Impact of mucosal healing on long-term outcomes in ulcerative colitis treated with infliximab: a multicenter experience

Authors


Correspondence to:

Dr D. Laharie, CHU de Bordeaux, Hôpital Haut-Leveque Hospital, Service d'Hepato-gastroenterologie, Pessac, F-33600 France.

E-mail: david.laharie@chu-bordeaux.fr

Summary

Background

Mucosal healing can be achieved with infliximab (IFX).

Aim

To assess the impact of mucosal healing on long-term outcomes in patients with ulcerative colitis (UC) when treated with infliximab (IFX) beyond 1 year.

Methods

All consecutive adult patients with refractory UC receiving maintenance treatment with IFX in five French referral centres were analysed retrospectively. Only patients who had endoscopic evaluation between 6 and 52 weeks following IFX initiation were included. According to their Mayo endoscopic sub-score, patients were categorised into mucosal healing (sub-score: 0–1) and no mucosal healing (2–3). Outcome measures were colectomy and IFX failure defined by drug withdrawal due to secondary failure among primary responders.

Results

Of the 63 patients (30 women; median age: 38 years), 30 (48%) achieved mucosal healing. The median follow-up duration was 27 (3–79) months. Colectomy-free survival rates at 12, 24 and 36 months were, respectively, 100%, 96% and 96% in patients with mucosal healing. The corresponding figures were, respectively, 80%, 65% and 65% in patients without mucosal healing (P = 0.004). By multivariate analysis, mucosal healing was the only factor associated with colectomy-free survival, with an odds ratio of 18.01 (95%CI: 1.58–204.92). IFX failure-free survival rates at 12, 24 and 36 months were, respectively, 76%, 69% and 64% in patients with mucosal healing, and 44%, 25% and 21% in those without mucosal healing (P = 0.003).

Conclusion

Patients with refractory UC who achieved mucosal healing after IFX initiation had better long-term outcomes, with significantly less colectomy and less IFX failure.

Introduction

Ulcerative colitis is a mucosal colorectal inflammatory disease characterised by active and remitting periods. Medical therapy aims to control disease flare, prevent relapse, avoid colectomy[1] and heal the gut mucosa, which is now considered as a major therapeutic goal in ulcerative colitis.[2, 3] Patients with ulcerative colitis who achieved mucosal healing had better outcomes, with less relapses and lower hospitalisation and colectomy rates.[4-7]

Mucosal healing can be achieved with conventional treatments of ulcerative colitis, including 5-aminosalicylates (5-ASA), corticosteroids, azathioprine and biologics.[8] Infliximab has been the first monoclonal antibody targeting tumour necrosis factor (TNF) alpha which demonstrated its efficacy in moderately to severely active ulcerative colitis, inducing remission in 22–39% of patients and mucosal healing in 55–62% in controlled trials.[9, 10] In patients with acute severe ulcerative colitis refractory to steroids, infliximab is also highly effective, inducing remission in 46% of patients and mucosal healing in 45% of them.[11, 12] An endoscopic post hoc analysis from the double-blind, placebo-controlled Active Ulcerative Colitis Trials (ACT) 1 and 2 studies demonstrated that patients achieving mucosal healing with infliximab at week 8 were less likely to progress to colectomy within 1 year than those with a remaining mucosal inflammation.[7]

Data on the impact of mucosal healing on disease outcomes in ulcerative colitis patients treated with infliximab are scarce beyond 1 year.[13] In addition, most available studies used the need for colectomy as a surrogate marker of the natural history of ulcerative colitis and did not assess clinical parameters such as secondary infliximab failure, which is a real problem in our clinical practice.

We therefore investigated the association of long-term outcomes – need for colectomy and infliximab failure rates – with mucosal healing in ulcerative colitis patients treated with infliximab in a real-life setting.

