Efficacy and Safety of Natalizumab and Vedolizumab for the Management of Crohn's Disease: A Systematic Review and Meta-analysis.

CLINICAL REVIEW ARTICLE

Efficacy and Safety of Natalizumab and Vedolizumab for the Management of Crohn’s Disease: A Systematic Review and Meta-analysis Apoorva K. Chandar, MBBS, MPH,* ,† Siddharth Singh, MD,‡ Mohammad Hassan Murad, MD, MPH,§ Laurent Peyrin-Biroulet, MD, PhD,jj and Edward V. Loftus, Jr, MD‡

Background: We assessed the risk-benefit profile of anti-a4-integrins, natalizumab (NAT), and vedolizumab (VEDO), in Crohn’s disease through a systematic review and meta-analysis of randomized controlled trials.

Methods: We searched multiple electronic databases through July 2014 and identified 8 randomized controlled trials in adults with Crohn’s disease comparing NAT (5 trials) or VEDO (3 trials) with placebo. Efficacy outcomes were induction of remission, response, and improvement in quality of life; safety outcomes were serious adverse events, infusion reactions, infections, and treatment discontinuation. We performed subgroup analysis based on anti–tumor necrosis factor (TNF)-a exposure and estimated summary relative risk (RR) or mean difference, with 95% confidence intervals (CIs).

Results: Anti-a4-integrins were superior to placebo for induction of remission (RR, 0.87; 95% CI, 0.84–0.91), with similar estimates for NAT (RR, 0.86; 95% CI, 0.80–0.93) and VEDO (RR, 0.87; 95% CI, 0.79–0.95). Both NAT and VEDO were equally efficacious for anti-TNF-naive (NAT: RR, 0.87; 95% CI, 0.75–1.00; VEDO: RR, 0.86; 95% CI, 0.79–0.94) and anti-TNF-exposed patients (NAT: RR, 0.86; 95% CI, 0.76–0.99; VEDO: RR, 0.89; 95% CI, 0.78–1.01). Anti-a4-integrins were effective in inducing clinical response and improving quality of life, with no significant difference between NAT and VEDO. Rates of serious adverse events, infusion reactions, infections, and treatment discontinuation were similar for NAT and VEDO. No cases of progressive multifocal leukoencephalopathy have been observed with VEDO to date.

Conclusions: NAT and VEDO are effective in inducing remission and response in patients with Crohn’s disease, with similar efficacy in anti-TNFnaive and anti-TNF-exposed patients. (Inflamm Bowel Dis 2015;21:1695–1708) Key Words: Crohn’s disease, anti-integrin monoclonal antibodies, meta-analysis, inflammatory bowel disease, GRADE

C

rohn’s disease (CD) affects approximately 1 in 300 adults in the United States, with a rising global incidence.1 It is associated

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.ibdjournal.org). Received for publication December 13, 2014; Accepted January 27, 2015. From the *Division of Gastroenterology and Liver Diseases, Case Western Reserve University, Cleveland, Ohio; †Digestive Health Institute, University Hospitals Case Medical Center, Cleveland, Ohio; ‡Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; § Knowledge and Evaluation Research Unit, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota; and jj Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Université de Lorraine, Vandoeuvre-lès-Nancy, France. E. V. Loftus has consulted for and has received research support from Janssen Biotech, AbbVie, UCB Pharma, and Takeda. L. Peyrin-Biroulet has received consulting fees from Merck, Abbott, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB Pharma, Hospira, Celltrion, Takeda, Boerhinger-Ingelheim, and Lilly; lecture fees from Merck, Abbott, Janssen, Ferring, Norgine, Tillots, Vifor, Therakos, and HAC Pharma. The remaining authors have no conflicts of interest to disclose. Reprints: Siddharth Singh, MD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905 (e-mail: [email protected]). Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000373 Published online 7 April 2015.

Inflamm Bowel Dis Volume 21, Number 7, July 2015

with significant morbidity, with frequent hospitalizations, surgery, and need for corticosteroids and immunosuppressive medications, and often results in poor quality of life and loss of workplace productivity.2,3 There is also a substantial financial burden associated with CD, with direct medical costs exceeding $18,000 per patient per year in the United States.3 Biologic therapy with anti–tumor necrosis factor-a (anti-TNF) medications, alone or in combination with immunomodulators, is currently the preferred strategy in inducing and maintaining clinical remission in patients with moderate-to-severe CD, with multiple randomized controlled trials (RCTs) demonstrating efficacy over placebo.4–9 However, anti-TNF therapy is not universally effective, with approximately 30% to 40% being primary nonresponders; In addition, patients with initial clinical response may gradually lose response due to formation of antidrug antibodies or may not tolerate therapy.9,10 Alternative therapeutic strategies are urgently warranted. Active IBD is characterized by the recruitment of large numbers of granulocytes, lymphocytes, and macrophages into the gastrointestinal mucosa.11 The recruitment of leukocytes to gastrointestinal tissue is a highly coordinated multistep process, which is regulated by the expression of a4b1 and a4b7 integrins and chemokine receptor 9 on leukocytes, and adhesion molecules, such as www.ibdjournal.org |

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mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expressed on endothelial cells.12 Antiadhesion molecules, which block adhesion between leukocytes and the vascular endothelium, reduce leukocyte infiltration into the inflamed mucosa. Pivotal trials of 2 anti-a4-integrins, natalizumab (NAT) and vedolizumab (VEDO), have demonstrated efficacy in the induction and maintenance of remission in patients with CD.13,14 However, the magnitude of benefit in various aspects of patient care, including symptoms, quality of life, and adverse events (AEs), is not well summarized. A previous meta-analysis had addressed the efficacy of NAT for induction and maintenance of remission and safety, but it did not address important aspects of effect on clinical response, quality of life or the differential efficacy of NAT in anti-TNF-naive and anti-TNF-exposed patients.10 In addition, the study did not objectively assess the quality of evidence using standard Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.15 In this systematic review, we sought to comprehensively study the efficacy and safety of anti-a4-integrins approved for clinical use in adult patients with CD, through a meta-analysis of RCTs comparing these agents to placebo or other active agents. In particular, we sought to assess differences in efficacy in subsets of anti-TNF-naive and anti-TNF-exposed patients. We used GRADE criteria to appraise the quality of evidence for each outcome.

METHODS We conducted this systematic review and meta-analysis according to the Cochrane collaboration’s systematic review methodology,16 and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines17; the process followed an a priori established protocol.

