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1100 Review article

Meta-analysis: efficacy and safety of combination therapy of infliximab and immunosuppressives for Crohn’s disease Ziwei Lina, Yu Baib and Ping Zhenga Although infliximab and immunosuppressives have both proved to be effective in the treatment of Crohn’s disease (CD), the efficacy and safety of the combination therapy remained undetermined yet. We performed a meta-analysis to evaluate the efficacy and safety of combination therapy of infliximab and immunosuppressives compared with monotherapy for maintaining steroid-free clinical remission on patients with CD. We searched PubMed, Cochrane Library, and EMBASE. The primary end point was steroid-free clinical remission after induction infusion and in short-term and long-term follow-ups. Total adverse events, severe adverse event, infection, severe infection, infusion reaction, sepsis, tuberculosis, and malignancy also were analyzed. Meta-analysis was carried out by combining the odds ratio (OR) between the combination therapy and monotherapy of the individual studies in a global OR, with statistical heterogeneity tested using the v2-test and the I2-test. Five studies with eight comparisons involving 1026 patients were included. In an overall analysis, combination therapy was more effective than monotherapy for induction of remission at weeks 10–12 [mean OR = 2.50; 95% confidence interval (CI) = 1.46–4.30; P = 0.0009)] and maintenance of remission at weeks 24–26 (mean OR = 2.32; 95% CI = 1.75–3.08; P < 0.00001) and weeks

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, which is defined by relapsing and remitting episodes with progression over time to complications of stricture, fistulas, or abscesses. American College of Gastroenterology guideline, 2009 [1] recommend initiating treatment with first-line agents, including mesalazine and systematic corticosteroids, followed by immunosuppressives, with infliximab reserved for patients in whom conventional therapies have failed. Infliximab was introduced into practice in 1998 and confirmed to be effective for induction and maintenance therapy in CD and immunosuppressives (such as azathioprine, 6-mercaptopurine, and methotrexate) were also an effective second-line treatment for CD. However, it remains to be determined about the efficacy and safety of the combination therapy of infliximab and immunosuppressives comparing with monotherapy of infliximab or immunosuppressives. No meta-analysis of its efficacy and safety is available. The aim of this study was to evaluate the efficacy and safety of combination therapy of infliximab and immunosuppressives in CD with a meta-analytic approach based on perspective studies. c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X

48–54 (mean OR = 1.83; 95% CI = 1.44–2.32; P < 0.00001). In all five studies, combination therapy did not increase the risk of total adverse event, severe adverse event, infection, severe infection, and infusion reaction. The combination therapy of infliximab and immunosuppressives was more effective than monotherapy in the induction and maintenance remission of CD, and adverse events did not increase. However, larger clinical trials with longer follow-up are warranted to further assess the efficacy and safety profile of combination therapy. Eur J Gastroenterol c 2011 Wolters Kluwer Health | Hepatol 23:1100–1110 Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2011, 23:1100–1110 Keywords: combination therapy, Crohn’s disease, immunosuppressives, infliximab a Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University and bDepartment of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China

Correspondence to Dr Ping Zheng, MD, Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 100 Haining Road, Shanghai 200080, China Tel: +86 21 63240090; fax: +86 21 63241377; e-mail: zhengpingdoctor@126.com Received 31 March 2011 Accepted 23 July 2011

We carried out a meta-analysis to compare the combination therapy with the monotherapy in induction and maintenance remission by comparing studies with similar designs. The safety profile was also analyzed in this review.

Methods Inclusion/exclusion criteria

Studies were included if they met the following criteria: (a) studies that evaluate the efficacy or safety of the combination therapy of infliximab and immunosuppressives for CD; (b) studies that are published as a full article; and (c) patients with diagnosis of CD. Studies were excluded if: (a) it is a review, comment, lecture, researches which cannot be extracted with statistic data; (b) patients are under 18 years, pregnant, hypersensitive to infliximab, with systemic disease, with gastrointestinal disease, and who were given biological treatment previously. Literature search results

We performed a search of the PubMed, Cochrane Library, and EMBASE up to December 2010. A search strategy DOI: 10.1097/MEG.0b013e32834b9544

Meta-analysis: combination IFX and ISS for CD Lin et al. 1101

was constructed by using a combination of the following words: infliximab and (azathioprine, 6-mercaptopurine, methotrexate, immunosuppresives, or immunomodulator) and CD. Articles published in any language were included. Reference lists from the trials selected by electronic searching were handsearched to identify further relevant studies. Finally, we identified five potentially eligible articles [2–7]. For efficacy, of the five studies that fulfilled the inclusion criteria, three trials (by Colombel et al. [2], ACCENT I (ClinicalTrials.gov number, NCT00207662) [5,6], and ACCENT II (ClinicalTrials.gov number, NCT00207766) [5,7]) had each studied three cohorts (combining group, infliximab group, and azathioprine group), which two comparisons could be extracted and finally five studies with eight comparisons were included; three(by Colombel et al. [2], Lemann et al. [3], and Schro¨der et al. [4]) of the five studies could be extracted with both induction and maintenance remission data, whereas the other two studies(ACCENT I and ACCENT II trials) could only be extracted with long-term maintenance remission data. Four comparisons compared the combination therapy with infliximab, whereas the other four comparisons compared the combination therapy with immunosuppressives. For safety, the same five studies were included. However, data of immunosuppressives monotherapy were not available in the ACCENT I and ACCENT II trials, therefore only six comparisons were included in the safety analysis. We originally planned to evaluate the total adverse event, severe adverse event, infection, severe infection, infusion reaction, sepsis, tuberculosis, and malignancy. However, in Lemann et al.’s study [3], some of the adverse events were reported in a number of events instead of in a number of patients. In a study conducted by Schro¨der et al. [4], data of infusion reaction, sepsis, and tuberculosis were not available and in the ACCENT I and ACCENT II trials [5], data of total adverse event, severe adverse event, sepsis, tuberculosis, and malignancy were not available. We contacted the authors by email, but received no response. Therefore, we only conducted a meta-analysis of total adverse event, severe adverse event, infection, severe infection, and infusion reaction at last. The quality of the studies was assessed using the score proposed by Jadad et al. [8] based on three items: (a) randomization; (b) double blinding; and (c) description of withdrawals and dropouts. The items were presented as questions to elicit yes or no answers. Points awarded for items 1 and 2 depended on the quality of the description of the methods to generate the sequence of randomization and/or on the quality of the description of the method of double blinding. The third item, withdrawals and dropouts, was awarded as zero points for a negative answer. For a positive answer, the number of withdrawals and dropouts and the reasons had to be stated in each of

