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Colectomy rate in acute severe ulcerative colitis in the infliximab era
Available online at www.sciencedirect.com
Digestive and Liver Disease 40 (2008) 821–826
Alimentary Tract
Colectomy rate in acute severe ulcerative colitis in the infliximab era A. Aratari a,∗ , C. Papi b , V. Clemente a , A. Moretti b , R. Luchetti b , M. Koch b , L. Capurso b , R. Caprilli a a
Gastroenterology Unit, Department of Clinical Sciences, University of Rome “La Sapienza”, Rome, Italy b Gastroenterology Unit, S. Filippo Neri Hospital, Rome, Italy Received 28 January 2008; accepted 26 March 2008 Available online 9 May 2008
Abstract Background. Severe ulcerative colitis is a potentially life-threatening condition. Due to advances in medical therapy, the mortality rate has dropped to <2% over the past 30 years, but the colectomy rate reaches 30%. Recently, infliximab has been shown to be effective as rescue therapy but little is known about long-term benefits. Aim. To evaluate short-and long-term colectomy rates for severe ulcerative colitis in the era of biological treatment and to identify predictive factors of long-term colectomy. Patients and methods. From 2001 to 2006 all in-patients with severe ulcerative colitis, according to Truelove and Witts criteria, were retrospectively reviewed. All patients had received intravenous steroid treatment; infliximab (5 mg/kg at 0, 2 and 6 weeks) was used as rescue therapy in steroid-refractory patients; colectomy was performed in patients who deteriorated whilst on steroid treatment or failed to respond to infliximab. Results. Of the 314 ulcerative colitis patients hospitalized during the study period, 52 (16.5%) met the criteria of severe ulcerative colitis. After median 7 days (range 4–15) on intravenous steroids, 37/52 (71%) patients showed a clinical response, while 15/52 (29%) were steroidrefractory. Of these, four underwent urgent colectomy and 11 received infliximab. A clinical response was observed in all infliximab-treated patients. In the long-term, another six patients underwent elective colectomy. The overall colectomy rate, following the acute attack, was 19%; the cumulative probability of a course without colectomy was 90%, 86%, 84%, 81%, after 6, 12, 18 and 24 months, respectively. No deaths occurred. The long-term colectomy risk was comparable in patients treated with infliximab and in steroid-responsive patients (18% vs. 11% respectively; OR 1.9; 95% CI 0.26–14.5). No predictive factors of colectomy, in the long-term, were identified. Conclusions. Surgery continues to play an important role in acute severe ulcerative colitis. Infliximab can avoid urgent colectomy in steroid-refractory patients but the risk of elective colectomy, in the long-term, is not modified. © 2008 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. Keywords: Colectomy; Infliximab; Severe ulcerative colitis; Steroids
1. Introduction Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease with a chronic relapsing course. Approximately 15% of patients with UC will develop an acute severe attack [1]. Severe UC is a potentially life-threatening condition although mortality has dropped dramatically over the ∗ Corresponding author at: UOC Gastroenterologia, Ospedale S Filippo Neri, Via Martinotti 20, 00135 Rome, Italy. Tel.: +39 06 33062245; fax: +39 06 33062641. E-mail address: [email protected] (A. Aratari).
