Upadacitinib Is Associated With Better Clinical and Biochemical Outcomes Than Tofacitinib in Refractory, Moderate-to-Severe Ulcerative Colitis.

Oral milk-derived exosomes loaded with tafatinib for anti-inflammatory therapy.

Therapeutic effect of tofacitinib combined with leflunomide for refractory Takayasu arteritis: pilot study.

Synergistic remodeling of psoriatic immune niche via ginsenoside CK/tofacitinib co-loaded dermal targeting transfersomes.

There is limited data on advanced therapy outcomes in second-line vs. first-line advanced treatment of patients with ulcerative colitis (UC) and Crohn's disease (CD). We conducted a retrospective health claims study of patients with UC and CD in Germany. We analyzed claims data from 2014 to 2021, and compared therapy persistence and dose escalation in first- (1L) and second-line (2L) advanced therapy. Our analysis included the approved therapies adalimumab (ADA), infliximab (IFX), ustekinumab (UST) and vedolizumab (VDZ) for both UC and CD patients and golimumab (GOL) and tofacitinib (TOF) for UC patients. 2,948 patients were included in the study and initiated 1L advanced therapy. Of these, 823 patients started a 2L advanced therapy. Time on treatment was generally shorter in 2L compared to 1L: In UC patients, persistence rates at 2 years ranged from 52.5% to 71.9% for 1L, and from 40.1% to 69.1% for 2L. In CD patients, persistence rates ranged from 66.6% to 86.6% for 1L, and from 59.9% to 74.3% for 2L. We observed more frequent dose escalations in 2L than in 1L for all advanced therapies except GOL in UC patients. Our study indicates that advanced therapies have shorter persistence and require higher doses when used as 2L treatment compared to 1L treatment. Future studies on reliable response predictors in patients with UC or CD receiving advanced treatments are likely to improve the selection of more efficacious 1L therapy.

The treatment of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease (MDA5+DM-ILD) remains a significant clinical challenge. To compare the effectiveness and safety of upadacitinib (UPA) versus tofacitinib (TOFA) upon 6-month lung transplantation-free survival in newly diagnosed MDA5+DM-ILD patients. This multi-centre cohort study in China enrolled MDA5+DM-ILD patients treated from January 2020 to February 2025. Prevalent/incident new users and non-inferior design along with inverse probability treatment weighting (IPTW) were implemented to emulate randomized controlled trial. In the eligible cohort, a total of 106 patients were treated with UPA and 328 with TOFA. The crude 6-month lung transplantation-free survival rates were 71.7% (76/106) in the UPA group and 67.4% (221/328) in the TOFA group. In the IPTW-adjusted cohort, UPA showed a trend toward higher survival than TOFA (p = 0.067), with a weighted risk difference of 10.3% (95% confidence interval -0.4% to 20.2%) meeting the non-inferiority margin (non-inferiority p = 0.003). Sensitivity and subgroup analyses showed consistent results, with potentially greater benefit of UPA in incident JAK inhibitor users (as first-line treatment), monotherapy recipients (without combination with other immunosuppressants except steroid), and those with rapidly progressive ILD. Safety profiles were comparable between groups. UPA was found to be non-inferior to TOFA in improving 6-month lung transplantation-free survival among patients with MDA5+DM-ILD, with comparable safety.

Redefining Initial Rheumatoid Arthritis Treatment: Tofacitinib Outperforms Methotrexate in Disease Control-An Open-Label Randomized Controlled Trial.

Investigation of the effects of organic acids on pH-independent drug release from extended-release hydrophilic matrix tablets: A case study with tofacitinib.

Rheumatoid arthritis (RA) is characterised by systemic inflammation, which elevates the risk of atherothrombotic cardiovascular (CV) events. Although Janus kinase inhibitors (JAKi) are effective in controlling RA inflammation, post-marketing data (ORAL Surveillance) have suggested an increased risk of major adverse CV events (MACE) in patients receiving tofacitinib (TOFA). The pathophysiological mechanisms for these findings remain unclear, especially regarding platelet aggregation and tissue factor (TF) expression, two key drivers of thrombosis. In this study, we aimed to investigate the effects of TOFA on platelet aggregation and TF-mediated coagulation pathways to elucidate potential pro- or anti-thrombotic properties at the cellular level. Platelet-rich plasma (PRP) from 12 healthy volunteers was incubated with TOFA (20 or 40 ng/mL), and maximal platelet aggregation (AGGmax) in response to ADP was measured by light transmission aggregometry (LTA) at 30, 60, and 90 minutes. In parallel, platelets from 14 RA patients were evaluated at baseline and at 1, 3, and 6 months of TOFA treatment (5 mg bid). Human umbilical vein endothelial cells (HUVECs) were exposed to TOFA (20 or 40 ng/mL) and/or IL-6 (0.5 ng/mL) to assess TF mRNA (by real-time PCR) and TF procoagulant activity (by factor Xa generation assay). TOFA did not alter ADP-induced platelet aggregation ex vivo in either healthy volunteers or RA patients. However, it significantly reduced IL-6-induced TF mRNA expression and activity in HUVECs. These in vitro results suggest that TOFA may counteract IL-6-mediated prothrombotic mechanisms at the endothelial level. Despite clinical concerns raised by ORAL Surveillance, our findings indicate no direct enhancement of platelet reactivity by TOFA. Instead, TOFA attenuated IL-6-driven TF expression in endothelial cells, pointing to a possible protective effect on vascular thrombogenic pathways. Further studies are warranted to reconcile these in vitro observations with real-world data on CV outcomes in RA.

