Dr C. W. Lees, Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. E-mail: Charlie.email@example.com
Background Forty per cent of patients with acute severe ulcerative colitis will not respond to intravenous corticosteroids and require second-line medical therapy or colectomy. A recent controlled trial has suggested that infliximab may be effective as rescue therapy.
Aim To assess the value of infliximab as rescue therapy for acute severe colitis in a retrospective cohort of ulcerative colitis patients in Scotland.
Methods All patients satisfied Truelove and Witts criteria on admission, failed to respond to intravenous corticosteroids and received infliximab (5 mg/kg) as rescue therapy. Response was defined as need for colectomy at hospital discharge and by 90 days.
Results A total of 39 patients (median age 31.7 years) were treated. 26/39 (66%) responded, avoiding colectomy during the acute admission, and were followed up for a median of 203 days (Interquartile range = 135.5–328.5). Hypoalbuminaemia was a consistent predictor of non-response on univariate and multivariate analysis. At day 3 of intravenous steroids, 9/18 (50.0%) with serum albumin <34 g/L had urgent colectomy vs. 1/13 (7.7%) ≥34 g/L (P = 0.02, OR = 12.0, C.I. 1.28–112.7). Two serious adverse events occurred – one death due to Pseudomonas pneumonia, and one post-operative fungal septicaemia.
Conclusions Infliximab represents a moderately effective rescue therapy for patients with acute severe ulcerative colitis. Serious adverse events, including death, do occur and should be discussed with patients prior to therapy.
The use of corticosteroids and appropriate early surgical intervention for acute severe ulcerative colitis (UC) has reduced the mortality from 31–60% to 1–2%.1 Reproducible data have demonstrated that 30–40% of patients will not respond to corticosteroid therapy and will need urgent colectomy.2–8 This may be a life saving procedure, but is feared by patients – quality of life is diminished,9 psychological morbidity may be considerable10 and a 48% reduction in female fecundity has been reported following pouch surgery.11 Rescue medical therapies have thus been sought. In 1994, Lichtiger et al. analysed the use of ciclosporin as rescue therapy for acute severe UC. In a small randomized-controlled trial of 20 patients, they observed significantly lower colectomy rates in patients given active drug (18%) rather than placebo (100%).12 Further randomized placebo-controlled trials have failed to achieve such high response rates13 and longer-term outcomes have been disappointing. A recent Cochrane meta-analysis of the use of ciclosporin in acute severe UC concluded that ‘…there is limited evidence that ciclosporin is more effective than standard treatment alone for severe UC. The relatively quick response makes the short-term use of ciclosporin potentially attractive, but the long-term benefit is unclear…’.14 This uncertainty, together with widely-held concerns regarding toxicity, has led to only sporadic use in UK or indeed worldwide.
The first randomized placebo control trial of infliximab in UC assessed 42 patients with moderately active steroid resistant UC.15 This was a negative but probably underpowered study. Observational case series implied modest response rates in heterogeneous groups of UC patients.16–22 In December 2005, the Centocor sponsored active ulcerative colitis trials ACT1 and ACT2 trials demonstrated the efficacy of infliximab in 728 patients with moderately active UC (mean mayo score 8.4).23 Patients were included if there was evidence of active UC together with previous lack of efficacy or intolerance of at least one treatment. In ACT2 this may have been 5ASA alone. Combined ACT1 and ACT2 data in patients treated with infliximab 5 mg/kg demonstrated an 8-week remission rate of 33.2%, a response in 66.9% (the primary efficacy endpoint) and mucosal healing (including mild inflammation) in 61.1%. There were no differences between the 5 mg/kg and 10 mg/kg doses. At 1 year (ACT1 only), sustained remission was seen in 19.8% and sustained response in 38.8% of patients; significantly better results being seen in patients on active treatment rather than placebo. It is of note that steroid-free remission was seen in only 22%. Colectomy data are not available for this trial.
