Introduction

Many patients (pts) with moderately to severely active ulcerative colitis (UC) treated with biologics fail to respond or lose response and require alternative therapy.^1,2 Upadacitinib (UPA), an oral reversible JAK inhibitor approved for treatment of adults with moderately to severely active UC, has shown efficacy in pts with an inadequate response, loss of response or intolerance to ≥1 biologic (biologic failure) or anti-TNF agent.³⁻⁵ However, data on the efficacy of UPA by the number and type of prior biologic therapies are limited.

Aims & Methods

This post hoc analysis evaluated clinical, endoscopic and safety outcomes of UPA in pts with UC with biologic failure by the number and type of prior biologics. After 8 weeks’ (wks’) induction therapy in the Phase 3 U-ACHIEVE or U-ACCOMPLISH trials, pts with clinical response to UPA 45 mg once daily (QD) were randomised to placebo (PBO), UPA 15 mg QD (UPA15) or UPA 30 mg QD (UPA30) for 52 wks in U‑ACHIEVE Maintenance. In this study, efficacy was analysed by number (0 prior biologics failed [Non-Bio-IR], 1 or ≥2) of prior biologics. Outcomes were assessed after 8 wks’ induction (pooled) and 52 wks’ maintenance. Results are presented using non-responder imputation incorporating multiple imputation to handle missing data.

Results

Baseline pt (induction [n=988]; maintenance [n=681]) characteristics were similar across treatment arms in each subgroup by number of prior biologics, except pts who failed ≥2 prior biologics who had longer disease duration. Clinical and endoscopic outcomes were achieved by more pts who received UPA vs PBO after induction and maintenance, and by more pts who received UPA30 vs UPA15 in the ≥2 prior biologics group after maintenance. Furthermore, more pts who received UPA30 vs UPA15 and failed ≥2 prior biologics maintained clinical remission from Wk 0 of maintenance to Wk 52 (Table). Adverse events (AEs) occurred at numerically higher rates for pts receiving UPA who failed ≥2 biologics in induction and maintenance studies. During induction, no malignancies or major adverse cardiovascular events (MACE) were reported, and there was 1 venous thromboembolic event (VTE) in the PBO group. During maintenance, across subgroups, rates of AEs of special interest were: malignancies (Non-Bio-IR: UPA15, 1.0 events/100 PY [E/100 PY]; UPA30, 1.8 E/100 PY; 1 prior biologic: PBO, 3.3 E/100 PY; UPA30, 5.5 E/100 PY; ≥2 prior biologics: UPA30, 1.8 E/100 PY), MACE (Non-Bio-IR: UPA30, 0.9 E/100 PY; 1 prior biologic: PBO, 3.3 E/100 PY) and VTE (Non-Bio-IR: UPA30, 1.8 E/100 PY), respectively. No AEs leading to death occurred in either study.

Table. Efficacy after 8 weeks’ induction and 52 weeks’ maintenance therapy

Conclusion

Clinical and endoscopic improvements were seen with UPA vs PBO in induction and maintenance therapy in pts with moderately to severely active UC, regardless of the number of prior biologics failed. During maintenance, numerically greater treatment benefits were seen with UPA30 vs UPA15 in the ≥2 prior biologics group. AEs occurred at numerically higher rates in pts who failed more biologics.

References

1. Koo HM, et al. Ther Adv Gastroenterol 2023;16:17562848231201728
2. Ma C, et al. J Clin Gastroenterol 2015;49:675–82
3. Danese S, et al. Lancet 2022;399:2113–28
4. Sandborn WJ, et al. Gastroenterology 2020;158:2139–49
5. Vermeire S, et al. Presentation at ECCO 2023, March 1–4, Copenhagen, Denmark (OP04)

Disclosure

RP has received consulting fees, speaker fees and research support from Abbott, AbbVie, Abivax, Alimentiv, Allergan, Amgen, AnaptysBio, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Cosmos Pharmaceuticals, Eisai, Élan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, GlaxoSmithKline, Janssen, Landos, LyfeMD, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Sanofi, Satisfai Health, Spyre, Sublimity Therapeutics, Takeda, Theravance, Union Therapeutics and Ventyx.
SD has received consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB and Vifor Pharma.
GP has received personal payments/honoraria/speaker fees and/or accepted travel grants or fellowships from AbbVie, Allergan, Bristol Myers Squibb, Celltrion, Ferring, Galapagos, Janssen, Napp, Takeda and Tillotts; and is a director and shareholder in Ampersand Health.
IB has received consulting fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celltrion, Ferring, Galapagos, Janssen, Pfizer, Shire and Takeda; and speaker fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Janssen, Mylan, Pfizer, Shire and Takeda.
DTR has received grant support from Takeda; and has served as a consultant for AbbVie, Altrubio, Arena, Bristol Myers Squibb, Genentech/Roche, Gilead, Iterative Scopes, Janssen, Lilly, Pfizer, Prometheus Biosciences, Takeda and Techlab Inc.
KT has received consulting fees from Thermo Fisher Diagnostics K.K.; research grants from AbbVie and Takeda; and has served as a speaker for AbbVie, Celltrion, EA Pharma, Janssen, Kyorin, Mochida, Takeda, Tanabe Mitsubishi and Zeria.
RV, VR, JK, EC, SS and CH are full-time employees of AbbVie and may hold AbbVie stock and/or stock options.
SV has received grant support from AbbVie, Galapagos, Johnson & Johnson, Pfizer and Takeda; and consulting and/or speaking fees from AbbVie, Abivax, Alimentiv (formerly Robarts Clinical Trials), Arena, Avaxia, Boehringer Ingelheim, Celgene, Dr. Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Janssen, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus Biosciences, Second Genome, Shire, Takeda, Theravance and Tillotts.

Acknowledgments/Funding: AbbVie and the authors thank all of the trial investigators and patients who participated in these clinical trials. AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review and approval of this publication. All authors had access to relevant data and participated in the drafting, review and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Carl Davies, MSc, of 2 the Nth (Cheshire, UK) and was funded by AbbVie.

Introduction

The eosinophilic esophagitis (EoE) endoscopic reference score (EREFS) is the validated scoring system for endoscopic findings of EoE. EREFS findings are currently scored cumulatively and correlate modestly with histological disease activity (HDA), symptoms, and adaptive behaviors. However, inflammatory and fibrotic findings may reflect different aspects of EoE, but this has never been evaluated.

Aims & Methods

We investigated the correlation of EREFS inflammatory and fibrotic subscores with HDA, symptoms and adaptive behaviors. In three tertiary referral centres for EoE, consecutive adults (>18 years) undergoing upper endoscopy for suspected or follow up EoE were prospectively enrolled. EREFS was scored as follows: edema 0-1; rings 0-3; exudates 0-2; furrows 0-2; stricture 0-1. The EREFS inflammatory sub-score (EREFS-i) combined the scores of edema, exudates and furrows. The EREFS fibrotic sub-score (EREFS-f) combined the scores of moderate-severe rings (score ≥2) and stricture. Subsequently, at least six esophageal biopsies were collected to assess HDA based on peak eosinophil count/high-power field (PEC/HPF) (active EoE PEC ≥15/HPF; EoE in remission: PEC<15/HPF). Symptoms were assessed using the dysphagia symptoms questionnaire (DSQ). Adaptive behaviors were assessed using the Pisa EoE Adaptation Questionnaire v1.0 (PiEAQ) [reference 1]. Clinical characteristics were recorded. Kruskal-Wallis Rank Sum Test and Pearson’s Chi-squared were used for comparisons. ROC curve analysis was used to calculate the diagnostic accuracy (AUC). Spearman’s test and linear regression models were used to assess relationships between variables. Significance threshold was p<0.05.

Results

121 patients were included. 58% had active EoE, 42% were in histological remission. Baseline clinical data are reported in Table 1. The EREFS total score had modest AUC for predicting HDA (0.68) and did not show significant correlation with DSQ and PiEAQ. In contrast, EREFS-i had AUC of 0.73, with 88.2% sensitivity and 51.4% specificity for predicting HDA, being significantly more accurate compared to the EREFS-f (p<0.001; Figure 1). There was a significant correlation between EREFS-i and PEC/HPF with Spearman’s Rho=0.5 (p<0.001), with linear regression showing that an increase of 1 point of any inflammatory feature corresponded to an increase of 12 eosinophils/HPF (p<0.0001). In contrast, EREFS-f correlated significantly with the use of adaptive behaviors assessed with PiEAQ [Spearman’s Rho of 0.6 (p<0.001); Figure 2], with linear regression showing that an increase of 1 point of any fibrotic feature corresponded to an increase of one adaptive behavior (p=0.001). EREFS, EREFS-i, and EREFS-f had nonsignificant negative correlation with DSQ (p>0.05 for all).

Conclusion

We confirmed that, while total EREFS provides a global assessment of endoscopic disease severity, it lacks correlation with histological and clinical disease activity. However, we demonstrated that EREFS-i correlates significantly with PEC and predicts PEC/HPF and that EREFS-f correlates significantly with the use of adaptive behaviors assessed with PiEAQ, which represent known clinical markers of disease activity. Neither EREFS-i nor EREFS-f correlated significantly with DSQ. In conclusion, we showed that, compared to the total EREFS, EREFS sub-scores improve the correlation between endoscopy findings with histology and clinical disease activity markers. Applied to clinical practice, our results represent another step towards precision medicine in the setting of EoE.

References

[reference 1] Visaggi P, Del Corso G, Solinas I, Ovidi F, Adamo G, Dulmin I, Baiano Svizzero F, Bellini M, Savarino EV, de Bortoli N. Adaptive Behaviors, Esophageal Anxiety, and Hypervigilance Modify the Association Between Dysphagia Perception and Histological Disease Activity in Eosinophilic Esophagitis. Am J Gastroenterol. 2024 Dec 30. doi: 10.14309/ajg.0000000000003272. Epub ahead of print. PMID: 39787341.

Disclosure

Speaker or consultancy for Apogee Therapeutics, Dr Falk Pharma, Malesci, JB Pharmaceuticals, Sanofi

Introduction

Tofacitinib, filgotinib, and upadacitinib, are Janus kinase inhibitors (iJAKs) approved for inflammatory bowel disease (IBD) treatment. Although no direct comparative studies exist, potential differences in efficacy and safety are attributed to in vitro-demonstrated affinity of each molecule for different JAK isoforms. JAK1 plays a crucial role in modulating cytokine-mediated immune responses, such as IL-6 and interferon, which are involved in inflammation and skin homeostasis. Its inhibition can promote conditions that may trigger acne.
Acne may be increased in iJAK-treated patients, meaning a clinical challenge for gastroenterologists.

Aims & Methods

A retrospective study was conducted at ten referral centers in Spain, including all IBD patients who had received iJAK therapy and had at least 3 months of follow-up. Demographic data, disease-related variables, and acne characteristics when appropriate, were collected. Univariate and multivariate logistic regressions were used to identify risk factors for acne; model discrimination was assessed by AUC.

Results

A total of 549 patients included: 258 (47%) were women; 354 (64%) had ulcerative colitis, 191 (35%) had Crohn’s disease and 1% had indeterminate colitis. Mean age was 41 years (IQR 30-52). 219 patients (40%) were treated with tofacitinib, 281 (51%) with upadacitinib, and 49 (9%) with filgotinib.
Ninety patients (16%) developed acne during iJAK treatment: 69% were mild, with only 4 severe cases (4%). Acne occurred early (median onset 42 days, IQR 7-122), predominantly on the face (56%), trunk (13%) or both (31%). Acne morphology included comedones (60%), papules (59%), pustules (39%), nodular-cystic (12%), scarring (9%); 48% showed more than one morphology.
Thirty-six patients received specific acne treatment: 89% topical (antiseptics, benzoyl peroxide, retinoids), 69% systemic (antibiotics, retinoids, antiandrogens), and 44% combined treatment. 83% of those patients responded to acne specific treatment, and only 8 patients (9% of those with acne; 1.5% overall) had to discontinue iJAK treatment, with acne resolving in all cases.
Acne developed in 26%, 6% and 6% of upadacitinib, tofacitinib and filgotinib treated patients respectively (p=0.001). Multivariate analysis showed that acne development was associated with upadacitinib (OR 10.28;IC95%=4,7–22,6; p<0,001) and history of acne (OR 3.52; IC95%=1,5–8,3; p=0,004), while older age (>35 years, OR 0.31; IC95% 0,11–0,83; p=0,02) and Crohn’s disease (OR 0.47; IC95% 0,25–0,90; p=0,02) showed to be protective. This model was reliable in predicting acne development (AUC 0.79). Additionally, univariate analysis showed high dose of iJAK was also associated with acne development, which could not be confirmed in multivariate analysis.

Conclusion

Acne occurred in a relevant proportion of iJAK-treated patients, was generally mild and manageable with dermatological care, and rarely required treatment discontinuation. Risk factors for iJAK-associated acne included use of upadacitinib (probably reflecting a greater affinity for JAK1) and history of acne, while older age and Crohn’s disease were protective.
Gastroenterologists should be aware of both likelihood and management of this specific adverse event when considering iJAK therapy.

Disclosure

Y G-L, MC, GB, ER, IB, DC, M B-dA, LM, I M-J, DG, IV have provided scientific advisory / participated in educational activities / received unrestricted research grants / received payments for lecturing from Johnson & Johnson, ​Takeda, Pfizer, Amgen, AbbVie, Lilly, AlfaSigma, Ferring, Gilead.