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Effectiveness and Safety of Vedolizumab Induction Therapy for Patients With Inflammatory Bowel Disease

Published:February 22, 2016DOI:https://doi.org/10.1016/j.cgh.2016.02.016

      Background & Aims

      Phase 3 trials have shown the efficacy of vedolizumab, which binds to integrin α4β7, in patients with Crohn’s disease (CD) or ulcerative colitis (UC). We investigated the effectiveness and safety of vedolizumab in patients who failed anti-tumor necrosis factor therapy.

      Methods

      From June through December 2014, there were 173 patients with CD and 121 patients with UC who were included in a multicenter nominative compassionate early access program granted by French regulatory agencies. This program provided patients with access to vedolizumab before it was authorized for marketing. Vedolizumab (300 mg) was administered intravenously at weeks 0, 2, and 6, and then every 8 weeks. Disease activity was assessed using the Harvey–Bradshaw Index for CD and the partial Mayo Clinic score for UC. We report results obtained after the 14-week induction phase.

      Results

      Among the 294 patients treated with vedolizumab (mean age, 39.5 ± 14.0 y; mean disease duration, 10.8 ± 7.6 y; concomitant steroids, 44% of cases), 276 completed the induction period, however, 18 discontinued vedolizumab because of a lack of response (n = 14), infusion-related reaction (n = 2), or infections (n = 2). At week 14, 31% of patients with CD were in steroid-free clinical remission and 51% had a response; among patients with UC, 36% were in steroid-free clinical remission and 50% had a response. No deaths were reported. Severe adverse events occurred in 24 patients (8.2%), including 15 (5.1%) that led to vedolizumab discontinuation (1 case of pulmonary tuberculosis and 1 rectal adenocarcinoma).

      Conclusions

      In a cohort of patients with CD or UC who failed previous anti–tumor necrosis factor therapy, approximately one third of patients achieved steroid-free clinical remission after 14 weeks of induction therapy with vedolizumab. This agent had an acceptable safety profile in these patients.

      Keywords

      Abbreviations used in this paper:

      ATU (Autorisation Temporaire d’Utilisation), CD (Crohn’s disease), CI (confidence interval), CRP (C-reactive protein), HBI (Harvey–Bradshaw Index), IBD (inflammatory bowel disease), OR (odds ratio), TNF (tumor necrosis factor), UC (ulcerative colitis)
      The advent of anti–tumor necrosis factor (TNF) has changed the way to treat inflammatory bowel disease (IBD) refractory to standard medications.
      • Amiot A.
      • Peyrin-Biroulet L.
      Currrent, new and future biological agents on the horizon for the treatment of inflammatory bowel diseases.
      Nevertheless, many patients fail to maintain a sustained response to anti-TNF therapy because of primary nonresponse, loss of response, or intolerance. Vedolizumab is the first biological agent that targets the integrin receptor and is approved for the treatment of patients with ulcerative colitis (UC) and Crohn’s disease (CD).
      • Feagan B.G.
      • Greenberg G.R.
      • Wild G.
      • et al.
      Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.
      Vedolizumab specifically inhibits the interaction between α4β7 integrin and mucosal addressin cell adhesion molecule-1.
      • Fiorino G.
      • Correale C.
      • Fries W.
      • et al.
      Leukocyte traffic control: a novel therapeutic strategy for inflammatory bowel disease.
      By inhibiting this binding, vedolizumab blocks the migration of a subset of memory gut-homing T lymphocytes into inflamed intestinal tissue.
      • Lobaton T.
      • Vermeire S.
      • Van Assche G.
      • et al.
      Review article: anti-adhesion therapies for inflammatory bowel disease.
      Three pivotal phase 3 clinical trials have shown the clinical efficacy of vedolizumab in patients with moderate-to-severe active UC and CD, leading to marketing authorization.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      • Sandborn W.J.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Vedolizumab as induction and maintenance therapy for Crohn’s disease.
      • Sands B.E.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed.
      In June 2014, a French regulatory agency approved a nominative compassionate early access program known as the Autorisation Temporaire d’Utilisation (ATU) that provided patients access to vedolizumab.
      • Hézode C.
      • Fontaine H.
      • Dorival C.
      • et al.
      Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis.
      The French Observatory on Efficacy and of Vedolizumab in Patients With Inflammatory Bowel Disease study is a cohort study that enrolled all IBD patients who benefitted from the ATU program. Here, we report the effectiveness and safety of vedolizumab induction therapy in patients with moderate-to-severe active UC and CD who failed anti-TNF therapy. We also investigated the predictive factors of vedolizumab efficacy in these patients.