past 30–40 years [2]. A subset of patients with severe UC may have more severe symptoms and a rapid progression towards local or systemic complications, such as toxic megacolon, massive haemorrhage, colonic perforation or multi organ dysfunction syndrome (MODS) [3,4]. Recently, both impending megacolon and toxic megacolon were found to be associated with the development of MODS, a condition responsible for the majority of deaths in severe UC [5,6]. At the beginning of the last century, overall mortality for UC reached 75% and, in the fifties, mortality was 22% in the first year after diagnosis [7]. When steroids were introduced in the medical treatment of UC, overall mortality decreased to 7% [8]. In the seven-
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ties, with the introduction of the “Oxford regimen”, mortality for a severe attack of UC decreased from 30% to <2%, with a colectomy rate of approximately 30% [9–16]. The mainstay of the “Oxford regimen” consisted of early recognition of the severity of colitis, intensive medical treatment, including high-dose intravenous and rectal steroids for 5–7 days, and early colectomy for patients who failed to respond to treatment or even deteriorated [9]. As colectomy has a negative impact on the quality of life and carries high peri-operative morbidity and high costs, further attempts have been made to avoid surgery in patients with severe UC not responding to intravenous steroids, while maintaining mortality at a low rate. The first attempt was to prolong the intravenous steroids for 7–10 days or more. This was a common policy in the eighties, but the colectomy rate remained as high as 30% [15,17]. A further attempt to avoid surgery was the introduction of the so-called “rescue therapies” for steroid-refractory severe UC. At the beginning of the nineties, intravenous cyclosporine consistently demonstrated its dramatic effect in patients who have failed to respond to a course of intravenous steroids for severe UC. In a randomized controlled trial, a response rate of 82% was reported in patients treated with cyclosporine, compared to 0% in patients who continued to receive intravenous steroids and placebo [18]. Later experience with cyclosporine showed that, although the remission rate reaches 70–80% in the short-term [18], approximately 50% of patients who initially respond will require colectomy in the long-term [19,20]. Moreover, cyclosporine carries the risk of severe and potentially fatal toxicities and, in many centres, it is not routinely used. In a recent systematic review, it has been shown that the short-term colectomy rate, in severe UC, has remained stable over the past 30 years despite the introduction of cyclosporine [21]. Infliximab has recently been used as rescue therapy in steroid-refractory UC. A randomised controlled trial in Sweden has shown that infliximab is effective for reducing short-term colectomy in severe UC [22]. Open label trials have confirmed this observation [23]. However, few data are available concerning the efficacy of infliximab on the long-term colectomy rate [24–27]. Aim of the present investigation was to evaluate the colectomy rate in patients with acute severe UC in the era of biological therapies and to identify predictive factors of colectomy in the long-term.
2. Patients and methods The records of all UC patients hospitalised between January 2001 and December 2006 in two GI Units of Rome (Department of Clinical Sciences, University “La Sapienza” and San Filippo Neri Hospital), were reviewed. The diagnosis of UC was established according to standard criteria [28]. All patients requiring hospitalization for a severe attack, according to Truelove and Witts criteria, were included in the study [8]. A severe attack was defined as the passage of ≥6 bloody
stools daily with one or more of the following criteria: temperature >37.8 ◦ C, pulse rate >90/min, haemoglobin <10.5 g/dl or Erythrocyte sedimentation rate (ESR) >30 mm/h [29]. Clinical and demographic characteristics of all patients were recorded upon admission: age, sex, duration of disease, extension of colitis (left sided or extensive), previous steroid treatment, and Powell-Tuck score. Powel-Tuck score is a composite score system that includes 10 clinical indicators and endoscopic features: a severe attack is defined as a score ≥9 [30]. Laboratory studies included evaluation of haemoglobin (Hb), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum electrolytes, serum albumin and arterial pH. Gastrointestinal distension (impending megacolon or toxic megacolon) was evaluated on plain abdominal X-rays in clinostatism. All patients with severe UC were treated according to a standard regimen: intravenous (iv) steroids (hydrocortisone 100 mg qid); rectal steroids, antibiotics (metronidazole 500 mg tid iv), fluid-electrolytes and albumin replacement. Total parenteral nutrition and blood transfusions were used, if appropriate. Intravenous steroids were administered for 7–15 days: patients who improved were shifted to oral steroids and the dose was tapered every 10–15 days with steroids weaning within 12–16 weeks. Mesalamine (≥2.4 g/day) or azathioprine (2.0–2.5 mg/kg/day), depending upon clinical judgment, were used as maintenance treatment. Infliximab was given as rescue therapy for patients who failed to respond to intravenous steroids. Infliximab was administered at the dose of 5 mg/kg i.v. at 0, 2 and 6 weeks; azathioprine, at the dose of 2.0–2.5 mg/kg/day, was started as maintenance treatment in all infliximab treated patients. Colectomy was performed in patients who deteriorated during steroid treatment or failed to respond to infliximab. The primary end-point was the cumulative colectomy rate in patients with severe UC. The secondary end-point was to identify predictive factors of colectomy in the long-term, particularly to evaluate whether infliximab could modify the need of colectomy in the long-term. Patients were, therefore, classified in to two groups: patients responding to intravenous steroids (group 1), and patients refractory to intravenous steroids but responders to infliximab (group 2). 2.1. Statistical analysis The Kaplan-Meier survival method was used to estimate the cumulative probability of a course without colectomy after the acute severe attack of UC. Differences between curves were tested using the log-rank test. As possible predictive factors of colectomy, in the long-term, the following covariates were considered: age, sex, duration of disease, extension of disease (left colitis or extensive colitis), Powell-Tuck score, presence of gastrointestinal distension (impending megacolon or toxic megacolon), laboratory findings (Hb, ESR, CRP, serum electrolytes, albumin and arterial pH), previous steroid treatment, duration of intensive treatment (less or more than 5 days), treatment with infliximab.