Selection Criteria Studies included in this meta-analysis were RCTs that met the following inclusion criteria: (1) patients—adults with established CD, (2) intervention—biologic therapy with anti-a4-integrins (NAT, VEDO) for induction and/or maintenance of remission, with a minimum duration of therapy of 14 days in trials reporting induction of remission in active disease, and minimum duration of therapy of 22 weeks in trials reporting maintenance of remission (prevention of relapse in patients with clinical remission to induction therapy), (3) comparator—placebo or an alternative active intervention, and (4) outcome—induction of clinical remission (Crohn’s Disease Activity Index [CDAI] score ,150), and maintenance of medically induced remission (among patients with clinical response to induction therapy). We excluded (1) observational studies, (2) trials of antiadhesion molecules in early investigational stages (such as the CCR9 antagonist, vercirnon,18 the anti-integrin agent, etrolizumab,19 or anti-MAdCAM-1 agents), and (3) pediatric studies.

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Search Strategy First, we conducted a comprehensive search of major electronic databases (MEDLINE, Scopus, EMBASE, Web of Science, and the Cochrane library) from 1985 to July 31, 2014, in adults with no language restrictions for RCTs of anti-integrin therapy in CD. The search strategy was designed and conducted by an experienced medical librarian, with input from the study’s investigators (S.S.), using controlled vocabulary supplemented with keywords, for RCTs of biologic therapy in IBD. The detailed search strategy is presented in the Appendix, Supplemental Digital Content 1, http://links.lww.com/IBD/A900. Two study investigators (S.S. and A.K.C.) independently reviewed titles and abstracts of studies identified in the search to exclude studies that did not address the research question of interest (efficacy and safety of anti-integrin therapy in CD), based on the aforementioned prespecified inclusion and exclusion criteria. After the title and abstract review process, the full text of the remaining articles was examined for inclusion in the systematic review. Conflicts in study selection at this stage were resolved by consensus, referring back to the original article in consultation with the principal investigator (E.V.L.). Second, we searched the bibliographies of these selected articles as well as other review articles to identify any additional studies. Third, we conducted a manual search of abstracts from major gastroenterology conferences (Digestive Disease Week, the American College of Gastroenterology annual meeting, the Advances in Inflammatory Bowel Diseases meeting organized by the Crohn’s and Colitis Foundation of America, and the European Crohn’s and Colitis Organization annual meeting) from 2005 to 2014 to identify additional abstracts on the topic.

Data Abstraction and Quality Assessment We abstracted data on the study, patient, disease, and treatment characteristics using a standardized data extraction template. The following data were collected for NAT and VEDO studies separately: (1) study characteristics—primary author, time period of study/year of publication, geographic location, and centers where study was conducted, duration of follow-up, (2) patient characteristics—age, sex, race/ethnicity, smoking history, body mass index, (3) CD characteristics—location of disease, duration, number of resectional surgeries for CD, use of concurrent medications, (4) treatment characteristics—dosing and schedule of intervention, (5) outcome assessments—definition of clinical remission and response, measurement time points, total number of patients in intervention and comparator group, proportion achieving the outcome of interest (as dichotomous variable), change in health-related quality of life (HRQoL, assessed using the IBD Questionnaire [IBD-Q]) scores (as a continuous variable), and C-reactive protein (CRP) at baseline in intervention and comparator groups, and (6) AEs—proportion of patients with serious adverse events (SAEs), infusion reactions, any and serious infections, and AEs requiring medication discontinuation. Data on the outcomes were abstracted for the entire group as a whole, as well as stratified by prior anti-TNF exposure. The a priori minimal

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clinically important difference (MCID) was an increase of $16 points from baseline on the IBD-Q.20 Two study investigators (A.K.C. and S.S.) independently rated the quality of included studies using the Cochrane Risk of Bias assessment tool.16 In this tool, studies were deemed to be at high, low, or unclear risk of bias based on adequacy of sequence generation, allocation concealment, blinding, method of addressing incomplete data, selective reporting, and other biases. The overall quality of evidence was assessed for each outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, including risk of bias, indirectness, imprecision, inconsistency, and additional GRADE criteria, such as publication bias and large magnitude of effect.15

Outcomes Assessed The primary outcome of interest was failure of induction of remission in active luminal CD (CDAI ,150) for induction trials, and relapse of disease activity in quiescent CD. Secondary efficacy outcomes of interest for induction trials were (1) failure of induction of clinical response (defined as a failure to achieve a reduction of $100 points in CDAI from baseline or CR-100); if CR-100 was not available for a trial, a failure of reduction of $70 points in CDAI or CR-70 was used as a clinical response indicator, and (2) improvement in HRQoL using the IBD-Q, which is a 32-item disease-specific, validated patient-reported outcome measure for measuring HRQoL in IBD. Scores on the IBD-Q range from 32 to 224 points, with higher scores indicating better quality of life.21,22 Secondary safety outcomes of interest included SAEs, infusion reactions, any and serious infections, and AEs requiring medication discontinuation. The timing of outcome assessment was up to 14 weeks for induction of remission trials, and up to 60 weeks for maintenance of remission trials; when outcomes at multiple time points were reported, we preferentially used outcomes 2 to 4 weeks after completion of induction regimen (Table 1) and at 52 to 60 weeks in maintenance of remission trials. If RCTs reported outcomes for multiple doses of NAT or VEDO, we decided a priori to combine data from all treatment groups. The denominator used in all trials was based on intention-to-treat analysis (i.e., all dropouts are assumed to be treatment failures) when available.

Subgroup and Sensitivity Analyses To assess differences in efficacy based on prior anti-TNF exposure, we performed stratified analysis in anti-TNF-naive and anti-TNF-exposed patients for induction of clinical remission and response. To assess for efficacy in a subset of patients with biochemical evidence of active disease (i.e., elevated CRP), we performed sensitivity analysis by restricting to patients with elevated CRP at baseline. We also performed sensitivity analysis based on standard induction dosing for each medication—NAT 300 mg at weeks 0, 4, and 8 and VEDO 300 mg at weeks 0, 2, and 6.

Anti-integrin Therapy for Crohn’s Disease

Statistical Analysis We used the random-effects model to estimate pooled relative risk (RR; for dichotomous outcomes) and mean difference (for continuous outcomes) and 95% confidence intervals (CIs), comparing failure to respond to anti-integrin therapy in comparison to failure to respond to placebo.29 We estimated number needed to treat from the summary estimates for the primary outcome, using the median control group risk of studies included in the meta-analysis.30,31 We assessed statistical heterogeneity using the I2 statistic, with I2 values over 50% indicating substantial heterogeneity.32 Given the small number of studies identified in our analysis, statistical tests for assessing publications bias were not performed.33 All calculations and graphs were performed using Review Manager (RevMan) v5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, 2012).