the comparison groups. Two of the studies (by Colombel et al. [2], Lemann et al. [3]) scored five points in Jadad et al. score [8], one (by Schro¨der et al. [4]) was three points for its open-labeled design, and the remaining two (ACCENT I [6] and ACCENT II [7]) was one point for its open-labeled and nonblinding design about the administration of immunosuppressives. Outcome measure

The efficacy end points were steroid-free clinical remission at weeks 10–12, weeks 24–26, and weeks 48–54. Weeks 10–12 were chosen because the induction infusion has just finished and it was suitable for evaluation of the short-term induction remission. Data of weeks 24–26 and weeks 48–54 were extracted for the evaluation of shortterm and long-term remission, respectively. For safety, we analyzed total adverse event, severe adverse event, infection, severe infection, sepsis, tuberculosis, and malignancy. A severe adverse event was defined as any untoward medical occurrence that at any dose resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect. Severe infection was defined as infection requiring antimicrobial therapy or hospitalization. Statistical analysis

For efficacy, we analyzed all the studies in three intervals (weeks 10–12, weeks 24–26, and weeks 48–54) with two subgroups (the combination therapy vs. infliximab, the combination therapy vs. immunosuppressives) in each interval. For safety, we performed an overall analysis of all studies on total adverse event, severe adverse event, infection, severe infection, and infusion reaction. The intention-to-treat (ITT) method, which includes in the analysis all patients who received at least one dose of anti-tumor necrosis factor or immunosuppressives, was used. When clinical remission rate was reported as a percentage, the number of patients with clinical remission was extrapolated from the total number of patients. Meta-analysis was performed by combining the ORs between the combination therapy and monotherapy of the individual studies in a global OR, with statistical heterogeneity tested using the w2-test and the I2-test, and P value of less than 0.10 or I2 value of more than 50% was considered to have substantial heterogeneity. A fixedeffects model was used when the heterogeneity test showed a P value of more than 0.10 and I2 value of less than 50%; if not, a random-effects model was used. We also performed the funnel plot graph, the Begg and Egger tests to evaluate for presence of publication bias. All analyses were conducted using RevMan 4.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2006) and Stata/SE 11.0 (StataCorp LP. 2009)

1102 European Journal of Gastroenterology & Hepatology 2011, Vol 23 No 12

Results

(2–3 mg/kg/day) or 6-mercaptopurine (1–1.5 mg/kg/day) were given at a stable dose except for leucopenia or transaminase increases. At baseline, all patients were treated with predisone (> 10mg/day) for 2 weeks, which were then tapered if there was a clinical remission (Crohn’s Disease Activity Index r 150) or increased if there was a relapse. Two patients allocated to the monotherapy group were not enrolled and did not receive the first infusion; therefore, we excluded them in our analysis according to the ITT method. Clinical remission rate was reported as a percentage in this trial; therefore, we extrapolated the number of patients with clinical remission from the total number.

Efficacy results

Five studies with eight comparisons involving 1026 patients were included (Table 1). There were 318 patients treated with infliximab combining immunosuppressives, 408 patients treated with infliximab alone, and 300 patients treated with immunosuppressives alone. Immunosuppressives included were azathioprine, 6-mercaptopurine, and methotrexate. In a randomized, double-blind, controlled trial conducted by Colombel et al. [2], all patients were naı¨ve to immunosuppressives and were either corticosteroid dependent or did not have a response to mesalazine or budesonide. Infliximab (5 mg/kg) were given at weeks 0, 2, and 6, and then every 8 weeks in combination therapy and infliximab groups. Oral azathioprine was given at a daily dose of 2.5 mg/kg in azathioprine group and combination therapy groups. Steroids were tapered after week 14. Corticosteroid-free clinical remission was defined as clinical remission in patients who had not received budesonide at a daily dose of more than 6 mg or systemic corticosteroids for at least 3 weeks. Five patients (one in azathioprine group, three in infliximab group, and one in combination therapy group) who underwent randomization but did not receive a study drug were excluded in our analysis though the investigator included them. After week 30, eight patients from the infliximab group, seven patients from the azathioprine group, and 16 patients from the combination therapy group refused to enter the trial extension of 20 weeks. The investigator kept the week 26 status carried forward through week 50 for patients who did not enter the trial extension. However, in our analysis, we assumed that they did not reach the end point through week 50 for the ITT principle.

In a randomized, open-label, controlled trial conducted by Schro¨der et al. [4], patients included were dependent or resistant to corticosteroids and resistant or intolerant to azathioprine. Infliximab (5 mg/kg) was given at weeks 0 and 2. Patients randomly assigned to be treated with concomitant methotrexate also received six injections of methotrexate (20 mg) at weeks 0–5, followed by weekly oral methotrexate at a dosage of 20 mg for 48 weeks. Patients receiving predisolone had to maintain a stable dose for 4 weeks, after which a defined tapering schedule was initiated in the case of an improvement in the patient’s condition. In ACCENT I [6], all patients received an infusion of infliximab (5 mg/kg) at week 0. Patients were assessed for clinical response at week 2 and randomly assigned to either placebo infusions at weeks 2, 6, and then every 8 weeks until week 46; infliximab 5 mg/kg at the same time points; or infliximab (5 mg/kg) at weeks 2 and 6 followed by a dose of 10 mg/kg every 8 weeks until week 46. At or beyond week 14, patients who lost response were eligible for crossover from placebo to episodic treatment with infliximab (5 mg/kg), or from their assigned infliximab maintenance dose to an episodic dose of 5 mg/kg or higher.

