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Cyclosporine and Infliximab as Rescue Therapy for Each Other in Patients With Steroid-Refractory Ulcerative Colitis
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:1112–1116
Cyclosporine and Infliximab as Rescue Therapy for Each Other in Patients With Steroid-Refractory Ulcerative Colitis ELANA A. MASER, DEEPTHI DECONDA, SIMON LICHTIGER, THOMAS ULLMAN, DANIEL H. PRESENT, and ASHER KORNBLUTH The IBD Center and Division of Gastroenterology, Mount Sinai Medical Center, and the Mount Sinai Consortium for Research in IBD, New York, New York
See D’Haens GR et al on page 1123 and Sandborn WJ et al on page 1130 in the October 2008 issue of Gastroenterology. Background & Aims: In patients with severe corticosteroidrefractory ulcerative colitis, cyclosporine or infliximab may be added in an effort to induce remission. If the patient then fails either of these drugs, it is unknown whether success can be achieved by using the other agent. The aim of this study was to assess outcomes of using cyclosporine after failure of infliximab, and vice versa. Methods: We retrospectively reviewed the charts of 19 patients with corticosteroid-refractory ulcerative colitis who received either infliximab after failed cyclosporine or cyclosporine after failed infliximab. Acute salvage therapy was defined as having received the alternate drug within 4 weeks of discontinuing the first agent. Results: Ten patients received infliximab after failing cyclosporine; 9 patients received cyclosporine after failing infliximab. Four patients (40%) in the infliximab-salvage group achieved remission, as did 3 (33%) in the cyclosporine-salvage group. Remission lasted a mean of 10.4 months (range, 4.4 –17.03 mo) and 28.5 months (range, 5.0 – 41.5 mo), respectively. Severe adverse events included one patient who developed sepsis and died after receiving infliximab salvage. One patient who received cyclosporine salvage developed herpetic esophagitis, and another patient who received cyclosporine salvage developed pancreatitis and bacteremia. Conclusions: In patients with severe corticosteroid-refractory ulcerative colitis who fail treatment with either cyclosporine or infliximab, remission rates using acute salvage therapy by crossing over to the other drug occur in approximately one third of patients and have limited duration. Serious adverse events occurred in 16%, including 1 death, suggesting that the risks of acute salvage therapy may outweigh the benefits.
B
oth infliximab and cyclosporine have been shown to be effective treatment for inducing remission in patients with severe ulcerative colitis that is refractory to high-dose corticosteroids. Acute remission rates with cyclosporine have ranged between 63% and 82% in previous trials.1–5 Doses of 2 to 4 mg/kg intravenously have shown efficacy,4,6 and 5.0 to 7.5 mg/kg orally are required to achieve remission.7 In a randomized, double-blind, controlled trial using a dose of 4 mg/kg, response rates were 82% within a mean of 7 days.4 In patients who were hospitalized for intravenous steroids to treat a flare of ulcerative colitis, therapy with infliximab resulted
in colectomy and mortality avoidance in 71% of patients at 90 days.8 Although both of these therapies may be beneficial to patients with corticosteroid-refractory ulcerative colitis, their sequential use in the event of failing the first is a potentially risky proposition, in light of the fact that the immune suppression induced by the first agent may persist during the use of the second. Serum levels of infliximab typically remain increased for at least 8 weeks.9 Therefore, if cyclosporine is initiated less than 8 weeks after receiving infliximab, there is potential that both drugs will be detected in the plasma. This raises the possibility of increased toxicity. The serum half-life of intravenous cyclosporine is 6.2 hours in healthy volunteers.10 The elimination time of oral or intravenous cyclosporine is reported as 10 to 27 hours (Thomson MICROMEDEX 2007). Although cyclosporine may therefore be absent from the bloodstream of patients receiving infliximab, it is unknown whether the addition of infliximab in patients who recently have completed cyclosporine treatment results in added immunosuppression. To date, there has been only one case reported in the literature of a patient with ulcerative colitis who received infliximab after therapy for cyclosporine for acute salvage therapy. This patient had an initial response to infliximab but proceeded to colectomy 4 weeks after induction.11 We aimed to determine the response of treatment-refractory ulcerative colitis to cyclosporine once infliximab had failed and vice versa. We also report on the toxicity of using these medications in close succession.
Materials and Methods Patients We retrospectively reviewed the records of patients with severe UC who had failed either intravenous steroids at a dose equivalent to at least 60 mg/d of prednisone, or patients who had failed at least one course of oral prednisone at a minimum dose of 40 mg/d for 2 weeks. We identified those patients who received cyclosporine first and then infliximab as acute salvage therapy (IFX-salvage), or who failed infliximab first and then received cyclosporine as acute salvage therapy (CSA-salvage). The search was conducted for patients treated between January 2000 and October 2006. Names of patients were gathered from clinicians in the Consortium of Research in IBD group at Mount Sinai with extensive experience in the treatment of ulcerative colitis with cyclosporine and infliximab. All patients were classified as severely Abbreviations used in this paper: ACT, active ulcerative colitis trials; IFX-salvage, infliximab salvage; CSA-Salvage, cyclosporine salvage. © 2008 by the AGA Institute 1542-3565/08/$34.00 doi:10.1016/j.cgh.2008.04.035
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CYCLOSPORINE AND INFLIXIMAB AS RESCUE THERAPY
Table 1. Lichtiger Score for the Evaluation of Patients with Ulcerative Colitis Symptom
Score
Diarrhea, no. of daily stools 0–2 3 or 4 5 or 6 7–9 10 Nocturnal diarrhea No Yes Visible blood in stool, % of movements 0 ⬍50 ⱖ50 100 Fecal incontinence No Yes Abdominal pain or cramping None Mild Moderate Severe General well-being Perfect Very good Good Average Poor Terrible Abdominal tenderness None Mild and localized Mild to moderate and diffuse Severe or rebound Need for antidiarrheal drugs No Yes
0 1 2 3 4 0 1 0 1 2 3 0 1 0 1 2 3 0 1 2 3 4 5
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of 300 to 400 ng/mL. For patients who responded, oral cyclosporine was prescribed at discharge, and dosed to achieve trough levels of 100 to 300 ng/mL. The duration of cyclosporine, infliximab use, and colectomy rates were noted. The co-primary end points for this study were a status of medical remission, response, or medical failure after acute salvage therapy. Remission was strictly defined as a normal number of bowel movements, the absence of rectal bleeding, and a discontinuation of corticosteroids within 3 months and a Lichtiger score of 3 or less. Patients were classified as having achieved remission after successfully tapering off steroids by 3 months. They were required to respond to salvage therapy before initiating the steroid taper. Failure was defined as colectomy or death within 1 year of salvage therapy or a Lichtiger score of 10 or greater. Response was defined as a Lichtiger score of 4 or higher, up to and including 10. Secondary end points included average length of remission after acute salvage therapy and length of time to colectomy. Statistical analyses were performed using SPSS version 15.0 (SPSS Inc, Chicago, IL). Comparisons between the IFX-salvage and CSA-salvage groups were examined using life-table methods and log-rank testing12 with significance set at 0.05. All serious adverse events occurring during or after treatment with both drugs were recorded. This study was approved by the Mount Sinai School of Medicine institutional review board and was performed in accordance with the Health Insurance Portability and Accountability Act of 1996 guidelines.