      Patients and Methods

       Study Population

      The Observatory on Efficacy and of Vedolizumab in Patients With Inflammatory Bowel Disease cohort is a national multicenter prospective cohort study conducted in 41 French centers. Adult patients were recruited through a vedolizumab nominative ATU granted by the French regulatory agency (Agence Nationale du Médicament et des Produits de Santé) between June 2014 and September 2014. All consecutive patients with active IBD who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or at least 1 anti-TNF agent therefore were eligible for inclusion within the framework of this program. Inclusions were extended to December 2014 at all participating centers.
      Each individual request was granted on a named-patient basis after patients received written information concerning the product. Physicians were committed by the Agence Nationale du Médicament et des Produits de Santé to collect efficacy and safety information on a prospective basis. No commercial entity had any role in the study. The protocol was approved by the ethics committee (Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé no. 15.403).
      Active IBD was defined according to a Harvey–Bradshaw Index (HBI) score greater than 4 for CD patients and a Mayo Clinic score of 6 or greater for UC patients.
      • 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.
      Exclusion criteria included unclassified colitis, extraintestinal manifestation without significant IBD activity as the initial indication for vedolizumab, prevention of CD postoperative recurrence, an ostomy, and pregnancy or lactation. Patient demographic and clinical characteristics were collected from medical records and included age at diagnosis, sex, smoking habits, CD location and behavior according to the Montreal classification, UC extent according to the Montreal classification, extraintestinal manifestation, smoking habits, history of medical and surgical treatment of IBD, and familial history of IBD.
      • Satsangi J.
      • Silverberg M.S.
      • Vermeire S.
      • et al.
      The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications.
      This article presents the week 14 efficacy and safety results of this study.

       Vedolizumab Induction Therapy

      Patients received intravenous vedolizumab at a dose of 300 mg at weeks 0, 2, and 6, and then every 8 weeks thereafter through week 52.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      • Sandborn W.J.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Vedolizumab as induction and maintenance therapy for Crohn’s disease.
      • Sands B.E.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed.
      Concomitant use of corticoids and/or immunomodulators including azathioprine (≥2 mg/kg/d), 6-mercaptopurine (≥1.5 mg/kg/d), or subcutaneous or intramuscular methotrexate (25 mg/wk) was permitted. No standardized protocol of steroid tapering and immunomodulatory maintenance was defined. In patients who did not have a response to vedolizumab therapy at weeks 10 to 14, the treating physician was free to optimize vedolizumab therapy at a dose of 300 mg every 4 weeks through week 52.

       Follow-Up Evaluation

      All patients were subjected to a standardized follow-up protocol at each vedolizumab infusion until week 52. At each visit, HBI and/or partial Mayo Clinic scores were calculated for CD and UC, respectively.
      • Rutgeerts P.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      Infliximab for induction and maintenance therapy for ulcerative colitis.
      • Harvey R.F.
      • Bradshaw J.M.
      A simple index of Crohn’s-disease activity.
      The partial Mayo Clinic score consisted of the Mayo Clinic score minus the endoscopic subscore and ranged from 0 to 9. Additional assessment at every visit included a physical examination and C-reactive protein (CRP) (mg/L), hemoglobin (g/dL), leukocyte (per mm3), and platelet (per mm3) counts. All adverse events were noted.

       Outcome Measures

      The primary outcome measure was a steroid-free clinical remission at week 14, which was defined as a HBI score of 4 or less for CD patients and a partial Mayo Clinic score of less than 3 with a combined stool frequency and rectal bleeding subscore of 1 or less.
      • 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.
      Secondary outcomes were clinical remission, clinical response, steroid-free clinical response rates at weeks 6 and 14, and safety at week 14. A clinical response was defined as a reduction in the HBI score of at least 3 points for CD patients and as a reduction in the partial Mayo Clinic score of at least 3 points and a decrease of at least 30%, with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1 from the baseline score for UC patients.
      • 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.
      Safety was assessed prospectively by the physician in charge and collected retrospectively from patient records. Adverse events were classified as severe when they lead to treatment interruption, hospitalization, disability or persistent damage, colectomy, and death.