Jarnerot et al. assessed the use of infliximab in acute severe UC in a publicly funded randomized placebo-controlled trial from Scandinavia.24 45 patients who were admitted to hospital with acute severe UC (defined by the Seo index) were randomized to receive a single infusion of infliximab 5 mg/kg (24 patients) or placebo (21 patients) either with fulminant colitis on day 4 or severe colitis on days 6–8. The primary outcome analysis was colectomy or death at 90 days. Patients who received infliximab required colectomy less frequently than those who received placebo [7/24 (29.2%) vs. 14/21 (66.7%), P = 0.017, OR 4.9, C.I. 1–4–17]. We observed very similar response rates in our preliminary report in 2006; six out of nine patients with acute severe UC (Truelove and Witts criteria) responded and avoided colectomy with relatively few adverse events.25 A Cochrane meta-analysis has concluded that in patients who do not respond to a combination of cortico-steroids and immunomodulators, infliximab is better than placebo for the induction of remission.26 It is also stated that although adverse events are relatively infrequent ‘…physicians should be aware of and be prepared to deal with potential adverse events such as anaphylactic reactions and infections’.
There thus exists a delicate balance between the desire to suppress mucosal inflammation, induce remission and avoid colectomy in patients with acute severe UC and on the other hand to avoid treatment-related morbidity and mortality. A critical appraisal of the available therapies is needed in order to avoid an increase in mortality above the low levels that currently observed in what many consider to be a surgically curable disease, a situation that differs from that seen in Crohn’s disease. Many of these issues have been raised previously.27 We therefore aimed to retrospectively examine the use of infliximab as rescue therapy for acute severe UC in a cohort of patients treated across Scotland.
All members of the Scottish Society of Gastroenterology were invited to participate in the study by e-mail, in November 2006. Patients were included in the study if they satisfied the following criteria: (i) Hospitalisation for acute severe UC, satisfying Truelove and Witts criteria for severe colitis; (ii) Failure to respond to intravenous (iv) corticosteroids; and (iii) Treatment with infliximab (5 mg/kg) as rescue therapy during the acute admission. Data were collected retrospectively by case note review on a standardized data collection form.
Data were collected on 39 patients, treated between May 2005 and November 2006, from eight different hospitals across Scotland [Western General Hospital, Edinburgh (n = 22); Ninewells Hospital, Dundee (n = 4); Victoria Infirmary, Glasgow (n = 4); St John’s Hospital, Livingston (n = 2); Borders General Hospital, Melrose (n = 2); Queen Margaret Hospital, Dunfermline (n = 2); Victoria Hospital, Kirkcaldy (n = 2); Queen Alexandra Hospital, Paisley (n = 1)]. Two additional sites indicated that they had patients treated with infliximab rescue therapy, but did not provide data or case notes for analysis despite repeated requests. Of the patients included, there were 23 males and 16 females, with a median age at diagnosis of 30.7 years. For 14/39 (35.9%) of patients the acute admission for severe UC was the first presentation of UC. The diagnosis of UC adhered to the criteria of Lennard-Jones28 and the disease was classified according to the Montreal classification.29 The demographics of the study population including concomitant medications are shown in Table 1. After admission all patients were treated with high-dose iv corticosteroids, either hydrocortisone 100 mg q.d.s., or methylprednisolone 60 mg/ 24 h by continuous infusion. The timing of infliximab therapy for each patient was at the discretion of the clinician responsible. All patients were treated with an initial infusion of 5 mg/kg infliximab (range 4.2–5.6 mg/kg).
Table 1. Demographics of study population
UC, ulcerative colitis; IQR, interquartile range.
* Disease extent is described by Montreal classification.29
23 Male; 16 Female
Median age at diagnosis
30.7 years (IQR 21.9–43.3)
Median age at admission
31.7 years (IQR 24.1–45.6)
Median duration diagnosis to admission
123 days (IQR 0–885)
First presentation at admission
Drugs on admission (prior diagnosis of UC)
Left-sided colitis (E2)
Extensive colitis (E3)
Smoking status at admission
The primary outcome measure of this study was colectomy. Patients were defined as initial responders if they were discharged from hospital without having surgery during the acute admission. Non-responders underwent urgent colectomy. Late non-responders were defined as those having colectomy in the 90 days following infliximab. Successfully withdrawal of corticosteroid therapy at day 90 was also assessed. Adverse events were assessed by a case note review.
