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Histologic Outcomes With Vedolizumab Versus Adalimumab in Ulcerative Colitis: Results From An Efficacy and Safety Study of Vedolizumab Intravenous Compared to Adalimumab Subcutaneous in Participants With Ulcerative Colitis (VARSITY)

Open AccessPublished:June 15, 2021DOI:https://doi.org/10.1053/j.gastro.2021.06.015

      Background and Aims

      VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis) showed superior clinical remission and endoscopic improvement in ulcerative colitis with vedolizumab vs adalimumab. This analysis compared histologic outcomes.

      Methods

      Patients in VARSITY were randomized 1:1 to maintenance with vedolizumab IV 300 mg every 8 weeks or adalimumab SC 40 mg every 2 weeks (both following standard induction). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52.

      Results

      In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Mean baseline histologic disease activity was similar between vedolizumab and adalimumab groups. Vedolizumab induced greater histologic remission than adalimumab at week 14 (Geboes: 16.7% vs 7.3%, Δ9.4% [95% confidence interval {CI}, 4.9%–13.9%], P < .0001; RHI: 25.6% vs 16.1%, Δ9.5% [95% CI, 3.8%–15.2%], P = .0011) and week 52 (Geboes: 29.2% vs 8.3%, Δ20.9% [95% CI, 15.6%–26.2%], P < .0001; RHI: 37.6% vs 19.9%, Δ17.6% [95% CI, 11.3%–23.8%], P < .0001) overall and in both anti–tumor necrosis factor (TNF)-naïve and -failure subgroups. Results were similar for minimal histologic disease activity. Histologic outcomes were generally better in anti–TNF-naïve vs -failure patients. At week 52, rates of mucosal healing (composite end point of histologic plus endoscopic improvement) were also higher with vedolizumab than adalimumab (Geboes: 25.6% vs 6.7%; RHI: 30.5% vs 14.5%).

      Conclusions

      Higher rates of histologic remission, minimal histologic disease activity, and combined histologic plus endoscopic outcomes were observed with vedolizumab than with adalimumab in ulcerative colitis in both anti–TNF-naïve and -failure subgroups.

      Registration

      ClinicalTrials.gov NCT02497469; EudraCT 2015-000939-33

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      CI (confidence interval), IV (intravenous), RHI (Robarts Histopathology Index), SC (subcutaneous), SD (standard deviation), TNF (tumor necrosis factor), UC (ulcerative colitis), VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous (IV) Compared to Adalimumab Subcutaneous (SC) in Participants With Ulcerative Colitis)

       Background and Context

      Combined endoscopic and histologic improvement is now considered the ultimate end point marking successful maintenance therapy for patients with ulcerative colitis in clinical trials and real-world practice.

       New Findings

      VARSITY showed greater histologic remission and minimal histologic disease activity at weeks 14 and 52 with vedolizumab than adalimumab in both anti–tumor necrosis factor-naïve and anti–tumor necrosis factor-failure subgroups. Histologic improvement correlated with endoscopic improvement.

       Limitations

      Study limitations included gut variability in histopathologic severity due to diffuse mucosal inflammation in ulcerative colitis and a lack of patient long-term follow-up.