In a randomized, double-blind, placebo-controlled trial conducted by Lemann et al. [3], 59 patients were naı¨ve to immunosuppressives, and 56 patients were failed with the immunosuppressive therapy. infliximab (5 mg/kg) were given at 0, 2, and 6 weeks for combining group, without a maintenance therapy; and azathioprine Table 1

For the four studies above, steroid-free clinical remission was defined as a score of less than 150 on the Crohn’s Disease Activity Index without systematic corticosteroid.

Characteristics of randomized controlled trials evaluating efficacy at weeks 10–14, 20–30, and 48–52 Steroids-free clinic remission or complete fistula response

Reference

Molecule

Colombel et al. [2] Infliximab Azathioprine Infliximab+azathioprine Lemann et al. [3] Azathioprine /6-mercaptopurine Infliximab+azathioprine /6-mercaptopurine Schro¨der et al. [4] Infliximab Infliximab+methotrexate ACCENT I [5,6] Infliximab Azathioprine/6-mercaptopurine /methotrexate Infliximab+azathioprine/6-mercaptopurine /methotrexate ACCENT II [5,7] Infliximab Azathioprine /6-mercaptopurine /methotrexate Infliximab+azathioprine /6-mercaptopurine /methotrexate

Duration Patients included (weeks) in the study 50 50 50 52 52 48 48 54 54 54 54 54 54

166 169 168 56 57 8 11 171 39 54 63 36 28

Weeks 10–14

Weeks 20–30

Weeks 48–52

63 41 79 21 41 4 9

75 51 96 15 31 3 6

59 41 78 11 22 2 5 55 8 20 24 7 9

(weeks (weeks (weeks (weeks (weeks (weeks (weeks NA NA NA NA NA NA

10) 10) 10) 12) 12) 12) 12)

(weeks (weeks (weeks (weeks (weeks (weeks (weeks NA NA NA NA NA NA

26) 26) 26) 24) 24) 24) 24)

(weeks (weeks (weeks (weeks (weeks (weeks (weeks (weeks (weeks (weeks (weeks (weeks (weeks

50) 50) 50) 52) 52) 48) 48) 54) 54) 54) 54) 54) 54)

NA, not available.

Meta-analysis: combination IFX and ISS for CD Lin et al. 1103

In ACCENT I [6] and ACCENT II [7], the dose of concomitant immunosuppressives remained constant as the patients entered the trials, whereas corticosteroids was to be tapered according to a defined schedule. Therefore, though the two trials were designed as randomized, openlabel, controlled trials, the part of immunosuppressives administration was not. Patients who crossed over to higher doses of infliximab in the two trials and patients with prohibited changes in concomitant medications, prohibited surgeries, discontinuation of study agent for lack of

In ACCENT II [7], all patients received intravenous infusions of infliximab (5 mg/kg) at weeks 0, 2 and 6. Patients were assessed for fistula response at weeks 10 and 14 and randomized at week 14 to receive placebo or infliximab (5 mg/kg) every 8 weeks through to week 46. At or beyond week 22, patients who lost response were eligible for crossover from placebo to infliximab (5 mg/ kg), or from infliximab dose 5 mg/kg to 10 mg/kg. Complete fistula response was defined as the absence of any draining fistulas.

Fig. 1

(a)

Review: Comparison: Outcome: Study or subcategory

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 01 Efficacy of combination therapy vs. monotherapy 01 Efficacy result at weeks 10–12 Combining therapy n/N

Monotherapy n/N

OR (random) 95% CI

Weight %

OR (random) 95% CI

4/8 63/166 174

6.00 35.85 41.84

4.50 [0.57–35.52] 1.45 [0.94–2.24] 1.60 [0.86–2.97]

21/56 41/169 225

23.39 34.77 58.16

4.27 [1.94–9.42] 2.77 [1.74–4.41] 3.10 [2.07–4.62]

399

100.00

2.50 [1.46–4.30]

01 Combination therapy vs. infliximab 9/11 Schröder et al. [4] 79/168 Colombel et al. [2] 179 Subtotal (95% CI) Total events: 88 (combining therapy), 67 (monotherapy) 2 2 Test for heterogeneity: = 1.10, df = 1 (P = 0.29), I = 9.4% Test for overall effect: Z = 1.48 (P = 0.14) 02 Combination therapy vs. immunosuppressives 41/57 Lemann et al. [3] 79/168 Colombel et al. [2] Subtotal (95% CI) 225 Total events: 120 (combining therapy), 62 (monotherapy) 2 2 Test for heterogeneity: = 0.85, df = 1 (P = 0.36), I = 0% Test for overall effect: Z = 5.53 (P < 0.00001) Total (95% CI) 404 Total events: 208 (combining therapy), 129 (monotherapy) 2 2 Test for heterogeneity: = 7.60, df = 3 (P = 0.05), I = 60.5% Test for overall effect: Z = 3.32 (P = 0.0009)

0.1 0.2 0.5 Favors monotherapy

(b)

Review: Comparison: Outcome: Study or subcategory

2 5 10 Favors combining

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 01 Efficacy of combination therapy vs. monotherapy 02 Efficacy result at weeks 24–26 Combining therapy n/N

