Loftus, Edward V

Abstract Background and Aims Patient-reported outcomes are recommended endpoints in Crohn’s disease [CD] trials. The association between patient-reported general well-being relative to symptoms of diarrhoea and abdominal pain [AP] in patients with moderate to severe CD was explored. Methods Patients from three randomized, placebo-controlled, double-blind adalimumab or upadacitinib studies with average daily very soft/liquid stool frequency [SF] ≥4 and/or AP score ≥2 at baseline were included. Using electronic diaries, patients reported general well-being [seven-point Likert scale; 1 = worst; 7 = best] in item 10 of the Inflammatory Bowel Disease Questionnaire [IBDQ]. Changes in well-being and clinical outcomes of SF and AP from baseline to week 12 or 16, and the relationship between well-being and clinical outcomes were evaluated using cumulative distribution function and probability density function curves. Results In total, 858 patients with CD were included [adalimumab, n = 695; upadacitinib, n = 163]. Patients who achieved clinical remission [SF ≤2.8, AP score ≤1.0, neither worse than baseline] were more likely than those not in clinical remission to report IBDQ item 10 response in the 6–7 group category but not IBDQ categories ≤5. Higher IBDQ score for item 10 [6–7] was associated with lower SF and AP score. Greater point increases in IBDQ item 10 were associated with a greater percentage decrease in clinical parameters; a ≥25–30% decrease in SF or AP was associated with a ≥1-point improvement in IBDQ. Conclusions An association between improvements in patient-reported general well-being and clinical remission/response was observed using outcomes of SF and AP, supporting the clinical remission/response endpoint definitions used in clinical studies of CD. Clinical Trial Registrations [ClinicalTrials.gov]: NCT00077779 [CHARM]; NCT00348283 [EXTEND]; NCT02365649 [CELEST].

INTRODUCTION: Vulvar involvement is a rare complication of Crohn's disease (CD). The optimal treatment of vulvar CD is unknown. METHODS: We conducted a 25-year retrospective cohort study of vulvar CD from 3 referral centers. Clinical features and outcomes were studied. RESULTS: Fifty patients were identified. The most common vulvar symptoms were pain (74%), edema (60%), ulcerations (46%), nodules (36%), and abscess (34%). Medical management leading to symptomatic improvement varied, and 5 patients ultimately required surgery. DISCUSSION: Vulvar CD manifests with a broad spectrum of symptoms. Aggressive medical management was frequently effective, although surgery was required in 10% of cases.

Abstract Background and Aims To report results from VISIBLE 2, a randomised, double-blind, placebo-controlled, phase 3 trial evaluating a new subcutaneous [SC] vedolizumab formulation as maintenance treatment in adults with moderately to severely active Crohn’s disease [CD]. Methods Following open-label vedolizumab 300 mg intravenous induction therapy at Weeks 0 and 2, Week 6 clinical responders (≥70-point decrease in CD Activity Index [CDAI] score from baseline) were randomised 2:1 to receive double-blind maintenance vedolizumab 108 mg SC or placebo every 2 weeks until Week 50. Assessments at Week 52 included clinical remission [primary endpoint; CDAI ≤150], enhanced clinical response [≥100-point decrease in CDAI from baseline], corticosteroid-free clinical remission among patients using a corticosteroid at baseline, clinical remission in anti-tumour necrosis factor [anti-TNF]-naïve patients, and safety. Results Following vedolizumab intravenous induction, 275 patients were randomised to vedolizumab SC and 135 to placebo maintenance. At Week 52, 48.0% of patients receiving vedolizumab SC versus 34.3% receiving placebo were in clinical remission [p = 0.008]. Enhanced clinical response at Week 52 was achieved by 52.0% versus 44.8% of patients receiving vedolizumab SC versus placebo, respectively [p = 0.167]. At Week 52, 45.3% and 18.2% of patients receiving vedolizumab SC and placebo, respectively, were in corticosteroid-free clinical remission, and 48.6% of anti-TNF-naïve patients receiving vedolizumab SC and 42.9% receiving placebo were in clinical remission. Injection site reaction was the only new safety finding observed for vedolizumab SC [2.9%]. Conclusions Vedolizumab SC is an effective and safe maintenance therapy in patients with CD who responded to two infusions of vedolizumab intravenous induction therapy.

Therapeutic drug monitoring (TDM) of biologics is a rapidly evolving field. We aimed to provide a consensus statement regarding the clinical utility of TDM for biologics in inflammatory bowel disease (IBD). A modified Delphi method was applied to develop consensus statements. A comprehensive literature review was performed regarding TDM of biologic therapies in IBD, and 45 statements were subsequently formulated on the potential application of TDM in IBD. The statements, along with literature, were then presented to a panel of 10 gastroenterologists with expertise in IBD and TDM who anonymously rated them on a scale of 1–10 (1 = strongly disagree and 10 = strongly agree). An expert consensus development meeting was held virtually to review, discuss, refine, and reformulate statements that did not meet criteria for agreement or that were ambiguous. During the meeting, additional statements were proposed. Panelists then confidentially revoted, and statements rated ≥7 by 80% or more of the participants were accepted. During the virtual meeting, 8 statements were reworded, 7 new statements were proposed, and 19 statements were rerated. Consensus was finally reached in 48/49 statements. The panel agreed that reactive TDM should be used for all biologics for both primary nonresponse and secondary loss of response. It was recommended that treatment discontinuation should not be considered for infliximab or adalimumab until a drug concentration of at least 10–15 μg/mL was achieved. Consensus was also achieved regarding the utility of proactive TDM for anti–tumor necrosis factor therapy. It was recommended to perform proactive TDM after induction and at least once during maintenance. Consensus was achieved in most cases regarding the utility of TDM of biologics in IBD, specifically for reactive and proactive TDM of anti–tumor necrosis factors.

Abstract Background and Aims Bowel urgency and abdominal pain are impactful, yet under-appreciated ulcerative colitis symptoms and not commonly assessed in clinical trials. We evaluated how these symptoms may improve with upadacitinib treatment and correlate with clinical and health-related quality of life [HRQOL] outcomes in the phase 2b U-ACHIEVE study. Methods Patients aged 18–75 years, with moderately to severely active ulcerative colitis, were randomised to receive placebo or upadacitinib (7.5, 15, 30, or 45 mg once daily [QD]). Bowel urgency and abdominal pain were evaluated at baseline and Weeks 2, 4, 6, and 8. Week 8 correlations were evaluated between bowel urgency/abdominal pain with clinical [Mayo subscores and high-sensitivity C-reactive protein and faecal calprotectin measurements] and HRQOL outcomes [Inflammatory Bowel Disease Questionnaire and 36-Item Short Form Health Survey scores]. Results A greater proportion of patients [n = 250] reported no bowel urgency and less abdominal pain with upadacitinib treatment compared with placebo, with improvements observed as early as 2 weeks. At Week 8, patients receiving the 45-mg QD dose had the greatest improvements versus placebo, with 46% reporting no bowel urgency [vs 9%; p ≤ 0.001] and 38% reporting no abdominal pain [vs 13%; p = 0.015]. At Week 8, moderate correlations were found between bowel urgency or abdominal pain and most clinical and HRQOL outcomes. Conclusions Induction treatment with upadacitinib demonstrated significant reductions in bowel urgency and abdominal pain compared with placebo. These symptoms also correlate to clinical and HRQOL outcomes, supporting their use to monitor disease severity and other treatment outcomes.

Abstract Background and Aims There remains a historical misconception that inflammatory bowel disease [IBD] patients are underweight. However, recent data suggest rates of obesity in IBD parallel to those of the general population. The impact obesity has on the natural history of IBD is unclear. We aimed to determine obesity rates at the time of IBD diagnosis in a population-based cohort of ulcerative colitis [UC] patients. Methods Chart review was performed on patients diagnosed with UC over 1970–2010. Data were collected on demographics, body mass index [BMI], disease characteristics, IBD-specific hospitalisations, intestinal resection, and corticosteroid use. The proportion of patients who were obese at the time of their diagnosis was evaluated over time, and survival free of IBD-related complications was assessed using Kaplan-Meier survival analysis. Results A total of 417 adults were diagnosed with UC over 1970–2010, 55.4% of whom were classified as either overweight [34.8%] or obese [20.6%]. The prevalence of obesity increased 2–3-fold over the 40-year study period. Obese patients had a 72% increased risk of hospitalisation (hazard ratio [HR],1.72; 95% confidence interval [CI], 1.10–2.71; p = 0.018) when compared with normal weight patients. Additionally, with each incremental increase in BMI by 1 kg/m2, the risk of hospitalisation increased by 5% [HR,1.05; 95% CI, 1.01–1.08; p = 0.008] and risk of corticosteroid use increased by 2.6% [HR,1.026; 95% CI, 1.00–1.05; p = 0.05]. Conclusions The prevalence of obesity in the UC population is increasing and may have negative prognostic implications, specifically regarding risk of future hospitalisation and corticosteroid use. Additional prospective studies are necessary to more clearly define these associations.