       Impact

      In VARSITY, vedolizumab showed superior treatment effects versus adalimumab in achieving all evaluated histologic outcomes in patients with moderate to severe ulcerative colitis in both anti–tumor necrosis factor-naïve and -failure subgroups.
      Ulcerative colitis (UC) is a chronic and disabling inflammatory bowel disease characterized by relapsing and remitting mucosal inflammation. The ultimate goals of treatment are to induce and maintain clinical remission and improve quality of life.
      • Turner D.
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      STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD.
      Conventional treatments for UC include mesalamine, thiopurines, oral immunomodulators, and corticosteroids. When these agents fail, biologic agents, such as anti–tumor necrosis factor (anti–TNF; eg, infliximab, adalimumab, and golimumab) and anti–integrin (vedolizumab) therapies, are commonly and widely used.
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      VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis; NCT02497469; EudraCT 2015-000939-33) is the first head-to-head comparison of the efficacy and safety of 2 biologic agents in UC.
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      Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis.
      Vedolizumab and adalimumab are both approved for use in patients with moderately to severely active UC and Crohn’s disease refractory to conventional therapies.
      ,
      The study showed superior clinical remission and endoscopic improvement at week 52 with vedolizumab vs adalimumab. Vedolizumab and adalimumab were both generally safe and well tolerated.
      • Sands B.E.
      • Peyrin-Biroulet L.
      • Loftus Jr., E.V.
      • et al.
      Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis.
      There is general consensus that aside from resolution of symptoms, endoscopic improvement is the ultimate end point marking successful maintenance therapy for patients with UC in clinical practice and trials.
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      Histologic remission: the ultimate therapeutic goal in ulcerative colitis?.
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      Systematic review: histological remission in inflammatory bowel disease. Is ‘complete’ remission the new treatment paradigm? An IOIBD initiative.
      However, endoscopic changes do not necessarily reflect quiescent microscopic disease, and complete resolution of mucosal inflammation can only be confirmed by histologic assessment.
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      Histological healing in inflammatory bowel disease: a still unfulfilled promise.
      ,
      • Bryant R.V.
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      • Travis S.P.
      • et al.
      Systematic review: histological remission in inflammatory bowel disease. Is ‘complete’ remission the new treatment paradigm? An IOIBD initiative.
      Thus, including histologic outcomes as treatment targets should be considered. Histologic outcomes can also be useful for assessing disease activity or treatment response.
      • Peyrin-Biroulet L.
      • Bressenot A.
      • Kampman W.
      Histologic remission: the ultimate therapeutic goal in ulcerative colitis?.
      ,
      • Pai R.K.
      • Jairath V.
      • Vande Casteele N.
      • et al.
      The emerging role of histologic disease activity assessment in ulcerative colitis.
      Histologic outcomes are not currently recommended as a therapeutic goal for UC in clinical practice. This is possibly because of the current lack of sufficient evidence to support consensus on standardized and validated scoring systems that could be implemented routinely.
      • Turner D.
      • Ricciuto A.
      • Lewis A.
      • et al.
      STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD.
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      • et al.
      An international consensus to standardize integration of histopathology in ulcerative colitis clinical trials.
      • Magro F.
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      ECCO position paper: harmonization of the approach to ulcerative colitis histopathology.
      • Peyrin-Biroulet L.
      • Sandborn W.
      • Sands B.E.
      • et al.
      Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target.
      The recently published Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE II) guidelines affirm that histologic healing is not a formal treatment target but could be assessed as a measure of the depth of clinical remission.
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      • Lewis A.
      • et al.
      STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD.
      Microscopic evaluation of biopsy samples are prone to sampling error and interobserver and intraobserver variability.
      • Peyrin-Biroulet L.
      • Sandborn W.
      • Sands B.E.
      • et al.
      Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target.
      • Freeman H.J.
      Limitations in assessment of mucosal healing in inflammatory bowel disease.
      • Mosli M.H.
      • Feagan B.G.
      • Sandborn W.J.
      • et al.
      Histologic evaluation of ulcerative colitis: a systematic review of disease activity indices.
      Despite these limitations, histologic outcomes in addition to endoscopic improvement may be associated with superior long-term clinical outcomes in UC
      • Peyrin-Biroulet L.
      • Bressenot A.
      • Kampman W.
      Histologic remission: the ultimate therapeutic goal in ulcerative colitis?.
      ,
      • Christensen B.
      • Hanauer S.B.
      • Erlich J.
      • et al.
      Histologic normalization occurs in ulcerative colitis and is associated with improved clinical outcomes.
      and may predict future UC relapse and complications.
      • Lobaton T.
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      • Ruiz-Cerulla A.
      • et al.
      Prognostic value of histological activity in patients with ulcerative colitis in deep remission: a prospective multicenter study.
      ,
      • Travis S.P.
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      • Orchard T.
      • et al.
      Review article: defining remission in ulcerative colitis.
      These outcomes are also predictive of future hospitalization, corticosteroid use, exacerbation of UC, and progression to advanced colorectal neoplasia.
      • Bryant R.V.
      • Burger D.C.
      • Delo J.
      • et al.
      Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up.
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      • Harpaz N.
      • Itzkowitz S.
      • et al.
      Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study.
      • Zenlea T.
      • Yee E.U.
      • Rosenberg L.
      • et al.
      Histology grade is independently associated with relapse risk in patients with ulcerative colitis in clinical remission: a prospective study.
      In many clinical trials, endoscopic improvement (based on the Mayo endoscopic subscore) has been included as a secondary end point. However, according to the most recent United States Food and Drug Administration guidance on UC clinical trial end points, the determination of mucosal healing must be supported by both endoscopic appearance of the mucosa and histologic assessment of the mucosa.
      U.S. Food and Drug Administration
      Guidance for Industry: Ulcerative Colitis-Clinical Trial Endpoints.
      Validated histologic scoring systems in UC include the Geboes Index score, the Robarts Histopathology Index (RHI), and the Nancy Index.
      • Pai R.K.
      • Jairath V.
      • Vande Casteele N.
      • et al.
      The emerging role of histologic disease activity assessment in ulcerative colitis.
      Data on mucosal healing assessed histologically with vedolizumab and adalimumab are currently limited.
      Here, we report further results from the VARSITY trial that more fully explore the histologic end points of histologic remission and minimal histologic disease activity associated with vedolizumab vs adalimumab treatment of UC as assessed using both the Geboes and RHI histologic scoring systems, including a composite endoscopic-histologic outcome end point.

      Patients and Methods

       Study Design

      VARSITY was a phase 3b, randomized, double-blind, double-dummy, multicenter, active-controlled study that evaluated the efficacy and safety of vedolizumab compared with adalimumab among adult patients with moderately to severely active UC over a 52-week treatment period and a subsequent 18-week follow-up period after the last dose. The trial was conducted from July 2015 through January 2019 at 245 sites in 34 countries. A comprehensive description of the VARSITY trial, the study protocol, and Institutional Review Board approvals was published with the primary efficacy and safety results.
      • Sands B.E.
      • Peyrin-Biroulet L.
      • Loftus Jr., E.V.
      • et al.
      Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis.

       Patient Eligibility

      Eligible patients were adults aged 18 to 85 years with moderately to severely active UC, defined as a complete Mayo score of 6 to 12 and an endoscopic subscore of ≥2, colonic involvement of ≥15 cm, and a confirmed diagnosis of UC for ≥3 months before screening. Anti–TNF-experienced patients (except adalimumab) who discontinued treatment due to documented reasons other than safety were eligible, with enrollment capped at 25%. Anti–TNF-naïve patients who were unresponsive to or had lost response to conventional treatments were also eligible. Patients on corticosteroids at baseline continued on the same dose until week 6, after which the dose was tapered based on physician’s clinical judgment (no forced tapering) if the patient exhibited a treatment response. Patients for whom corticosteroid tapering was not possible were withdrawn from the study and recorded as treatment failures.
      • Sands B.E.
      • Peyrin-Biroulet L.
      • Loftus Jr., E.V.
      • et al.
      Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis.
      The main criteria for patient exclusion included extensive colonic resection, colectomy, evidence of active infection, and prior exposure to vedolizumab, natalizumab, efalizumab, adalimumab, etrolizumab, rituximab, or anti–mucosal addressin cell adhesion molecule-1 antibodies. No topical treatment was allowed at baseline or during the study.