01 Combination therapy vs. infliximab Schröder et al. [4] 6/11 96/168 Colombel et al. [2] Subtotal (95% CI) 179 Total events: 102 (combining therapy), 78 (monotherapy) Test for heterogeneity: 2 = 0.05, df = 1 (P = 0.83), I 2 = 0% Test for overall effect: Z = 2.29 (P = 0.02) 02 combination therapy vs. immunosuppresives Lemann et al. [3] 31/57 Colombel et al. [2] 96/168 Subtotal (95% CI) 225 Total events: 127 (combining therapy), 66 (monotherapy)

Monotherapy n/N

OR (fixed) 95% CI

Weight %

OR (fixed) 95% CI

3/8 75/166 174

2.52 51.65 54.17

2.00 [0.31–12.84] 1.62 [1.05–2.49] 1.64 [1.07–2.49]

15/56 51/169 225

11.02 34.81 45.83

3.26 [1.48–7.17] 3.08 [1.97–4.83] 3.13 [2.12–4.62]

399

100.00

2.32 [1.75–3.08]

2 2 Test for heterogeneity: = 0.01, df = 1 (P = 0.91), I = 0%

Test for overall effect: Z = 5.73 (P < 0.00001) Total (95% CI) 404 Total events: 229 (combining therapy), 144 (monotherapy) 2 2 Test for heterogeneity: = 4.96, df = 3 (P = 0.17), I = 39.5%

Test for overall effect: Z = 5.80 (P < 0.00001) 0.1

0.2

0.5

Favors monotherapy Favors combining

Overall analysis of studies evaluating the efficacy of the combination therapy of infliximab and immunosuppresives for induction remission at weeks 10–12 (a), and maintenance remission at weeks 24–26 (b) and weeks 48–54 (c). CD, Crohn’s disease; CI, confidence interval; OR, odds ratio.

1104 European Journal of Gastroenterology & Hepatology 2011, Vol 23 No 12

(c)

Review:

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001)

Comparison:

01 Efficacy of combination therapy vs. monotherapy

Outcome:

03 Efficacy result at weeks 48–54

Study or subcategory

Combination therapy n/N

Monotherapy n/N

01 Combination therapy vs. infliximab Accent I 20/54 9/28 Accent II 5/11 Schröder et al. [4] 78/168 Colombel et al. [2] Subtotal (95% CI) 261 Total events: 112 (combination therapy), 140 (monotherapy) 2 Test for heterogeneity: = 2.26, df = 3 (P = 0.52), I 2 = 0% Test for overall effect: Z = 1.84 (P = 0.07)

OR (fixed) 95% CI

Weight %

OR (fixed) 95% CI

55/171 24/63 2/8 59/166 408

16.89 10.18 1.28 32.31 60.66

1.24 0.77 2.50 1.57 1.36

[0.65–2.35] [0.30–1.97] [0.34–18.33] [1.01–2.44] [0.98–1.90]

8/39 7/36 11/56 41/169 300

5.94 4.22 6.92 22.25 39.34

2.28 1.96 2.57 2.71 2.54

[0.88–5.91] [0.62–6.16] [1.10–6.00] [1.70–4.30] [1.78–3.62]

708

100.00

02 combination therapy vs. immunosppressives 20/54 Accent I 9/28 Accent II 22/57 Lemann et al. [3] 78/168 Colombel et al. [2] Subtotal (95% CI) 307 Total events: 129 (combination therapy), 67 (monotherapy) 2 2 Test for heterogeneity: = 0.32, df = 3 (P = 0.96), I = 0% Test for overall effect: Z = 5.13 (P < 0.00001) Total (95% CI) 568 Total events: 241 (combination therapy), 207 (monotherapy) 2 2 Test for heterogeneity: = 8.78, df = 7 (P = 0.27), I = 20.3% Test for overall effect: Z = 4.92 (P < 0.00001)

0.1

0.2

0.5

Favors monotherapy

1.83 [1.44–2.32]

Favors combining

Fig 1. (Continued ).

efficacy, or insufficient data in all studies were considered not to be in clinical remission or complete fistula response. Besides, data of induction remission and short-term maintenance remission was not available. We have tried to contact the authors by email, but received no response. Induction remission

In overall analysis, combination therapy was more effective than monotherapy for induction of remission (Fig. 1a) at weeks 10–12. OR and 95% CI were 2.50 and 1.46–4.30 (P = 0.0009), respectively. Subgroups analysis was performed to assess the specific effects of combination therapy comparing with infliximab and immunosuppressives, respectively, which also favored combination therapy. Exclusion of any of the comparisons did not change the overall efficacy of combination therapy. Maintenance remission

In overall analysis, combination therapy was more effective than monotherapy at weeks 24–26 (Fig. 1b) and weeks 48–54 (Fig. 1c). OR and 95% CI were 2.32 and 1.75–3.08 (P < 0.00001) at weeks 24–26, and 1.83 and 1.44–2.32 (P < 0.00001) at weeks 48–54, respectively. The subgroup analysis also favored combination therapy. Exclusion of any of the comparisons did not change the overall efficacy of combination therapy. Statistical heterogeneity between trials and publication bias

By using the Cochrane Q-test, statistical heterogeneity was only found for weeks 10–14 (P = 0.05, I2 = 60.5%), and no statistical heterogeneity was found in its subgroups (P = 0.29, I2 = 9.4%, and P = 0.36, I2 = 0%,

respectively). Therefore, we performed a random-effects model for weeks 10–12 and a fixed-effect model for weeks 24–26 and weeks 48–54. Funnel plots performed for remission at weeks 10–12, weeks 24–26, and weeks 48–54 (Fig. 2), respectively, were roughly symmetrical, and the Begg and Egger tests also suggested the absence of publication bias (P = 0.586, 0.741, 0.863, respectively). Safety results

