Rates of Postoperative Recurrence of Crohn's Disease and Effects of Immunosuppressive and Biologic Therapies.

BACKGROUND & AIMS: The Rutgeerts' scoring system is used to evaluate patients with Crohn's disease (CD) following ileocolic resection, based on endoscopic findings at the anastomosis and in the neoterminal ileum. We investigated rates of clinical and surgical recurrence of CD after surgery and effect of therapy modification based on post-operative endoscopic findings. METHODS: We collected data from 365 adults with CD (20% with Rutgeerts' score i0, 10% with score i1, 49% with score i2, 12% with score i3, 9% with score i4) who underwent ileocolonoscopy within 12 months of ileocolic resection with anastomosis from 2000 through 2013 at 2 centers in Belgium and France. Patients were followed for 3 y or more after the ileocolonoscopy. Clinical post-operative recurrence (POR) was defined as occurrence of CD symptoms along with biologic, radiologic, and/or endoscopic features of disease activity; modified surgical POR was defined as either an endoscopic or surgical intervention. RESULTS: After a median follow-up time of 88 months, 48% of patients had clinical POR and 26% had modified surgical POR. Rates of survival without clinical POR or a modified surgical POR were lower in patients with Rutgeerts' scores of i2, i3, or i4 compared to patients with scores of i0 or i1 (P < .001 and P = .02). New immunosuppressant or biological therapy was initiated following endoscopy in 129/254 patients (51%) with Rutgeerts' score of i2, i3, or i4 vs 7/111 patients (6%) with scores of i0 or i1 (odds ratio for new therapy, 14.9; 95% CI, 7.1-36.8; P < .001). A modest decrease in risk of clinical POR was observed for patients with Rutgeerts scores of i3 or i4 after initiation of immunosuppressive or biological therapy based on endoscopic findings (Breslow P = .03), but this was not observed for patients with scores of i2 (Breslow P = .46). CONCLUSIONS: Use of immunosuppressants and tumor necrosis factor antagonists to treat patients with an asymptomatic endoscopic post-operative recurrence of CD did not reduce long-term risk of clinical recurrence in patients with Rutgeerts' scores of i2, but it had a small effect in patients with scores of i3 or i4.

Reliability of Endoscopic Evaluation of Postoperative Recurrent Crohn's Disease.

Endoscopic evaluation for postoperative recurrence of Crohn's disease (CD) is routinely integrated into clinical practice. The Rutgeerts score (RS) was developed to grade the severity of endoscopic postoperative CD recurrence and has been integrated into clinical practice guidelines and utilized as an endpoint in interventional trials.1,2 However, the operating properties of the RS have not been fully assessed. Furthermore, the RS i2 grade groups purely anastomotic ulcerations with those in the neoterminal ileum, whereas the modified Endoscopic Postoperative Recurrence Score (mEPRS) distinguishes lesions limited to the ileocolic anastomosis (i2a) from those in the neoterminal ileum (i2b). Accurate characterization of endoscopic recurrence is an important determinant for initiating postoperative medical therapy. Therefore, variability in endoscopic scoring may result in inappropriate therapeutic decisions.3 We evaluated the reliability of endoscopic assessment of postoperative CD recurrence among independent blinded central readers.

Correlation of Stool Frequency and Abdominal Pain Measures With Simple Endoscopic Score for Crohn's Disease.