       Randomization and Treatment

      Patients were randomized 1:1 to vedolizumab or adalimumab. Patients in the vedolizumab treatment group received a 300-mg IV infusion on day 1 and again at weeks 2, 6, 14, 22, 30, 38, and 46, plus placebo SC injections on day 1 (4 injections), week 2 (2 injections), and a single injection every 2 weeks thereafter until week 50. Patients assigned to adalimumab received multiple SC injections on days 1 and 2 (4 injections of 40 mg each on 1 day or two 40-mg injections per day for 2 consecutive days, totaling 160 mg), week 2 (two 40-mg injections on 1 day, totaling 80 mg), and single 40-mg injections every 2 weeks thereafter until week 50, as well as placebo IV infusions at day 1 and weeks 2, 6, 14, 22, 30, 38, and 46. Vedolizumab and adalimumab were both administered according to their US prescribing guidelines.
      ,
      Randomization was performed centrally using computer-generated randomization schedules and stratified by prior use of anti–TNF agents and concomitant use of oral corticosteroids. Patients who did not respond to treatment based on the investigator’s discretion were withdrawn and treated with the local standard of care. No dose escalation was permitted for either treatment group.

       Assessment and Outcomes

      Flexible sigmoidoscopy was performed at screening, at weeks 14 and 52, or at early termination. Procedure videos were sent to and read by a central reader blinded to patient details, study visit, and treatment. One rectosigmoid biopsy specimen was obtained from the most severely affected area of inflammation from each patient to evaluate histology. Biopsy specimens were read by a single central reader blinded to patient details, study visit, and treatment. Regular study visits occurred through week 52, with a final safety follow-up visit at week 68.
      Prespecified histologic exploratory end points included histologic remission and minimal histologic disease activity based on the Geboes and RHI scoring systems at study week 14 and week 52. Histologic outcomes were assessed in the overall population and in patient subgroups with or without prior anti–TNF agent use. The thresholds for histologic remission and minimal disease activity on the 2 scores were each predefined individually based on available literature on each system at the time of the study design, before the establishment of new standards and guidance.
      Histologic remission was defined as Geboes grade <2 (with no neutrophils or eosinophils) and minimal histologic disease activity as Geboes grade ≤3.1. The Geboes Index is a validated and reproducible histologic scoring system, with particular focus/interest for pathologists. It includes 6 grades: structural changes (0), chronic inflammatory infiltrates (1), neutrophils and eosinophils in lamina propria (2), neutrophils in epithelium (3), crypt destruction (4), and erosion or ulceration (5), each subdivided into 4 to 5 subgrades. The grades and subgrades can be assigned numeric values to produce a continuous Geboes score between 0 and 22 (as used for baseline histologic disease assessment).
      • Geboes K.
      • Riddell R.
      • Ost A.
      • et al.
      A reproducible grading scale for histological assessment of inflammation in ulcerative colitis.
      Geboes subgrade 2B.0 is defined as having no neutrophils and subgrade 2A.0 as no increase in eosinophils within the lamina propria, whereas Geboes grade 3.1 is defined as having neutrophils in the epithelium with <5% crypts involved (see Supplementary Table 1).
      • Geboes K.
      • Riddell R.
      • Ost A.
      • et al.
      A reproducible grading scale for histological assessment of inflammation in ulcerative colitis.
      Histologic remission was also defined as an RHI score ≤2 and minimal histologic disease activity as an RHI score ≤4. The RHI is also a valid and reproducible scoring system developed after a model-building process. Scores range from 0 to 33 based on 4 main parameters: chronic inflammatory infiltrates, lamina propria neutrophils, neutrophils in the epithelium, and surface epithelial injury.
      • Mosli M.H.
      • Feagan B.G.
      • Zou G.
      • et al.
      Development and validation of a histological index for UC.
      An RHI score of ≤2 denotes histologic remission as long as there are no neutrophils in the lamina propria and in the epithelium, whereas an RHI score of ≤4 can involve some chronic inflammatory infiltrate plus some increase in neutrophils in the lamina propria or epithelium.
      • Mosli M.H.
      • Feagan B.G.
      • Zou G.
      • et al.
      Development and validation of a histological index for UC.
      Full details of the RHI are provided in Supplementary Table 2.
      Post hoc exploratory end points included assessment of mucosal healing based on composite outcomes of histologic remission or minimal histologic disease activity and endoscopic improvement (defined as a Mayo endoscopic subscore of ≤1 point) at week 52, and evaluation of potential statistical associations between histologic outcomes and endoscopic improvement at weeks 14 and 52.

       Statistical Analysis

      Efficacy was analyzed in the full analysis set (all randomized patients who received ≥1 dose of study drug, according to treatment allocation). All statistical inference was 2-sided at a .05 level of significance. All proportion-based efficacy end points were analyzed using the Cochran-Mantel-Haenszel tests adjusting for randomization stratification factors, producing nominal P values and point estimates of treatment difference along with 95% confidence intervals (CIs). All patients with missing data for determination of end point status were considered treatment failures (ie, nonresponders) in the analyses.
      The associations between histologic outcomes and endoscopic improvement were explored in a post hoc fashion based on observed data. To assess the degree of agreement (eg, concordance) between histologic and endoscopic measurements, Cohen’s κ coefficient statistics were generated for binary histologic outcomes and endoscopic improvement using pooled data for both treatment arms at week 14 and week 52. The κ values were interpreted as follows: <0, disagreement; 0–0.20, slight agreement; 0.21–0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, substantial agreement; and 0.81–1.00, almost perfect agreement.
      • Tang W.
      • Hu J.
      • Zhang H.
      • et al.
      Kappa coefficient: a popular measure of rater agreement.
      To evaluate potential correlations between endoscopy and the 2 histologic scoring systems, Spearman’s correlation coefficients (ρ) were determined for binary histologic outcomes, endoscopic improvement, and numeric histologic scores and Mayo endoscopic subscores using pooled data for both treatment arms at week 14 and week 52. Spearman’s ρ values were interpreted as follows: 0–0.30, negligible positive correlation; 0.30–0.50, low/weak positive correlation; 0.50–0.70, moderate positive correlation; 0.70–0.90, high/strong positive correlation; and 0.90-1.00, very high/strong positive correlation.
      • Hinkle D.
      • Wiersma W.
      • Jurs S.
      Applied Statistics for the Behavioral Sciences.
      All authors had access to the study data and reviewed and approved the final manuscript.

      Results

       Patient Characteristics

      There were 1285 patients screened for eligibility, 771 patients were enrolled, and 769 patients were randomized and received ≥1 dose of adalimumab SC (n = 386) or vedolizumab IV (n = 383). Patient characteristics were generally comparable between treatment groups (Table 1). Discontinuation of treatment due to lack of efficacy occurred in 82 patients on adalimumab and 41 on vedolizumab.
      Table 1Patient Demographics and Baseline Disease Characteristics
      VariableAdalimumab SCVedolizumab IV
      (n = 386)(n = 385)
      Age, mean (SD), y40.5 (13.4)40.8 (13.7)
      Male sex, n (%)216 (56.0)234 (60.8)
      Weight at week 0, mean (SD), kg [n]73.4 (18.4) [386]72.7 (17.0) [383]
      Does not include 2 patients randomized but not treated.
      Duration of UC, mean (SD), y [n]6.4 (6.0) [385]
      One patient in the adalimumab group had an unknown duration of UC.
      7.3 (7.2) [383]
      Does not include 2 patients randomized but not treated.
      Prior anti–TNF agent use, n (%)
      As reported in the interactive web response system.
      81 (21.0)80 (20.8)
      Concomitant steroids, n (%)
      As reported in the interactive web response system.
      140 (36.3)139 (36.1)
      Concomitant immunomodulators, n (%)100 (25.9)101 (26.2)
      Baseline complete Mayo score, n (%)
       Mild (Mayo score <6)5 (1.3)9 (2.3)
       Moderate (Mayo score = 6–8)169 (43.8)154 (40.0)
       Severe (Mayo score = 9–12)210 (54.4)217 (56.4)
      Fecal calprotectin, mean (SD), μg/g, [n]2770.8 (4064.5) [332]2928.6 (5920.4) [341]
      Geboes Index score,
      Continuous Geboes Index score (on a scale of 0–22).
      mean (SD) [n]
      15.1 (5.0) [354]15.0 (4.9) [365]
      RHI score, mean (SD) [n]19.6 (8.9) [356]19.5 (8.7) [365]
      a Does not include 2 patients randomized but not treated.
      b One patient in the adalimumab group had an unknown duration of UC.
      c As reported in the interactive web response system.
      d Continuous Geboes Index score (on a scale of 0–22).
      Median duration of exposure was 477 days (range, 127–630 days) for vedolizumab (calculated as the date of last dose − date of first dose + 1 + 126 [5 half-lives after the last dose of vedolizumab]
      ) and 420 days (range, 71–454 days) for adalimumab (calculated as the date of last dose − date of first dose + 1 + 70 [5 half-lives after the last dose of adalimumab]
      ). Mean baseline histologic disease activity was similar between groups (Table 1), with a mean (standard deviation [SD]) Geboes continuous score of 15.0 (4.9) for vedolizumab and 15.1 (5.0) for adalimumab and an RHI score of 19.5 (8.7) for vedolizumab and 19.6 (8.9) for adalimumab.

       Geboes Grade

       Histologic Remission

      Histologic remission at week 14 (Geboes grade <2) was observed in 16.7% of patients in the vedolizumab group and in 7.3% in the adalimumab group (difference, 9.4%; 95% CI, 4.9%–13.9%; P < .0001) (Figure 1A). Overall, histologic remission at week 52 was 29.2% with vedolizumab vs 8.3% with adalimumab (difference, 20.9%; 95% CI, 15.6%–26.2%; P < .0001) (Figure 1B). Histologic remission at week 52 was greater with vedolizumab than with adalimumab in the anti–TNF-naïve patient subgroup (32.2% vs 9.5%; difference, 22.7%; 95% CI, 16.5%–29.0%; P < .0001) and in the anti–TNF exposure/failure subgroup (17.7% vs 3.7%; difference, 14.0%; 95% CI, −1.2% to 29.4%; P = .0045).
      Figure thumbnail gr1
      Figure 1Histologic remission (Geboes Index grade <2) at (A) week 14 and (B) week 52. Point estimates and 95% CIs were obtained using the Cochran-Mantel-Haenszel method with stratification by randomization stratification factor: concomitant use of oral corticosteroids (yes/no) and prior use of anti–TNF agents (yes/no) or by the Fisher’s exact method if the numerator was ≤5. Patients with missing end point data were considered treatment failures (ie, nonresponders). Q2W, every 2 weeks; Q8W, every 8 weeks. aNominal P value.

       Minimal Histologic Disease Activity

      Minimal histologic disease activity at week 14, defined as Geboes grade ≤3.1, occurred in 45.2% of patients on vedolizumab and in 30.6% on adalimumab (difference, 14.5%; 95% CI, 7.8%–21.2%; P < .0001) (Figure 2A). Vedolizumab outperformed adalimumab in achieving minimal histologic disease activity at week 52 (45.7% vs 30.8%; difference, 14.8%; 95% CI, 8.0%–21.5%; P < .0001) (Figure 2B). More patients achieved minimal histologic disease activity with vedolizumab than with adalimumab at week 52 in both anti–TNF-naïve (48.0% vs 34.1%; difference, 13.9%; 95% CI, 6.2%–21.7%; P = .0005) and anti–TNF-failure (36.7% vs 18.5%; difference, 18.0%; 95% CI, 4.5%–31.5%; P = .0107) cohorts.
      Figure thumbnail gr2
      Figure 2Minimal histologic disease activity (Geboes Index grade ≤3.1) at (A) week 14 and (B) week 52. Point estimates and 95% CIs were obtained using the Cochran-Mantel-Haenszel method with stratification by randomization stratification factor: concomitant use of oral corticosteroids (yes/no) and prior use of anti–TNF agents (yes/no) or by the Fisher’s exact method if the numerator was ≤5. Patients with missing end point data were considered treatment failures (ie, nonresponders). Q2W, every 2 weeks; Q8W, every 8 weeks; aNominal P value.

       Histologic Improvement

      The mean (SD) change from baseline in continuous Geboes score was −3.4 (7.38) at week 14 and −5.4 (7.65) at week 52 in the adalimumab group compared with −5.2 (7.26) at week 14 and −7.8 (7.01) at week 52 in the vedolizumab group.

       RHI Score

       Histologic Remission

      RHI scores showed a differentiation between treatment arms in patients achieving histologic remission at week 14 (25.6% with vedolizumab and 16.1% with adalimumab; difference, 9.5%; 95% CI, 3.8%–15.2%; P = .0011) (Figure 3A). Similar treatment differentiation was observed at week 52 with histologic remission defined as RHI score ≤2 (37.6% with vedolizumab and 19.9% with adalimumab; difference, 17.6%; 95% CI, 11.3%–23.8%; P < .0001) (Figure 3B) and in the anti–TNF-naïve (39.8% vs 22.6%; difference, 17.2%; 95% CI, 9.9%–24.4%; P < .0001) and anti–TNF-failure (29.1% vs 9.9%; difference, 19.0%; 95% CI, 7.1%–31.0%; P = .0022) patient subgroups.
      Figure thumbnail gr3
      Figure 3Histologic remission (RHI score ≤2) at (A) week 14 and (B) week 52. Point estimates and 95% CIs were obtained using the Cochran-Mantel-Haenszel method with stratification by randomization stratification factor: concomitant use of oral corticosteroids (yes/no) and prior use of anti–TNF (yes/no) or by the Fisher’s exact method if the numerator was ≤5. Patients with missing end point data were considered treatment failures (ie, nonresponders). Q2W, every 2 weeks; Q8W, every 8 weeks. aNominal P value. From N Engl J Med, Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al, Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. 381, 1215–1226. Copyright (c) 2020 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

       Minimal Histologic Disease Activity

      Minimal histologic disease activity at week 14 (RHI score ≤4) favored vedolizumab (37.3%) over adalimumab (24.4%) (difference, 12.9%; 95% CI, 6.5%–19.4%; P < .0001) (Figure 4A). Week 52 rates of minimal histologic disease activity were 42.3% with vedolizumab vs 25.6% with adalimumab (difference, 16.6%; 95% CI, 10.0%–23.1%; P < .0001) (Figure 4B). Vedolizumab was superior to adalimumab in achieving minimal histologic disease activity at week 52 among the anti–TNF-naïve (45.1% vs 27.9%; difference, 17.2%; 95% CI, 9.6%–24.7%; P < .0001) and anti–TNF-failure (31.6% vs 17.3%; difference, 14.1%; 95% CI, 1.1%–27.2%; P = .0364) subgroups.
      Figure thumbnail gr4
      Figure 4Minimal histologic disease activity (RHI score ≤4) at (A) week 14 and (B) week 52. Point estimates and 95% CIs were obtained using the Cochran-Mantel-Haenszel method with stratification by randomization stratification factor: concomitant use of oral corticosteroids (yes/no) and prior use of anti–TNF agent (yes/no) or by the Fisher’s exact method if the numerator was ≤5. Patients with missing end point data were considered treatment failures (ie, nonresponders). Q2W, every 2 weeks; Q8W, every 8 weeks. aNominal P value. From N Engl J Med, Sands BE, Peyrin-Biroulet L, Loftus EV, Jr, et al, Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. 381, 1215–1226. Copyright (c) 2020 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

       Histologic Improvement

      The mean (SD) change from baseline in RHI was −5.0 (12.19) at week 14 and −8.1 (13.08) at week 52 in the adalimumab group compared with −7.5 (11.75) at week 14 and −10.9 (11.04) at week 52 in the vedolizumab group.

