Introduction

In perianal fistulizing Crohn’s disease (PFCD), higher infliximab (IFX) serum trough concentrations are associated with improved outcomes. Most PFCD patients require dose intensification to achieve therapeutic target concentrations. IFX pharmacokinetics (PK) in PFCD have not been previously characterized. We hypothesized that IFX clearance (CL) is increased in PFCD compared to Crohn’s disease with luminal disease only (CD).

Aims & Methods

Patients with CD and PFCD starting standard-dose intravenous IFX (5 mg/kg at week 0, 2, 6, thereafter every 8 weeks) were enrolled. Pre-infusion samples were collected from week 2 to 26 to measure IFX trough levels (TL), and anti-drug antibodies if IFX TL was below 1.0 μg/mL. Target TL were 20 μg/mL (week 2), 15 μg/mL (week 6), and 10 μg/mL (week 14) for PFCD, and 5.0 μg/mL (week 14) for CD. A population PK model was constructed using nonlinear mixed-effects modeling and adjusted for clinically relevant covariates.

Results

A total of 148 patients were included (63 PFCD, 85 CD), contributing 761 serum samples. Baseline demographics were comparable, except for higher luminal disease activity and concomitant immunomodulator use in CD. During induction, target IFX TL were achieved in significantly fewer PFCD patients (43% vs. 57%, P = .038). At week 14, median IFX TLs were lower in PFCD (2.8 μg/mL [IQR 1.0-5.4] than in CD (4.8 μg/mL [IQR 2.0–6.6], P = .014), with target TL attainment in only 9% of PFCD versus 46% of CD patients (P < .001). In multivariate regression analysis, PFCD was independently associated with a sevenfold increased risk of underdosing at week 14 (adjusted risk ratio [aRR] = 7.14, P < .001). Anti-drug antibodies (ADA) against infliximab were detected in 10/19 (53%) of PFCD patients and 9/25 (36%) CD patients with IFX TL below 1 μg/mL (P = .36) after a median of 20 weeks, with 35% of cases being transient during follow-up. While more PFCD patients had very low infliximab levels at week 14 (<1 μg/mL; 22% vs. 10%, P = .07), ADA presence and median ADA levels at that time did not differ significantly between these groups (P = .99 and P = .25, respectively).
IFX PK was described by a two-compartment model with linear elimination. Population PK modeling of the first 14 weeks revealed an 18% increase in IFX CL among patients with active perianal fistulas adjusted for dose, weight, serum albumin and presence of anti-drug antibodies (P < 0.01).

Conclusion

Active perianal fistulas are independently associated with increased infliximab clearance in patients with Crohn’s disease, resulting in significantly lower and frequently subtherapeutic serum trough levels despite standard induction dosing. At week 14, patients with PFCD had a sevenfold higher risk of underexposure compared to those with luminal CD only. These findings highlight a critical need for intensified or personalized infliximab dosing strategies during induction in PFCD to optimize therapeutic exposure and improve clinical outcomes.

Introduction

Evidence from rheumatology supports a within-class treatment switch for JAK-inhibitors (JAKi) but less is known for patients with ulcerative colitis (UC). We aimed to assess the effectiveness and safety of using a second JAKi in patients with UC already experienced to a single JAKi.

Aims & Methods

We carried out a multicentre retrospective observational study across 45 Centres. We included patients with UC starting a second JAKi after prior exposure to a first JAKi and with a minimum follow-up of 12 weeks. The primary outcome was steroid-free clinical remission (SFCR) (stool frequency subscore≤1 and rectal bleeding subscore=0 without any steroid formulation) at week 12. Secondary outcomes included SCFR at week 26 and 52, clinical response (decrease of≥1 point in rectal bleeding and stool frequency subscores from baseline) at week 12, biochemical remission (faecal calprotectin<250μg/g) at week 12, 26 and 52, endoscopic improvement (Mayo≤1) and endoscopic remission (Mayo=0) at early (<26 weeks) and late (52±8 weeks) timepoints. Adverse events were recorded. Univariate and multivariate logistic regressions were performed. Non-responder imputation was applied for missing data.

Results

We included a total of 243 patients, whose main characteristics are reported in Table:

Baseline characteristics			Switch information
Males [number (n)]		138 (57%)	Switch direction (n)	Tofacitinib to Upadacitinib	165 (68%)
Age [years, median (interquartile range)]		36 (25-49)		Tofacitinib to Filgotinib	23 (10%)
Extensive colitis (n)		145 (60%)		Filgotinib to Upadacitinib	47 (19%)
History of EIMs and/or other IMIDs (n)		73 (30%)		Other	8 (3%)
Bio-experienced (n)		237 (98%)	Reason for discontinuation of first JAKi (n)	Primary failure	97 (40%)
Second JAKi (n)	Tofacitinib	7 (3%)		Secondary loss-of-response	119 (49%)
	Filgotinib	24 (10%)		Adverse event	19 (8%)
	Upadacitinib	212 (87%)		Remission	8 (3%)

