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Abstract Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of UC. Safety and efficacy of tofacitinib were demonstrated in Phase (P)2/3 induction studies, a 52-week, P3 maintenance study, and are being further investigated in an ongoing, open-label, long-term extension (OLE) study.1,2 Here, we provide an updated analysis of age as a risk factor for adverse events (AEs) in the tofacitinib UC clinical programme.3 Methods Proportions of AEs and serious AEs (SAEs), and incidence rates (IRs; unique patients with events per 100 patient-years) for AEs of special interest (AESIs), were determined for two cohorts: the Maintenance Cohort (patients who received placebo or tofacitinib 5 or 10 mg twice daily [BID] in the maintenance study) and the Overall Cohort (all tofacitinib 5 or 10 mg BID-treated patients in the P2/P3/OLE studies; as of May 2019), stratified by age. Multivariable Cox proportional hazards regression analyses were performed to assess whether older age was associated with increased risk of AESIs in the Overall Cohort. Results In the Maintenance Cohort, IRs of AEs and SAEs were generally similar between treatment groups, with no age-related trend in the proportions of AEs in tofacitinib-treated patients. AESIs were infrequent in both treatment groups; however, herpes zoster (HZ; non-serious and serious) IRs were numerically higher in the ≥40 to <50 and ≥50 years age groups for patients treated with tofacitinib 10 mg BID vs. placebo and tofacitinib 10 vs. 5 mg BID. In the Overall Cohort, IR of serious infections was generally similar between age groups, while IRs of opportunistic infections (OIs) and HZ (non-serious and serious), malignancy (excl. non-melanoma skin cancer [NMSC]), NMSC and major adverse cardiovascular events increased with increasing age. The IRs of HZ and NMSC were significantly greater in patients ≥50 years compared with patients <30 years, and in patients ≥30 to <40 years for NMSC. In multivariate analyses, older age was identified as a significant predictor of malignancy (excl. NMSC), NMSC and HZ. Conclusion In the Overall Cohort, there was a trend for an increase in the rates of OIs, HZ, malignancy (excl. NMSC) and NMSC with increasing age. In multivariate analyses, older age was associated with increased risk of malignancy (excl. NMSC), NMSC and HZ. The results of this analysis are generally consistent with previous studies suggesting older age may be associated with an increased risk of certain AESIs in patients with UC, and in some instances in the general population.4 References

Abstract Background Anaemia is a frequent complication in patients with Crohn’s disease and ulcerative colitis (UC), and patients who respond to treatment generally show improvement in anaemia. Decrease in haemoglobin (Hgb) levels and anaemia may be associated with Janus kinase (JAK) inhibitors. Upadacitinib (UPA), an oral JAK1 selective inhibitor, has demonstrated favourable dose-dependent efficacy in patients with moderately to severely active UC.1 This analysis of data from the U-ACHIEVE study addressed effects of UPA treatment on Hgb levels in patients with UC. Methods U-ACHIEVE (NCT02819635) was a randomised, double-blind, placebo (PBO)-controlled phase 2b clinical trial. Adults with moderately to severely active UC were randomised to receive 7.5, 15, 30, or 45 mg UPA or PBO once daily (QD) for 8 weeks. Hgb levels were measured for all groups at baseline (BL) and weeks 2, 4, 6, and 8. Mean change from BL was calculated for each group. p-values for comparison between UPA and PBO groups were calculated using one-way ANOVA; no multiplicity adjustment was applied. Percentage of patients with Hgb values grade 2 (15–20 g/l Hgb decrease from BL), grade 3 (<80 g/l Hgb level or 21–29 g/l Hgb decrease from BL), and grade 4 (<70 g/l Hgb level or >29 g/l Hgb decrease BL) anaemia were determined for all treatment groups using the Common Terminology Criteria for Adverse Events version 5. Adverse events (AE) were reported by investigators. Results Included in the analysis were 250 patients (mean age ± SD, 42.3 ± 14.2 years; disease duration, 8.2 ± 2.5 years). At BL, most treatment groups had similar mean Hgb levels, except for the 15 mg UPA group, which had significantly lower Hgb levels vs. PBO group (Table). Increased or stable mean levels of Hgb at week 8 vs. BL were observed in most UPA treatment groups. The PBO group had the greatest decrease in Hgb vs. BL at week 8 compared with UPA treatment groups (Figure). Grade ≥2 anaemia was reported in 17.4% of patients receiving PBO and 14.4% of all patients receiving UPA (14.9%, 12.2%, 12.0%, and 17.9% of patients receiving 7.5, 15, 30, and 45 mg UPA, respectively). Grade ≥3 anaemia was reported in 8.7% of patients receiving PBO and 5% of all patients receiving UPA (6.4%, 6.1%, 6.0%, and 1.8% of patients receiving 7.5, 15, 30, and 45 mg UPA, respectively). One subject receiving 7.5 mg QD UPA had grade 4 anaemia. AE of anaemia was reported in 6.5% of patients receiving PBO and in 2.1%, 8.2%, and 3.8% of patients receiving 7.5, 15, and 30 mg UPA, respectively, but not in the 45 mg UPA group. Conclusion Decreased Hgb levels over time were observed more frequently in the PBO group. The maintenance of Hgb levels in patients receiving UPA was likely because of improvement of underlying UC. Reference

