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Crohn's disease has a substantial negative impact on health-related quality of life (HRQoL).To examine the effects of risankizumab on HRQoL in Crohn's disease METHODS: We analysed data from patients with Crohn's disease from 12-week induction trials ADVANCE (N = 850) and MOTIVATE (N = 569) with risankizumab 600 mg or 1200 mg intravenous (IV) versus placebo IV and a 52-week maintenance trial FORTIFY (N = 462) with risankizumab 180 or 360 mg subcutaneous (SC) versus placebo SC. Outcomes included Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), 36-item Short Form Health Survey (SF-36), EuroQol 5-Dimension-5-Level (EQ-5D-5L) and work productivity. The mean change and percentages of patients achieving clinically meaningful improvement in all outcomes were determined at weeks 12 and 52.At week 12, more patients in the risankizumab 600 or 1200 mg groups achieved IBDQ response than with placebo (ADVANCE: 70.2%, 75.5% vs. 47.8%, p ≤ 0.001; MOTIVATE: 61.7%, 68.5% vs. 48.2%, p ≤ 0.01) and FACIT-F response (ADVANCE: 51.3%, 48.0% vs. 35.7%, p ≤ 0.01; MOTIVATE: 44.2%, 49.1% vs. 33.7%, p 0.05). These improvements persisted at week 52 with risankizumab maintenance treatment. Similar trends were observed for SF-36 physical and mental component summary scores, EQ-5D-5L and activity impairment within work productivity measures.Risankizumab induction therapy (600 or 1200 mg IV) led to clinically meaningful improvements in disease-specific and general patient-reported outcomes, including fatigue, in patients with moderate to severe Crohn's disease. These improvements were sustained after 52 weeks of risankizumab (180 or 360 mg SC) maintenance therapy.

BACKGROUND Recently, there has been a growing recognition of the bidirectional link between sleep and inflammation. Several studies have reported the prevalence of sleep disturbances in those with Inflammatory Bowel Disease (IBD) and found poor sleep has the potential to increase the risk of disease relapse. Additionally, sleep loss may adversely affect cognitive performance, mental health, metabolism, and pain perception. While previous research has indicated potential associations between sleep and symptoms commonly reported in IBD, few studies use objective measures of sleep. Wrist actigraphy can objectively and non-invasively measure sleep-wake cycles and has been found feasible for use in the IBD population. This study aimed to examine the relationship between self-reported sleep, wrist actigraphy, and symptoms among adults with IBD. METHODS Participants with IBD (ages 18-55) completed demographic and sleep questionnaires, a 28-day symptom diary, and wore a wrist actigraph for up to 15 days. Sleep questionnaires were the Pittsburgh Sleep Quality Index (PSQI), Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance, and PROMIS sleep-related impairment. Participants rated symptoms on a 4-point Likert scale, including gastrointestinal-related symptoms such as abdominal pain, diarrhea, bloating, constipation, fatigue, and extraintestinal symptoms, including anxiety, depression, and stress. Data analysis included descriptive statistics and Pearson correlations. RESULTS Twenty-five participants (Crohn’s Disease=18; Ulcerative Colitis=7) were included. The mean age was 33.5 (SD 8.3) years of age, 60% were female, 92% were White, 88% were non-Hispanic or Latino, and 36% had active endoscopic disease. Most (64%) participants had poor quality sleep (PSQI global ≥ 5). In contrast, the averages for onset latency, efficiency, wake after sleep onset (WASO), and total sleep time were all within normal values at 17.4 min (SD 26.7), 84.2% (SD 7.5), 48.7 min (SD 27.3), and 435.8 min (69.2), respectively. PROMIS sleep disturbance was significantly correlated with abdominal pain (r=0.56), bloating (r=0.43), constipation (r=0.46), fatigue (r=0.50), and stress (r=0.42). PROMIS sleep-related impairment was significantly correlated with bloating (r=0.47), constipation (r=0.50), fatigue (r=0.60), depression (r=0.42), and stress (r=0.46). Onset latency was significantly correlated with anxiety (r=0.41) and stress (r=0.42). Sleep time was significantly correlated with fatigue (r=0.42). CONCLUSION This study highlights sleep disturbances are prevalent in those with IBD and significantly correlated with both GI and extraintestinal symptoms. Future work is needed to explore these relationships further and the potential benefit of sleep interventions in this population.

Background Patients with Crohn’s disease (CD) experience intestinal inflammation. Ontamalimab (SHP647), a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1, is a potential novel CD treatment. OPERA II, a multicenter, open-label, phase 2 extension study, assessed the long-term safety and efficacy of ontamalimab in patients with moderate-to-severe CD. Methods Patients had completed 12 weeks of blinded treatment (placebo or ontamalimab at 22.5, 75, or 225 mg subcutaneously) in OPERA (NCT01276509) or had a clinical response to ontamalimab 225 mg in TOSCA (NCT01387594). Participants received ontamalimab at 75 mg every 4 weeks (weeks 0–72), then were followed up every 4 weeks for 24 weeks. One-time dose reduction to 22.5 mg or escalation to 225 mg was permitted at the investigator’s discretion. The primary end points were safety and tolerability outcomes. Secondary end points included changes in serum drug and biomarker concentrations. Efficacy end points were exploratory, and used non-responder imputation methods. Results Overall, 149/268 patients completed the study. The most common adverse event leading to study discontinuation was CD flare (19.8%). Two patients died; neither death was considered to be drug related. No dose reductions occurred; 157 patients had their dose escalated. Inflammatory biomarker concentrations decreased. Serum ontamalimab levels were consistent with known pharmacokinetics. Remission rates (Harvey-Bradshaw Index [HBI] ≤ 5; baseline, 48.1%; week 72, 37.3%) and response rates (baseline [decrease in Crohn’s Disease Activity Index ≥ 70 points], 63.1%; week 72 [decrease in HBI ≥ 3], 42.5%) decreased gradually. Conclusions Ontamalimab was well tolerated; treatment responses appeared to be sustained over 72 weeks. ClinicalTrials.gov ID: NCT01298492.

