Incidence of Colectomy During Long-term Follow-up After Cyclosporine-Induced Remission of Severe Ulcerative Colitis

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4: Incidence of Colectomy During Long-term Follow-up After Cyclosporine-Induced Remission of Severe Ulcerative Colitis DAVID N. MOSKOVITZ, GERT VAN ASSCHE, BENEDIKTE MAENHOUT, JORIS ARTS, MARC FERRANTE, SEVERINE VERMEIRE, and PAUL RUTGEERTS Department of Internal Medicine, University Hospital, Gasthuisberg Herestraat, Leuven, Belgium Background & Aims: Cyclosporine (CSA) has been shown to be effective in steroid-refractory ulcerative colitis (UC) and as an alternative to glucocorticosteroids in patients with severe attacks of UC. Our aim was to investigate the long-term efficacy of CSA. Methods: We conducted a retrospective cohort study of all patients admitted to our institution with an attack of UC treated with intravenous CSA between November 1992 and October Patients who responded to intravenous CSA were switched to Neoral for 3 months. Kaplan Meier curves were used for survival analysis with quantitative variables compared using a 2-tailed Student t test with qualitative variables and differences compared with a 2 analysis. Results: A total of 118 (83%) of the 142 patients had an initial response to CSA and avoided colectomy during hospitalization. Of the 118 patients, 64 (54%) required a future colectomy. The rate of colectomy in those already on azathioprine compared with those starting azathioprine concurrently with CSA was 59% vs 31%, respectively (P <.05). Also, 88% of patients already on azathioprine and requiring colectomy underwent surgery within the first year of receiving CSA. Life-table analysis shows that although only 33% of patients require colectomy at 1 year, 88% will require colectomy at 7 years. Conclusions: CSA is an effective short- to medium-term treatment for patients with severe UC but at 7 years, 88% of patients will require a colectomy. Azathioprinenaive patients have better outcomes. Severe and fulminant ulcerative colitis (UC) occurs in only 15% of UC patients but is associated with severe morbidity necessitating hospitalization in most patients. 1 The immunosuppressant cyclosporine (CSA) has proven to be highly efficacious at inducing remission in patients with severe UC. The first controlled evidence to support the use of CSA in this indication stems from a trial by Lichtiger et al 2 in a group of steroid-refractory patients with UC. Results from that study suggested that 82% of patients treated with CSA respond and ultimately avoid colectomy in the short term. For several reasons CSA has become an attractive drug in the treatment of severe UC. The only effective drugs for patients with severe attacks of UC are glucocorticosteroids. Glucocorticosteroids fail to achieve an improvement in 40% of patients. 3 Furthermore, a significant number of side effects have been attributed to glucocorticosteroid use including avascular necrosis, psychosis, diabetes mellitus, hypertension, and osteoporosis. Failing improvement with glucocorticosteroids, the other options for inducing remission in patients with severe UC are infliximab or total proctocolectomy with or without ileoanal anastomosis. Jarnerot et al 4 reported the use of 5 mg/kg of infliximab in severe to moderately severe UC that did not respond to conventional treatment. They reported an odds ratio of 4.9 and a 95% confidence interval of in favor of infliximab over placebo as rescue therapy in patients with moderate to severe UC. Although patients achieve symptomatic improvement of their UC with surgical procedures, studies suggest a reduced quality of life after colectomy when compared with colon-sparing measures. 5 CSA may be effective not only in patients with severe UC who have failed intravenous glucocorticosteroids, but D Haens et al 6 suggested that CSA is as effective as intravenous glucocorticosteroids as first-line management of severe UC. A starting intravenous (IV) dose of 4 mg/kg CSA was used in both controlled trials, but recent evidence has shown that 2 mg/kg IV CSA daily as a starting dose achieves the same efficacy and may improve the short-term side-effect profile. 7,8 Severe UC can present de novo in patients who otherwise were healthy. More commonly, patients with severe UC present after years of illness. As a result, patients, before receiving CSA, often have been treated with either mesalamine products or immunomodulators such as azathioprine or 6-mercaptopurine. Cohen et al 9 showed that the probability of avoiding colectomy in Abbreviations used in this paper: AZA, azathioprine; CSA, cyclosporine; IV, intravenous; UC, ulcerative colitis by the American Gastroenterological Association Institute /06/$32.00 doi: /j.cgh