Results Patient Demographics
0 1 2 3 0 1
ill with a score according to Lichtiger et al4 that was greater than 10 before acute salvage therapy (Table 1). Acute salvage therapy was defined as having received the alternate agent within 4 weeks of discontinuing the first agent. Salvage therapy included either a minimum of 1 week of intravenous cyclosporine or a minimum of 1 infusion of infliximab. There was a minimum of 24 hours after stopping the first drug and starting the second. In all cases, cyclosporine was administered intravenously for 1 week, dosed to achieve trough levels
Nineteen patients, 9 men and 10 women, underwent acute salvage therapy with either cyclosporine or infliximab within 4 weeks of discontinuing the other. Demographic data are shown in Table 2. Ten patients who failed cyclosporine were treated with infliximab as acute salvage therapy (IFX-salvage group), 9 patients who failed infliximab received cyclosporine as acute salvage therapy (CSA-salvage group). In all patients, the reason for switching to cyclosporine or infliximab was failure to achieve an adequate clinical response to the initial drug. There were no patients who discontinued the first drug because of an adverse event. Patients who received cyclosporine first, had initially failed intravenous steroids at a dose equivalent to 60 mg of oral prednisone for at least 3 to 5 days. Three of the 9 patients who received infliximab first were treated initially with intravenous steroids at the same doses. The remaining 6 patients were treated with oral steroids, 2 of whom were unable to taper below 60 mg/d of prednisone.
Table 2. Demographic Data Demographics
IFX-salvage (n ⫽ 10)
IFX-salvage remission (n ⫽ 4)
CSA-salvage (n ⫽ 9)
CSA-salvage remission (n ⫽ 3)
Mean age, y Male sex Mean disease duration, y Extensive colitis Left-sided colitis
34.3 50% (5/10) 8.6 33.3% (3/10) 66.6% (7/10)
37.4 50% (2/4) 8.0 25% (1/4) 75% (3/4)
43.8 55.6% (5/9) 8.7 100% (9/9) 0% (0/9)
35.5 66.7% (2/3) 10.6 100% (3/3) 0% (0/3)
Left sided, rectum to splenic flexure; extensive, rectum to beyond splenic flexure.
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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 10
Table 3. Salvage Information Salvage information
IFX-Salvage (n ⫽ 10)
IFX-salvage remission (n ⫽ 4)
CSA-salvage (n ⫽ 9)
CSA-salvage remission (n ⫽ 3)
Median number of infliximab infusions Median duration of cyclosporine, mo Average interval between 2 drugs, d (range) Concomitant use of immunosuppressants Median duration of remission, mo
3 3 17 (1–30) 77% (7/9) 13.6
3 1.6 25.5 (1–30) 100% (4/4) 10.2
1.9 6.2 21 (5–31) 66% (6/9) 21.0
1.5 1.4 12.7 (5–15) 100% (3/3) 39.0
The average age of patients was 34.3 years in the IFX-salvage group and 43.8 years for the CSA-salvage group. Disease duration was similar in each group (8.6 and 8.7 y, respectively). Fewer patients in the IFX-salvage group had extensive colitis (determined by their initial colonoscopy) than in the CSAsalvage group (33% vs 100%; P ⫽ .45). However, initial colonoscopy may underestimate their disease activity at the time of acute salvage therapy because patients at our institution do not generally undergo full colonoscopy at the time of a severe flare.