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Table 1 Clinical characteristics of patients
nv: normal values.
BioMedical Data Processing (BMDP dynamic version 7, University of California, Los Angeles, CA, USA) was used for all calculations. A p value <0.05 was considered statistically significant. Chi-square and Mann–Whitney Rank-Sum test were used where appropriate.
3. Results From January 2001 to December 2006, 314 UC patients were admitted to our GI Units: 52 patients (16.5%) met the criteria of severe UC. The clinical characteristics of patients with severe UC are outlined in Table 1 (grey box). All patients received intravenous steroids for median 7 days (range 4–15). A substantial clinical response was observed in 37 out of the 52 patients (71%), while the remaining 15 (29%) failed to respond to steroid treatment. Seven patients developed complications: in three patients colonic dilatation was present at admission but resolved within 24 h on intravenous steroids, while in four patients complications occurred during intravenous steroids treatment (two patients had massive bleeding on the 4th hospital day, and two patients developed toxic megacolon, complicated by colonic perforation in one and by MODS in the other, on the 10th day). All these four patients underwent emergency colectomy. The overall colectomy rate, in an emergency setting, was 7.7% (4 out of 52 patients) (Fig. 1): the indication for colectomy was the occurrence of complications in all patients. The remaining 11 patients not responding to intravenous steroids received infliximab after median 10 days (range 4–14) of steroids treatment. A clinical response was observed in all infliximab treated patients and none required urgent colectomy. All 48 patients who avoided urgent colectomy (patients responders to intravenous steroids or infliximab) received mesalamine (n = 16) or azathioprine (n = 32) as maintenance
treatment. The median follow-up following discharge from hospital was 26 months (range 3–77). During follow-up, six patients underwent elective colectomy for chronic relapsing symptoms (Fig. 1). The overall colectomy rate (urgent or elective surgery) after an acute attack of severe UC was 19% (10 out of 52 patients). The cumulative probability of a course without colectomy after the acute attack was 90%, 86%, 84%, 81% after 6, 12, 18 and 24 months, respectively (Fig. 2A). No deaths were recorded. As far as concerns predictive factors for elective colectomy during follow-up, none of the variables evaluated (Table 1) was associated with the long-term surgical outcome. The probability of elective colectomy during follow-up was evaluated in patients who responded to first line treatment with intravenous steroids (n = 37, group 1) and in patients achieving response after rescue therapy with infliximab (n = 11, group 2). At baseline, the clinical characteristics were similar in the two groups (Table 1, white box). The long-term colectomy rate was 11% group 1 and 18% in group 2 (OR
Fig. 1. Flow chart showing outcomes of severe UC patients.
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Fig. 2. (A) Cumulative probability of a disease course without colectomy following the acute severe UC attack (urgent and elective colectomy are considered). (B) Cumulative probability of a disease course without colectomy in patients with severe UC who responded to intravenous steroids (group 1) and in steroid-refractory patients who achieved remission following infliximab (group 2).
1.9; 95% CI 0.26–14.5). The cumulative probability of a disease course without colectomy after a severe acute attack was similar in the two groups (log-rank test p = 0.35) (Fig. 2B). Patients treated with infliximab had a shorter disease course free of colectomy compared to patients responding to intravenous steroids (15 ± 10 vs. 21 ± 24 months, respectively), although this difference is not statistically significant.
