery in ulcerative colitis: milestones of the seriousness of the disease. Inflamm Bowel Dis. 2013;19(9):2001–2010.

Lutgens MW, van Oijen MG, van der Heijden GJ, Vleggaar FP, Siersema PD, Oldenburg B. Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies. Inflamm Bowel Dis. 2013;19(4):789–799.

Cohen RD, Yu AP, Wu EQ, Xie J, Mulani PM, Chao J. Systematic review: the costs of ulcerative colitis in Western countries. Aliment Pharmacol Ther. 2010;31(7):693–707.

Kappelman MD, Rifas-Shiman SL, Porter CQ, et al. Direct health care costs of Crohn’s disease and ulcerative colitis in US children and adults. Gastroenterology. 2008;135(6):1907–1913.

Nguyen GC, Tuskey A, Dassopoulos T, Harris ML, Brant SR. Rising hospitalization rates for inflammatory bowel disease in the United States between 1998 and 2004. Inflamm Bowel Dis. 2007;13(12):1529–1535.

Pant C, Anderson MP, Deshpande A, et al. Trends in hospitalizations of children with inflammatory bowel disease within the United States from 2000 to 2009. J Investig Med. 2013;61(6):1036–1038.

Xavier RJ, Podolsky DK. Unraveling the pathogenesis of inflammatory bowel disease. Nature. 2007;448(7152):427–434.

International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) . Hinxton: Wellcome Trust Sanger Institute; 2012 . Available from: http://www.ibdgenetics.org. Accessed October 25, 2013.

Knights D, Lassen KG, Xavier RJ. Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut. 2013;62(10):1505–1510.

Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural history, and progression of ulcerative colitis. A long-term follow-up of 1116 patients. Dig Dis Sci. 1993;38(6):1137–1146.

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(10):1079–1087.

Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J. 1955;2(4947):1041–1048.

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(26):1625–1629.

Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Eng J Med. 2005;353(23):2462–2476.

Nguyen GC, Kaplan GG, Harris ML, Brant SR. A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients. Am J Gastroenterol. 2008;103(6):1443–1450.

Murthy SK, Steinhart AH, Tinmouth J, Austin PC, Daneman N, Nguyen GC. Impact of Clostridium difficile colitis on 5-year health outcomes in patients with ulcerative colitis. Aliment Pharmacol Ther. 2012;36(11–12):1032–1039.

Kandiel A, Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease. Am J Gastroenterol. 2006;101(12):2857–2865.

Carbonnel F, Lavergne A, Lemann M, et al. Colonoscopy of acute colitis. A safe and reliable tool for assessment of severity. Dig Dis Sci. 1994;39(7):1550–1557.

Terheggen G, Lanyi B, Schanz S, et al. Safety, feasibility, and tolerability of ileocolonoscopy in inflammatory bowel disease. Endoscopy. 2008;40(8):656–663.

Navaneethan U, Parasa S, Venkatesh PG, Trikudanathan G, Shen B. Prevalence and risk factors for colonic perforation during colonoscopy in hospitalized inflammatory bowel disease patients. J Crohns Colitis. 2011;5(3):189–195.

Navaneethan U, Kochhar G, Phull H, et al. Severe disease on endoscopy and steroid use increase the risk for bowel perforation during colonoscopy in inflammatory bowel disease patients. J Crohns Colitis. 2012;6(4):470–475.

Anupindi SA, Terreblanche O, Courtier J. Magnetic resonance enterography: inflammatory bowel disease and beyond. Magn Reson Imaging Clin N Am. 2013;21(4):731–750.

Ordas I, Rimola J, Garcia-Bosch O, et al. Diagnostic accuracy of magnetic resonance colonography for the evaluation of disease activity and severity in ulcerative colitis: a prospective study. Gut. 2013;62(11):1566–1572.

Pola S, Patel D, Ramamoorthy S, et al. Strategies for the care of adults hospitalized for active ulcerative colitis. Clin Gastroenterol Hepatol. 2012;10(12):1315–1325. e4.