Response to Acute Salvage Therapy Four of the 10 patients (40%) treated with IFX-salvage therapy achieved remission. Among the CSA-salvage patients, 3 of 9 (33%) achieved remission. Before acute salvage therapy, the IFX-salvage patients received a median of 1.6 months of cyclosporine therapy (range, 0.5–9.8 mo), and, with salvage, a median of 2 (range, 1–9) infliximab infusions. CSA-salvage patients received a median of 2 infusions of infliximab (range, 1–3) before treatment with cyclosporine, which they received for a median of 2.0 months (range, 0.3–37.5 mo). The average interval between CSA and infliximab salvage was 17 days (range, 1–30 d) and was 21 days (range, 5–31 d) for the CSA-salvage group (Table 2). During treatment with the salvage drug, the majority of both groups (66% in the IFX-salvage group and 77% in the CSAsalvage group) were being treated with either 6-mercaptopurine or azathioprine. Four patients in each group were on either 6-mercaptopurine or azathioprine before either initial therapy. In the IFX-salvage group, 3 started 6-mercaptopurine or azathioprine after cyclosporine and 2 started after infliximab salvage therapy. In the CSA-salvage group, 3 started on 6-mercaptopurine or azathioprine with the infliximab and 2 started after receiving cyclosporine salvage therapy. Four of 10 (40%) patients in the IFX-salvage group failed acute salvage therapy. The median time to colectomy or death was 2 months (range, 0.9 –5.2 mo). In the CSA-salvage group, 4 of 9 (44%) patients met the criteria for failure. The median time to colectomy in this group was 3.8 months (range, 0.1–11.6 mo). In total, of the 19 patients in this study, 8 (42%) had a colectomy within 1 year. In both groups, all patients who required colectomy or died had a Lichtiger score of greater than 10. Two additional patients in each group (4 of 19) responded to acute salvage therapy but did not meet the criteria for remission. These patients met the criteria for response (Lichtiger score ⱖ4, up to and including 10). Three of these patients remain on steroids at 2.0, 2.1, and 5.2 months after salvage. All had minimal or no rectal bleeding but continued to have an increase in stool frequency. Patients in both the IFX-salvage and the CSA-salvage groups who achieved remission had similar demographics compared
with patients who did not achieve remission (Table 3). However, in both groups, all patients who achieved remission were taking concomitant immunosuppressant medications. Immunosuppressant medications included azathioprine or 6-mercaptopurine (Table 3). In the CSA-salvage group, patients who achieved remission had a nonsignificant, shorter interval between completing infliximab and starting cyclosporine than all patients in the CSA-salvage group (12.7 vs 21 d, respectively; P ⫽ .22 by logistic regression). In contrast, patients in the IFX-salvage group who achieved remission had a longer interval between drugs than all patients who received IFX-salvage (17.0 vs 25.5 d, respectively; P ⫽ .74 by logistic regression).
Duration of Response Duration of remission was defined as the time at discontinuation of steroids after salvage therapy to the time of relapse, which was defined as the need to restart corticosteroids or colectomy. Among the 7 patients who achieved remission, the median duration of remission was 13.6 months (range, 4.4 –17.0 mo) in the IFX-salvage group and 21.0 months (range, 5.0 – 41.5 mo) in the CSA-salvage group. Of the 4 patients who met the criteria for response, 3 remain symptomatic 2.1, 16.7, and 53.9 months after salvage therapy. The remaining patient was lost to follow-up evaluation beyond the initial assessment. Time to colectomy was calculated from the time of initiation of acute salvage therapy to the time of colectomy, and is illustrated in Figure 2. The average duration of follow-up evaluation was 7.8 months for those who received IFX-salvage and 17.7 months for CSA-salvage. None of the patients were lost to follow-up evaluation.
Figure 1. Remission, response, and failure rates after receiving acute salvage therapy.
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ing cyclosporine alone. A third patient developed a nonproductive cough for 3 weeks after cyclosporine salvage without evidence of infection. The reason for switching to cyclosporine or infliximab was failure to achieve an adequate clinical response to the initial drug. None of the patients discontinued the first drug because of an adverse event.
Discussion
Figure 2. Kaplan-Meier evaluation comparing subjects who received CSA first with those who received IFX first. No difference was found between the groups with a P value of .93 via log-rank testing. CSA first group, ( – – – ), all subjects, ( · · · · ); IFX first group; ⫹, censored for last colectomy-free follow-up evaluation.
Adverse Events Adverse events were attributed to acute salvage therapy if they occurred within 4 weeks of receiving the salvage drug and if they were thought to be caused by immune suppression or known metabolic toxicities of either cyclosporine or infliximab. Overall, there were serious adverse events in 3 patients, which are outlined in Table 4. One patient developed gram-negative sepsis and died after acute salvage therapy with infliximab. She was being treated for an exacerbation of her colitis symptoms at an outside institution. Her cyclosporine was discontinued and she received an infusion of infliximab the following day. After her second dose of infliximab, she developed gram-negative sepsis and was admitted to the hospital. She died 2 weeks later. Another patient who received acute salvage therapy with CSA developed severe pancreatitis 10 days after discontinuing cyclosporine. He had been on cyclosporine for 2.8 months, was not taking corticosteroids, and had been off azathioprine for 2 months. On the same hospital admission, he developed Klebsiella and Enterococcus bacteremia. Herpes esophagitis developed in one patient 11 days after receiving a 7-day course of intravenous cyclosporine. There were 3 other minor adverse events. One patient experienced fatigue, leg cramps, and weakness, and another patient developed fatigue and tingling in her fingers after cyclosporine salvage. These side effects have been well described after receiv-
Patients with severe ulcerative colitis who fail high-dose corticosteroids have limited medical options to achieve remission and avoid colectomy. Patients often are referred to our center because they are reluctant to undergo colectomy and are seeking additional medical therapy. This is primarily owing to known complications of J-pouch surgery, including frequent bowel movements, incontinence, decreased fecundity, and others.13 We found that in patients who failed to achieve remission with either cyclosporine or infliximab, the likelihood of having achieved a corticosteroid-free remission using acute salvage therapy with the other drug was modest. In this retrospective series from a single tertiary referral center with extensive experience in the management of severely ill ulcerative colitis patients, the combined remission rate of 37% for acute salvage therapy was disappointing. It is worth noting that our criteria for remission were stringent, requiring normal bowel frequency, the absence of rectal bleeding, and a complete taper off corticosteroids. Nevertheless, our results were not dissimilar from the infliximab-induced remission rates in the ACT 1 and ACT 2 studies.14 The ACT trials involved patients with moderate-severe active ulcerative colitis treated as outpatients. In those studies patients requiring 60 mg/d of prednisone were excluded, indicating a group with less severe disease than the patients investigated here. As opposed to the ACT trials and other studies involving either infliximab or cyclosporine, our results were associated with a sobering serious adverse event rate of 16%, including one death. Although a steroid-free clinical remission is an appropriate end point for both patients and clinicians, colectomy avoidance is an additional end point worth considering. The subgroup of patients who achieved remission avoided colectomy for an average of 21.4 months. In the present study, the decision about which agent to use first after the failure of corticosteroids was determined by the treating physician introducing the risk of selection bias. At our institution, cyclosporine is believed to be a more effective agent and therefore used for sicker patients. However, 6 of 9 (67%) patients who received infliximab first were treated initially with infliximab by outside physicians and then were referred to our institution because they were not comfortable prescribing cy-
Table 4. Serious Adverse Event Profiles SAE total: 16% (3/19) Death: gram-negative sepsis Pancreatitis followed by Enterococcus, and Klebsiella bacteremia Herpes esophagitis SAE, serious adverse event.