BACKGROUND: The Crohn's Disease Activity Index (CDAI) has been criticized for being weakly correlated with bowel inflammation. We assessed correlation between Simple Endoscopic Score for Crohn's Disease (SES-CD) and individual CDAI items stratified by disease location to better understand this relationship. METHODS: We pooled patient-level data from 3 placebo-controlled Crohn's disease (CD) trials that tested adalimumab, upadacitinib, and risankizumab. Disease location was defined as ileum only, colon only, or ileocolonic based upon colonoscopy at study entry. Pearson correlation coefficients and linear regression assessed correlations between items of the CDAI and SES-CD. RESULTS: A total of 353 patients were included (20.7% ileal, 30.6% colonic, 48.7% ileocolonic disease). Crohn's Disease Activity Index and SES-CD scores were moderately correlated (R = 0.33; P < 0.001). Among CDAI items, the strongest correlations with SES-CD were seen with very soft or liquid stool frequency (SF) and patient-reported outcome 2 (PRO2; which includes SF and abdominal pain score; both R = 0.36; P < 0.001); these correlations were numerically stronger in colonic disease (SF: R = 0.46; P < 0.001; PRO2: R = 0.44; P < 0.001) than in ileal disease (SF: R = 0.14; P = 0.23; PRO2: R = 0.21; P = 0.07), although a test for interaction was not significant. In adjusted linear regression models, the proportion of mucosa that was inflamed and the proportion of mucosa with ulceration were positively correlated, whereas the presence of strictures was inversely correlated with SF. CONCLUSIONS: The SF item of the CDAI is moderately correlated with SES-CD and independently correlated with mucosal ulceration, inflammation, and strictures. Understanding why bowel inflammation as measured endoscopically does not correlate more strongly with patients' symptoms could help develop scales that link CD pathology to patient experience.

IM-UNITI: Three-year Efficacy, Safety, and Immunogenicity of Ustekinumab Treatment of Crohn's Disease.

BACKGROUND AND AIMS: Following induction/maintenance treatment in the UNITI/IM-UNITI studies of ustekinumab for Crohn's disease, patients entered a long-term extension for up to 5 years from induction. Efficacy through 152 and safety through 156 weeks are reported. METHODS: At IM-UNITI Week 44, 567 ustekinumab-treated patients entered the long-term extension and continued to receive blinded subcutaneous ustekinumab on their assigned dose interval, without any subsequent dose adjustment. Placebo-treated patients discontinued after study unblinding [after IM-UNITI Week 44 analyses]. Efficacy data in the long-term extension [LTE] were collected every 12 weeks [q12w] before unblinding and then at q12w/q8w dosing visits. RESULTS: Through Week 156, 29.6% of ustekinumab-treated patients discontinued. In an intent-to-treat analysis of randomised patients from IM-UNITI Weeks 0-152, 38.0% of ustekinumab induction responders receiving the drug q12w and 43.0% q8w were in remission at Week 152. Among patients entering the long-term extension in their original randomised groups, 61.9% of q12w and 69.5% of q8w patients were in remission at Week 152. Across all ustekinumab-treated patients [randomised and non-randomised] entering the long-term extension, remission rates at Week 152 were 56.3% and 55.1% for q12w and q8w, respectively. Safety events [per 100 patient-years] were similar among all ustekinumab-treated patients entering the long-term extension and placebo [overall adverse events 389.70 vs 444.17; serious adverse events, 18.97 vs 19.54; serious infections, 4.21 vs 3.97]. Rates of antibodies to ustekinumab through Week 156 remained low, 4.6% in all randomised ustekinumab-treated patients; lowest among patients in the original randomised q8w group [2/82, 2.4%]. CONCLUSIONS: Continued treatment with subcutaneous ustekinumab maintained clinical response and remission through 3 years in a majority of patients who responded to induction therapy and was well-tolerated. ClinicalTrials.gov number NCT01369355.

Effects of Ustekinumab on Histologic Disease Activity in Patients With Crohn's Disease.

BACKGROUND & AIMS: Although ustekinumab is an effective therapy for moderate to severe Crohn's disease (CD), its effects on the microscopic manifestations of CD are unknown. METHODS: We evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs). RESULTS: At week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P = .0137 for every 8 weeks vs placebo and P = .3529 for every 12 weeks vs placebo in the randomized population; P = .0168 for every 8 weeks vs placebo and P = .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r = .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline. CONCLUSIONS: In an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355.

Early Dose Optimisation of Golimumab in Nonresponders to Induction Treatment for Ulcerative Colitis Is Effective and Supported by Pharmacokinetic Data.