4. Discussion This study focuses on long-term outcome of severe UC in two referral centres between 2001 and 2006. Of the 314 UC patients hospitalized during the study period, a diagnosis of severe UC, according to standard criteria, has been established in 16.5%. This figure is similar to the prevalence of severe UC reported in the literature [1,15,17,22]. In accordance with our clinical practice, all patients with a diagnosis of severe UC have been treated with a standard regimen: intravenous steroids, antibiotics, fluid-electrolytes and albumin replacement, and, if clinically appropriate, total parenteral nutrition and blood transfusions. Infliximab was used as rescue therapy in patients who failed to respond to intravenous steroids. In our experience, intravenous cyclosporine has been used only occasionally for steroid refractory severe UC, and, in the period 2001–2006 none of the patients were treated with cyclosporine. In our series, the response
rate and refractoriness to intravenous steroids (71% and 29%, respectively) are similar to those reported by others [1,15,17,22]. Of the 15 not responding patients, 11 (73%) were successfully treated with infliximab and avoided urgent colectomy; only four patients (27%) underwent urgent colectomy because of complications (massive bleeding, toxic megacolon, colonic perforation or MODS). During followup, another six patients underwent elective colectomy for chronic relapsing symptoms. The overall colectomy rate of 19% is less than that reported in earlier studies in the literature (45–53%) [12,15,16]. The lower colectomy rate, in the last few decades, could be related to various factors, such as, for example, early recognition of prognostic factors, careful monitoring and improved overall management of severe UC in more recent years. These same factors could also account for the reduction in the incidence of severe complications, from 11% in the seventies to 6% at the end of the eighties [31]. When local or systemic complications occur, the need for urgent colectomy has been reported to be as high as 45–61% with a mortality rate of approximately 50% [3–10]. In our series, complications occurred in almost 2% of patients with severe UC and the urgent colectomy rate of 57% is similar to that reported by others [3,10], but no mortality was recorded. Before the introduction of rescue therapies, all steroidrefractory patients were candidate to colectomy; thus, in our series, the potential need for colectomy during the hospitalization was 29%. Infliximab therapy has considerably reduced the need for urgent colectomy to almost 8% and has limited the indication to surgery only for patients with more severe or complicated disease. This figure is similar to that reported in clinical trials but a clinically relevant question concerns the potential role of infliximab in reducing the long-term colectomy rate. In the literature, the overall colectomy rate, following infliximab treatment in severe UC, ranges from 0% to 75% [23,24,26,27,32–44]. Several factors could account for this wide range, such as patient selection, definition of severity, number of infliximab infusions, geographic areas, study design, and duration of follow-up. In studies with a larger sample size the long-term colectomy rate is as high as 30–40% [22,24]. In our series, the longterm colectomy rate, in infliximab-treated patients, is similar to that of patients responding to intravenous steroids. However, patients treated with infliximab present a shorter disease course free of colectomy compared to patients responding to intravenous steroids. This difference is not statistically significant but a beta error cannot be excluded due to the small number of infliximab-treated patients in our study. We can speculate that steroid-refractory patients, who achieve remission with infliximab, have a more severe disease compared to steroid-responsive patients: this can explain the shorter disease course free of colectomy in infliximab treated patients. The long-term colectomy rate is not affected by clinical variables such as age, sex, duration of disease, extension of disease, Powell-Tuck score, presence of gastrointestinal distension, Hb, ESR, CRP, serum electrolytes, albumin and
A. Aratari et al. / Digestive and Liver Disease 40 (2008) 821–826
arterial pH, previous steroid treatment, duration of intensive treatment (less or more than 5 days). In conclusion, surgery continues to play an important role in acute severe UC. Infliximab, used as rescue therapy, following failure of steroids, appears to be useful in avoiding urgent colectomy but the risk of elective colectomy, in the long-term, is not modified.
Practice points • Severe ulcerative colitis is still a potentially life-threatening condition. • Although the mortality rate has dropped to <2% over the past 30 years, the colectomy rate remains high. • Infliximab, used as rescue therapy, appears to be useful in avoiding urgent colectomy but the risk of elective colectomy, in the longterm, seems to be not modified. • Surgery continues to play an important role in acute severe ulcerative colitis.
Research agenda • Prospective long-term studies with adequate sample size are needed. • Predictors of long-term colectomy risk are needed.
Conflict of interest statement None declared.
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ANNOUNCEMENT CASE REPORTS AND BRIEF CLINICAL OBSERVATIONS
Digestive and Liver Disease receives many more case reports and brief clinical observations than it is possible to publish in the limited space available. Because of the large backlog of accepted case reports currently awaiting publication, we are unable to consider any further submissions of this type until further notice.