Other immune suppression
Drug sequence
Medication interval
Time of SAE after salvage drug
Azathioprine, prednisone None
IFX-salvage CSA-salvage
1d 4 wk
2 weeks after first infliximab infusion 10 days after discontinuing cyclosporine
Prednisone taper (20 mg)
CSA-salvage
5d
11 days after discontinuing cyclosporine
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closporine, again raising another potential source of bias. Before choosing infliximab, their patients were corticosteroid refractory, however, their criteria for initiating infliximab may have been different than ours. Another potential bias in this study is that all of the patients who were treated with infliximab salvage therapy failed intravenous steroids before initiating cyclosporine. This is in contrast to the CSA-salvage group in which 3 of 9 (33%) patients received intravenous steroids before initial therapy with infliximab. This suggests that the IFX-salvage group may have had a disadvantage in that these patients may have represented the most refractory group. The patients who achieved remission had a somewhat shorter interval between completing infliximab and starting cyclosporine, suggesting that the efficacy of these drugs may be based on their simultaneous presence in the serum. This potentially additive or synergistic effect, however, is not without risk. The incidence of adverse events using cyclosporine or infliximab alone is significant. Cyclosporine has reported side effects that include (but are not limited to) nephrotoxicity, Pneumocystis carinii pneumonia, grand mal seizures, and hypertension.2– 4 Reactivation of latent tuberculosis, infusion reactions, delayed hypersensitivity reactions, and respiratory infections are some of the reported side effects of infliximab.8,14 Two recent studies highlighted the increased morbidity of infliximab when used as rescue therapy for patients with intravenous steroid-refractory ulcerative colitis. Kohn et al15 reported 2 cases of pneumonia. One was caused by Legionella pneumophila and the other was unidentified. They also described one case of herpes virus infection. Lees et al16 reported one death caused by pseudomonas pneumonia in a 71-year-old man with multiple comorbidities and one postoperative fungal septicemia in an otherwise healthy 22-year-old man. In this current series, the incidence of a serious adverse event was 16% including one death. This suggests that the risks of poor outcomes are substantial with acute salvage therapy. In fact, it may be of clinical utility to check the trough serum infliximab level to ensure that it is undetectable before initiating cyclosporine to minimize the likelihood of toxicity. At a minimum, caution and a thoughtful discussion of these risks with ulcerative colitis patients refractory to corticosteroids and either cyclosporine or infliximab is warranted. The outcomes and adverse event profiles in patients who received delayed salvage therapy with an interval of greater than 4 weeks was not addressed in this study. Our study did not address whether cyclosporine or infliximab should be the preferred initial medical therapy in severe, steroid-refractory UC. A controlled trial randomizing patients to receive either infliximab or cyclosporine would be needed to answer this important question. Our series addressed the likelihood of remission with the use of either cyclosporine or infliximab as acute salvage therapy after failing the other. Patients who are seeking an alternative to surgery can be informed that the likelihood of achieving a steroid-free remission using salvage therapy with the other drug is modest. Given the significant associated toxicity, acute salvage therapy should be considered high risk and needs to be considered carefully when evaluating the risk-benefit ratio. (Figure 1).
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 10
References 1. Actis GC, Fadda M, David E, et al. Colectomy rate in steroidrefractory colitis initially responsive to cyclosporin: a long-term retrospective cohort study. BMC Gastroenterol 20077:13. 2. Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol 1999; 94:1587–1592. 3. Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet 1990;336:16 –19. 4. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841–1845. 5. Weber A, Fein F, Koch S, et al. Treatment of ulcerative colitis refractory to steroid therapy by oral microemulsion cyclosporine (neoral). Inflamm Bowel Dis 2006;12:1131–1135. 6. 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: 1025–1031. 7. Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults (update): American college of gastroenterology, practice parameters committee. Am J Gastroenterol 2004; 99:1371–1385. 8. 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;128:1805–1811. 9. Maser EA, Villela R, Silverberg MS, et al. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol 2006;4:1248 –1254. 10. Ptachcinski RJ, Venkataramanan R, Burckart GJ, et al. Cyclosporine kinetics in healthy volunteers. J Clin Pharmacol 1987;27:243–248. 11. Lam EC, Bailey RJ. Infliximab salvage therapy after cyclosporine in an acute flair of chronic ulcerative colitis. Can J Gastroenterol 2003;17:198. 12. Peto R, Peto J. Asymptomatically efficient rank invariant test procedures. J R Stat Soc [Ser A] 1972;135:185–207. 13. Lovegrove RE, Heriot AG, Constantinides V, et al. Meta-analysis of short-term and long-term outcomes of J, W and S ileal reservoirs for restorative proctocolectomy. Colorectal Dis 2007;9:310 –320. 14. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–2476. 15. 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;26:747–756. 16. Lees CW, Heys D, Ho GT, et al, Scottish Society of Gastroenterology Infliximab Group. A retrospective analysis of the efficacy and safety of infliximab as rescue therapy in acute severe ulcerative colitis. Aliment Pharmacol Ther 2007;26:411– 419.
Address requests for reprints to: Elana Maser, MD, FRCPC, Department of Medicine, Division of Gastroenterology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1069, New York, New York 10029. e-mail: [email protected]; fax: (212) 241-5142. The authors acknowledge Anthony Weiss, MD, James George, MD, Peter Legnani, MD, and Adam Steinlauf, MD for their contributions. E.A.M., D.D., and D.H.P. have no conflicts of interest to disclose; S.L. received research grants from Centocor (not for this project); T.U. received speaking and consulting fees from Abbott, Centocor, and UCB Pharmaceuticals; and A.K. received advisory board and speaking fees from Abbott, Centocor, and UCB Pharmaceuticals. Potential investigator conflicts of interest were not disclosed to subjects (study participants); they were disclosed to all authors involved.