Abstract INTRODUCTION Intestinal fibrosis is a serious complication of Crohn’s disease (CD) and is caused by the excess deposition of extracellular matrix (ECM) by intestinal myofibroblasts. Currently, there are no approved treatments. Identification of potential treatments is impeded by intestinal myofibroblasts being difficult to obtain and having a limited lifespan in vitro. Human intestinal organoids (HIOs) derived from induced pluripotent stem cells (iPSCs) contain a mesenchymal cell population that is analogous to intestinal myofibroblasts. iPSCs can be generated from peripheral blood mononuclear cells (PBMCs) and proliferate indefinitely meaning an unlimited number of patient-specific mesenchymal cells can be obtained. Our goal was to use our model of CD patients’ iPSC-derived mesenchymal (iPSC-MES) cells for high-throughput screening (HTS) and compare that their responses were similar to their paired intestinal fibroblasts of each patient. Methodology PBMCs and biopsy-derived (BD) ileal and colonic fibroblasts were obtained from 6 CD patients with a history of intestinal fibrosis. All PBMCs were reprogrammed to iPSCs, directed to HIOs and the mesenchymal cell population was purified. These cells were treated with TNFα/TGFβ (TT) for 48hrs to induce ECM deposition, and the antifibrotic potential of various therapeutics was examined. Selection of potential hits compared the z-score (z) of the compounds against baseline fibrosis (TTz=0), and a significant change was defined as a z ≥|±2|. Selected hits were then examined in BD ileal and colonic fibroblasts. RESULTS Our fibrosis model of iPSC-MES found a robust antifibrotic effect from the JAK1/2 inhibitor ruxolitinib (RXz=-4.91), in all 6 iPSC-MES lines. RX produced a significant reduction in ECM deposition in iPSC-MES cells (-34.81%) and similarly in patient matched BD-ileal (-53.76%) and -colonic fibroblasts (-43.14%) (Fig.1). Moreover, proteome enrichment analysis on iPSC-MES found that while TT produced a significant increase in a fibrosis-associated pathways, RX resulted in a decrease, namely: assembly of collagen fibrils (TTNES=4.80; RXNES=-2.83) and ECM organization (TTNES=5.39; RXNES=-2.65). We then evaluated other JAK inhibitors currently prescribed for the treatment of IBD: filgotinib (FG), tofacitinib (TF) and upadacitinib (UPA). While FG (-21.13%) and TF (-16.30%) showed a significant reduction in ECM, UPA (-39.22%) had the strongest antifibrotic activity, similar to RX (Fig.2). CONCLUSION We demonstrate the feasibility of utilizing iPSC-MES cells for HTS to identify potential antifibrotic therapies. This approach overcomes the limitations of biopsy-derived myofibroblasts, illustrates the potential utility of JAK inhibitors and thus opens up a new more feasible approach for studying precision-based treatments.