BACKGROUND AND AIMS: In nonresponders to golimumab induction for ulcerative colitis, we assessed clinical response rates and golimumab serum concentrations when the 100-mg dose was used early in the course of maintenance. METHODS: This post-hoc analysis of golimumab maintenance dosing [in the PURSUIT-M study] examined clinical outcomes and golimumab concentrations in early [Week 6] responders and nonresponders to induction, including subgroups based on body weight. RESULTS: In nonresponders to golimumab induction [assessed at Week 6], the 100-mg maintenance dose [starting at Week 6] resulted in a meaningful proportion [28.1%] of patients achieving a partial Mayo response at Week 14. After 1 year of maintenance, clinical outcome [response, remission, mucosal healing, corticosteroid-free state] rates in these "late" [Week 14] responders were similar to those in early [Week 6] responders. Golimumab concentrations in early nonresponders were approximately half those of early responders, suggesting that early nonresponders had more rapid golimumab clearance. Examined by body weight, the early nonresponders weighing <80 kg and receiving 100 mg had golimumab concentrations similar to the early responders [weighing <80 kg or ≥80 kg and receiving 50 mg or 100 mg, respectively]. CONCLUSIONS: Early use of the 100-mg maintenance dose leads to positive clinical outcomes in a meaningful proportion of patients who did not respond to golimumab at Week 6. Early nonresponders <80 kg who received the 100-mg maintenance dose achieved adequate golimumab concentrations and a clinically meaningful proportion of these patients had a late clinical response.PURSUIT-M protocol number C0524T18; ClinicalTrials.gov, NCT00488631; EudraCT, 2006-003399-37.

Efficacy and Safety of Adalimumab by Disease Duration: Analysis of Pooled Data From Crohn's Disease Studies.

BACKGROUND AND AIMS: Analyses of Crohn's Disease [CD] studies of anti-TNF agents, including adalimumab, have reported higher remission rates among patients with shorter disease duration. To further explore the relationship between disease duration and clinical efficacy, we analysed a larger patient cohort. METHODS: Data were pooled from 10 clinical trials in patients with moderately to severely active CD who received treatment with either adalimumab or placebo. Analyses of efficacy using Crohn's Disease Activity Index [CDAI] endpoints [remission, clinical response [CR]-70, CR-100, patient-reported outcome [PRO] remission] or Harvey-Bradshaw Index [HBI] endpoints [remission/response] were conducted for induction and maintenance treatment periods. Logistic regression was used for comparisons between adalimumab and placebo treatment. Cochran-Armitage trend tests were used for comparisons between disease-duration subgroups [<1 year, ≥1-<2 years, 2-≤5 years, and >5 years]. RESULTS: During induction, the proportion of patients achieving CDAI remission was higher in adalimumab- versus placebo-treated patients [p <0.001] and was highest [adalimumab: 45.8%] in the <1 year subgroup compared with longer disease-duration subgroups [≥1-<2 years: 31.0%; 2-≤5 years: 23.1%; >5 years: 23.6%, Cochran-Armitage p = 0.026]. In the majority of maintenance treatment analyses, patients with <1 year disease duration had the highest efficacy responses, with statistically significant differences in remission rates across disease-duration subgroups. CONCLUSIONS: This analysis demonstrates that earlier initiation of adalimumab treatment shortly after diagnosis in patients with moderately to severely active CD leads to improved long-term clinical outcomes.

Immunogenicity of Golimumab and its Clinical Relevance in Patients With Ulcerative Colitis.