Five studies with six comparisons involving 1158 patients were included (Table 2). There were 396 patients in the combination therapy group, 545 patients in the infliximab monotherapy group, and 217 patients in the immunosupressives monotherapy group. The median follow-up was 51.6 weeks (range 48–54 weeks) for the five trials included in safety analysis. In a study conducted by Colombel et al. [2], the safety population for the combination therapy group included 11 patients who were assigned to one of the monotherapy groups but inadvertently given at least one dose of each therapy (eight patients in the azathioprine group and three in the infliximab group). In a study conducted by Lemann et al. [3], adverse events were reported in a number of events, instead of in a number of persons as the other two studies. Therefore, we only extracted part of the data (total adverse event, severe adverse event, infusion reaction, malignancy) for analysis. In the ACCENT I and ACCENT II trial [5], data of total adverse event, severe adverse event, sepsis, tuberculosis and

Meta-analysis: combination IFX and ISS for CD Lin et al. 1105

Fig. 2 Review: Comparison: Outcome:

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 01 Efficacy of combination therapy vs. monotherapy 01 Efficacy result at weeks 10–12

Review: Comparison: Outcome:

(b)

0.0

0.4

0.2 SE(log OR)

SE(log OR)

(a)

0.8

1.2

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 01 Efficacy of combination therapy vs. monotherapy 02 Efficacy result at weeks 24–26

0.4

0.6

0.8

1.6

0.1

0.2

0.5

1 OR (fixed)

Review: Comparison: Outcome:

(c)

0.1

0.5

0.2

1 OR (fixed)

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 01 Efficacy of combination therapy vs. monotherapy 03 Efficacy result at weeks 48–54

0.0

SE(log OR)

0.4

0.8

1.2

1.6

0.1

0.2

0.5

OR (fixed)

Funnel plot of randomized controlled trials evaluating the efficacy of the combination therapy of infliximab and immunosuppresives for induction remission at weeks 10–14 (a), and maintenance remission at weeks 24–26 (b), and weeks 48–54 (c). CD, Crohn’s disease; OR, odds ratio.

Table 2

Characteristics of randomized controlled trials evaluating safety Adverse events Patients included in the study

Total adverse event

Severe adverse event

Infliximab

163

145

Azathioprine infliximab+azathioprine Azathioprine/6-mercaptopurine

161 179 56

144 161 28

42 37 3

73 75 NA

9 7 NA

9 9 0

1 0 NA

0 1 NA

2 0 0

Azathioprine/6-mercaptopurine +infliximab Infliximab

11 282 103

7 NA NA

0 NA NA

6 143 51

0 11 3

NA 92 17

NA NA NA

0 NA NA

Reference Colombel et al. [2]

Lemann et al. [3]

Schro¨der et al. [4]

Molecule

Infliximab+methotrexate ACCENT I [5,6] Infliximab Infliximab+azathioprine/ 6-mercaptopurine /methotrexate ACCENT II Infliximab [5,7] Infliximab+azathioprine / 6-mercaptopurine /methotrexate

Severe Infusion Infection infection reaction Sepsis Tuberculosis Malignancy

NA, not available.

malignancy were not available. The incidence of infections, severe infections, and infusion reaction were summarized using the total number of maintenance-treated patients.

Besides, data of patients randomized to the placebo maintenance groups were available; therefore, we failed to extract the data of the immunosuppressives monotherapy group.

1106 European Journal of Gastroenterology & Hepatology 2011, Vol 23 No 12

Total adverse events

In overall analysis, there was no significant difference in the frequency of total adverse events between combination therapy and monotherapy (OR = 1.07; 95% CI = 0.72–1.59; P = 0.75; Fig. 3a). In subgroup analysis, the difference between combination therapy and infliximab or immunosuppressives was not significant either. Other adverse events

In overall analysis, there was no significant difference in the frequency of severe adverse event (OR = 0.91; 95% CI = 0.64–1.30; P = 0.61; Fig. 3b), infection (OR = 0.88;

95% CI = 0.69–1.11; P = 0.27; Fig. 3c), severe infection (OR = 0.68; 95% CI = 0.37–1.24; P = 0.21; Fig. 3d), and infusion reaction (OR = 0.58; 95% CI = 0.31–1.08; P = 0.08; Fig. 3e) between combination therapy and monotherapy. The subgroup analysis of severe adverse event, infection, and severe infection showed no difference between the two groups. However, the combination therapy versus infliximab subgroup in the infusion reaction analysis seemed to favor the combination therapy group (OR = 0.48; 95% CI = 0.23–1.00; P = 0.05). Lacking of data, we failed to make an analysis of the risk of sepsis, tuberculosis, and malignancy.

Fig. 3

(a)

Review: Comparison: Outcome: Study or subcategory

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 02 Safety of combination therapy vs. monotherapy 01 Total adverse events Combining therapy n/N

01 Combining therapy vs. infliximab Schröder et al. [4] 7/11 Colombel et al. [2] 161/179 190 Subtotal (95% CI) Total events: 168 (combining therapy), 150 (monotherapy) Test for heterogeneity: 2 = 0.00, df = 1 (P = 0.96), I 2 = 0% Test for overall effect: Z = 0.30 (P = 0.77) 02 Combining therapy vs. immunosuppressives Lemann et al. [3] 29/57 Colombel et al. [2] 161/179 Subtotal (95% CI) 236 Total events: 190 (combining therapy), 172 (monotherapy) Test for heterogeneity: 2 = 0.00, df = 1 (P = 0.97), I 2 = 0% Test for overall effect: Z = 0.17 (P = 0.86) Total (95% CI) 426 Total events: 358 (combining therapy), 322 (monotherapy) 2 Test for heterogeneity: = 0.02, df = 3 (P = 1.00), I 2 = 0% Test for overall effect: Z = 0.32 (P =0.75)

Monotherapy n/N

OR (fixed) 95% CI

4.53 32.83 37.36

1.05 [0.16–6.92] 1.11 [0.56–2.22] 1.10 [0.58–2.11]

