IBD Surgery in the Biologic Therapy Era
IBD Surgery in the Biologic Therapy Era
Biologic agents are usually employed with the intent to help avoid operative intervention in patients with moderately to severely active IBD who have demonstrated an inadequate response to conventional therapies. Ananthakrishnan et al. analyzed data from the Nationwide Inpatient Sample to assess whether this desired outcome has been realized in patients requiring hospitalization for their IBD. They compared the proportion of hospitalizations resulting in surgery for either Crohn's disease or ulcerative colitis based on disease severity for the years 1998, 2004, and 2007. The overall absolute number of hospitalizations for Crohn's disease resulting in nonelective bowel surgery remained relatively constant between 1998 and 2007, with the low-severity cohort experiencing an actual decrease in the absolute number of nonelective operations. However, the relative number of people requiring nonelective bowel surgery was unchanged between 1998 and 2007 [odds ratio (OR) 0.88; 95% confidence interval (CI) 0.75–1.02] in patients presenting with severe Crohn's disease. In ulcerative colitis, the proportion of nonelective colectomies decreased by more than 50% in 2007 contrasted to 1998 in patients presenting with the lowest severity of disease. But once again, patients with severe colitis were just as likely to undergo nonelective colectomy in 2007 as compared to those with severe disease admitted in 1998 (OR 0.88; 95% CI 0.61–1.29). In summary, it appears that the era of biologic therapy is associated with a reduction in the relative number of IBD patients with mild disease requiring nonelective surgery, but the incidence of emergent or urgent surgery in patients with severe disease is unchanged.
Peyrin-Biroulet et al., from the University Hospital of Nancy, sought to determine whether azathioprine and anti-TNF treatment decreased the need for surgery in newly diagnosed Crohn's disease patients. They found that azathioprine treatment of less than 1.5 months (hazard ratio 2.00; 95% CI 1.20–3.34) and anti-TNF therapy for less than 16 months (hazard ratio 3.86; 95% CI 1.77–8.45) were independent positive predictors for major abdominal surgery; both stricturing (hazard ratio 12.01; 95% CI 5.97–24.17) and penetrating disease (hazard ratio 10.77; 95% CI 4.87–23.80) also independently increased the risk for surgery. Leombruno et al. reported similar findings when they matched 338 infliximab users with Crohn's disease to at least one comparison patient employing a propensity score matching. Patients who were treated with infliximab experienced a significantly lower risk of requiring a disease-related bowel resection (hazard ratio 0.64; 95% CI 0.51–0.81) or hospitalization (hazard ratio 0.73; 95% CI 0.63–0.85). However, regular maintenance therapy instead of episodic treatment with biologic agents is likely required to experience these benefits because the later approach yielded no difference in the rates of patients requiring resection surgery of their Crohn's disease within 3 years of diagnosis.
In a review of the recent literature related to adult patients with Crohn's disease, Bougen and Peyrin-Biroulet concluded that data from both population-based cohorts and referral center studies suggested only a modest or no impact of biologic agents on the need for operative intervention. Moreover, they noted that the often quoted randomized trials were not designed to assess the impact of anti-TNF therapy on surgical rates and cautioned that the reported results should be carefully interpreted.
Five centers from France reviewed their collective experience to determine the impact of infliximab on the need for colectomy in patients with ulcerative colitis. Between 2000 and 2009, 191 patients with ulcerative colitis received infliximab therapy and the median follow-up period was 18 months. Colectomy was required in 36 (19%) of the patients and predictors of colectomy after multivariate analysis were no clinical response after infliximab induction (hazard ratio 7.06; 95% CI 3.36–14.83), C-reactive protein greater than 10 mg/l at infliximab initiation (hazard ratio 5.11; 95% CI 1.77–14.76), and prior treatment with ciclosporin (hazard ratio 2.53; 95% CI 1.22–5.28). Hemoglobin less than 9.4 g/dl at infliximab initiation (OR 4.36; 95% CI 1.81–10.42) was a predictor of primary nonresponse to infliximab, and episodic infliximab usage (OR 4.01; 95% CI 2.71–5.94) was a predictor of infliximab failure among initial responders.
One of the five centers, the group from University Hospital of Nancy, subsequently studied the need for surgery in patients presenting with newly diagnosed ulcerative colitis of varying severity. Their retrospective review of a prospectively maintained database yielded 151 incident cases of ulcerative colitis presenting between 2000 and 2008 and followed for a median of 58 months. In this group, 15 (9%) patients received ciclosporin for severe or refractory disease, 46 (30%) received at least one anti-TNF agent, and 21 (14%) ultimately underwent colectomy. Previous treatment with ciclosporin was the only factor found to be predictive of the need for colectomy suggesting a cohort of patients with more severe disease.