BACKGROUND: Antidrug antibody (ADA) detection with standard bridging enzyme immunoassays (EIA) can yield false-negative results or underestimate titers through drug interference. A more sensitive assay was needed to determine clinical impact of antigolimumab antibodies. METHODS: A high-sensitivity, drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original EIA, and samples from induction/maintenance studies in golimumab-treated patients with ulcerative colitis were analyzed for ADAs using both methods. Immunogenicity results were compared, and pharmacokinetic, efficacy, and safety associations were evaluated. RESULTS: An 8-fold increase in ADA-positive patients (21.8% DT-EIA vs 2.8% EIA) reflected DT-EIA improved sensitivity and drug tolerance. Most newly detected ADA-positive patients (using DT-EIA) had low antibody titers, whereas most with high antibody titers were ADA-positive with original EIA. With DT-EIA, week 44 median trough serum golimumab concentrations among ADA-positive patients were approximately half vs ADA-negative (0.51 vs 0.85 µg/mL [50 mg q4w]; 0.85 vs 1.60 µg/mL [100 mg q4w]). Antidrug antibody impact on golimumab concentrations was more notable at titers ≥1:100. During induction, ADAs had no notable impact on efficacy. During maintenance, proportions of patients maintaining clinical response through week 54 were lower using DT-EIA: 38.1% ADA-positive and 52.8% ADA-negative. Antidrug antibody status had no impact on injection-site reaction incidence. CONCLUSIONS: A more sensitive DT-EIA identified higher proportions of ADA-positive patients. A trend of decreasing drug concentrations with increasing ADA titers was observed. Pharmacokinetic impact was better elucidated with DT-EIA. Although development of ADA did not preclude efficacy, a trend toward decreased efficacy in ADA-positive vs ADA-negative patients was observed during maintenance treatment. Antidrug antibody status did not impact safety.

Gene and Mirna Regulatory Networks During Different Stages of Crohn's Disease.

BACKGROUND AND AIMS: Early treatment of Crohn's disease [CD] is required in order to optimize patient outcomes. To this end, we need to gain a better understanding of the molecular changes at the onset of CD. METHODS: As a model for the earliest mucosal CD lesions, we study post-operative recurrent CD [Rutgeerts score ≥ i2b]. We are the first to analyse gene and microRNA [miRNA] expression profiles in ileal biopsies from these patients, and compare them with those of newly diagnosed [≤18 months] and late-stage [>10 years after diagnosis] CD patients. RESULTS: Except for one gene [WNT5A], there are no differential genes in CD patients without post-operative recurrence [i0], showing that previous disease did not influence gene expression in the neoterminal ileum, and that this model can be used to study early mucosal CD lesions. Gene expression and co-expression network dysregulation is more pronounced in newly diagnosed and late-stage CD than in post-operative recurrent CD, with most important modules associated with [a]granulocyte adhesion/diapedesis, and cholesterol biosynthesis. In contrast, we found a role for snoRNAs/miRNAs in recurrent CD, highlighting the potential importance of regulatory RNAs in early disease stages. Immunohistochemistry confirmed the expression of key dysregulated genes in damaged/regenerating epithelium and immune cells in recurrent CD. CONCLUSIONS: Aside from regulatory RNAs, there are no clear gene signatures separating post-operative recurrent, newly diagnosed, and late-stage CD. The relative contribution of dysregulated genes and networks differs, and suggests that surgery may reset the disease at the mucosal site, and therefore post-operative recurrent CD might be a good model a good model to study to study early mucosal CD lesions.

No Change in Determining Crohn's Disease Recurrence or Need for Endoscopic or Surgical Intervention With Modification of the Rutgeerts' Scoring System.

The postoperative endoscopic recurrence score, commonly referred to as the Rutgeerts score, was designed to predict clinical recurrence risk in Crohn's disease (CD) patients undergoing ileocolonic resection based on early endoscopic findings at the anastomosis and in the neoterminal ileum.1 In the pivotal publication, the i2 category, including aphthous lesions in the terminal ileum as well as ileocolonic anastomosis lesions, had a heterogeneous recurrence risk. Because anastomotic ulcers were suspected to be postsurgical ischemic lesions and less predictive of progressive disease,2 a modified Rutgeerts score (mRS) was proposed: i2a, lesions confined to the anastomosis ±<5 isolated aphthous ulcers in the ileum; i2b, more than 5 aphthous ulcers in the ileum with normal mucosa in between, ± anastomotic lesions.3,4.

Continuous Clinical Response Is Associated With a Change of Disease Course in Patients With Moderate to Severe Ulcerative Colitis Treated With Golimumab.