Chang KH, Burke JP, Coffey JC. Infliximab versus cyclosporine as rescue therapy in acute severe steroid-refractory ulcerative colitis: a systematic review and meta-analysis. Int J Colorectal Dis. 2013;28(3):287–293.

Herrinton LJ, Liu L, Fireman B, et al. Time trends in therapies and outcomes for adult inflammatory bowel disease, Northern California,1998–2005. Gastroenterology. 2009;137(2):502–511.

Chande N. Prevention of venous thromboembolism in hospitalized patients with inflammatory bowel disease. Inflamm Bowl Dis. 2013;19(3):669–671.

Murthy SK, Nguyen GC. Venous thromboembolism in inflammatory bowel disease: an epidemiological review. Am J Gastroenterol. 2011;106(4):713–718.

Fumery M, Xiaocang C, Dauchet L, Gower-Rousseau C, Peyrin-Biroulet L, Colombel JF. Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: a meta-analysis of observational studies. J Crohns Colitis. Epub October 29, 2013.

Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet. 2010;375(9715):657–663.

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(9):2272–2280.

Wallaert JB, De Martino RR, Marsicovetere PS, et al. Venous thromboembolism after surgery for inflammatory bowel disease: are there modifiable risk factors? Data from ACS NSQIP. Dis Colon Rectum. 2012;55(11):1138–1144.

Ra G, Thanabalan R, Ratneswaran S, Nguyen GC. Predictors and safety of venous thromboembolism prophylaxis among hospitalized inflammatory bowel disease patients. J Crohns Colitis. 2013;7(10):e479–e485.

Marshall JK, Thabane M, Steinhart AH, Newman JR, Anand A, Irvine EJ. Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis . Cochrane Database Syst Rev. 2010;1:CD004115.

Gionchetti P, Rizzello F, Venturi A, et al. Comparison of oral with rectal mesalazine in the treatment of ulcerative proctitis. Dis Colon Rectum. 1998;41(1):93–97.

Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis. Gut. 1997;40(6):775–781.

Cohen RD, Woseth DM, Thisted RA, Hanauer SB. A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol. 2000;95(5):1263–1276.

Regueiro M, Loftus EV Jr, Steinhart AH, Cohen RD. Clinical guidelines for the management of left-sided ulcerative colitis and ulcerative proctitis: summary statement. Inflamm Bowel Dis. 2006;12(10):972–978.

Sandborn WJ, Hanauer SB. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment Pharmacol Ther. 2003;17(1):29–42.

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(7):893–902.

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):1–8.

Flourie B, Hagege H, Tucat G, et al. Randomised clinical trial: once- vs twice-daily prolonged-release mesalazine for active ulcerative colitis. Aliment Pharmacol Ther. 2013;37(8):767–775.

Sandborn WJ, Regula J, Feagan BG, et al. Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis. Gastroenterology. 2009;137(6):1934–1943.

Kane S, Huo D, Magnanti K. A pilot feasibility study of once daily versus conventional dosing mesalamine for maintenance of ulcerative colitis. Clin Gastroenterol Hepatol. 2003;1(3):170–173.

Raedler A, Behrens C, Bias P. Mesalazine (5-aminosalicylic acid) micropellets show similar efficacy and tolerability to mesalazine tablets in patients with ulcerative colitis – results from a randomized-controlled trial. Aliment Pharmacol Ther. 2004;20(11–12):1353–1363.

Dignass AU, Bokemeyer B, Adamek H, et al. Mesalamine once daily is more effective than twice daily in patients with quiescent ulcerative colitis. Clin Gastroenterol Hepatol. 2009;7(7):762–769.

Sandborn WJ, Korzenik J, Lashner B, et al. Once-daily dosing of delayed-release oral mesalamine (400-mg tablet) is as effective as twice-daily dosing for maintenance of remission of ulcerative colitis. Gastroenterology. 2010;138(4):1286–1296.