RESULTS The search strategy resulted in a total of 1656 citations of which 8 trials were eligible for inclusion (1170 patients on NAT, 1301 patients on VEDO, and 948 on placebo).13,14,23–28 There were 5 trials comparing NAT to placebo,13,25–28 and 3 trials comparing VEDO to placebo.14,23,24 Two maintenance studies (reported in same articles as induction therapy) were summarized qualitatively.13,14 Figure 1 shows the PRISMA flow diagram describing study identification and selection.

Characteristics and Quality of Included Studies Study characteristics are described in Table 1. All studies were multicenter placebo-controlled trials. In 1 trial, all randomized subjects were on concurrent therapy with infliximab.25 Overall, 54% of patients were female. Study subjects were mostly white (91%), had a mean age of 37 6 11 years, and CD involvement was mostly ileocolonic (54%). Twenty-five percent of patients were current or former smokers. All studies allowed concurrent immunomodulators. The methodological quality of included studies is detailed in Table 2, and Figs. A and B, Supplemental Digital Content 2, http://links.lww.com/IBD/A786. All included studies were judged to be at low risk of bias.

Induction Therapy Efficacy Outcomes Primary outcome: failure of induction of remission. Eight trials of anti-a4-integrin therapy (5 trials of NAT, 3 trials of VEDO; 2672 patients) reported induction of clinical remission outcome.13,14,23–28 Meta-analysis demonstrated fewer failures in induction of remission with NAT and VEDO as compared with placebo (RR, 0.87; 95% CI, 0.84–0.91), with no evidence of heterogeneity (I2 ¼ 0%) (Fig. 2). The summary effect sizes were www.ibdjournal.org |

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TABLE 1. Characteristics of Induction Trials of NAT and Vedolizumab for the Management of CD Age

Females, N (%)

Disease Distribution, %

Concomitant Medications at Baseline, %

Disease Duration

36 (12.7)

58.3

NR

5-ASA ¼ 55

8.8 (8.3)

38.5 (13.1)

59.7

5-ASA ¼ 42

8 (7.9)

34.5 (11.3) 35.7 (11.9)

48.3 516 (53.4)

5-ASA ¼ 47 CS ¼ 34.7 IS ¼ 16.1

9.1 (8.3) 9.2 (7.8)

38.6 (13.2)

79 (53.4)

CS ¼ 30.4 IS ¼ 16.9

8.2 (7.8)

VEDO 300 mg at week 0, 2, and 6; IV ¼ 207

36.9 (20–69)b

118 (56)

CS ¼ 53 5-ASA ¼ 33 IS ¼ 34

8.4 (0.3–41.8)b

Placebo ¼ 209

34.8 (19–77)b

118 (57)

CS ¼ 52 5-ASA ¼ 29 IS ¼ 33

8 (0.3–42.9)b

NAT 300 mg at week 0, 4, and 8; IV ¼ 259

38.1

154 (59)

10.1

Placebo ¼ 250

37.7

102 (41)

NAT 3 mg/kg at week 0 and 2a; IV ¼ 66

36

36 (55)

CS ¼ 42 5-ASA ¼ 49 IS ¼ 37 CS ¼ 38 5-ASA ¼ 48 IS ¼ 38 CS ¼ 56 5-ASA ¼ 62

NAT 6 mg/kg at week 0 and 2; IV ¼ 51

35

26 (51)

Placebo ¼ 63

34

33 (52)

NAT 3 mg/kg IV at week 0; IV ¼ 18

36 (13.2)

11 (61)

Placebo ¼ 12

34.4 (8.8)

7 (58)

Study Vedolizumab trials Feagan et al23

Sandbornet al14 (GEMINI-2)

VEDO, 0.5 mg/kg at week 0 and 4; IV ¼ 62 VEDO, 2 mg/kg at week 0 and 4; IV ¼ 65 Placebo ¼ 58 VEDO 300 mg at week 0 and 2; IV ¼ 967 Placebo ¼ 148

Sands et al24 (GEMINI 3)

NAT trials Targan et al25 (ENCORE)

Ghosh et al26

Gordon et al27

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I ¼ 16.5 C ¼ 28.2 IC ¼ 55.2 FD ¼ 36.6 I ¼ 14.2 C ¼ 29.1 IC ¼ 56.8 FD ¼ 37.8 I ¼ 16 C ¼ 23 IC ¼ 61 FD ¼ 34 I ¼ 14 C ¼ 25 IC ¼ 61 FD ¼ 37 I ¼ 22 C ¼ 27 IC ¼ 52 I ¼ 26 C ¼ 26 IC ¼ 48 I ¼ 26 C ¼ 24 IC ¼ 50 FD ¼ 12 I ¼ 24 C ¼ 31 IC ¼ 45 FD ¼ 25 I ¼ 24 C ¼ 17 IC ¼ 59 FD ¼ 10 I ¼ 39 C ¼ 28 IC ¼ 28 I ¼ 42 C ¼ 25 IC ¼ 33

10

8.1 (0.5–21.9)c

CS ¼ 63 5-ASA ¼ 59

7.8 (0.6–29)c

CS ¼ 49 5-ASA ¼ 48

8.9 (0.3–64.3)c

CS ¼ 56 5-ASA ¼ 17 IS ¼ 33 CS ¼ 75 5-ASA ¼ 17 IS ¼ 17

8.5 (9.6)

8.4 (6)





TABLE 1 (Continued) Age

Females, N (%)

Disease Distribution, %

Concomitant Medications at Baseline, %


38 (12)

413 (57)

Placebo ¼ 181

39 (14)

108 (60)


39.9 (12.6)

28 (54)

Placebo ¼ 27

38.9 (13.2)

10 (37)

I ¼ 27 C ¼ 22 IC ¼ 52 I ¼ 26 C ¼ 27 IC ¼ 46 I ¼ 21 C ¼ 25 IC ¼ 54 I ¼ 15 C ¼ 30 IC ¼ 56

CS ¼ 37 5-ASA ¼ 47 IS ¼ 34 CS ¼ 39 5-ASA ¼ 44 IS ¼ 29 CS ¼ 27 5-ASA ¼ 46 IS ¼ 50 CS ¼ 30 5-ASA ¼ 37 IS ¼ 56

Study Sandborn et al13 (ENACT-1)

Sands et al28

Study Vedolizumab trials Feagan et al23

Definition and Timing of Clinical Remission

CDAI ,150; week 8

CDAI ,150; week 6 (induction trial) and week 52 (maintenance trial) CDAI ,150; week 10

Sandbornet al14 (GEMINI-2) Sands et al24 (GEMINI 3) NAT trials Targan et al25 (ENCORE) Ghosh et al26

CDAI ,150; week 6

Gordon et al27

CDAI ,150; week 2

Sandborn et al13 (ENACT-1) Sands et al28

CDAI ,150; week 10 (induction trial) and week 60 (maintenance trial) CDAI ,150; week 10