Digestive and Liver Disease 40 (2008) 821–826
Alimentary Tract
Colectomy rate in acute severe ulcerative colitis in the infliximab era A. Aratari a,∗ , C. Papi b , V. Clemente a , A. Moretti b , R. Luchetti b , M. Koch b , L. Capurso b , R. Caprilli a a
Gastroenterology Unit, Department of Clinical Sciences, University of Rome “La Sapienza”, Rome, Italy b Gastroenterology Unit, S. Filippo Neri Hospital, Rome, Italy Received 28 January 2008; accepted 26 March 2008 Available online 9 May 2008
Abstract Background. Severe ulcerative colitis is a potentially life-threatening condition. Due to advances in medical therapy, the mortality rate has dropped to <2% over the past 30 years, but the colectomy rate reaches 30%. Recently, infliximab has been shown to be effective as rescue therapy but little is known about long-term benefits. Aim. To evaluate short-and long-term colectomy rates for severe ulcerative colitis in the era of biological treatment and to identify predictive factors of long-term colectomy. Patients and methods. From 2001 to 2006 all in-patients with severe ulcerative colitis, according to Truelove and Witts criteria, were retrospectively reviewed. All patients had received intravenous steroid treatment; infliximab (5 mg/kg at 0, 2 and 6 weeks) was used as rescue therapy in steroid-refractory patients; colectomy was performed in patients who deteriorated whilst on steroid treatment or failed to respond to infliximab. Results. Of the 314 ulcerative colitis patients hospitalized during the study period, 52 (16.5%) met the criteria of severe ulcerative colitis. After median 7 days (range 4–15) on intravenous steroids, 37/52 (71%) patients showed a clinical response, while 15/52 (29%) were steroidrefractory. Of these, four underwent urgent colectomy and 11 received infliximab. A clinical response was observed in all infliximab-treated patients. In the long-term, another six patients underwent elective colectomy. The overall colectomy rate, following the acute attack, was 19%; the cumulative probability of a course without colectomy was 90%, 86%, 84%, 81%, after 6, 12, 18 and 24 months, respectively. No deaths occurred. The long-term colectomy risk was comparable in patients treated with infliximab and in steroid-responsive patients (18% vs. 11% respectively; OR 1.9; 95% CI 0.26–14.5). No predictive factors of colectomy, in the long-term, were identified. Conclusions. Surgery continues to play an important role in acute severe ulcerative colitis. Infliximab can avoid urgent colectomy in steroid-refractory patients but the risk of elective colectomy, in the long-term, is not modified. © 2008 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. Keywords: Colectomy; Infliximab; Severe ulcerative colitis; Steroids
1. Introduction Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease with a chronic relapsing course. Approximately 15% of patients with UC will develop an acute severe attack [1]. Severe UC is a potentially life-threatening condition although mortality has dropped dramatically over the ∗ Corresponding author at: UOC Gastroenterologia, Ospedale S Filippo Neri, Via Martinotti 20, 00135 Rome, Italy. Tel.: +39 06 33062245; fax: +39 06 33062641. E-mail address: [email protected] (A. Aratari).