Sandborn WJ, Kamm MA, Lichtenstein GR, Lyne A, Butler T, Joseph RE. MMX Multi Matrix System mesalazine for the induction of remission in patients with mild-to-moderate ulcerative colitis: a combined analysis of two randomized, double-blind, placebo-controlled trials. Aliment Pharmacol Ther. 2007;26(2):205–215.

Safdi M, DeMicco M, Sninsky C, et al. A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis. Am J Gastroenterol. 1997;92(10):1867–1871.

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(7):960–965.

Campieri M, De Franchis R, Bianchi Porro G, Ranzi T, Brunetti G, Barbara L. Mesalazine (5-aminosalicylic acid) suppositories in the treatment of ulcerative proctitis or distal proctosigmoiditis. A randomized controlled trial. Scand J Gastroenterol. 1990;25(7):663–668.

Lamet M, Ptak T, Dallaire C, et al. Efficacy and safety of mesalamine 1g HS versus 500 mg BID suppositories in mild to moderate ulcerative proctitis: a multicenter randomized study. Inflamm Bowel Dis. 2005;11(7):625–630.

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(6):1894–1898.

Hanauer SB; US PENTASA Study Group. Dose-ranging study of mesalamine (PENTASA) enemas in the treatment of acute ulcerative proctosigmoiditis: results of a multicentered placebo-controlled trial. Inflamm Bowel Dis. 1998;4(2):79–83.

Ardizzone S, Doldo P, Ranzi T, et al; SAF-3 Study Group. Mesalazine foam (Salofalk foam) in the treatment of active distal ulcerative colitis. A comparative trial vs Salofalk enema. Ital J Gastroenterol Hepatol. 1999;31(8):677–684.

Biancone L, Gionchetti P, Del Vecchio Blanco G, et al. Beclomethasone dipropionate versus mesalazine in distal ulcerative colitis: a multicenter, randomized, double-blind study. Dig Liver Dis. 2007;39(4):329–337.

Hanauer SB, Robinson M, Pruitt R, et al; US Budesonide Enema Study Group. Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-ranging study. Gastroenterology. 1998;115(3):525–532.

Sandborn WJ, Travis S, Moro L, et al. Once-daily budesonide MMX® extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study. Gastroenterology. 2012;143(5):1218–1226.

Travis SP, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut. 2014;63(3):433–441.

Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis . Cochrane Database Syst Rev. 2012;10:CD000543.

Sutherland L, Macdonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis . Cochrane Database Syst Rev. 2006;2:CD000543.

Baron JH, Connell AM, Kanaghinis TG, Lennard-Jones JE, Jones AF. Out-patient treatment of ulcerative colitis. Comparison between three doses of oral prednisone. Br Med J. 1962;2(5302):441–443.

Turner D, Walsh CM, Steinhart AH, Griffiths AM. Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression. Clin Gastroenterol Hepatol. 2007;5(1):103–110.

Tourner M, Loftus EV Jr, Harmsen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134(4):929–936.

Gisbert JP, Linares PM, McNicholl AG, Mate J, Gomollon F. Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther. 2009;30(2):126–137.

Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi Porro G. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut. 2006;55(1):47–53.

Relling MV, Gardner EE, Sandborn WJ, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther. 2011;89(3):387–391.

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(2):83–88.

Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as a rescue therapy in severe to moderately severe ulcerative colitis: a randomized placebo-controlled study. Gastroenterology. 2005;128(7):1805–1811.

Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011;60(6):780–787.

Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142(2):257–265.

Feagan BG, Sandborn WJ, Lazar A, et al. Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis. Gastroenterology. 2014;146(1):110–118.

Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):85–95.

Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):96–109.

Dinesen LC, Walsh AJ, Protic MN, et al. The pattern and outcome of acute severe colitis. J Crohns Colitis. 2010;4(4):431–437.

Travis SP, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis. Gut. 1996;38(6):905–910.