CDAI ,150; week 12

Disease Duration 10.1 (7.7)

9.2 (7.8)

12.5 (9.1)

12 (10.3)

Baseline CDAI Score

Baseline CRP Level

Smoking History, N (%)

Prior Anti-TNF Prior Surgeries, Therapy, N (%) N (%)

296.6 (55.4) 288.1 (48.6) 288 (45.8) 323 (68) 325 (78) 313.9 (53.2) 301.3 (55)

2.5 (3.6) 2.0 (2.1) 2.5 (2.9) 10.6d 13.7d 19 (23.2) 18.5 (22)

41.5 46.8 32.8 264 (27.3) 34 (23) NR NR

0 0 0 617 (63.8) 72 (48.6) 158 (76) 157 (76)

NR NR NR 412 (42.6) 54 (36.5) 92 (44) 89 (43)

303.9 (64.8) 299.5 (63.2) 300 298 300 258 (122–436)b 273 (191–420)b 302 (60) 303 (65) 263.8 (89.3) 243.6 (57.1)

23 (27.8) 23.4 (27.9) NR NR NR 14 (12) 35 (42) 20 (31) 23 (26) 6.5 (11.1) 5.9 (10.3)

57 (22) 48 (19) NR NR NR NR NR 164 (23) 44 (24) NR NR

130 (50) 112 (45) 0 0 0 0 0 291 (40) 69 (38) 100 100

NR NR NR NR NR NR NR 300 (41) 73 (40) NR NR

a

We excluded the 1 infusion of 3 mg/kg arm from the analysis. Median and range. c Mean and range. d Median CRP levels. 5-ASA, 5-aminosalicylate; C, colonic; CS, corticosteroid; FD, fistulizing disease; I, ileal; IC, ileocolonic; IS, immunosuppressant; NR, not reported. b

similar for both NAT (RR, 0.86; 95% CI, 0.80–0.93) and VEDO (RR, 0.87; 95% CI, 0.79–0.95), with no significant difference between the 2 medications (P ¼ 0.95). Using an assumed control risk of 0.77 (because it was the median risk in the control group), the number needed to treat for NAT and VEDO for induction of remission were 9 and 10, respectively. On stratified analysis based on prior anti-TNF exposure, we observed that NAT was effective in inducing remission in both anti-TNF-naive (3 studies; 755 patients; RR, 0.87; 95% CI,

0.75–1.00)13,26,27 and anti–TNF-exposed patients (2 studies; 439 patients; RR, 0.86; 95% CI, 0.76–0.99),13,28 as compared with placebo, with no significant differences between the treatmentnaive and treatment-exposed subgroups (P ¼ 0.98) (Fig. 3A). Likewise, we observed that there was no difference in the efficacy of VEDO in inducing remission in anti-TNF-naive (3 studies; 479 patients; RR, 0.86; 95% CI, 0.79–0.94)14,23,24 and anti-TNF-exposed patients (2 studies; 415 patients; RR, 0.89; 95% CI, 0.78–1.01) (P ¼ 0.72) (Fig. 3B).14,24 www.ibdjournal.org |

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FIGURE 1. Study selection flowchart.

Secondary Outcomes Failure of induction of clinical response. Six trials of anti-a4integrin therapy (3 trials of NAT,13,25,26 3 trials of VEDO14,23,24) reported induction of clinical response outcome. Of these, 3 reported CR-100, whereas 3 reported CR-70; importantly, all trials of NAT reported only CR-70, whereas trials of VEDO reported CR-100 as a measure of clinical response. On meta-analysis, there were fewer failures in induction of response with NAT and VEDO as compared with placebo (RR, 0.76; 95% CI, 0.67–0.87); substantial heterogeneity was observed in this analysis (I2 ¼ 67%) (see Fig., Supplemental Digital Content 3, http://links.lww.com/ IBD/A787). The summary effect sizes for NAT (RR, 0.72; 95% CI, 0.59–0.89) and VEDO (RR, 0.80; 95% CI, 0.65–0.97) were not significantly different (P ¼ 0.51). Improvement in health-related quality of life. Five induction trials of anti-a4-integrin therapy (4 trials of NAT,13,25–27 1 trial of VEDO14) reported change in HRQoL, as measured by IBD-Q. Of the 4 studies that reported change in IBD-Q in NAT, 1 study was excluded from the meta-analysis, as data were not extractable.27 Meta-analysis of the remaining trials showed that when compared with placebo, patients with CD on anti-integrins had a change of 7.9 points on the IBD-Q (4 studies; 953 patients; 95% CI, 3.16– 12.63); this did not cross the a priori MCID for IBD-Q. There was

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substantial heterogeneity between studies (I2 ¼ 63%). Improvement in IBD-Q scores for NAT (3 studies; 768 patients; mean difference, 10.00; 95% CI, 3.71–16.21) and VEDO (1 study; 185 patients; mean difference, 5.46; 95% CI, 5.28–5.64) were not significantly different (P ¼ 0.15).

Safety Outcomes Serious adverse events. Seven induction trials of anti-a4integrin therapy (4 trials of NAT,13,25,26,28 3 trials of VEDO14,23,24) reported rates of SAEs (Table 3). Overall, 6.8% of NAT, 8.8% of VEDO, and 8.5% of placebo-treated patients developed SAEs; on meta-analysis, there was no significant difference in the rates of any AEs with NAT and VEDO, as compared with placebo (RR, 0.86; 95% CI, 0.65–1.15); no heterogeneity was detected in this analysis (I2 ¼ 0%). Rates of AEs with NAT (RR, 0.79; 95% CI, 0.54–1.18) and VEDO (RR, 0.94; 95% CI, 0.65–1.15) were not significantly different (P ¼ 0.56). Infusion reactions. Seven induction trials of anti-a4-integrin therapy (4 trials of NAT,13,25,26,28 3 trials of VEDO14,23,24) reported rates of infusion reactions (acute and hypersensitivitylike) (Table 3). In trials of NAT, 155/1151 (13.5%) patients treated with NAT versus 36/521 (6.9%) patients treated with placebo developed infusion reactions, corresponding to a 73%





TABLE 2. Quality Assessment of Included Studies Study

Allocation Concealment

Vedolizumab trials Feagan et al23

Y

Sandborn et al14

Y

Sands et al24

Y

NAT trials Targan et al25

Blinding

Patients: Y Physicians: Y Data collectors: ? Adjudicators: ? Data analysts: ? Patients: Y Physicians: Y Data collectors: ? Adjudicators: ? Data analysts: ?

