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ARTICLES: Inflammatory Bowel Disease

Comparative Effectiveness of Biologics for Endoscopic Healing of the Ileum and Colon in Crohn's Disease

Narula, Neeraj MD, MPH, FRCPC1; Wong, Emily C.L. BHSc1; Dulai, Parambir S. MD2; Marshall, John K. MD, MSc, FRCPC1; Jairath, Vipul MD, PhD3; Reinisch, Walter MD, PhD4

Author Information
The American Journal of Gastroenterology: July 2022 - Volume 117 - Issue 7 - p 1106-1117
doi: 10.14309/ajg.0000000000001795

Abstract

INTRODUCTION

Crohn's disease (CD) is an inflammatory bowel disease (IBD) characterized by transmural inflammation of any area of the gastrointestinal tract. Healing of ulcers is an important target of treatment in CD and is often referred to as endoscopic healing (EH) (1,2). The association between achievement of EH and improved outcomes is well established (3–5). Given the chronic and progressive nature of CD, it is important for treatments to demonstrate the ability to heal ulcers and is a requirement to obtain regulatory approval for labeling claims. Treatment in CD has evolved from immunosuppressants (e.g., methotrexate, azathioprine, and 6-mercaptopurine) to more efficacious and safer biologic therapies that target specific cytokines and receptors implicated in the inflammatory pathway. Current biologics approved by Health Canada, the US Food and Drug Association, and the European Medicines Agency for use in CD are adalimumab, infliximab, ustekinumab, and vedolizumab. Adalimumab and infliximab are monoclonal antibodies that target the tumor necrosis factor-alpha (TNF-α) protein. Ustekinumab blocks interleukin-12 and interleukin-23 while vedolizumab targets integrin-α4β7 (6,7). Clinical trials that have led to the approval of these therapies are placebo-controlled without an active comparator. The paucity of head-to-head clinical trial data between CD treatments has led to uncertainty regarding the positioning of treatments (8). Recently, the SEAVUE trial compared ustekinumab and adalimumab and found no difference in rates of clinical remission or EH. However, patients who entered this study had a lower mean baseline Simple Endoscopic Score for CD (SES-CD) than traditional trials of moderate-severe disease by nature of inclusion criteria, resulting in a more moderate disease population (9). As the number of biologics and modes of action increase, clinicians and patients need to make treatment choices in the absence of empirical comparative effectiveness data.

Although several treatment algorithms have been proposed (8,10), it is unclear whether certain agents confer an advantage over others for healing of specific ileocolonic segments, which may be a treatment differentiator. In clinical trials of CD and in practice, the SES-CD is a validated endoscopic tool that is used to quantify endoscopic activity in CD (11). However, as demonstrated with the novel internally validated Modified Multiplier of the SES-CD, the degree of endoscopic disease in individual segments confers a differential prognostic impact on the ability of a patient to achieve 1-year endoscopic outcomes (12). In particular, previous studies have demonstrated that EH is not uniform across bowel segments and may be more difficult to achieve in the ileum and rectum (13). However, comparative effectiveness of approved biologics for CD for achieving segment-specific EH has not been reported. Thus, we conducted this study to compare the efficacy of adalimumab, infliximab, ustekinumab, and vedolizumab on the ability to achieve EH overall and in the ileum and colon separately after 1 year of therapy in patients with CD.

METHODS

Study design

This was a post hoc analysis of pooled participant-level data from several clinical trials of patients with moderate-to-severe CD. Although numerous trials of moderate-to-severe CD are available on the Yale University Open Data Access (YODA) Project and Vivli platforms, only trials with 1-year endoscopic assessments evaluating the efficacy of biologic therapies were requested for this analysis. Data from centrally read endoscopic assessments were used for this analysis, and videos were not re-reviewed or re-scored for this study. Specifically, data were obtained from the induction and maintenance UNITI studies (ClinicalTrials.gov identifier: NCT01369329, NCT01369342, and NCT01369355) from the YODA Project under protocol #2021-4778 (14) and by permission from Janssen (15,16). Data from the VERSIFY study (NCT02425111) and the EXTEND study (NCT00348283) were obtained through Vivli under protocol #00007387 and by permission from Takeda and AbbVie, respectively (16,17). Because there were no available clinical trials of infliximab for moderate-to-severe CD with 1-year endoscopic assessments through YODA or Vivli, we obtained data from a clinical trial of biosimilar and originator infliximab (NCT02096861), herein referred to as the CT-P13 study, by permission from Celltrion (18). The Hamilton Integrated Research Ethics Board determined that local ethics review was unnecessary because data were previously collected and deidentified.

Participants

UNITI.

