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A Panel to Predict Long-term Outcome of Infliximab Therapy for Patients With Ulcerative Colitis
Clinical Gastroenterology and Hepatology 2014;-:-–-
A Panel to Predict Long-term Outcome of Infliximab Therapy for Patients With Ulcerative Colitis Maria Theresa Arias,* Niels Vande Casteele,‡ Séverine Vermeire,* Anthony de Buck van Overstraeten,§ Thomas Billiet,* Filip Baert,* Albert Wolthuis,§ Gert Van Assche,* Maja Noman,* Ilse Hoffman,k Andre D’Hoore,§ Ann Gils,‡ Paul Rutgeerts,* and Marc Ferrante* *Department of Gastroenterology, University Hospitals Leuven, ‡Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, §Department of Abdominal Surgery, kDepartment of Pediatrics, KU Leuven–University of Leuven, Leuven, Belgium BACKGROUND & AIMS:
Infliximab is effective for patients with refractory ulcerative colitis (UC), but few factors have been identified that predict long-term outcome of therapy. We aimed to identify a panel of markers associated with outcome of infliximab therapy to help physicians make personalized treatment decisions.
METHODS:
We collected data from the first 285 patients with refractory UC (41% female; median age, 39 y) treated with infliximab before July 2012 at University Hospitals Leuven, in Belgium. We performed a Cox regression analysis to identify independent factors that predicted relapse-free and colectomy-free survival, and used these factors to create a panel of markers (risk panel).
RESULTS:
During a median follow-up period of 5 years, 61% of patients relapsed and 20% required colectomy. Independent predictors of relapse-free survival included short-term complete clinical response (odds ratio [OR], 3.75; 95% confidence interval [CI], 2.35–5.97; P < .001), mucosal healing (OR, 1.87; 95% CI, 1.17–2.98; P [ .009), and absence of atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) (OR, 1.96; 95% CI, 1.23–3.12; P [ .005). Independent predictors of colectomy-free survival included short-term clinical response (OR, 7.74; 95% CI, 2.76–21.68; P < .001), mucosal healing (OR, 4.02; 95% CI, 1.16–13.97; P [ .028), baseline level of C-reactive protein (CRP) of 5 mg/L or less (OR, 2.95; 95% CI, 1.26–6.89; P [ .012), and baseline level of albumin of 35 g/L or greater (OR, 3.03; 95% CI, 1.12–8.22; P [ .029). Based on serologic analysis of a subgroup of 112 patients, levels of infliximab greater than 2.5 mg/mL at week 14 of treatment predicted relapse-free survival (P < .001) and colectomy-free survival (P [ .034). A risk panel that included levels of pANCA, CRP, albumin, clinical response, and mucosal healing identified patients at risk for UC relapse or colectomy (both P < .001).
CONCLUSIONS:
Clinical response and mucosal healing were confirmed as independent predictors of long-term outcome from infliximab therapy in patients with UC. We identified additional factors (levels of pANCA, CRP, and albumin) to create a risk panel that predicts long-term outcomes of therapy. Serum levels of infliximab at week 14 of treatment also were associated with patient outcomes. Our risk panel and short-term serum levels of infliximab therefore might be used to guide therapy.
Keywords: Drug; Response To Therapy; Prognostic Factor; Biomarker.
n 2005, the landmark Active Ulcerative Colitis Trials (ACT1 and ACT2) showed a significant benefit for the use of infliximab (IFX) in patients with moderate-to-severe ulcerative colitis (UC).1 In these double-blind, placebocontrolled trials, patients randomized to IFX not only experienced higher clinical response and remission rates, but also higher mucosal healing rates, lower hospitalization rates, and lower colectomy rates during up to 1 year of follow-up evaluation.1,2 In parallel, a Scandinavian placebo-controlled
I
Abbreviations used in this paper: ACT, Active Ulcerative Colitis Trials; ASCA, anti-Saccharomyces cerevisiae antibodies; ASUC, acute severe ulcerative colitis; CI, confidence interval; CRP, C-reactive protein level; CS, corticosteroids; IFX, infliximab; IMM, immunomodulatory agents; IQR, interquartile range; OR, odds ratio; pANCA, atypical perinuclear antineutrophil cytoplasmic antibodies; UC, ulcerative colitis. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.07.055
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trial provided evidence for the use of IFX in patients with acute severe ulcerative colitis (ASUC) refractory to intravenous corticosteroids (CS).3,4 Most recently, the Groupe d’Étude Thérapeutique des Affections Inflammatoires du Tube Digestif group showed that IFX was at least as efficacious as cyclosporine for this indication.5 In the past decade, several real-life, open-label cohort studies have provided more data on the efficacy and safety of IFX in patients with refractory UC.6–9 Short-term clinical response, short-term normalization of C-reactive protein level (CRP), and short-term mucosal healing were among the predictors of colectomy-free survival.7,8,10,11 In contrast, an increased baseline CRP level, a shorter disease duration before IFX, and previous treatment with intravenous cyclosporine have been associated with a higher colectomy risk.7,9 In a Canadian trial, detectable IFX serum levels were associated with higher clinical remission rates, higher endoscopic improvement rates, and lower colectomy rates, but no firm conclusions could be drawn on their predictive value.12 In 2008, we presented the outcome of the first 121 outpatients with refractory UC treated with IFX in our center.6 With the current study we aimed to explore the extended long-term outcome of a larger cohort of patients with refractory UC treated with IFX in our tertiary referral center. Furthermore, we defined predictors of long-term, relapsefree and colectomy-free survival, and specifically evaluated the predictive value of IFX serum levels. Based on the provided risk factors, we developed a risk panel to predict longterm outcome to IFX. This risk panel may guide personalized therapy in patients starting IFX for refractory UC.
Methods Patient Population All patients with refractory UC who received a first infusion of IFX before July 2012 were included in this study, allowing a follow-up period of at least 6 months. Eligible patients did not respond to CS alone, immunomodulatory agents (IMM) alone, or a combination of both, were intolerant to any of these drugs, or were unable to taper CS. We identified 285 patients (41% female), with a median age at first IFX of 39.1 years (interquartile range [IQR], 28.8–50.6 y). Among these 285 patients, 39 received IFX for ASUC refractory to intravenous CS. Before IFX initiation, latent tuberculosis, cytomegalovirus, and Clostridium difficile infection were excluded. All individuals provided written informed consent for this study, which was approved by the local ethics committee of the Catholic University of Leuven. Patients’ characteristics are listed in Table 1.
Serologic and Genetic Markers Data on levels of CRP, hemoglobin, thrombocytes, and albumin were collected prospectively as part of a
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standardized follow-up evaluation of all patients treated with IFX. The presence of anti–Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) were evaluated through an enzyme-linked immunosorbent assay. Serum samples were collected at baseline and at week 14 immediately before the fourth IFX administration (trough level). Serum IFX levels were measured using an in-house–developed enzyme-linked immunosorbent assay. Based on a previously reported association with the need for colectomy,13 we assessed the multidrug resistance gene 1 C3435T genotype by TaqMan genotyping assay (Applied Biosystems Inc, Carlsbad, CA).
Definitions The extent of disease was categorized using the Montreal classification.14 Endoscopic severity of disease before IFX was determined according to the Mayo endoscopic subscore in 265 patients.15 Short-term response to IFX was assessed after 10 to 14 weeks and was defined as complete if there was an absence of diarrhea and blood, and partial if there was marked clinical improvement (less diarrhea, less abdominal pain) but still persistent rectal blood loss.16 To assess shortterm mucosal healing, endoscopy was performed in 200 patients both before and 10 to 14 weeks after the first IFX infusion. Mucosal healing was defined as a Mayo endoscopic subscore of 0 or 1, and was assessed only in patients with a Mayo endoscopic subscore of 2 or 3 at inclusion (n ¼ 200).16 Normalization of CRP level was analyzed in patients with an increased baseline CRP level (>5 mg/L) if a second CRP level was available 10 to 14 weeks after first IFX infusion (n ¼ 149). Long-term outcome was evaluated at last follow-up evaluation. Relapse-free survival was defined as the absence of clinical relapse requiring IFX dose optimization, medical rescue therapy, or colectomy, and was evaluated only in patients who initially responded to the therapy and received maintenance IFX therapy. Colectomy-free survival was evaluated in all patients and was defined as the absence of colectomy throughout follow-up evaluation, regardless of clinical findings and the need for medical interventions. Of note, patients who underwent colectomy for neoplastic lesions (n ¼ 5) also were included in the analysis for colectomy-free survival.