Incomplete Outcome Data

Comments

—

—

3 loss to follow-up 27 withdrew consent 30 lack of efficacy 1 protocol violation 2 “Other” reasons

Outcomes mentioned here are only for the induction phase of the trial

Patients: Y Physicians: Y Data collectors: Y Adjudicators: Y Data analysts: Y

11 withdrew consent 1 protocol violation 18 “Other” reasons

Only the site pharmacist was aware of the treatment assignments

Y


1 patient who was not randomized received NAT and was only included in the safety analysis

Ghosh et al26

Y


1 loss to follow-up 7 withdrew consent 3 due to investigator’s discretion 3 noncompliant 6 “Other” reasons 2 “Unreported” 4 ineligible 2 loss to follow-up 5 due to investigator’s discretion 7 lack of efficacy 3 due to patient’s request

Gordon et al27

Y

2 lack of efficacy 1 loss to follow-up

Sandborn et al13

Y

Patients: Y Physicians: Y Data collectors: Y Adjudicators: Y Data analysts: Y Patients: Y Physicians: Y Data collectors: Y Adjudicators: Y Data analysts: Y

Sands et al28

Y

Patients: Y Physicians: Y Data collectors: ? Adjudicators: ? Data analysts: ?

2 withdrew 1 loss to follow-up

Details NR

4 patients did not receive the allotted dose after randomization since they were found to be ineligible

—

1 person randomized to NAT did not receive study drug

—

Y ¼ yes; N ¼ no; ? ¼ unclear.

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FIGURE 2. Summary efficacy estimates from RCTs of anti-integrin agents, NAT, and VEDO, versus placebo in inducing remission in active luminal CD.

higher risk of infusion reactions with NAT as compared with placebo (RR, 1.73; 95% CI, 1.21–2.46). In induction trials of VEDO, 11/556 (2.0%) patients versus 9/413 (2.2%) patients treated with placebo developed infusion reactions (RR, 0.85; 95% CI, 0.36–2.04). Combined, across both NAT and VEDO induction trials, the overall rate of infusion reactions with anti-integrin therapy was 166/1707 (9.7%) versus 45/934 (4.8%) in placebotreated patients (RR, 1.56; 95% CI, 1.13–2.17). In comparing overall rates of infusion reactions in these induction trials, the rate of infusion reaction was higher for NAT-treated patients than VEDO-treated patients (P value for interaction between subgroups ¼ 0.007). Any and serious infections. Seven induction trials of anti-a4integrin therapy (4 trials of NAT,13,25,26,28 3 trials of VEDO14,23,24) reported rates of any infections; all except Ghosh et al26 reported rates of serious infections (Table 3). Overall, 40.7% of NAT, 13.5% of VEDO, and 24.8% of placebo-treated patients developed any infections; on meta-analysis, there was no significant difference in the rates of infections with NAT and VEDO, as compared with placebo (RR, 1.09; 95% CI, 0.96–1.24); no heterogeneity was detected in this analysis (I2 ¼ 0%). Rates of any infections with NAT (RR, 1.12; 95% CI, 0.97–1.29) and VEDO (RR, 0.99; 95% CI, 0.71–1.36) were not significantly different (P ¼ 0.48). Overall, 2.6% of NAT, 0.7% of VEDO, and 2.3% of placebo-treated patients developed serious infections. On metaanalysis, there was no significant difference in the rates of serious infections with NAT and VEDO, as compared with placebo (RR, 0.74; 95% CI, 0.43–1.29); no heterogeneity was detected in

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this analysis (I2 ¼ 0%). Rates of serious infections with NAT (RR, 0.78; 95% CI, 0.43–1.41) and VEDO (RR, 0.59; 95% CI, 0.10–3.41) were not significantly different (P ¼ 0.76). Treatment discontinuation. Six induction trials of anti-a4integrin therapy (3 trials of NAT,13,25,28 3 trials of VEDO14,23,24) reported rates of treatment discontinuation. Overall, 8.6% of NAT, 2.8% of VEDO, and 6.9% of placebo-treated patients required treatment discontinuation; on meta-analysis, there was no significant difference in the rates of treatment discontinuation with NAT and VEDO as compared with placebo (RR, 0.95; 95% CI, 0.60–1.50); minimal heterogeneity was observed in this analysis (I2 ¼ 33%) (Fig. 4). Treatment discontinuations with NAT (RR, 1.15; 95% CI, 0.55–2.41) and VEDO (RR, 0.74; 95% CI, 0.36–1.54) were not significantly different (P ¼ 0.41).

Sensitivity Analysis On sensitivity analysis, restricting to patients with elevated CRP at baseline, we observed that there were fewer failures in induction of remission with NAT and VEDO as compared with placebo (3 studies; 966 patients; RR, 0.86; 95% CI, 0.78–0.95) (see Fig., Supplemental Digital Content 4, http://links.lww.com/IBD/A788).13,14,28 The summary effect estimates for both NAT (2 studies; 695 patients; RR, 0.82; 95% CI, 0.73–0.92) and VEDO (1 study; 271 patients; RR, 0.91; 95% CI, 0.85–0.97) were not significantly different (P ¼ 0.15). In addition, on sensitivity analysis by excluding studies that used nonstandard induction dosing of NAT26,27 or VEDO,23 we did not observe any significant change in the overall effect





FIGURE 3. Summary efficacy estimates of (A) NAT and (B) VEDO in inducing remission in active luminal CD, stratified based on prior anti-TNF exposure.

estimate for induction of remission (RR, 0.88; 95% CI, 0.84–0.92; I2 ¼ 0%); the effect size for NAT (3 studies; 1493 patients; RR, 0.87; 95% CI, 0.81–0.95) and VEDO (2 studies; 784 patients; RR, 0.87; 95% CI, 0.78–0.98) were similar. We also conducted sensitivity analysis for RCTs on NAT after excluding 1 study in which all patients received concomitant therapy with infliximab.28 Exclusion of this study did not substantially influence the effect estimate for NAT (RR, 0.86; 95% CI, 0.80–0.93).