The study design and inclusion criteria of the UNITI studies have been published previously (15). In brief, adult patients with moderate-to-severe CD, as defined by a Crohn's Disease Activity Index (CDAI) score of 220–450, were eligible for the induction studies, UNITI-1 and UNITI-2. Participants in UNITI-1 had previous primary or secondary nonresponse to anti-TNFs, and participants in UNITI-2 did not respond to conventional therapy, including immunosuppressants or glucocorticoids. All participants in UNITI-2 were anti-TNF-naive. In UNITI-1 and UNITI-2, participants were required to demonstrate evidence of at least 1 objective measure of active inflammation, including C-reactive protein >3 mg/L, fecal calprotectin >250 mg/kg, or mucosal ulceration in any ileocolonic segment based on endoscopy. Subsequently, participants who responded to ustekinumab 130 mg or a weight-based dose of approximately 6 mg/kg at the end of induction therapy (week 8) were enrolled in IM-UNITI, the maintenance portion of the study. Participants in IM-UNITI subsequently received subcutaneous injections of ustekinumab 90 mg every 8 weeks, every 12 weeks, or placebo. The entire study duration was 52 weeks (8 weeks for the induction studies and 44 weeks for the maintenance study). Although endoscopy was not required in the UNITI studies, a cohort of participants was enrolled in an endoscopic substudy with ileocolonoscopies performed at baseline, week 8 (end of UNITI-1 and UNITI-2), and week 52 (week 44 of IM-UNITI). Although responders to ustekinumab were enrolled in IM-UNITI, nonresponders in the endoscopic substudy were offered open-label ustekinumab and continued in the endoscopic substudy. Thus, there was no risk for selection bias in the endoscopy cohort used for this study because those enrolled after baseline endoscopy would continue ustekinumab, regardless of their response to induction therapy. All ileocolonoscopies were centrally read.

VERSIFY.

The design and eligibility criteria for the VERSIFY study have been detailed previously (16). Briefly, 101 patients with active CD for a minimum duration of 3 months received open-label vedolizumab 300 mg intravenously on day 1, week 2, week 6, and every 8 weeks thereafter. Patients must have evidence of active disease, defined by a CDAI score of 220–450, SES-CD score ≥7, mucosal ulcerations identified during endoscopy, and prior nonresponse to conventional therapy. While the main study ended at week 26, patients could participate in the extension substudy, which enrolled 56 of the 101 patients to continue vedolizumab for a total duration of 52 weeks, with infusions at weeks 30, 38, and 46. Endoscopy was performed at baseline, week 14, week 26, and week 52 for patients enrolled in the extension substudy. All endoscopies were centrally read.

EXTEND.

The EXTEND trial enrolled patients with a CDAI score of 220–450 and mucosal ulcerations (17). Details regarding the design and eligibility criteria have been published previously. In summary, participants who did not adequately respond to conventional therapy (e.g., immunomodulators, glucocorticoids, or secondary nonresponse to anti-TNFs) were eligible. All participants received adalimumab induction therapy 160 mg at week 0, followed by 80 mg at week 2, and clinical response was assessed at week 4. After week 4, participants were randomized to continue adalimumab 40 mg every other week or switch to placebo. The entire study duration was 52 weeks. Endoscopy was performed at baseline, week 8 or 12, and week 52, which were all centrally read.

CT-P13.

The CT-P13 study included adults with a CDAI score of 220–450 and were randomized to receive CT-P13 (biosimilar infliximab) followed by CT-P13 at week 30, CT-P13 followed by originator infliximab at week 30, originator infliximab followed by CT-P13 at week 30, and originator infliximab followed by originator infliximab at week 30 (18). Participants followed standard induction (standard doses at weeks 0, 2, and 6) and maintenance protocols (5 mg/kg intravenously every 8 weeks) of infliximab. For this analysis, we did not distinguish between originator and biosimilar infliximab because previous studies have demonstrated no appreciable differences (18,19). The total study duration was 54 weeks. Ileocolonoscopies were performed twice in the study, at baseline and at week 54 (end of study), which were all centrally read.

Data availability statement

Data can be made available on request to third parties.

Variables

This post hoc analysis included data from 299 participants treated with ustekinumab, vedolizumab, adalimumab, and infliximab throughout the UNITI, VERSIFY, EXTEND, and CT-P13 studies, respectively. These 299 participants had endoscopic data available at baseline and at least 1 segment with a SES-CD score of ≥3 at enrollment. A total of 334 patients participated in the UNITI endoscopic substudy, of which 210 received ustekinumab to week 8 of the induction studies (Figure 1). Of these 210 patients, 41 continued ustekinumab throughout the endoscopic substudy of IM-UNITI and were included in this analysis. In VERSIFY, of the 101 patients who received vedolizumab with endoscopic data at baseline, 56 were treated with vedolizumab for 1 year and were included in the analysis. Regarding the EXTEND study, a total of 64 patients received continuous adalimumab, of which 61 had endoscopic data at baseline and were included in this analysis. Finally, of the 220 patients enrolled in the CT-P13 study, 141 had endoscopic data available at baseline and the end of study/week 54 and were therefore included in the analysis. All analyses were conducted on an intention-to-treat basis.

F1
Figure 1.:
Flowchart of participants included. *Participants in the endoscopic substudy with endoscopic data available at baseline with SES-CD ≥3 in at least 1 segment. SES-CD, Simple Endoscopic Score for Crohn's disease.