2 June 2006 CSA REMISSION OF SEVERE UC 761 patients who received CSA and 6-mercaptopurine/azathioprine was 66% at 5.5 years compared with 40% in those who received CSA alone, suggesting a benefit with combination CSA and immunomodulation. Despite the controlled evidence supporting the use of cyclosporine in severe UC, it has not been accepted widely in clinical practice. Furthermore, the role of immunomodulation in combination with CSA has yet to be delineated. Reports from clinical experience in large academic centers, however, confirm the data from controlled trials. Arts et al 10 performed the most comprehensive retrospective analysis of the use of CSA at a single center. The investigators were able to show an 83.7% response rate to CSA in the short-term management of severe UC, defined as a response to CSA during the initial hospital stay with an avoidance of colectomy. In another longterm study, Cohen et al 9 showed that at 5.5 years 70% of patients who initially respond to CSA will avoid colectomy. The most concerning result from the Arts et al 10 study was the 3.5% mortality rate attributed to CSA use. There have been suggestions that the immunosuppressive properties of CSA put patients at risk for perioperative complications. Previous reports have suggested no increased incidence of morbidity associated with the use of IV CSA in the perioperative period 11 ; however, postmarketing data on CSA do not extend beyond 5 years. The purpose of this analysis was to look at the long-term efficacy of cyclosporine use beyond 5 years and to study the effect of concomitant immunomodulation on the outcome. Methods Patients and Treatment Regimen The medical charts and progress notes of all patients admitted to the Gastroenterology Department of the university hospital of Leuven (Belgium) with a severe attack of UC who were treated with IV CSA between November 1992 and October 2004 were included in the study. This study was an extension of the study performed by Arts et al. 10 For patient identification we used the pharmacy records. Before treatment with IV CSA was initiated all patients were treated with IV glucocorticosteroids (minimum, 40 mg methylprednisolone/ day). Patients were considered for CSA if their clinical condition did not improve after 5 7 days of IV steroid treatment or when there was a subjective or objective deterioration in their condition. Patients received CSA at a dose of 4 mg/kg/day or 2 mg/kg/day as a continuous IV infusion for a total of 7 days. The conditions of all patients were assessed daily by the treating physician and the consulting surgeon and when patients failed to improve after 7 10 days or when their medical condition worsened, they were scheduled for immediate colectomy. During IV treatment, CSA blood levels were kept between 250 and 450 ng/ml (4 mg/kg) or between 150 and 250 ng/ml (2 mg/kg). Patients who had a response were switched to oral treatment with Neoral (Novartis, Basel, Switzerland) at an initial dose of 8 mg/kg/day and the dose was adjusted to blood levels between 150 and 250 ng/ml. Intravenous glucocorticosteroids were continued at stable doses during IV CSA treatment. Those patients who achieved a response to IV CSA were switched to a tapering dose of oral glucocorticosteroids. CSA was continued in responders for a total of 3 months. Patients who already were taking azathioprine or 6-mercaptopurine were continued at their current levels. Those patients not taking azathioprine or 6-mercaptopurine were started at a dose of 2.5 mg/kg and 1.5 mg/kg, respectively, at the time of response to CSA during their hospitalization, if they had no known intolerance. Side effects and postoperative complications were recorded retrospectively from hospital records and clinic notes. Outcomes and Statistics The major outcomes in this trial were the risk for early colectomy during IV CSA treatment and late colectomy during follow-up evaluation, as well as symptomatic recurrence in those patients not requiring colectomy. Secondary outcomes included the role of immunomodulation in the long-term risk for colectomy, and long-term morbidity and mortality. Quantitative variables were compared with a 2-tailed Student t test. Qualitative variables and differences were compared with 2 analysis. Kaplan Meier curves were used for survival analysis. Results Patient Demographics A total of 142 (65 female, 46%) patients were identified and records for all patients were recovered. The mean age of the patients was 41 years (range, y). The mean duration of IV CSA was 9.3 days. The mean duration of oral CSA therapy of the responders to IV CSA was 97 days. Short-term Response to Intravenous Cyclosporine A total of 118 of the initial 142 (81%) patients had a response to IV CSA and avoided colectomy during their initial hospitalization. Of these 118 patients, 20 achieved a partial response to CSA and continued to experience abdominal pain and bloody diarrhea, however, all were able to be discharged from the hospital and avoided colectomy. The duration of IV CSA administration averaged 9.3 days (range, 1 28 days). The mean interval to surgery in patients not responding to CSA was 23 days (range, days). In responders, the mean number of days on oral CSA was 97 (Table 1). Twenty-three patients required a second dose of IV CSA with 12 (52%) of those patients requiring surgery.