Two hundred-sixteen (89%) and 136 (56%) patients had available data for week 26 and 52, while 221/243 (91%), 176/216 (81%), and 108/136 (79%) were still on treatment at week 12, 26 and 52, respectively. At week 12, 116 patients (48%) had SFCR. At univariate analysis, patients who discontinued the first JAKi due to secondary loss of response were more likely to achieve SFCR at week 12 compared to those with primary failure to the first JAKi (OR 1.89; 95%CI 1.09-3.26, p=0.02), although this was not confirmed at multivariate analysis. A higher clinical disease activity and concomitant steroid use at baseline were associated with reduced chance of week 12 SFCR at both univariate (OR 0.69; 95%CI 0.61-0.80, p<0.01 and OR 0.17; 95%CI 0.09-0.30, p<0.01, respectively) and multivariate (OR 0.74; 95%CI 0.64-0.87, p<0.01 and OR 0.24; 95%CI 0.13-0.45, p<0.01, respectively) analyses. At week 12, 50% and 37% of patients had clinical response and biochemical remission, respectively. At week 26, 49% and 33% of patients had SFCR and biochemical remission, respectively. At week 52, 28% and 21% of patients reached the same outcomes. Endoscopic remission was reported in 20/92 (22%) and 27/79 (34%) of patients at the early and late timepoint, respectively, while endoscopic improvement in 51/92 (55%) and 45/79 (57%). Of the 67 patients who discontinued the treatment, the majority (87%) had a primary or secondary failure. Finally, we observed 66 adverse events in 56 (23%) patients, predominantly acne (38%) and upper respiratory tract infections (24%), without major cardiovascular or venous thromboembolic events.

Conclusion

Treatment with a second JAKi is effective and safe in patients with UC already exposed to JAKi. Primary failure to a first JAKi and steroid use at initiation of the second JAKi might be associated with a reduced probability of success with a second JAKi.

Disclosure

Tommaso Innocenti reports speaker’s fees from Ferring. Jurij Hanžel reports speaker's fees from Abbvie, Eli Lilly, and Takeda, and consulting fees from Alimentiv Inc and Janssen. Hannah Gordon reports consulting fees from AbbVie, Galapagos, Takeda, J&J, and speaker fees from AbbVie, Ferring, IBDscope, J&J and Takeda. Anneline Cremer reports speaker and/or consultancy fees from Pfizer, Abbvie, Celltrion, Johnson & Johnson, Takeda and Alfasigma. Alessia Todeschini served as a speaker and/or advisory board member for Abbvie, Janssen, Ferring, Celltrion, Lion Health. Olga Maria Nardone served as advisory board member for Nestle and J&J, and as a speaker for AbbVie, J&J, Ferring, Eli Lilly, Pfizer, Alfa Sigma, Noòs. Flavio Caprioli served as consultant to Abbvie, MSD, Takeda, Janssen, Roche, Celgene, Bristol-Meyers Squibb, Galapagos, Gilead, Pfizer, Mundipharma, Biogen, Ferring, Eli-Lilly, Nestlè, Lionhealth, AlfaSigma, Dr Falk, Celltrion, received lecture fees from Abbvie, Ferring, Takeda, Allergy Therapeutics, Janssen, Pfizer, Biogen, Sandoz, Tillotts Pharma, Vifor Pharma, AlfaSigma, Celltrion, and unrestricted research grants from Giuliani, Sofar, MSD, Takeda, Abbvie, Celltrion, Pfizer, Actial. Franco Scaldaferri reports funding from Janssen, Abbvie, Takeda, Lilly, Pfizer, Ferring, Sandoz, Celltrion, Sanofi, MSD, Alfasigma, Abivax. Charlotte RH Hedin served as a speaker and/or advisory board member for AstraZeneca, Abbvie, Dr Falk Pharma and the Falk Foundation, Galapagos, Janssen, Pfizer, Ferring, Takeda, Tillotts Pharma, and received grant support from Tillotts and Takeda. Annalisa Aratari served as advisory board member for Takeda, Galapagos, Pfizer, Abbvie. Alice De Bernardi has served as a speaker/advisory board member for Johnson & Johnson and Malesci. Konstantinos Karmiris has served as speaker, consultant and/or advisory board member for Abbvie, Amgen, Bristol Myers Squibb, Ferring, Galenica, Genesis, Janssen, MSD, Pfizer, Roche, Takeda and Vianex. Ana Gutierrez Casbas has served as speaker, consultant and/or advisory board member for Abbvie, Ferring, FAES, J&J, MSD, Pfizer, Fresenius, Takeda, Celltrion, Kern Pharma, Adacyte, Falk, Lilly and Sandoz. Carla Felice served in advisory board for AbbVie and Johnson & Johnson. Daniela Pugliese served ad Advisory board member and/or consultant for Abbvie, Galapagos, Johnson & Johnson, Takeda, Alfasigma, Pfizer. Lieven Pouillon received advisory board fees from AbbVie, Alphasigma, Celltrion, Galápagos, Janssen-Cilag, Sandoz and Takeda; consultancy fees from Ipsos NV and Ismar Healthcare funded by Viatris; presentation fees from AbbVie, Alphasigma, Celltrion, Eli Lilly, Ferring, Galápagos and Pfizer; and personal fees (congress support) from AbbVie, Ferring, Galápagos, Janssen-Cilag, Norgine and Takeda. Gerassimos Mantzaris reports speaker fees or consultancy fees from Aenorasis, AbbVie, BMS, Celtrion, CUBE, Falk Pharma, Ferring, Genesis, Janssen, MSD, Pfizer, Sandoz, Takeda, και Vianex, and research grants from AbbVie, Ferring, MSD, and Vianex. Gabriele Dragoni reports speaker fees from Alfasigma, Ferring, Johnson & Johnson, Novartis, Pfizer, and Takeda, and has served in advisory board for AbbVie, Celltrion Healthcare, Eli Lilly, Johnson & Johnson and Pfizer. The other authors have no conflict of interests to declare.