Descriptive data were displayed as median values with interquartile ranges (IQR). Predictors of response (clinical parameters: sex, age at diagnosis, smoking status, disease extent; laboratory parameters on admission and at day 3 of iv corticosteroid therapy: stool frequency, C reactive protein (CRP) and serum albumin) were analysed by univariate analysis, using chi-squared or Mann–Whitney U testing for categorical and continuous data respectively. P-value ≤0.05 was considered significant and odds ratios (OR) were given with 95% confidence intervals (C.I.) and two-sided P -values. A logistic regression model was used for multivariate analysis incorporating the clinical and laboratory factors listed above (Minitab Statistical Software, version 13.20, State College, PA, USA). Sensitivity and specificity of predictive values were generated by a receiver-operator characteristic curve in GraphPad Prism (version 4.00 for Windows, GraphPad Software, San Diego, CA, USA).
Twenty-six out of 39 (66.6%) patients given infliximab as ‘rescue therapy’ for acute severe UC avoided urgent colectomy at the point of hospital discharge and were defined as early responders. The median duration from admission to infliximab therapy was 9 days (IQR 5.5–12). This time interval was non-significantly longer in patients for whom this was the first presentation of UC, compared with patients with known UC at admission (7.5 days, IQR 5–10.8 vs. 10.5 days, IQR 7.8–12.5, P = 0.11). 13/39 (33.3%) of patients underwent urgent colectomy, before hospital discharge (non-responders), at a median of 5 days (range 1–8 days) following infliximab therapy (Figure 1). Early responders were discharged from hospital a median of 6 days following infliximab (IQR 4.3–6.8).
Predictors of response
Serum albumin predicted response to infliximab. On univariate testing, albumin levels were significantly lower in patients undergoing urgent colectomy at both time of admission and on day 3 of iv steroid therapy (Table 2 and Figure 2). Patients with a serum albumin of <30 g/L at admission were more likely to undergo colectomy than those with levels of ≥30 g/L [4/6 (66.6%) vs. 7/31 (22.6%), P = 0.05, OR 6.86, C.I. 1.03–45.6]. Serum albumin of <34 g/L on day 3 of iv corticosteroids (recorded in 31/39 patients) was highly predictive of colectomy [9/18 (50.0%) <34 g/L vs. 1/13 (7.7%) ≥34 g/L, P = 0.02, OR 12.0, C.I. 1.28–112.7], with a sensitivity of 57.1% (C.I. 34.0–78.2%) and specificity of 90.0% (C.I. 55.5–99.8%). Stool frequency, CRP, faecal calprotectin, age at diagnosis, disease extent, sex and smoking status did not predict response to infliximab. When all these clinical and laboratory variables were put into a multivariate regression model, serum albumin remained predictive of colectomy at P = 0.05. There were more urgent colectomies in patients for whom this was the first presentation of UC [7/15 (46.7%)] than in those with a known diagnosis at admission [6/24 (25.0%), P = 0.16, OR 2.63, C.I. 0.67–10.4].
Table 2. Patient characteristics at point of admission and at day 3 of intravenous (iv) corticosteroids, in responders (no colectomy at hospital discharge) and non-responders (colectomy before discharge). Medians are displayed with interquartile ranges (IQR). Two-sided P-values were calculated by Mann–Whitney U-testing
CRP, C reactive protein.
