BACKGROUND:This post hoc analysis evaluated the corticosteroid-sparing effects of risankizumab (RZB) versus ustekinumab (UST) in patients with moderate to severe Crohn's disease (CD) with prior inadequate response or intolerance to ≥ 1 anti-tumor necrosis factor (TNF) therapy. METHODS:SEQUENCE (NCT04524611) was an open-label, multicenter, randomized, efficacy assessment-blinded study. Patients were randomized 1:1 to receive RZB (intravenous [IV] 600 mg induction dose at weeks 0, 4, and 8, then a subcutaneous [SC] 360 mg maintenance dose every 8 weeks [Q8w] starting at week 12) or UST (single weight-based IV induction dose, then a SC 90 mg maintenance dose Q8w starting at week 8) up to week 48. Patients tapered corticosteroids beginning at week 2. Achievement of clinical, endoscopic, and quality of life outcomes without concomitant use of steroids ("corticosteroid-free") and safety were assessed. RESULTS:In patients taking corticosteroids at baseline, response rate differences by the week 24 and 48 timepoints with RZB versus UST were 10.5% and 25.4% (P ≤ .01) for corticosteroid-free clinical remission per CD activity index and 20.4% (P ≤ .001) and 29.2% (P ≤ .01) per stool frequency/abdominal pain score, and 23.0% and 20.2% (both P ≤ .01) for corticosteroid-free endoscopic remission. Similar results were also observed for additional corticosteroid-free endpoints, including endoscopic, composite (clinical + endoscopic), and quality of life outcomes. Numerically higher exposure-adjusted event rates of serious infections and hypersensitivity with RZB and UST were observed with corticosteroid use. CONCLUSION:In patients with CD refractory to anti-TNF therapy, higher rates of corticosteroid-free clinical, endoscopic, and quality of life outcomes were achieved with RZB versus UST. Both treatments were well-tolerated. CLINICAL TRIAL REGISTRATION NUMBER:NCT04524611.

The long-term efficacy and safety of the selective JAK inhibitor upadacitinib (UPA) in patients with moderate-to-severe Crohn’s disease (CD) are currently being evaluated in the ongoing U-ENDURE long-term extension (LTE) study.1 Here, we report the efficacy of 2 years of UPA treatment in the U-ENDURE LTE (3 years of total maintenance treatment) stratified by prior inadequate response or intolerance to biologic therapy (Bio-IR) at baseline. This post hoc analysis included patients who completed 52 weeks of maintenance treatment in U-ENDURE and continued their previously assigned treatment (UPA 15 mg [UPA15] or UPA 30 mg [UPA30] once daily [QD]) for an additional 96 weeks in the LTE study. Patients who demonstrated IR to UPA during the treatment period and required medical treatment could receive rescue therapy. Efficacy outcomes during the LTE were assessed by baseline Bio-IR status (yes, no) and included clinical remission (per CD activity index [CDAI] and per stool frequency/abdominal pain score [SF/APS]), endoscopic response, endoscopic remission, ulcer-free endoscopy, and deep remission (endpoints defined in Figure footnotes). Data are presented as observed (AO). All available measurements before initiation of rescue were analysed; values for missing data were not imputed.1 Safety by Bio-IR status has been reported previously.2 In the Bio-IR group, 70 patients received UPA15, and 119 patients received UPA30; in the nonBio-IR group, 37 patients received UPA15, and 54 patients received UPA30. From week 0 to week 96 of the LTE, ≥ 63.0% of patients achieved and sustained clinical remission per SF/APS, and ≥ 59.1% of patients achieved and sustained endoscopic response, in both Bio-IR and nonBio-IR subgroups, irrespective of treatment group (Figure). In both subgroups and treatment groups, ≥ 71.0% of patients achieved and sustained clinical remission per CDAI throughout the LTE. For the endoscopic endpoints of remission and ulcer-free endoscopy, as well as the clinical and endoscopic composite endpoint of deep remission, efficacy rates were either sustained during the 96-week LTE or were numerically higher at week 96 versus week 0 in both Bio-IR and non-Bio-IR patients, irrespective of UPA treatment group. Sustained clinical and endoscopic efficacy was observed in patients who completed up to 3 years of UPA maintenance therapy in U-ENDURE, regardless of Bio-IR status at baseline. This analysis supports the long-term efficacy of UPA in patients with CD regardless of prior inadequate response or intolerance to biologic therapy. References: 1. Loftus, Jr EV, J Crohn’s Colitis. 2025;19(8):jjaf138. 2. Peyrin-Biroulet L Clin Gastroenterol Hepatol. 2024;22(10):2096-2106. Conflict of interest: Atreya, Raja: RA has served as a speaker, or consultant, or received research grants from AbbVie, Abivax, AlfaSigma, Arena Pharmaceuticals, Astra-Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Galapagos, Gilead, GlaxoSmithKline, InDex Pharmaceuticals, Johnson & Johnson, Lilly, Materia Prima, Merck Sharpe & Dohme, Pfizer, Roche Pharma, Takeda Pharma, Viatris. Panaccione, Remo: Consultant for: Abbott, AbbVie, Abbivax, Alimentiv,Amgen, AnaptysBio, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Inviva,Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mirador, Novartis, Oppilan Pharma, Odyssey, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Sanofi, Satisfai Health, Shire, Sublimity Therapeutics, Spyre Therapeutics, Takeda Pharmaceuticals, Teva,, Tillots, Trellus, Union Biopharma, Viatris, Ventyx, UCB Speaker’s Fees for: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda Pharmaceuticals Advisory Boards for: AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Sanofi, Sublimity Therapeutics, Takeda Pharmaceuticals, Ventyx. Louis, Edouard: Education and Reserach Grants for my department: Abbvie, Takeda, Johnson and Johnson, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Johnson and Johnson, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Rubin, David T.: Grant support: Takeda Pharmaceuticals Consultant: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Mirador, Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx. Cunneen, Colla: A full-time employee of AbbVie and may own AbbVie stock or options. Garrison, Andrew: Contractor at AbbVie and may own AbbVie stock or options. Dubcenco, Elena: Full-time employee of AbbVie and may own AbbVie stock or options. Naling, Grace: Full-time employee of AbbVie and may own AbbVie stock or options. El Ouali, Sara: Speaker and/or consulting fees from Takeda, Eli Lilly, Janssen, Abbvie.

IMPORTANCE AND OBJECTIVE:Upadacitinib, an oral, reversible Janus kinase inhibitor, is approved for the treatment of moderate-to-severe Crohn's disease (CD). Limiting corticosteroid exposure is an important goal in treating CD. This posthoc analysis evaluated the corticosteroid-sparing effects of upadacitinib in patients with CD. DESIGN AND SETTING:This study included pooled data from two phase 3, multicenter, double-blind induction trials and one maintenance trial. Randomization was stratified by corticosteroid use at induction baseline, with a mandatory corticosteroid taper starting at induction week 4. Efficacy was evaluated by baseline corticosteroid use and by achieving corticosteroid-free outcomes through year 2 of maintenance therapy. Safety was also assessed. RESULTS:At baseline, 34.7% (234/674) and 35.7% (124/347) of upadacitinib 45 mg and placebo-treated patients were taking corticosteroids, respectively. At induction week 12 and maintenance week 52, higher rates of upadacitinib-treated patients were corticosteroid-free among all patients and among patients with baseline corticosteroid use compared with placebo; upadacitinib-treated patients achieved higher rates of corticosteroid-free outcomes, compared with placebo, including corticosteroid-free clinical remission (stool frequency/abdominal pain score [SF/APS]: 42.7% vs 16.1%; CD activity index [CDAI]: 41.2% vs 23.4%) and corticosteroid-free endoscopic response (37.0% vs 8.1%), with similar results observed among responders to upadacitinib induction therapy at maintenance week 52. Corticosteroid-free outcomes were sustained through year 2 of maintenance therapy. The safety profile was similar to the overall population, with no new safety risks identified. CONCLUSIONS AND RELEVANCE:The results from pivotal studies demonstrated that upadacitinib effectively induced early and sustainable corticosteroid-free clinical remission with a manageable safety profile in patients with moderate-to-severe CD. CLINICAL TRIAL IDENTIFIERS:U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.

Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of moderate-to-severe Crohn’s disease (CD). This post hoc analysis reports the efficacy and safety of upadacitinib for CD in patients in East Asia enrolled in the phase 3 clinical trials. In two induction studies (U-EXCEL [NCT03345849], U-EXCEED [NCT03345836]), adults with moderately to severely active CD were randomized 2:1 to once-daily upadacitinib 45 mg or placebo for 12 weeks. In the 52-week U-ENDURE maintenance study (NCT03345823), patients with clinical response to upadacitinib induction therapy were rerandomized 1:1:1 to once-daily upadacitinib 15 mg, upadacitinib 30 mg, or placebo. Data from patients in East Asia were evaluated. In the induction studies, achievement of clinical and endoscopic outcomes occurred at higher rates with upadacitinib vs placebo at week 12 among the 204 patients in East Asia. Clinical remission per CD Activity Index (CDAI) and endoscopic response were achieved by 50.7

Introduction Patients with rheumatoid (RA) or psoriatic (PsA) arthritis can experience debilitating pain. Methods Post hoc analyses of phase 3, double-blind studies in patients with active disease despite treatment (SELECT-COMPARE, SELECT-PsA 1) assessed the effects of upadacitinib or adalimumab versus placebo on pain in patients with attenuation of inflammation (AoI) versus remaining inflammation at weeks 12 and 24/26 (PsA/RA). Further, a mediation analysis assessed the direct/indirect effect of treatment on pain using the Patient's Global Assessment of pain (PtGA) and 28 tender joint count (TJC28) at weeks 2/12/26 in RA, and weeks 16/24 in PsA. Results In patients with RA+AoI, PtGA scores improved more with upadacitinib (least squares mean change, -42.9) versus adalimumab (-34.7 (p<0.05)) or placebo (-33.1 (p<0.05)) at week 12 from baseline; improvements were similar across groups by week 26. For PsA+AoI, improvement was greater with upadacitinib (week 12, -2.7; week 24, -3.8) versus placebo (-1.8 (p<0.05); -2.8 (p<0.001), respectively) and similar to adalimumab (-2.8, -3.6). For RA, the direct effect on pain was nearly two times greater with upadacitinib versus placebo compared with adalimumab at weeks 12/26. For PsA, total effects on pain (TJC28 improvement) at weeks 16/24 were greater with upadacitinib (2.16 and 2.30) and adalimumab (1.35 and 1.71) versus placebo. Conclusions Upadacitinib effectively reduced pain in active RA and PsA, including in patients with AoI. The greater pain relief observed in RA with upadacitinib versus adalimumab might indicate both direct (relieving non-inflammatory pain) and indirect (suppressing inflammation) effects

Abstract Background Patients with ulcerative colitis (UC) may experience debilitating symptoms that impact their quality of life. This post hoc analysis evaluates changes in patient-reported outcomes (PROs) and biomarkers over time during maintenance treatment with risankizumab (RZB), a specific inhibitor of IL-23, among patients who responded to RZB induction treatment. Methods Patients with a clinical response to 12 weeks of intravenous (IV) RZB treatment from the Phase 2b and Phase 3 INSPIRE induction studies were randomised 1:1:1 to subcutaneous (SC) placebo (PBO) withdrawal, 180 mg RZB SC, or 360 mg RZB SC every 8 weeks during maintenance (COMMAND). Individual PROs were examined as no bowel urgency, no abdominal pain, no nocturnal bowel movements, no tenesmus, no faecal incontinence, no UC-related sleep interruption, and no fatigue (Functional Assessment of Chronic Illness-Fatigue [FACIT-F] ≥ 40). Biomarkers examined were faecal calprotectin (FCP) and high-sensitivity C-reactive protein (hs-CRP). Results were reported as the percentage of patients achieving each outcome for all PROs and median values for biomarkers at Week (wk) 0 of induction and every 8 wks from wk 0–52 of maintenance, unless otherwise stated for FACIT-F ≥ 40.1, hs-CRP and FCP. Non-responder imputation with no special data handling for missing data due to logistic restrictions (COVID-19 or the geo-political conflict in Ukraine and surrounding impacted regions) was used for missing data. Results In total, 548 patients (PBO SC, n=183; RZB 180 mg SC, n=179; RZB 360 mg SC, n=186) were randomised into the maintenance study. A higher proportion of patients achieved PROs at maintenance wk 0 compared to the induction baseline (Figures 1 and 2). Throughout maintenance, achievement of PROs persisted in patients receiving RZB, regardless of dosage, except for no nocturnal bowel movements, no fecal incontinence, and no UC-related sleep interruption, which showed a slight decrease in response for all treatment groups. A decline in achievement of all PROs in the PBO withdrawal arm was seen from wk 32 onwards. Both biomarkers showed a decrease in median levels from induction wk 0 to maintenance wk 0. During maintenance, median FCP levels were lower for both RZB doses compared to PBO. Lower median hs-CRP levels persisted during maintenance but were similar among all treatment groups. Conclusion Improvements in most PROs and biomarkers were sustained throughout maintenance, with declines seen in the PBO maintenance group likely due to the withdrawal of RZB from RZB induction treatment. These findings show that RZB may decrease common UC-related symptoms and may improve patients’ quality of life and inflammatory burden.

Lungs receive blood supply from the pulmonary and bronchial arteries. After transplantation, lungs uniquely suffer from ischemia and injury to the airways, in part due to the surgical sacrifice of the bronchial artery circulation during procurement and implantation. Ex-vivo lung perfusion (EVLP) offers a platform to rehabilitate and assess donor lungs; however, it traditionally excludes bronchial circulation. We hypothesized that bronchial artery perfusion during EVLP may enhance airway preservation. A dual-circulation EVLP platform was developed using swine donor lungs with preserved bronchial arteries. Blood was separately routed to the pulmonary artery and to the bronchial arteries. Laser speckle contrast imaging (LASCA) was performed pre- and post-initiation of bronchial perfusion, and perfusion units were compared within lungs. Endpoint lung function and tissue integrity were assessed via histology and TUNEL staining after 6 h of perfusion. Six porcine lungs were successfully mounted on the dual-circulation EVLP system. Bronchial perfusion significantly increased airway perfusion (p = 0.03), with trends toward improved parenchymal perfusion as well. Histology demonstrated preserved architecture and less necrosis in the airways of dually perfused lungs. TUNEL staining demonstrated significantly reduced bronchial epithelial apoptosis in dual-perfused lungs compared to PA-only perfusion (p < 0.001). This study demonstrates the feasibility of dual-circulation EVLP in a large animal model and reveals early protective effects of bronchial artery perfusion on airway tissues. These findings suggest that incorporating bronchial perfusion into EVLP platforms may mitigate early ischemic airway injury, a key contributor to post-transplant complications and chronic lung allograft dysfunction. Further investigation is warranted to assess functional outcomes and long-term benefits, and to evaluate integration with bronchial artery revascularization strategies.

Objectives Evaluate the risks and benefits of upadacitinib 15 mg vs adalimumab in rheumatoid arthritis (RA) patients with an inadequate response to methotrexate based on cardiovascular (CV) risk.Methods In SELECT-COMPARE, patients received upadacitinib 15 mg, placebo or adalimumab 40 mg every other week, with background methotrexate. This post hoc analysis assessed patients with lower (age <65 years; no CV risk factors) and higher CV risk (age ≥65 years and/or ≥1 CV risk factor). Safety and efficacy outcomes were compared between upadacitinib and adalimumab over the short term (~6 months) and long term (5 years) based on CV risk.Results The study included 211 lower-risk patients (upadacitinib, n=129; adalimumab, n=82) and 767 higher-risk patients (upadacitinib, n=522; adalimumab, n=245). Rates of malignancy excluding nonmelanoma skin cancer (NMSC), major adverse cardiovascular event and venous thromboembolism were comparable between upadacitinib and adalimumab in both risk groups but numerically higher in the higher-risk group. Upadacitinib showed higher rates of herpes zoster versus adalimumab in both risk groups and numerically higher rates of serious infection and NMSC in the higher-risk group. Upadacitinib demonstrated consistently better efficacy outcomes, including 28-joint Disease Activity Score (C reactive protein) <2.6, Clinical Disease Activity Index remission and Boolean remission at 6 months, which were generally maintained through 5 years.Conclusions Regardless of baseline CV risk, upadacitinib demonstrated comparable safety to adalimumab, except for higher rates of herpes zoster in both CV risk groups and NMSC and serious infections in the higher-risk group. Upadacitinib consistently showed better clinical and functional outcomes than adalimumab. The benefit–risk profile of upadacitinib in RA patients was favourable, independent of CV risk category, in both short and long term.