SES-CD and ulcer size.

The SES-CD is an endoscopic scoring tool that comprised 4 parameters (presence and size of ulcerations, extent of ulcerated surface, extent of affected surface, and presence of narrowings). Each parameter is scored from a scale of 0–3 across all 5 ileocolonic segments. Therefore, the total segment SES-CD ranges from 0 to 12. The size of ulcers is evaluated as 0 (none), 1 (small, 0.1 to <0.5 cm), 2 (large, 0.5 to <2 cm), and 3 (very large, >2 cm), which are referred to accordingly throughout the article.

Biologics for CD.

Four biologics approved for the treatment of CD were evaluated in this analysis: ustekinumab (data obtained from the UNITI studies), vedolizumab (VERSIFY study), adalimumab (EXTEND study), and infliximab (CT-P13 study). In our analysis, biologics were treated as categorical variables without any meaningful hierarchy to the assignment of categories. Therefore, the worst-performing biologic in each segment analyzed was the comparator for pairwise comparisons.

Subgroup analyses.

Subgroup analyses were planned to evaluate the effect of prior biologic exposure on the ability to achieve outcomes. The decision to include this analysis was based on data from the UNITI studies demonstrating lower rates of EH at week 8 among patients with prior biologic experience compared with biologic-naive patients (20).

Outcomes

The primary objective of our study was to compare the efficacy of 4 approved biologics for CD on achieving 1-year overall EH, defined as overall SES-CD <3. Secondary outcomes included 1-year EH of the ileum and colon separately, defined as a SES-CD of 0 in the segment assessed. One-year EH of the colon was defined as a SES-CD of 0 in the entire colon. For each individual colon segment, 1-year EH of the segment was defined as a SES-CD of 0 in the segment assessed. Additional subgroup analyses were planned to evaluate outcomes across each colonic segment and to compare outcomes in biologic-naive patients. Finally, sensitivity analyses were conducted to evaluate outcomes among patients with very large or large ulcers (as defined by the SES-CD) using an alternative definition of 1-year EH as the absence of ulcers in the segment assessed. Although our study included patients with SES-CD ≥3 in at least 1 segment at baseline, clinical trials may require higher amounts of endoscopic activity for enrollment (21). To evaluate whether more stringent criteria for endoscopic disease would affect the positioning of therapies, we also evaluated outcomes among patients with SES-CD ≥7 at baseline. Endoscopic assessments at week 52 or 54 were used for assessment of 1-year outcomes from all trials.

Statistical analyses

Results of each comparison were presented using descriptive statistics. Categorical variables were presented as proportions or percentages and compared using the χ2 test. Pairwise comparisons were also performed using the worst-performing biologic as the comparator for each segment assessed. Continuous variables were presented as means with SDs or medians with interquartile ranges (IQRs). Multivariate logistic regression models evaluated the relationship between biologics and outcomes of interest at 1 year. Adjustments for known confounders of EH were performed, including disease duration, concomitant corticosteroid use, and prior anti-TNF failure. Results are presented as unadjusted odds ratios (ORs) and adjusted ORs (aORs), with 95% confidence intervals (CIs) and associated P values. Statistical significance was chosen to be at a P value of <0.05. Data were analyzed using Stata/IC version 15.0.

RESULTS

Demographics

Baseline characteristics of the 299 participants included in this analysis are provided in Table 1. A total of 184 participants (61.5%) had a SES-CD of ≥3 in the ileum, 133 (44.5%) in the ascending colon, 119 (39.8%) in the transverse colon, 166 (55.5%) in the descending colon, and 132 (44.1%) in the rectum. There were fewer very large ulcers in the ileum (24/184, 13.0%) compared with any of the colonic segments (ascending colon [22/133, 16.5%], transverse colon [21/119, 17.6%], descending colon [38/166, 22.9%], and rectum [29/132, 22.0%]). Overall, participants included had moderate-to-severe endoscopic disease because the median SES-CD score at baseline was 12.0 (IQR 8.0–17.0). The mean age was 36.9 years (SD 13.0), and 134 participants (44.8%) were male. The median disease duration was 5.6 years (IQR 2.0–11.5), and 68 participants (22.7%) were previously exposed to anti-TNFs. A total of 66 participants (22.1%) used corticosteroids, and 147 (49.2%) used immunomodulators concomitantly. Overall, more patients were treated with infliximab (141, 47.2%) compared with vedolizumab (56, 18.7%), adalimumab (61, 20.4%), and ustekinumab (41, 13.7%).