Maintenance Therapy Two studies (1 on NAT and 1 on VEDO) were long-term maintenance therapy studies. ENACT-2 was a randomized NAT maintenance therapy study, which comprised of patients who exhibited a clinical

response (CDAI ,220, with either NAT or placebo induction) in the ENACT-1 study at weeks 10 and 12.13 These patients were rerandomized 1:1 to receive either 300 mg of NAT (168 patients) or placebo (171 patients). The primary efficacy end point of ENACT-2 was the proportion of NAT patients with sustained clinical response through week 36 with the maximum length of follow-up being 60 weeks. One hundred three patients of 168 on NAT (61.3%) had a sustained clinical response at 36 weeks compared with 48 patients of 170 on placebo (28.2%). In addition, 57 patients of 130 on NAT (43.8%) had substantiated remission through week 36 compared with 31 patients of 120 on placebo (25.8%). At the end of the follow-up (week 60), 55% of patients on NAT had sustained remission as opposed to 22% for those on placebo. In terms of AEs, in ENACT-2, there was no statistically www.ibdjournal.org |

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TABLE 3. Safety Outcomes in Induction and Maintenance Trials of Anti-integrin Therapy SAEs

Induction trials—NAT Ghosh et al26 Gordon et al27 ENACT-113 ENCORE25 Sands et al28 Induction trials—VEDO Feagan et al23 GEMINI-214,c GEMINI-324 Maintenance trials—NAT ENACT-213 Maintenance trials—VEDO GEMINI-214

Infusion Reactiona

Any Infections

Serious Infections

Malignancy

Placebo

Active

Placebo

Active

Placebo

Active

Placebo

Active

Placebo

Active

7/63 NR 12/181 24/250 1/27

12/116 NR 52/723 13/260 1/52

0/63 NR 17/181 19/250 0/27

2/116 NR 117/723 33/260 3/52

8/63 NR 78/181 75/250 8/27

12/116

NR

0

0

352/723 90/260 14/52

4/181 4/250 NR

12/723 1/260 0

0 0 0

0 0

10/58 9/148 16/207

16/127 20/220 13/209

0/58 7/148 2/207

1/127 6/220 4/209

2/58b 26/148 35/207

1/127b 34/220 40/209

2/58b 2/148 0/207

1/127b 1/220 2/209

0 0 0

0 0 0

21/214

18/214

20/214

20/214

119/214

132/214

5/215

6/214d

1/214

1/214

46/301

199/814

14/301

33/814

121/301

359/814

9/301

45/814

1/301

4/814

a

Acute infusion reaction and hypersensitivity-like reaction. No infection reported during study, but 3 serious infections developed during poststudy follow-up. c AEs reported only for randomized induction trial and not the open-label induction arm. d One patient developed PML. b

significant difference in the incidence of SAEs (NAT versus placebo, 8.4% versus 9.8%), infections (61.7% versus 55.6%), and malignant neoplasms (0.005% versus 0.005%) in NAT- and placebo-treated groups. There were significantly fewer AEs leading to treatment discontinuation in the NAT group (14%) when compared with those rerandomized to placebo (29%). However, 1 patient who was randomized to NAT in ENACT-1 and

rerandomized to placebo in ENACT-2 developed fatal progressive multifocal leukoencephalopathy (PML) after receiving open-label NAT (5 doses) after early discontinuation from the trial. GEMINI-2 was a randomized VEDO induction and maintenance therapy study, which comprised of a conventional induction trial and an open-label induction arm, followed by a maintenance trial in patients who exhibited a 6-week clinical

FIGURE 4. Rates of medication discontinuation of anti-integrin agents, relative to placebo, in RCTs of induction of remission in active luminal CD.

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response (CR-70) with either VEDO or placebo induction.14 These 6-week responders were rerandomized in a 1:1:1 fashion to receive either VEDO every 4 weeks (154 patients) or 8 weeks (154 patients) or placebo (153 patients). The primary efficacy end point was clinical remission at week 52. Fifty-six patients of 154 patients on VEDO every 4 weeks (36.5%) and 60 patients of 154 receiving VEDO every 8 weeks (39.0%) were in clinical remission at week 52, compared with 33 patients of 153 on placebo (21.6%). In addition, 48% of patients on VEDO every 4 weeks and 46% on VEDO every 8 weeks achieved a CR-100 clinical response in comparison to 32% on placebo in the maintenance trial. In GEMINI-2, there was no statistically significant difference in the incidence of SAEs (VEDO versus placebo, 17.2% versus 15.0%), infections (45.5% versus 41.8%), and malignant neoplasms (0.003% versus 0%) in the VEDO- and placebo-treated groups.

Quality of Evidence Using the GRADE framework, the quality of evidence across studies was rated as high for induction of clinical remission and moderate for induction of clinical response using NAT or VEDO in adults with CD, whereas evidence quality for improvement in HRQoL was rated as low. The GRADE summary of findings is reported in Table 4.

DISCUSSION After anti-TNF agents, inhibition of leukocyte trafficking to the gut mucosa during the inflammatory process has become the second major therapeutic target of biological agents in IBD. Currently approved lymphocyte homing antagonists include antia4-integrins, NAT (humanized IgG4 monoclonal antibody against a4b1 and a4b7 integrins), and VEDO (humanized IgG1 monoclonal antibody against a4b7 integrin). In this systematic review and meta-analysis of 8 placebo-controlled RCTs of NAT and VEDO in adults with CD, we made several key observations. First, we confirmed that anti-a4-integrins are effective in inducing and maintaining clinical remission and response in adults with CD, without significant increase in SAEs or infections, based on moderate- to high-quality evidence (using GRADE methodology). Although they are also effective in improving HRQoL, the improvement did not reach the a priori MCID. Using GRADE methodology, we rated down the HRQoL outcome twice because of GRADE criteria of inconsistency (I2 ¼ 63%) and imprecision (95% CI did not include the MCID for IBD-Q and wide CI). Second, we observed that the efficacy of NAT and VEDO is similar for all important endpoints (clinical remission, response, and improvement in quality of life), and other factors including long-term safety may be more relevant in deciding agent of choice; however, there was no direct comparison of NAT and VEDO. Third, we observed that there is no significant difference in the efficacy of anti-a4-integrins in anti-TNF-naive and antiTNF-exposed patients.