Cyclosporine and Infliximab as Rescue Therapy for Each Other in Patients With Steroid-Refractory Ulcerative Colitis ELANA A. MASER, DEEPTHI DECONDA, SIMON LICHTIGER, THOMAS ULLMAN, DANIEL H. PRESENT, and ASHER KORNBLUTH The IBD Center and Division of Gastroenterology, Mount Sinai Medical Center, and the Mount Sinai Consortium for Research in IBD, New York, New York
See D’Haens GR et al on page 1123 and Sandborn WJ et al on page 1130 in the October 2008 issue of Gastroenterology. Background & Aims: In patients with severe corticosteroidrefractory ulcerative colitis, cyclosporine or infliximab may be added in an effort to induce remission. If the patient then fails either of these drugs, it is unknown whether success can be achieved by using the other agent. The aim of this study was to assess outcomes of using cyclosporine after failure of infliximab, and vice versa. Methods: We retrospectively reviewed the charts of 19 patients with corticosteroid-refractory ulcerative colitis who received either infliximab after failed cyclosporine or cyclosporine after failed infliximab. Acute salvage therapy was defined as having received the alternate drug within 4 weeks of discontinuing the first agent. Results: Ten patients received infliximab after failing cyclosporine; 9 patients received cyclosporine after failing infliximab. Four patients (40%) in the infliximab-salvage group achieved remission, as did 3 (33%) in the cyclosporine-salvage group. Remission lasted a mean of 10.4 months (range, 4.4 –17.03 mo) and 28.5 months (range, 5.0 – 41.5 mo), respectively. Severe adverse events included one patient who developed sepsis and died after receiving infliximab salvage. One patient who received cyclosporine salvage developed herpetic esophagitis, and another patient who received cyclosporine salvage developed pancreatitis and bacteremia. Conclusions: In patients with severe corticosteroid-refractory ulcerative colitis who fail treatment with either cyclosporine or infliximab, remission rates using acute salvage therapy by crossing over to the other drug occur in approximately one third of patients and have limited duration. Serious adverse events occurred in 16%, including 1 death, suggesting that the risks of acute salvage therapy may outweigh the benefits.
B
oth infliximab and cyclosporine have been shown to be effective treatment for inducing remission in patients with severe ulcerative colitis that is refractory to high-dose corticosteroids. Acute remission rates with cyclosporine have ranged between 63% and 82% in previous trials.1–5 Doses of 2 to 4 mg/kg intravenously have shown efficacy,4,6 and 5.0 to 7.5 mg/kg orally are required to achieve remission.7 In a randomized, double-blind, controlled trial using a dose of 4 mg/kg, response rates were 82% within a mean of 7 days.4 In patients who were hospitalized for intravenous steroids to treat a flare of ulcerative colitis, therapy with infliximab resulted
in colectomy and mortality avoidance in 71% of patients at 90 days.8 Although both of these therapies may be beneficial to patients with corticosteroid-refractory ulcerative colitis, their sequential use in the event of failing the first is a potentially risky proposition, in light of the fact that the immune suppression induced by the first agent may persist during the use of the second. Serum levels of infliximab typically remain increased for at least 8 weeks.9 Therefore, if cyclosporine is initiated less than 8 weeks after receiving infliximab, there is potential that both drugs will be detected in the plasma. This raises the possibility of increased toxicity. The serum half-life of intravenous cyclosporine is 6.2 hours in healthy volunteers.10 The elimination time of oral or intravenous cyclosporine is reported as 10 to 27 hours (Thomson MICROMEDEX 2007). Although cyclosporine may therefore be absent from the bloodstream of patients receiving infliximab, it is unknown whether the addition of infliximab in patients who recently have completed cyclosporine treatment results in added immunosuppression. To date, there has been only one case reported in the literature of a patient with ulcerative colitis who received infliximab after therapy for cyclosporine for acute salvage therapy. This patient had an initial response to infliximab but proceeded to colectomy 4 weeks after induction.11 We aimed to determine the response of treatment-refractory ulcerative colitis to cyclosporine once infliximab had failed and vice versa. We also report on the toxicity of using these medications in close succession.
Materials and Methods Patients We retrospectively reviewed the records of patients with severe UC who had failed either intravenous steroids at a dose equivalent to at least 60 mg/d of prednisone, or patients who had failed at least one course of oral prednisone at a minimum dose of 40 mg/d for 2 weeks. We identified those patients who received cyclosporine first and then infliximab as acute salvage therapy (IFX-salvage), or who failed infliximab first and then received cyclosporine as acute salvage therapy (CSA-salvage). The search was conducted for patients treated between January 2000 and October 2006. Names of patients were gathered from clinicians in the Consortium of Research in IBD group at Mount Sinai with extensive experience in the treatment of ulcerative colitis with cyclosporine and infliximab. All patients were classified as severely Abbreviations used in this paper: ACT, active ulcerative colitis trials; IFX-salvage, infliximab salvage; CSA-Salvage, cyclosporine salvage. © 2008 by the AGA Institute 1542-3565/08/$34.00 doi:10.1016/j.cgh.2008.04.035
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CYCLOSPORINE AND INFLIXIMAB AS RESCUE THERAPY
Table 1. Lichtiger Score for the Evaluation of Patients with Ulcerative Colitis Symptom
Score
Diarrhea, no. of daily stools 0–2 3 or 4 5 or 6 7–9 10 Nocturnal diarrhea No Yes Visible blood in stool, % of movements 0 ⬍50 ⱖ50 100 Fecal incontinence No Yes Abdominal pain or cramping None Mild Moderate Severe General well-being Perfect Very good Good Average Poor Terrible Abdominal tenderness None Mild and localized Mild to moderate and diffuse Severe or rebound Need for antidiarrheal drugs No Yes
0 1 2 3 4 0 1 0 1 2 3 0 1 0 1 2 3 0 1 2 3 4 5
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of 300 to 400 ng/mL. For patients who responded, oral cyclosporine was prescribed at discharge, and dosed to achieve trough levels of 100 to 300 ng/mL. The duration of cyclosporine, infliximab use, and colectomy rates were noted. The co-primary end points for this study were a status of medical remission, response, or medical failure after acute salvage therapy. Remission was strictly defined as a normal number of bowel movements, the absence of rectal bleeding, and a discontinuation of corticosteroids within 3 months and a Lichtiger score of 3 or less. Patients were classified as having achieved remission after successfully tapering off steroids by 3 months. They were required to respond to salvage therapy before initiating the steroid taper. Failure was defined as colectomy or death within 1 year of salvage therapy or a Lichtiger score of 10 or greater. Response was defined as a Lichtiger score of 4 or higher, up to and including 10. Secondary end points included average length of remission after acute salvage therapy and length of time to colectomy. Statistical analyses were performed using SPSS version 15.0 (SPSS Inc, Chicago, IL). Comparisons between the IFX-salvage and CSA-salvage groups were examined using life-table methods and log-rank testing12 with significance set at 0.05. All serious adverse events occurring during or after treatment with both drugs were recorded. This study was approved by the Mount Sinai School of Medicine institutional review board and was performed in accordance with the Health Insurance Portability and Accountability Act of 1996 guidelines.