3 762 MOSKOVITZ ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 6 Table 1. Characteristics of Patients Who Responded and Who Did Not Respond to CSA No colectomy Colectomy All N Female/Male 55/63 10/14 65/77 Age, y Disease duration, 1979 (5.4) 2086 (5.7) 2015 (5.5) days (y) Left sided 57 (49%) 17 (71%) 74 (52%) Pancolitis 60 (51%) 7 (28%) 67 (48%) Duration of IV CSA De novo AZA 69 (58%) 5 (21%) 74 (52%) Already on AZA 33 (28%) 11 (46%) 44 (31%) No AZA 16 (14%) 8 (33%) 24 (17%) Mean C-reactive 65 (1 377) 109 (15 283) 73 (1 377) protein level (range), mg/l Mean albumin level (range), g/dl 34 (17 52) 32 (17 39) 34 (17 52) AZA, azathioprine. One patient required a third IV dose of CSA and 1 patient required a fourth. Factors predicting failure of IV CSA and the need for colectomy were left-sided disease and prior treatment with azathioprine (P.01) (Table 2). Long-term Response Forty-one (35%) of the 118 patients who responded to CSA eventually required colectomy. The mean number of days before requiring colectomy was 542 (range, days). Table 3 compares the characteristics of those patients who required a colectomy with those who did not require colectomy. Life-table analysis of avoidance of colectomy is shown in Figure 1. The probability to avoid colectomy after successful CSA therapy was 63% at 1 year, 41% at 4 years, 16% at 6 years, and 12% at 7 years. Also, most patients without colectomy experienced symptom recurrence during follow-up evaluation and as shown in Figure 2 only 14% had not experienced a symptom relapse at 7 years. Table 3. Characteristics of Patients Requiring Colectomy After Initially Responding to CSA Compared With Patients Who Were Colectomy Free No colectomy Colectomy N Female Male Age Disease duration, days (y) 1985 (5.4) 2086 (5.7) Left sided 39 (51%) 21 (51%) Pancolitis 38 (49%) 20 (49%) Duration of IV CSA, days Duration of oral CSA, days De novo AZA 50 (65%) 19 (46%) Already on AZA 18 (23%) 15 (37%) AZA, azathioprine. Influence of Immunomodulation Forty-four patients (31%) already were treated with immunosuppressives at the time of CSA therapy; 74 others (52%) were started de novo on immunosuppressives. For those patients requiring a colectomy, 26 (41%) were already on azathioprine compared with 18 (23%) patients already on azathioprine who did not require colectomy (P.01). Twenty-three (88%) of the 26 patients already on azathioprine had a colectomy within 1 year. Only 12 (52%) of 23 patients who started azathioprine at the same time as CSA required colectomy within 1 year (Figure 3). Table 2. Odds Ratio for Patients With Left-Sided Disease and Already on Azathioprine Colectomy Odds ratio 95% CI P Total 24/142 Left-sided disease 17/74 (23%) Already on azathioprine 11/44 (25%) CI, confidence interval. Figure 1. Kaplan Meier curve for those patients who remain colectomy free. N number at risk.