Background The majority of patients with Crohn’s disease (CD) will not achieve endoscopic remission on current therapy. Addition of tofacitinib to biologics may improve remission rates. Methods We retrospectively assessed safety and clinical and endoscopic effectiveness of off-label tofacitinib and biologics for CD. Results We identified 19 patients treated with tofacitinib and a biologic for refractory CD between 2017 and 2019. Tofacitinib was added for luminal disease on colonoscopy (n = 13), luminal disease on capsule (n = 3), and pyoderma gangrenosum (n = 3). The mean age was 41.2 years (28–62), mean disease was duration 16.9 years (6–36), and prior exposure to biologics was a median of 4 (1–6). Mean treatment duration was 9.6 months (SD, 3.3). Adverse events (AEs) were reported in 36.8% of patients, most commonly minor infection or CD flare, and no patients had a serious AE; 80.0% (n = 8) achieved clinical response, and 60.0% (n = 6) achieved clinical remission based on Harvey-Bradshaw Index. Endoscopic improvement occurred in 54.5% (n = 6), endoscopic remission in 18.2% (n = 2), and endoscopic healing in 18.2% (n = 2) of patients. Mean Simple Endoscopic Score in CD significantly improved from 13.6 ± 5.2 to 6.5 ± 4.0 after treatment (P < .01). Conclusions In patients treated with tofacitinib in combination with a biologic, no new safety signals were observed. Combination tofacitinib and a biologic was effective in achieving clinical and endoscopic improvement in some patients with severe, refractory CD, although a larger sample size is needed to further assess the efficacy and long-term safety of this treatment strategy.

We report the case of a 51-year-old male with Crohn’s disease (CD) who developed a reproducible pustular rash after ustekinumab (UST) administration. The patient first presented with a pustular rash on his hands, body, extremities, and scalp starting 5 weeks after his initial weight-based UST induction. The rash resolved spontaneously, then recurred 4 weeks after his first subcutaneous maintenance dose of UST 90 mg. Biopsy of the affected area demonstrated subcorneal pustular dermatosis (SPD). UST was discontinued and the rash resolved. Unfortunately, the patient experienced clinical recurrence of CD, and given prior failure of multiple CD medications, UST was restarted with premedication. Two weeks after UST re-induction, the rash recurred, though less severe. Given improvement in CD symptoms, UST was continued and the rash managed with topical corticosteroids. This is the first case of drug-induced SPD associated with UST. One case report has previously described de novo pustular psoriasis associated with UST in a patient with CD and enteropathic arthritis. Notably, SPD and pustular psoriasis can be histologically indistinguishable. The development of a paradoxical psoriasiform rash is thought to be one of the few dose and duration dependent side effects of TNF-antagonist therapy but has not previously been established as a side effect of UST. This case demonstrates a new potential side effect of UST.

BACKGROUND Neihulizumab (ALTB-168) is a novel immune checkpoint agonistic antibody that binds to human CD162 (PSGL-1), and leads to downregulation of activated T-cells. Early-phase trials of neihulizumab have suggested a benefit in patients with immune conditions, including psoriasis, psoriatic arthritis and steroid-refractory acute graft-versus-host disease. Here, we report the results of a Phase II study investigating the use of neihulizumab for ulcerative colitis (UC) (ClinicalTrials.gov Identifier: NCT03298022). AIMS The aims of this study were to evaluate efficacy, safety, tolerability and immunogenicity of neihulizumab in patients with moderate to severe active UC who are refractory or intolerant to anti-TNFα and/or anti-integrin therapy. METHODS Two regimens were tested: 5 weekly IV doses plus 3 bi-weekly IV doses of 9 mg/kg neihulizumab (5 + 3 regimen), and 8 weekly IV doses plus 2 bi-weekly IV doses of 9 mg/kg neihulizumab (8 + 2 regimen). The primary efficacy outcome is the proportion of patients with clinical response at Week 12. The key secondary efficacy outcomes are the proportion of patients with clinical remission, mucosa healing, histological healing and the change in Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS 24 subjects enrolled in this study; study demographics and baseline disease characteristics are shown in Table 1. In the 5 + 3 regimen, 10 subjects were enrolled into this study and 2 (20%) subjects completed the study. The mean duration of study treatment exposure was 59.5 days. Among 10 enrolled subjects, 9 subjects were included in the efficacy analysis: 2 (22%) subjects achieved clinical response at Week 12 and 1 (11%) subject achieved clinical response at Week 2. The overall efficacy is summarized in Table 2. In this regimen, 9/10 (90%) subjects reported an AE: 7 (70%) subjects with AEs related to study treatment, 9 (90%) subjects with AEs that were not related to study treatment, 1 (10%) subject with an SAE not related to study treatment, and no deaths were reported in this regimen. In the 8 + 2 regimen, 14 subjects were enrolled into this study and 9 (64%) subjects completed the study. The mean duration of study treatment exposure was 78.1 days. Among 14 enrolled subjects, 7 (50%) subjects achieved clinical response at Week 12 and 5 (36%) subjects achieved clinical response at Week 26 (Table 2). In this regimen, 13/14 (93%) of subjects reported an AE: 2 (14%) subjects with AEs related to study treatment and 12 (86%) subjects with AEs that were not related to study treatment; there was no SAE reported and no deaths. CONCLUSIONS This phase 2 study of neihulizumab suggest efficacy and safety signals in treatment-refractory UC that warrant further investigation.

Background Bowel urgency is commonly experienced by patients with ulcerative colitis (UC) and is associated with reduced health-related quality of life (QoL). Mirikizumab, a humanized monoclonal antibody directed against the p19 subunit of IL-23, significantly reduced bowel urgency in a double-blind, randomized, placebo-controlled Phase 2 clinical trial in patients with moderate-to-severe UC (NCT02589665). Methods All patients (N = 249) reported symptoms including absence or presence of bowel urgency. Absence of urgency was defined as no urgency for the 3 consecutive days prior to each scheduled visit. Missing urgency data were imputed as present. After 12 weeks of induction treatment, patients who achieved clinical response continued maintenance mirikizumab treatment through Week 52. We assessed the relationship of urgency with QoL, clinical outcomes, and inflammatory biomarkers at Weeks 12 and 52. Results Patients with absence of urgency demonstrated significantly greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) scores even after adjusting for rectal bleeding (RB) and stool frequency (SF), significantly higher rates of all clinical outcomes at Weeks 12 and 52, and a greater decrease in inflammatory biomarkers C-reactive protein and fecal calprotectin compared to those with presence of urgency. Absence of urgency at Week 12 was associated with improved IBDQ scores at Week 52, while Week 12 RB or SF status was not. Conclusions Absence of urgency is strongly associated with improvement in QoL as well as clinical measures of UC disease activity. These findings suggest urgency may be a useful surrogate marker of disease activity and an important treatment target for UC.