Integrins comprise a family of ab heterodimeric transmembrane receptors that are constitutively expressed and mediate the attachment of cells to the extracellular matrix and participate in specialized cell–cell interactions.34 The a4b7 integrin is highly expressed on a subpopulation of memory T cells, which have been shown to preferentially home in to the gut.35 The ligand mediating a4b7 T-cell gut-homing is MAdCAM-1, which is selectively expressed in the gut endothelium and is upregulated in the presence of active IBD, in response to proinflammatory cytokines.36 By blocking this interaction, both NAT and VEDO prevent lymphocyte migration into the inflamed tissue and hence, decrease IBD-associated inflammation. Multiple clinical trials have demonstrated the efficacy of these agents in patients with moderate-to-severe CD, and our meta-analysis confirmed these findings. Both NAT and VEDO were more efficacious than placebo in inducing clinical remission and response, improving quality of life and maintaining remission in patients with quiescent CD. This benefit was seen even after restricting analysis to a subset of patients administered standard FDA-approved formulation and dose of agents, and in a subset of patients with biochemical evidence of active disease. The summary effect sizes for each of these efficacy end points was comparable for NAT and VEDO, suggesting comparable efficacy in the absence of a confirmatory direct head-to-head comparison trial. Similar to findings from this direct treatment comparison meta-analysis, on Bayesian network meta-analysis combining direct and indirect evidence on the relative efficacy of all biologic agents in CD, we had observed no difference in the comparative efficacy of VEDO over NAT for induction (RR, 1.03; 95% credible interval, 0.35–3.08) or maintenance of remission (RR, 0.52; 95% credible interval, 0.04–6.62).37 With comparable efficacy of these agents, the choice of agents is driven by safety. Although in our meta-analysis of induction and maintenance phase trials of NAT and VEDO, there were no specific safety signals (risk of SAEs, any and serious infections), and rates of medication discontinuation were comparable with each other and to placebo, postmarketing surveillance of NAT has revealed the occurrence of rare but fatal PML.38 This is caused by the nonselective inhibition of a4b1 integrin, which allows lymphocyte homing to the brain promoting reactivation of the JC virus. As of April 3, 2014, among approximately 123,000 patients who have received NAT worldwide in the postmarketing setting, 454 have developed PML, with an estimated incidence of 3.6 per 1000 patient-years.39 In contrast, the selectivity of VEDO as an a4b7 integrin antagonist without activity against a4b1 integrin, makes the risk of PML very low, and during multiple clinical trials of VEDO, no case of PML has been reported. As of June 27, 2013, there have been 3129 patients with CD or UC who received VEDO in 11 clinical studies for a median of 313 days, and no case of PML has been observed to date.24 Hence, VEDO would potentially be a favored agent over NAT in patients with moderate-to-severe CD, given a more favorable risk-benefit profile. www.ibdjournal.org |

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1706 TABLE 4. GRADE Summary of Findings Table on the Efficacy and Safety of Anti-integrin Agents in the Management of CD Question: Should Anti-a4-integrins vs Placebo Be Used for CD? Bibliography: Own Review Quality Assessment

Summary of Findings Study Event rates (%)

Participants (Studies) Followup

Risk of Bias

Inconsistency

Indirectness

Imprecision

Publication Bias

Overall Quality of Evidence

Failure of induction of remission (critical outcome; assessed with: CDAI with a score ,150 indicating remission) No serious No serious Undetected 4444 High 2672 (8 studies) No serious No serious inconsistency indirectness imprecision 2–12 wk risk of bias

With Placebo

753/946 (79.6)

With Antiintegrins

Anticipated Absolute Effects Relative Effect (95% CI)

1156/1726 RR, 0.87 (67) (0.84– 0.91)

Failure of induction of treatment response (important outcome; assessed with: CDAI with a score ‡70 points indicating clinical response) 2563 (6 studies) No serious Seriousb 580/907 790/1656 No serious No serious Undetected 444⊝ 2–12 wk risk of (63.9) (47.7) indirectness imprecision Moderateb bias due to inconsistency

RR, 0.76 (0.67– 0.87)

Risk with Placebo Moderatea 771 remission failures per 1000

Moderatea 654 response failures per 1000

Risk Difference with Anti-a4integrins (95% CI)

100 fewer remission failures per 1000 (from 69 fewer to 123 fewer)

157 fewer response failures per 1000 (from 85 fewer to 216 fewer)

a

Median risk chosen as the assumed control risk as there was little variation in control group risk across studies included in the meta-analysis. I ¼ 67%. c 2 I ¼ 63%. d 95% CI does not include the MCID for IBD-Q. e This was the mean IBD-Q of the control group in Ghosh et al.26 b 2



Improvement in HRQoL (important outcome; measured with: IBD-Q with a score ‡16 points indicating a MCID; range of scores: 32–224; better indicated by lower values) 953 (4 studies) No serious Seriousc 398 555 — The mean No serious Seriousd Undetected 44⊝⊝ Lowc,d The mean 2–12 wk risk of improvement in indirectness improvement in due to bias HRQoL in the HRQoL in the inconsistency, control groups intervention imprecision was 145 pointse groups was 7.89 higher (3.16– 12.63 higher) AEs leading to Rx discontinuation (important outcome; assessed with: treatment discontinuations) No serious No serious Undetected 4444 High 62/896 (6.9) 101/1504 RR, 0.95 Moderatea 2400 (6 studies) No serious No serious inconsistency indirectness imprecision (6.7) (0.6–1.5) 43 therapy 2–12 wk risk of 2 fewer therapy bias discontinuations discontinuations per 1000 per 1000 (from 17 fewer to 22 more)


On meta-analysis stratified by prior anti-TNF-exposure, we observed the efficacy of these anti-integrin agents was comparable in anti-TNF-naive and anti-TNF-exposed patients. The overall effect size was small with number needed to treat to induce remission with NAT and VEDO of 9 and 10, respectively. Within subgroups, the efficacy of VEDO in patients with prior anti-TNFexposure was not statistically significant—this likely represents a type 2 error due to small sample size (subgroup analyses of 2 studies). Patients with prior anti-TNF failure (either primary nonresponse or with loss of response) may represent a distinct subset of patients when compared to anti-TNF-naive patients, usually have high rates of long-standing disease, prior CD surgery, history of fistulizing disease, elevated baseline CRP, and fecal calprotectin, and may have non-CD related causes for symptoms (such as visceral hypersensitivity, bile salt diarrhea, small intestinal bacterial overgrowth, etc.).24 The strengths of our systematic review include (1) comprehensive and simultaneous assessment of the relative efficacy and safety of all FDA-approved anti-integrin agents for induction and maintenance of remission in adults with moderate-to-severe CD, (2) a priori distinction of patients based on anti-TNFexposure status, (3) evaluation of multiple efficacy end points including conventional CDAI-based measures as well as patientreported outcomes (HRQoL measured using IBD-Q); (d) subgroup and sensitivity analyses to evaluate the stability of findings and identify potential factors responsible for inconsistencies, and (4) the application of GRADE, an established framework to rate evidence (outcome) quality. However, there are several limitations, both at the metaanalysis level and at the individual study level, that merit discussion. First, because of the absence of head-to head studies comparing NAT to VEDO, direct comparisons of the 2 antiintegrin agents could not be made. There were inherent (presumably, nondirectional) differences in the distribution of prognostic factors, such as disease duration, disease phenotype, history of prior surgery, and concomitant use of immunosuppressive medications across studies. Second, there were subtle differences in study design, which could introduce heterogeneity in the analysis. For example, there were differences in timing of assessment of outcomes for RCTs of different agents. In addition, all trials of NAT defined clinical response as CR-70, whereas trials of VEDO defined clinical response as CR-100, a stricter end point. At a meta-analysis level, we tried to minimize this conceptual heterogeneity by using a predefined hierarchy for the assessment of timing of outcome assessment (preferably 2–4 wk after completion of induction therapy). Third, our study does not address the relative efficacy of anti-integrin therapy as compared with anti-TNF therapy. Hence, it is unclear which should be the first biologic agent of choice in the management of moderate-tosevere CD. Through a Bayesian network meta-analysis on the comparative effectiveness of all biologic agents in biologicnaive patients with CD, we had observed that as a class, antiTNF agents are comparable with anti-integrin agents, but at an individual agent level, infliximab seemed to be superior to NAT