Patients and methods

Study population

This was a retrospective study carried out in a multicenter cohort of patients recruited in five French academic Gastroenterology departments (Lyon-Sud, Nancy, Nice, Pessac, Saint-Etienne). Patients’ characteristics and infliximab clinical efficacy results of this multicenter experience have been previously reported in extenso.[14]

All adults who received infliximab for ulcerative colitis in the five participating centres before September 2009 were eligible for inclusion in the present endoscopic sub-study if they have had endoscopic evaluations before starting infliximab and between 6 and 52 weeks after their first infusion. The diagnosis of ulcerative colitis was based on the European Crohn's and Colitis Organization criteria.[15] Infliximab was administered according to an induction regimen with three 5 mg/kg infliximab infusions at weeks 0, 2 and 6. Initial responders to the drug received further infusions episodically on-demand or scheduled every 8 weeks according to clinical need and experienced physician advice during the inclusion period. In addition, patients initiated on episodic therapy were converted to scheduled maintenance therapy in cause of loss of response to infliximab.

Patients were included if they had received at least four infliximab infusions. Of note, nonprimary responders to infliximab following induction therapy, as judged by their treating physician, were excluded from the study.

All patients received treatment according to clinical need. Drugs used were those normally employed in ulcerative colitis, according to licensed or published doses and frequency. All patients received treatment and had flexible colonoscopy only after full and informed consent.

Inclusion date was defined as that of the first infliximab infusion. The medical records of patients were retrospectively reviewed and the following data were collected at baseline: date of birth, gender, disease duration, age at diagnosis, disease extent according to Montreal classification,[16] indication for infliximab (refractory non severe ulcerative colitis with an inadequate response to oral steroids or acute severe ulcerative colitis refractory to intravenous steroids), previous response to steroids, past treatment with immunosuppressants, concomittant treatment (5-ASA, steroids, thiopurines, methotrexate), as well as serum C-reactive protein (CRP), haemoglobin and serum albumin levels.

Endoscopic examinations were routinely performed by experienced gastroenterologists in inflammatory bowel disease who were not blinded to the medications taken by the patients. The following data were collected regarding endoscopy: time since inclusion, type of exploration (flexible sigmoidoscopy or colonoscopy) and length of bowel explored (in cm from the anal verge), indication (disease activity with remnant symptoms or systematic control in a patient off symptoms) and Mayo endoscopic sub-score and elemental lesions (vascular pattern, erythema, erosion, friability, bleeding, ulcers and severe endoscopic lesions: deep ulcers, mucosal detachment and well-like ulcerations). The more severe endoscopic lesions were retained for scoring.

During the follow-up period, from inclusion to July 2011, colectomy and infliximab failure – defined by drug withdrawal due to secondary failure among primary responders – were systematically recorded.

Outcome measures and objectives

Patients were categorised into two subgroups according to their Mayo endoscopic sub-score: mucosal healing (sub-score: 0–1) and no mucosal healing (sub-score: 2–3), as previously described.[7]

Outcome measures were colectomy-free survival and infliximab failure-free survival during the follow-up period.

The main objective was to determine the colectomy-free survival rate according to the initial endoscopic response to infliximab, comparing patients with and without mucosal healing. We also evaluated infliximab failure rates according to the initial endoscopic response to infliximab and looked for factors associated with these outcomes.

Statistics

Continuous variables are presented as medians and range; categorical variables are presented as percentages. Continuous data were analysed using Mann–Whitney's test. Categorical data were analysed using the Pearson's chi-squared test, or Fisher's exact test if any cell number was <5, for frequencies. Colectomy-free survival and infliximab-failure survival curves were calculated for each subgroup from inclusion to end of the follow-up using Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate analyses of prognosis factors of colectomy-free survival and lack of infliximab failure survival were performed to assess impact of mucosal healing, clinical, disease, and treatment variables. Continuous variables were dichotomised according to the median. Variables analysed were gender, age at inclusion, disease duration, disease location, previous and current treatments (oral 5-ASA, systemic steroids, thiopurines, methotrexate, and cyclosporine), indication for infliximab (refractory non severe ulcerative colitis vs. acute severe ulcerative colitis refractory to intravenous steroids), infliximab regimen (scheduled vs. episodic) indication for colonoscopy, Mayo endoscopic sub-score (0–1 vs. 2–3), severe endoscopic lesions, CRP level (mg/L). Difference between mucosal healing and nonhealing groups was assessed by χ² or Fisher's exact tests when appropriate. A logistic regression model was created using significantly associated variables (P < 0.20), and the odds ratios (OR) for the variables that remained significant (P < 0.05) in the model determined. All analyses were performed with SPSS software. Significance threshold was 0.05 for all analyses.