Background: Responders to induction treatment sustain continuous clinical response (CCR) through 1 year in about 50% of patients in PURSUIT-M trial with golimumab maintenance in ulcerative colitis (UC). This post hoc analysis of PURSUIT-M describes the 1-year clinical, endoscopic, quality of life (QoL), and biomarker and 4-year clinical outcome in patients with sustained response to golimumab therapy for UC. Methods: We compared clinical, endoscopic, QoL, and calprotectin outcomes in CCR and non-CCR patients through 54 weeks in PURSUIT-M. Persistence on golimumab therapy and clinical response at 4 years was assessed for CCR and non-CCR patients. The relationship of colectomy with CCR status was determined. Results: Among patients receiving golimumab maintenance, greater proportions of patients with vs without CCR at week 54 achieved clinical remission (67.1% vs 1.9%), corticosteroid-free remission (61.6% vs 1.9%), endoscopic remission (Mayo endoscopy score 0 [47.9% vs 1.3%]), and normal QoL (inflammatory bowel disease questionnaire score ≥170 [75.0% vs 24.4%]). CCR but not non-CCR patients maintained normalized calprotectin levels during maintenance. Among patients who entered the long-term extension study, a greater proportion of patients with vs without CCR maintained PGA 0 through week 216 (58% vs 42%). Colectomy was performed in 47 induction nonresponders and in 13 induction responders. None of the patients going onto colectomy achieved CCR through 54 weeks in PURSUIT-M. Conclusions: Continuous clinical response is associated with favorable short- and long-term clinical, endoscopic, QoL, and biomarker responses that may result in changing the course of disease and may prevent colectomy in patients with moderate to severe UC treated with golimumab. 10.1093/ibd/izy229_video1izy229.video15806022773001.

Combination Therapy With Infliximab and Azathioprine Improves Infliximab Pharmacokinetic Features and Efficacy: A Post Hoc Analysis.

BACKGROUND & AIMS: Among immunosuppressive- and biologic-naïve patients with moderately-to-severely active Crohn's disease (CD), a higher proportion of those treated with the combination of infliximab and azathioprine achieved corticosteroid-free remission at week 26 (CSFR26) than those given infliximab monotherapy; patients given the combination therapy also had higher serum concentrations of infliximab. Enhanced benefit of combination therapy may occur through synergistic modes of action or the influence of azathioprine on infliximab pharmacokinetics. METHODS: We analyzed data from 206 patients from whom week 30 serum samples were available: 97 received infliximab monotherapy (5 mg/kg, n = 97) and 109 received combination therapy (2.5 mg/kg/day; n = 109). Proportions of patients achieving CSFR26 and mucosal healing (absence of ulcers) at week 26 were calculated for each quartile of serum concentrations of infliximab, and exposure-response relationships were compared. RESULTS: Within quartiles of serum concentrations of infliximab, CSFR26 did not differ significantly between patients who received combination therapy vs monotherapy. However, among patients in the lowest quartile of serum concentration of infliximab, twice as many patients who received infliximab monotherapy achieved CSFR26 vs combination therapy. Anti-drug antibodies were detected only in the lowest quartile of serum concentrations of infliximab-in 35.9% of patients given monotherapy and 8.3% of patients given combination therapy. CONCLUSION: Among patients with CD and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. Combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. ClinicalTrials.gov, NCT00094458.

Difference in Pathomechanism Between Crohn's Disease and Ulcerative Colitis Revealed by Colon Transcriptome.

BACKGROUND: We aim to identify the differences in colonic mucosal transcriptome between Crohn's disease (CD) and ulcerative colitis (UC) for a better understanding of the molecular pathology. METHODS: Differentially expressed genes (DEG) in the colonic mucosa of CD and UC were identified with a global gene expression microarray dataset generated from the colon biopsies of CD and UC patients and normal controls. The DEGs were then processed to identify altered pathways and modularized DEGs and pathways. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis with an independent cohort of samples was performed to validate the microarray data. RESULTS: At the pathway level, virus infection and autoimmune pathways were upregulated in CD but not in UC when compared with controls. Some of the relevant DEGs (such as TAP1 and TAP2) were elevated in both CD and UC, with CD exhibiting more pronounced elevations. Gene expression levels in viral infection pathways were correlated with those of autoimmune pathways. In contrast, pattern recognition-mediated innate immune pathways (TLR4 and TLR2) were significantly elevated in UC but not in CD. Similar results were observed with an independent cohort by qRT-PCR. CONCLUSIONS: Our data support the hypothesis that viral infection induced autoimmunity may represent a pathomechanism for IBD, especially CD. However, pattern recognition-mediated innate immunity targeting microbiome may play a more important role in UC compared with CD. Our findings identified different intervention targets for CD and UC, which may lead to more effective treatments for IBD patients.