This article reviews therapeutic drug monitoring (TDM) use for current inflammatory bowel disease (IBD) treatments. IBD comprises Crohn's disease and ulcerative colitis-chronic gastrointestinal inflammatory disorders. Treatment options for moderate to severe IBD include thiopurines; methotrexate; biologic agents targeting tumor necrosis factor, α4β7 integrin or interleukins 12 and 23; and Janus kinase inhibitors. TDM is recommended to guide treatment decisions for some of these agents. Published literature concerning TDM for IBD treatments was reviewed. S.D.L., R.S., and E.V.L. drew on their clinical experiences. Polymorphisms resulting in altered enzymatic activity inactivating thiopurine metabolites can lead to myelotoxicity and hepatotoxicity. Increased elimination of biologic agents can result from immunogenicity or higher disease activity, leading to low drug concentration and consequent nonresponse or loss of response. TDM may aid treatment and dose decisions for individual patients, based on monitoring metabolite levels for thiopurines, or serum drug trough concentration and antidrug antibody levels for biologic agents. Challenges remain around TDM implementation in IBD, including the lack of uniform assay methods and guidance for interpreting results. The Janus kinase inhibitor tofacitinib is not impacted by enzyme polymorphisms or disease activity, and is not expected to stimulate the formation of neutralizing antidrug antibodies. TDM is associated with implementation challenges, despite the recommendation of its use for guiding many IBD treatments. Newer small molecules with less susceptibility to patient variability factors may fulfill the unmet need of treatment options that do not require TDM, although further study is required to confirm this.

Summary Distinct histomorphologic features of colitis-associated dysplasia (CAD) or neoplastic precursors in inflammatory bowel disease (IBD) have never been clearly identified. In this study, we tried to further explore the differentiating morphologic features of CAD by retrospectively reviewing the lesions that were clearly associated with carcinomas (carcinoma-related lesions) and by comparing between endoscopically nonpolypoid (non–adenoma-like) lesions and polypoid (adenoma-like) lesions and sporadic conventional adenomas found in the noncolitic mucosa and in patients without IBD. Our study results have revealed that (1) precursor lesions related to IBD-associated colorectal carcinomas were almost always nonpolypoid in macroscopic/endoscopic appearance; (2) nearly half of the carcinoma-related lesions and nonpolypoid lesions were similarly nonadenomatous (nonconventional) lesions, largely serrated type, with no or only mild/focal adenomatous dysplasia, and commonly had mixed adenomatous and nonadenomatous features; (3) carcinoma-related and nonpolypoid adenomatous dysplastic lesions frequently showed some peculiar histocytologic features that we observed and described for the first time, including mixed features of inflammatory pseudopolyps or granulation tissue, pleomorphic and disarrayed nuclei, micropapillary or hobnailing surface epithelial cells, and microvesicular or bubbling cytoplasm of dysplastic cells; and (4) polypoid lesions in the colitic mucosa were identical to sporadic adenomas in the noninflamed mucosa and in patients without IBD, and they lacked the aforementioned features. The seemingly distinctive morphologic characteristics that we proposed here, although still not absolutely specific or unique, can be used as the features of inclusion for identifying CAD on endoscopic biopsies when the endoscopy images are not readily available to pathologists and thus to alert clinicians for a closer follow-up.

BACKGROUND & AIMS: Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC). METHODS: In a phase 2, proof-of-concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs) (stool frequency, rectal bleeding, and endoscopy findings) of 4-9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) for 12 weeks. The study was performed from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the article, although the study was statistically powered to draw conclusions only on the primary endpoint. RESULTS: At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% confidence interval, 0.30-1.68; P = .009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% confidence interval, reduction of 0.24 to increase of 1.11; nominal P = .15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P = .003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously all patients had evidence of atrioventricular block before etrasimod exposure. CONCLUSIONS: In patients with moderately to severely active ulcerative colitis, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov, Number: NCT02447302. ispartof: GASTROENTEROLOGY vol:158 issue:3 pages:550-561 ispartof: location:United States status: published

Background Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis to assess the safety and effectiveness of dual biologic therapy (DBT), or small molecule combined with a biologic therapy (SBT) in IBD patients. Methods We searched MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and Clinical trials.gov until November 3, 2020, including studies with 2 or more IBD patients on DBT or SBT. Main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination. Effectiveness was reported as pooled rates of clinical, endoscopic, and/or radiographic response and remission. The certainty of evidence was rated according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Results Of the 3688 publications identified, 13 studies (1 clinical trial, 12 observational studies) involving 266 patients on 7 different combinations were included. Median number of prior biologics ranged from 0 to 4, and median duration of follow-up was 16–68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-tumor necrosis factor (aTNF, n = 56) or tofacitinib (Tofa, n = 57), respectively. Pooled rates of SAE for these were 9.6% (95% confidence interval [CI], 1.5–21.4) for VDZ-aTNF and 1.0% (95% CI, 0.0–7.6) for Tofa-VDZ. The overall certainty of evidence was very low due to the observational nature of the studies, and very serious imprecision and inconsistency. Conclusions DBT or SBT appears to be generally safe and may be effective in IBD patients, but the evidence is very uncertain.