Administration of Infliximab and Concomitant Therapy At study start, patients received either a single dose of 5 or 10 mg IFX per kilogram of body weight, or an induction scheme with IFX at weeks 0, 2, and 6. Six patients received 1 (n ¼ 5) or 2 (n ¼ 1) extra infusions of IFX before week 14. Fifteen patients from the 214 patients showing clinical response discontinued IFX after
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Table 1. Patient Characteristics Whole cohort (N ¼ 285) Female (%) Median (IQR) age at first IFX infusion, y Median (IQR) duration of disease, y Median (IQR) weight at first IFX, kg Extent of colitis Proctitis (%) Left-sided colitis (%) Extensive colitis (%) Backwash ileitis (%) Mayo endoscopic subscore before IFX Mayo 1 (%) Mayo 2 (%) Mayo 3 (%) Acute severe IV steroid refractory colitis Primary sclerosing cholangitis (%) Smoking behavior at first IFX Never (%) Former (%) Active (%) Laboratory values at first IFX Median (IQR) CRP level, mg/L CRP level >5 mg/L (%) Median (IQR) albumin level, g/L Albumin level <35 g/L Median (IQR) Hb level, g/dL Hb level <12 g/dL (female) or <14 g/dL (male) Median (IQR) thrombocyte level, 109/L Thrombocyte level > 450 109/L pANCA positive ASCA positive MDR1 3435 TT genotype Concomitant therapy at first IFX Mesalamine (%) Corticosteroids (%) Median (IQR) of corticosteroids, mg Immunosuppressant drugs (%) Previous treatment with IV steroids (%) Dose of first IFX 5 mg/kg body weight (%) 10 mg/kg body weight (%) Induction therapy with IFX (%) Combination therapy during first 14 weeks (%) Maintenance therapy with IFX (%)
Subgroupa (n ¼ 112)
116/285 39.1 5.2 72
(41) (28.8–50.6) (1.6–10.8) (60–83)
50/112 38.0 4.5 72
(45) (28.3–49.8) (1.5–10.8) (63–85)
4/285 95/285 186/285 19/248
(2) (33) (65) (8)
2/112 37/112 73/112 6/100
(2) (33) (65) (6)
11/265 122/265 132/265 39/285 17/285
(4) (46) (50) (14) (6)
3/110 57/110 50/110 17/112 5/112
(3) (52) (45) (15) (4)
136/285 (48) 121/285 (42) 28/285 (10)
56/112 (50) 44/112 (39) 12/112 (11)
6.4 155/283 41.2 54/266 12.8 149/278 325.0 47/277 152/283 13/285 74/259
(1.7–23.5) (55) (37.3–44.0) (20) (11.3–14.0) (54) (266.5–415.5) (17) (54) (5) (29)
6.4 64/112 42.0 17/109 12.9 53/111 334.0 20/111 63/112 6/112 32/97
(2.1–20.5) (57) (39.0–44.8) (16) (11.7–14.2) (48) (279.0–425.0) (18) (56) (5) (33)
201/285 130/285 0 136/285 103/285
(71) (46) (0-20) (48) (36)
81/112 45/112 0 50/112 41/112
(72) (40) (0-19) (45) (37)
268/285 17/285 191/285 162/285 184/199
(94) (6) (67) (57) (92)
105/112 7/112 112/112 61/112 112/112
(94) (6) (100) (54) (100)
ASCA, anti–Saccharomyces cerevisiae antibodies; Hb, hemoglobin; IV, intravenous; MDR1, multidrug resistance gene 1. a Subgroup of 112 patients with refractory ulcerative colitis who received infliximab at weeks 0, 2, 6, and 14 in whom infliximab serum levels at week 14 were available.
induction. From the remaining 199 patients, 182 (92%) received maintenance therapy with IFX therapy every 8 weeks thereafter. The remaining 15 patients (8%) received episodic therapy. IFX optimization was performed by shortening the interval or increasing the IFX dose in patients who presented with symptoms of active disease. The decision to use concomitant therapy with azathioprine, 6-mercaptopurine, or methotrexate was made individually. Combination therapy with an IMM was defined as the use of azathioprine, 6-mercaptopurine, or methotrexate during the first 14 weeks of IFX administration (induction period).
Statistics All statistical analyses were performed using the IBM SPSS 22.0 software packages (SPSS, Inc, Chicago, IL). Predictors of short-term clinical response and short-term mucosal healing were evaluated through appropriate statistics (chi-square, Fisher exact, or Mann–Whitney). Backward Wald multiple binary logistic regression including all potential predictors with a P value less than .1 in univariate analysis was performed to identify independent predictors of short-term outcome. Relapsefree and colectomy-free survival were estimated by Kaplan–Meier analyses. We used log-rank tests to
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compare hazard rates in populations defined by one variate at a time. A P value less than .05 was considered significant. All variables listed in Table 1 were included in the univariate analyses. The evaluation of the predictive role of IFX serum levels at week 14 was limited to a homogenous subgroup of 112 patients with moderate-to-severe UC who received a standard induction with IFX at weeks 0, 2, 6, and 14 (Table 1). To define the best cut-off value for IFX serum levels at week 14 a receiver operating characteristic curve was produced with relapse-free survival at 6 months as a binary classifier. Cox proportional hazard models including all variables with a log-rank P value of less than .1, were performed to identify independent predictors of relapse-free and colectomy-free survival. Because normalization of CRP level was evaluated only in patients with an increased baseline CRP level, and IFX serum levels at week 14 were assessed only in patients who received standard IFX therapy, these variables were not included in the Cox proportional hazards models. A risk panel for long-term outcome was constructed by combining factors that were associated independently with either relapse-free or colectomy-free survival. By using data from life tables, chi-square analyses were performed to evaluate the value of this risk panel in predicting clinical relapse at 12 months, and in predicting colectomy at 60 months.
Results Short-Term Response Short-term clinical response was achieved by 71% of 285 patients, of whom 47% showed complete and 24% showed partial clinical response 10 to 14 weeks after initiation of IFX. Eleven more patients achieved clinical response after an extra infusion of IFX, leading to a total cohort of 214 patients (75%) who showed clinical response to IFX. In multivariate analysis, no independent predictors of short-term clinical response could be identified.
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Of the 149 patients with an increased baseline CRP level, 54% achieved short-term CRP normalization. Mucosal healing was achieved in 52% of the 200 patients who underwent repeat flexible sigmoidoscopy. In multivariate analysis, age younger than 40 years at baseline (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.10–3.50; P ¼ .023), and a baseline Mayo endoscopic subscore of 2 (OR, 2.18; 95% CI, 1.22–3.91; P ¼ .009) were associated with short-term mucosal healing rates.
Infliximab Regimen From the 214 patients achieving clinical response, 7 patients stopped IFX after induction because it was introduced as bridging therapy for an IMM. In addition, 6 patients stopped IFX because of adverse events and 2 because of advanced pregnancy. From the remaining 199 patients, 15 patients initially were treated episodically, and the remaining 184 patients were treated with IFX maintenance therapy every 8 weeks. Overall, a median of 10 IFX infusions (IQR, 3–26 IFX infusions) were administered during a median of 15.6 months (IQR, 3.0–46.5 mo).
