Raffals, Laura E.

Lay Summary In this prospective, multicenter observational study of highly refractory patients with Crohn’s disease of the pouch, risankizumab achieved the primary outcome of clinical remission in 50% and the more stringent secondary outcome of antibiotic- and steroid-free remission in 30.8% at 12 weeks.

Abstract Introduction The aim of this case–control study was to determine if exposure to tumor necrosis factor alpha inhibitors (TNFIs) or immunomodulators (thiopurines or methotrexate) was associated with development of primary gastrointestinal lymphoma (PGIL) in patients with chronic inflammatory conditions. Methods Patients with PGIL and controls evaluated at a tertiary care center over 20 years were matched 1:3 using a medical record informatics search engine based on their chronic inflammatory condition (Crohn’s disease [CD], ulcerative colitis [UC], rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and duration of follow-up. Patients who started on TNFI within 3 months of PGIL diagnosis were excluded. We extracted demographics, medical history, and medications used. Univariate models using conditional logistic regression were used due to the small number of matched pairs. Results Twenty PGIL cases matched with 60 controls were followed for a mean 9.9 ± 6.9 and 9.7 ± 8.6 years, respectively. Mean age at time of PGIL diagnosis was 47.5 ± 22.0 (standard deviation) years and the majority (75%) were males. The most common inflammatory diagnosis was inflammatory bowel disease (80% of cases; 45% with UC and 35% with CD). Development of PGIL was not associated with TNFI (odds ratio [OR] = 2.6; 95% confidence interval [CI] 0.69–11.01; P = .18), but with use of TNFI in combination with thiopurines (OR = 8.93; 95% CI 1.43–80.25; P = .014). Risk of PGIL increased with every additional TNFI (2.277 (1.002–5.713); P = .0494). All cases exposed to multiple TNFI were also exposed to thiopurines. Use of thiopurines (alone or in combination) was the greatest risk factor (OR = 6.32; 95% CI 1.55–37.05; P = 0.006) to develop PGIL. Conclusions TNFI therapy was not associated with increased risk for PGIL unless used in combination with thiopurines and with every switch to a different TNFI.

Abstract Background Abdominal pain (AP) is common in patients with active inflammatory bowel disease (IBD) and has been associated with poor quality of life (QOL). Despite greater therapeutic options, symptoms persist in a subset of patients. Data is lacking regarding AP in patients with objectively documented quiescent disease. Among endoscopic quiescent disease: (1) estimate prevalence of AP, (2) assess predictors of worse AP, (3) describe its impact on validated QOL measures. Methods This cross-sectional study used prospectively collected data from SPARC (Study of a Prospective Adult Research Cohort) IBD, a multicenter longitudinal study of well-phenotyped adult IBD patients initiated by the Crohn’s & Colitis Foundation in 2016. Quiescent IBD was defined as Mayo endoscopy score <2 for ulcerative colitis (UC) and SES-CD score <3 for Crohn’s disease (CD). Patient reported outcomes (PROs) within 30 days of endoscopy were analyzed. Patients with ostomy or IPAA were excluded. Self-reported AP was categorized as none, mild, or moderate/severe. Univariate statistics used Pearson’s Chi-square and Kruskal-Wallis tests. Results A total of 973 patients with quiescent IBD (606 CD; 367 UC) were included in the study (Table 1). AP was more commonly reported in quiescent CD (31.2% mild, 15.5% moderate/severe) as compared to quiescent UC (23.4% mild, 10.1% moderate/severe) (p<0.001). In the entire quiescent cohort, those with mild or moderate/severe AP were more likely to be female sex (63.1% mild; 67.4% moderate/severe; p<0.001), higher BMI (28.4 mild; 30.0 moderate/severe; p=0.008) and have more recent tobacco use (p=0.004). Ileocolonic involvement was more commonly seen in moderate/severe AP. Mild and moderate/severe AP was associated with subjective fecal urgency, stool frequency, and bloody stool (all p<0.001). Disease behavior in CD was not associated with abdominal pain. General well-being was poorer for those with more severe AP (p<0.001), though this did not appear to result in more frequent recent ED visits or hospitalizations. Figure 1 depicts the PROMIS responses. Overall, worse AP was associated with universal worse scores on all PROMIS measures and subscales (all p<0.001). Data suggested that more severe AP had the greatest impacts on the "Fatigue" subscale. Conclusion In this study of patients in SPARC IBD with endoscopic quiescent IBD the overall prevalence of AP was 41.7% overall and more commonly reported in CD as compared to UC. AP was associated with a greater prevalence of other symptoms, worse general well-being, and poorer quality of life across all measures. Further research is needed to elucidate the pathophysiology for presence of AP in quiescent IBD and develop personalized management approaches.