Gene Expression Signature for Prediction of Golimumab Response in a Phase 2a Open-Label Trial of Patients With Ulcerative Colitis.

Golimumab, a tumor necrosis factor antagonist, is an effective treatment for patients with moderate-to-severe ulcerative colitis (UC); however, more than 50% of initial responders lose their response to the drug within the first year of therapy. A gene expression signature identified in colon biopsies collected before treatment was associated with response to infliximab, and was subsequently refined to associate with mucosal healing in response to golimumab. We performed a phase 2a open-label study of 103 golimumab-treated patients with moderate-to-severe UC to test whether the baseline gene expression signature could be used to predict which patients would achieve mucosal healing, clinical response, and clinical remission at weeks 6 and 30 of treatment. The gene expression signature identified patients who went on to achieve mucosal healing at treatment week 6 with an area under the receiver operating characteristic curve (AUCROC) of 0.688 (P = .002) and at week 30 with an AUCROC of 0.671 (P = .006). The signature identified patients with mucosal healing with 87% sensitivity, but only 34% specificity, limiting its clinical utility. The baseline gene expression signature did not identify patients who went on to achieve clinical remission or clinical response with statistical significance. Further studies are needed to identify biomarkers that can be used to predict which patients with UC will respond to treatment with anti-tumor necrosis factor agents. ClinicalTrials.gov no: NCT01988961.

Long-Term Benefit of Golimumab for Patients with Moderately to Severely Active Ulcerative Colitis: Results from the PURSUIT-Maintenance Extension.

BACKGROUND AND AIMS: To evaluate the safety and efficacy of 3 additional years of subcutaneous golimumab maintenance in patients with moderately to severely active ulcerative colitis. METHODS: The PURSUIT-maintenance long-term extension enrolled patients who had completed placebo or golimumab 50 mg or 100 mg treatment every 4 weeks [q4w] through Week 52 and evaluations at Week 54 [n = 666]; treatment continued through Week 212. Patients receiving placebo were discontinued after study unblinding. Efficacy endpoints, golimumab concentrations, and anti-drug antibodies were summarized as observed for golimumab-induction responders who continued golimumab therapy during the long-term extension. Observations relating to safety were summarized for all treated patients. RESULTS: Overall, 63% of patients who were receiving golimumab at the beginning of the extension remained on treatment through the end of the study. Among all treated patients in the extension, rates of adverse events of special interest [e.g. tuberculosis, demyelination, and malignancy] were infrequent. Nine deaths occurred during the extension [1 placebo, 1 golimumab 50 mg, and 7 golimumab 100 mg]. Serum golimumab concentrations were dose-proportional and were maintained over time. During the extension through Week 228, anti-drug antibody rates with golimumab 50 mg and 100 mg were 4.4% and 3.7%, respectively. Among golimumab-induction responders, 99.3% had no disease or mild disease activity as per the Physician's Global Assessment, 92.5% were corticosteroid-free, and 76.1% had an Inflammatory Bowel Disease Questionnaire score of ≥170 at Week 216. CONCLUSIONS: Subcutaneous golimumab treatment of moderately to severely active ulcerative colitis for up to 3 additional years during the extension maintained clinical benefit with no new safety signals observed.ClinicalTrials.gov number NCT00488631.

Efficacy of Ustekinumab for Inducing Endoscopic Healing in Patients With Crohn's Disease.

