Introduction

Upadacitinib (UPA) is a novel, highly selective Janus kinase 1 inhibitor that has received regulatory approval for moderately to severely active ulcerative colitis (UC) and for moderately to severely active Crohn’s disease (CD). Acne was one of the most frequently reported adverse events (AE) in the pivotal trials of UPA for UC and CD and was the most commonly reported AE in our large prospective real-world experience. However, risk factors for this AE are not known. Here we present the real-world experience of patient-reported acne as an AE in patients with inflammatory bowel disease (IBD).

Aims & Methods

We performed a prospective, real-world analysis of incidence of acne in patients receiving UPA for IBD at our institution. Clinical follow-up to assess effectiveness and safety occurred at predetermined intervals during weeks 0, 2, 4, 8, and 12. This included standard questions about extra-intestinal manifestations or AEs, including acne. Disease-, drug-, and patient-related variables were assessed related to acne occurrence. Analysis of covariance (ANCOVA), Shapiro-Wilk normality test, Mann-Whitney test, and multivariate logistical regression (MLR) were performed for predictive variables. Time (in days) to acne occurrence was analyzed using a quartile analysis.

Results

A total of 119 patients with IBD were assessed for the first 3 months on UPA (63 UC, 44 CD, 5 IBD-U, 6 pouchitis (P)); 109 receiving 45 mg/d; 10 receiving 15 mg/d). 35 patients (29%; 23 UC, 10 CD, 1 IBD-U, 1 P all receiving 45 mg/d) reported an AE of acne primarily of the face, but also involving the scalp and back. Treatment discontinuation due to the acne occurred in only 2 patients (5.7%). Of acne-reporting patients, the median time from initiation of UPA to occurrence of acne was 31 days (IQR: 18-49). MLR of all examined variables (AUC=0.6737) demonstrated age stratified by decade (P=0.047) significantly correlated younger age with incidence of acne. Female sex (P=0.08), type of IBD (P=0.11), smoking status (P=0.16), and use of concomitant immunomodulator therapy (P=0.58) or concomitant corticosteroids (P=0.67) were not related to the development of acne on UPA (Table 1).

Table 1. Results of multivariate linear regression for acne observed in IBD patients (n=119) treated with upadacitinib (UPA).

Conclusion

In our large real-world experience in patients with IBD treated with upadacitinib, we report a 29% incidence of acne which mostly occurred within the first 31 days of treatment, only with the 45 mg/d dose, and in younger patients. Concomitant steroids or immune therapies were not associated with increased risk of acne. These findings are of considerable interest, and will assist in patient communication and inform a prospective prevention trial for this AE.

References

Colombel J-F, Panes J, Lacerda AP, et al. Gastroenterology. 2022;162(7):S-1394.
Danese S, Vermeire S, Zhou W, et al. [published correction appears in Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-2128.
Friedberg S, Choi D, Hunold T, et al. Clin Gastroenterol Hepatol. 2023;S1542-3565(23)00173-8.
Lee SD, Ahn HJ, Shin MK. JAAD Case Rep. 2022;30:11-16.
Sandborn WJ, Feagan BG, Loftus EV Jr, et al. Gastroenterology. 2020;158(8):2123-2138.e8.
Sandborn WJ, Ghosh S, Panes J, et al. Gastroenterology. 2020;158(8):2139-2149.e14.

Disclosure

NKC, DKC, SF, NMG, have no relevant disclosures.
DTR has received grant support from Takeda; and has served as a consultant for AbbVie, Alimentiv Inc., Altrubio, Amgen, Arena Pharmaceuticals, Aslan Pharmaceuticals, Boston Consulting Group, Boehringer Ingelheim Ltd., Bristol-Myers Squibb, Buhlmann Diagnostics Corp., Celgene, ClostraBio, Connect BioPharma, Datos Health, EcoR1, Ferring Pharma, Genentech/Roche, Gilead Sciences, IBD RPM dba Chronicles Health, IAG, Iterative Health, Janssen Pharmaceuticals, Kaleido Biosciences, Lilly Eli & Co, Menten AI, Pfizer, Prometheus Biosciences, Reistone Biopharma, Sangamo Therapeutics, Shanghai Pharma Biotherapeutics USA, Syneos, Takeda, Target RWE, Techlab Inc., Trellus Health.