Abstract Background Vedolizumab (VDZ) is a gut-selective α 4β 7 integrin monoclonal antibody approved for IV administration for moderate to severe ulcerative colitis (UC). The phase 3 VISIBLE 1 study evaluated SC VDZ for UC maintenance therapy. After 2 IV doses, 56.1% patients had a clinical response at week 6; among patients who received a third induction infusion, clinical response rates were 79.7%. In this post hoc analysis, we examined baseline characteristics as predictors of clinical response to IV induction with VDZ. Methods In the VISIBLE 1 study (NCT02611830; EudraCT 2015-000480-14), patients (patients) received IV VDZ 300 mg at Weeks 0 and 2. At Week 6, clinical responders were randomised to maintenance SC therapy; nonresponders were given a third IV dose and reassessed at Week 14. As endoscopy was only available at Week 6, the clinical response at Week 6 was defined as ≥3 points and ≥30% reduction in complete Mayo score from Week 0 and at Week 14 as a ≥2 points and ≥25% reduction in partial Mayo score from Week 0. Both definitions also included an accompanying decrease in rectal bleeding subscore ≥1 or absolute subscore ≤1. Results Overall, 383 patients received ≥1 dose of IV VDZ. Of these, 56.1% responded at Week 6 after 2 VDZ doses. Of the 143 patients who received 3 IV doses, 79.7% responded at Week 14. No clinically meaningful differences in baseline demographic and disease characteristics were observed between patients who responded after 2 or 3 IV doses (Table). Differences in disease location and partial Mayo score (< or ≥6) were observed between the responders and nonresponders in the 3 IV dose group. Baseline characteristics were evaluated descriptively to assess predictors of clinical response after 2 or 3 IV VDZ doses. Conclusion Clinical response was achieved by most patients after either 2 or 3 IV VDZ infusions in the VISIBLE 1 trial. Post hoc analyses revealed no clinically meaningful differences in baseline characteristics or disease characteristics that could serve as predictors of response following 2 or 3 VDZ infusions. Further real-world experience may elucidate potential predictors of response to VDZ.

Abstract Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were demonstrated in patients with moderate to severe UC in 3 Phase 3 studies.1 Here, we present data from an ongoing, open-label, long-term extension (OLE) study.2 Methods We present updated safety and efficacy data from the OLE study (OCTAVE Open, NCT01470612; as of May 2019, database not locked). Eligible patients included non-responders (Week 8 data) in OCTAVE Induction 1 and 2 (NCT01465763; NCT01458951) and completers (Week 52 data) or treatment failures (early-termination data) in OCTAVE Sustain (NCT01458574). Patients in remission (total Mayo score ≤2, no individual subscore >1, rectal bleeding [RB] subscore 0) at Week 52 of OCTAVE Sustain (central read) received tofacitinib 5 mg twice daily (BID); all others received 10 mg BID. Induction non-responders without clinical response (≥3-point and ≥30% decrease from induction study baseline total Mayo score, plus ≥1-point RB subscore decrease or absolute RB subscore ≤1) at Month 2 of the OLE study were withdrawn. Incidence rates (IRs) for adverse events (AEs) of special interest were calculated (no. of unique patients with events per 100 patient-years). Efficacy endpoints were derived from Mayo score (local read) with non-responder and last observation carried forward imputation (NRI-LOCF) [a]. Results Of 944 patients who received ≥1 dose of tofacitinib, 769 (81.5%) received 10 mg BID (median duration [range]: 5 mg BID 1170 [36–2066]; 10 mg BID 668 [1–2159] days). In total, 338 (35.8%) and 93 (9.9%) patients discontinued due to insufficient clinical response and AEs (excl. worsening UC), respectively. IRs (95% confidence interval) in the Tofacitinib. All group were: deaths 0.18 (0.05, 0.47); serious infections 1.57 (1.08, 2.19); herpes zoster (non-serious and serious) 3.27 (2.54, 4.14); major adverse cardiovascular events 0.14 (0.03, 0.40); malignancies excl. non-melanoma skin cancer (NMSC) 0.92 (0.56, 1.42); NMSC 0.74 (0.43, 1.21); deep vein thrombosis 0.05 (0.00, 0.25); pulmonary embolism 0.18 (0.05, 0.47) (Table). At Month 36 (NRI-LOCF), 58.9% (n = 103) and 33.5% (n = 257) were in remission, 64.6% (n = 113) and 37.0% (n = 284) had mucosal healing (Mayo endoscopic subscore of 0 or 1) [b] and 66.9% (n = 117) and 40.2% (n = 309) showed clinical response, in the 5 and 10 mg BID groups, respectively. Conclusion Incidence of AEs remained generally consistent in patients with moderate to severe UC in the OLE study compared with a previous analysis.2 Data continue to support long-term efficacy with tofacitinib up to 36 months beyond Week 52 of OCTAVE Sustain. References