BACKGROUND & AIMS: We evaluated the ability of ustekinumab, a monoclonal antibody against the p40 subunit of interleukins 12 and 23, to induce endoscopic healing in patients with moderate to severe Crohn's disease (CD). METHODS: We performed an endoscopy substudy of 334 patients with moderate to severe CD participating in 3 randomized controlled phase 3 studies to determine the safety and efficacy of ustekinumab induction and maintenance therapy. All patients underwent colonoscopy at baseline and week 8 of the induction studies and at week 44 of the maintenance study; all colonoscopies were assessed by a blinded central reader. During the induction studies, patients were randomly assigned to groups given intravenous ustekinumab (130 mg or 6 mg/kg) or placebo. At the baseline time point of the maintenance study (week 8 of the induction studies), patients with a clinical response to ustekinumab were randomly assigned to groups given subcutaneous ustekinumab (90 mg every 12 weeks or 8 weeks) or placebo. Additional maintenance analysis populations were patients who did not respond to ustekinumab or placebo during the induction studies, and patients who responded to placebo during the induction studies; we performed a post-hoc pooled analysis of randomly assigned and non-randomly assigned patients of the maintenance study. We analyzed data from patients with an ulcer in at least 1 segment at baseline of the induction studies. The primary end point was change in the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), from baseline, at week 8. We also assessed the efficacy of maintenance therapy. RESULTS: Patients given ustekinumab had a greater reduction in SES-CD from the induction baseline time point until week 8 than placebo (reduction of 2.8 in patients given ustekinumab vs a reduction of 0.7 points in patients given placebo; P = .012). Results were similar among patients in different induction studies and patients given different doses of ustekinumab. At week 44, reductions in the SES-CD from the induction baseline were greater in patients given ustekinumab (for combined groups, a reduction of 2.5; P = .176 and for every 8 weeks, a reduction of 3.1; P = .107) than patients given placebo (reduction of 1.9 points). Maintenance results were similar for the larger pooled post-hoc analysis. CONCLUSIONS: In an analysis of data from 3 trials of patients with moderate to severe CD, ustekinumab (intravenous induction and subcutaneous maintenance) reduces SES-CD compared with placebo. We observed significant reductions in endoscopic disease activity at week 8 of induction therapy with ustekinumab. (ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355).

Performance of Crohn's disease Clinical Trial Endpoints based upon Different Cutoffs for Patient Reported Outcomes or Endoscopic Activity: Analysis of EXTEND Data.

Background: Clinical trial endpoints for Crohn's disease (CD) activity correlate poorly with mucosal inflammation; to assess treatment efficacy, patient-reported outcomes and endoscopic assessments are preferred. This study assessed the impact on treatment efficacy estimations of using different definitions of clinical and endoscopic remission and endoscopic response, and of using site- or central-based endoscopy evaluation. Methods: This post hoc analysis of data fromEXTEND (extend the safety and efficacy of adalimumab through endoscopic healing), a placebo (PBO)-controlled, randomized trial of adalimumab (ADA) for mucosal healing, included adults with moderate-to-severe CD. Subsets of patients meeting specified Simplified Endoscopic Score for CD (SES-CD) inclusion criteria, according to site or central reading, and baseline stool frequency (SF) and/or abdominal pain score (AP) thresholds were evaluated. Various endpoint definitions based on the Crohn's Disease Activity Index (CDAI), its SF and AP components, SES-CD, and composite endpoints were compared between treatment groups. Results: Increased stringency of Week 12 clinical endpoints compared to CDAI<150 to SF≤3.0/1.5&AP≤1.0 reduced PBO response rates by ≥12% and increased treatment effects by ≤10%. Amending the SES-CD endpoint from ≤4 to ≤2 reduced the treatment effect from 24% to 8%. Composite endpoints further diminished response rates and effect sizes. Site-based evaluation was associated with lower remission rates versus central reading in the PBO group and, thus, greater ADA-related treatment effects. Conclusions: This analysis is the first to demonstrate that increasing the stringency of clinical and endoscopic endpoint definitions in CD trials, especially lowering SF or SES-CD definitions, reduces the ability to detect treatment-related change in CD activity; focus on endpoints that reflect clinical change is warranted.