T1
Table 1.:
Baseline characteristics of the study population

Overall EH

The relative ability of infliximab, vedolizumab, adalimumab, and ustekinumab to achieve overall EH, defined using a definition of total SES-CD <3, was assessed. Results from this analysis are presented in Table 2. Patients treated with adalimumab (17/61 [27.9%]) and infliximab (39/141 [27.7%]) had the highest rate of 1-year EH, followed by ustekinumab (7/41 [17.1%]) and vedolizumab (4/56 [7.1%]). Compared with vedolizumab-treated patients, adalimumab-treated patients had a greater than five-fold likelihood of achieving 1-year EH, which remained significant after adjustment for covariates (aOR: 5.79, 95% CI: 1.77–18.95, P = 0.004) (Table 4). Similarly, after adjustment, patients treated with infliximab had a greater likelihood of achieving 1-year EH compared with those treated with vedolizumab (aOR: 4.59, 95% CI: 1.48–14.22, P = 0.008). No significant differences were observed between ustekinumab and vedolizumab. Of the 299 patients included in this analysis, a total of 242 patients had large ulcers at baseline. Vedolizumab (2/47 [4.3%]) and ustekinumab (5/34 [14.7%]) demonstrated the lowest rates of 1-year EH in patients with large ulcers, whereas adalimumab (11/51 [21.6%]) and infliximab (27/110 [24.6%]) had higher rates of 1-year EH. Compared with vedolizumab, adalimumab demonstrated a significantly greater ability to achieve 1-year EH in those with large ulcers at baseline after adjustment for covariates (aOR: 6.45, 95% CI: 1.32–31.38, P = 0.021). Similarly, this was observed among patients treated with infliximab (aOR: 6.04, 95% CI: 1.31–27.82, P = 0.021). To evaluate whether a higher SES-CD enrollment threshold would affect the relative positioning of therapies, sensitivity analyses were performed on the study population restricted to 250 patients with baseline SES-CD ≥7, of which 108 were treated with infliximab, 32 with ustekinumab, 54 with adalimumab, and 56 with vedolizumab. Similar rates of 1-year EH were observed in this sensitivity analysis, with infliximab-treated patients achieving the highest rate of 1-year EH (28/108 [25.9%]), followed closely by adalimumab (12/54 [22.2%]), whereas ustekinumab (5/32 [15.6%]) and vedolizumab (4/56 [7.1%]) were the worst-performing (P = 0.035). No difference was observed between ustekinumab and vedolizumab for achieving 1-year EH in patients with large ulcers at baseline. Similar trends were observed for those with very large ulcers at baseline (n = 90) and are also presented in Table 2.

T2
Table 2.:
Endoscopic outcomes at 1 year among all participants

Overall EH among biologic-naive patients

Among the 299 participants included in this analysis, a total of 240 participants were biologic-naive. Table 3 summarizes the 1-year endoscopic outcomes of these participants. Adalimumab demonstrated the highest rate of 1-year EH (12/36 [33.3%]), followed by infliximab (39/141 [27.7%]), ustekinumab (5/22 [22.7%]), and vedolizumab (4/41 [9.8%]). Compared with vedolizumab, again, adalimumab demonstrated a significantly greater ability to achieve 1-year EH after adjustment for covariates (aOR: 4.68, 95% CI: 1.34–16.30, P = 0.015) (see Supplementary Table 1, Supplementary Digital Content 1, https://links.lww.com/AJG/C508). Similar findings were observed for infliximab (aOR: 3.99, 95% CI: 1.27–12.51, P = 0.018). No significant differences were observed between vedolizumab and ustekinumab. Similar trends were observed among biologic-naive patients with very large or large ulcers.

T3
Table 3.:
Endoscopic outcomes at 1 year among biologic-naive participants

EH of the ileum

Supplementary Table 2 (see Supplementary Digital Content 1, https://links.lww.com/AJG/C508) summarizes the number of patients with ileal involvement at baseline and the proportion achieving endoscopic outcomes at 1 year. In total, 184 patients had a SES-CD of ≥3 in the ileum. Vedolizumab demonstrated the lowest rate of ileal EH at 1 year (8/43 [18.6%]). Compared with vedolizumab, infliximab demonstrated the highest rate of ileal EH at 1 year (29/79 [36.7%]), followed by adalimumab (12/40 [30%]) and ustekinumab (5/22 [22.7%). After adjustment for covariates, no significant difference in the rate of ileal EH was observed between vedolizumab and infliximab (aOR: 2.25, 95% CI: 0.85–5.96, P = 0.102), adalimumab (aOR: 2.02, 95% CI: 0.69–5.97, P = 0.202), or ustekinumab (aOR: 1.81, 95% CI: 0.47–6.91, P = 0.389) (Table 4). Sensitivity analysis using the outcome of absence of ileal ulcers was performed on 119 patients with large ileal ulcers at baseline. Vedolizumab had the lowest rate of absent ileal ulcers at 1 year (2/23 [8.7%]). Compared with vedolizumab, infliximab demonstrated the highest rate of absence of ileal ulcers at 1 year (20/49 [40.8%], aOR: 5.39, 95% CI: 1.03–28.05, P = 0.045). This was followed by adalimumab (9/30 [30%]) and ustekinumab (3/17 [17.7%]), which were not significant after adjustment for covariates (P = 0.077 and P = 0.259, respectively). Among 24 participants with very large ulcers at baseline, none of the 7 participants who were treated with vedolizumab achieved absence of ileal ulcers at 1 year. By contrast, 3 of 5 infliximab-treated patients (60%) and 1 of 6 adalimumab-treated patients (16.7%) with very large ileal ulcers had clearance of ileal ulcers.