Abstract Background Complex perianal fistulas are a serious complication in patients with Crohn’s disease (CD). Darvadstrocel (DVS), a suspension of expanded adult allogeneic adipose-derived mesenchymal stem cells, is approved in Europe and Japan for treatment of complex Crohn’s perianal fistulas (CPF). The global ADMIRE-CD II phase 3 randomized double-blind placebo-controlled study evaluated the efficacy and safety of DVS for treatment of complex CPF. Methods Patients aged 18–75 years with clinically controlled, inactive or mildly active CD and complex CPF (≤2 internal openings [IO] and ≤3 external openings [EOs]) who had an inadequate, or a loss of response to immunosuppressive agents or biologics were included. Patients were randomized 1:1 to receive a local injection of DVS as a single dose (120 x 106 cells/24 mL) or placebo. In all patients, fistula preconditioning included vigorous curettage and seton placement 2–3 weeks before treatment, and seton removal, a further curettage and closure of IOs immediately before treatment. The primary endpoint was combined remission (closure of all treated EOs that were draining at baseline, despite gentle finger compression, and absence of collections >2 cm confirmed by MRI) at 24 weeks. Secondary endpoints included combined remission at 52 weeks, clinical remission (closure of all treated EOs without MRI confirmation) at 24 and 52 weeks, and time to clinical remission at 24 weeks. Safety was monitored up to 52 weeks. Results From 19 Oct 2017 to 26 Jul 2023, 568 patients received DVS (n = 283) or placebo (n = 285) with fistula preconditioning; 56.3% of patients enrolled in Europe and Israel, and 43.7% in North America. Mean (SD) age, sex and race were similar in the DVS and placebo arms (38.4 [11.9] vs 37.7 [10.8] years; 42.8% vs 45.6% female; 85.9% vs 89.1% White). Combined remission rates at 24 weeks did not statistically differ between treatments (48.8% DVS vs 46.3% placebo) and there were no differences in secondary endpoints (Table 1; Figure 1). Based on health authority guidelines, post hoc analyses of patients randomized before COVID-19 (11 March 2020; n = 141 DVS, n = 143 placebo) were performed: combined remission rates at 24 weeks were 46.8% (DVS) and 38.5% (placebo). The safety profile for DVS was consistent with prior studies with no new safety signals (Table 1). Conclusion The efficacy outcomes assessed did not statistically differ between DVS and placebo, and the placebo response rate (with fistula preconditioning) was higher than expected. Post hoc analyses revealed lower placebo response rates in patients randomized before COVID-19 (similar to the pivotal ADMIRE CD I study) than the overall placebo arm. DVS was well tolerated.

Abstract Background Patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) frequently undergo restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for medically refractory disease or colonic dysplasia/neoplasia. Subtotal colectomy with ileosigmoid or ileorectal anastomosis may have improved outcomes but is not well studied. Due to increased risk for colorectal cancer in PSC-IBD, there is hesitancy to perform subtotal colectomy. We aim to describe the frequency of colorectal dysplasia/neoplasia following IPAA vs subtotal colectomy in PSC-IBD patients. Methods We completed a retrospective study from 1972 to 2022 of patients with PSC-IBD who had undergone total proctocolectomy with IPAA or subtotal colectomy. We abstracted demographics, disease characteristics, and endoscopic surveillance data from the EMR. Results Of 125 patients (99 IPAA; 26 subtotal), the indication for surgery was rectal sparing medically refractory disease (51% vs 42%), dysplasia (37% vs 30%) and neoplasia (11% vs 26%) in IPAA vs subtotal colectomy patients, respectively. On endoscopic surveillance of IPAA patients, 2 (2%) had low-grade dysplasia (LGD) in the ileal pouch and 2 (2%) had LGD in the rectal cuff after an average of 8.4 years and 12.3 years of follow-up, respectively. One (1%) IPAA patient developed neoplasia of the rectal cuff after 17.8 years of surgical continuity. No subtotal colectomy patients had dysplasia/neoplasia in the residual colon or rectum. Conclusions In patients with PSC-IBD, there was no dysplasia or neoplasia in those who underwent subtotal colectomy as opposed to the IPAA group. Subtotal colectomy may be considered a viable surgical option in patients with rectal sparing PSC-IBD if adequate endoscopic surveillance is implemented.