Parameters at admission
Stool frequency/24 h
Parameters at day 3 iv corticosteroid therapy
Stool frequency/24 h
Patients treated with infliximab 5 days or less after admission were more likely to undergo urgent colectomy than those treated after 6 or more days, although this did not reach significance [5/9 (55.6%) vs. 7/29 (24.1%), P = 0.11, OR 3.93, C.I. 0.82–18.8]. The only clinically relevant parameter that approached statistical significance was stool frequency at day 3 of iv steroids. This was higher in those treated early [13 (3.5–14) vs. 5 (2.5–7.50, P = 0.06, Table 3]. This might be a marker of severity in this group; however, the CRP and albumin was equivalent in both groups at admission and at day 3 of iv steroid therapy. In patients with known UC at admission, previous treatment with azathioprine/mercaptopurine (MP) did not affect urgent colectomy rates (33.3% in azathioprine treated vs. 23.5% in azathioprine naive, P = 0.47).
Table 3. Clinical and laboratory parameters at admission and at day 3 of intravenous (iv) steroids in patient treated early with infliximab (5 or less days) compared with those treated later (6 or more days). P-values were generated by Mann–Whitney U testing
Patients treated ≤5 days after admission
Patients treated ≥6 days after admission
CRP, C reactive protein.
Parameters at admission
Stool frequency/24 h
Parameters at day 3 of iv corticosteroid therapy
Stool frequency/24 h
Ninety day follow-up data were available on 24/26 (92.3%) responders; of these, 17/24 (70.8%) had successfully withdrawn from corticosteroid therapy. 20/24 (83.3%) of these patients were established on azathioprine/MP immunosuppression [median azathioprine dose 1.67 mg/kg (IQR 1.38–2.15)]. The median daily prednisolone dose for those who had not successfully tapered by day 90 was 8.75 mg (IQR 4.5–15.0). No additional patients underwent colectomy during this time period. During a median total follow-up of 203.0 days (IQR 135.5–328.5), there were two additional colectomies reported, one in a patient on established 6-MP immunosuppression at acute presentation, another in a patient with prior azathioprine intolerance.
Ten out of 26 (38.5%) responders had more than one infusion of infliximab. Five patients received a predefined 3-dose induction regime (0, 2, 6 weeks) as directed by their physician. One of these patients went onto 8 weekly maintenance treatment; another had a second infusion 26 weeks later. Successful withdrawal of steroids at day 90 was comparable in those treated with either a single infusion or a 3-dose induction [3/5 (60.0%) vs. 14/19 (73.7%), P = 0.61]. Both of the additional colectomies in the total follow-up period were in patients treated with a single infusion of infliximab. Five additional patients had a second infusion of infliximab to treat a clinical relapse of disease (2, 10, 12, 26 and 39 weeks after first infusion). The patient re-treated after a drug holiday of 39 weeks had a delayed hypersensitivity reaction to the second infusion of infliximab (concomitant azathioprine therapy had been discontinued by the patient 6 months previously).
Serious adverse events
There was one death following infliximab therapy, in a 71-year-old gentleman, an ex-smoker (quit 2 years prediagnosis) with a past medical history of ischaemic heart disease (myocardial infarction 6 and 13 years previously), transient ischaemic attack and mild chronic obstructive pulmonary disease (treated with inhalers only). He was diagnosed with left-sided UC (E2) 4 months prior to admission and treated with oral balsalazide. 9 days after admission (after 8 days of iv corticosteroid therapy), he was treated with 5 mg/kg infliximab. He successfully responded to infliximab, and was discharged home 1 week after therapy on 40 mg prednisolone, 1.8 mg/kg azathioprine and balsalazide. Two weeks later he represented with bronchopulmonary pneumonia, and despite 2–3 days of intensive care unit therapy with invasive ventilation, high-dose inotropes and broad-spectrum antibiotics he died from overwhelming septicaemia. Pseudomonas aeruginosa was grown from bronchiolar-lavage fluid and peripheral blood cultures.
There was one other major complication of infliximab therapy. An otherwise healthy 22-year-old patient, in whom the acute admission was the first presentation of UC, was treated with 5 mg/kg infliximab 7 days following acute admission. He failed to respond to medical therapy and underwent urgent colectomy 2 days after infliximab. Post-operatively he became critically unwell with septicaemia that failed to respond to broad-spectrum antibiotic therapy, and was presumed to have fungaemia complicating infliximab therapy. He eventually recovered with intravenous anti-fungal treatment, total parenteral nutrition and high-dependency support and was discharged 6 weeks postcolectomy. All adverse events are listed in Table 4.