past 30–40 years [2]. A subset of patients with severe UC may have more severe symptoms and a rapid progression towards local or systemic complications, such as toxic megacolon, massive haemorrhage, colonic perforation or multi organ dysfunction syndrome (MODS) [3,4]. Recently, both impending megacolon and toxic megacolon were found to be associated with the development of MODS, a condition responsible for the majority of deaths in severe UC [5,6]. At the beginning of the last century, overall mortality for UC reached 75% and, in the fifties, mortality was 22% in the first year after diagnosis [7]. When steroids were introduced in the medical treatment of UC, overall mortality decreased to 7% [8]. In the seven-
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ties, with the introduction of the “Oxford regimen”, mortality for a severe attack of UC decreased from 30% to <2%, with a colectomy rate of approximately 30% [9–16]. The mainstay of the “Oxford regimen” consisted of early recognition of the severity of colitis, intensive medical treatment, including high-dose intravenous and rectal steroids for 5–7 days, and early colectomy for patients who failed to respond to treatment or even deteriorated [9]. As colectomy has a negative impact on the quality of life and carries high peri-operative morbidity and high costs, further attempts have been made to avoid surgery in patients with severe UC not responding to intravenous steroids, while maintaining mortality at a low rate. The first attempt was to prolong the intravenous steroids for 7–10 days or more. This was a common policy in the eighties, but the colectomy rate remained as high as 30% [15,17]. A further attempt to avoid surgery was the introduction of the so-called “rescue therapies” for steroid-refractory severe UC. At the beginning of the nineties, intravenous cyclosporine consistently demonstrated its dramatic effect in patients who have failed to respond to a course of intravenous steroids for severe UC. In a randomized controlled trial, a response rate of 82% was reported in patients treated with cyclosporine, compared to 0% in patients who continued to receive intravenous steroids and placebo [18]. Later experience with cyclosporine showed that, although the remission rate reaches 70–80% in the short-term [18], approximately 50% of patients who initially respond will require colectomy in the long-term [19,20]. Moreover, cyclosporine carries the risk of severe and potentially fatal toxicities and, in many centres, it is not routinely used. In a recent systematic review, it has been shown that the short-term colectomy rate, in severe UC, has remained stable over the past 30 years despite the introduction of cyclosporine [21]. Infliximab has recently been used as rescue therapy in steroid-refractory UC. A randomised controlled trial in Sweden has shown that infliximab is effective for reducing short-term colectomy in severe UC [22]. Open label trials have confirmed this observation [23]. However, few data are available concerning the efficacy of infliximab on the long-term colectomy rate [24–27]. Aim of the present investigation was to evaluate the colectomy rate in patients with acute severe UC in the era of biological therapies and to identify predictive factors of colectomy in the long-term.
2. Patients and methods The records of all UC patients hospitalised between January 2001 and December 2006 in two GI Units of Rome (Department of Clinical Sciences, University “La Sapienza” and San Filippo Neri Hospital), were reviewed. The diagnosis of UC was established according to standard criteria [28]. All patients requiring hospitalization for a severe attack, according to Truelove and Witts criteria, were included in the study [8]. A severe attack was defined as the passage of ≥6 bloody
stools daily with one or more of the following criteria: temperature >37.8 ◦ C, pulse rate >90/min, haemoglobin <10.5 g/dl or Erythrocyte sedimentation rate (ESR) >30 mm/h [29]. Clinical and demographic characteristics of all patients were recorded upon admission: age, sex, duration of disease, extension of colitis (left sided or extensive), previous steroid treatment, and Powell-Tuck score. Powel-Tuck score is a composite score system that includes 10 clinical indicators and endoscopic features: a severe attack is defined as a score ≥9 [30]. Laboratory studies included evaluation of haemoglobin (Hb), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum electrolytes, serum albumin and arterial pH. Gastrointestinal distension (impending megacolon or toxic megacolon) was evaluated on plain abdominal X-rays in clinostatism. All patients with severe UC were treated according to a standard regimen: intravenous (iv) steroids (hydrocortisone 100 mg qid); rectal steroids, antibiotics (metronidazole 500 mg tid iv), fluid-electrolytes and albumin replacement. Total parenteral nutrition and blood transfusions were used, if appropriate. Intravenous steroids were administered for 7–15 days: patients who improved were shifted to oral steroids and the dose was tapered every 10–15 days with steroids weaning within 12–16 weeks. Mesalamine (≥2.4 g/day) or azathioprine (2.0–2.5 mg/kg/day), depending upon clinical judgment, were used as maintenance treatment. Infliximab was given as rescue therapy for patients who failed to respond to intravenous steroids. Infliximab was administered at the dose of 5 mg/kg i.v. at 0, 2 and 6 weeks; azathioprine, at the dose of 2.0–2.5 mg/kg/day, was started as maintenance treatment in all infliximab treated patients. Colectomy was performed in patients who deteriorated during steroid treatment or failed to respond to infliximab. The primary end-point was the cumulative colectomy rate in patients with severe UC. The secondary end-point was to identify predictive factors of colectomy in the long-term, particularly to evaluate whether infliximab could modify the need of colectomy in the long-term. Patients were, therefore, classified in to two groups: patients responding to intravenous steroids (group 1), and patients refractory to intravenous steroids but responders to infliximab (group 2). 2.1. Statistical analysis The Kaplan-Meier survival method was used to estimate the cumulative probability of a course without colectomy after the acute severe attack of UC. Differences between curves were tested using the log-rank test. As possible predictive factors of colectomy, in the long-term, the following covariates were considered: age, sex, duration of disease, extension of disease (left colitis or extensive colitis), Powell-Tuck score, presence of gastrointestinal distension (impending megacolon or toxic megacolon), laboratory findings (Hb, ESR, CRP, serum electrolytes, albumin and arterial pH), previous steroid treatment, duration of intensive treatment (less or more than 5 days), treatment with infliximab.