Background Risankizumab (RZB), an IL-23 inhibitor, is being investigated for Crohn’s disease (CD). MOTIVATE (NCT03105128) and ADVANCE (NCT03104413) were two double-blind, randomised, placebo (PBO)-controlled phase 3 trials evaluating the efficacy and safety of RZB as induction therapy for CD after inadequate response or intolerance to biologic treatment, or conventional or biologic treatment. We investigated the effect of RZB on patient-reported outcomes (PROs) in these two trials. Methods Patients with moderately to severely active CD (CD activity index of 220–450, Simple Endoscopic Score for CD excluding the narrowing component ≥ 6 or ≥ 4 for isolated ileal disease, and average daily stool frequency ≥ 4 and/or average daily abdominal pain score ≥ 2) were randomised 1:1:1 (MOTIVATE; N=569) or 2:2:1 (ADVANCE; N=850) to intravenous RZB 600 mg, RZB 1200 mg or PBO at Weeks 0, 4 and 8. PROs assessed were Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Health Survey (SF 36). Least-squares mean change from baseline to Week 4 and 12 were assessed for each PRO. Additionally, the proportion of patients achieving IBDQ remission (IBDQ total score ≥ 170 points) was evaluated. Comparisons between RZB dosage groups and PBO were based on Cochran-Mantel-Haenszel or chi-square/Fisher’s exact tests; missing data were reported using non-responder imputation. Results In the MOTIVATE (100% biologic inadequate responder [bio-IR]) and ADVANCE (57% bio-IR) trials, significant (P Conclusion Patients with active CD and an inadequate response to conventional or biologic treatment who received RZB (600 mg or 1200 mg) induction therapy reported significant improvements in disease-specific (IBDQ) and general health-related PROs (FACIT and SF-36) compared with PBO, with improvements seen as early as Week 4. Funding statement: Study was funded by AbbVie. Acknowledgement: Medical writing support was provided by Joann Hettasch of Fishawack Facilitate Ltd, and was funded by AbbVie.

Tumor necrosis factor antagonists (TNFs) are effective for moderate–severe Crohn’s disease (CD). Approximately one-third of patients have primary-nonresponse to TNFs, which is reported to predict worse response to subsequent TNF therapy. However, this is based on treatment with subcutaneously (SC) administered, fixed-dose TNFs after failure of intravenously (IV) administered, weight-based TNFs. No study has specifically assessed the clinical and endoscopic effectiveness of IV TNFs following primary-nonresponse to SC TNFs. We hypothesize that IV, weight-based TNF dosing offers advantages over SC, fixed-dose TNFs and may be effective despite primary-nonresponse to previous SC fixed-dose TNFs. This retrospective cohort study identified patients with moderate–severe CD with primary-nonresponse to one or more SC TNFs who subsequently received the IV TNF, infliximab for ≥ 12 weeks. We described baseline characteristics, and clinical, endoscopic and biochemical response to therapy. Key characteristics of 17 patients are described in Table 1. After ≥ 12 weeks of infliximab, 11 of 15 (73.3%) patients with clinical data reported clinical response and remission. Of 11 patients with endoscopic data, restaging colonoscopy revealed mucosal improvement in seven (63.6%) patients. Of these, five (45.5%) had endoscopic remission and three (27.3%) had mucosal healing. Patients with moderate–severe CD with prior primary-nonresponse to SC, fixed-dose TNFs, subsequently treated with IV, weight-based TNF have high rates of clinical and endoscopic response and remission. Therefore, despite primary-nonresponse to SC TNFs, patients may benefit from IV TNF therapy and may not require a change to a different class of biologic therapy.