Introduction

Swallowed topical corticosteroids (STC) are a treatment option for eosinophilic esophagitis (EoE); however, they are associated with side effects and some patients (pts) may not respond. Dupilumab demonstrated improvements in histologic, symptomatic, and endoscopic features in adult and adolescent pts with EoE over 24 weeks (Phase 3 LIBERTY EoE TREET study, NCT03633617) and is approved in the US and EU for the treatment of EoE. Here we assess the effect of long-term dupilumab on histologic, symptomatic, and endoscopic aspects of EoE in pts with/without prior use of STC and with/without prior inadequate response, intolerance, or contraindication to STC.

Aims & Methods

In Part B, pts received dupilumab 300 mg or placebo weekly (qw) for 24 weeks (W24). Eligible pts who completed Part B entered Part C and received dupilumab 300 mg qw for 28 weeks (W52). Clinicians categorized pts as with/without prior STC use and with/without prior inadequate response, intolerance, or contraindication to STC at screening. Assessed outcomes were: proportion of pts achieving ≤6 and <15 eosinophils per high-power field (eos/hpf), absolute change in Dysphagia Symptom Questionnaire (DSQ) score, mean change in Endoscopic Reference Score (EREFS), and Histologic Scoring System (HSS) grade/stage scores.

Results

In Part B, 80 pts received dupilumab and 79 placebo; in Part C, 74 continued dupilumab and 37 switched from placebo to dupilumab. Among pts who enrolled in Part C from Part B, 70% (78/111) had prior STC use. At W24, dupilumab improved vs placebo proportion of pts achieving ≤6 eos/hpf (with prior STC use 69% vs 7%, without 57% vs 0%), <15 eos/hpf (92% vs 11%, 83% vs 0%), and DSQ score (absolute mean [SD] change -27.3 [-15.8] vs -13.6 [12.5], -23.1 [15.6] vs -19.6 [15.0]). Pts continuing dupilumab in Part C further improved at W52: proportion achieving ≤6 eos/hpf (with prior STC use 86%, without 81%) and DSQ score (absolute mean [SD] change ‑31.4 [15.8], ‑27.7 [14.6]); all pts achieved <15 eos/hpf regardless of prior STC use. Pts switching from placebo to dupilumab at W24 improved at W52: proportion achieving ≤6 eos/hpf (with 70%, without 60%), <15 eos/hpf (82%, 70%), and DSQ score (‑26.1 [12.6], ‑29.9 [8.4]). At W52, EREFS and HSS grade/stage scores further improved or were maintained in pts continuing dupilumab and improved in pts switching to dupilumab (Table). Similar results were observed in pts with/without prior inadequate response, intolerance, or contraindication to STC.

Table. Peak eosinophil count in patients with or without prior swallowed topical corticosteroid use to Week 52

Conclusion

Dupilumab 300 mg qw for 52 weeks led to histologic remission (<6 eos/hpf) and sustained improvements in histologic, symptomatic, and endoscopic aspects of EoE, regardless of prior use or inadequate response, intolerance, or contraindication to STC.

Disclosure

AJB: Dr Falk Pharma, Norgine, Nutricia, Sanofi, SST, and Thelial – research funding; Alimentiv, Aqilion, AstraZeneca, Dr. Falk Pharma, Laborie, Medtronic, Regeneron Pharmaceuticals Inc., and Sanofi – consulting fees.
ESD: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Celgene/Receptos/BMS, GSK, Meritage, Miraca, Nutricia, Regeneron Pharmaceuticals Inc., Revolo, Shire/Takeda – research funding; Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, Gossamer Bio, GSK, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nextstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron Pharmaceuticals Inc., Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio – consulting fees; Allakos, Holoclara, and Invea – educational funding.
IH: Allakos, AstraZeneca, Calyx/Parexel, Eli Lilly, Ellodi/Adare Pharma, EsoCap, Gossamer Bio, GSK, Nextstone, Pfizer/Arena Pharmaceuticals, Phathom, Receptos/BMS, Sanofi/Regeneron Pharmaceuticals Inc., and Shire/Takeda – consulting fees; Allakos, Ellodi/Adare Pharma Solutions, Receptos/BMS, Regeneron Pharmaceuticals Inc., and Shire/Takada – research funding.
AJL: Dr Falk Pharma and EsoCap – consulting fees; Dr Falk Pharma, Ellodi Pharmaceuticals, Regeneron Pharmaceuticals Inc. – research funding.
CS: Adare Pharmaceuticals Inc., AstraZeneca, Calypso, Dr. Falk Pharma, EsoCap, GmbH, and Regeneron Pharmaceuticals Inc. – consulting fees.
AS, EM, JM, and XS: employees of Regeneron Pharmaceuticals Inc. and may hold stock and/or stock options in the company.
EL and LG: employees of Sanofi and may hold stock and/or stock options in the company.