Results

Baseline characteristics of the 63 patients

Of the 191 ulcerative colitis patients who received infliximab therapy between January 2000 and August 2009,[14] 42 nonprimary responders and 86 patients in maintenance therapy who had no endoscopic assessment between the weeks 6 and 52 after initiation of the drug were excluded from the analysis. Therefore, 63 (33%) patients were included in the present endoscopic sub-study. Their main characteristics are presented in Table 1. To summarise among the 63 included patients, 30 (48%) were female, median age at inclusion was 38 (range: 18–79) years, median ulcerative colitis duration was 36 (range: 0–295) months, type of disease was E1 in 4 (6%) patients, E2 in 22 (35%) and E3 in 37 (59%) according to the Montreal classification and infliximab was given because of refractory disease in 46 (73%) or acute severe flare in 17 (27%) patients.

Table 1. Characteristics of the 63 ulcerative colitis patients
n 63
  1. UC, ulcerative colitis; 5-ASA, 5-amino-salicylates; Hb, haemoglobin; CRP, C-reactive protein.

Female gender, n (%) 30 (48%)
Median age, years [range]38 [18–79]
Median disease duration, months [range]36 [0–295]
Montreal classification, n (%):
E14 (6%)
E222 (35%)
E337 (59%)
Indication for infliximab, n (%):
Non severe refractory UC46 (73%)
Acute severe UC17 (27%)
Associated treatments at baseline, n (%):
5-ASA20 (32%)
Steroids47 (75%)
Azathioprine34 (54%)
Median Hb, (g/dL) [range]11.7 [6.8–14.4]
Median CRP, (mg/L) [range]11 [0–150]
Median albumin, (g/L) [range]33.0 [23.4–41.6]

Primary infliximab responders received further infusions administered episodically on-demand in 32 patients (52%) or scheduled every 8 weeks in 30 patients (48%). In addition, in 21 of 32 patients (66%) who were initiated on episodic therapy, therapy was converted to scheduled maintenance therapy because of loss of response to infliximab.

Endoscopic findings

The median time from inclusion to endoscopic assessment was 18 (range: 6–51) weeks. A flexible sigmoidoscopy was performed in 45 (71%) patients and a complete colonoscopy in 18 (29%) patients. The median length of bowel explored and the median number of segments explored were 30 (range: 20–70) cm and 2 (range: 1–5) respectively. The median number of bowel segments analysed was 2 (1–5) – i.e. sigmoid and rectum. Endoscopy was performed in patients with clinically active disease in 34 (54%) cases and to monitor patients in clinical remission in 29 (46%) of cases. The Mayo endoscopic sub-score was 0 in 12 patients, 1 in 18, 2 in 22, and 3 in 11 subjects. When patients were categorised into two subgroups, infliximab induced mucosal healing (sub-score: 0–1) in 30 (48%) patients while no mucosal healing (sub-score: 2–3) was observed in 33 (52%) patients.

The median follow-up duration was 27 (3–79) months.

Colectomy rates according to mucosal healing

Fourteen (22%) patients underwent colectomy during the follow-up: none of the 12 patients with a Mayo endoscopic sub-score of 0, only one of 18 (6%) with a sub-score of 1, 7/22 (32%) patients with a sub-score of 2, and 6/11 (55%) subjects with a sub-score of 3. Hence, only 1/30 (3%) patient who achieved mucosal healing and 13/33 (39%) without mucosal healing had a colectomy during the follow-up (P = 0.004). Colectomy-free survival rates at 12, 24 and 36 months were, respectively, 100%, 96% and 96% in patients with mucosal healing, while these figures were, respectively, 80%, 65% et 65% in those without mucosal healing (Figure 1).