Background: Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis (SRMA) to assess the safety and effectiveness of dual biologic therapy (DBT) or small molecule combined with a biologic therapy (SBT) in IBD patients. Methods: MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Clinical trials.gov were reviewed from inception to Nov 3, 2020. Studies with two or more IBD patients on DBT or SBT were included while single-case reports were excluded. The main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination category. Effectiveness was reported as pooled rates of clinical, endoscopic and/or radiographic response and remission. Random-effects modeling was performed for between-study heterogeneity using the I² statistic. The SRMA was registered with PROSPERO (CRD4202018361). Findings: Of the 3,688 publications identified, 13 studies involving 266 patients on seven different combinations were included. Median number of prior biologics ranged from 0-4, and median duration of follow-up was 16-68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-Tumour Necrosis Factor (aTNF, n=56) or tofacitinib (Tofa, n=57), respectively. Pooled rates of SAE for these were 9·6% (95% CI, 1·5 – 21·4; 8 studies; I2 0%) for VDZ-aTNF and 1·0% (95% CI, 0·0 – 7·6; 5 studies; I2 0%) for Tofa-VDZ. Pooled clinical remission rates for these were 55·1% (95% CI, 19·6 – 88·5; 8 studies; 53 TTs; I2 81%) for VDZ-aTNF and 47·8% (95% CI, 19·0 – 77·4; 5 studies; 49 TTs; I2 69%) for Tofa-VDZ. No new safety signal was reported for any combination. There was considerable heterogeneity across studies (I2, 0 to 87%). Interpretation: DBT or SBT appears to be generally safe and effective in IBD patients with conclusions on effectiveness limited by between-study heterogeneity. This data needs to be confirmed in prospective studies. Registration: The SRMA was registered with PROSPERO (CRD4202018361). Funding Statement: None. Declaration of Interests: Kindra Clark-Snustad: Dr. Clark-Snustad reports personal fees from BMS, personal fees from Pfizer, outside the submitted work; Anish Patel: Dr. Patel reports personal fees from JANSSEN, personal fees from TAKEDA, personal fees from ABBVIE, outside the submitted work; Andres Yarur: Dr. Yarur reports personal fees from Takeda, personal fees from Prometheus Bioscience, personal fees from Arena Pharmaceutical, personal fees from Bristol Myers Squibb, during the conduct of the study; Benjamin L. Cohen: Dr. Cohen reports personal fees from Abbvie, personal fees and nonfinancial support from Pfizer, personal fees from Bristol Myers Squibb, personal fees from Janssen, personal fees from Target RWE, personal fees from Sublimity Therapeutics, outside the submitted work; Matthew A. Ciorba: Dr. Ciorba reports grants and personal fees from Pfizer, grants and personal fees from Takeda, outside the submitted work; Scott D. Lee MD: Dr. Lee reports grants and personal fees from Abbvie, grants and personal fees from UCB, grants and personal fees from JANSSEN, grants and personal fees from TAKEDA, grants from BMS, grants from ABGENOMICS, grants and personal fees from ELI LILLY, grants from ARENA, outside the submitted work; Edward V. Loftus, Jr.: Dr. Loftus reports grants and personal fees from AbbVie, personal fees from Allergan, grants and personal fees from Amgen, personal fees from Arena, personal fees from Boehringer Ingelheim, grants and personal fees from Bristol-Myers Squibb, personal fees from Calibr, grants and personal fees from Celgene, personal fees from Celltrion Healthcare, personal fees from Eli Lilly, grants and personal fees from Genentech, grants and personal fees from Gilead, personal fees from Iterative Scopes, grants and personal fees from Janssen, personal fees from Ono Pharma, grants and personal fees from Pfizer, grants from Receptos, grants from Robarts Clinical Trials, personal fees from Sun Pharma, grants and personal fees from Takeda, grants from Theravance, grants and personal fees from UCB, outside the submitted work; David Fudman: Dr. Fudman reports personal fees from Pfizer, outside the submitted work; Bincy P. Abraham: Dr. Abraham reports personal fees from Abbvie, personal fees from Ferring, grants and personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Medtronics, personal fees from Samsung bioepis, personal fees from Bristol-Myers Squibb, outside the submitted work; Jean-Frederic Colombel: Dr. Colombel reports grants and personal fees from Abbvie, personal fees from Amgen, personal fees from Allergan, personal fees from Arena Phramaceuticals, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers-Squibb, personal fees from Celgene Corporation, personal fees from Celltrion, personal fees from Eli Lilly, personal fees from Enterome, personal fees from Ferring Phramaceuticals, personal fees from Genentech, personal fees from Gilead, personal fees from Iterative Scopes, personal fees from Ipsen, personal fees from Immunic, personal fees from Imtbio, personal fees from Inotrem, grants and personal fees from Janssen Pharmaceuticals, personal fees from Landos, personal fees from Limmatech, personal fees from Medimmune, personal fees from Merck, personal fees from Novartis, personal fees from OMass, personal fees from Otsuka, personal fees from Pfizer, personal fees from Shire, grants and personal fees from Takeda, personal fees from Tigenix, personal fees from VielaBio, outside the submitted work; Parakkal Deepak: Dr. Deepak reports personal fees from Janssen, personal fees from Pfizer, personal fees from Prometheus Biosciences, other from Boehringer Ingelheim, personal fees from Arena Pharmaceuticals, grants from Takeda Pharmaceuticals, grants from Arena Pharmaceuticals, grants from Bristol Myers Squibb-Celgene, grants from Boehringer Ingelheim, outside the submitted work; All other authors declare no competing interests.

BACKGROUND Monitoring disease activity in Crohn’s disease is important as achieving endoscopic remission significantly improves clinical outcomes. Fecal calprotectin is a common non-invasive biomarker for monitoring disease activity. However, fecal calprotectin does not always correlate with other disease activity assessments and stool samples can be difficult to collect and inconvenient to return. Thus, we aimed to compare the association between calprotectin levels in stool, saliva, and blood, and assess to their correlation with endoscopic and histologic outcomes among patients with Crohn’s disease. METHODS Nineteen patients with Crohn’s disease were included in the data analysis. Patients collected stool, blood and saliva samples within 2 days of colonoscopy. Samples were processed and stored at -80C, then assessed for calprotectin via ELISA. The Simple Endoscopic Score – Crohn’s Disease (SES-CD) was scored at the time of colonoscopy. The biopsy sample with the most severe disease activity was assessed by a single pathologist for the Robarts Histological Index (RHI). RESULTS All participants had endoscopic data and blood samples (n=19), 18 had saliva samples, and 18 had stool samples. Participants had a mean age of 32.4 (SD: 7.4). Seventy percent (n=14) were female and 45% were on biologics. The median calprotectin levels were 65.4 ug/g (IQR: 8.5, 385.0) for fecal calprotectin, 23.9 ng/ml (IQR: 15.9, 40.8) for plasma calprotectin, 977.7 ng/ml (IQR: 733.3, 1207.5) for serum calprotectin, and 3761.6 ng/ml (IQR: 874.0, 8267.2) for salivary calprotectin. Correlations (as represented by Pearson’s correlation coefficients) with endoscopic disease activity (SES-CD) were 0.83 for fecal calprotectin, 0.28 for plasma calprotectin, 0.24 for serum calprotectin, and 0.02 for salivary calprotectin. Correlations with histologic disease activity (RHI) were 0.80 for fecal calprotectin, 0.56 for plasma calprotectin, 0.16 for serum calprotectin, and -0.03 for salivary calprotectin. CONCLUSION We present preliminary findings of the relationship between calprotectin from fecal, blood, and saliva samples with endoscopic and histologic outcomes in a small sample of patients with Crohn’s disease. Larger sample sizes are needed to further examine the possible role of blood-based calprotectin assessments. In the current study, only two participants had very high SES-CD scores which influenced our ability to understand the relationship of calprotectin to endoscopic disease activity in this subset. Of interest, plasma calprotectin had a higher correlation with histology than serum, which aligns with previous studies.