T4
Table 4.:
Likelihood of achieving endoscopic outcomes at 1 yeara

EH of the ileum among biologic-naive patients

Outcomes of the 145 patients with ileal disease at baseline who were biologic-naive are presented in Supplementary Table 3 (see Supplementary Digital Content 1, https://links.lww.com/AJG/C508). Vedolizumab demonstrated the lowest rate of ileal EH at 1 year (7/32 [21.9%]). Ustekinumab demonstrated the highest rate of ileal EH at 1 year (4/10 [40%], aOR: 2.13, 95% CI: 0.43–10.46, P = 0.354), followed by adalimumab (9/24 [37.5%], aOR: 1.88, 95% CI: 0.55–6.38, P = 0.313) and infliximab (29/79 [36.7%], aOR: 1.96, 95% CI: 0.59–6.45, P = 0.270). When biologics among biologic-naive patients with large ileal ulcers were compared, again, vedolizumab had the lowest rate of absence of ileal ulcers at 1 year (2/17 [11.8%]). Adalimumab demonstrated the highest rate of absence of ileal ulcers at 1 year (7/17 [42.3%], aOR: 3.75, 95% CI: 0.60–23.30, P = 0.156) compared with infliximab (20/49 [40.8%], aOR: 3.10, 95% CI: 0.48–20.04, P = 0.234) and ustekinumab (2/7 [28.6%], aOR: 1.92, 95% CI: 0.18–20.24, P = 0.589). Similar trends were observed among the 14 biologic-naive participants with very large ileal ulcers. Once adjusted for covariates, no significant differences were observed between biologics for any of the ileal outcomes above among biologic-naive patients.

EH of the colon

Supplementary Table 4 (see Supplementary Digital Content 1, https://links.lww.com/AJG/C508) summarizes the outcomes of patients with disease in any of the colonic segments at baseline and the proportion achieving endoscopic outcomes at 1 year. In total, 232 patients had at least 1 colonic segment with a SES-CD of ≥3. Ustekinumab had the lowest rate of colonic EH (9/31 [29.0%]). Compared with ustekinumab, the highest proportion of patients achieving segment EH at 1 year were treated with adalimumab (30/48 [62.5%], aOR: 3.97, 95% CI: 1.45–10.90, P = 0.007), followed by infliximab (55/105 [52.4%], aOR: 2.08, 95% CI: 0.82–5.27, P = 0.121). There was no significant difference in colonic EH between ustekinumab and vedolizumab (aOR: 1.00, 95% CI: 0.35–2.80, P = 0.995). Among the 176 patients with large colonic ulcers at baseline, ustekinumab again had the lowest rate of absence of colonic ulcers at 1 year (8/27 [29.6%]). Infliximab demonstrated the highest rate of absence of colonic ulcers at 1 year (55/78 [70.5%], aOR: 3.82, 95% CI: 1.35–10.81, P = 0.012), followed by adalimumab (24/37 [64.9%], aOR: 4.27, 95% CI: 1.37–13.31, P = 0.012). There were no significant differences between vedolizumab and ustekinumab (aOR: 1.42, 95% CI: 0.46–4.41, P = 0.540) (Table 4). Similar results were obtained when evaluating biologics and absence of colonic ulcers at 1 year among patients with very large colonic ulcers at baseline.

EH of the colon among biologic-naive patients

Among the 184 biologic-naive patients with colonic ulcers at baseline, ustekinumab had the lowest rate of segment EH at 1 year (5/17 [29.4%]). Adalimumab demonstrated the highest rate of segment EH at 1 year (18/27 [66.7%], aOR: 4.96, 95% CI: 1.29–19.03, P = 0.020), followed by infliximab (55/105 [52.4%], aOR: 2.71, 95% CI: 0.89–8.27, P = 0.081) and vedolizumab (13/35 [37.1%], aOR: 1.48, 95% CI: 0.41–5.38, P = 0.548) (see Supplementary Table 1/5, Supplementary Digital Content 1, https://links.lww.com/AJG/C508). Sensitivity analyses among those with large colonic ulcers at baseline (n = 133) using the outcome of absence of colonic ulcers at 1 year demonstrated that ustekinumab again had the lowest rate of absence of colonic ulcers at 1 year (5/14 [35.7%]). Infliximab had the highest rate of absence of colonic ulcers at 1 year (55/78 [70.5%], aOR: 4.73, 95% CI: 1.40–15.94, P = 0.012), followed by adalimumab (13/19 [68.4%], aOR: 4.33, 95% CI: 0.96–19.55, P = 0.057) and vedolizumab (12/22 [54.6%], aOR: 2.47, 95% CI: 0.59–10.27, P = 0.213). Among the 51 patients with very large colonic ulcers at baseline, compared with ustekinumab (2/9 [22.2%]), adalimumab (7/9 [77.8%]) demonstrated the highest rate of absence of colonic ulcers at 1 year (aOR: 18.53, 95% CI: 1.68–204.51, P = 0.017). After adjustment for known confounders, infliximab (19/25 [76.0%]) also demonstrated a significantly higher rate of absence of colonic ulcers at 1 year compared with ustekinumab (aOR: 15.71, 95% CI: 2.26–109.12, P = 0.005). No significant difference was observed when ustekinumab and vedolizumab were compared.