Abstract Background Extraintestinal manifestations (EIMs) of inflammatory bowel diseases (IBDs) are a common and debilitating feature of disease, occurring in up to 40% of patients with IBD, yet predicting who may develop them is difficult. The goal of our study was to better characterize which patients may be at highest risk of developing not only 1 EIM, but also multiple EIMs, across both diseases. Methods A retrospective study of participants enrolled in the SPARC IBD (Study of Prospective Adult Research Cohort with IBD) registry was performed, and demographic and clinical data were analyzed. A total of 1211 patients with data available on EIMs were included, and differences among variables with vs without EIMs were assessed. Results A total of 329 participants with at least 1 EIM were identified, compared with 882 participants without any EIMs. Crohn’s disease patients and women were more likely to have 2 or more EIMs (P = .005 and P ≤ .001, respectively). Participants with ocular manifestations were likeliest to have at least 2 EIMs (P ≤ .001). Even when diagnosis was controlled for, involvement of the right colon (P = .021) was predictive of IBD-associated arthritis across both diseases in a multivariate generalized linear model. Conclusions This is the first comprehensive large-cohort assessment of how EIMs relate to one another at the individual vs systems levels. Further, our analysis is the first to recognize specific locations of colon involvement associated with EIMs of IBD, regardless of IBD type. These results are important in identifying patients at risk of developing future EIMs and may help with risk stratification when choosing treatments.

INTRODUCTION: There is a paucity of data on the real-world effectiveness of therapies in patients with Crohn's disease of the pouch. METHODS: This was a prospective multicenter study evaluating the primary outcome of remission at 12 months of therapy for Crohn's disease of the pouch. RESULTS: One hundred thirty-four patients were enrolled. Among the 77 patients with symptoms at baseline, 35 (46.7%) achieved remission at 12 months. Of them, 12 (34.3%) changed therapy. There was no significant association between therapy patterns and remission status. DISCUSSION: Approximately 50% with symptoms at enrollment achieved clinical remission at 12 months, most of whom did so without a change in therapy.

Abstract Background Patients with ulcerative colitis and total abdominal proctocolectomy with ileal pouch-anal anastomosis have a 50% risk of pouchitis and a 5% to 10% risk of chronic pouchitis. Aims The goal of the study was to compare pouch microbiota and stool bile acid composition in patients with chronic pouchitis, chronic pouchitis and primary sclerosing cholangitis, and normal pouch. Methods Patients with ulcerative colitis and ileal pouch-anal anastomosis were recruited from March 20, 2014, to August 6, 2019, and categorized into normal pouch, chronic pouchitis, and chronic pouchitis/primary sclerosing cholangitis groups. Stool samples were subjected to bile acid quantification and 16S rRNA gene sequencing. Statistical comparisons of absolute bile acid abundance and pouch microbiota α-diversity, β-diversity, and taxa abundance were performed among the patient groups. Results A total of 51 samples were analyzed. Both α-diversity (P = .01, species richness) and β-diversity (P = .001) significantly differed among groups. Lithocholic acid was significantly lower in patients with chronic pouchitis/primary sclerosing cholangitis than in those with chronic pouchitis (P = .01) or normal pouch (P = .03). Decreased α-diversity was associated with an increased primary to secondary bile acid ratio (P = .002), which was also associated with changes in β-diversity (P = .006). Conclusions Pouch microbiota α- and β-diversity differed among patients with normal pouch, chronic pouchitis, and chronic pouchitis/primary sclerosing cholangitis. Lithocholic acid level and primary to secondary bile acid ratio were highly associated with pouch microbiota richness, structure, and composition. These findings emphasize the associations between pouch microbiota and bile acid composition in dysbiosis and altered metabolism, suggesting that secondary bile acids are decreased in chronic pouchitis.