28/56 144/161 217

29.85 32.80 62.64

1.04 [0.50– 2.17] 1.06 [0.52–2.13] 1.05 [0.63–1.74]

388

100.00

1.07 [0.72–1.59]

0.2

0.5

Study or subcategory

Favors monotherapy

Favors combining Review: Comparison: Outcome:

OR (fixed) 95% CI

5/8 145/163 171

0.1

(b)

Weight %

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 02 Safety of combination therapy vs. monotherapy 02 Severe adverse events Combining therapy n/N

01 Combining therapy vs. infliximab Schröder et al. [4] 0/11 Colombel et al. [2] 37/179 Subtotal (95% CI) 190 Total events: 37 (combining therapy), 30 (monotherapy) 2 2 Test for heterogeneity: = 0.99, df = 1 (P = 0.32), I = 0% Test for overall effect: Z = 0.49 (P = 0.63) 02 Combining therapy vs. immunosuppressives Lemann et al. [3] 3/57 Colombel et al. [2] 37/179 236 Subtotal (95% CI) Total events: 40 (combining therapy), 45 (monotherapy) 2 2 Test for heterogeneity: = 0.11, df = 1 (P = 0.75), I = 0% Test for overall effect: Z = 1.13 (P = 0.26) Total (95% CI) 426 Total events: 77 (combining therapy), 75 (monotherapy) 2 2 Test for heterogeneity: = 2.41, df = 3 (P = 0.49), I = 0% Test for overall effect: Z = 0.51 (P = 0.61)

Monotherapy n/N

OR (fixed) 95% CI

Weight %

OR (fixed) 95% CI

1/8 29/163 171

2.58 37.82 40.40

0.22 [0.01–6.07] 1.20 [0.70–2.07] 1.14 [0.67–1.94]

3/56 42/161 217

4.50 55.10 59.60

0.98 [0.19–5.08] 0.74 [0.45–1.22] 0.76 [0.47–1.23]

388

100.00

0.91 [0.64–1.30]

0.1 0.2 0.5 Favors combining

2 5 10 Favors monotherapy

Overall analysis of randomized controlled trials evaluating the total adverse events (a), severe adverse events (b), infections (c), severe infection (d), and infusion reactions (e), of the combination therapy of infliximab and immunosuppresives for Crohn’s disease (CD). CI, confidence interval; OR, odds ratio.

Meta-analysis: combination IFX and ISS for CD Lin et al. 1107

(c)

Review: Comparison: Outcome: Study or sub category

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 02 Safety of combination therapy vs. monotherapy 03 Infection Combining therapy n/N

01 Combining therapy vs. infliximab Accent I 51/103 21/46 Accent II 6/11 Schröder et al. [4] 75/79 Colombel et al. [2] 339 Subtotal (95% CI) Total events: 153 (combining therapy), 272 (monotherapy) Test for heterogeneity: 2 = 2.80, df = 3 (P = 0.42), I 2 = 0% Test for overall effect: Z = 0.91 (P = 0.36) 02 Combining therapy vs. immunosuppressives 75/179 Colombel et al. [2] 179 Subtotal (95% CI) Total events: 75 (combining therapy), 73 (monotherapy) Test for heterogeneity: not applicable Test for overall effect: Z = 0.64 (P = 0.52) 518 Total (95% CI) Total events: 228 (combining therapy), 345 (monotherapy) Test for heterogeneity: 2 = 2.80, df = 4 (P = 0.59), I 2 = 0% Test for overall effect: Z =1.11 (P = 0.27)

Monotherapy n/N

OR (fixed) 95% CI

25.96 12.66 0.71 30.66 69.99

0.95 0.65 3.60 0.85 0.88

73/161 161

30.01 30.01

0.87 [0.57–1.34] 0.87 [0.57–1.34]

706

100.00

0.88 [0.69–1.11]

0.2

0.5

Favors combining

Review: Comparison: Outcome: Study or sub category

OR (fixed) 95% CI

143/282 52/92 2/8 75/163 545

0.1

(d)

Weight %

[0.61–1.50] [0.32–1.32] [0.49–26.40] [0.55–1.30] [0.66–1.16]

Favors monotherapy

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 02 Safety of combination therapy vs. monotherapy 04 Severe infection Combining therapy n/N

01 Combining therapy vs. infliximab Accent I 3/103 Accent II 0/46 Schröder et al. [4] 0/11 7/179 Colombel et al. [2] 339 Subtotal (95% CI) Total events: 10 (combining therapy), 23 (mono) 2 Test for heterogeneity: = 0.71, df = 2 (P = 0.70), I 2 = 0% Test for overall effect: Z = 1.03 (P = 0.30)

OR (fixed) 95% CI

Mono n/N

Weight %

OR (fixed) 95% CI

11/282 4/92 0/8 8/163 545

22.10 11.56 31.12 64.78

0.74 [0.20–2.70] 0.21 [0.01–4.01] Not estimable 0.79 [0.28–2.22] 0.67 [0.31–1.44]

9/161 161

35.22 35.22

0.69 [0.25–1.89] 0.69 [0.25–1.89]

706

100.00

0.68 [0.37–1.24]

02 Combining therapy vs. immunosuppressives 7/179 Colombel J.F. 2 179 Subtotal (95% CI) Total events: 7 (combining therapy), 9 (mono) Test for heterogeneity: not applicable Test for overall effect: Z = 0.73 (P = 0.47) 518 Total (95% CI) Total events: 17 (combining therapy), 32 (mono) Test for heterogeneity: 2 = 0.70, df = 3 (P = 0.87), I 2 = 0% Test for overall effect: Z = 1.26 (P = 0.21)

0.1 0.2 0.5 Favors combining

(e)