Abstract Background Patients with ulcerative colitis (UC) experience substantial impairment in quality of life (QOL). Patient QOL endpoints are important measures of treatment outcome. We evaluated the effects of intravenous vedolizumab vs. adalimumab on QOL in VARSITY, the first head-to-head trial comparing the efficacy and safety of biologics in patients with moderately to severely active UC. Methods VARSITY was a phase 3b, double-blind, double-dummy, randomised trial (NCT02497469; EudraCT 2015-000939-33). QOL was assessed using the inflammatory bowel disease questionnaire (IBDQ) at baseline, Week (Week) 30, and Week 52. Endpoints included clinically meaningful IBDQ improvement (defined as an increase in total score of ≥16 points from baseline to Week 52), IBDQ remission (defined as a total score of >170 points at Week 52) and change from baseline in IBDQ-specific domain scores (bowel symptoms, systemic symptoms, emotional function, and social function) at Week 30 and Week 52. Serum C-reactive protein (CRP) and faecal calprotectin (FCP) were also assessed as indicators of disease activity. Results Among randomised patients, 383 (vedolizumab) and 386 (adalimumab) patients received ≥1 dose of study drug (N=769). At Week 52, clinically meaningful IBDQ improvement was observed in 52.0% (vedolizumab) vs. 42.2% (adalimumab) of patients (treatment difference 9.7%; 95% confidence interval [CI], 2.7% to 16.7%), while IBDQ remission was achieved by 50.1% (vedolizumab) vs. 40.4% (adalimumab) of patients (treatment difference 9.6%; 95% CI, 2.8% to 16.5%). Mean (standard deviation [SD]) changes in IBDQ total score from baseline for observed cases favoured vedolizumab over adalimumab (Week 30: 61.3 [39.8] vs. 52.6 [42.8]; Week 52: 66.1 [41.8] vs. 60.4 [42.2]; Figure 1). IBDQ subscores showed similar favourable trends for vedolizumab (Figure 2). At Week 52, mean (SD) changes from baseline in CRP for patients treated with vedolizumab vs. adalimumab were –50.9 (174.8) nmol/l vs. –37.2 (169.2) nmol/l and for FCP were –2187.3 (7440.4) µg/g vs. –1846.6 (4560.6) µg/g (Figure 3). Among patients with FCP >250 µg/g at baseline, the proportion of patients achieving FCP ≤250 µg/g was 33.9% vs. 24.5% at Week 30 and 35.2% vs. 28.9% at Week 52 for patients treated with vedolizumab vs. adalimumab, respectively. Conclusion Based on IBDQ total score and subscores, more patients with UC treated with vedolizumab than with adalimumab achieved clinically meaningful improvement and clinical remission. Reduced inflammation, as indicated by improvements in CRP and FCP, was consistent with improvements in QOL.