BACKGROUND Patients with inflammatory bowel disease (IBD) report more sleep disturbances than healthy controls. Self-reported sleep disturbances have been associated with active clinical disease. Few studies have examined the relationship between self-reported sleep and endoscopic disease activity, and IBD sleep studies have yet to consider the discrepancies that exist between clinical and endoscopic disease measures. The purpose of this pilot study was to examine self-reported sleep based on endoscopic and clinical disease activity among patients with IBD. METHODS Patients with IBD were recruited from a single medical center. Patients ages 18-55 with a scheduled endoscopy were included. Patients completed informed consent, wore a wrist actigraph for 10 days, and answered baseline demographic, clinical disease activity, and sleep questionnaires including Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance, PROMIS sleep-related impairment, and the Pittsburg Sleep Quality Index (PSQI). For both the PROMIS and PSQI, higher scores indicate greater sleep/wake disturbances. Endoscopic disease activity (Mayo or Simple Endoscopic Score) within three months was obtained from the medical record. RESULTS The study included 27 participants with a mean age of 33.3 (SD: 8.2) years and a disease duration of 11 (SD: 7.2) years. The sample predominantly had Crohn’s disease (75%) and 61% were female. Sixty-three percent of the total sample were classified as poor sleepers based on the PSQI. When comparing self-reported sleep based on clinical disease activity, patients with active clinical disease had higher self-reported sleep disturbance (57.3 vs. 49.7, D=1.28) and sleep-related impairment (58.1 vs. 52.8, D=0.51) compared to those with inactive clinical disease. However, self-reported sleep and endoscopic disease activity had the opposite interpretation. Only 40% of patients with active endoscopic disease were poor sleepers compared to 76.5% of patients with inactive endoscopic disease. Patients with active endoscopic disease had lower self-reported sleep disturbance (49.2 vs 52.6, D=-0.53) and sleep-related impairment (49.7 vs. 56.6, D=-0.71) compared to those with inactive endoscopic disease. CONCLUSION The relationship between self-reported sleep and disease activity differs based on the measure of disease activity. Our findings of self-reported sleep disturbances and active clinical disease are similar to previous studies. However, when examining the relationship based on endoscopic disease activity, patients with active endoscopic disease had less self-reported sleep disturbance than patients with inactive endoscopic disease. Further research is needed to better characterize the relationship between sleep and disease activity, and determine the underlying mechanisms related to poor sleep in the IBD population.

Background & Aims Oral therapies targeting the integrin α4β7 may offer unique advantages for the treatment of inflammatory bowel disease. We characterized the oral α4β7 antagonist peptide PTG-100 in preclinical models and established safety, pharmacokinetic/pharmacodynamic relationships, and efficacy in a phase 2a trial in patients with ulcerative colitis (UC). Methods In vitro studies measured binding properties of PTG-100. Mouse studies measured biomarkers and drug concentrations in blood and tissues. The phase 1 study involved healthy volunteers. In phase 2a, patients with moderate to severe active UC were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12-weeks. Results PTG-100 potently and selectively blocks α4β7. Oral dosing of PTG-100 in mice showed high levels of target engagement and exposure in gut-associated lymphoid tissues. In healthy volunteers, PTG-100 showed dose-dependent increases in plasma exposure and blood target engagement. Although this phase 2a study initially did not meet the primary endpoint, a blinded reread of the endoscopy videos by a third party indicated clinical efficacy in conjunction with histologic remission at doses correlating with less than 100% receptor occupancy in peripheral blood. Conclusions PTG-100 showed local gastrointestinal tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and showed a dose response reflecting similar activities in preclinical models and healthy individuals. These data suggest that local gut activity of an oral α4β7 integrin antagonist, distinct from full target engagement in blood, are important for efficacy and the treatment of UC. (ClinicalTrials.gov, Number NCT02895100; EudraCT, Number 2016-003452-75)

Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib in patients (pts) with UC were evaluated in two 8-week, Phase 3 induction studies (OCTAVE Induction 1&2), a 52-week, Phase 3 maintenance study (OCTAVE Sustain), and an open-label, long-term extension study. Here, we evaluate tofacitinib efficacy in OCTAVE Sustain (NCT01458574) by baseline Mayo endoscopic subscore (ES). Methods Pts with an OCTAVE Sustain baseline ES of 0 or 1 were included. Proportion of pts achieving efficacy endpoints at Week 52 of OCTAVE Sustain (responders from OCTAVE Induction 1&2; tofacitinib 5 or 10 mg twice daily [BID] or placebo [PBO]) was evaluated in relation to OCTAVE Sustain baseline ES. Using logistic regression, the difference in treatment effect (tofacitinib vs PBO) between baseline ES (0 vs 1) for each efficacy endpoint was assessed. Cox proportional hazards regression was used to model the difference in treatment effect between baseline ES (0 vs 1) for time to treatment failure and loss of response. Results At Week 52 of OCTAVE Sustain, a numerically higher proportion of pts with a baseline ES of 0 achieved remission and endoscopic improvement vs pts with a baseline ES of 1, regardless of tofacitinib dose (Table). Logistic regression analyses showed a larger treatment effect of tofacitinib 5 mg BID at Week 52 in pts with a baseline ES of 0 vs 1 (p=0.0306) for clinical response (Table). Treatment effect of tofacitinib 10 mg BID was not significantly different between baseline ES 0 vs 1 for any endpoint (Table). In tofacitinib 5 mg BID-treated pts, Cox proportional hazards regression showed difference in risk vs PBO to be larger in pts with a baseline ES of 0 vs 1 for treatment failure (p=0.0231) and loss of response (p=0.0209); corresponding differences for 10 mg BID-treated pts were not significant (p=0.9239 and p=0.9613, respectively). Conclusion In general, at Week 52 of OCTAVE Sustain, a higher proportion of tofacitinib-treated pts achieved endpoints with a baseline ES of 0 vs 1. Based on proportions, the treatment effect of tofacitinib 5 mg BID was more evident in pts with a baseline ES of 0 vs 1. This difference in treatment effect related to baseline ES was not observed with tofacitinib 10 mg BID. Baseline ES may be an important factor in predicting outcomes, and suggests that aiming for a deeper remission after induction may allow successful maintenance with tofacitinib 5 mg BID. These analyses were post hoc and limited by the small sample sizes.

ObjectiveThis phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn’s disease (CD).DesignEligible adults were aged 18–75 years, with active moderate-to-severe CD (Crohn’s Disease Activity Index (CDAI) 220–450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12.ResultsIn all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen.ConclusionsClinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β7+ central memory T cells.Trial registration numberNCT01276509; Results.