Review: Comparison: Outcome: Study or sub category

1 2 5 10 Favors monotherapy

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 02 Safety of combination therapy vs. monotherapy 05 Infusion reaction Combining therapy n/N

01 Combining therapy vs. infliximab 17/103 Accent I 8/46 Accent II 9/179 Colombel et al. [2] 328 Subtotal (95% CI) Total events: 34 (combining therapy), 133 (monotherapy) 2 Test for heterogeneity: = 5.71, df = 2 (P = 0.06), I 2 = 64.9% Test for overall effect: Z = 1.95 (P = 0.05)

Monotherapy n/N

Weight %

OR (random) 95% CI

92/282 14/92 27/163 537

30.18 20.86 24.65 75.69

0.41 1.17 0.27 0.48

0/56 9/161 217

3.41 20.90 24.31

3.00 [0.12–75.22] 0.89 [0.35–2.31] 0.98 [0.40–2.45]

754

100.00

0.58 [0.31–1.08]

[0.23–0.73] [0.45–3.04] [0.12–0.59] [0.23–1.00]

02 Combining therapy vs. immunosuppressives 1/57 Lemann et al. [3] Colombel et al. [2] 9/179 Subtotal (95% CI) 236 Total events: 10 (combining therapy), 9 (monotherapy) Test for heterogeneity: 2 = 0.50, df = 1 (P = 0.48), I 2 = 0% Test for overall effect: Z = 0.03 (P = 0.97) 564 Total (95% CI) Total events: 44 (combining therapy), 142 (monotherapy) 2 Test for heterogeneity: = 8.64, df = 4 (P = 0.07), I 2 = 53.7% Test for overall effect: Z = 1.73 (P = 0.08)

0.1

0.2

0.5

Favors combining

Favors monotherapy

Fig 3. (Continued ).

Statistical heterogeneity between trials and publication bias

By using the Cochran Q test, no heterogeneity was found in the total adverse event (P = 1.00, I2 = 0%), the severe

adverse event (P = 0.49, I2 = 0%), infection (P = 0.59, I2 = 0%), and severe infection analysis (P = 0.87, I2 = 0%), then a fixed-effect model was performed. While heterogeneity was found in the infusion reaction analysis

1108 European Journal of Gastroenterology & Hepatology 2011, Vol 23 No 12

Fig. 4 Review: Comparison: Outcome:

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 02 Safety of combination therapy vs. monotherapy 01 Total adverse events

(b)

0.0

0.2

0.4

0.6

0.1

(c)

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 02 Safety of combination therapy vs. monotherapy 02 Severe adverse events

0.8

1.2

1.6

0.8

0.2

Review: Comparison: Outcome:

0.5

1 OR (fixed)

0.1

Efficacy and Safety of combination of infliximab and immunosuppressives for CD (001) 02 Safety of combination therapy vs. monotherapy 03 Infection

(d)

Review: Comparison: Outcome:

0.0

0.4

0.4 SE (log OR)

SE (log OR)

Review: Comparison: Outcome:

0.0

SE (log OR)

(a)

0.8

1.2

0.5

1 OR (fixed)

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 02 Safety of combination therapy vs. monotherapy 04 Severe infection

0.8

1.2

1.6

0.1

0.2

0.5

0.1

0.2

0.5

(e)

OR (fixed)

OR (fixed) Review: Comparison: Outcome:

Efficacy and safety of combination of infliximab and immunosuppressives for CD (001) 02 Safety of combination therapy vs. monotherapy 05 Infusion reaction

0.0

SE (log OR)

0.4

0.8

1.2

1.6

0.1

0.2

0.5

1 OR (fixed)

Funnel plot of randomized controlled trials evaluating the total adverse event (a), severe adverse events (b), infections (c), severe infection (d), and infusion reactions (e), of the combination therapy of infliximab and immunosuppresives for Crohn’s disease (CD). OR, odds ratio.

(P = 0.07, I2 = 53.7%), and a random-effects model was performed. Funnel plots performed for the total adverse event, severe adverse event, infection and infusion reaction, respectively (Fig. 4), were roughly symmetrical. The Begg and Egger tests also suggested the absence of publication bias (P = 0.811, 0.64, 0.324, 0.158, respectively). However, a publication bias was present in the severe infection analysis (P = 0.095).

Discussion To the best of our knowledge, this is the first metaanalysis of combination therapy of infliximab with immunosuppressives for CD. Comparing with the monotherapy, the efficacy of combination therapy was about double for both induction and maintenance of steroids-free clinical remission and complete fistula response (OR = 2.50, 2.32, 1.83 at weeks 10–12, 24–26, 48–54, respectively). With subgroup