Introduction

Surveillance is recommended in patients with colonic inflammatory bowel disease (IBD) given their increased risk of colorectal cancer (CRC). Present risk stratification strategies do not discriminate sufficiently between risk groups. We aimed to develop and validate a dynamic multivariable prediction model for advanced colorectal neoplasia (aCRN, including high-grade dysplasia and CRC) in IBD.

Aims & Methods

We pooled data from six existing surveillance cohort studies (two unpublished).^1-3 Patients with IBD and an indication for CRC surveillance were included if they underwent at least one follow-up procedure. Exclusion criteria included prior aCRN, prior colectomy, or an unclear indication for surveillance. Predictors were selected based on the results of a recent meta-analysis,⁴ frequency, and data availability: extensive disease, prior dysplasia (indefinite for dysplasia or low-grade dysplasia), primary sclerosing cholangitis, male sex, IBD type, post-inflammatory polyps, age, and maximal endoscopic inflammation. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modelling.⁵ Model performance was assessed with Harrell’s c-statistic and by calibration curves, adjusted for optimism by internal cross-validation. In a sensitivity analysis model performance was assessed in data ≥2010 only (internal validation). Generalizability across the surveillance cohorts was evaluated by internal-external cross-validation.

Results

The surveillance cohorts encompassed time periods 1973-2021 and comprised 3,731 patients (54% male sex; 75% ulcerative colitis or IBD-unclassified and 25% Crohn’s disease) with a median follow-up of 5.7 years (interquartile interval 3.3-9.6; 26,336 patient-years of follow-up); 146 individuals were diagnosed with aCRN (see table 1 for patient characteristics). The final model contained eight predictors, with a cross-validation median c-statistic of 0.74 and 0.75 and calibration slope of 0.77 and 0.83 for, respectively, a 5- and 10-year prediction window in overall analyses. Calibration plots showed good calibration. Ninety percent of 10-year predicted aCRN risks were between 0.9 and 18.7%. Model discrimination improved in data ≥2010 and calibration results remained unchanged (48% of all procedures ≥2010). Internal-external cross-validation results showed medium discrimination and reasonable to good calibration.

Conclusion

We generated a model based on clinical factors that predicts future aCRN risk, with moderate to good model discrimination and good calibration. However, generalizability results vary and are impacted by varying cohort sizes and should be interpreted with caution. Future research should focus on formal external validation, relate predicted aCRN risks to surveillance intervals, and investigate the impact of this new model in daily clinic prior to clinical application.

References

1. Choi CR, Al Bakir I, Ding NJ, et al. Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study. Gut 2019;68:414-422.
2. Mahmoud R, Shah SC, Ten Hove JR, et al. No Association Between Pseudopolyps and Colorectal Neoplasia in Patients With Inflammatory Bowel Diseases. Gastroenterology 2019;156:1333-1344 e3.
3. Ten Hove JR, Shah SC, Shaffer SR, et al. Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with inflammatory bowel disease with long-standing colitis: results of a 15-year multicentre, multinational cohort study. Gut 2019;68:615-622.
4. Wijnands AM, de Jong ME, Lutgens M, et al. Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis. Gastroenterology 2021;160:1584-1598.
5. van Houwelingen, H., & Putter, H. (2012). Dynamic Prediction in Clinical Survival Analysis (1st ed.). CRC Press. https://doi.org/10.1201/b11311:

Disclosure

Laurent Beaugerie: Research grants: Biogen, Celltrion, Takeda, Ferring, Celltrion, Viatris; Personal fees: Takeda, Nordic Pharma, Janssen, BMS, and Viatris.
Charles N. Bernstein: Dr Bernstein is supported by the Bingham Chair in Gastroenterology. Dr. Bernstein has served on advisory Boards for AbbVie Canada, Amgen Canada, Bristol Myers Squibb Canada, Eli Lilly Canada, Roche Canada, Janssen Canada, Sandoz Canada, Takeda Canada, and Pfizer Canada; Educational grants from Abbvie Canada, Amgen Canada, Bristol Myers Squibb Canada, Ferring Canada, Organon Canada, Pfizer Canada, Takeda Canada, and Janssen Canada. Speaker’s panel for Abbvie Canada, Janssen Canada, Pfizer Canada, and Takeda Canada. Received research funding from Abbvie Canada, Amgen Canada, Sandoz Canada, Takeda Canada, and Pfizer Canada.
Steven H. Itzkowitz: Dr Itzkowitz has served on Advisory Board for Exact Sciences Corporation and a consultant for Geneoscopy. He has received research support from Exact Sciences Corporation and Freenome.
Julien Kirchgesner: Lecture fees from Janssen and Lilly, and consulting fees from Roche, Gilead, Pfizer, Janssen, Celltrion, Lilly, Takeda, and Abbvie.
Cyriel Y. Ponsioen: Received grant support from Gilead and Perspectum and speaker’s fees from Tillotts

Introduction

Currently there is no single strategy that has a clear benefit as primary therapy for Eosinophilic Esophagitis (EoE). Because of the continuous emergence of randomized clinical trials on various pharmacological and nonpharmacological approaches, we conducted a network meta-analysis in order to evaluate the efficacy and safety of available treatments for EoE in adult patients.

Aims & Methods

Histologic remission, clinical and endoscopic response, and serious adverse events (SAEs) were evaluated. Direct and indirect comparisons between treatments (proton pump inhibitors (PPI), swallowed topical corticosteroids (STC), monoclonal antibodies (mAb), placebo) were performed. Results are expressed as risk ratio (RR) and 95% confidence interval (CI).

Results

A total of eight eligible randomized controlled trials (1057 patients) were included in the meta-analysis. When the three interventions were compared with each other, none was significantly more effective in terms of histologic remission (STC vs mAb RR 5.03, 95% CI 0.96-26.24, PPI vs mAb RR 0.87, 95% CI 0.41-3.12, PPI vs STC RR 0,75, 95% CI 0.60-5.09) while all three interventions were significantly superior to placebo (mAb vs placebo RR 31, 95% CI 10.91-88, STC vs placebo RR 54.26, 95% CI 12.1-241.83, PPI vs placebo RR 10.78, 95% CI 5.33-21.78). STC and mAB resulted as the best interventions (SUCRA 0.93 and 0.78, respectively) followed by PPI (SUCRA 0.38). None of the interventions tested resulted in a significant increase in SAE rate compared with placebo (mAb vs placebo RR 3.41, 95% CI 0.61-19.12, STC vs placebo RR 1.28, 95% CI 0.25-6.44). As a consequence, placebo ranked as the safest treatment (SUCRA 0.73), followed by STC (SUCRA 0.63) and mAb (SUCRA 0.51).

Conclusion

The results of this network meta-analysis show that mAb and STC were the most effective treatments among those available for EoE as assessed by histologic remission, both with a relatively low rate of serious adverse events.

Clinical Case Summary

Colorectal lymphomas are a rare cause of colonic neoplasia (0.2-0.6% malignant neoplasms of large bowel). Approximately 10% are primary colorectal lymphomas, while the rest correspond to colonic extension of systemic lymphoproliferative diseases.
We present the case of a 66-year-old woman with a history of rectum and pancreas adenocarcinoma (both in remission). During a follow-up CT, a thickening of the cecal pole was identified, with no adenopathy or other relevant findings (Photo1). The patient had no abdominal pain or B symptoms (night sweats, weight loss or fever).
The diagnosis was completed with a PET-CT that showed pathological uptake in the cecum (Photo2), so a colonoscopy was performed, which revealed a large polypoid lesion (30 mm) at the ileocecal level, with nodular areas with small ulcerations and no clear loss of the glandular pattern (Photo 3), from which multiple biopsies were taken.
Biopsies showed lymphoid proliferation with a ‘starry sky’ pattern, mitosis and apoptosis, and positive immunohistochemistry for CD45, CD20, CD10, BCL6, BCL2 and C-MYC, together with a high proliferation index (Ki-67 > 95%), all compatible with high-grade B-lymphoproliferative syndrome with Burkitt morphology (Photo 4).
Burkitt's lymphoma is a rare B-cell lymphoma (15% of GI lymphomas), associated with chromosomal translocation (8:14, 8:22 and 2:8) and overexpression of c-myc oncogene.
There are three clinical variants: endemic (common in Africa and associated with EBV and malaria), HIV-associated and sporadic (20%).
It is common in children and its most frequent symptoms are abdominal pain and weight loss, so diagnosis is often delayed. Although the yield of endoscopic biopsies is low (<20%), it is a key tool in its diagnosis, along with targeted biopsy of abdominal adenopathies.
Despite its aggressiveness, treatment with targeted chemotherapy achieves rates of more than 90%, and early diagnosis is essential to avoid complications and ensure adequate medical treatment.

