Cohen, Benjamin L.

Abstract Background Pivotal trials have shown that ustekinumab is effective in ulcerative colitis (UC). However, the population included in these trials do not represent the cohort of patients treated in the real world. In this study, we aimed to describe the effectiveness and safety of ustekinumab in a clinical cohort of patients with UC. Methods We performed a multicenter retrospective cohort study and included patients with active UC starting ustekinumab. Variables collected included demographics, clinical data, and disease activity (measured using partial Mayo score [PMS] and endoscopic Mayo score) at follow-up. The primary outcomes were cumulative rates of steroid-free clinical and biochemical remission (SFCBR), defined as a PMS <2 while off steroids and a normal C-reactive protein and/or fecal calprotectin. Results A total of 245 patients met inclusion criteria. The median time of follow-up was 33 (interquartile range, 17-53) weeks, and 214 (87.3%) had previous exposure to a biologic and/or tofacitinib. Rates of SFCBR, clinical remission, and endoscopic remission at 6 and 12 months were 12.0% (n = 16 of 139), 29.0% (n = 71 of 175), and 18.0% (n = 7 of 39), and 23.8% (n = 15 of 63), 54.3% (n = 57 of 105), and 31.0% (n = 9 of 29), respectively. Non-Hispanic White race, higher baseline PMS, and the use of concomitant corticosteroids were independently associated with failure to achieve SFCBR. Of the 73 that were dose escalated, 28.4% did not respond, 49.3% experienced a benefit, and 21.6% achieved remission. Conclusions In a population enriched with refractory UC, ustekinumab was well tolerated and induced remission in a significant number of patients. Larger studies with a longer follow-up are warranted.

Abstract Background Improvement in clinical outcomes and normalisation of objective markers of inflammation, high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP), are considered treatment targets per STRIDE-II guidelines.1 We evaluated the effect of the oral selective Janus kinase inhibitor upadacitinib (UPA) on changes in hs-CRP, FCP, and clinical outcomes in patients with Crohn’s disease (CD). Methods In 2 phase 3, randomized, double-blind, placebo-controlled induction studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836), patients with moderate-to-severe CD received 12-week treatment with UPA 45 mg (UPA45) once daily (QD) or placebo (PBO). Patients with clinical response to UPA45 were rerandomised in U-ENDURE (NCT03345823) to receive 52-week maintenance treatment with UPA 30 mg QD (UPA30), UPA 15 mg QD (UPA15), or PBO. Endpoints included marker normalisation (hs-CRP ≤ 5 mg/L, FCP ≤ 250 µg/g) in patients with elevated baseline marker levels, normal marker and clinical remission by Crohn’s Disease Activity Index (CDAI < 150) or very soft/liquid stool frequency (SF)/abdominal pain score (APS) (average daily SF ≤ 2.8 and average daily APS ≤ 1, neither greater than baseline), and ≥ 50% reduction from baseline in marker values with a decrease of at least 100 points in CDAI from baseline. Median changes from baseline in marker levels were also evaluated. Non-responder imputation with no special data handling for missing data due to COVID-19 was used. Results Of 1021 enrolled patients, 645 (63.2%) had elevated hs-CRP (> 5 mg/L) and 750 (73.5%) had elevated FCP (> 250 µg/g) levels at baseline. Significantly greater proportions of patients with elevated baseline marker levels achieved normalisation with UPA compared with PBO at week 12 (Fig 1A/B) and week 52 (Fig 2A/B; nominal P < .001 for all). Decreases in marker levels from baseline with UPA were observed as early as week 2 and were significantly greater than with PBO through week 12 (Fig 1C) and week 52 (Fig 2C; nominal P < .001 for all). Patients achieved clinical endpoints and improvements in markers at significantly higher rates with UPA45 vs PBO at week 12 (Fig 1D–F) and with UPA15 and UPA30 vs PBO at week 52 (Fig 2D–F; P < .001 for all). The safety profile of UPA in CD was previously reported and no new safety concerns were identified. Conclusion Improvements in clinical endpoints and normalisation of objective markers of inflammation were achieved as early as week 2 with UPA45 induction and sustained with UPA15 and UPA30 maintenance therapy in patients with CD. Median changes in hs-CRP and FCP with UPA support continued improvement of inflammation up to week 52. 1. Turner D., et al. Gastroenterology. 2021;160(5):1570–1583.