Effect of vedolizumab (anti-α4ß7-integrin) therapy on histological healing and mucosal gene expression in patients with UC.

OBJECTIVE: Lymphocyte recruitment to the inflamed gut is increased in UC. Inhibition of this cell trafficking by vedolizumab (VDZ) was successful in inducing and maintaining remission and in induction of endoscopic mucosal healing. There are no data on histological healing with VDZ. We studied histological changes following VDZ therapy and compared gene expression in patients with UC before and after therapy. DESIGN: Forty-one patients with UC from GEMINI I and LTS were studied before and at three time points (weeks 6/12/52) following VDZ therapy. Colonic biopsies were scored using the Geboes index and correlated with Mayo endoscopic subscore. Gene expression was analysed using Affymetrix gene arrays. RESULTS: Fifty-five per cent of patients achieving endoscopic healing (= Mayo endoscopic subscore 0-1) with VDZ at the studied time points also had histological healing (= Geboes grade 0-1). In most healers, some residual histological changes (eg, disturbed architecture and increased mononuclear cell infiltrate) were still observed, although this was less at week 52. VDZ restored expression of many inflammatory genes in patients with endoscopic healing only at week 52 and not before. In VDZ healers, the expression of many genes remained dysregulated at weeks 6/12/52 compared with controls. CONCLUSIONS: VDZ induces histological healing in >50% of patients with endoscopic healing, with maximal effect at week 52. VDZ also restored, although incompletely, the colonic expression of many immune-related genes in patients with UC achieving endoscopic healing at week 52. However, persistent histological and gene dysregulations did remain even in healers, suggesting that maintenance therapy will be necessary to control the intestinal inflammation. TRIAL REGISTRATION NUMBERS: NCT00783718 and NCT00790933; post-results.

Mucosal Healing and Long-term Outcomes of Patients With Inflammatory Bowel Diseases Receiving Clinic-Based vs Trough Concentration-Based Dosing of Infliximab.

BACKGROUND & AIMS: The Trough Concentration Adapted Infliximab Treatment (TAXIT) trial demonstrated that maintaining infliximab trough concentrations at 3 to 7 µg/mL is most effective at inducing remission in patients with inflammatory bowel diseases (IBDs), with fewer flares than clinic-based dosing. We performed a follow-up analysis of study participants to explore the correlation between trough dosing strategy and mucosal healing, continued infliximab use, and rates of hospitalization, surgery, and steroid use. METHODS: This was a retrospective single-center study of 226 patients with IBD who completed the maintenance phase of TAXIT, performed at the University Hospitals of Leuven in Belgium. Baseline patient characteristics, laboratory test results, and endoscopic data were obtained at the end of that study between June 2012 and December 2013 (n = 125). Long-term outcome data (IBD-related hospitalization, abdominal surgery, and systemic steroid use) were collected from the time of the last TAXIT study visit (August 2012-April 2013) until April 1, 2016. We also collected data on continued use of infliximab and trough concentrations. RESULTS: At baseline, 91% of patients in the clinic-based dosing group and 90% of patients in the trough concentration-based dosing group had mucosal healing. After a median follow-up time of 41 months (interquartile range, 39-42 mo), infliximab treatment was continued by 81 of 108 patients (75%) from the clinic-based dosing group and 86 of 107 (80%) from the trough concentration-based dosing group. However, within 1 year, infliximab was discontinued by 10 of 27 patients (37%) from the clinic-based dosing group and 2 of 21 patients (10%) from the trough concentration-based dosing group (P = .04). The rates of hospitalization, surgery, and steroid use were below 15% in both groups. CONCLUSIONS: At the end of a trial of clinic-based dosing vs trough concentration-based dosing of infliximab in patients with IBD, most patients had mucosal healing. Most patients (≥75%) in both groups continued taking infliximab for more than 3 years after the trial, but a significantly higher proportion of patients in the clinic-based dosing group discontinued infliximab in the first year after the end of the trial. Both groups had low rates of hospitalization, surgery, and steroid use.