       Statistical Analysis

      No sample size was predefined. All included patients were evaluated at week 14 and analyzed on an intent-to-treat basis in the present study. Nominal and ordinal data were compared using the chi-square test, whereas parametric data were compared using the Mann–Whitney tests and the Wilcoxon matched-pair, signed-rank test whenever appropriate. Variables with a P value less than .10 in univariate analysis were considered to be potential adjustment variables for the multivariate analysis. To identify independent factors of steroid-free clinical remission and clinical remission, binary logistic regression models then were adjusted to the earlier-mentioned variables whenever appropriate with an ascending stepwise procedure. All analyses were 2-tailed, and P values less than .05 were considered significant. All statistical evaluations were performed using SPSS statistical software (v17; SPSS, Inc, Chicago, IL). All authors had access to the study data and reviewed and approved the final manuscript.

      Results

       Patient Characteristics

      A total of 300 patients with IBD were evaluated for eligibility; 6 patients with refractory pouchitis were excluded from the analysis. A total of 294 patients were enrolled in this cohort study, including 173 patients with CD and 121 patients with UC. Patient demographic data, baseline disease characteristics, and medication history are listed in Table 1. All patients had active disease at the time of enrolment according to the HBI score for CD patients and the Mayo Clinic score for UC patients. Patients in the CD group were younger, had a higher proportion of males, a lower body mass index, and a longer disease duration at the time of enrolment, compared with the same parameters in the UC group. CD patients have been treated more frequently with methotrexate and at least 2 lines of anti-TNF therapy. Four patients had not been treated previously with anti-TNF agents, 1 in the CD group and 3 in the UC group (2 patients with multiple sclerosis and 2 patients with primary sclerosing cholangitis). Patients were treated with vedolizumab alone in 125 (42%) cases. Vedolizumab was given with concomitant steroid therapy in 100 (34%) cases, concomitant immunomodulator alone in 40 cases (14%), or both in 30 cases (10%).
      Table 1Demographic and Baseline Disease Characteristics and Medication Histories of Ulcerative Colitis and Crohn’s Disease Patients
      CharacteristicCrohn’s disease (n = 173)Ulcerative colitis (n = 121)P
      Age, y37.3 ± 11.842.8 ± 16.1.001
      Male sex, n (%)64 (37%)67 (55%).002
      BMI, kg/m220.9 ± 3.923.3 ± 4.6<.001
      Smoking habits, n (%)
       Past smoker85 (55%)37 (31%)<.001
       Active smoker44 (29%)5 (4%)<.001
      Duration of disease, y12.1 ± 7.68.8 ± 7.1<.001
      Extraintestinal manifestation37 (21%)18 (15%).22
       Primary sclerosing cholangitis4 (2%)8 (7%).07
       Ankylosing spondylitis17 (10%)6 (5%).19
      Familial history of inflammatory bowel disease19 (14%)9 (9%).31
      Age at diagnosis34.2 ± 16.424.6 ± 11.1<.001
       A1: ≤16 y40 (23%)10 (8%).001
       A2: 17–40 y119 (69%)73 (60%).13
       A3: >40 y14 (8%)38 (31%)<.001
      Crohn’s disease
       Disease location, n (%)
      Ileal33 (19%)--
      Colonic40 (23%)--
      Ileocolonic100 (58%)--
      Upper gastrointestinal tract10 (6%)--
       Disease phenotype, n (%)
      Nonstructuring, nonpenetrating77 (45%)--
      Stricturing64 (37%)--
      Penetrating32 (18%)--
       Perianal disease, n (%)77 (46%)--
       Harvey–Bradshaw Index10.2 ± 4.2--
      Ulcerative colitis
       Proctitis-9 (7%)-
       Left-sided colitis-29 (24%)-
       Pancolitis-83 (69%)-
      Mayo Clinic score-8.3 ± 2.4-
      Prior medications
       Immunosuppressant169 (97%)115 (95%).02
      Purine analogues169 (97%)114 (94%).24
      Methotrexate87 (50%)39 (32%).003
       Anti-TNF therapy, n (%)
      One anti-TNF agent172 (99%)118 (98%).31
      ≥1 anti-TNF agents157 (91%)83 (69%)<.001
      Concomitant medications
       Glucocorticoids only59 (34%)41 (34%).99
       Immunosuppressants only26 (15%)14 (12%).49
       Glucocorticoids and immunosuppressants18 (10%)12 (10%).99
       No glucocorticoids or immunosuppressants71 (41%)54 (45%).55
      Biologic variables
       Hemoglobin level, g/L12.2 ± 2.411.9 ± 3.2.34
       Leukocyte count, 109/L9326 ± 38287730 ± 4393.002
       Platelet count, 109/L349 ± 128353 ± 120.80
      High sensitive CRP level, mg/L29.8 ± 29.719.5 ± 21.2<.001
      NOTE. Variables are presented as n (%), mean ± SD, or median (interquartile range).
      BMI, body mass index.