EH of the individual colonic segments

Endoscopic outcomes across individual colonic segments and among patients who were biologic-naive were also evaluated. Overall, adalimumab demonstrated the highest rate of segment EH in the ascending colon, transverse colon, and descending colon while infliximab had the highest rate of segment EH in the rectum. Among patients who were biologic-naive, adalimumab demonstrated the greatest ability to achieve segment EH across all colonic segments. Among patients with large ulcers, adalimumab continued to demonstrate the highest rate of absence of ulcers in the ascending colon (5/11 [45.5%]), transverse colon (6/14 [42.9%]), and descending colon (14/25 [56.0%]), although no significant differences were observed after adjustment for covariates. Similarly, infliximab continued to demonstrate the highest rate of absence of ulcers in the rectum among patients with large rectal ulcers at baseline, although this was not statistically significant compared with the worst-performing biologic, ustekinumab (12/28 [42.9%] vs 0/18 [0%]).

DISCUSSION

As more biologic therapies come to market to treat IBD, positioning of drugs becomes increasingly challenging. Although head-to-head trials are the preferred way for comparing efficacy of biologics, there are still relatively few trials which have been conducted in IBD. SEAVUE was the first head-to-head trial of biologics in CD and did not find superiority of ustekinumab over adalimumab regarding 1-year clinical remission or endoscopic improvement. Further head-to-head studies will likely come within the next several years, but until then, clinicians and patients need guidance on how and when to choose which biologics in IBD. In this post hoc analysis of 4 clinical trial programs, we found that the TNF antagonists had superior rates of 1-year overall EH and colonic EH compared with vedolizumab and ustekinumab. For overall EH, pairwise comparisons were significant for infliximab and adalimumab, which remained significant after adjustment for covariates. Similar findings were observed among biologic-naive participants. For ileal EH, there were no significant differences once adjusted for covariates between biologic therapies among all patients and biologic-naive patients. However, among those with ileal ulcers >0.5 cm, pairwise comparisons were significant for infliximab compared with vedolizumab. Regarding the rate of colonic EH, TNF-α antagonists were superior to ustekinumab and vedolizumab for achieving 1-year EH. After adjustment for covariates, patients treated with adalimumab had a nearly 4-fold greater likelihood of achieving colonic EH, with a similar trend observed for infliximab. This finding was persistent in subgroup analyses limited to biologic-naive patients.

It has previously been suggested that the ileum does not heal as well as the colon, both with anti-TNF-α biologics and other advanced therapies (16,22,23). A recent post hoc analysis of the TAILORIX trial reported lower rates of EH in the ileum compared with that in the colon (24). Similarly, assessments performed using balloon-assisted endoscopy, which can evaluate more small bowel than seen on ileocolonoscopy, have also suggested that ulcers in the small bowel were more difficult to heal than ulcers in the colon (25,26). Given the relative difficulty of achieving healing in the small bowel/ileum, future studies should consider separating results of patients with only small bowel/ileal disease to better inform positioning of therapies. It is unclear why the small bowel is more challenging to heal, but differences in immune tolerance and microbiome profiles have been hypothesized to account for differences in healing of the ileum as compared with the colon (27). We previously reported that larger and deeper ulcers of the ileum were very unlikely to heal as compared with smaller or superficial ulcers when using infliximab (13). However, the findings of this study may suggest that TNF-α antagonists could be preferred agents for patients with ileal predominant disease, particularly those with large or very large ulcers, given their superiority to vedolizumab.

In our study, although we found that vedolizumab and ustekinumab performed less well compared with anti-TNFs in both the ileum and the colon, the difference in healing with vedolizumab among patients with ileal disease compared with those with colonic disease (18.6% vs 31.3%) was numerically greater than the difference observed with ustekinumab (22.7% vs 29%). Among patients who were biologic-naive, the difference in the rate of healing in the ileum and colon was less pronounced between vedolizumab (21.9% vs 37.1%) and ustekinumab (40.0% vs 29.4%). These observations lend support to previous mechanistic work demonstrating preferential ileal homing and underscore the need to understand differences in healing rates between biologic-naive and experienced populations (28). Vedolizumab was evaluated for its ability to achieve endoscopic outcomes in the prospective LOVE CD trial, which found that nearly one-third of patients achieved endoscopic remission (defined as SES-CD <4) at 1 year (29). Dose intensification was permitted in the trial, which found an association between serum concentration of vedolizumab and improved outcomes. While serum drug levels could help inform the interpretation of our findings, serial drug monitoring was not performed in all trials included in this analysis. Given the use of dose intensification and lack of data availability, data from the LOVE CD trial were not included in this analysis.