BACKGROUND Anti-drug antibodies (ADAbs) may decrease the efficacy of biologics and increase the risk of adverse events. A single positive test may not preclude further treatment because of variations in assays used, test timing, and patient variables. We evaluated the longitudinal patterns of immunogenicity during 7 years of antitumor necrosis factor-alpha drug certolizumab pegol (CZP) treatment for moderate-to-severe Crohn's disease. METHODS PRECiSE 3 patients (n = 595) received open-label CZP 400 mg every 4 weeks up to 7 years. CZP-ADAb expression, plasma CZP concentration, Harvey-Bradshaw Index, C-reactive protein, and fecal calprotectin concentrations were measured multiple times. Longitudinal data, examined for CZP-ADAb positivity and categorized as transient (with temporary/no effect on CZP concentration), persistent, or negative, were correlated with clinical and biological variables. RESULTS Of the CZP-ADAb-positive patients, 40 (22.6%) had transient CZP-ADAbs and 94 (77.4%) had persistent CZP-ADAbs. Demographic characteristics were similar between groups. Median C-reactive protein and fecal calprotectin were higher (P < 0.05 at some visits) and plasma CZP concentrations were significantly lower (P < 0.0001 at all visits) in the persistent CZP-ADAb-positive group relative to the CZP-ADAb-negative group. Transient CZP-ADAb-positive and CZP-ADAb-negative patients had similar plasma CZP, C-reactive protein, and fecal calprotectin concentrations. Median Harvey-Bradshaw Index scores and rates of adverse events were similar among groups. CONCLUSIONS This analysis demonstrates that persistent CZP-ADAb has negative effects on drug levels and efficacy, whereas transient expression may not. Serial measurements may be needed to characterize ADAb positivity. www.clinicaltrials.gov, Number NCT00160524.

Introduction Fatigue is often the most prevalent symptom in inflammatory bowel disease (IBD). Previous research has highlighted that patients with active clinical disease activity have greater levels of fatigue compared to those with inactive clinical disease activity. Endoscopic assessment of inflammation is considered the best measure of disease activity; yet, clinical disease activity does not necessarily correlate with endoscopic inflammation. Therefore, there is a need to examine the relationship between endoscopic inflammation and fatigue. Methods A retrospective chart review was conducted of adult patients at an academic medical center. Participants were included in the review if they had a diagnosis of ulcerative colitis or Crohn’s disease, a clinic visit between 2018–2019 with completed Short Inflammatory Bowel Disease Questionnaire and clinical disease activity measures (Harvey Bradshaw Index [HBI] or Simple Clinical Colitis Activity Index [SCCAI]), and had a scored endoscopic disease activity score (Mayo Score of Ulcerative Colitis or the Simple Endoscopic Score for Crohn’s Disease) within 6 months of the clinic visit. Fatigue (range 1–7) was reversed scored; a higher number indicated increased fatigue. Descriptive statistics were calculated using STATA 14. Results Individuals (N=43) had a mean age of 37.4 (SD=12.3) and 54% were female. Disease location was 9% ileal, 53% ileocolonic, and 37% colonic; 54% were in endoscopic remission. The mean fatigue score was 4.2 (SD=1.7). There was no difference in fatigue between individuals in endoscopic remission (M=4.2, SD=1.6) compared to individuals with active endoscopic disease (M=4.2, SD=1.9; p=0.97). Fatigue was correlated with clinical disease activity measures including the HBI (r=0.61) and the SCCAI (r=0.58). Increased levels of fatigue were associated with abnormal c-reactive protein (p Conclusions The majority of the sample reported fatigue; however, fatigue did not correlate with endoscopic disease activity despite previous research suggesting that clinical disease activity correlates with fatigue. Further confounding our understanding of disease activity’s association with fatigue is the fact that clinical disease activity and biochemical abnormalities (CRP, ESR, albumin) did correlate with fatigue. Additional research is clearly needed to characterize the cause of fatigue among individuals with IBD.

Background Mirikizumab (miri; LY3074828) is a humanized monoclonal antibody directed against the p19 subunit of IL-23, which demonstrated efficacy and was well-tolerated in a phase 2 randomized clinical trial (NCT02589665) in patients with ulcerative colitis (UC). Bowel movement urgency is one of the most bothersome symptoms experienced by patients with UC with an often-overlooked impact of their quality of life (QoL). Here we show the effect of miri on patient-reported urgency. Methods Patients were randomized 1:1:1:1 to receive intravenous placebo (PBO), miri 50mg or 200mg with possibility of exposure-based dose increases, or fixed miri 600mg every 4 weeks (Q4W), with efficacy assessment at Week 12. Patients who achieved clinical response to miri at Week 12 (decrease in 9-point Mayo score ≥ 2 points and ≥ 35% from baseline, and either a decrease in rectal bleeding (RB) subscore ≥1 or RB subscore of 0 or 1) were re-randomized 1:1 to double-blind maintenance treatment with miri 200mg subcutaneously (SC) every 4 (Q4W) or 12 (Q12W) weeks and were treated through Week 52. Patients reported daily symptoms, including absence or presence of bowel movement urgency. Logistic regression analysis was conducted to evaluate the treatment differences in absence of urgency among patients who had urgency at baseline for the first 12 weeks, with absence of urgency defined as no urgency symptom for three consecutive days prior to each scheduled visit. The proportion of patients with no urgency was calculated for the maintenance period among patients who had urgency at baseline and reached clinical response at Week 12, irrespective of urgency status at Week 12. Patients who had missing urgency data were imputed as having experienced urgency. Results At Week 12 patients in the 200mg and 600mg miri groups showed significantly higher rates of achieving absence of urgency compared to the PBO group (PBO: 10/55, 18.2% [CI: 8.0–28.4]; miri 50mg: 18/59, 30.5% [CI: 18.8–42.3]; 200mg: 22/56, 39.3% [CI: 26.5, 52.1], p=0.016; 600mg: 22/51, 43.1% [CI: 29.5, 56.7], p=0.006, Figure 1). Induction clinical responders who continued onto the maintenance period sustained this improvement in urgency with minimal variation (Figure 2). Conclusion In patients who reported bowel movement urgency at baseline, mirikizumab treatment resulted in significantly higher proportions of patients with no bowel movement urgency compared to placebo at Week 12, with numerical improvement observed as early as Week 4 and statistically significant improvement by Week 8. The reduction in bowel movement urgency was sustained through Week 52.