       Efficacy of Vedolizumab at Week 6

      A total of 280 patients completed this induction period. Fourteen patients discontinued vedolizumab therapy before the end of the 6-week induction period. Eleven of these patients were referred to surgery because of IBD exacerbation or complication, 2 patients experienced an infusion-related reaction, and 1 patient developed tuberculosis despite a negative pretherapeutic screening. At week 6, 54 (31%) and 39 (32%) patients were in clinical remission in the CD and UC groups, respectively, of whom 33 (19%) and 26 (21%), respectively, were in steroid-free clinical remission (Figure 1). In addition, 98 (57%) and 50 (41%) patients presented with a clinical response at week 6 in the CD and UC groups, respectively, of whom 60 (35%) and 32 (26%), respectively, presented with steroid-free clinical response. The HBI score in CD patients and the partial Mayo Clinic score in UC patients decreased between week 0 and week 6 (10.2 ± 4.2 vs 7.2 ± 4.8 and 6.1 ± 1.7 vs 3.9 ± 2.6; P < .001 and < .001, respectively), whereas the CRP level in the overall study population did not decrease (26.1 ± 26.2 vs 24.0 ± 31.1; P = .32) (Figure 2). Vedolizumab therapy was optimized at a dose of 300 mg every 4 weeks in 20 patients at week 6 owing to inadequate response to the drug. Four patients discontinued vedolizumab therapy at week 6, leaving 276 patients who continued vedolizumab therapy; 3 patients had refractory active IBD and 1 patient moved abroad.
      Figure thumbnail gr1
      Figure 1Outcome measures at week 14 for vedolizumab therapy in patients with (A) Crohn’s disease and (B) ulcerative colitis. *P value less than .005 when comparing week 6 and week 14 efficacy results.
      Figure thumbnail gr2
      Figure 2Changes in the (A) Harvey–Bradshaw Index, (B) partial ulcerative colitis disease activity index, and (C) C-reactive protein level at baseline and at weeks 6 and 14 after vedolizumab therapy was started.

       Efficacy of Vedolizumab at Week 14

      Among the remaining 276 patients who completed the induction period, 4 patients discontinued vedolizumab therapy before week 14 (3 patients were referred to surgery for IBD exacerbation or complication and 1 patient for acute cholecystitis). Five patients were optimized at a dose of vedolizumab 300 mg every 4 weeks at week 10. At week 14, 63 (36%) and 47 (39%) patients were in clinical remission in the CD and UC groups, respectively, of whom 53 (31%) and 43 (36%), respectively, were in steroid-free clinical remission (Figure 1). In addition, 110 (64%) and 69 (57%) patients presented with a clinical response at week 14 in the CD and UC groups, respectively, of whom 88 (51%) and 60 (50%), respectively, presented with steroid-free clinical response. The partial Mayo Clinic score in UC patients decreased between weeks 6 and 14 (3.9 ± 2.6 vs 3.2 ± 2.6; P = .85 and .002, respectively), whereas the HBI score in CD patients and the CRP level in the overall IBD population did not decrease (7.0 ± 4.8 vs 6.9 ± 4.9 and 24.0 ± 31.5 vs 26.8 ± 43.5; P = .85 and .32, respectively) even when comparing patients who achieved steroid-free clinical remission at week 14 and those who had not (Figure 2 and Supplementary Figure 1). Thirty-five patients discontinued vedolizumab therapy at week 14 because of a lack of clinical response, leaving 237 patients still on vedolizumab therapy. Among the 166 patients who did not achieve clinical remission, vedolizumab therapy was optimized at a dose of 300 mg every 4 weeks in 79 patients after week 14 (14 patients with CD and 6 patients with UC).