Results Patient Demographics
0 1 2 3 0 1
ill with a score according to Lichtiger et al4 that was greater than 10 before acute salvage therapy (Table 1). Acute salvage therapy was defined as having received the alternate agent within 4 weeks of discontinuing the first agent. Salvage therapy included either a minimum of 1 week of intravenous cyclosporine or a minimum of 1 infusion of infliximab. There was a minimum of 24 hours after stopping the first drug and starting the second. In all cases, cyclosporine was administered intravenously for 1 week, dosed to achieve trough levels
Nineteen patients, 9 men and 10 women, underwent acute salvage therapy with either cyclosporine or infliximab within 4 weeks of discontinuing the other. Demographic data are shown in Table 2. Ten patients who failed cyclosporine were treated with infliximab as acute salvage therapy (IFX-salvage group), 9 patients who failed infliximab received cyclosporine as acute salvage therapy (CSA-salvage group). In all patients, the reason for switching to cyclosporine or infliximab was failure to achieve an adequate clinical response to the initial drug. There were no patients who discontinued the first drug because of an adverse event. Patients who received cyclosporine first, had initially failed intravenous steroids at a dose equivalent to 60 mg of oral prednisone for at least 3 to 5 days. Three of the 9 patients who received infliximab first were treated initially with intravenous steroids at the same doses. The remaining 6 patients were treated with oral steroids, 2 of whom were unable to taper below 60 mg/d of prednisone.
Table 2. Demographic Data Demographics
IFX-salvage (n ⫽ 10)
IFX-salvage remission (n ⫽ 4)
CSA-salvage (n ⫽ 9)
CSA-salvage remission (n ⫽ 3)
Mean age, y Male sex Mean disease duration, y Extensive colitis Left-sided colitis
34.3 50% (5/10) 8.6 33.3% (3/10) 66.6% (7/10)
37.4 50% (2/4) 8.0 25% (1/4) 75% (3/4)
43.8 55.6% (5/9) 8.7 100% (9/9) 0% (0/9)
35.5 66.7% (2/3) 10.6 100% (3/3) 0% (0/3)
Left sided, rectum to splenic flexure; extensive, rectum to beyond splenic flexure.
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Table 3. Salvage Information Salvage information
IFX-Salvage (n ⫽ 10)
IFX-salvage remission (n ⫽ 4)
CSA-salvage (n ⫽ 9)
CSA-salvage remission (n ⫽ 3)
Median number of infliximab infusions Median duration of cyclosporine, mo Average interval between 2 drugs, d (range) Concomitant use of immunosuppressants Median duration of remission, mo
3 3 17 (1–30) 77% (7/9) 13.6
3 1.6 25.5 (1–30) 100% (4/4) 10.2
1.9 6.2 21 (5–31) 66% (6/9) 21.0
1.5 1.4 12.7 (5–15) 100% (3/3) 39.0
The average age of patients was 34.3 years in the IFX-salvage group and 43.8 years for the CSA-salvage group. Disease duration was similar in each group (8.6 and 8.7 y, respectively). Fewer patients in the IFX-salvage group had extensive colitis (determined by their initial colonoscopy) than in the CSAsalvage group (33% vs 100%; P ⫽ .45). However, initial colonoscopy may underestimate their disease activity at the time of acute salvage therapy because patients at our institution do not generally undergo full colonoscopy at the time of a severe flare.
Response to Acute Salvage Therapy Four of the 10 patients (40%) treated with IFX-salvage therapy achieved remission. Among the CSA-salvage patients, 3 of 9 (33%) achieved remission. Before acute salvage therapy, the IFX-salvage patients received a median of 1.6 months of cyclosporine therapy (range, 0.5–9.8 mo), and, with salvage, a median of 2 (range, 1–9) infliximab infusions. CSA-salvage patients received a median of 2 infusions of infliximab (range, 1–3) before treatment with cyclosporine, which they received for a median of 2.0 months (range, 0.3–37.5 mo). The average interval between CSA and infliximab salvage was 17 days (range, 1–30 d) and was 21 days (range, 5–31 d) for the CSA-salvage group (Table 2). During treatment with the salvage drug, the majority of both groups (66% in the IFX-salvage group and 77% in the CSAsalvage group) were being treated with either 6-mercaptopurine or azathioprine. Four patients in each group were on either 6-mercaptopurine or azathioprine before either initial therapy. In the IFX-salvage group, 3 started 6-mercaptopurine or azathioprine after cyclosporine and 2 started after infliximab salvage therapy. In the CSA-salvage group, 3 started on 6-mercaptopurine or azathioprine with the infliximab and 2 started after receiving cyclosporine salvage therapy. Four of 10 (40%) patients in the IFX-salvage group failed acute salvage therapy. The median time to colectomy or death was 2 months (range, 0.9 –5.2 mo). In the CSA-salvage group, 4 of 9 (44%) patients met the criteria for failure. The median time to colectomy in this group was 3.8 months (range, 0.1–11.6 mo). In total, of the 19 patients in this study, 8 (42%) had a colectomy within 1 year. In both groups, all patients who required colectomy or died had a Lichtiger score of greater than 10. Two additional patients in each group (4 of 19) responded to acute salvage therapy but did not meet the criteria for remission. These patients met the criteria for response (Lichtiger score ⱖ4, up to and including 10). Three of these patients remain on steroids at 2.0, 2.1, and 5.2 months after salvage. All had minimal or no rectal bleeding but continued to have an increase in stool frequency. Patients in both the IFX-salvage and the CSA-salvage groups who achieved remission had similar demographics compared
with patients who did not achieve remission (Table 3). However, in both groups, all patients who achieved remission were taking concomitant immunosuppressant medications. Immunosuppressant medications included azathioprine or 6-mercaptopurine (Table 3). In the CSA-salvage group, patients who achieved remission had a nonsignificant, shorter interval between completing infliximab and starting cyclosporine than all patients in the CSA-salvage group (12.7 vs 21 d, respectively; P ⫽ .22 by logistic regression). In contrast, patients in the IFX-salvage group who achieved remission had a longer interval between drugs than all patients who received IFX-salvage (17.0 vs 25.5 d, respectively; P ⫽ .74 by logistic regression).