Table 4. Adverse events in patients treated with infliximab as rescue therapy for acute severe ulcerative colitis
Pelvic collection (managed conservatively)
Uncomplicated urinary tract infection
Severe psychological morbidity relating to stoma formation
Death from Pseudomonas pneumonia
Cellulites associated with intravenous cannula
Acute infusion reaction
Delayed hypersensitivity reaction (re-treatment after 9 month drug free interval)
The efficacy of infliximab in Crohn’s disease is now well established.30, 31 However, prior to 2005 there was no evidence for efficacy in UC. The large ACT1/2 trials have partially addressed the use of infliximab in moderate to severe UC in the out-patient setting.23 Jarnerot et al. have provided compelling data from a small, but well-conducted randomized placebo-controlled trial that infliximab is an effective ‘rescue’ therapy in acute severe, intravenous steroid refractory, UC.24 The data presented here represent the largest cohort of patients with acute severe UC treated with infliximab (n = 39, compared with 24 patients treated with infliximab in the Scandinavian study). This retrospective series provides substantive ‘real-world’ data on the risks and benefits of infliximab use in this setting. To avoid selection bias, we have attempted to report on all patients treated in Scotland during the study period, although we know of at least two additional cases that were not provided for inclusion in this dataset. The efficacy data mirror the Jarnerot experience closely, but the serious adverse events experienced in this study are of clear importance in clinical decision-making. In the present study, 33% of patients underwent urgent colectomy during the acute admission, despite infliximab therapy. The latest colectomy was performed 8 days after infliximab, with no further operations carried out during 90 days. There was a trend for patients treated with infliximab early (5 days or less after admission) to come to urgent colectomy more frequently than those treated later. This has clear parallels to Jarnerot’s study, where the patients randomized on day 3 of iv corticosteroid therapy by a fulminant colitis index demonstrated relatively less benefit from infliximab that those randomized later (days 6–8 on the Seo index).24
Whilst it is clear from the protocol of the Scandinavian study that those treated earlier with infliximab or placebo had more severe disease, there were no consistent trends to severity in those patients from the Scottish cohort treated early. The additional duration of intensive corticosteroid therapy may be important in determining outcome in these patients, although this hypothesis is not supported by published data. However, we noted that serum albumin (at admission and day 3 of iv steroids) predicted response to infliximab. This is consistent with Jarnerot’s observation that patients with severe disease responded less well to therapy. Hypoalbuminaemia is well-recognised as a feature of severe colitis feature of acute severe UC,32 and is a poor prognostic marker at day 3 of iv steroids.5 In our cohort, a serum albumin on day 3 of less than 34 g/L had a sensitivity of 57.1% and specificity of 90.0% for colectomy (negative predictive value 92.3%).
At present, the most widely used therapies for acute severe UC failing iv steroid therapy are ciclosporin and colectomy. The short-term efficacy of ciclosporin has been documented, with up to 86% of patients avoiding colectomy during the acute admission in two large retrospective studies.33–35 However, the team from Leuven suggested that colectomy is avoided in only 55% at 3 years, and they encountered three immunosuppression-related deaths (3.5%; two cases of Pneumocystis carinii pneumonia and one of systemic aspergillosis) during the follow-up period.33 A follow-up study from the same unit pointed out that although only 33% will require colectomy at 1 year, 88% require colectomy by 7 years.35 However, de novo co-prescription of azathioprine/ MP immunosuppression with ciclosporin significantly reduced the incidence of delayed colectomy.34, 35 Whilst we await the longer-term follow-up of the present Scottish infliximab cohort to determine delayed colectomy rates and the effect of immunosuppression, it was notable that the two patients undergoing colectomy after the acute admission (at days 141 and 203 after infliximab) both had prior azathioprine exposure.