       Predictors of Steroid-Free Remission at Week 14

      Predictors of steroid-free remission at week 14 were assessed separately in the CD and UC cohorts. In the CD cohort, the concomitant steroid use (P < .001), HBI score greater than 10 (P < .001), clinical response at week 6 (P < .001), and CRP level greater than 20 mg/L (P = .10) were predictive of steroid-free remission at week 14. Logistic regression analysis showed that patients with the concomitant steroid (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.16–0.77; P = .009) and HBI score greater than 10 (OR, 0.11; 95% CI, 0.05–0.27; P < .001) were less likely to achieve steroid-free clinical remission at week 14 after vedolizumab induction therapy whereas patients who showed a clinical response at week 6 (OR, 11.2; 95% CI, 4.3–28.8; P < .001) were more likely to achieve steroid-free clinical remission at week 14. In the UC cohort, a clinical response at week 6 (P < .001), a Mayo Clinic score greater than 9 (P = .002), a CRP level greater than 20 mg/L (P = .005), a leukocyte count greater than 8500 × 10-9/L (P = .02), and male sex (P = .09) were predictive of steroid-free remission at week 14. Logistic regression analysis showed that patients with a CRP level greater than 20 mg/L (OR, 0.30; 95% CI, 0.11–0.80; P = .02) and a Mayo Clinic score greater than 9 (OR, 0.21; 95% CI, 0.08–0.57; P = .002) were less likely to achieve steroid-free clinical remission at week 14 after vedolizumab induction therapy whereas patients who showed a clinical response at week 6 (OR, 5.3; 95% CI, 2.2–13.1; P < .001) were more likely to be in steroid-free clinical remission.

       Safety

      The analysis of adverse events was performed on all patients who received at least 1 dose of vedolizumab. Adverse events occurred in 93 (31.6%) of 294 patients, with serious adverse events in 24 patients (8.2%), and adverse events leading to vedolizumab discontinuation in 15 patients (5.1%) (Table 2). Headache (n = 16) and paresthesia (n = 13) were common adverse events. Nine of 13 patients who experienced paresthesia after vedolizumab was started underwent brain magnetic resonance imaging and electromyography analysis, which did not show any abnormality. Paresthesia tends to disappear over time in almost all patients. Twelve patients experienced IBD exacerbation, and 12 other patients experienced a dermatologic complication of unknown significance that could be either paradoxic or infectious. One 33-year-old man who presented with locally advanced rectal cancer had increased rectal bleeding at the time of the second vedolizumab infusion.
      Table 2Adverse Events Affecting Patients Treated With Vedolizumab Therapy in Patients With Crohn’s Disease and Ulcerative Colitis
      EventPatients with inflammatory bowel disease (n = 294)
      Adverse event93 (31.6%)
       Headache16 (5.4%)
       Paresthesia13 (4.4%)
       IBD exacerbation12 (4.1%)
       Paradoxic skin manifestation12 (4.1%)
       Infusion-related reaction2 (0.7%)
       Arthralgia1 (0.3%)
       Vertigo1 (0.3%)
       Deep venous thrombosis1 (0.3%)
       Pruritis1 (0.3%)
       Stroke1 (0.3%)
       Liver test abnormalities1 (0.3%)
      Any serious adverse event
      A serious adverse event was defined as any adverse event leading to treatment interruption, hospitalization, disability or persistent damage, colectomy, and death.
      24 (8.2%)
      Adverse event of infection37 (12.6%)
       Rhinopharyngitis12 (4.1%)
       Upper respiratory tract infection6 (2.0%)
       Gastrointestinal infection5 (1.7%)
      Gastrointestinal infection includes 4 cases of C difficile infection and 2 cases with a negative work-up.
       Flu or flu-like infection3 (1.0%)
       Sinusitis3 (1.0%)
       pharyngitis3 (1.0%)
       Miscellaneous11 (3.7%)
      Any serious infection
      A serious infection was defined as a serious adverse event of infection.
      7 (2.4%)
      Any cancer
      The cancer was a rectal carcinoma, which occurred in a 33-year-old patient with long-lasting rectal disease and an oversewn rectal stump. Diagnosis was made on the vedolizumab week 2 infusion. FOLFOX therapy permitted achieving an objective response, but was discontinued for sensory neurotoxicity. FOLFIRI therapy currently is being administered.
      1 (0.3%)
      NOTE. Patients with more than 1 adverse event were listed as separate events.
      FOLFIRI, FOLinic acid, 5-fluorouracil and IRInotecan; FOLFOX-4, FOLinic acid, 5-fluorouracil and OXaliplatin.
      a A serious adverse event was defined as any adverse event leading to treatment interruption, hospitalization, disability or persistent damage, colectomy, and death.
      b Gastrointestinal infection includes 4 cases of C difficile infection and 2 cases with a negative work-up.
      c A serious infection was defined as a serious adverse event of infection.
      d The cancer was a rectal carcinoma, which occurred in a 33-year-old patient with long-lasting rectal disease and an oversewn rectal stump. Diagnosis was made on the vedolizumab week 2 infusion. FOLFOX therapy permitted achieving an objective response, but was discontinued for sensory neurotoxicity. FOLFIRI therapy currently is being administered.

      Discussion

      In this study of 294 refractory IBD patients who had an inadequate response or intolerance to an anti-TNF agent, we showed that vedolizumab therapy was effective at inducing steroid-free clinical remission at week 14 in either CD or UC in approximately one third of cases, whereas almost two thirds of the patients eventually presented with a clinical response. This was a large IBD cohort of patients treated with vedolizumab and the focused on patients who required alternative treatment to anti-TNF agents.
      • Shelton E.
      • Allegretti J.R.
      • Stevens B.
      • et al.
      Efficacy of vedolizumab as induction therapy in refractory IBD patients: a multicenter cohort.
      In our study, the primary end point was steroid-free clinical remission at week 14. Indeed, steroids are associated with high rates of steroid dependency and toxicity. As a result, steroid-free clinical remission increasingly has been recognized as the ultimate goal of IBD management.
      • 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 choice of the week 14 evaluation differed from the GEMINI trials that assessed the efficacy of vedolizumab induction protocol at weeks 6 and 10.
      • Lobaton T.
      • Vermeire S.
      • Van Assche G.
      • et al.
      Review article: anti-adhesion therapies for inflammatory bowel disease.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      • Sandborn W.J.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Vedolizumab as induction and maintenance therapy for Crohn’s disease.
      This choice reflects the belief that vedolizumab needs more time than anti-TNF agents to exert its complete efficacy, especially in CD patients. Indeed, anti-TNF agents usually are evaluated for induction therapy after a week 4- to 8-week period.
      • Amiot A.
      • Peyrin-Biroulet L.
      Currrent, new and future biological agents on the horizon for the treatment of inflammatory bowel diseases.
      In the GEMINI-2 trial, vedolizumab failed to induce a clinical response at week 6 as compared with the placebo.
      • Sandborn W.J.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Vedolizumab as induction and maintenance therapy for Crohn’s disease.
      The hypothesis that vedolizumab could exert its efficacy more slowly than anti-TNF agents was evaluated in the GEMINI 3 trial, which included only CD patients who previously had failed anti-TNF therapy.
      • Sands B.E.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed.
      In the latter study, vedolizumab showed a higher clinical remission rate at week 10 compared with placebo, but not at week 6. Accordingly, almost all of the week 14 clinical response and remission rates with or without steroid, in either CD or UC were higher than those observed at week 6 in our study.
      Based on the results of the GEMINI trials, it has been speculated that the benefits of vedolizumab are more evident in UC patients than in CD patients.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      • Sandborn W.J.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Vedolizumab as induction and maintenance therapy for Crohn’s disease.
      • Sands B.E.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed.
      Indeed, vedolizumab is characterized by a gut selectivity that theoretically limits the effect of the drug on the trafficking of lymphocytes to other organs.
      • Feagan B.G.
      • Greenberg G.R.
      • Wild G.
      • et al.
      Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.
      As a result, the transmural nature of CD associated with a systemic inflammatory burden could limit the action of vedolizumab in patients with CD and in patients with UC with a systemic inflammatory burden.
      • Pineton de Chambrun G.
      • Peyrin-Biroulet C.
      • Lemann M.
      • et al.
      Clinical implications of mucosal healing for the management of IBD.
      In the present study, although CD patients were characterized by a higher CRP level compared with that of UC patients, there was no difference in the week 6 and week 14 clinical remission and response rates between CD and UC patients. The exception to this was a higher clinical response rate at week 6 in favor of CD patients. Because clinical scoring systems remain poorly correlated with objective markers of inflammation, such as CRP, achieving clinical response and, more importantly, clinical remission, should not be the only goal in the management of IBD. In the present study, there was no decrease in the CRP level at week 6 and week 14 (Figure 2), even in patients who achieved steroid-free clinical remission at week 14 (Supplementary Figure 1). A high systemic inflammatory burden defined in this study as a CRP level greater than 20 mg/L also was associated with lower steroid-free clinical remission rates in patients with either UC or CD. Further studies are warranted to determine whether patients with a high systemic inflammatory burden should be treated predominantly with anti-TNF agents.
      An ongoing controversy remains regarding whether anti-TNF agents and more largely biological agents should be prescribed with a concomitant immunomodulator.
      • Dulai P.S.
      • Siegel C.A.
      • Colombel J.-F.
      • et al.
      Systematic review: monotherapy with antitumour necrosis factor α agents versus combination therapy with an immunosuppressive for IBD.
      Although the benefits of combination therapy were shown for infliximab in 2 large randomized controlled trials, there is no evidence for such benefits in fully humanized anti-TNF agents.
      • Colombel J.F.
      • Sandborn W.J.
      • Reinisch W.
      • et al.
      Infliximab, azathioprine, or combination therapy for Crohn’s disease.
      • Panaccione R.
      • Ghosh S.
      • Middleton S.
      • et al.
      Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis.
      • Jones J.L.
      • Kaplan G.G.
      • Peyrin-Biroulet L.
      • et al.
      Effects of concomitant immunomodulator therapy on efficacy and safety of anti-tumor necrosis factor therapy for Crohn’s disease: a meta-analysis of placebo-controlled trials.
      In the GEMINI trials, vedolizumab did not show a significant immunogenic pattern. Indeed, among the 1643 vedolizumab-treated patients, 59 (3.6%) were positive samples for antidrug antibodies at any time point and 6 (0.4%) had persistent antibodies.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      • Sandborn W.J.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Vedolizumab as induction and maintenance therapy for Crohn’s disease.
      • Sands B.E.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed.
      Treatment with a concomitant immunomodulator was associated with decreased immunogenicity in the 3 trials. In our study, treatment with a concomitant immunomodulator or a steroid at the time of inclusion were noted in 24% and 44% of the patients, respectively. No benefit of a concomitant immunomodulator was observed for steroid-free clinical remission in either CD, UC, or pooled IBD populations. However, concomitant steroid use was associated with poorer clinical outcomes in CD patients, suggesting a deleterious effect of the steroids or a selection bias for more severe patients. No safety issues were raised in patients with either a concomitant immunomodulator or steroid.
      The safety profile of vedolizumab was good and consistent with the results of the GEMINI trials.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      • Sandborn W.J.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Vedolizumab as induction and maintenance therapy for Crohn’s disease.
      • Sands B.E.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed.
      Adverse events occurred in 31.6%. Adverse events were classified as serious in 8.2% of cases, and led to vedolizumab discontinuation in 5.1%. Adverse infectious events of infection occurred in 12.6% of patients and mostly consisted of nasopharyngitis, upper respiratory tract infection, and gastrointestinal infection including some cases of Clostridium difficile superinfection. There was no predictor of adverse events of infection and especially no association between infection and older age or concomitant use of immunomodulators or steroids. Twelve patients (4.2%) experienced dermatologic complications suggestive of paradoxic complications often treated with a topical steroid.
      • Cleynen I.
      • Vermeire S.
      Paradoxical inflammation induced by anti-TNF agents in patients with IBD.
      One case of cancer occurred after the week 2 infusion but seemed more related to long-standing severe CD than to vedolizumab.
      In the present study, clinical activity was assessed using the HBI score for CD and the partial Mayo Clinic score for UC. Although the HBI has never been validated on a prospective basis, it has been used in some clinical trials and is correlated highly with the Crohn's Disease Activity Index, which is incompatible with daily practice use.
      • Harvey R.F.
      • Bradshaw J.M.
      A simple index of Crohn’s-disease activity.
      Both scores recently were recommended by a consensus report based on a systematic literature review and the agreement of a steering committee of 28 IBD specialists.
      • 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 cut-off values defining either clinical remission or response were also in line with the latter consensus report with a HBI of 4 points or less for clinical remission and a 3-point decrease for clinical response in CD, and with a partial Mayo Clinic score of 1 or less for clinical remission and a 2-point decrease for clinical response in UC.
      • Lewis J.D.
      • Lichtenstein G.R.
      • Deren J.J.
      • et al.
      Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial.
      • Vermeire S.
      • Schreiber S.
      • Sandborn W.J.
      • et al.
      Correlation between the Crohn’s disease activity and Harvey-Bradshaw indices in assessing Crohn’s disease severity.
      Although patients were included prospectively in this study, the retrospective nature of the data collection may have underestimated the safety profile and particular clinical issues. The results of such case series also may be impaired by recruitment bias and by an inadequate number of patients. However, patients were recruited in a named-patient basis that ensured that every single patient treated in France during the study period was included in this study. Furthermore, the fact that physicians were committed by the French regulatory agencies to collect efficacy and safety information in this program ensures the quality of the data collection and avoided potential commercial conflicts of interest.