Relapse-Free Survival During a median follow-up period of 56.4 months (IQR, 30.6–78.7 mo), 113 of 184 patients (61%) on maintenance therapy relapsed (Figure 1A). As illustrated in Table 2 and Supplementary Figure 1, factors associated with relapse-free survival in univariate analysis were short-term complete clinical response, short-term CRP level normalization, short-term mucosal healing, and absence of pANCA. In multivariate analysis, shortterm complete clinical response (OR, 3.75; 95% CI, 2.35–5.97; P < .001), short-term mucosal healing (OR, 1.87; 95% CI, 1.17–2.98; P ¼ .009), and absence of pANCA (OR, 1.96; 95% CI, 1.23–3.12; P ¼ .005) were independent predictors of relapse-free survival. IFX dose optimization was performed in 91 patients with clinical relapse, and was successful in half of them. In patients with clinical relapse, dose optimization was
Figure 1. Relapse-free and colectomy-free survival. (A) Overall relapse-free survival in 184 patients on maintenance therapy with IFX, and (B) overall colectomy-free survival in 285 patients treated with infliximab for refractory ulcerative colitis.
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Risk Panel for IFX Outcome in UC
Table 2. Predictive Factors of Relapse-Free Survival
Short-term complete clinical response Short-term CRP level normalization Short-term mucosal healing pANCA negative
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Table 3. Predictive Factors of Colectomy-Free Survival
Univariate analysis Multivariate analysis (n ¼ 184) (n ¼ 146)
Univariate analysis (N ¼ 285)
Multivariate analysis (n ¼ 195)
Log-rank P value
P OR (95% CI) value
Log-rank P value
Odds ratio (95% CI)
P value
<.001
3.75 (2.35–5.97) <.001
<.001
7.74 (2.76–21.68)
<.001
4.02 (1.16–13.97)
.028
.026 .009
2.95 (1.26–6.89)
.012
.025
3.03 (1.12–8.22)
.029
.014 <.001
1.87 (1.17–2.98)
.009
.052
1.96 (1.23–3.12)
.005
NOTE. The multivariate analysis was conducted on 146 patients for whom all factors significant for long-term relapse-free survival in univariate analysis were known.
performed after a median of 6.51 months (IQR, 3.56–11.11 mo). In 14 patients the dose was increased to 10 mg/kg body weight, and in 39 patients the interval between 2 infusions was shortened to every 6 (n ¼ 28) or every 4 weeks (n ¼ 11). In the remaining 38 patients both a shortening of the interval between infusions and an increase in the IFX dose was performed. From the 130 patients receiving CS at baseline, 78% were able to stop CS during IFX therapy.
Colectomy-Free Survival During a median follow-up period of 64.4 months (IQR, 33.2–90.9 mo), 57 of 285 patients (20%) needed a colectomy (Figure 1B). Five patients underwent colectomy because of a neoplastic lesion and 52 patients because of intractable UC. Factors associated with colectomy-free survival in univariate analysis were short-term (partial or complete) clinical response, short-term CRP level normalization, short-term mucosal healing, disease duration of at least 2 years at start of IFX, a baseline CRP level of 5 mg/L or less, a baseline albumin level of 35 g/L or greater, no extensive colitis, no baseline endoscopic Mayo subscore of 3, and no previous need of intravenous CS (Table 3 and Supplementary Figure 2). In multivariate analysis, independent predictors of colectomy-free survival were short-term clinical response (OR, 7.74; 95% CI, 2.76–21.68; P < .001), short-term mucosal healing (OR, 4.02; 95% CI, 1.16–13.97; P ¼ .028), a baseline CRP level of 5 mg/L or less (OR, 2.95; 95% CI, 1.26–6.89; P ¼ .012), and a baseline albumin level of 35 g/L or greater (OR, 3.03; 95% CI, 1.12–8.22; P ¼ .029).
Predictive Role of Infliximab Serum Levels IFX serum levels at week 14 were available in 112 patients with refractory UC (45% female; median age, 38 y) who received IFX at weeks 0, 2, 6, and 14 (Table 1). Median IFX serum levels were significantly higher in
Short-term clinical response Short-term CRP level normalization Short-term mucosal healing Disease duration 2 y Baseline CRP level 5 mg/L Baseline albumin level 35 g/L No extensive colitis Mayo endoscopic subscore < 3 No previous need for intravenous CS
.010 <.001
.053 .027 .016
NOTE. The multivariate analyses was conducted on 195 patients for whom all factors significant for long-term colectomy-free survival in univariate analysis were known.
patients receiving concomitant IMM therapy (6.48 mg/mL; IQR, 3.01–11.30 mg/mL; vs 2.85 mg/mL; IQR, 1.36–6.80 mg/mL; P < .001), in patients with short-term complete clinical response (5.96 mg/mL; IQR, 2.97–10.79 mg/mL; vs 2.20 mg/mL; IQR, 1.30–4.85 mg/mL; P < .001), in patients with short-term CRP level normalization (6.27 mg/mL; IQR, 3.05–9.24 mg/mL; vs 2.02 mg/mL; IQR, 0.30–3.02 mg/mL; P < .001), and in patients with short-term mucosal healing (5.96 mg/mL; IQR, 3.05–10.59 mg/mL; vs 1.74 mg/mL; IQR, 0.88–2.92 mg/mL; P < .001) (Supplementary Figure 3). A receiver operating characteristic curve analysis of IFX serum levels at week 14 is shown in Supplementary Figure 4. A serum level higher than 2.5 mg/mL was associated with the absence of clinical relapse within 6 months of baseline (sensitivity, 81%; specificity, 75%; area under the receiver operating characteristic curve, 0.77; 95% CI, 0.66–0.88). As shown in Figure 2, a serum level higher than 2.5 mg/mL at week 14 was predictive not only of relapse-free survival (P < .001), but also of colectomy-free survival (P ¼ .034).
Development and Performance of a Risk Panel Predictors of long-term relapse-free or colectomyfree survival from multivariate analysis were included in a risk panel. The risk panel was composed of 5 different factors, namely absence of short-term complete clinical response, absence of short-term mucosal healing, pANCA, baseline hypoalbuminemia (albumin, <35 g/L), and baseline CRP increase (CRP, >5 mg/L).
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Figure 2. Predictive role of infliximab serum levels at week 14. (A) Relapse-free and (B) colectomy-free survival based on infliximab serum levels at week 14.
The predictive value of this risk panel is illustrated Figure 3A and B. As shown in Figure 3C, clinical relapse within 12 months was observed in 25% of 57 patients with 0 or 1 risk factor, 40% of 46 patients with 2 risk factors, 57% of 18 patients with 3 risk factors, and 83% of 18 patients with 4 or 5 risk factors (linear-by-linear association; P < .001). Similarly, as shown in Figure 3D, colectomy within 60 months was observed in 2% of 60 patients with 0 or 1 risk factor, 13% of 65 patients with 2 risk factors, 16% of 37 patients with 3 risk factors, and 51% of 32 patients with 4 or 5 risk factors (linear-bylinear association; P < .001).
Figure 3. Predictive role of risk panel. Relapse and colectomy rate based on a risk panel including 5 independent risk factors, namely absence of short-term complete clinical response, absence of short-term mucosal healing, pANCA positivity, baseline albumin level less than 35 g/L, and baseline CRP level greater than 5 mg/L: (A) time to relapse, (B) time to colectomy, (C) clinical relapse rate within 12 months, and (D) colectomy rate within 60 months.
Discussion Since the landmark ACT1 and ACT2 trials, IFX has had a prominent role in the treatment of patients with refractory UC. However, several patients lose response and a new therapeutic class of anti-integrin molecules likely will be introduced in the coming years. Therefore, there is a clear need for the identification of predictors of longterm outcome of IFX therapy to provide tailored therapy. In this article we extended our knowledge on the use of IFX in a tertiary referral center, including 285 consecutive patients with refractory UC and a median follow-up
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period of more than 5 years. We identified several independent risk factors for both long-term clinical relapse and the need for colectomy, which were included in a risk panel. Clinical relapse was observed in 61% of patients on maintenance therapy with IFX, however, 20% of patients needed a colectomy. A risk panel containing clinical response, short-term mucosal healing, pANCA level, CRP level, and albumin level was developed. Patients with 0 or 1 risk factor present had the lowest risk in the long term (25% clinical relapse within 12 months and 2% colectomy within 60 months), whereas patients with 4 or 5 risk factors present had the highest risk (83% clinical relapse within 12 months and 51% colectomy within 60 months). In addition, IFX serum levels at week 14 less than 2.5 mg/mL also were predictive of clinical relapse and colectomy. The main limitations of this study were its retrospective analysis, the somewhat heterogeneous study population, the absence of an endoscopic evaluation in all patients, and the absence of standardized criteria for disease activity at baseline and moment of relapse. Furthermore, because of the pharmacodynamic properties of IFX, the predictive value of IFX serum levels at week 14 was evaluated only in a subgroup of 112 patients who received their first 4 doses of IFX at fixed time points, namely weeks 0, 2, 6, and 14, and hence could not be included in the risk panel. Short-term clinical response and short-term mucosal healing were observed in 71% and 52% of patients, respectively, which is comparable with the ACT1 and ACT2 data.1 Previously observed risk factors for absence of shortterm clinical response, such as older age at first IFX treatment, pANCA positivity, lower baseline hemoglobin level, and lower baseline albumin level, could not be confirmed.7,16–18 However, a younger age at baseline and a baseline Mayo endoscopic subscore of 2 or less were associated independently with short-term mucosal healing. The previously reported improved long-term outcome data in patients achieving a clinical response and mucosal healing after induction therapy with IFX was confirmed in our analysis. Data from the ACT1 and ACT2 trials already showed that mucosal healing at week 8 was associated with lower colectomy rates at week 54.10 In a French multicentric cohort study, an absence of clinical response and an absence of mucosal healing were independent predictors of hospitalization and surgery.7,11 These data support the use of short-term endoscopic evaluation after initiation of IFX therapy to guide further treatment. Although a pANCAþ or pANCAþ/ASCA-serotype previously has been associated with a worse short-term clinical response,16,17 this time pANCA was associated with an increased clinical relapse risk. The presence of pANCA therefore should prompt more strict follow-up evaluation and early treatment optimization. Of note, pANCA expression previously has been associated with distinct clinical UC phenotypes, including more aggressive disease course,19 need for early surgical intervention, and development of chronic pouchitis in patients
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undergoing colectomy.20 It therefore may be suggested that patients with a high pANCA level are predisposed to develop a more vigorous immune response to bacterial products. Although in our cohort long-term outcome data were not significantly different for patients with ASUC compared with outpatients with refractory UC, patients with a higher baseline CRP and lower baseline albumin levels more frequently required colectomy. Increased CRP and decreased albumin levels may be surrogate markers for more active disease. Interestingly, low albumin levels have been associated with an increased clearance of IFX.21 Previously, Seow et al12 showed a clear association between IFX serum levels and clinical remission, endoscopic improvement, and colectomy. In our cohort, IFX trough levels less than 2.5 mg/mL at week 14 were predictive of both clinical relapse and colectomy. A similar predictive value recently was shown in a Czech cohort of 48 patients with CD,22 as well as in a post hoc analysis of the A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Longterm Treatment Regimen 1 study including 192 patients with CD.23 IFX trough levels greater than 3.0 mg/mL at week 14 or 22 (Czech study) or greater than 3.5 mg/mL at week 14 (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen 1 study) were associated with a sustained response to infliximab. Measurement of trough IFX levels early after induction therapy with IFX therefore seems worthwhile to dose-optimize early enough and decrease long-term relapse and colectomy rates. The value of a tailored approach in patients receiving IFX therapy based on the serum levels (target between 3 and 7 mg/mL) currently is under investigation.24 In conclusion, we were able to confirm the short-term and long-term efficacy of IFX in both outpatients with refractory UC and patients with ASUC refractory to intravenous CS. Furthermore, we identified independent predictors of both long-term clinical relapse and need for colectomy, which were included in a risk panel. The application of this risk panel in daily clinical practice could help us to stratify patients before and early after initiation of IFX therapy. The observation of a better long-term outcome in patients with IFX serum levels greater than 2.5 mg/mL may guide treatment optimization before clinical relapse, but the benefit of such a tailored approach needs confirmation in a prospective setting.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2014.07.055.
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20. Fleshner PR, Vasiliauskas EA, Kam LY, et al. High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis. Gut 2001;49:671–677. 21. Fasanmade AA, Adedokun OJ, Ford J, et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol 2009;65:1211–1228.
6. Ferrante M, Vermeire S, Fidder H, et al. Long-term outcome after infliximab for refractory ulcerative colitis. J Crohns Colitis 2008; 2:219–225.
22. Bortlik M, Duricova D, Malickova K, et al. Infliximab trough levels may predict sustained response to infliximab in patients with Crohn’s disease. J Crohns Colitis 2013;7:736–743.
7. Oussalah A, Evesque L, Laharie D, et al. A multicenter experience with infliximab for ulcerative colitis: outcomes and predictors of response, optimization, colectomy, and hospitalization. Am J Gastroenterol 2010;105:2617–2625. 8. Armuzzi A, Pugliese D, Danese S, et al. Infliximab in steroiddependent ulcerative colitis: effectiveness and predictors of clinical and endoscopic remission. Inflamm Bowel Dis 2013; 19:1065–1072.
23. Cornillie F, Hanauer SB, Diamond RH, et al. Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. Gut 2014 Epub ahead of print.
9. Mir SA, Nagy-Szakal D, Smith EO, et al. Duration of disease may predict response to infliximab in pediatric ulcerative colitis. J Clin Gastroenterol 2014;48:248–252. 10. Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology 2011; 141:1194–1201. 11. Laharie D, Filippi J, Roblin X, et al. Impact of mucosal healing on long-term outcomes in ulcerative colitis treated with infliximab: a multicenter experience. Aliment Pharmacol Ther 2013;37: 998–1004. 12. Seow CH, Newman A, Irwin SP, et al. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut 2010;59:49–54. 13. McGovern DPB, Ahmad T, van Heel D, et al. A genetic panel strongly predicts the need for colectomy in ulcerative colitis. Gastroenterology 2004;126:A68. 14. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005; 19(Suppl A):5–36. 15. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317: 1625–1629. 16. Ferrante M, Vermeire S, Katsanos KH, et al. Predictors of early response to infliximab in patients with ulcerative colitis. Inflamm Bowel Dis 2007;13:123–128. 17. Jurgens M, Laubender RP, Hartl F, et al. Disease activity, ANCA, and IL23R genotype status determine early response to infliximab in patients with ulcerative colitis. Am J Gastroenterol 2010; 105:1811–1819.
24. Vande Casteele N, Compernolle G, Ballet V, et al. Results on the Optimisation Phase of the Prospective Controlled Trough Level Adapted Infliximab Treatment (TAXIT) Trial. Gastroenterology 2012;142:S211–S212.
Reprint requests Address requests for reprints to: Marc Ferrante, MD, PhD, Department of Gastroenterology, University Hospitals Leuven, Herestraat 49, B3000 Leuven, Belgium. e-mail: [email protected]; fax: (32) 16-34-44-19. Acknowledgments The authors thank Vera Ballet and Griet Compernolle for maintaining the patient database and performing the enzyme-linked immunosorbent assays. Conflicts of interest These authors disclose the following: Séverine Vermeire, Gert Van Assche, and Marc Ferrante received grant support from Merck, Janssen Biologics, Abbvie, and UCB. Niels Vande Casteele has been a consultant for Merck and Janssen Biologics; Séverine Vermeire has received financial support for research from UCB Pharma, Merck, and Abbvie, has received lecture fees from Abbvie, Merck, Ferring, UCB Pharma, and Centocor; and has been a consultant for UCB Pharma, AstraZeneca, Ferring, Abbvie, Merck, Ferring, Shire, Pfizer, and MSD; Filip Baert has received lecture fees from Merck and Abbvie; Gert Van Assche has received financial support for research from Abbvie and Ferring, has received lecture fees from Janssen-Cilag, Merck, and Abbvie, and has been a consultant for PDL BioPharma, UCB Pharma, Sanofi-Aventis, Abbvie, Ferring, Novartis, Biogen Idec, Janssen Biologics, NovoNordisk, Zealand Pharma A/S, Millenium/Takeda, Shire, and BMS; Ann Gils has been a consultant for Merck, Janssen Biologics, and Abbvie; Paul Rutgeerts has received financial support for research from UCB Pharma, Abbvie, Janssen Biologics, Merck, Prometheus, and Bristol-Meyers Squibb; has received lecture fees from Abbvie and Merck, and has been a consultant for Amgen, Merck, UCB Pharma, Genentech, BMS, Abbvie, Janssen Biologics, Millenium, Neovacs, Actogenics, Prometheus, Pfizer, Falk Pharma, and Tillotts; and Marc Ferrante has received financial support for research from Janssen Biologics, has received lecture fees from Merck, Tillotts, Ferring, and Abbvie, and has been a consultant for Abbvie, Merck, and Janssen Biologics. The remaining authors disclose no conflicts. Funding This study was supported in part by the Research Foundation–Flanders, Belgium (G.0617.12). Niels Vande Casteele is a postdoctoral fellow, and Séverine Vermeire, Gert Van Assche, and Marc Ferrante are Senior Clinical Investigators for the Research Foundation–Flanders, Belgium.
A Panel to Predict Long-term Outcome of Infliximab Therapy for Patients With Ulcerative Colitis Maria Theresa Arias,* Niels Vande Casteele,‡ Séverine Vermeire,* Anthony de Buck van Overstraeten,§ Thomas Billiet,* Filip Baert,* Albert Wolthuis,§ Gert Van Assche,* Maja Noman,* Ilse Hoffman,k Andre D’Hoore,§ Ann Gils,‡ Paul Rutgeerts,* and Marc Ferrante* *Department of Gastroenterology, University Hospitals Leuven, ‡Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, §Department of Abdominal Surgery, kDepartment of Pediatrics, KU Leuven–University of Leuven, Leuven, Belgium BACKGROUND & AIMS:
Infliximab is effective for patients with refractory ulcerative colitis (UC), but few factors have been identified that predict long-term outcome of therapy. We aimed to identify a panel of markers associated with outcome of infliximab therapy to help physicians make personalized treatment decisions.
METHODS:
We collected data from the first 285 patients with refractory UC (41% female; median age, 39 y) treated with infliximab before July 2012 at University Hospitals Leuven, in Belgium. We performed a Cox regression analysis to identify independent factors that predicted relapse-free and colectomy-free survival, and used these factors to create a panel of markers (risk panel).
RESULTS:
During a median follow-up period of 5 years, 61% of patients relapsed and 20% required colectomy. Independent predictors of relapse-free survival included short-term complete clinical response (odds ratio [OR], 3.75; 95% confidence interval [CI], 2.35–5.97; P < .001), mucosal healing (OR, 1.87; 95% CI, 1.17–2.98; P [ .009), and absence of atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) (OR, 1.96; 95% CI, 1.23–3.12; P [ .005). Independent predictors of colectomy-free survival included short-term clinical response (OR, 7.74; 95% CI, 2.76–21.68; P < .001), mucosal healing (OR, 4.02; 95% CI, 1.16–13.97; P [ .028), baseline level of C-reactive protein (CRP) of 5 mg/L or less (OR, 2.95; 95% CI, 1.26–6.89; P [ .012), and baseline level of albumin of 35 g/L or greater (OR, 3.03; 95% CI, 1.12–8.22; P [ .029). Based on serologic analysis of a subgroup of 112 patients, levels of infliximab greater than 2.5 mg/mL at week 14 of treatment predicted relapse-free survival (P < .001) and colectomy-free survival (P [ .034). A risk panel that included levels of pANCA, CRP, albumin, clinical response, and mucosal healing identified patients at risk for UC relapse or colectomy (both P < .001).
CONCLUSIONS:
Clinical response and mucosal healing were confirmed as independent predictors of long-term outcome from infliximab therapy in patients with UC. We identified additional factors (levels of pANCA, CRP, and albumin) to create a risk panel that predicts long-term outcomes of therapy. Serum levels of infliximab at week 14 of treatment also were associated with patient outcomes. Our risk panel and short-term serum levels of infliximab therefore might be used to guide therapy.
Keywords: Drug; Response To Therapy; Prognostic Factor; Biomarker.
n 2005, the landmark Active Ulcerative Colitis Trials (ACT1 and ACT2) showed a significant benefit for the use of infliximab (IFX) in patients with moderate-to-severe ulcerative colitis (UC).1 In these double-blind, placebocontrolled trials, patients randomized to IFX not only experienced higher clinical response and remission rates, but also higher mucosal healing rates, lower hospitalization rates, and lower colectomy rates during up to 1 year of follow-up evaluation.1,2 In parallel, a Scandinavian placebo-controlled
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Abbreviations used in this paper: ACT, Active Ulcerative Colitis Trials; ASCA, anti-Saccharomyces cerevisiae antibodies; ASUC, acute severe ulcerative colitis; CI, confidence interval; CRP, C-reactive protein level; CS, corticosteroids; IFX, infliximab; IMM, immunomodulatory agents; IQR, interquartile range; OR, odds ratio; pANCA, atypical perinuclear antineutrophil cytoplasmic antibodies; UC, ulcerative colitis. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.07.055
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trial provided evidence for the use of IFX in patients with acute severe ulcerative colitis (ASUC) refractory to intravenous corticosteroids (CS).3,4 Most recently, the Groupe d’Étude Thérapeutique des Affections Inflammatoires du Tube Digestif group showed that IFX was at least as efficacious as cyclosporine for this indication.5 In the past decade, several real-life, open-label cohort studies have provided more data on the efficacy and safety of IFX in patients with refractory UC.6–9 Short-term clinical response, short-term normalization of C-reactive protein level (CRP), and short-term mucosal healing were among the predictors of colectomy-free survival.7,8,10,11 In contrast, an increased baseline CRP level, a shorter disease duration before IFX, and previous treatment with intravenous cyclosporine have been associated with a higher colectomy risk.7,9 In a Canadian trial, detectable IFX serum levels were associated with higher clinical remission rates, higher endoscopic improvement rates, and lower colectomy rates, but no firm conclusions could be drawn on their predictive value.12 In 2008, we presented the outcome of the first 121 outpatients with refractory UC treated with IFX in our center.6 With the current study we aimed to explore the extended long-term outcome of a larger cohort of patients with refractory UC treated with IFX in our tertiary referral center. Furthermore, we defined predictors of long-term, relapsefree and colectomy-free survival, and specifically evaluated the predictive value of IFX serum levels. Based on the provided risk factors, we developed a risk panel to predict longterm outcome to IFX. This risk panel may guide personalized therapy in patients starting IFX for refractory UC.
Methods Patient Population All patients with refractory UC who received a first infusion of IFX before July 2012 were included in this study, allowing a follow-up period of at least 6 months. Eligible patients did not respond to CS alone, immunomodulatory agents (IMM) alone, or a combination of both, were intolerant to any of these drugs, or were unable to taper CS. We identified 285 patients (41% female), with a median age at first IFX of 39.1 years (interquartile range [IQR], 28.8–50.6 y). Among these 285 patients, 39 received IFX for ASUC refractory to intravenous CS. Before IFX initiation, latent tuberculosis, cytomegalovirus, and Clostridium difficile infection were excluded. All individuals provided written informed consent for this study, which was approved by the local ethics committee of the Catholic University of Leuven. Patients’ characteristics are listed in Table 1.
Serologic and Genetic Markers Data on levels of CRP, hemoglobin, thrombocytes, and albumin were collected prospectively as part of a
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standardized follow-up evaluation of all patients treated with IFX. The presence of anti–Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) were evaluated through an enzyme-linked immunosorbent assay. Serum samples were collected at baseline and at week 14 immediately before the fourth IFX administration (trough level). Serum IFX levels were measured using an in-house–developed enzyme-linked immunosorbent assay. Based on a previously reported association with the need for colectomy,13 we assessed the multidrug resistance gene 1 C3435T genotype by TaqMan genotyping assay (Applied Biosystems Inc, Carlsbad, CA).
Definitions The extent of disease was categorized using the Montreal classification.14 Endoscopic severity of disease before IFX was determined according to the Mayo endoscopic subscore in 265 patients.15 Short-term response to IFX was assessed after 10 to 14 weeks and was defined as complete if there was an absence of diarrhea and blood, and partial if there was marked clinical improvement (less diarrhea, less abdominal pain) but still persistent rectal blood loss.16 To assess shortterm mucosal healing, endoscopy was performed in 200 patients both before and 10 to 14 weeks after the first IFX infusion. Mucosal healing was defined as a Mayo endoscopic subscore of 0 or 1, and was assessed only in patients with a Mayo endoscopic subscore of 2 or 3 at inclusion (n ¼ 200).16 Normalization of CRP level was analyzed in patients with an increased baseline CRP level (>5 mg/L) if a second CRP level was available 10 to 14 weeks after first IFX infusion (n ¼ 149). Long-term outcome was evaluated at last follow-up evaluation. Relapse-free survival was defined as the absence of clinical relapse requiring IFX dose optimization, medical rescue therapy, or colectomy, and was evaluated only in patients who initially responded to the therapy and received maintenance IFX therapy. Colectomy-free survival was evaluated in all patients and was defined as the absence of colectomy throughout follow-up evaluation, regardless of clinical findings and the need for medical interventions. Of note, patients who underwent colectomy for neoplastic lesions (n ¼ 5) also were included in the analysis for colectomy-free survival.
Administration of Infliximab and Concomitant Therapy At study start, patients received either a single dose of 5 or 10 mg IFX per kilogram of body weight, or an induction scheme with IFX at weeks 0, 2, and 6. Six patients received 1 (n ¼ 5) or 2 (n ¼ 1) extra infusions of IFX before week 14. Fifteen patients from the 214 patients showing clinical response discontinued IFX after
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Table 1. Patient Characteristics Whole cohort (N ¼ 285) Female (%) Median (IQR) age at first IFX infusion, y Median (IQR) duration of disease, y Median (IQR) weight at first IFX, kg Extent of colitis Proctitis (%) Left-sided colitis (%) Extensive colitis (%) Backwash ileitis (%) Mayo endoscopic subscore before IFX Mayo 1 (%) Mayo 2 (%) Mayo 3 (%) Acute severe IV steroid refractory colitis Primary sclerosing cholangitis (%) Smoking behavior at first IFX Never (%) Former (%) Active (%) Laboratory values at first IFX Median (IQR) CRP level, mg/L CRP level >5 mg/L (%) Median (IQR) albumin level, g/L Albumin level <35 g/L Median (IQR) Hb level, g/dL Hb level <12 g/dL (female) or <14 g/dL (male) Median (IQR) thrombocyte level, 109/L Thrombocyte level > 450 109/L pANCA positive ASCA positive MDR1 3435 TT genotype Concomitant therapy at first IFX Mesalamine (%) Corticosteroids (%) Median (IQR) of corticosteroids, mg Immunosuppressant drugs (%) Previous treatment with IV steroids (%) Dose of first IFX 5 mg/kg body weight (%) 10 mg/kg body weight (%) Induction therapy with IFX (%) Combination therapy during first 14 weeks (%) Maintenance therapy with IFX (%)
Subgroupa (n ¼ 112)
116/285 39.1 5.2 72
(41) (28.8–50.6) (1.6–10.8) (60–83)
50/112 38.0 4.5 72
(45) (28.3–49.8) (1.5–10.8) (63–85)
4/285 95/285 186/285 19/248
(2) (33) (65) (8)
2/112 37/112 73/112 6/100
(2) (33) (65) (6)
11/265 122/265 132/265 39/285 17/285
(4) (46) (50) (14) (6)
3/110 57/110 50/110 17/112 5/112
(3) (52) (45) (15) (4)
136/285 (48) 121/285 (42) 28/285 (10)
56/112 (50) 44/112 (39) 12/112 (11)
6.4 155/283 41.2 54/266 12.8 149/278 325.0 47/277 152/283 13/285 74/259
(1.7–23.5) (55) (37.3–44.0) (20) (11.3–14.0) (54) (266.5–415.5) (17) (54) (5) (29)
6.4 64/112 42.0 17/109 12.9 53/111 334.0 20/111 63/112 6/112 32/97
(2.1–20.5) (57) (39.0–44.8) (16) (11.7–14.2) (48) (279.0–425.0) (18) (56) (5) (33)
201/285 130/285 0 136/285 103/285
(71) (46) (0-20) (48) (36)
81/112 45/112 0 50/112 41/112
(72) (40) (0-19) (45) (37)
268/285 17/285 191/285 162/285 184/199
(94) (6) (67) (57) (92)
105/112 7/112 112/112 61/112 112/112
(94) (6) (100) (54) (100)
ASCA, anti–Saccharomyces cerevisiae antibodies; Hb, hemoglobin; IV, intravenous; MDR1, multidrug resistance gene 1. a Subgroup of 112 patients with refractory ulcerative colitis who received infliximab at weeks 0, 2, 6, and 14 in whom infliximab serum levels at week 14 were available.
induction. From the remaining 199 patients, 182 (92%) received maintenance therapy with IFX therapy every 8 weeks thereafter. The remaining 15 patients (8%) received episodic therapy. IFX optimization was performed by shortening the interval or increasing the IFX dose in patients who presented with symptoms of active disease. The decision to use concomitant therapy with azathioprine, 6-mercaptopurine, or methotrexate was made individually. Combination therapy with an IMM was defined as the use of azathioprine, 6-mercaptopurine, or methotrexate during the first 14 weeks of IFX administration (induction period).
Statistics All statistical analyses were performed using the IBM SPSS 22.0 software packages (SPSS, Inc, Chicago, IL). Predictors of short-term clinical response and short-term mucosal healing were evaluated through appropriate statistics (chi-square, Fisher exact, or Mann–Whitney). Backward Wald multiple binary logistic regression including all potential predictors with a P value less than .1 in univariate analysis was performed to identify independent predictors of short-term outcome. Relapsefree and colectomy-free survival were estimated by Kaplan–Meier analyses. We used log-rank tests to
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compare hazard rates in populations defined by one variate at a time. A P value less than .05 was considered significant. All variables listed in Table 1 were included in the univariate analyses. The evaluation of the predictive role of IFX serum levels at week 14 was limited to a homogenous subgroup of 112 patients with moderate-to-severe UC who received a standard induction with IFX at weeks 0, 2, 6, and 14 (Table 1). To define the best cut-off value for IFX serum levels at week 14 a receiver operating characteristic curve was produced with relapse-free survival at 6 months as a binary classifier. Cox proportional hazard models including all variables with a log-rank P value of less than .1, were performed to identify independent predictors of relapse-free and colectomy-free survival. Because normalization of CRP level was evaluated only in patients with an increased baseline CRP level, and IFX serum levels at week 14 were assessed only in patients who received standard IFX therapy, these variables were not included in the Cox proportional hazards models. A risk panel for long-term outcome was constructed by combining factors that were associated independently with either relapse-free or colectomy-free survival. By using data from life tables, chi-square analyses were performed to evaluate the value of this risk panel in predicting clinical relapse at 12 months, and in predicting colectomy at 60 months.
Results Short-Term Response Short-term clinical response was achieved by 71% of 285 patients, of whom 47% showed complete and 24% showed partial clinical response 10 to 14 weeks after initiation of IFX. Eleven more patients achieved clinical response after an extra infusion of IFX, leading to a total cohort of 214 patients (75%) who showed clinical response to IFX. In multivariate analysis, no independent predictors of short-term clinical response could be identified.
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Of the 149 patients with an increased baseline CRP level, 54% achieved short-term CRP normalization. Mucosal healing was achieved in 52% of the 200 patients who underwent repeat flexible sigmoidoscopy. In multivariate analysis, age younger than 40 years at baseline (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.10–3.50; P ¼ .023), and a baseline Mayo endoscopic subscore of 2 (OR, 2.18; 95% CI, 1.22–3.91; P ¼ .009) were associated with short-term mucosal healing rates.
Infliximab Regimen From the 214 patients achieving clinical response, 7 patients stopped IFX after induction because it was introduced as bridging therapy for an IMM. In addition, 6 patients stopped IFX because of adverse events and 2 because of advanced pregnancy. From the remaining 199 patients, 15 patients initially were treated episodically, and the remaining 184 patients were treated with IFX maintenance therapy every 8 weeks. Overall, a median of 10 IFX infusions (IQR, 3–26 IFX infusions) were administered during a median of 15.6 months (IQR, 3.0–46.5 mo).
Relapse-Free Survival During a median follow-up period of 56.4 months (IQR, 30.6–78.7 mo), 113 of 184 patients (61%) on maintenance therapy relapsed (Figure 1A). As illustrated in Table 2 and Supplementary Figure 1, factors associated with relapse-free survival in univariate analysis were short-term complete clinical response, short-term CRP level normalization, short-term mucosal healing, and absence of pANCA. In multivariate analysis, shortterm complete clinical response (OR, 3.75; 95% CI, 2.35–5.97; P < .001), short-term mucosal healing (OR, 1.87; 95% CI, 1.17–2.98; P ¼ .009), and absence of pANCA (OR, 1.96; 95% CI, 1.23–3.12; P ¼ .005) were independent predictors of relapse-free survival. IFX dose optimization was performed in 91 patients with clinical relapse, and was successful in half of them. In patients with clinical relapse, dose optimization was
Figure 1. Relapse-free and colectomy-free survival. (A) Overall relapse-free survival in 184 patients on maintenance therapy with IFX, and (B) overall colectomy-free survival in 285 patients treated with infliximab for refractory ulcerative colitis.
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Table 2. Predictive Factors of Relapse-Free Survival
Short-term complete clinical response Short-term CRP level normalization Short-term mucosal healing pANCA negative
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Table 3. Predictive Factors of Colectomy-Free Survival
Univariate analysis Multivariate analysis (n ¼ 184) (n ¼ 146)
Univariate analysis (N ¼ 285)
Multivariate analysis (n ¼ 195)
Log-rank P value
P OR (95% CI) value
Log-rank P value
Odds ratio (95% CI)
P value
<.001
3.75 (2.35–5.97) <.001
<.001
7.74 (2.76–21.68)
<.001
4.02 (1.16–13.97)
.028
.026 .009
2.95 (1.26–6.89)
.012
.025
3.03 (1.12–8.22)
.029
.014 <.001
1.87 (1.17–2.98)
.009
.052
1.96 (1.23–3.12)
.005
NOTE. The multivariate analysis was conducted on 146 patients for whom all factors significant for long-term relapse-free survival in univariate analysis were known.
performed after a median of 6.51 months (IQR, 3.56–11.11 mo). In 14 patients the dose was increased to 10 mg/kg body weight, and in 39 patients the interval between 2 infusions was shortened to every 6 (n ¼ 28) or every 4 weeks (n ¼ 11). In the remaining 38 patients both a shortening of the interval between infusions and an increase in the IFX dose was performed. From the 130 patients receiving CS at baseline, 78% were able to stop CS during IFX therapy.
Colectomy-Free Survival During a median follow-up period of 64.4 months (IQR, 33.2–90.9 mo), 57 of 285 patients (20%) needed a colectomy (Figure 1B). Five patients underwent colectomy because of a neoplastic lesion and 52 patients because of intractable UC. Factors associated with colectomy-free survival in univariate analysis were short-term (partial or complete) clinical response, short-term CRP level normalization, short-term mucosal healing, disease duration of at least 2 years at start of IFX, a baseline CRP level of 5 mg/L or less, a baseline albumin level of 35 g/L or greater, no extensive colitis, no baseline endoscopic Mayo subscore of 3, and no previous need of intravenous CS (Table 3 and Supplementary Figure 2). In multivariate analysis, independent predictors of colectomy-free survival were short-term clinical response (OR, 7.74; 95% CI, 2.76–21.68; P < .001), short-term mucosal healing (OR, 4.02; 95% CI, 1.16–13.97; P ¼ .028), a baseline CRP level of 5 mg/L or less (OR, 2.95; 95% CI, 1.26–6.89; P ¼ .012), and a baseline albumin level of 35 g/L or greater (OR, 3.03; 95% CI, 1.12–8.22; P ¼ .029).
Predictive Role of Infliximab Serum Levels IFX serum levels at week 14 were available in 112 patients with refractory UC (45% female; median age, 38 y) who received IFX at weeks 0, 2, 6, and 14 (Table 1). Median IFX serum levels were significantly higher in
Short-term clinical response Short-term CRP level normalization Short-term mucosal healing Disease duration 2 y Baseline CRP level 5 mg/L Baseline albumin level 35 g/L No extensive colitis Mayo endoscopic subscore < 3 No previous need for intravenous CS
.010 <.001
.053 .027 .016
NOTE. The multivariate analyses was conducted on 195 patients for whom all factors significant for long-term colectomy-free survival in univariate analysis were known.
patients receiving concomitant IMM therapy (6.48 mg/mL; IQR, 3.01–11.30 mg/mL; vs 2.85 mg/mL; IQR, 1.36–6.80 mg/mL; P < .001), in patients with short-term complete clinical response (5.96 mg/mL; IQR, 2.97–10.79 mg/mL; vs 2.20 mg/mL; IQR, 1.30–4.85 mg/mL; P < .001), in patients with short-term CRP level normalization (6.27 mg/mL; IQR, 3.05–9.24 mg/mL; vs 2.02 mg/mL; IQR, 0.30–3.02 mg/mL; P < .001), and in patients with short-term mucosal healing (5.96 mg/mL; IQR, 3.05–10.59 mg/mL; vs 1.74 mg/mL; IQR, 0.88–2.92 mg/mL; P < .001) (Supplementary Figure 3). A receiver operating characteristic curve analysis of IFX serum levels at week 14 is shown in Supplementary Figure 4. A serum level higher than 2.5 mg/mL was associated with the absence of clinical relapse within 6 months of baseline (sensitivity, 81%; specificity, 75%; area under the receiver operating characteristic curve, 0.77; 95% CI, 0.66–0.88). As shown in Figure 2, a serum level higher than 2.5 mg/mL at week 14 was predictive not only of relapse-free survival (P < .001), but also of colectomy-free survival (P ¼ .034).
Development and Performance of a Risk Panel Predictors of long-term relapse-free or colectomyfree survival from multivariate analysis were included in a risk panel. The risk panel was composed of 5 different factors, namely absence of short-term complete clinical response, absence of short-term mucosal healing, pANCA, baseline hypoalbuminemia (albumin, <35 g/L), and baseline CRP increase (CRP, >5 mg/L).
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Figure 2. Predictive role of infliximab serum levels at week 14. (A) Relapse-free and (B) colectomy-free survival based on infliximab serum levels at week 14.
The predictive value of this risk panel is illustrated Figure 3A and B. As shown in Figure 3C, clinical relapse within 12 months was observed in 25% of 57 patients with 0 or 1 risk factor, 40% of 46 patients with 2 risk factors, 57% of 18 patients with 3 risk factors, and 83% of 18 patients with 4 or 5 risk factors (linear-by-linear association; P < .001). Similarly, as shown in Figure 3D, colectomy within 60 months was observed in 2% of 60 patients with 0 or 1 risk factor, 13% of 65 patients with 2 risk factors, 16% of 37 patients with 3 risk factors, and 51% of 32 patients with 4 or 5 risk factors (linear-bylinear association; P < .001).