The major complication rate in the present study was 5.2%, with mortality of 2.6%, which is probably comparable with ciclosporin. Whilst the death occurred in a relatively older patient with not inconsiderable co-morbidity, the opportunistic infection was probably attributable to infliximab. It remains to be determined whether prophylactic antibiotics are required in this setting. In the ACT studies, there were significantly more infectious adverse events requiring antimicrobial therapy in infliximab-treated patients compared with placebo, including one case of tuberculosis and one of fatal histoplasmosis.23, 27 Hospitalized patients with acute severe UC are probably more likely to have sub-clinical sepsis ‘unmasked’ by anti-tumour necrosis factor (TNF) therapy than the ambulatory ACT1/2 study population. In addition to the infectious complications, three neurological events and four malignancies were documented in infliximab-treated patients from ACT1/2.23 With at least one-third of infliximab-treated patients undergoing urgent colectomy at a median of 5 days from anti-TNFα therapy in our study, and 8 days in Jarnerot’s infliximab-treated cohort, it is important to determine whether treatment adversely affects post-operative outcome. In the present study, there was a severe case of post-operative fungaemia (Table 4). In the Scandinavian study, post-operative complications were not increased in the infliximab group over those given placebo.24 This is consistent with reports from the Crohn’s literature where infliximab does not appear to adversely affect surgical outcome;36, 37 however, serious post-operative infections were predicted by anti-TNFα therapy in a cohort of rheumatoid arthritis patients undergoing orthopaedic surgery.38 In two small datasets comparing patients with and without peri-operative ciclosporin for UC, there was no different in postcolectomy complications.39, 40
There are insufficient data at present to determine the most efficacious induction regime for infliximab in acute severe UC. Although the numbers are too small for definitive analysis, there was no difference in delayed colectomy or steroid withdrawal rates at 90 days in the present study. A single infusion does raise the issue of how to treat future relapses. The one patient in this study who was re-treated after a drug-free interval of 9 months suffered a delayed hypersensitivity reaction. Such patients may in the future be treated with one of the newer generation of anti-TNFα antibodies that, in Crohn’s disease, are well tolerated in patients with previous infliximab intolerance.41–44 However, at present there are no data to support the use of these agents in UC. The concerns about hepato-splenic T cell lymphoma in Crohn’s patients on concomitant infliximab and azathioprine45 are an important safety caveat to anti-TNF therapy that may influence this debate.
In conclusion, infliximab appears to be efficacious as rescue therapy for patients with acute severe UC, but serious adverse events do occur. These need to be factored into the risk/benefit analysis and compared with surgery that remains a ‘curative’ option in UC, despite the well documented short- and long-term problems with pouch formation which include, in a minority of patients, pouch dysfunction, pouchitis, infertility and incontinence.46–48 The long-term out-come of patients rescued from acute colectomy by infliximab therapy remains to be determined. The optimal dosing regime of infliximab +/− azathioprine for induction and maintenance of remission in acute severe UC is unknown. The data presently available would suggest that the efficacy of infliximab and ciclosporin rescue therapies is probably equivalent. Ultimately, the treating physician/surgeon must determine which patients are suitable for rescue medical therapy and risk delaying appropriate surgical intervention. Both rescue agents may serve to bridge patients onto long-term immunosuppression. Furthermore, the usefulness of a bridge to a psycho-socially acceptable time for semi-elective colectomy has probably previously been underestimated. In the meantime, there remains a pressing need for a head-to-head randomized control trial of infliximab and ciclosporin in this setting.
The authors would like to acknowledge the other members of the Scottish Society of Gastroenterology Infliximab Group (I. D. Penman, K. R. Palmer, H. Jafferbhoy, H. Gillett, C. Evans, J. Todd, K. Vaidya and J. Rose). Declaration of personal interests: J.S. has served as a speaker a consultant and an advisory board member for Schering-Plough, Abbott and UCB. I.D.R.A. has served as a speaker, a consultant and an advisory board member for Schering-Plough and Shire Pharmaceuticals. Declaration of funding interests: J.S. has received research funding from Schering-Plough, Abbott, UCB and Elan Pharmaceuticals.