Abstract Background and Aims Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. Here, we evaluate the efficacy and safety of tofacitinib re-treatment following treatment interruption in patients with ulcerative colitis. Methods Here, patients with clinical response to tofacitinib 10 mg b.d. induction therapy were randomised to receive placebo in OCTAVE Sustain. Those experiencing treatment failure after Week 8 of OCTAVE Sustain entered OCTAVE Open and re-initiated tofacitinib 10 mg b.d. [re-treatment subpopulation]; efficacy and safety data are presented up to Month 36 of OCTAVE Open. Results Median time to treatment failure following interruption was 169 (95% confidence interval [CI], 94.0–179.0) and 123 [95% CI, 91.0–168.0] days for induction remitters, and induction responders but non-remitters, respectively. Following re-treatment with tofacitinib, rates (non-responder imputation after a patient discontinued; latest observation carried forward imputation after a patient advanced to a subsequent study [NRI-LOCF]) of clinical response, remission, and endoscopic improvement were 74.0%, 39.0%, and 55.0% at Month 2, and 48.5%, 37.4%, and 42.4% at Month 36, respectively. Among induction remitters and induction responders but non-remitters, clinical response rates at Month 36 were 60.6% and 42.4% [NRI-LOCF], respectively. Efficacy was recaptured regardless of prior tumour necrosis factor inhibitor failure status. The safety profile of tofacitinib 10 mg b.d. re-treatment was consistent with the overall cohort and demonstrated no new safety risks associated with exposure of ≤36 months. Conclusions Median time to treatment failure was numerically higher in induction remitters versus induction responders but non-remitters. Following treatment interruption, efficacy was safely and successfully recaptured with tofacitinib 10 mg b.d. re-treatment in a substantial proportion of patients [ClinicalTrials.gov:NCT01458574;NCT01470612].

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program. Methods Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis. Results Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years’ treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors. Conclusions For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

Background: Patients with inflammatory bowel disease (IBD) are at significantly increased risk for Clostridioides difficile infection (CDI) with an increased risk of adverse outcomes including increased in-hospital mortality, IBD treatment failure, re-hospitalization, and high CDI recurrence rates. The existing literature on predictors of these adverse outcomes is limited. We evaluated four potentially modifiable novel risk factors [body mass index (BMI), statin use, opioid use, and antidepressant use] on CDI risk and adverse outcomes in these patients. Methods: Using a retrospective design, variables were abstracted from records for patients with IBD and CDI from 2008 to 2013. Statistical analysis comprised descriptive statistics and univariate and multivariate logistic regression analyses. Results: There were 137 patients with IBD and CDI included in this study. On multivariate analysis controlling for age, 43% of patients in the overweight BMI category had severe or severe, complicated CDI, compared with 22% of patients in the underweight/normal BMI [odds ratio (OR) 2.85, p = 0.02] and 19% in the obese category (OR 3.95, p = 0.04). Statin use was associated with severe or severe, complicated CDI when controlling for age and BMI (OR 5.66, p = 0.01). There was no association between statin use and IBD exacerbations following CDI. Opioid and antidepressant use were not associated with disease severity or frequency of IBD exacerbations following CDI. Conclusions: An overweight BMI and statin use were associated with severe or severe, complicated CDI in IBD patients. Further studies are needed to better understand how these factors impact management of patients with IBD to improve clinical outcomes and potentially reduce the risk of complications from CDI.