Most real-world comparisons have compared anti-TNF agents with each other and with anti-integrin agents, but comparisons of EH are limited, and furthermore, no analysis has specifically compared EH by subsegment (30–34). More recent real-world studies have compared ustekinumab with vedolizumab in patients with prior anti-TNF treatment and have suggested that ustekinumab may be superior for improvement of clinical outcomes, but these studies do not inform clinicians of effectiveness in biologic-naive patients, nor do they inform how these agents compare with TNF-α antagonists (35,36). Conclusions from these studies are limited because of selection bias in real-world treatment patterns, which is partly overcome in our analysis by using post hoc data from clinical trial programs with subgroup analyses of biologic-naive patients.

The only head-to-head randomized controlled trial of biologic therapies in CD was SEAVUE, which did not demonstrate any significant statistical differences in clinical or endoscopic remission in patients treated with ustekinumab as compared with adalimumab (9). However, it remains possible that disease distribution was different in ustekinumab-treated patients compared with adalimumab-treated patients, and breakdown of EH by segment could further inform the utility of these biologics for treating CD. Furthermore, patients enrolled in SEAVUE had a milder burden of disease based on lower SES-CD scores compared with typical placebo-controlled trials. In SEAVUE, the median SES-CD score of patients treated with adalimumab and ustekinumab was 8.0 and 7.0, respectively, suggesting that this patient population had mild-moderate endoscopic disease burden. However, in our analysis, the median SES-CD of adalimumab-treated and ustekinumab-treated patients was 14.0 and 12.0, respectively, suggesting a moderate-severe patient population, which is similar to what was observed in other studies included in the current analysis (infliximab 11.0 and vedolizumab 14.0). These findings suggest that ustekinumab and adalimumab perform comparably for patients with milder endoscopic disease, but those with moderate-severe endoscopic disease at baseline are more likely to respond to anti-TNF therapy. One caveat however may be inclusion of patients within UNITI in our analysis who received ustekinumab every 12 weeks during maintenance, for which endoscopic improvement may be less than those using it every 8 weeks.

Our study has several strengths which include the use of 4 high-quality clinical trial data sets which included patients with continuous treatment with different biologic therapies for a duration of 1 year. All included trials had central blinded reading of endoscopic assessments using the SES-CD. This is also the first study to compare several different available biologic options for CD regarding their ability to heal within each of the segments of the colon and the ileum. Another strength was that comparisons were made using a uniform definition for global EH (SES-CD <3) and segment EH (SES-CD = 0) because different definitions used within the studies prevent comparisons using other indirect methodologies such as network meta-analyses (e.g., definition of endoscopic remission used in VERSIFY was SES-CD ≤4 and that in EXTEND was the absence of mucosal ulcers). Although several network meta-analyses have been performed to compare the relative efficacy of biologics for achieving clinical remission (37–39), none have compared 1-year EH largely due to a lack of uniform EH definition across trials and small sample sizes.

This study however has some limitations. First, it cannot substitute for head-to-head trials of biologics in CD because we cannot account for all confounding variables. We did try to account for this limitation by performing subgroup analyses to account for biologic-naive patients only and also by performing multiple logistic regression analyses to account for confounding variables, which may have had an impact on the outcome of interest. It is important to note that some analyses had very few patients who met the outcome of interest, which can lead to overfitting of logistic regression models in certain cases (40). Second, we compare biologics which have different rapidity of onset and likely differences in how long treatment should be continued before EH can be observed (41). However, all therapies assessed are believed to have the ability for inducing EH at time frames of less than 1 year, so the 1-year outcomes presented here should be fair and reasonable comparisons. Third, comparisons were performed with standard doses of biologics, and it remains possible that there would be further differences observed if some biologics could be optimized further using combination therapy with an immunomodulator (42) or with early drug-level monitoring and optimization of dosing (43,44). In addition, patients who received infliximab in our analysis differ from the rest of our study population as they had lower disease duration, lower baseline SES-CD, and greater concomitant immunomodulator use. This contrasts with the patients who received adalimumab who had similar baseline characteristics to patients who received ustekinumab or vedolizumab. However, similar results were observed for patients treated with adalimumab and infliximab, thus providing confidence in the results observed for anti-TNFs. In addition, trials included in this analysis had some differences in the study design. For example, participants included in the VERSIFY trial received open-label vedolizumab compared with trials of active therapy vs placebo in other studies included. There may be differences in patients' willingness to persist on therapy when blinded within placebo-controlled trials, compared with patients receiving open-label therapy or an active comparator such as in the CT-P13 study. However, the trial design should not be a substantial confounder, given that all trials had centrally read endoscopy and participants in VERSIFY were included in the extension study regardless of response status by week 26. There are several other differences between trials that also may potentially confound our findings. First, a cohort of participants was selected to participate in the UNITI endoscopic substudy, and we cannot rule out the potential for selection bias in those chosen for the endoscopic substudy. Second, of the 299 patients included in this analysis, 74 (25%) did not have 1-year endoscopic assessments and were deemed nonremitters (20/41 from IM-UNITI, 10/56 from VERSIFY, 9/61 from EXTEND, and 35/141 from CT-P13). Third, the trials included in this analysis were conducted across different time periods. Fourth, the clinical trials included in our analysis had varying criteria for endoscopic disease at enrollment. Although the minimum SES-CD required for inclusion in our analysis was ≥3, we also ran sensitivity analyses evaluating outcomes among patients with baseline SES-CD ≥7 with similar results, as vedolizumab consistently demonstrated lower rates of 1-year EH among the 4 biologics evaluated. This provides further confidence that endoscopic criteria at entry did not sufficiently bias against vedolizumab in our analysis. Finally, some of the above analyses (e.g., very large ulcer analyses in Supplementary Table 2/3, Supplementary Digital Content 1, https://links.lww.com/AJG/C508) have very low sample sizes, and results should be considered hypothesis-generating rather than confirming a prior hypothesis. Future studies are warranted, particularly using real-world data, and should be adequately powered with correction for multiple comparisons.