       Post Hoc Analysis of Mucosal Healing (Composite Histologic and Endoscopic Outcomes)

      Patients who achieved histologic remission or minimal histologic disease activity (Geboes or RHI) plus endoscopic improvement rates at week 52 are shown in Figures 5 and 6. More patients treated with vedolizumab achieved histologic remission plus endoscopic improvement than those treated with adalimumab (vedolizumab: 30.5% [RHI] and 25.6% [Geboes]; adalimumab: 14.5% [RHI] and 6.7% [Geboes]). This pattern was the same for minimal histologic disease activity plus endoscopic improvement (vedolizumab: 33.7% [RHI] and 35.0% [Geboes]; adalimumab: 18.1% [RHI] and 20.2% [Geboes]).
      Figure thumbnail gr5
      Figure 5Histologic remission by (A) Geboes Index grade <2, and (B) RHI score ≤2 plus endoscopic improvement (Mayo endoscopic subscore ≤1) at week 52. Point estimates and 95% CIs were obtained using the Cochran-Mantel-Haenszel method with stratification by randomization stratification factor: concomitant use of oral corticosteroids (yes/no) and prior use of anti–TNF (yes/no) or by the Fisher’s exact method if the numerator was ≤5. Patients with missing end point data were considered treatment failures (ie, nonresponders). Q2W, every 2 weeks; Q8W, every 8 weeks. aNominal P value.
      Figure thumbnail gr6
      Figure 6Minimal histologic disease activity assessed by (A) Geboes Index grade ≤3.1 and (B) RHI score ≤4 plus endoscopic improvement (Mayo endoscopic subscore ≤1) at week 52. Point estimates and 95% CIs were obtained using the Cochran-Mantel-Haenszel method with stratification by randomization stratification factor: concomitant use of oral corticosteroids (yes/no) and prior use of anti–TNF agents (yes/no) or by the Fisher’s exact method if the numerator was ≤5. Patients with missing end point data were considered treatment failures (ie, nonresponders). Q2W, every 2 weeks; Q8W, every 8 weeks. aNominal P value.

       Subgroup Analysis by Use of Baseline Corticosteroids or Immunomodulators

      Subgroup data on patients who were on corticosteroids or immunomodulators at baseline showed a consistent treatment effect for all histologic end points, although the data are not sufficiently powered to draw any conclusions (Supplementary Figure 1).

       Post Hoc Analysis of Associations Between Histologic and Endoscopic Outcomes

      We used κ statistics to assess the agreement between histologic remission or minimal histologic disease activity and endoscopic improvement in UC using the RHI and Geboes scoring systems. When week 14 and week 52 time points and both treatment arms were pooled, the RHI and Geboes scores both showed moderate agreement between minimal histologic disease activity and endoscopic improvement (RHI: κ = 0.53; 95% CI, 0.48–0.58; Geboes: κ = 0.55; 95% CI, 0.51–0.60). The RHI scores also showed moderate agreement between histologic remission and endoscopic improvement (κ = 0.47; 95% CI, 0.42–0.52), as did Geboes grades (κ = 0.36; 95% CI, 0.31–0.41).
      Using pooled data for both treatment arms at week 14 and week 52, we found Spearman’s correlation coefficients between histologic remission and endoscopic improvement were ρ = 0.48, P < .0001 for RHI and ρ = 0.63, P < .0001 for Geboes. Spearman’s correlations between minimal histologic disease activity and endoscopic improvement were moderate using both scoring systems, at ρ = 0.53, P < .0001 for RHI and ρ = 0.56, P < .0001 for Geboes. Correlations were also moderate both between numeric RHI scores and Mayo endoscopic subscores (ρ = 0.63, P < .0001) and between numeric continuous Geboes scores and Mayo endoscopic subscores (ρ = 0.64, P < .0001).