and VEDO for induction of remission.37 However, the quality of evidence derived from this indirect treatment comparison was low. Fourth, we did not study the relative efficacy of these agents in the treatment of fistulizing CD, due to a paucity of data. At the study level, there were limitations related to early studies performed, which did not use standard induction dosing. However, on sensitivity analysis limiting to studies which used standard induction dosing of these agents, the efficacy of these agents was confirmed. Most of the included RCTs focused on clinical remission, with limited data on achievement of mucosal healing and impact on patient-reported outcomes. Safety data were limited to 12 weeks for induction trials and up to 60 weeks for maintenance trials; data on long-term safety are lacking, especially for VEDO, for which postmarketing studies are warranted. In conclusion, through a systematic review and metaanalysis of 8 RCTs, we observed that NAT and VEDO are both safe and efficacious in induction of remission and response in adults with CD, with comparable efficacy. There was no significant difference in efficacy in subsets of anti-TNF-naive and anti-TNF-exposed patients. Future comparative effectiveness studies to understand the relative positioning of individual agents in the management of moderate-to-severe CD are warranted, that is, which should be first line, second line, etc. In addition, studies evaluating different strategies of using anti-integrin agents (monotherapy versus combination therapy, therapeutic drug monitoring with pharmacokinetic- or clinical-monitoring–guided dose modification, step-up versus top-down, etc.) are warranted.

ACKNOWLEDGMENTS The authors thank Ms. Patricia Erwin, Medical Librarian at the Mayo Clinic Library for helping in the literature search for this systematic review and meta-analysis. Author contributions: Study concept and design, S. Singh; acquisition of data, S. Singh and A. K. Chandar; analysis and interpretation of data, S. Singh, A. K. Chandar, and M. H. Murad; drafting of the article, S. Singh and A. K. Chandar; critical revision of the article for important intellectual content, M. H. Murad, L. PBiroulet, and E. V. Loftus; approval of the final article, S. Singh, A. K. Chander, M. H. Murad, L. P-Biroulet, and E. V. Loftus; study supervision, E. V. Loftus; guarantor of the article, S. Singh.

REFERENCES 1. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54. 2. Cohen RD. The quality of life in patients with Crohn’s disease. Aliment Pharmacol Ther. 2002;16:1603–1609. 3. Gibson TB, Ng E, Ozminkowski RJ, et al. The direct and indirect cost burden of Crohn’s disease and ulcerative colitis. J Occup Environ Med. 2008;50:1261–1272. 4. Lichtenstein GR, Hanauer SB, Sandborn WJ, et al. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104:465–483; quiz 464, 484. 5. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med. 1997;337:1029–1035. www.ibdjournal.org |

1707


Chandar et al

6. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359: 1541–1549. 7. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132:52–65. 8. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357:228–238. 9. Singh S, Pardi DS. Update on anti-tumor necrosis factor agents in crohn disease. Gastroenterol Clin North Am. 2014;43:457–478. 10. Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106:644–659. 11. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380: 1590–1605. 12. von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N Engl J Med. 2000;343:1020–1034. 13. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353: 1912–1925. 14. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–721. 15. Falck-Ytter Y, Kunz R, Guyatt GH, et al. How strong is the evidence? Am J Gastroenterol. 2008;103:1334–1338. 16. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Accessed February 23, 2015. 17. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339: b2700. 18. Keshav S, Vanasek T, Niv Y, et al. A randomized controlled trial of the efficacy and safety of CCX282-b, an orally-administered blocker of chemokine receptor CCR9, for patients with Crohn’s disease. PLoS One. 2013;8:e60094. 19. Rutgeerts PJ, Fedorak RN, Hommes DW, et al. A randomised phase I study of etrolizumab (rhuMAb beta7) in moderate to severe ulcerative colitis. Gut. 2013;62:1122–1130. 20. Irvine EJ. Development and subsequent refinement of the inflammatory bowel disease questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1999;28: S23–S27. 21. Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn’s Relapse Prevention Trial Study Group. Gastroenterology. 1994;106:287–296. 22. de Boer AG, Wijker W, Bartelsman JF, et al. Inflammatory Bowel Disease Questionnaire: cross-cultural adaptation and further validation. Eur J Gastroenterol Hepatol. 1995;7:1043–1050.

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23. Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn’s disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol Hepatol. 2008;6:1370–1377. 24. Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment had failed. Gastroenterology. 2014;147: 618–627. 25. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE trial. Gastroenterology. 2007;132:1672–1683. 26. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn’s disease. N Engl J Med. 2003;348:24–32. 27. Gordon FH, Lai CW, Hamilton MI, et al. A randomized placebocontrolled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn’s disease. Gastroenterology. 2001;121:268–274. 28. Sands BE, Kozarek R, Spainhour J, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis. 2007;13:2–11. 29. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. 30. Schünemann H, Bro_zek J, Guyatt G, et al. eds. GRADE handbook for grading quality of evidence and strength of recommendations. The GRADE Working Group, 2013. Available from www.guidelinedevelopment.org/ handbook. Accessed February 23, 2015. 31. Murad MH, Montori VM, Walter SD, et al. Estimating risk difference from relative association measures in meta-analysis can infrequently pose interpretational challenges. J Clin Epidemiol. 2009;62:865–867. 32. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. 33. Sterne JA, Egger M, Smith GD. Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ. 2001;323:101–105. 34. van der Flier A, Sonnenberg A. Function and interactions of integrins. Cell Tissue Res. 2001;305:285–298. 35. Tilg H, Kaser A. Vedolizumab, a humanized mAb against the alpha4beta7 integrin for the potential treatment of ulcerative colitis and Crohn’s disease. Curr Opin Investig Drugs. 2010;11:1295–1304. 36. Souza HS, Elia CC, Spencer J, et al. Expression of lymphocyteendothelial receptor-ligand pairs, alpha4beta7/MAdCAM-1 and OX40/ OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease. Gut. 1999;45:856–863. 37. Singh S, Garg SK, Pardi DS, et al. Comparative efficacy of biologic therapy in biologic-naïve patients with Crohn disease: a systematic review and network meta-analysis. Mayo Clin Proc. 2014;89:1621–1635. 38. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med. 2005;353:362–368. 39. Saruta M, Papadakis KA. Lymphocyte homing antagonists in the treatment of inflammatory bowel diseases. Gastroenterol Clin North Am. 2014;43:581–601.



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