In conclusion, we observed that TNF-α antagonist therapies had superior rates of inducing EH overall compared with anti-integrin and anti-p40 therapies. The evolving importance for EH and the known disconnect between symptoms and objective measures of disease activity make the superiority of TNF-α antagonist therapies for EH important when considering which agents should be used first-line in routine practice. Safety, convenience, and cost of therapy also influence decision making, and the availability of biosimilar TNF-α antagonist therapies in routine practice adds additional consideration for cost-effectiveness in population health decisions. Further randomized controlled trials comparing biologic therapies in CD are warranted to confirm or refute the findings of this study.

CONFLICTS OF INTEREST

Guarantor of the article: Neeraj Narula, MD, MPH, FRCPC.

Specific author contributions: N.N.: study concept and design, acquisition and compilation of data, statistical analysis, data interpretation, and drafting of the article. E.C.L.W.: acquisition and compilation of data, statistical analysis, and drafting of the article. P.S.D.: study concept and design, data interpretation, and drafting of the article. J.K.M. and V.J.: study design and drafting of the article. W.R.: study concept and design, acquisition and compilation of data, data interpretation, and drafting of the article. All authors approved the final version of the article.

Financial support: None to report.

Potential competing interests: N.N. holds a McMaster University Department of Medicine Internal Career Award and has received honoraria from Janssen, AbbVie, Takeda, Pfizer, Merck, Sandoz, Novartis, and Ferring. P.S.D. has received consulting and/or research support from Takeda, Pfizer, Janssen, BMS, Gilead, Novartis, Lily; stock options DigbiHealth; and royalties: PreciDiag. J.K.M. has received honoraria from Janssen, AbbVie, Allergan, Bristol Myers Squibb, Ferring, Janssen, Lilly, Lupin, Merck, Pfizer, Pharmascience, Roche, Shire, Takeda, and Teva. V.J. has received consulting/advisory board fees from AbbVie, Alimentiv (formerly Robarts Clinical Trials), Arena pharmaceuticals, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genetech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Reistone Biopharma, Roche, Sandoz, Takeda, Teva, and TopiVert; speaker's fees from AbbVie, Ferring, Galapagos, Janssen Pfizer Shire, and Takeda. W.R. has received support for the following: Speaker for Abbott Laboratories, AbbVie, AESCA, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult; consultant for Abbott Laboratories, AbbVie, AESCA, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Cellerix, ChemoCentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernst & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Med Ahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Peri Consulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpoint Medical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, TiGenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; advisory board member for Abbott Laboratories, AbbVie, AESCA, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Cellerix, ChemoCentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpoint Medical, Takeda, Therakos, TiGenix, UCB, Zealand, Zyngenia, and 4SC. No other authors have any relevant conflicts of interest.

Data availability statement: This study, carried out under YODA Project #2021-4778, used data obtained from the Yale University Open Data Access Project, which has an agreement with Janssen Research & Development, LLC. The interpretation and reporting of research using these data is solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or Janssen Research & Development, LLC. This publication (Vivli protocol #00007387) is based on research using data from AbbVie and Takeda that have been made available through Vivli. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication. Data were also obtained by permission from Celltrion.

Study Highlights

WHAT IS KNOWN

  • ✓ The association between achievement of endoscopic healing (EH) and improved outcomes is well established.
  • ✓ Comparative effectiveness of approved biologics for Crohn's disease for achieving segment-specific EH has not been reported.

WHAT IS NEW HERE

  • ✓ Compared to vedolizumab, adalimumab and infliximab had superior rates of one-year EH.
  • ✓ No significant difference was observed between and vedolizumab and ustekinumab.
  • ✓ Among patients with large (>0.5 cm) ileal ulcers, infliximab had superior rates of one-year absence of ileal ulcers.
  • ✓ Compared to ustekinumab, adalimumab had superior rates of one-year EH in the colon.

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