4 June 2006 CSA REMISSION OF SEVERE UC 763 Table 4. Side Effects of CSA Therapy Side effect Number (%) Renal 5 (3.5) Hypertension 8 (5.6) Gingivitis 10 (7.0) Infection 25 (17.6) Tremor 17 (12) Death 4 (2.8) Hypertrichosis 14 (10) Transaminitis 3 (2.1) Parasthesia 3 (2.1) Anaphylaxis 1 (.7) Headache 5 (3.5) Figure 2. Patients who did not have a colectomy who still are asymptomatic. N number at risk. Adverse Events The most common side effect experienced by patients taking CSA was the development of an opportunistic infection (25 patients; 17.6%). Table 4 lists the side effects experienced by all of the patients taking CSA. There were 4 (2.8%) deaths. Three patients died of an opportunistic infection, all within 3 months of taking CSA. Systemic aspergillosis was the cause of death in 1 patient and Pneumocystis carinii pneumonia was the cause in 2 patients. The fourth patient died of complications related to chronic myelomonocytic leukemia after 6 years of UC disease remission induced by IV CSA and maintained with azathioprine 2.5 mg/kg. Of the 63 patients undergoing colectomy there were 25 (40%) complications experienced by 22 (35%) patients. Table 5 details the specific complications experienced. Comparing those patients with and without complications, there was no difference in the sex, age, disease % De Novo AZA Already on AZA Never on AZA colectomy no colectomy Figure 3. Influence of immunomodulation on rate of colectomy. duration, disease location, or the duration of CSA use (Table 6). Interestingly, there was no difference in the rate of complications for those patients who had a colectomy while on cyclosporine and those who were off cyclosporine for longer than 3 months (Table 7). Discussion CSA is effective in inducing remission in patients with severe UC. We report an 81% response to IV CSA. Our short-term results that suggest that 48% of patients avoid colectomy at 3 years are similar to other reports. 9,12 Novel data in this study, however, indicate that at 7 years only 12% of patients remain colectomy free. Furthermore, in those patients who have avoided colectomy, 48% are symptomatic at 3 years, with 82% being symptomatic at 7 years. This suggests that a significant majority of patients will require a colectomy after CSA treatment, with virtually all patients experiencing symptomatic recurrence of their UC. The approach to the management of UC typically involves inducing remission and then maintaining patients in an asymptomatic and surgically free state. The mesalamine class of drugs generally are reserved for those with mild to moderate disease, but may be indicated more largely for prophylaxis of colorectal cancer. 13 Those patients with more active disease often are maintained on immunomodulators such as azathioprine or 6-mercapto- Table 5. Postoperative Complications Complications Number Abdominal abscess 10 Anastomotic leak 4 Venous thrombosis 3 Wound dehiscence 1 Pouch necrosis 1 Sepsis 2 Peritonitis 1 Wound infection 2 Bleed 1

5 764 MOSKOVITZ ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 6 purine. In our study, 74 (52%) patients were started on immunomodulators at the same time as IV CSA, with 44 (31%) already receiving immunomodulators. We show that 23 of 26 (88%) patients already on azathioprine at the start of IV CSA had a colectomy within 1 year. This compares with 12 of 23 (52%) who started azathioprine at the same time as IV CSA. Furthermore, there is a statistically significant difference in the initial response to CSA (colectomy rate) for those already on azathioprine compared with those starting azathioprine. This is contradictory to previous reports from Cohen et al 9 who showed that 77% of the nonsurgical patients compared with 44% of patients who required surgery received 6-mercaptopurine/azathioprine. Our data suggest that patients taking immunomodulators before starting CSA may represent a group of patients with more severe refractory disease who may not benefit from CSA treatment. The side effects of CSA have been documented previously There were 4 deaths attributed to CSA use in this study; 3 of the deaths occurred secondary to the development of an opportunistic infection. In all cases the patients were taking CSA, azathioprine, and methylprednisolone. None of these patients received antibiotic prophylaxis. In those patients receiving sulfamethoxazol/trimethoprim prophylaxis (for P carinii pneumonia) there were no deaths attributed to opportunistic infections. The fourth patient died from complications related to chronic myelomonocytic leukemia. The patient had received CSA 5 years before developing chronic myelomonocytic leukemia. Furthermore, his UC was stable before his death. The mortality rate observed in this trial is higher than what has been reported in other series, 10 probably partially owing to the lack of P carinii pneumonia prophylaxis. However, it should be Table 6. Characteristics of Patients Experiencing Postoperative Complications Complication No complication N Female 9 19 Male Age Disease 3385 (9.3) 2928 (8.0) duration, days (y) Disease location 10 (45%)/12 (55%) 17 (40%)/25 (60%) L/P Duration of IV CSA Already on AZA 8/44 (18%) 36/44 (82%) De novo AZA or never received AZA 17/100 (17%) 86/100 (86%) L/P, left/pancolitis; AZA, azathioprine. Table 7. Effect of Current Use of CSA on Complication Rate compared with the mortality associated with emergency and elective total colectomies. Furthermore, our study confirms previous reports that the use of CSA does not increase the rate of postoperative complications. 