Duration of Response Duration of remission was defined as the time at discontinuation of steroids after salvage therapy to the time of relapse, which was defined as the need to restart corticosteroids or colectomy. Among the 7 patients who achieved remission, the median duration of remission was 13.6 months (range, 4.4 –17.0 mo) in the IFX-salvage group and 21.0 months (range, 5.0 – 41.5 mo) in the CSA-salvage group. Of the 4 patients who met the criteria for response, 3 remain symptomatic 2.1, 16.7, and 53.9 months after salvage therapy. The remaining patient was lost to follow-up evaluation beyond the initial assessment. Time to colectomy was calculated from the time of initiation of acute salvage therapy to the time of colectomy, and is illustrated in Figure 2. The average duration of follow-up evaluation was 7.8 months for those who received IFX-salvage and 17.7 months for CSA-salvage. None of the patients were lost to follow-up evaluation.
Figure 1. Remission, response, and failure rates after receiving acute salvage therapy.
October 2008
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ing cyclosporine alone. A third patient developed a nonproductive cough for 3 weeks after cyclosporine salvage without evidence of infection. The reason for switching to cyclosporine or infliximab was failure to achieve an adequate clinical response to the initial drug. None of the patients discontinued the first drug because of an adverse event.
Discussion
Figure 2. Kaplan-Meier evaluation comparing subjects who received CSA first with those who received IFX first. No difference was found between the groups with a P value of .93 via log-rank testing. CSA first group, ( – – – ), all subjects, ( · · · · ); IFX first group; ⫹, censored for last colectomy-free follow-up evaluation.
Adverse Events Adverse events were attributed to acute salvage therapy if they occurred within 4 weeks of receiving the salvage drug and if they were thought to be caused by immune suppression or known metabolic toxicities of either cyclosporine or infliximab. Overall, there were serious adverse events in 3 patients, which are outlined in Table 4. One patient developed gram-negative sepsis and died after acute salvage therapy with infliximab. She was being treated for an exacerbation of her colitis symptoms at an outside institution. Her cyclosporine was discontinued and she received an infusion of infliximab the following day. After her second dose of infliximab, she developed gram-negative sepsis and was admitted to the hospital. She died 2 weeks later. Another patient who received acute salvage therapy with CSA developed severe pancreatitis 10 days after discontinuing cyclosporine. He had been on cyclosporine for 2.8 months, was not taking corticosteroids, and had been off azathioprine for 2 months. On the same hospital admission, he developed Klebsiella and Enterococcus bacteremia. Herpes esophagitis developed in one patient 11 days after receiving a 7-day course of intravenous cyclosporine. There were 3 other minor adverse events. One patient experienced fatigue, leg cramps, and weakness, and another patient developed fatigue and tingling in her fingers after cyclosporine salvage. These side effects have been well described after receiv-
Patients with severe ulcerative colitis who fail high-dose corticosteroids have limited medical options to achieve remission and avoid colectomy. Patients often are referred to our center because they are reluctant to undergo colectomy and are seeking additional medical therapy. This is primarily owing to known complications of J-pouch surgery, including frequent bowel movements, incontinence, decreased fecundity, and others.13 We found that in patients who failed to achieve remission with either cyclosporine or infliximab, the likelihood of having achieved a corticosteroid-free remission using acute salvage therapy with the other drug was modest. In this retrospective series from a single tertiary referral center with extensive experience in the management of severely ill ulcerative colitis patients, the combined remission rate of 37% for acute salvage therapy was disappointing. It is worth noting that our criteria for remission were stringent, requiring normal bowel frequency, the absence of rectal bleeding, and a complete taper off corticosteroids. Nevertheless, our results were not dissimilar from the infliximab-induced remission rates in the ACT 1 and ACT 2 studies.14 The ACT trials involved patients with moderate-severe active ulcerative colitis treated as outpatients. In those studies patients requiring 60 mg/d of prednisone were excluded, indicating a group with less severe disease than the patients investigated here. As opposed to the ACT trials and other studies involving either infliximab or cyclosporine, our results were associated with a sobering serious adverse event rate of 16%, including one death. Although a steroid-free clinical remission is an appropriate end point for both patients and clinicians, colectomy avoidance is an additional end point worth considering. The subgroup of patients who achieved remission avoided colectomy for an average of 21.4 months. In the present study, the decision about which agent to use first after the failure of corticosteroids was determined by the treating physician introducing the risk of selection bias. At our institution, cyclosporine is believed to be a more effective agent and therefore used for sicker patients. However, 6 of 9 (67%) patients who received infliximab first were treated initially with infliximab by outside physicians and then were referred to our institution because they were not comfortable prescribing cy-
Table 4. Serious Adverse Event Profiles SAE total: 16% (3/19) Death: gram-negative sepsis Pancreatitis followed by Enterococcus, and Klebsiella bacteremia Herpes esophagitis SAE, serious adverse event.