AbstractBackgroundClostridioides difficile infection (CDI) is associated with poor outcomes in inflammatory bowel disease (IBD) patients. Data are scarce on efficacy of fecal microbiota transplant (FMT) for recurrent CDI in IBD patients.MethodsWe reviewed health records of IBD patients (18 years of age or older) with recurrent CDI who underwent FMT. Outcomes of FMT for CDI were assessed on the basis of symptoms and stool test results.ResultsWe included 145 patients (75 women [51.7%]; median age, 46 years). Median IBD duration was 8 (range, 0–47) years, 36.6% had Crohn disease, 61.4% had ulcerative colitis, and 2.1% had indeterminate colitis. Median number of prior CDI episodes was 3 (range, 3–20), and 61.4% had received vancomycin taper. Diarrhea resolved after FMT in 48 patients (33.1%) without further testing. Ninety-five patients (65.5%) underwent CDI testing owing to post-FMT recurrent diarrhea; 29 (20.0%) had positive results. After FMT, 2 patients received empiric treatment of recurrent CDI without symptom resolution, suggesting IBD was the cause of symptoms. The overall cure rate of CDI after FMT was 80.0%, without CDI recurrence at median follow-up of 9.3 (range, 0.1–51) months. Forty-three patients (29.7%) had planned IBD therapy escalation after CDI resolution; none de-escalated or discontinued IBD therapy. Overall, 7.6% had worsening IBD symptoms after FMT that were treated as new IBD flares. No clinical predictors of FMT failure were identified.ConclusionsFew patients had new IBD flare after FMT. Fecal microbiota transplantation effectively treats recurrent CDI in IBD patients but has no apparent beneficial effect on the IBD course.

BACKGROUND: Vedolizumab (VDZ) is a gut-selective, humanized monoclonal antibody approved for moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD). Although VDZ efficacy and safety are well established, there are limited publications on longer-term (>3 years) treatment persistence. This study evaluated VDZ treatment persistence for up to 5 years in a GEMINI long-term safety (LTS) VDZ de novo cohort. METHODS: All patients in GEMINI LTS (NCT00790933) were treated with VDZ every 4 weeks. A post hoc analysis of data from patients not previously treated with VDZ before Week 0 of GEMINI LTS (de novo cohort) was conducted, with VDZ treatment persistence assessed using Kaplan-Meier survival analysis. Treatment discontinuations due to adverse events (AEs) or lack of efficacy were considered for the analysis; discontinuations due to protocol deviation, patient withdrawal, or loss to follow-up were censored. Treatment persistence analyses were further stratified by Week 12 treatment response (primary response/nonresponder), prior anti-tumor necrosis factor (anti-TNF) failure (Yes/No), type of anti-TNF failure (primary/secondary nonresponse), and concomitant therapy (corticosteroids, 5-aminosalicylates, immunomodulators, or their combinations) at baseline (Yes/No); a log-rank test assessed statistical differences between subgroups. RESULTS: The GEMINI LTS de novo cohort included 421 patients (UC 190; CD 231) with a mean disease duration of 8.7 (UC) and 10.6 (CD) years, 6.0 mean partial Mayo score (UC) and 11.1 mean Harvey-Bradshaw Index; 61% of patients with UC and 74% with CD had prior anti-TNF failure. Up to 5 years follow-up, 276 patients (66%) total discontinued VDZ: 16% with UC and 17% with CD due to AEs, and 24% with UC and 33% with CD due to lack of efficacy. Survival probabilities for VDZ treatment persistence at 54 months were 53% for UC and 41% for CD. These VDZ 54-month survival probabilities were higher in patients with VDZ treatment response at Week 12 vs without (UC, 60% vs 26%, respectively, P < 0.0001; CD, 42% vs 35%, respectively, P = 0.001) and in patients without prior anti-TNF failure vs with (UC, 63% vs 47%, respectively, P = 0.046; CD, 47% vs 42%, respectively, P = 0.016). Among patients with baseline anti-TNF failure, survival probabilities for VDZ treatment persistence at 54 months were higher in UC patients who were secondary nonresponders vs those who were primary nonresponders (65% vs 15%, respectively, P < 0.0001); this difference was not observed in CD patients (44% vs 40%, respectively, P = 0.573). There were no differences in survival probabilities of continuing VDZ at 54 months among patients with UC or CD who initiated VDZ therapy with vs without any concomitant medications. CONCLUSION(S): More than half of patients with UC and 4 of every 10 patients with CD persisted on VDZ for 54 months. Treatment persistence rates in UC and CD cohorts were significantly higher in Week 12 responders and patients without prior anti-TNF failure, whereas there were no differences in persistence rates with baseline use of concomitant medications. Vedolizumab discontinuation rates due to AEs were low. These findings from GEMINI LTS support the longer-term effectiveness and safety of VDZ in patients with moderately to severely active UC and CD.