Meta-analysis: combination IFX and ISS for CD Lin et al. 1109

analysis, results still favored the combination therapy. The greater efficacy of combination therapy in our analysis may be partially due to the suppression of immunogenicity, as antibodies against infliximab shorten the duration of response [9]. It may also be due to the additive effects of the two drugs, which have been shown to share mechanisms of action, such as apoptosis [10]. Other evidence [11] suggested that the increase in 6thioguanine nucleotide (the active metabolites of azathioprine) level of greater than 400 pmol/8 108 erythrocytes was strongly related to a better tolerance and a favourable response to infliximab. Although we failed to collect the whole safety data, we could still observe a trend with those available numbers. Combination therapy did not increase the overall total adverse events, severe adverse events, infections, severe infection, and infusion reaction comparing with monotherapy. It even seemed to favor the combining therapy more than the infliximab monotherapy in the combining therapy versus infliximab subgroup analysis of infusion reaction (OR = 0.48; 95% CI = 0.23–1.00; P = 0.05). It may be due to the suppression of immunogenicity [9,12]. Lichtenstein GR had studies ACCENT I, ACCENT II, ACT I (Clinical Trials.gov number, NCT00036439), and ACT II (Clinical Trials.gov number, NCT00096655) trials, and found that patients who did not receive immunomodulators had a higher incidence of antibodies to infliximab compared with patients who received immunomodulators [5]. A publication bias was present in the severe infection analysis (P = 0.095), suggesting that the result of severe infection analysis should be considered. The risk of sepsis, tuberculosis, and malignancy in the two groups was similar. Definitive conclusions cannot be drawn because of the limited sample size. The enhanced efficacy of the combination therapy had already been observed in some retrospective studies for fistulizing CD [13–15], which demonstrated that concomitant and long-term immunomodulators therapy could prolong the effect of an initial infliximab therapy on perianal fistulas, and relapse could be successfully treated with repeated infusion. Counterviews were concluded in a retrospective study by Kinney et al. [16], which revealed no improved patient response (clinical response rate, dose reduction of prednisone, fistula response, and mean intervals between infliximab infusions) with concomitant use of immunomodulators and infliximab, despite a trend of decreased drug reactions. In another retrospective study by Regueiro et al. [17], concomitant immunomodulators had also been found invalid in preventing relapses of CD. However, all of the trials included in our metaanalysis are perspective study, and the overall result supported the view that combination therapy is safe and more effective. Therefore, we assumed that the counter results of the retrospective studies may be due to their nonrandomized and noncontrolled design. Besides, a recent RAND analysis by Melmed et al. [18] suggested that concomitant immunomodulators were appropriate for

those with extensive disease, shorter duration of disease, perianal involvement, prior surgery, females, and older patients (> 26 years), and inappropriate for young males, uncomplicated disease. Therefore, we assumed that the diverse baselines of the patients included in these studies could lead to diverse results. Besides the safety and better efficacy concluded in our study, the studies included also found other trends. In a study conducted by Schro¨der et al. [4], a clear trend was observed that patients assigned for treatment with infliximab and concomitant methotrexate achieved earlier remission than those receiving infliximab alone: the median time to achieve remission was 2 weeks (interquartile range, 2–12 weeks) in combination therapy group compared with 18 weeks (interquartile range, 7–48 weeks) in methotrexate group (P = 0.08). From the study by Lemann et al. [3], another trend was found that the immunosuppressive-naı¨ve group had a better remission rate compared with the immunosuppressive-failure group. For the sake of the small sample size, no statistical significance was reached. If the hypothesis is confirmed, it will serve as a good indication for patient selection of combination therapy. Besides the adverse events we observed, Schro¨der et al. [4] also found a clear trend towards more frequent adverse events in the methotrexate group known to be associated with this drug (abnormal liver function tests, fatigue, and headache). For the lack of similar observation, we failed to make a meta-analysis. Further studies are needed to confirm these results. Besides, we found a randomized controlled trial evaluating the efficacy and safety of combination therapy but with different design. In this randomized controlled trial by Assche et al. [19], patients enrolled were with controlled disease at least 6 months after the start of infliximab combined with immunosuppressives. In the Dis group, immunosuppressives were interrupted while infliximab was regularly given for 104 weeks; and in the Con group both of the drugs were continued at the same dose as before. They found a similar proportion of patients needed a change in infliximab dosing interval (Con 24/40 vs. Dis 22/40) or stopped infliximab therapy (Con 11/40 vs. Dis 9/40), and came to the conclusion that continuation of immunosuppressives beyond 6 months offered no clear benefit over scheduled infliximab monotherapy, while toxic effects had been reported. This conclusion was contrary to that of our analysis, which needed our serious consideration. We tried to include it in our analysis and our result remained unchanged, may be due to its small sample size. However, considering its clinical and statistical heterogeneity, we still excluded it. Considering both our result and the different opinions, we assumed that the combination therapy at the beginning followed by a withdrawal of the immunosuppressives will probably reach a better end with the lowest complication

1110 European Journal of Gastroenterology & Hepatology 2011, Vol 23 No 12

rate and highest efficacy. Oussalah et al. [20] identified three predictors of infliximab failure after azathioprine withdrawal: infliximab–azathioprine exposure duration of 881 days or more, C-reactive protein level of more than 5 mg/l, and platelet count of more than 298 109/l. Our assumption and the withdrawal time need to be furtherly confirmed by studies with longer follow-up duration and larger sample size. There are still limitations in our study. First of all, the quantity of studies included in our study is limited. More studies are needed to further support our conclusion. Second, some data for the efficacy and safety analysis are unavailable. We tried to contact the authors, but did not get an answer. Third, not all the confounding factors can be controlled in these studies and some important parameters, for example, the type of immunosuppressives (azathioprine, 6-mercaptopurine, or methotrexate), need to be considered in the assessment of efficacy and safety. For the sake of the limited quantity of studies, we failed to make a meta-analysis of each immuosuppressive. Lastly, there are differences in design between the three studies included. In ACCENT I, ACCENT II, and the study by Colombel et al. [2], infliximab was given regularly throughout the whole study, whereas in studies conducted by Lemann et al. [3] and Schro¨der et al. [4], infliximab was given only two to three times. However, no statistical heterogeneity was found in the maintenance analysis. Lemann et al. [3] considered the infusion of infliximab as a bridge, waiting for the delayed effect of immunosuppressives. But a potential drawback of the bridge strategy is that the interruption of infliximab after an induction scheme could facilitate the development of anti-infliximab antibody, and thus compromise a retreatment with infliximab, if necessary. Maybe with future studies, it can be decided which scheme is more effective.

References 1 2

Overall, the results of our meta-analysis demonstrated that combination therapy of infliximab and immunosuppressives is safe and more effective compared with monotherapy in patients with CD refractory to first-line therapy. However, further clinical trials with longer follow-up duration and larger sample size are required to better assess the efficacy and safety profile of combination therapy.

Acknowledgements

17 18

Declaration of personal interests: we are indebted to the authors of the primary studies. 20

Conflicts of interest

There are no conflicts of interest.

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