AbstractBackgroundRisk factors for intervention in terminal ileal (TI) stricturing Crohn's disease (CD) are poorly defined. Novel and rigorous definitions for TI strictures recently became available.ObjectiveWe aimed to describe the rates of symptoms or need for endoscopic balloon dilation (EBD) or surgery as well as risk factors of progression in a well‐defined stricturing CD cohort.MethodsConsecutive adult patients with non‐penetrating stricturing TI CD, as defined by centrally‐read magnetic resonance enterography CONSTRICT criteria, were separated into a derivation and validation cohort. Clinical and imaging characteristics were collected following prespecified scoring conventions. Primary outcome was a composite endpoint of EBD or surgery (“intervention”). Multivariable analysis was performed.ResultsEighty‐six patients (48.8% female, median age 36 years) met selection criteria, 17.4% had prior EBD, 59.3% previously received biologics and 58.1% of strictures were anastomotic. Median follow‐up was 63.4 [95% CI: 57, 68.9] months. In the derivation cohort, at 12 and 48 months, 26% and 45% of patients had intervention, respectively. Multivariable analysis showed obstructive symptoms (Hazard ratio [HR] 1.444; 95% CI 1.126–1.852), stricture duration (HR 0.974; 95% CI, 0.954–0.995) and length (HR 1.039; 95% CI, 1.011–1.069) predicted intervention. The concordance index for split‐sample validation was 0.74 and 0.67, respectively. Biologics were not associated with intervention. An online risk calculator was constructed.ConclusionIn patients with TI stricturing CD, 26% and 45% required intervention at 1 and 4 years. Obstructive symptoms, stricture duration and length were independent and validated predictors of the need for intervention. These findings are important for clinical practice and aid in the design of future trials for CD strictures.

SummaryBackground and aimsExtra‐intestinal manifestations (EIMs) are a common complication of inflammatory bowel diseases (IBD), affecting up to half of the patients. Despite their high prevalence, information on standardised definitions, diagnostic strategies, and treatment targets is limited.MethodsAs a starting point for a national EIM study network, an interdisciplinary expert panel of 12 gastroenterologists, 4 rheumatologists, 3 ophthalmologists, 6 dermatologists, and 4 patient representatives was assembled. Modified Delphi consensus methodology was used. Fifty‐four candidate items were derived from the literature review and expert opinion focusing on five major EIMs (erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis) were rated in three voting rounds.ResultsFor use in a clinical practice setting and as part of the creation of a prospective registry of patients with EIMs, the panel developed definitions for erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis; identified the appropriate and optimal subspecialists to diagnose and manage each; provided methods to monitor disease course; offered guidance regarding monitoring intervals; and defined resolution and recurrence.ConclusionsConsensus criteria for appropriate and optimal means of diagnosing and monitoring five EIMs have been developed as a starting point to inform clinical practice and future trial design. Key findings include straightforward diagnostic criteria, guidance regarding who can appropriately and optimally diagnose each, and monitoring options that include patient and physician‐reported outcomes. These findings will be used in a national multicenter study network to optimise the management of EIMs.