      Discussion

      VARSITY data analyses suggest superior treatment effects of vedolizumab vs adalimumab in achieving all histologic outcomes in patients with moderate to severe UC. This finding is consistent with the superior clinical and endoscopic efficacy outcomes with vedolizumab vs adalimumab already reported from the VARSITY trial.
      • Sands B.E.
      • Peyrin-Biroulet L.
      • Loftus Jr., E.V.
      • et al.
      Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis.
      Patients achieved higher rates of histologic remission and minimal histologic disease activity at weeks 14 and 52 on vedolizumab than on adalimumab. Anti–TNF-naïve patients generally had superior histologic outcomes relative to patients with prior anti–TNF exposure, which was similar to the previously reported finding that clinical remission was higher among anti–TNF-naïve than -exposed patients for both vedolizumab and adalimumab.
      • Sands B.E.
      • Peyrin-Biroulet L.
      • Loftus Jr., E.V.
      • et al.
      Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis.
      Vedolizumab was superior to adalimumab in achieving histologic remission and minimal histologic disease activity in nearly all anti–TNF–naïve and prior anti–TNF–exposure/failure subgroup comparisons. In addition, subgroup data on baseline corticosteroid or immunomodulator use showed a consistent treatment effect of vedolizumab with or without baseline corticosteroid or immunomodulator use; however, caution should be exercised when interpreting these data because the study was not designed for such analysis.
      Histologic outcomes may be important treatment targets for patients with UC. However, a standard histologic scoring system is still lacking. This study used common scoring system definitions reported in the current literature. With both Geboes and RHI scores, vedolizumab outperformed adalimumab in achieving histologic outcomes. More patients had mucosal healing (histologic outcomes and endoscopic improvement) at week 52 with vedolizumab than with adalimumab. When treatment outcomes in clinical trials are compared, the RHI score is likely more appropriate than the Geboes score due to its reproducibility, its sensitivity to change, and its relative ease of interpretation.
      • Pai R.K.
      • Jairath V.
      • Vande Casteele N.
      • et al.
      The emerging role of histologic disease activity assessment in ulcerative colitis.
      Despite the importance of microscopic activity for disease assessment, histologic remission has yet to be recommended as a therapeutic goal for UC in clinical practice or in clinical trials.
      • Turner D.
      • Ricciuto A.
      • Lewis A.
      • et al.
      STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD.
      ,
      • Ma C.
      • Sedano R.
      • Almradi A.
      • et al.
      An international consensus to standardize integration of histopathology in ulcerative colitis clinical trials.
      ,
      U.S. Food and Drug Administration
      Guidance for Industry: Ulcerative Colitis-Clinical Trial Endpoints.
      Multiple studies have assessed the use of histologic outcome as a measure of disease activity or clinical outcomes and its association with achieving endoscopic remission.
      • Bryant R.V.
      • Burger D.C.
      • Delo J.
      • et al.
      Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up.
      • Gupta R.B.
      • Harpaz N.
      • Itzkowitz S.
      • et al.
      Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study.
      • Zenlea T.
      • Yee E.U.
      • Rosenberg L.
      • et al.
      Histology grade is independently associated with relapse risk in patients with ulcerative colitis in clinical remission: a prospective study.
      ,
      • Rosenberg L.
      • Nanda K.S.
      • Zenlea T.
      • et al.
      Histologic markers of inflammation in patients with ulcerative colitis in clinical remission.
      One study found a statistically significant overall association between the histologic (using the Geboes and RHI scores) and endoscopic (using the Mayo endoscopic subscore) scores, with Kendall’s τ = 0.482 (P < .0001) showing the best correlation.
      • Lemmens B.
      • Arijs I.
      • Van Assche G.
      • et al.
      Correlation between the endoscopic and histologic score in assessing the activity of ulcerative colitis.
      Another study showed a good agreement between the Geboes histologic score and the Mayo endoscopic subscore (Spearman’s ρ = 0.65, P < .001).
      • Rosenberg L.
      • Nanda K.S.
      • Zenlea T.
      • et al.
      Histologic markers of inflammation in patients with ulcerative colitis in clinical remission.
      In a cohort study of 34 patients with UC who received vedolizumab for more than a year, a statistically significant association between histologic and endoscopic improvement was observed (r2 = 0.61, P < .001). Most of the patients with endoscopic improvement also had histologically quiescent disease.
      • Noman M.
      • Ferrante M.
      • Bisschops R.
      • et al.
      Vedolizumab induces long-term mucosal healing in patients with Crohn’s disease and ulcerative colitis.
      This study was the first head-to-head study of biologics in inflammatory bowel disease, and its multiple outcomes and assessments allow treatment effects across a range of outcomes to be explored, including histology using 2 well-known, robust scoring systems: the Geboes score, which is commonly used, and RHI, which has advantages for use in the clinical trial setting.
      This study had some limitations. First, only 2 histologic scoring systems (Geboes Index grade and RHI) were used despite the availability of other validated scoring systems for UC, such as the Nancy Index.
      • Peyrin-Biroulet L.
      • Bressenot A.
      • Kampman W.
      Histologic remission: the ultimate therapeutic goal in ulcerative colitis?.
      ,
      • Pai R.K.
      • Jairath V.
      • Vande Casteele N.
      • et al.
      The emerging role of histologic disease activity assessment in ulcerative colitis.
      The Geboes and RHI thresholds used to define the histologic outcomes, in particular for minimal disease activity, should not be viewed as directly comparable without providing additional context around the presence or absence of neutrophils in the lamina propria or epithelium due to differences in the way the final RHI score can be reached (see Supplementary Tables 1 and 2).
      Second, only 1 rectosigmoid biopsy sample was taken for each patient. Because UC presents with diffuse mucosal inflammation, variability in the histopathologic severity within the colonic mucosa may occur.
      • Bryant R.V.
      • Winer S.
      • Travis S.P.
      • et al.
      Systematic review: histological remission in inflammatory bowel disease. Is ‘complete’ remission the new treatment paradigm? An IOIBD initiative.
      ,
      • Freeman H.J.
      Limitations in assessment of mucosal healing in inflammatory bowel disease.
      One study showed microscopic heterogeneity in biopsy samples of patients with UC.
      • Harpaz N.
      • Ballentine S.
      • Colombel J.F.
      • et al.
      Microscopic heterogeneity in ulcerative colitis: implications for microscopic measurement of disease activity.
      Sampling errors could be reduced by taking multiple samples with visible endoscopic inflammation for histologic assessment.
      • Villanacci V.
      • Antonelli E.
      • Geboes K.
      • et al.
      Histological healing in inflammatory bowel disease: a still unfulfilled promise.
      ,
      • Bryant R.V.
      • Winer S.
      • Travis S.P.
      • et al.
      Systematic review: histological remission in inflammatory bowel disease. Is ‘complete’ remission the new treatment paradigm? An IOIBD initiative.
      ,
      • Mosli M.H.
      • Feagan B.G.
      • Sandborn W.J.
      • et al.
      Histologic evaluation of ulcerative colitis: a systematic review of disease activity indices.
      However, endoscopists were mandated to select the most severely affected area. Future studies may benefit from sampling multiple areas.
      Third, the study protocol did not specify a schedule for corticosteroid tapering, which can vary between clinicians.
      Fourth, dose escalation was not possible in either treatment arm to maintain treatment group blinding.
      Finally, no long-term follow-up was conducted among these patients, which could have been useful to determine changes in histologic outcomes along the natural course of disease. The duration of disease and treatment could have affected the biopsy results.
      • Villanacci V.
      • Antonelli E.
      • Geboes K.
      • et al.
      Histological healing in inflammatory bowel disease: a still unfulfilled promise.
      ,
      • Mosli M.H.
      • Feagan B.G.
      • Sandborn W.J.
      • et al.
      Histologic evaluation of ulcerative colitis: a systematic review of disease activity indices.
      Large, prospective studies are also recommended to assess the impact of histologic outcomes on the natural disease course.