Introduction

Difficult-to-treat Crohn’s disease (CD), as defined by the International Organization for the Study of IBD (IOIBD), encompasses patients with persistent disease activity despite advanced therapies, complex phenotypes (e.g., penetrating complications), or post-surgical recurrence. Upadacitinib, a selective JAK1 inhibitor, has demonstrated efficacy in Western populations, yet data in Asian cohorts remain sparse. This study evaluates the effectiveness and safety of standardized induction regimen of upadacitinib (45mg qd) in Asian patients meeting IOIBD criteria for difficult-to-treat CD.

Aims & Methods

To assess the efficacy and safety of upadacitinib in Asian patients with difficult-to-treat CD, providing evidence for clinical decision-making, a retrospective, multicenter study was conducted from 8 Chinese tertiary centers (January 2023–January 2025) on difficult-to-treat Crohn’s disease patients who met IOIBD criteria. All patients received upadacitinib 45mg qd for 12 weeks. Clinical outcomes were assessed using the Crohn's Disease Activity Index (CDAI), with the primary outcome being clinical remission (CDAI <150) and the secondary outcome being clinical response (CDAI reduction ≥70) at week 12. Adverse events (AEs) were systematically recorded.

Results

We finally collected 151 patients who met IOIBD criteria(Table1). Among them, 147 patients presented failure of ≥2 biologics with distinct mechanisms, 3 patients had complex perianal disease and 1 patient had postoperative recurrence. The mean disease duration of these patients was 7.6 years (SD 4.5 years). At week 12, 71 patients (47.0%) achieved clinical remission, 66 patients (43.7%) showed clinical response, and 14 patients (9.3%) were non-responders. Adverse events occurred in 40 patients (26.5%): acne (n=13), anemia (n=13), leukopenia (n=3), fever (n=4), urinary tract infection (n=2), herpes zoster (n=2), folliculitis (n=1), amenorrhea (n=1), elevated creatine phosphokinase (n=1), and mediastinal tuberculosis (n=1). Most AEs were mild and resolved with oral medications.

Table1. Baseline Characteristics of Patients with Difficult-to-Treat CD Treated with UPA

Patient characteristics		N=151
Age, median (IQR) (start of UPA)		32.4（16-71）
Female sex		61（40.4%）
CD location(N=151)		CD behavior(N=151)
L1	14（9.3%）	B1	30（19.9%）
L2	5（3.3%）	B2	85（56.3%）
L3	132（87.4%）	B3	48（31.8%）
L4	21（13.9%）	Perianal disease	87（57.6%）
Previous Immunomodulator usage（N=151）		104（68.9%）
Previous Corticosteroid usage（N=151）		100（66.2%）

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Conclusion

This is the largest Asian cohort study of upadacitinib for difficult-to-treat CD. The drug demonstrated robust efficacy and a favorable safety profile. Notably, tuberculosis reactivation was rare. Standard dosing showed comparable effectiveness and tolerability to European data, underscoring upadacitinib as a strong therapeutic option in Asian populations.

References

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2. Parigi TL, Massimino L, Carini A, et al. Prevalence, Characteristics, Management, and Outcomes of Difficult-to-Treat Inflammatory Bowel Disease. J Crohns Colitis. 2025;19(3):jjae145. doi:10.1093/ecco-jcc/jjae145
3. Bezzio C, Franchellucci G, Savarino EV, et al. Upadacitinib in Patients With Difficult-to-Treat Crohn's Disease [published correction appears in Crohns Colitis 360. 2025 Mar 25;7(1):otaf022. doi: 10.1093/crocol/otaf022.]. Crohns Colitis 360. 2024;6(4):otae060. Published 2024 Oct 24. doi:10.1093/crocol/otae060
4. Devi J, Xu A, Stone M, et al. Real-World Effectiveness and Safety of Upadacitinib in Crohn's Disease: A Multicenter Study. Clin Gastroenterol Hepatol. Published online March 8, 2025. doi:10.1016/j.cgh.2025.01.012