      Conclusions

      Vedolizumab shows very promising potential in IBD patients who had an inadequate response to anti-TNF agents by promoting steroid-free clinical remission in up to one third of cases with a good safety profile. To guide treatment decisions and pre-emptive optimization before the achievement of the 14-week induction period, we identified the following predictors of steroid-free clinical remission: a clinical response at week 6, a low clinical activity score, a CRP level greater than 20 mg/L in UC, and the use of concomitant steroids in CD. The ability of vedolizumab to regulate the immune system had some limitations controlling the systemic inflammatory burden. Further studies are warranted to determine whether those parameters should be taken into account before starting vedolizumab therapy.

      Acknowledgments

      All members of the Observatory on Efficacy and of Vedolizumab in Patients With Inflammatory Bowel Disease study group are listed in the Appendix.

      Appendix

      All the members of the Observatory on Efficacy and of Vedolizumab in Patients With Inflammatory Bowel Disease study group are as follows: Aurelien Amiot, Charlotte Gagniere, Jean-Charles Grimaud, Laurent Peyrin-Biroulet, Camille Zallot, Marc-Andre Bigard, Jerome Filippi, Xavier Hebuterne, Benjamin Pariente, Maria Nachury, Pierre Desreumaux, Xavier Roblin, Emilie Del Tedesco, Anthony Buisson, Gilles Bommelaer, Carmen Stefanescu, Arnaud Boureille, Caroline Trang-Poisson, Romain Altwegg, Philippe Marteau, Xavier Dray, Franck Carbonnel, Philippe Seksik, Laurent Beaugerie, Jacques Cosnes, Harry Sokol, Cecilia Landman, Stephane Nancey, Gilles Boschetti, David Laharie, Florian Poullenot, Matthieu Allez, Jean-Marc Gornet, Clautilde Baudry, Guillaume Savoye, Jacques Moreau, Charlotte Gagniere, Lucine Vuitton, Stephane Koch, Stephanie Viennot, Alexandre Aubourg, Laurence Picon, Anne-Laure Pelletier, Gaelle Sickersen, Guillaume Bouguen, Vered Abitbol, Stanislas Chaussade, Yoram Bouhnik, Stephane Nahon, Betsy Winkfield, Hedia Brixi-Benmansour, Rodica Gincul, Jean-Christophe Barberis, Bruno Bonaz, Christophe Michiels, Franck Zerbib, Marie Bourrier de Beauregard, Christophe Locher, Sophie Davin-Couve, Armelle Poirette, Laurence Guillem, Monica Stetiu-Mocanu, Sylvain Beorchia, and Jawad Al Qaddi.
      Figure thumbnail fx1
      Supplementary Figure 1Changes according to the presence of steroid-free clinical remission at week 14 according to the (A) Harvey–Bradshaw Index, (B) partial ulcerative colitis disease activity index, and (C) C-reactive protein level at baseline and at weeks 6 and 14 after vedolizumab therapy was started.

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