Figure 1.

Colectomy-free survival according to initial endoscopic response to infliximab.

Factors associated with colectomy

Factors associated with colectomy in univariate analysis are presented in the Table S1. Those retained for the multivariate analysis were prior response to steroids (P = 0.088), maintenance regimen with episodic infliximab (P = 0.077), systemic steroids at baseline (P = 0.185), Mayo endoscopic sub-score 2–3 (P = 0.004) and severe endoscopic lesions (P = 0.125).

In multivariate analysis, the only factor associated with colectomy was the absence of mucosal healing, with an OR of 18.01 (95%CI: 1.58–204.92; P = 0.020) (Table 2).

Table 2. Factors associated with colectomy (multivariate analysis)
 OR95%CI P
Mayo endoscopic sub-score 2–3 vs 0–118.01(1.58–204.92)0.020

Infliximab failure rates according to mucosal healing

Thirty-six patients experienced infliximab failure during the follow-up: 4/12 (33%) patients with Mayo endoscopic sub-score of 0, 7/18 (39%) with a sub-score of 1, 15/22 (68%) with a sub-score of 2, and 10/11 (91%) with a sub-score of 3. Hence, 11/30 (37%) patients with mucosal healing and 25/33 (76%) without mucosal healing experienced infliximab failure during the follow-up (P = 0.003). Survival without infliximab failure at 12, 24 and 36 months was, respectively, 76%, 69% and 64% in patients with mucosal healing, and 44%, 25% and 21% in those without mucosal healing (Figure 2).

Figure 2.

Survival without infliximab failure according to initial endoscopic response to infliximab.

Factors associated with infliximab failure

Factors associated with infliximab failure in univariate analysis are presented in the Table S2. Those retained for the multivariate analysis were disease location (P = 0.150), tobacco consumption (P = 0.172), prior response to steroids (P = 0.040), maintenance infliximab regimen (P < 0.001), disease activity at baseline (P = 0.146), steroids at baseline (= 0.081), Mayo endoscopic subscore (P = 0.003), severe endoscopic lesions (P = 0.183).

Concerning predictors of infliximab failure, three independent predictors were identified in multivariate analysis: episodic infliximab maintenance regimen vs. scheduled (OR = 4.88 95%CI: 2.14–11.10; P < 0.001), absence of mucosal healing, i.e. Mayo endoscopic subscore 2–3 vs. 0–1 (OR=3.23 95%CI: 1.48–7.03; = 0.003) and steroid-refractoriness at inclusion vs. steroid-dependent disease (OR = 2.56, 95%CI: 1.17–5.59; P = 0.018) (Table 3).

Table 3. Prognostic factors associated with infliximab failure (multivariate analysis)
 OR95%CI P
Maintenance infliximab regimen (episodic vs. scheduled)4.88(2.14–11.10)<0.001
Mayo endoscopic subscore (2–3 vs. 0–1)3.23(1.48–7.03)0.003
Response to steroids at inclusion (refractoriness vs. dependent disease)2.56(1.17–5.59)0.018

Discussion

In this cohort study, we found that patients with ulcerative colitis who achieved mucosal healing after starting inflximab therapy had better long-term outcomes, with significantly lower colectomy rates and less infliximab failure in a real life setting.