Figure 3. Predictive role of risk panel. Relapse and colectomy rate based on a risk panel including 5 independent risk factors, namely absence of short-term complete clinical response, absence of short-term mucosal healing, pANCA positivity, baseline albumin level less than 35 g/L, and baseline CRP level greater than 5 mg/L: (A) time to relapse, (B) time to colectomy, (C) clinical relapse rate within 12 months, and (D) colectomy rate within 60 months.
Discussion Since the landmark ACT1 and ACT2 trials, IFX has had a prominent role in the treatment of patients with refractory UC. However, several patients lose response and a new therapeutic class of anti-integrin molecules likely will be introduced in the coming years. Therefore, there is a clear need for the identification of predictors of longterm outcome of IFX therapy to provide tailored therapy. In this article we extended our knowledge on the use of IFX in a tertiary referral center, including 285 consecutive patients with refractory UC and a median follow-up
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period of more than 5 years. We identified several independent risk factors for both long-term clinical relapse and the need for colectomy, which were included in a risk panel. Clinical relapse was observed in 61% of patients on maintenance therapy with IFX, however, 20% of patients needed a colectomy. A risk panel containing clinical response, short-term mucosal healing, pANCA level, CRP level, and albumin level was developed. Patients with 0 or 1 risk factor present had the lowest risk in the long term (25% clinical relapse within 12 months and 2% colectomy within 60 months), whereas patients with 4 or 5 risk factors present had the highest risk (83% clinical relapse within 12 months and 51% colectomy within 60 months). In addition, IFX serum levels at week 14 less than 2.5 mg/mL also were predictive of clinical relapse and colectomy. The main limitations of this study were its retrospective analysis, the somewhat heterogeneous study population, the absence of an endoscopic evaluation in all patients, and the absence of standardized criteria for disease activity at baseline and moment of relapse. Furthermore, because of the pharmacodynamic properties of IFX, the predictive value of IFX serum levels at week 14 was evaluated only in a subgroup of 112 patients who received their first 4 doses of IFX at fixed time points, namely weeks 0, 2, 6, and 14, and hence could not be included in the risk panel. Short-term clinical response and short-term mucosal healing were observed in 71% and 52% of patients, respectively, which is comparable with the ACT1 and ACT2 data.1 Previously observed risk factors for absence of shortterm clinical response, such as older age at first IFX treatment, pANCA positivity, lower baseline hemoglobin level, and lower baseline albumin level, could not be confirmed.7,16–18 However, a younger age at baseline and a baseline Mayo endoscopic subscore of 2 or less were associated independently with short-term mucosal healing. The previously reported improved long-term outcome data in patients achieving a clinical response and mucosal healing after induction therapy with IFX was confirmed in our analysis. Data from the ACT1 and ACT2 trials already showed that mucosal healing at week 8 was associated with lower colectomy rates at week 54.10 In a French multicentric cohort study, an absence of clinical response and an absence of mucosal healing were independent predictors of hospitalization and surgery.7,11 These data support the use of short-term endoscopic evaluation after initiation of IFX therapy to guide further treatment. Although a pANCAþ or pANCAþ/ASCA-serotype previously has been associated with a worse short-term clinical response,16,17 this time pANCA was associated with an increased clinical relapse risk. The presence of pANCA therefore should prompt more strict follow-up evaluation and early treatment optimization. Of note, pANCA expression previously has been associated with distinct clinical UC phenotypes, including more aggressive disease course,19 need for early surgical intervention, and development of chronic pouchitis in patients
Risk Panel for IFX Outcome in UC
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undergoing colectomy.20 It therefore may be suggested that patients with a high pANCA level are predisposed to develop a more vigorous immune response to bacterial products. Although in our cohort long-term outcome data were not significantly different for patients with ASUC compared with outpatients with refractory UC, patients with a higher baseline CRP and lower baseline albumin levels more frequently required colectomy. Increased CRP and decreased albumin levels may be surrogate markers for more active disease. Interestingly, low albumin levels have been associated with an increased clearance of IFX.21 Previously, Seow et al12 showed a clear association between IFX serum levels and clinical remission, endoscopic improvement, and colectomy. In our cohort, IFX trough levels less than 2.5 mg/mL at week 14 were predictive of both clinical relapse and colectomy. A similar predictive value recently was shown in a Czech cohort of 48 patients with CD,22 as well as in a post hoc analysis of the A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Longterm Treatment Regimen 1 study including 192 patients with CD.23 IFX trough levels greater than 3.0 mg/mL at week 14 or 22 (Czech study) or greater than 3.5 mg/mL at week 14 (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen 1 study) were associated with a sustained response to infliximab. Measurement of trough IFX levels early after induction therapy with IFX therefore seems worthwhile to dose-optimize early enough and decrease long-term relapse and colectomy rates. The value of a tailored approach in patients receiving IFX therapy based on the serum levels (target between 3 and 7 mg/mL) currently is under investigation.24 In conclusion, we were able to confirm the short-term and long-term efficacy of IFX in both outpatients with refractory UC and patients with ASUC refractory to intravenous CS. Furthermore, we identified independent predictors of both long-term clinical relapse and need for colectomy, which were included in a risk panel. The application of this risk panel in daily clinical practice could help us to stratify patients before and early after initiation of IFX therapy. The observation of a better long-term outcome in patients with IFX serum levels greater than 2.5 mg/mL may guide treatment optimization before clinical relapse, but the benefit of such a tailored approach needs confirmation in a prospective setting.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2014.07.055.
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Reprint requests Address requests for reprints to: Marc Ferrante, MD, PhD, Department of Gastroenterology, University Hospitals Leuven, Herestraat 49, B3000 Leuven, Belgium. e-mail: [email protected]; fax: (32) 16-34-44-19. Acknowledgments The authors thank Vera Ballet and Griet Compernolle for maintaining the patient database and performing the enzyme-linked immunosorbent assays. Conflicts of interest These authors disclose the following: Séverine Vermeire, Gert Van Assche, and Marc Ferrante received grant support from Merck, Janssen Biologics, Abbvie, and UCB. Niels Vande Casteele has been a consultant for Merck and Janssen Biologics; Séverine Vermeire has received financial support for research from UCB Pharma, Merck, and Abbvie, has received lecture fees from Abbvie, Merck, Ferring, UCB Pharma, and Centocor; and has been a consultant for UCB Pharma, AstraZeneca, Ferring, Abbvie, Merck, Ferring, Shire, Pfizer, and MSD; Filip Baert has received lecture fees from Merck and Abbvie; Gert Van Assche has received financial support for research from Abbvie and Ferring, has received lecture fees from Janssen-Cilag, Merck, and Abbvie, and has been a consultant for PDL BioPharma, UCB Pharma, Sanofi-Aventis, Abbvie, Ferring, Novartis, Biogen Idec, Janssen Biologics, NovoNordisk, Zealand Pharma A/S, Millenium/Takeda, Shire, and BMS; Ann Gils has been a consultant for Merck, Janssen Biologics, and Abbvie; Paul Rutgeerts has received financial support for research from UCB Pharma, Abbvie, Janssen Biologics, Merck, Prometheus, and Bristol-Meyers Squibb; has received lecture fees from Abbvie and Merck, and has been a consultant for Amgen, Merck, UCB Pharma, Genentech, BMS, Abbvie, Janssen Biologics, Millenium, Neovacs, Actogenics, Prometheus, Pfizer, Falk Pharma, and Tillotts; and Marc Ferrante has received financial support for research from Janssen Biologics, has received lecture fees from Merck, Tillotts, Ferring, and Abbvie, and has been a consultant for Abbvie, Merck, and Janssen Biologics. The remaining authors disclose no conflicts. Funding This study was supported in part by the Research Foundation–Flanders, Belgium (G.0617.12). Niels Vande Casteele is a postdoctoral fellow, and Séverine Vermeire, Gert Van Assche, and Marc Ferrante are Senior Clinical Investigators for the Research Foundation–Flanders, Belgium.