      Conclusion

      VARSITY demonstrated favorable histologic outcomes with vedolizumab compared with adalimumab, with vedolizumab showing consistent superiority across multiple therapeutic end points, including the key outcome of histologic remission. Associations between histologic outcomes and endoscopic improvement in this study were greater using the RHI scoring system. This is important given the recent position statement from the European Crohn’s and Colitis Organisation supporting the need to consider mucosal healing based on endoscopy and histology.
      • Magro F.
      • Doherty G.
      • Peyrin-Biroulet L.
      • et al.
      ECCO position paper: harmonization of the approach to ulcerative colitis histopathology.

      Acknowledgments

      This study was sponsored by Takeda. Statistical and programming support was provided by Sharon Hunter, MS, Hui Zeng, PhD, and Decai Deng of Takeda. Medical writing support was provided by Kathryn Kaye dela Cruz, MD, of ProEd Communications, Inc, and Paul Hassan, PhD, of Excel Scientific Solutions and was funded by Takeda.

      CRediT Authorship Contributions

      Laurent Peyrin-Biroulet, MD, PhD (Conceptualization: Equal; Investigation: Equal; Methodology: Equal; Supervision: Lead; Writing – original draft: Lead; Writing – review & editing: Equal).
      Edward V. Loftus Jr, MD (Conceptualization: Equal; Investigation: Equal; Methodology: Equal; Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal).
      Jean-Frédéric Colombel, MD (Conceptualization: Equal; Investigation: Equal; Methodology: Equal; Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal).
      Silvio Danese, MD (Conceptualization: Equal; Investigation: Equal; Methodology: Equal; Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal).
      Raquel Rogers, MD (Conceptualization: Equal; Investigation: Equal; Methodology: Equal; Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal).
      Jeffrey D. Bornstein, MD (Conceptualization: Equal; Investigation: Equal; Methodology: Equal; Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal).
      Jingjing Chen, PhD (Conceptualization: Equal; Data curation: Lead; Formal analysis: Lead; Investigation: Equal; Methodology: Equal; Supervision: Supporting; Validation: Lead; Writing – original draft: Supporting; Writing – review & editing: Equal).
      Stefan Schreiber, MD, PhD (Conceptualization: Equal; Investigation: Equal; Methodology: Equal; Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal).
      Bruce E. Sands, MD (Conceptualization: Equal; Investigation: Equal; Methodology: Equal; Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal).
      Richard A. Lirio, MD (Conceptualization: Equal; Investigation: Equal; Methodology: Equal; Supervision: Lead; Validation: Lead; Writing – original draft: Lead; Writing – review & editing: Equal).

      Supplementary Material

      Figure thumbnail fx2
      Supplementary Figure 1Subgroup analysis for efficacy end points at week 52 by use of baseline (A) corticosteroids and (B) baseline immunomodulators. MHDA, Minimal histologic disease activity; RHI, Robarts Histopathology Index; ADA adalimumab; VDZ, vedolizumab
      Supplementary Table 1Geboes Index Grade and Continuous Scale
      VariableCategorical GeboesContinuous Geboes
      Structural (architectural changes)Grade 0
       No abnormality0.00
       Mild abnormality0.11
       Mild or moderate diffuse or multifocal abnormalities0.22
       Severe diffuse or multifocal abnormalities0.33
      Chronic inflammatory infiltrateGrade 1
       No increase1.03
       Mild but unequivocal increase1.14
       Moderate increase1.25
       Marked increase1.36
      Lamina propria neutrophils and eosinophilsGrade 2
      2A Eosinophils
       No increase2A.06
       Mild but unequivocal increase2A.17
       Moderate increase2A.28
       Marked increase2A.39
      2B Neutrophils
       No increase2B.09
       Mild but unequivocal increase2B.110
       Moderate increase2B.211
       Marked increase2B.312
      Neutrophils in epitheliumGrade 3
       None3.012
       <5% crypts involved3.113
       <50% crypts involved3.214
       >50% crypts involved3.315
      Crypt destructionGrade 4
       None4.015
       Probable–local excess of neutrophils in part of crypt4.116
       Probable–marked attenuation4.217
       Unequivocal crypt destruction4.318
      Erosion or ulcerationGrade 5
       No erosion, ulceration or granulation tissue5.018
       Recovering epithelium + adjacent inflammation5.119
       Probable erosion focally stripped5.220
       Unequivocal erosion5.321
       Ulcer or granulation tissue5.422
      Supplementary Table 2Robarts Histopathology Index
      VariableRobarts CriteriaRobarts Multiplier
      Chronic inflammatory infiltrate
       No increase0
       Mild but unequivocal increase1X1
       Moderate increase2
       Marked increase3
      Lamina propria neutrophils
       No increase0
       Mild but unequivocal increase1X2
       Moderate increase2
       Marked increase3
      Neutrophils in epithelium
       None0
       <5% crypts involved1X3
       <50% crypts involved2
       >50% crypts involved3
      Erosion or ulceration
       No erosion, ulceration or granulation tissue0
       Recovering epithelium + adjacent inflammation1
       Probable erosion focally stripped1X5
       Unequivocal erosion2
       Ulcer or granulation tissue3
      NOTE. Total score range: 0–33 (no disease activity to severe disease activity).

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