References

- Photo 1: Thickening of the cecal pole seen in CT-Scan.
- Photo 2: Pathological uptake in the caecal area as seen on PET-CT Scan.
- Photo 3: Polypoid lesion in ileocecal area at colonoscopy
- Photo 4: Pathological anatomy of endoscopic biopsies: starry sky imaging and immunohistochemistry of Bcl-2 and C-myc

Clinical Case Summary

Introduction: The most common complications of ERCP include acute pancreatitis, post-sphincterotomy bleeding, and intestinal perforation. Traumatic arterio-biliary fistulas, although rare, have been reported following manipulation. This case presents severe haemorrhage secondary to an arterio-biliary fistula.
Case Report: A 61-year-old male, chronic alcoholic with chronic liver disease (BCLC-B) and distal bile duct stricture of filarial aetiology, was admitted for biliary stent replacement. Post-procedure, the patient developed worsening clinical parameters, including abdominal pain, leucocytosis, and elevated cholestasis markers. Imaging revealed the proximal end of the stent was in the cystic duct, requiring a second ERCP for repositioning.
The patient's condition deteriorated with severe acute cholangitis, haemorrhagic rectal bleeding, and haemodynamic instability. CT showed further biliary dilatation and haematic content within the bile ducts. A third ERCP was performed to remove clots and place a covered metallic stent to control the bleeding. Despite this, haemorrhage persisted. CT-angiography revealed a 9 mm pseudoaneurysm from the pancreaticoduodenal arcade and pancreatic artery (Figure 1). Selective embolisation was successful (Figure 2), with follow-up confirming no further aneurysm filling (Figures 3 and 4).
Discussion: Arterio-biliary fistulas are typically iatrogenic or traumatic, often following biliary or hepatic procedures like liver biopsy or cholecystectomy. Post-ERCP incidence is rare, with only three reported cases. Diagnosis requires high clinical suspicion and angiography. Fistulas can cause pseudoaneurysms, which may lead to haemobilia, presenting as gastrointestinal bleeding. Management is multidisciplinary; conservative treatment is suitable for small, non-bleeding fistulas, while endoscopic or radiological interventions are used for severe cases. Early intervention is key to favourable outcomes.

References

1. Rai R. Potentially fatal haemobilia due to inappropriate use of an expanding biliary stent. World Journal of Gastroenterology. 2003;9(10):2377.
2. Berry R, Han J, Mohit Girotra, Tabibian JH. Hemobilia: Perspective and Role of the Advanced Endoscopist. 2018 Jul 12;2018:1–12.
3. Delayed Massive Hemobilia After Biliary Stenting. Endoscopy. 2003 Nov;35(11):976–7.
4. Siu, W. T., Chau, C. H., Ka Bo Law, B., Yau, K. K., Luk, Y. W., & KaWah Li, M. Non-operative management of endoscopic iatrogenic haemobilia: case report and review of literature. Acta gastro-enterologica Belgica. 2005;68(4): 428–431.
5. Panno, C., Gutiérrez, S. C., Echeverría, R., Garbe, C., Milocco, M., Ianniccillo, H., Valenzuela, M., Cubilla, A., Alvarez, F., & Alvarez, E. Hemobilia secundaria a pseudoaneurisma de la arteria hepática [Hemobilia secondary to hepatic artery pseudoaneurysm]. Acta gastroenterologica Latinoamericana. 2015;45(2):133–136.