Over the past years, some studies evaluated the impact of mucosal lesions on the need for colectomy in ulcerative colitis outside the setting of acute severe colitis. In a retrospective single centre study, a longer colectomy-free survival was observed among ulcerative colitis patients who achieved mucosal healing at week 4 or 10.[13] In a substudy of the ACT1 and ACT2 trials, a lower colectomy rate was reported within the first 54 weeks of follow-up in patients with ulcerative colitis randomised to infliximab compared to placebo (10% vs. 17%, respectively, P = 0.02).[17] In a Norwegian population-based cohort study, 2% of ulcerative colitis patients with mucosal healing at one year needed a surgical resection by 5 years compared to 7% of patients without mucosal healing (P = 0.02).[4] More recently, Ardizzone et al. showed that the lack of mucosal healing after first course of corticosteroid therapy was associated with higher need for colectomy in newly diagnosed ulcerative colitis (HR: 8.397; 95%CI: 1.278–55.186; P = 0.0268).[5]

Overall, the impact of mucosal healing on long-term outcomes in ulcerative colitis treated with infliximab remains poorly known beyond 1 year in a real life setting. By using a multicentre study, we could first confirm that early mucosal healing induced by infliximab therapy was associated with a lower need for colectomy. With a similar follow-up duration, (33 and 27 months, respectively), our 22% colectomy rate is comparable to the 17% rate from the Leuven experience.[13] Managing infliximab failure is a challenge in clinical practice. Gisbert and Panes showed that secondary loss of response is relatively frequent with infliximab in Crohn's disease.[18] Our results demonstrate for the first time that infliximab-induced mucosal healing is associated with lower rates of infliximab withdrawal due to secondary failure, further underscoring the need to consider mucosal healing a major therapeutic goal in our clinical practice in ulcerative colitis.

Although this study was retrospective and enrolled one-third of the entire cohort of infliximab-treated ulcerative colitis patients, due to the lack of systematic endoscopic assessment in clinical practice, it reflects a multicenter real-life experience.

Whatever the drug studied – 5-ASA, steroids, immunosuppressants or biologics – ulcerative colitis patients achieving mucosal healing have better disease outcomes.[3] As ulcerative colitis is characterised by a distal ascending inflammation, the assessment of mucosal activity is simple with flexible sigmoidoscopy and can be routinely performed. Little is known about the kinetics of healing in ulcerative colitis and if a flexible sigmoidoscopy is sufficient or could overestimate healing because of the patchy nature of that process. Alternative approaches to endoscopy with faecal biomarkers or cross-sectional imaging have been also evaluated to avoid subsequent endoscopies. Although well correlated with mucosal lesions, faecal calprotectine or lactoferrine[19, 20] appears less attractive in ulcerative colitis than in Crohn's disease. In a recent study, magnetic resonance colonography has shown a high accuracy for assessing endoscopic activity.[21] However, flexible sigmoidoscopy remains the gold standard for assessing disease activity in ulcerative colitis.

More than the colorectal mucosa, histologic healing could be a more advanced therapeutic goal in ulcerative colitis as it is associated with fewer clinical relapses.[22, 23] Unfortunately, biopsies were not systematically taken in our cohort study and features associated with more relapse, such as basal plamocytosis, acute inflammatory cell infiltrate or crypt abscesses, could not be assessed.

In conclusion, patients with refractory ulcerative colitis treated with infliximab achieving an early mucosal healing have better long-term outcomes, with significantly less colectomy and less treatment failure. Several questions remain to be answered: should mucosal healing be systematically used in clinical practice? Should we optimise therapies to achieve mucosal healing? What is the degree of intestinal healing that is required to change the disease course? Large prospective studies addressing these issues are needed.

Authorship

Guarantor of the article: D. Laharie.

Author contributions: DL: study design, data collection and analysis, statistical analysis, writing. JF, XR, SN, JBC, XH, BF: data collection and relecture of the manuscript. MC: statistical analysis and relecture of the manuscript. LPB: study design, data collection, writing. All authors approved the final version of the manuscript.

Acknowledgements

Declaration of personal interests: D. Laharie, X. Roblin and L. Peyrin-Biroulet have served as speakers and consultants for MSD. J. Filippi, S. Nancey, J. B. Chevaux, X. Hebuterne and B. Flourie have served as speakers for MSD. Declaration of funding interests: None.

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