Aceituno M, García-Planella E, Heredia C, et al. Steroid-refractory ulcerative colitis: predictive factors of response to cyclosporine and validation in an independent cohort. Inflamm Bowel Dis. 2008;14(3):347–352.

Message L, Bourreille A, Laharie D, et al. Efficacy of intravenous cyclosporin in moderately severe ulcerative colitis refractory to steroids. Gastroenterol Clin Biol. 2005;29(3):231–235.

Sood A, Midha V, Sood N, et al. Cyclosporine in the treatment of severe steroid refractory ulcerative colitis: a retrospective analysis of 24 cases. Indian J Gastroenterol. 2008;27(6):232–235.

Actis GC, Volpes R, Rizzetto M. Oral microemulsion cyclosporin to reduce steroids rapidly in chronic active ulcerative colitis. Eur J Gastrenterol Hepatol. 1999;11(8):905–908.

Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994;330(26):1841–1845.

Ogata H, Matsui T, Nakamura M, et al. A randomized dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut. 2006;55(9):1255–1262.

Benson A, Barrett T, Sparberg M, Buchman AL. Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn’s disease: a single-center experience. Inflamm Bowel Dis. 2008;14(1):7–12.

Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU. 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(5):1048–1056.

Fellermann K, Ludwig D, Stahl M, David-Walek T, Stange EF. Steroid-unresponsive acute attacks of inflammatory bowel disease: immunomodulation by tacrolimus (FK506). Am J Gastroenterol. 1998;93(10):1860–1866.

Schmidt KJ, Herrlinger KR, Emmrich J, et al. Short-term efficacy of tacrolimus in steroid-refractory ulcerative colitis – experience in 130 patients. Aliment Pharmacol Ther. 2013;37(1):129–136.

Leblanc S, Allez M, Seksik P, et al. Successive treatment with cyclosporine and infliximab in steroid-refractory ulcerative colitis. Am J Gastroenterol. 2011;106(4):771–777.

Ananthakrishnan AN, Issa M, Beaulieu DB, et al. History of medical hospitalization predicts future need for colectomy in patients with ulcerative colitis. Inflamm Bowel Dis. 2009;15(2):176–181.

Tøttrup A, Erichsen R, Svaerke C, Laurberg S, Srensen HT. Thirty-day mortality after elective and emergency total colectomy in Danish patients with inflammatory bowel disease: a population-based nationwide cohort study. BMJ Open. 2012;2(2):e000823.

Coakley BA, Telem D, Nguyen S, Dallas K, Divino CM. Prolonged preoperative hospitalization correlates with worse outcomes after colectomy for acute fulminant ulcerative colitis. Surgery. 2013;153(2):242–248.

Grucela A, Steinhagen RM. Current surgical management of ulcerative colitis. Mt Sinai J Med. 2009;76(6):606–612.

Cohen JL, Strong SA, Hyman NH, et al. Practice parameters for the surgical treatment of ulcerative colitis. Dis Colon Rectum. 2005;48(11):1997–2009.

Hicks CW, Hodin RA, Bordeianou L. Possible overuse of 3-stage procedures for active ulcerative colitis. JAMA Surg. 2013;148(7):658–664.

Burke DA, Axon AT, Clayden SA, Dixon MF, Johnston D, Lacey RW. The efficacy of tobramycin in the treatment of ulcerative colitis. Aliment Pharmacol Ther. 1990;4(2):123–129.

Lobo AJ, Burke DA, Sobala GM, Axon AT. Oral tobramycin in ulcerative colitis: effect on maintenance of remission. Aliment Pharmacol Ther. 1993;7(2):155–158.

Turunen UM, Farkkila MA, Hakala K, et al. Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study. Gastroenterology. 1998;115(5):1072–1078.

Mantzaris GJ, Archavlis E, Christoforidis P, et al. A prospective randomized controlled trial of oral ciprofloxacin in acute ulcerative colitis. Am J Gastroenterol. 1997;92(3):454–456.