11,17 This study advances our understanding regarding the use of CSA in patients with severe UC. Our data suggest that a clear role exists for the use of CSA in the shortterm management of severe UC. CSA may be used in those patients failing IV glucocorticosteroids and possibly used as first-line treatment for those with severe UC. Given that patients often not only are immunosuppressed from medications (CSA, glucocorticosteroids, azathioprine) but also from their disease state, it is necessary to start antibiotic prophylaxis. The use of azathioprine or 6-mercaptopurine before receiving CSA is a predictor of poor short- and long-term response to CSA. In those patients already taking azathioprine or 6-mercaptopurine, a discussion with the patient regarding surgical management of their disease is warranted. We propose that CSA is not indicated in patients who have failed azathioprine at a correct dose. With the results of the ACT 1 and 2 studies and the Jarnerot et al 4 study infliximab could be a valuable alternative for CSA and a randomized comparative trial is necessary. 18,19 CSA should be looked at as a short-term bridge to more definitive management of disease, either long-term immunomodulation therapy or elective colectomy. The low long-term symptomatic and surgical remission rate in patients receiving CSA stresses the need for studies that will look at better methods of disease control in patients with severe UC. References 1. Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis. Part 1 short term prognosis. Gut 1963;4: Lichtiger G, Rolny P, Sandberg-Gertzen H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology 1985;89: Jarnerot G, Rolny P, Sandberg-Gertzen H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology 1985;89: 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: Cohen RD, Brodsky AL, Hanauer SB. A comparison of the quality of life in patients with severe ulcerative colitis after total colec- N Complication No complication Patient had surgery while on CSA (73%) 30 (75%) Patient had surgery after being 16 6 (27%) 10 (25%) off CSA for 3 mo

6 June 2006 CSA REMISSION OF SEVERE UC 765 tomy versus medical treatment with intravenous cyclosporine. Inflamm Bowel Dis 1999;5: D Haens G, Lemmens L, Geboes K, et al. Intravenous cyclosporine versus intravenous glucocorticosteroids as a single therapy for severe attacks of ulcerative colitis. Gastroenterology 2001; 120: Actis GC, Ottobrelli A, Pera A, et al. Continuously infused cyclosporine at low dose is sufficient to avoid emergency colectomy in acute attacks of ulcerative colitis without the need for high-dose steroids. J Clin Gastroenterol 1993;17: Van Assche G, D Haens G, Noman M, et al. Randomized, doubleblind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology 2003;125: Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporine in ulcerative colitis: a five-year experience. Am J Gastroenterol 1999;94: Arts J, D Haens G, Zeegers M, et al. Long-term outcome of treatment with intravenous cyclosporine in patients with severe ulcerative colitis. Inflamm Bowel Dis 2004;10: Fleshner PR, Michelassi F, Rubin M, et al. Morbidity of subtotal colectomy in patients with severe ulcerative colitis unresponsive to cyclosporin. Dis Colon Rectum 1995;38: Eaden J, Abrams K, Ekbom A, et al. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 2000;14: 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: Wijdicks EF, Wiesner RH, Krom RA. Neurotoxicity in liver transplant recipients with cyclosporine immunosuppression. Neurology 1995;45: de Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis 2000;35: Porter GA, Bennett WM, Sheps SG. Cyclosporine-associated hypertension. National High Blood Pressure Education Program. Arch Intern Med 1990;150: Hyde GM, Jewell DP, Kettlewell MGW, et al. Cyclosporin for severe ulcerative colitis does not increase the rate of perioperative complications. Dis Colon Rectum 2001;44: Rutgeerts P, Feagan BG, Olson A, et al. A randomized placebocontrolled trial of infliximab therapy for active ulcerative colitis: Act 1 trial. Gastroenterology 2005;128(Suppl 1):A Sandborn WJ, Rachmilewitz D, Hanauer SB, et al. Infliximab induction and maintenance therapy for ulcerative colitis: the Act 2 trial. Gastroenterology 2005;128(Suppl 1):A688. Address requests for reprints to: Gert Van Assche, MD, PhD, Department of Internal Medicine, University Hospital, Gasthuisberg Herestraat, 49, B-3000, Leuven, Belgium. gert.vanassche@uz.kuleuven.ac.be; fax: (32)

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