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Table 1 Clinical characteristics of patients
nv: normal values.
BioMedical Data Processing (BMDP dynamic version 7, University of California, Los Angeles, CA, USA) was used for all calculations. A p value <0.05 was considered statistically significant. Chi-square and Mann–Whitney Rank-Sum test were used where appropriate.
3. Results From January 2001 to December 2006, 314 UC patients were admitted to our GI Units: 52 patients (16.5%) met the criteria of severe UC. The clinical characteristics of patients with severe UC are outlined in Table 1 (grey box). All patients received intravenous steroids for median 7 days (range 4–15). A substantial clinical response was observed in 37 out of the 52 patients (71%), while the remaining 15 (29%) failed to respond to steroid treatment. Seven patients developed complications: in three patients colonic dilatation was present at admission but resolved within 24 h on intravenous steroids, while in four patients complications occurred during intravenous steroids treatment (two patients had massive bleeding on the 4th hospital day, and two patients developed toxic megacolon, complicated by colonic perforation in one and by MODS in the other, on the 10th day). All these four patients underwent emergency colectomy. The overall colectomy rate, in an emergency setting, was 7.7% (4 out of 52 patients) (Fig. 1): the indication for colectomy was the occurrence of complications in all patients. The remaining 11 patients not responding to intravenous steroids received infliximab after median 10 days (range 4–14) of steroids treatment. A clinical response was observed in all infliximab treated patients and none required urgent colectomy. All 48 patients who avoided urgent colectomy (patients responders to intravenous steroids or infliximab) received mesalamine (n = 16) or azathioprine (n = 32) as maintenance
treatment. The median follow-up following discharge from hospital was 26 months (range 3–77). During follow-up, six patients underwent elective colectomy for chronic relapsing symptoms (Fig. 1). The overall colectomy rate (urgent or elective surgery) after an acute attack of severe UC was 19% (10 out of 52 patients). The cumulative probability of a course without colectomy after the acute attack was 90%, 86%, 84%, 81% after 6, 12, 18 and 24 months, respectively (Fig. 2A). No deaths were recorded. As far as concerns predictive factors for elective colectomy during follow-up, none of the variables evaluated (Table 1) was associated with the long-term surgical outcome. The probability of elective colectomy during follow-up was evaluated in patients who responded to first line treatment with intravenous steroids (n = 37, group 1) and in patients achieving response after rescue therapy with infliximab (n = 11, group 2). At baseline, the clinical characteristics were similar in the two groups (Table 1, white box). The long-term colectomy rate was 11% group 1 and 18% in group 2 (OR
Fig. 1. Flow chart showing outcomes of severe UC patients.
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Fig. 2. (A) Cumulative probability of a disease course without colectomy following the acute severe UC attack (urgent and elective colectomy are considered). (B) Cumulative probability of a disease course without colectomy in patients with severe UC who responded to intravenous steroids (group 1) and in steroid-refractory patients who achieved remission following infliximab (group 2).
1.9; 95% CI 0.26–14.5). The cumulative probability of a disease course without colectomy after a severe acute attack was similar in the two groups (log-rank test p = 0.35) (Fig. 2B). Patients treated with infliximab had a shorter disease course free of colectomy compared to patients responding to intravenous steroids (15 ± 10 vs. 21 ± 24 months, respectively), although this difference is not statistically significant.