Abstract Background and Aims We aimed to evaluate the relationship of serum adalimumab trough levels (ATL) with disease activity of inflammatory bowel disease (IBD) patients in a large, well-characterized referral center-based cohort. Methods We compared serum ATL between those with clinical, biochemical, or endoscopic/radiologic disease activity and those without. Results A total of 236 patients with IBD were included. Higher cutoff levels were associated with endoscopic and/or radiologic responses (cutoff value: 5.3 mcg/mL, P = 0.003) compared with improvement in C-reactive protein (cutoff value: 4.3 mcg/mL, P = 0.031). Conclusions Higher cutoff ATL was associated with endoscopic and/or radiologic response.

Goals: The study aimed to compare the level and characteristics of disease-related knowledge of patients with inflammatory bowel disease (IBD) between the West and the East using an international version of a questionnaire regarding knowledge of inflammatory bowel disease (IBD-KNOW). Background: The authors recently developed a new questionnaire regarding IBD-KNOW, which showed excellent test characteristics in Korea. Study: The IBD-KNOW questionnaire was administered to 100 patients with IBD from tertiary referral hospitals in the United States and Korea. Scores were calculated and compared between US and Korean patients, and factors associated with high scores were analyzed. Results: A total of 196 (100 US and 96 Korean) patients with IBD completed the questionnaires. Analysis of the baseline characteristics revealed that male sex, smoking status, disease duration, history of IBD-related operations, family history of IBD, and use of corticosteroids or biologics were significantly different between US and Korean patients. The mean IBD-KNOW score was higher in US patients than in Korean patients (14.8 vs. 11.3; P<0.001). Multivariate analyses showed that a high IBD-KNOW score (top 25%) was associated with a positive family history of IBD (odds ratio, 2.90; P=0.025) in US patients with IBD and with the use of biologics (odds ratio, 3.65; P=0.008) in Korean patients with IBD. Conclusions: The IBD-KNOW questionnaire, an updated assessment tool of IBD-related knowledge, is simple, reliable, and available in various patient populations. IBD-KNOW can be used to identify the factors affecting the level of IBD-related knowledge to improve the quality of care in patients with IBD through a personalized approach.

Abstract Background Tumor necrosis factor (TNF)-α antagonist therapy has revolutionized the practice of management of inflammatory bowel disease (IBD); however, these medications carry a boxed warning from the Food and Drug Administration for risk of serious infection. We aimed to study the invasive fungal infection, histoplasmosis, in the setting of TNF-α antagonist therapy. Methods We performed a retrospective review of patients with IBD receiving TNF-α antagonist therapy who developed histoplasmosis during the time period January 2001–May 2018 at the Mayo Clinic, Rochester, MN. The medical records of patients were reviewed for demographics, medications, symptoms, diagnosis, treatment, and outcomes including mortality. IBD was diagnosed by biopsy, radiographic, or endoscopic evidence of disease. Results We identified 49 patients (age range 19–74; median 44 years) with a confirmed diagnosis of histoplasmosis while receiving a TNF-α antagonist. 73.5% of cases were classified as disseminated. Median time from starting TNF-α antagonist to histoplasmosis diagnosis was 2.1 years. Liposomal amphotericin B was given in 17 cases as the initial treatment. Itraconazole was given to all 49 patients. Initial treatment was split evenly between inpatient (49%) and outpatient (51%) locations with 6 patients (12%) requiring ICU-level care. Median length of stay was 9.5 days. The total length of treatment for all antifungals was 38.4 weeks, with 20.4% of patients developing documented antifungal side effects. TNF-α antagonist was continued in 9 patients (18.4%) and another 10 patients resumed TNF-α antagonist. Half of those who resumed TNF-α antagonists were on antifungal therapy. There was one histoplasmosis recurrence while off TNF-α antagonist, and three deaths (6%). Conclusion Histoplasmosis outcomes in IBD patients on TNF-α antagonists were mostly favorable; however, approximately half required hospitalization. Many patients were young with few co-morbidities, and over one-third were able to continue or resume TNF-α antagonists without documented recurrence of histoplasmosis. Practitioners should be vigilant for histoplasmosis infections in this patient population who reside in histoplasma-endemic regions. Disclosures All authors: No reported disclosures.