Long-term follow-up of patients initially responding to infliximab is somewhat lacking because this agent was not US FDA-approved until September 2005. However, Gustavsson et al. from Örebro, Sweden, reported the 3-year efficacy of infliximab as a rescue therapy in a previous placebo-controlled trial of infliximab used for acute steroid-refractory ulcerative colitis. In the initial trial, 7 of 24 patients (29%) and 14 of 21 patients (67%) treated with infliximab or placebo, respectively, underwent colectomy after 3 months of follow-up. After 3 years, a total of 12 of 24 patients (50%) treated with infliximab and 16 of 21 patients (76%) provided placebo had undergone colectomy (P = 0.012). Interestingly, the two treatment groups did not differ in their perceived health-related quality of life as measured by responses to the Short Form (SF)-36 and Short Health Score questionnaires at the time of follow-up.
Ciclosporin is commonly used at some centers for the management of patients with corticosteroid-refractory ulcerative colitis, although it is not US FDA-approved in this setting. Infliximab has been used when ciclosporin therapy fails, but the efficacy and safety of this sequential approach is uncertain. Chaparro et al. from several centers across Spain addressed these issues in a retrospective review of 47 infliximab-naïve patients treated with infliximab after both corticosteroids and ciclosporin failed to control a flare of ulcerative colitis. The mean time between the last ciclosporin dose and the initial infliximab infusion was 6 days. After this initial treatment, 6 (13%) and 35 (74%) patients achieved a complete or partial response, respectively. Of the 35 patients who received three infliximab infusions, 21 (60%) achieved remission and another 12 (37%) experienced a partial response. Overall, 33 patients (70%) avoided colectomy, and the only variable predictive of an improved response to salvage infliximab therapy was the concomitant use of thiopurines. However, one death (2.1%) occurred in a 40-year-old patient whose postoperative course after failed infliximab therapy was complicated by a fatal nosocomial pneumonia.
Adalimumab has also been used in Spain for patients with ulcerative colitis who have recently experienced a diminished response or failure to treatment with infliximab. Taxonera et al. reported their experience with 30 such patients and found that clinical remission was noted in 3 (10%) and 8 patients (27%) at 4 and 12 weeks, respectively; another 16 (53%) and 18 patients (60%) demonstrated a partial response at 4 and 12 weeks, respectively. Overall, six patients (20%) required a colectomy and all patients achieving a clinical response after 12 weeks were colectomy-free at a median follow-up of 48 weeks.
Impact on Incidence of Operation
Biologic agents are usually employed with the intent to help avoid operative intervention in patients with moderately to severely active IBD who have demonstrated an inadequate response to conventional therapies. Ananthakrishnan et al. analyzed data from the Nationwide Inpatient Sample to assess whether this desired outcome has been realized in patients requiring hospitalization for their IBD. They compared the proportion of hospitalizations resulting in surgery for either Crohn's disease or ulcerative colitis based on disease severity for the years 1998, 2004, and 2007. The overall absolute number of hospitalizations for Crohn's disease resulting in nonelective bowel surgery remained relatively constant between 1998 and 2007, with the low-severity cohort experiencing an actual decrease in the absolute number of nonelective operations. However, the relative number of people requiring nonelective bowel surgery was unchanged between 1998 and 2007 [odds ratio (OR) 0.88; 95% confidence interval (CI) 0.75–1.02] in patients presenting with severe Crohn's disease. In ulcerative colitis, the proportion of nonelective colectomies decreased by more than 50% in 2007 contrasted to 1998 in patients presenting with the lowest severity of disease. But once again, patients with severe colitis were just as likely to undergo nonelective colectomy in 2007 as compared to those with severe disease admitted in 1998 (OR 0.88; 95% CI 0.61–1.29). In summary, it appears that the era of biologic therapy is associated with a reduction in the relative number of IBD patients with mild disease requiring nonelective surgery, but the incidence of emergent or urgent surgery in patients with severe disease is unchanged.
Peyrin-Biroulet et al., from the University Hospital of Nancy, sought to determine whether azathioprine and anti-TNF treatment decreased the need for surgery in newly diagnosed Crohn's disease patients. They found that azathioprine treatment of less than 1.5 months (hazard ratio 2.00; 95% CI 1.20–3.34) and anti-TNF therapy for less than 16 months (hazard ratio 3.86; 95% CI 1.77–8.45) were independent positive predictors for major abdominal surgery; both stricturing (hazard ratio 12.01; 95% CI 5.97–24.17) and penetrating disease (hazard ratio 10.77; 95% CI 4.87–23.80) also independently increased the risk for surgery. Leombruno et al. reported similar findings when they matched 338 infliximab users with Crohn's disease to at least one comparison patient employing a propensity score matching. Patients who were treated with infliximab experienced a significantly lower risk of requiring a disease-related bowel resection (hazard ratio 0.64; 95% CI 0.51–0.81) or hospitalization (hazard ratio 0.73; 95% CI 0.63–0.85). However, regular maintenance therapy instead of episodic treatment with biologic agents is likely required to experience these benefits because the later approach yielded no difference in the rates of patients requiring resection surgery of their Crohn's disease within 3 years of diagnosis.