Background Preoperative immunosuppressive use among patients with Crohn's disease or ulcerative colitis may lead to an increased risk of postoperative complications. There is limited information on the preoperative safety profile of methotrexate (MTX) in inflammatory bowel disease (IBD). Methods A retrospective study of patients who underwent abdominal surgery for IBD between 1993 and 2012 was performed and records abstracted, including preoperative use of MTX, azathioprine/6-mercaptopurine, antitumor necrosis factor, and corticosteroids. Early postoperative complications, including death, septic, and nonseptic complications were identified. A meta-analysis was also performed on the use of preoperative MTX in patients with IBD or rheumatoid arthritis. Results A total of 180 patients with IBD underwent abdominal surgery. A total of 15 patients received MTX either monotherapy or in combination therapy. Total early postoperative complications were identified in 71 (39%) patients, specifically 5 patients on oral MTX. A total of 51 cases (28%) of septic complications and 20 (11%) nonseptic. No significant association between the use of MTX and early postoperative complications was found. The odds ratio (OR) of complications versus no complications associated with MTX was 0.75 (95% CI, 0.25-2.29) and with azathioprine/6-mercaptopurine, OR 1.48 (95% CI, 0.77-2.84). The odds of a septic complication associated with MTX were 0.58 (95% CI, 0.09-3.73), and higher in azathioprine/6-mercaptopurine, OR 3.97 (95% CI, 1.03-15.3). Our meta-analysis also did not reveal an increased risk of postoperative complications in IBD or rheumatoid arthritis on preoperative MTX (OR 0.62, 95% CI, 0.34-1.15). Conclusions Preoperative MTX use does not seem to be associated with early postoperative complications in IBD.

Crohn's disease is a lifelong, incurable inflammatory disease of the gastrointestinal tract that often arises in the earlier decades of life and is characterized by periods of exacerbation and remission. Tumor necrosis factor (TNF) α has a central role in the pathogenesis of inflammatory bowel diseases, and specific inhibition of this pleotropic cytokine with biological anti-TNF agents has been a major advancement in the treatment of these diseases including Crohn's disease.1,2 Anti-TNF therapy is generally well tolerated.3–5 However, because these agents have immunosuppressive properties, long-term use may increase the risk of serious infections,6 and careful consideration is given to the initiation of therapy. Only 3 anti-TNF therapies, including infliximab, adalimumab, and certolizumab pegol, are currently approved for the treatment of moderate to severe Crohn's disease in the United States. In randomized controlled trials, approximately 40% to 60% of patients with Crohn's disease had an initial response to induction therapy with anti-TNF therapy during the first 2 to 6 weeks, and of those approximately 40% to 60% were in remission after 6 months of therapy.3–5,7 However, the duration of clinical response varies widely among patients. Results of PRECiSE 2, a randomized, placebo-controlled study of certolizumab pegol maintenance therapy in patients with moderate to severe Crohn's disease, showed that approximately 40% of initial responders lost response within 6 months after treatment initiation.5 In clinical practice, 30% to 40% of patients treated with adalimumab required dose escalation; however, approximately one-third of those who received increased doses failed to maintain responses longer than 6 months.8 These examples illustrate that both primary and secondary failure to anti-TNF therapy remain significant challenges in the treatment of patients with Crohn's disease. Given the need for long-term maintenance therapy and the small number of available anti-TNF therapies, identifying strategies to maximize the benefit that a patient can derive from each agent is important. Recent studies have shown that reinduction therapy with another9 or the same10 anti-TNF agent in patients with secondary treatment failure provides clinically important short-term benefits. However, the longer-term benefit of reintroducing the same therapy to patients with primary and secondary treatment failure, including patients who previously received as little as 1 dose of induction treatment, has not been explored. Certolizumab pegol is a recombinant, humanized, polyethylene glycol–conjugated antigen-binding antibody fragment (Fab') with specificity for human TNFα. Two randomized, double-blind, placebo-controlled phase 3 studies, PRECiSE 17 and PRECiSE 2,5 demonstrated that certolizumab pegol is effective in the induction and maintenance of clinical response and remission in patients with moderate to severe Crohn's disease. Unlike patients in PRECiSE 2, who were randomized to maintenance treatment with placebo or certolizumab pegol after responding to 6 weeks of induction therapy with certolizumab pegol, patients in PRECiSE 1 were randomized to consecutive induction and maintenance treatment with either placebo or certolizumab pegol at the start of the trial. Patients who completed PRECiSE 1 or PRECiSE 2 were eligible for inclusion in PRECiSE 3, an open-label, 7-year extension study.11 In contrast, PRECiSE 4 (NCT00160706) was an open-label extension study for patients who withdrew from either treatment arm of PRECiSE 1 or PRECiSE 2 owing to exacerbation of Crohn's disease and was designed to assess the safety and efficacy of chronic certolizumab pegol therapy for up to 7 years. Here, we report efficacy and safety outcomes from the PRECiSE 4 study, which included patients with no previous exposure to certolizumab pegol, as well as patients with primary or secondary certolizumab pegol treatment failure.

The initial diagnosis of inflammatory bowel disease (IBD) requires multiple diagnostic modalities; however, endoscopic evaluation as a diagnostic test is considered the gold standard. Endoscopic evaluation includes colonoscopy with ileoscopy, esophagogastroduodenoscopy, enteroscopy, and capsule endoscopy. IBD encompasses Crohn's disease, ulcerative colitis, and IBD unclassified. Colonoscopy with ileoscopy along with biopsy collection is essential in most IBD cases for diagnosis and to rule out alternative findings that may mimic IBD including ischemia, diverticulitis, segmental colitis associated with diverticulosis, neoplasia, radiation enteritis, and drug-induced colitis. Esophagogastroduodenoscopy, enteroscopy, and capsule endoscopy are used in the initial workup of specific groups of patients with IBD. The role of endoluminal diagnostic studies in the initial diagnosis of IBD is discussed in detail in this article.

Summary Background Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. Aim To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. Methods We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. Results Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. Conclusion This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis.