Loss of response to intravenous (IV) infliximab occurs over time due to subtherapeutic levels and immunogenicity [1]. Subcutaneous (SC) infliximab produces higher, more stable trough concentrations and may reduce treatment failure [2-3]. Observational studies show high effectiveness and tolerability of SC infliximab [4], but whether switching inflammatory bowel disease (IBD) patients in stable steroid-free remission from IV to SC improves long-term disease control is unknown. We conducted a prospective, multicentre, randomised controlled basket trial in IBD patients in ≥ 6 months of steroid-free clinical and biochemical remission. Participants were randomised 1:1, stratified by Crohn’s disease (CD) and ulcerative colitis (UC), to continue IV infliximab or switch to SC infliximab. The primary endpoint was treatment failure at week 48 (modified intention-to-treat), defined as clinical relapse, discontinuation due to adverse event, therapeutic drug level failure, or patient withdrawal. Secondary endpoints included clinical relapse, biochemical flare, treatment failure by disease subtype, and per-protocol analyses. Participants completing 48-week follow-up by 2 Nov 2025 were analysed. A total of 199 patients were enrolled (CD n = 125; UC n = 74; median age 37; 43% female). Of these, 100 remained on IV and 99 switched to SC. Treatment failure was lower with SC (14/99, 14.1%) versus IV (35/100, 35.0%; absolute risk reduction (ARR) 20.9%, 95%CI 9.2–32.5; P = 0.001). In CD, switching significantly reduced treatment failure (12.9% vs 36.5%; ARR 23.6%, 95%CI 9.1–38.1; P = 0.002). In UC, a numerical reduction was observed (16.2% vs 32.4%; ARR 16.2%, 95%CI –3.0–35.4; P = 0.10). Benefit was greatest in patients on standard-dose 5 mg/kg q8w (P = 0.002) and not seen in dose-escalated regimens (P = 0.32). Anti-drug antibodies developed in three patients, all on IV. Adverse and serious adverse event rates were similar between groups. On multivariate analysis, SC therapy (HR 0.36, 95%CI 0.19–0.66; P = 0.001), corticosteroid exposure (HR 0.52, 95%CI 0.29–0.95; P = 0.026), and lower baseline white cell count (HR 1.16, 95%CI 1.00–1.35; P = 0.05) were associated with maintenance of remission; bio-exposure, baseline escalated infliximab dosing, immunomodulator use, age and gender were not (P > 0.05). Switching from IV to SC infliximab in IBD patients in sustained remission resulted in superior maintenance of remission at 48 weeks (significant in CD and numerical in UC) without increased adverse events or immunogenicity. Anti-drug antibodies occurred more often with IV than SC infliximab. ANZCTR: ACTRN12621001498886. References: 1. Louis E, et al. Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn’s disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol. 2023 Mar;8(3):215-227. 2. Schreiber S, et al. Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease. Gastroenterology. 2021 Jun;160(7):2340-2353. 3. Chetwood JD, et al. Meta-Analysis: Intravenous Versus Subcutaneous Infliximab in Inflammatory Bowel Disease. Aliment Pharmacol Ther. 2025 Aug;62(4):380-388. 4. Chetwood JD, et al. Intravenous Versus Subcutaneous Infliximab in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis. 2024 Sep 3;18(9):1440-1449. Conflict of interest: Chetwood, John: Speaker fees: Novartis, Eli Lilly, Dr Falk Pharma, Johnson&Johnson Redmond, Diane: No conflict of interest Kermeen, Melissa: No conflict of interest Kariyawasam, Viraj: No conflict of interest Thin, Lena: No conflict of interest Lightowler, Daniel: Speaker Fees: Pfizer, DrFalk, Eli Lily Advisory Board: AbbVie, Eli Lily, Menarini, Janssen, AGPAL Travel: Pfizer, Celgene, Allergen, Janssen, AbbVie Research Support: Janssen, Ferring Education: DrFalk, AbbVie, Janssen, Pfizer Corte, Crispin: Grants: Ferring, GESA Consulting: Abbvie, Ferring, Celltrion, Chiesi, Janssen, Takeda. Support for travel for meetings to support study: Pfizer, Takeda, Celltrion, Chiesi, Ferring, Falk. Ding, Nik John Sheng: No conflict of interest Ward, Mark G.: No conflict of interest Little, Robert: No conflict of interest Kwan, Vu: No conflict of interest De Cruz, Peter: No conflict of interest Lee, Lok Hin: No conflict of interest Duong, Tuan Anh: No conflict of interest Lee, Esther: No conflict of interest Menon, Shankar: No conflict of interest Khaing, Myat Myat: No conflict of interest Beswick, Lauren: No conflict of interest Lagumbay, Lea: No conflict of interest Walker, Timothy: No conflict of interest Paramsothy, Sudarshan: SP has served as a consultant for Finch Therapeutics and has received speaker / advisory board fees from AbbVie, Dr Falk Pharma, Ferring, Janssen and Takeda. Leong, Rupert: RWL reports personal fees from AbbVie, personal fees from Aspen, personal fees from Ferring, grants and personal fees from Hospira/ Pfizer, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from Shire, personal fees from Celgene, personal fees from Dr Falk Pharma, personal fees from Novartis, personal fees from MSD, personal fees from Chiesi, personal fees from BMS, personal fees from Glutagen, outside the submitted work.

There is increasing interest in using ≥2 advanced therapies in inflammatory bowel disease (IBD) for refractory disease, multi-organ involvement and concurrent autoimmune conditions. However, data on prescribing practices are extremely limited, and comparative efficacy and safety remain largely unknown. Prior meta-analyses have included <280 patients, primarily from small case series with heterogeneous reporting and mostly without objective outcomes [1]. We collected a comprehensive binational registry (Australia & Taiwan) of patients with IBD on combined advanced therapies (ATs)/combined immunosuppressive therapies outside of regular prescribing practice used in overlap ≥1 month. There were 307 combinations in 257 patients, median age 37 years, 146/257 (56.8%) Crohn’s disease (CD) & 110/257 (42.8%) ulcerative colitis, 111/257 (43.2%) female primarily from Australia (220/257, 85.6%; Taiwan 37/257, 14.4%). Commonest combinations were: Vedolizumab (VED) + Janus kinase inhibitor (JAK) (n = 57, 18.6%), JAK + ustekinumab (UST) (n = 52, 16.9%) & VED + tumour necrosis factor inhibitor (TNFi) (n = 44, 14.3%). Overall, via 5-point Likert scale, the combinations were deemed effective by the clinician in 66.8%. p19 inhibitors (p19i) + JAK, UST + JAK, UST + TNF had the greatest clinician-deemed efficacy rates (effective ≥70%) whereas UST + tacrolimus (TAC), JAK + TAC, & TNFi + JAK were deemed the poorest (<60%) (P=0.032). Clinical remission was achieved in 174/307 (56.7%). In 198/307 (65%), there was confirmed objective improvement (biochemically, endoscopically, and/or radiologically). The commonest adverse events (AEs) were from uncontrolled disease (n = 17, 5.5%), though there were 5/307 (1.6%) serious infections & 11/307 (3.6%) opportunistic infections. Two combinations were associated with life-threatening AEs (Common Terminology Criteria for Adverse Events (CTCAE): 4), both associated with uncontrolled IBD activity. The commonest serious AE (CTCAE 3) was from uncontrolled IBD activity (4/307, 1.3%). There were three deaths, two from uncontrolled IBD activity, one from myeloma progression in a patient with liver cirrhosis. AEs were more frequent in combinations containing JAK & tacrolimus (21/87 (24.1%) & 17/63 (27.0%) respectively, & least frequent with Th17 inhibition (p19i & UST, 16/118 (13.6%), P = 0.03). This comprehensive binational registry of combined advanced therapies in IBD, the largest to date, shows that combination use in treatment-resistant IBD is effective in the majority with acceptable safety. However, despite combination of agents, medication inefficacy remains a key area of concern. We demonstrate signals for greater efficacy & safety using several combinations that require further investigation. References: [1]Alayo QA, et al. Systematic Review With Meta-analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Disease. Crohns Colitis 360. 2022 Feb 10;4(1):otac002. Conflict of interest: Dr. Chetwood, John: JDC has received speaker fees from Novartis, Takeda, Johnson & Johnson, and Eli Lilly. Le, Puo-Hsien: No conflict of interest Wei, Shu Chen: Consultancy fees: AbbVie, Bristol Myers Squibb, Cornerstones, Ferring Pharmaceuticals Inc., Janssen/J & ampJ, Pfizer, Sanofi, SPYRE, Takeda, ThermoFisher. Lectures and/or speakers’ bureau payments: AbbVie, Bristol Myers Squibb, Celltrion, CornerStones, Excelisior, Ferring Pharmaceuticals Inc., Janssen/J & ampJ, Pfizer, Takeda, ThermoFisher. Wu, Hsin-Yun: No conflict of interest Corte, Crispin: Grants: Ferring, GESA Consulting: Abbvie, Ferring, Celltrion, Chiesi, Janssen, Takeda. Support for travel for meetings to support study: Pfizer, Takeda, Celltrion, Chiesi, Ferring, Falk. Lightowler, Daniel: Speaker Fees: Pfizer, DrFalk, Eli Lily Advisory Board: AbbVie, Eli Lily, Menarini, Janssen, AGPAL Travel: Pfizer, Celgene, Allergen, Janssen, AbbVie Research Support: Janssen, Ferring Education: DrFalk, AbbVie, Janssen, Pfizer Gilmore, Robert: Grant support from the Gastroenterological Society of Australia (GESA) and speaker honoraria from Johnson and Johnson, Pfizer, and education or conference support from Pfizer Chin, Simone: No conflict of interest Garg, Mayur: No conflict of interest Bahmani Kashkooli, Soleiman: Research grants from AbbVie and Janssen. Xu, Ziheng: No conflict of interest Wright, Emily Kate: Speaker Fees, Consultancy and Advisory Boards: AbbVie, Celltrion, Falk, Ferring, Janssen, Pfizer. Research funding/support: AbbVie, Ferring, Janssen. Sparrow, Miles P.: Educational grants or research support – Gilead, Celltrion Speaker’s fees – Janssen, Abbvie, Ferring, Takeda, Pfizer, Celltrion, Eli Lilly, Dr. Falk Pharma Advisory boards or consultancy fees – Janssen, Takeda, Pfizer, Celgene, Abbvie, MSD, Emerge Health, Gilead, BMS, Celltrion, Eli Lilly, Alimentiv O’Donnell, Jonathan: Grants: AVANT Foundation, Medical Insurance Group of Australia (MIGA) Lewindon, Peter: No conflict of interest Subramanian, Kavitha: No conflict of interest Huang Fu, Janny: No conflict of interest Moore, Gregory Thomas: Advisory boards: AbbVie, Celltrion, Eli Lilly, Gilead, J&J, Pfizer, Takeda Speakers fees: AbbVie, Falk, Ferring, J&J, Pfizer, Roche, Sandoz, Takeda Research support: MRFF, NHMRC, CCA, GESA, Gutsy Group, AbbVie, Janssen, Pfizer, Shire, Takeda Subhaharan, Deloshaan: No conflict of interest Mohsen, Waled: No conflict of interest Tan, Zhi: No conflict of interest Thin, Lena: Pfizer- advisory board fees, research grants Takeda- research grant, advisory board fees JNJ- advisory board fees Abbvie- advisory board fees Neuroscientific - advisory committee Celltriom- advisory board fees Ghali, Mark: No conflict of interest Ghaly, Simon: Speaker fees, research grants and travel grants from Dr. Falk pharma, Janssen, Pfizer, AbbVie, Sandoz and Ferring and served on advisory boards for Pfizer and AbbVie. De Cruz, Peter: No conflict of interest Lo, Sheng Wei: No conflict of interest Paramsothy, Sudarshan: SP has served as a consultant for Vedanta Biosciences and has received speaker / advisory board fees from AbbVie, Dr Falk Pharma, Ferring, Janssen and Takeda. Leong, Rupert: advisory board: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda, Spyre, Roche research grants: Joanna Tiddy USYD, McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer

Background:Patients with Inflammatory bowel disease (IBD) are at an increased risk of osteoporosis. There are limited studies internationally showing low screening rates for osteoporosis in IBD patients. There are no studies of osteoporosis screening in an Australian IBD cohort. Aim:To determine the screening rate of osteoporosis in patients with IBD in an Australian tertiary IBD clinic using an extensive risk factor assessment. Methods:A retrospective clinical audit; 252 individual patient records were reviewed from IBD clinic lists. A hybridized screening criterion was created from the European Crohn's and Colitis Organisation, British Society of Gastroenterology and Royal Australian College of General Practitioners guidelines. If patients were not up to date with screening, they were assessed as to whether they had met screening criteria during 2020/2021 and if they were recommended for a dual energy x-ray absorptiometry (DEXA) scan. If patients met criteria, DEXA scan results were collated. Results:173 patients with IBD were included, 23 patients were up to date with screening and 150 required risk assessment. 101 patients met screening criteria, 12 had a DEXA completed during the study period. In the 35 DEXAs completed before or during the study, 37% showed osteoporosis, 40% showed osteopenia and 23% were normal. Conclusion:A minority of patients who were identified as at risk of osteoporosis had a DEXA scan completed. Rates of reduced bone mineral density were high in the DEXA scans completed. Future directions should focus on validating expanded Medicare criteria to ensure at-risk patients may be screened.

ABSTRACT Background Ustekinumab is an effective therapy for the management of Crohn's disease. Australia is unique, as ustekinumab can be prescribed as first‐line biologic therapy, and there is high concomitant immunomodulator use. Aim To evaluate the real‐world efficacy and safety of ustekinumab in moderate to severe Crohn's disease. Methods A multicentre prospective cohort study was conducted at 19 Australian centres between September 2019 and April 2022. Clinical assessments were performed at baseline, 3, 9 and 15 months. Logistic regression analyses were performed to identify predictors of clinical response and remission. Results 197 patients (male 45.2%) were included: 58.9% were biologic‐naïve and 50.0% were on concomitant immunomodulators. Clinical response rates were 75.4%, 75.5% and 72.3% at 3, 9 and 15 months, respectively with corresponding clinical remission rates of 45.8%, 51.6% and 55.5%. Clinical response and remission rates at 3 and 9 months were significantly higher in bio‐naïve patients compared with biologic‐exposed (p < 0.01); but no significant differences were seen with concomitant immunomodulator use. Dose escalation was required in 31.5% of patients. Ustekinumab was discontinued in 12.7% of patients. The cumulative probability of maintaining ustekinumab treatment at 15 months was 84.4%. Despite 161 adverse events reported, including 41 hospitalizations, only eight patients required treatment discontinuation due to adverse events. Conclusions This real‐world study on the use of ustekinumab in Crohn's disease showed that short‐term clinical response and remission rates are higher in bio‐naïve compared with bio‐exposed patients, with a high persistence rate at 15 months. The addition of an immunomodulator did not significantly impact outcomes. Ustekinumab was found to be safe in most patients.

Background: An inverse relationship exists between inflammation and testosterone concentrations in non-inflammatory bowel disease (IBD) immune conditions but has not been objectively explored in the IBD male population. We aimed to characterize the distribution of testosterone concentrations in a cohort of males with IBD and identify any relationship between testosterone levels and disease activity. Methods: We conducted a prospective cross-sectional study of male IBD patients. Demographics, disease characteristics, sex-hormone concentration, gonadotropins, C-reactive protein, fecal calprotectin, and patient-reported outcomes on quality of life and erectile function were collected. Relationships between disease activity, biomarkers, patient-reported outcome scores, and testosterone levels were analyzed using univariate and multivariate linear regression analyses. Results: A total of 85 male IBD patients were included with a mean age 44 +/- 14.1 years, of which 49.4% had Crohn's disease. Mean testosterone concentration was 15.4 +/- 5.2 nmol/L and 17.6% had a serum testosterone <10.4 nmol/L. Active disease was associated with lower testosterone concentrations in univariate analysis (beta +/- SE = -0.25 +/- -1.99, P = .02) but not in multivariate analysis (beta -0.18 +/- 1.75, P = .06). Testosterone concentrations were independently associated with sex hormone-binding globulin levels (beta +/- SE = 0.45 +/- 0.04, P < .0001) and a younger age (beta +/- SE = -0.32 +/- 0.04, P <.0001). Erectile function scores (5-item International Index of Erectile Function) were lower in IBD patients with a longer duration of disease (beta +/- SE = -0.24 +/- 0.006, P = .04). Conclusions: Lower testosterone concentrations in men with IBD may reflect confounding from other factors and are not independently associated with disease activity. Greater awareness and screening for sexual dysfunction should occur in males with IBD, particularly in those with a longer disease duration. Lay Summary Sexual dysfunction in men with inflammatory bowel disease (IBD) is multifactorial. We explored the underlying hormonal profile of men with IBD and characterized the distribution of testosterone levels. Almost 1 in 5 males with IBD have a level that is considered low by international definitions (<10.4 nmol/L).

Background/Aims: Upadacitinib is a novel selective Janus kinase inhibitor approved for use in ulcerative colitis. Clinical trials had rigorous criteria and excluded many patient subgroups. Given limited real-world effectiveness data, we examined outcomes of patients treated with upadacitinib for ulcerative colitis in a real-world population. Methods: Patients that commenced upadacitinib for moderate-to-severe ulcerative colitis from September 2022 until March 2023 were identified at 13 inflammatory bowel disease centers across Australia. Clinical, biochemical, endoscopic, and intestinal ultrasound outcomes were recorded retrospectively at baseline, week 8, and week 16. Results: One hundred and fifty-two patients (61 female [40%], median age 38 years [interquartile range, 28-50]) were included. The primary endpoint of clinical remission was met in 79% at week 8, and 84% at week 16. A total of 42 patients (28%) with prior tofacitinib exposure were included. No significant difference in clinical remission was observed by week 16 between tofacitinib experienced compared to tofacitinib na & iuml;ve patients (86% vs. 84%, P= 0.67). Complete intestinal ultrasound data was available for 36 patients, showing transmural remission in 64% at week 8 and 81% at week 16, with a decrease in median bowel wall thickness of 2.3 mm and 2.4 mm, respectively. Conclusions: Upadacitinib resulted in high rates of clinical remission at 8 and 16 weeks in this large real-world cohort of ulcerative colitis patients. Upadacitinib is effective in patients with prior tofacitinib exposure. Intestinal ultrasound shows significant rates of transmural remission at week 8, sustained through week 16. (Intest Res, Published online )

Abstract Background Upadacitinib is a novel selective Janus Kinase (JAK) inhibitor which has recently been approved for use in ulcerative colitis. Clinical trials have rigorous criteria and excluded patients with prior exposure to JAK inhibitors. Given limited real-world effectiveness data we examined outcomes of patients treated with upadacitinib for ulcerative colitis in a real-world population, with a focus on prior tofacitinib exposure. Methods This retrospective, multi-centre study recruited patients commencing upadacitinib for moderate-to-severe ulcerative colitis from September 2022 until March 2023 from 13 Inflammatory Bowel Disease centres across Australia. Clinical, biochemical, endoscopic and intestinal ultrasound outcomes were recorded at baseline, week 8 and week 16. The primary outcome was a comparison between clinical remission using PRO2 definitions (STRIDE II guidelines) in those with prior Tofacitinib exposure compared with Tofacitinib-naïve. Secondary endpoints included clinical response, corticosteroid free clinical remission (CFCR), biochemical response and transmural remission assessed by intestinal ultrasound (IUS). Adverse events in both cohorts were also recorded. Results 152 patients were identified and included (Table 1) – 42 tofacitinib-exposed and 110 tofacitinib-naïve. Complete clinical data was available for all patients at baseline, week 8, and week 16. For the overall cohort, the rate of clinical remission was 20% (30/152) at baseline, 78% (119/152) at week 8 and 85% (129/152) at week 16. In patients with prior tofacitinib exposure, the rate of clinical remission was 23% (10/42) at baseline, 72% (30/42) at week 8 and 86% (36/42) at week 16. In tofacitinib-naïve patients, the rate of clinical remission was 19% (21/110) at baseline, 78% (86/110) at week 8 and 84% (92/110) at week 16 (Figure 1). There was no statistically significant difference in rate of clinical remission at baseline (p=0.23), week 8 (p=0.13) or week 16 (p=0.67). There was no statistically significant difference in clinical response, CFCR, biochemical response or transmural remission by IUS between the cohorts. Adverse events were seen in 40 (26%) patients over the course of 16 weeks follow-up. Most common were acne (12%), rash (4%) and nasopharyngitis (4%). No venous thromboembolism, systemic infection or cardiovascular events were observed. These events were spread evenly among both groups (p=0.37). Conclusion This is the largest real-world study to show that upadacitinib is effective and safe for patients with moderate to severe ulcerative colitis and prior tofacitinib exposure.

Abstract Background Ustekinumab (UST) is a monoclonal antibody targeting IL-12 and IL-23 through their shared p40 subunit. This study aimed to determine the clinical outcomes after UST treatment in Crohn’s disease (CD) patients in a real-world setting, and to investigate the association of clinical outcomes with IL-12, IL-23 and UST levels. Methods A multi-centre prospective observational cohort study of UST for moderate to severe CD was conducted. Patients were recruited from 19 Australian centres between Sep 2019 and Apr 2022. Clinical assessments were performed at baseline study visit (SV) 1 and post-induction (SV2). Patients were assessed every 6 months during maintenance therapy to 18 months (SV4). Clinical response and remission rates were determined using PRO2 definitions (STRIDE II guidelines). Logistic regression analyses were performed to identify predictors of clinical response and remission. UST levels were measured post induction and interleukin levels including IL12p40 and IL-23p19 were measured at SV1 and SV2 using ProQuantum ELISA assays. Results A total of 198 patients were recruited: median age 40.7 years, 54.3% male, median duration of disease 90.5 months, 12.8% active smokers, and 49.7% on concomitant immunomodulatory therapy. The majority (58.4%) were biologic-naïve and 82 patients were previously exposed to biologics (51.9%; IFX n=42, ADA n=50, VDZ n=9). Clinical response was achieved in 137 patients (75.7%), and remission in 84 (46.4%) with higher rates of response (85.2% vs 61.6%, p=0.001) and remission (54.6% vs 34.2%, p=0.006) in biologic naïve patients compared to biologic-exposed. For the 114 patients with 18 months (SV4) of follow-up, durable clinical response was maintained in 66.8% and remission in 50.0%. Dose escalation (90mg 4 weekly) was administered to 13 patients (6.6%) during induction, 48 (42.1%) in maintenance, and 15 patients (13.2%) received IV re-induction during maintenance. There was a significant reduction in IL-12 and IL-23 levels from SV1 to SV2 in responders (p=0.0001), but no significant reduction in non-responders (Figure 1). Clinical response at SV4 (n=101) was associated with higher post-induction UST levels (p=0.03) (Table 1). The combination of IL-12. IL-23 and UST level at SV2 predicted long-term response at SV4 (Sn 73%, Sp 71%, AUROC 0.765), but not at SV2 (Figure 2). Conclusion This large real-world study confirms that UST is most effective in bio-naïve CD patients with significantly higher response and remission rates than bio-experienced patients. The combination of post-induction IL-12, IL-23, and UST levels was associated with response at 18 months and could represent a novel predictor of long-term clinical outcomes.