Other immune suppression
Drug sequence
Medication interval
Time of SAE after salvage drug
Azathioprine, prednisone None
IFX-salvage CSA-salvage
1d 4 wk
2 weeks after first infliximab infusion 10 days after discontinuing cyclosporine
Prednisone taper (20 mg)
CSA-salvage
5d
11 days after discontinuing cyclosporine
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closporine, again raising another potential source of bias. Before choosing infliximab, their patients were corticosteroid refractory, however, their criteria for initiating infliximab may have been different than ours. Another potential bias in this study is that all of the patients who were treated with infliximab salvage therapy failed intravenous steroids before initiating cyclosporine. This is in contrast to the CSA-salvage group in which 3 of 9 (33%) patients received intravenous steroids before initial therapy with infliximab. This suggests that the IFX-salvage group may have had a disadvantage in that these patients may have represented the most refractory group. The patients who achieved remission had a somewhat shorter interval between completing infliximab and starting cyclosporine, suggesting that the efficacy of these drugs may be based on their simultaneous presence in the serum. This potentially additive or synergistic effect, however, is not without risk. The incidence of adverse events using cyclosporine or infliximab alone is significant. Cyclosporine has reported side effects that include (but are not limited to) nephrotoxicity, Pneumocystis carinii pneumonia, grand mal seizures, and hypertension.2– 4 Reactivation of latent tuberculosis, infusion reactions, delayed hypersensitivity reactions, and respiratory infections are some of the reported side effects of infliximab.8,14 Two recent studies highlighted the increased morbidity of infliximab when used as rescue therapy for patients with intravenous steroid-refractory ulcerative colitis. Kohn et al15 reported 2 cases of pneumonia. One was caused by Legionella pneumophila and the other was unidentified. They also described one case of herpes virus infection. Lees et al16 reported one death caused by pseudomonas pneumonia in a 71-year-old man with multiple comorbidities and one postoperative fungal septicemia in an otherwise healthy 22-year-old man. In this current series, the incidence of a serious adverse event was 16% including one death. This suggests that the risks of poor outcomes are substantial with acute salvage therapy. In fact, it may be of clinical utility to check the trough serum infliximab level to ensure that it is undetectable before initiating cyclosporine to minimize the likelihood of toxicity. At a minimum, caution and a thoughtful discussion of these risks with ulcerative colitis patients refractory to corticosteroids and either cyclosporine or infliximab is warranted. The outcomes and adverse event profiles in patients who received delayed salvage therapy with an interval of greater than 4 weeks was not addressed in this study. Our study did not address whether cyclosporine or infliximab should be the preferred initial medical therapy in severe, steroid-refractory UC. A controlled trial randomizing patients to receive either infliximab or cyclosporine would be needed to answer this important question. Our series addressed the likelihood of remission with the use of either cyclosporine or infliximab as acute salvage therapy after failing the other. Patients who are seeking an alternative to surgery can be informed that the likelihood of achieving a steroid-free remission using salvage therapy with the other drug is modest. Given the significant associated toxicity, acute salvage therapy should be considered high risk and needs to be considered carefully when evaluating the risk-benefit ratio. (Figure 1).
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References 1. Actis GC, Fadda M, David E, et al. Colectomy rate in steroidrefractory colitis initially responsive to cyclosporin: a long-term retrospective cohort study. BMC Gastroenterol 20077:13. 2. Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol 1999; 94:1587–1592. 3. Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet 1990;336:16 –19. 4. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841–1845. 5. Weber A, Fein F, Koch S, et al. Treatment of ulcerative colitis refractory to steroid therapy by oral microemulsion cyclosporine (neoral). Inflamm Bowel Dis 2006;12:1131–1135. 6. 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: 1025–1031. 7. Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults (update): American college of gastroenterology, practice parameters committee. Am J Gastroenterol 2004; 99:1371–1385. 8. 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;128:1805–1811. 9. Maser EA, Villela R, Silverberg MS, et al. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol 2006;4:1248 –1254. 10. Ptachcinski RJ, Venkataramanan R, Burckart GJ, et al. Cyclosporine kinetics in healthy volunteers. J Clin Pharmacol 1987;27:243–248. 11. Lam EC, Bailey RJ. Infliximab salvage therapy after cyclosporine in an acute flair of chronic ulcerative colitis. Can J Gastroenterol 2003;17:198. 12. Peto R, Peto J. Asymptomatically efficient rank invariant test procedures. J R Stat Soc [Ser A] 1972;135:185–207. 13. Lovegrove RE, Heriot AG, Constantinides V, et al. Meta-analysis of short-term and long-term outcomes of J, W and S ileal reservoirs for restorative proctocolectomy. Colorectal Dis 2007;9:310 –320. 14. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–2476. 15. 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;26:747–756. 16. Lees CW, Heys D, Ho GT, et al, Scottish Society of Gastroenterology Infliximab Group. A retrospective analysis of the efficacy and safety of infliximab as rescue therapy in acute severe ulcerative colitis. Aliment Pharmacol Ther 2007;26:411– 419.
Address requests for reprints to: Elana Maser, MD, FRCPC, Department of Medicine, Division of Gastroenterology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1069, New York, New York 10029. e-mail: [email protected]; fax: (212) 241-5142. The authors acknowledge Anthony Weiss, MD, James George, MD, Peter Legnani, MD, and Adam Steinlauf, MD for their contributions. E.A.M., D.D., and D.H.P. have no conflicts of interest to disclose; S.L. received research grants from Centocor (not for this project); T.U. received speaking and consulting fees from Abbott, Centocor, and UCB Pharmaceuticals; and A.K. received advisory board and speaking fees from Abbott, Centocor, and UCB Pharmaceuticals. Potential investigator conflicts of interest were not disclosed to subjects (study participants); they were disclosed to all authors involved.