4. Discussion This study focuses on long-term outcome of severe UC in two referral centres between 2001 and 2006. Of the 314 UC patients hospitalized during the study period, a diagnosis of severe UC, according to standard criteria, has been established in 16.5%. This figure is similar to the prevalence of severe UC reported in the literature [1,15,17,22]. In accordance with our clinical practice, all patients with a diagnosis of severe UC have been treated with a standard regimen: intravenous steroids, antibiotics, fluid-electrolytes and albumin replacement, and, if clinically appropriate, total parenteral nutrition and blood transfusions. Infliximab was used as rescue therapy in patients who failed to respond to intravenous steroids. In our experience, intravenous cyclosporine has been used only occasionally for steroid refractory severe UC, and, in the period 2001–2006 none of the patients were treated with cyclosporine. In our series, the response
rate and refractoriness to intravenous steroids (71% and 29%, respectively) are similar to those reported by others [1,15,17,22]. Of the 15 not responding patients, 11 (73%) were successfully treated with infliximab and avoided urgent colectomy; only four patients (27%) underwent urgent colectomy because of complications (massive bleeding, toxic megacolon, colonic perforation or MODS). During followup, another six patients underwent elective colectomy for chronic relapsing symptoms. The overall colectomy rate of 19% is less than that reported in earlier studies in the literature (45–53%) [12,15,16]. The lower colectomy rate, in the last few decades, could be related to various factors, such as, for example, early recognition of prognostic factors, careful monitoring and improved overall management of severe UC in more recent years. These same factors could also account for the reduction in the incidence of severe complications, from 11% in the seventies to 6% at the end of the eighties [31]. When local or systemic complications occur, the need for urgent colectomy has been reported to be as high as 45–61% with a mortality rate of approximately 50% [3–10]. In our series, complications occurred in almost 2% of patients with severe UC and the urgent colectomy rate of 57% is similar to that reported by others [3,10], but no mortality was recorded. Before the introduction of rescue therapies, all steroidrefractory patients were candidate to colectomy; thus, in our series, the potential need for colectomy during the hospitalization was 29%. Infliximab therapy has considerably reduced the need for urgent colectomy to almost 8% and has limited the indication to surgery only for patients with more severe or complicated disease. This figure is similar to that reported in clinical trials but a clinically relevant question concerns the potential role of infliximab in reducing the long-term colectomy rate. In the literature, the overall colectomy rate, following infliximab treatment in severe UC, ranges from 0% to 75% [23,24,26,27,32–44]. Several factors could account for this wide range, such as patient selection, definition of severity, number of infliximab infusions, geographic areas, study design, and duration of follow-up. In studies with a larger sample size the long-term colectomy rate is as high as 30–40% [22,24]. In our series, the longterm colectomy rate, in infliximab-treated patients, is similar to that of patients responding to intravenous steroids. However, patients treated with infliximab present a shorter disease course free of colectomy compared to patients responding to intravenous steroids. This difference is not statistically significant but a beta error cannot be excluded due to the small number of infliximab-treated patients in our study. We can speculate that steroid-refractory patients, who achieve remission with infliximab, have a more severe disease compared to steroid-responsive patients: this can explain the shorter disease course free of colectomy in infliximab treated patients. The long-term colectomy rate is not affected by clinical variables such as age, sex, duration of disease, extension of disease, Powell-Tuck score, presence of gastrointestinal distension, Hb, ESR, CRP, serum electrolytes, albumin and
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arterial pH, previous steroid treatment, duration of intensive treatment (less or more than 5 days). In conclusion, surgery continues to play an important role in acute severe UC. Infliximab, used as rescue therapy, following failure of steroids, appears to be useful in avoiding urgent colectomy but the risk of elective colectomy, in the long-term, is not modified.
Practice points • Severe ulcerative colitis is still a potentially life-threatening condition. • Although the mortality rate has dropped to <2% over the past 30 years, the colectomy rate remains high. • Infliximab, used as rescue therapy, appears to be useful in avoiding urgent colectomy but the risk of elective colectomy, in the longterm, seems to be not modified. • Surgery continues to play an important role in acute severe ulcerative colitis.
Research agenda • Prospective long-term studies with adequate sample size are needed. • Predictors of long-term colectomy risk are needed.
Conflict of interest statement None declared.
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ANNOUNCEMENT CASE REPORTS AND BRIEF CLINICAL OBSERVATIONS
Digestive and Liver Disease receives many more case reports and brief clinical observations than it is possible to publish in the limited space available. Because of the large backlog of accepted case reports currently awaiting publication, we are unable to consider any further submissions of this type until further notice.