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(9):971–974.

Dickinson RJ, O’Connor HJ, Pinder I, Hamilton I, Johnston D, Axon AT. Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut. 1985;26(12):1380–1384.

Mantzaris GJ, Hatzis A, Kontogiannis P, Triadaphyllou G. Intravenous tobramycin and metronidazole as an adjunct to corticosteroids in acute, severe ulcerative colitis. Am J Gastroenterol. 1994;89(1):43–46.

Chapman RW, Selby WS, Jewell DP. Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut. 1986;27(10):1210–1212.

Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet. 1974;1(7866):1067–1070.

Truelove SC, Willoughby CP, Lee EG, Kettlewell MG. Further experience in the treatment of severe attacks of ulcerative colitis. Lancet. 1978;2(8099):1086–1088.

Jarnerot G, Rolny P, Sandberg-Gertzen H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology. 1985;89(5):1005–1013.

Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699–710.

Schwab N, Hohn KG, Schneider-Hohendorf T, et al. Immunological and clinical consequences of treating a patient with natalizumab. Mult Scler. 2012;18(3):335–344.

Flanagan ME, Blumenkopf TA, Brissette WH, et al. Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection. J Med Chem. 2010;53(24):8468–8484.

Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367(7):616–624.

Janke KH, Raible A, Bauer M, et al. Questions on life satisfaction (FLZM) in inflammatory bowel disease. Int J Colorectal Dis. 2004;19(4):343–353.

Randell RL, Long MD, Martin CF, et al. Patient perception of chronic illness care in a large inflammatory bowel disease cohort. Inflamm Bowel Dis. 2013;19(7):1428–1433.

Kane S, Shaya F. Medication non-adherence is associated with increased medical health care costs. Dig Dis Sci. 2008;53(4):1020–1024.

Mitra D, Hodgkins P, Yen L, Davis KL, Cohen RD. Association between oral 5-ASA adherence and health care utilization and costs among patients with active ulcerative colitis. BMC Gastroenterol. 2012;12:132.

Yen L, Wu J, Hodgkins PL, Cohen RD, Nichol MB. Medication use patterns and predictors of nonpersistence and nonadherence with oral 5-aminosalicylic acid therapy in patients with ulcerative colitis. J Manag Care Pharm. 2012;18(9):701–712.

Robinson A, Hankins M, Wiseman G, Jones M. Maintaining stable symptom control in inflammatory bowel disease: a retrospective analysis of adherence, medication switches and the risk of relapse. Aliment Pharmacol Ther. 2013;38(5):531–538.

Lopez A, Billioud V, Peyrin-Biroulet C, Peyrin-Biroulet L. Adherence to anti-TNF therapy in inflammatory bowel diseases: a systematic review. Inflamm Bowel Dis. 2013;19(7):1528–1533.

Baars JE, Siegel CA, Kuipers EJ, van der Woude CJ. Patient’s perspectives important for early anti-tumor necrosis factor treatment in inflammatory bowel disease. Digestion. 2009;79(1):30–35.

Kane S, Becker B, Harmsen WS, Kurian A, Morisky DE, Zinsmeister AR. Use of a screening tool to determine nonadherent behavior in inflammatory bowel disease. Am J Gastroenterol. 2012; 107(2):154–160.

Iglesias-Rey M, Barreiro-de Acosta M, Caamano-Isorna F, et al. Psychological factors are associated with changes in the health-related quality of life in inflammatory bowel disease. Inflamm Bowel Dis. 2014;20(1):92–102.

Elkjaer M, Shuhaibar M, Burisch J, et al. E-health empowers patients with ulcerative colitis: a randomised controlled trial of the web-guided “Constant-care” approach. Gut. 2010;59(12):1652–1661.

Charles C, Gafni A, Whelan T. Shared decision-making in the medical encounter: what does it mean? (or it takes at least two to tango). Soc Sci Med. 1997;44(5):681–692.

Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130(3):940–987.

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