AbstractBackgroundThe World Trade Center (WTC) general responder cohort (GRC) was exposed to environmental toxins possibly associated with increased risk of developing autoimmune conditions.ObjectivesTwo study designs were used to assess incidence and risks of autoimmune conditions in the GRC.MethodsThree clinically trained professionals established the status of possible GRC cases of autoimmune disorders adhering to diagnostic criteria, supplemented, as needed, by specialists’ review of consenting responders’ medical records. Nested case‐control analyses using conditional logistic regression estimated the risk associated with high WTC exposure (being in the 9/11/2001 dust cloud or ≥median days' response worked) compared with low WTC exposure (all other GRC members'). Four controls were matched to each case on age at case diagnosis (±2 years), sex, race/ethnicity, and year of program enrollment. Sex‐specific and sensitivity analyses were performed. GRC age‐ and sex‐adjusted standardized incidence ratios (SIRs) were compared with the Rochester Epidemiology Project (REP). Complete REP inpatient and outpatient medical records were reviewed by specialists. Conditions meeting standardized criteria on ≥2 visits were classified as REP confirmed cases.ResultsSix hundred and twenty‐eight responders were diagnosed with autoimmune conditions between 2002 and 2017. In the nested case‐control analyses, high WTC exposure was not associated with autoimmune domains and conditions (rheumatologic domain odds ratio [OR] = 1.03, 95% confidence interval [CI] = 0.77, 1.37; rheumatoid arthritis OR = 1.12, 95% CI = 0.70, 1.77). GRC members had lower SIR than REP. Women's risks were generally greater than men's.ConclusionsThe study found no statistically significant increased risk of autoimmune conditions with WTC exposures.

Abstract Background Pivotal trials have shown that ustekinumab (UST) is effective in ulcerative colitis (UC). However, the population included in these trials do not always represent the cohort of patients treated in the “real world”. In this study, we aimed to describe the effectiveness and safety of UST in a clinical cohort of patients with UC Methods We performed a multi-center cohort study and included patients with active UC starting UST. Variables collected included demographics, previous and current UC medications, disease activity (measured using partial and endoscopic Mayo score [PMS and EMS]) at 8 weeks, 6 months and end of follow-up. We also abstracted UST drug level and anti-UST antibodies (AUA), albumin and C-reactive protein levels. Primary outcomes were clinical response at week 8 defined as a reduction of 3 points in the PMS or PMS<2. Secondary outcomes were clinical remission defined as a PMS <2 and endoscopic remission defined as a MES ≤1, and the development of an adverse event (AE) attributed to UST. Results Ninety-five patients were included with a median age of 42 years (IQR:32-57) and 53 (56%) were female. Median follow-up was 5 months (IQR:2.2-7.4). Only 4 (4.3%) were naïve to biologics or tofacitinib and 62 (66%) had previous exposure to at least 2 other biologics. No variables were found to be associated with response at week 8 (Figure 2). Those patients who responded at week 8 had higher median albumin levels vs those who did not (median of 4.4 [IQR: 4.1-4.6] vs 4.1 g/dL [IQR:3.8-4.3]; p=0.02). There were no differences in baseline CRP levels (1mg/dL [IQR:0.6-2.8] vs 0.6 mg/dL [0.3-1.5]; p=0.06). Among the 33 patients who had follow-up endoscopic assessment, 7 (21.2%) had achieved endoscopic remission and 4 (12%) achieved histologic remission. Median UST level was 4.1 mcg/ml (IQR:2.5-5.1) and no patients had detectable AUA. Five patients underwent colectomy (5.3%). Only 6 patients (6.6%) presented with an AE (all minor that included, rash, headaches, arthralgias and infection). Conclusion In a population enriched with refractory UC, UST was well tolerated and induce response and remission in a significant number of patients. The rate of response was lower in obese patients and those with extensive colitis but was not associated with previous exposure to biologics and/or tofacitinib. Larger studies with a longer follow-up are warranted. Figure 1: Rates of clinical response and remission in patients with UC receiving ustekinumab Figure 2: Association between several baseline characteristics and response to ustekinumab in UC

AbstractBackgroundGaps exist in our understanding of the clinical course of pouch-related disorders.MethodsWe evaluated baseline disease activity and longitudinal treatment patterns among patients with inflammatory conditions of the pouch.ResultsAmong 468 patients with an ileal pouch-anal anastomosis (IPAA), 94 (20%) had acute pouchitis, 96 (21%) had chronic pouchitis, and 192 (41%) had Crohn disease of the pouch. Following an IPAA, 38% of patients were treated with a biologic and 11% underwent inflammatory bowel disease- or bowel-related surgery.ConclusionsTreatment patterns after IPAA indicate that pouch-related disorders have a significant impact on individual patients and the healthcare system.