In a review of the recent literature related to adult patients with Crohn's disease, Bougen and Peyrin-Biroulet concluded that data from both population-based cohorts and referral center studies suggested only a modest or no impact of biologic agents on the need for operative intervention. Moreover, they noted that the often quoted randomized trials were not designed to assess the impact of anti-TNF therapy on surgical rates and cautioned that the reported results should be carefully interpreted.
Five centers from France reviewed their collective experience to determine the impact of infliximab on the need for colectomy in patients with ulcerative colitis. Between 2000 and 2009, 191 patients with ulcerative colitis received infliximab therapy and the median follow-up period was 18 months. Colectomy was required in 36 (19%) of the patients and predictors of colectomy after multivariate analysis were no clinical response after infliximab induction (hazard ratio 7.06; 95% CI 3.36–14.83), C-reactive protein greater than 10 mg/l at infliximab initiation (hazard ratio 5.11; 95% CI 1.77–14.76), and prior treatment with ciclosporin (hazard ratio 2.53; 95% CI 1.22–5.28). Hemoglobin less than 9.4 g/dl at infliximab initiation (OR 4.36; 95% CI 1.81–10.42) was a predictor of primary nonresponse to infliximab, and episodic infliximab usage (OR 4.01; 95% CI 2.71–5.94) was a predictor of infliximab failure among initial responders.
One of the five centers, the group from University Hospital of Nancy, subsequently studied the need for surgery in patients presenting with newly diagnosed ulcerative colitis of varying severity. Their retrospective review of a prospectively maintained database yielded 151 incident cases of ulcerative colitis presenting between 2000 and 2008 and followed for a median of 58 months. In this group, 15 (9%) patients received ciclosporin for severe or refractory disease, 46 (30%) received at least one anti-TNF agent, and 21 (14%) ultimately underwent colectomy. Previous treatment with ciclosporin was the only factor found to be predictive of the need for colectomy suggesting a cohort of patients with more severe disease.
Long-term follow-up of patients initially responding to infliximab is somewhat lacking because this agent was not US FDA-approved until September 2005. However, Gustavsson et al. from Örebro, Sweden, reported the 3-year efficacy of infliximab as a rescue therapy in a previous placebo-controlled trial of infliximab used for acute steroid-refractory ulcerative colitis. In the initial trial, 7 of 24 patients (29%) and 14 of 21 patients (67%) treated with infliximab or placebo, respectively, underwent colectomy after 3 months of follow-up. After 3 years, a total of 12 of 24 patients (50%) treated with infliximab and 16 of 21 patients (76%) provided placebo had undergone colectomy (P = 0.012). Interestingly, the two treatment groups did not differ in their perceived health-related quality of life as measured by responses to the Short Form (SF)-36 and Short Health Score questionnaires at the time of follow-up.
Ciclosporin is commonly used at some centers for the management of patients with corticosteroid-refractory ulcerative colitis, although it is not US FDA-approved in this setting. Infliximab has been used when ciclosporin therapy fails, but the efficacy and safety of this sequential approach is uncertain. Chaparro et al. from several centers across Spain addressed these issues in a retrospective review of 47 infliximab-naïve patients treated with infliximab after both corticosteroids and ciclosporin failed to control a flare of ulcerative colitis. The mean time between the last ciclosporin dose and the initial infliximab infusion was 6 days. After this initial treatment, 6 (13%) and 35 (74%) patients achieved a complete or partial response, respectively. Of the 35 patients who received three infliximab infusions, 21 (60%) achieved remission and another 12 (37%) experienced a partial response. Overall, 33 patients (70%) avoided colectomy, and the only variable predictive of an improved response to salvage infliximab therapy was the concomitant use of thiopurines. However, one death (2.1%) occurred in a 40-year-old patient whose postoperative course after failed infliximab therapy was complicated by a fatal nosocomial pneumonia.
Adalimumab has also been used in Spain for patients with ulcerative colitis who have recently experienced a diminished response or failure to treatment with infliximab. Taxonera et al. reported their experience with 30 such patients and found that clinical remission was noted in 3 (10%) and 8 patients (27%) at 4 and 12 weeks, respectively; another 16 (53%) and 18 patients (60%) demonstrated a partial response at 4 and 12 weeks, respectively. Overall, six patients (20%) required a colectomy and all patients achieving a clinical response after 12 weeks were colectomy-free at a median follow-up of 48 weeks.
Source...