To evaluate the efficacy and safety of tofacitinib (TOF) plus iguratimod (IGU) in treating progressive fibrosing rheumatoid arthritis-associated interstitial lung disease (PF-RA ILD). This historical-controlled study enrolled 28 PF-RA ILD patients (13 received TOF plus IGU; 15 received the biologic/conventional synthetic disease-modifying anti-rheumatic drugs (b/csDMARDs). Disease activity, pulmonary function (PFTs), high-resolution computed tomography (HRCT) scores, and safety were assessed longitudinally and between groups. Baseline characteristics were comparable (P>0.05). The TOF plus IGU group showed significant improvements: C-reactive protein (CRP) decreased (30.5 ± 23.1 to 5.1 ± 3.3 mg/L, P < 0.05), erythrocyte sedimentation rate: 46.2 ± 18.8 to 20.1 ± 18.9 mm/h, P = 0.012). The disease activity score 28-joint count with CRP declined from high to low activity, and rheumatoid factor titers dropped (79.7 ± 64.2 to 23.4 ± 21.7 IU/mL at 12 months, P = 0.023). Similarly, anti-cyclic citrullinated peptide levels declined from 157 ± 57.5 RU/mL to 109.8 ± 32.6 RU/mL at 6 months (P = 0.028). Pulmonary function improved, with forced vital capacity increasing from 79.5 ± 12.9% to 85.3 ± 13.6% at 6 months (P = 0.008). HRCT fibrosis scores decreased from 9.6 ± 2.5 to 5.1 ± 1.6 (P = 0.026). Compared to controls, TOF plus IGU demonstrated superior outcomes: lower CRP (8.5 vs 20.2 mg/L, P = 0.002), higher diffusing capacity for carbon monoxide at 3 months (73.1 ± 19.6% vs 61.1 ± 14.5%, P = 0.045), and lower fibrosis scores at 12 months (5.1 vs 7.5, P = 0.004). At 12 months, imaging stability/regression occurred in 92.3% vs 60.0% (P = 0.047). All TOF plus IGU patients tapered prednisone. No thromboembolic events or severe infections occurred. TOF plus IGU demonstrated dual efficacy in controlling synovitis and lung fibrosis, with a favorable safety profile.

Background/Objectives: Rheumatoid arthritis is an autoimmune disease that induces joint deformity and disability. There are great expectations for biomarkers that would predict the response to treatment. CHI3L1 and CHI3L2 are chitinase-like proteins (CLPs) which lack enzymatic activity. CHI3L1 is expressed by a variety of cells, while reports on CHI3L2 are limited. The aim of the current study is to evaluate gene and protein CHI3L1 and CHI3L2 expressions before and after treatment of patients with RA and to search for correlations with ultrasonography and conventional laboratory parameters. Methods: Twenty-four newly diagnosed RA patients (19 females and five males) were enrolled in the study. Fourteen patients were treated with tofacitinib (TOFA) and 10 patients with methotrexate (MTX) for twenty-four weeks. Conventional biochemical and immunological markers were examined at the start of the treatment and after the follow-up period. The activity of RA was assessed via the Disease Activity Score 28 (DAS28). Gene expression and protein analysis were performed. Results: Ultrasonographic and clinical laboratory parameters showed improvement after therapy in both groups. A decrease in plasma levels of CHI3L1 (p = 0.04 *) and CHI3L2 (p = 0.03 *) were found after treatment with TOFA. No changes in either protein level were detected after MTX therapy, nor were any differences discovered in the gene expression of CLPs after treatment with both therapeutics. Strong correlations between CRP, GUS7 and CLPs were also established. Conclusions: The similar dynamics of CLPs expression in naïve RA patients and their distinct interplay with disease-related parameters after therapy suggest that both proteins may display different functions in RA pathophysiology.

Abstract Background Despite the progress in advanced therapies (AT) for ulcerative colitis (UC), selecting a second-line treatment after failure remains challenging. Recent guidelines recommend Ustekinumab (UST), Tofacitinib (TOFA), or Upadacitinib (UPA) as high-efficacy options after prior AT failure. However, no real-world studies have compared all three therapies simultaneously. Methods Retrospective multicentre study (9 centres) of UC patients who failed ≥1 AT. Patients were stratified into UST, TOFA, or UPA groups and assessed at 16 and 52 weeks. The primary outcome was steroid-free clinical remission (SFCR) based on the Patient Reported Outcomes-2. Secondary outcomes included biochemical remission based on faecal calprotectin levels and endoscopic remission (Mayo Endoscopic Subscore = 0). A subanalysis assessed only second-line therapy after anti-TNF failure. Multivariable models were adjusted for demographics, disease activity and prior treatments. Results We evaluated 312 patients [57.1% female (n = 178); mean age at diagnosis 32.6 ± 8.4 years] who initiated UST (n = 135; 43.3%), UPA (n = 103; 33.0%), or TOFA (n = 74; 23.7%). Baseline disease duration and extent were comparable across groups, and 53.2% (n = 166) had failed ≥2 prior advanced therapies. In the multivariate model, at week 16, UPA had 4 times higher odds of achieving SFCR than UST (OR 3.89; p &amp;lt; 0.001) and 2 times compared to TOFA (OR 2.31; p = 0.016). At week 52, UPA showed 3 times higher odds of SFCR than UST (OR 3.34; p = 0.003) and than TOFA (OR 2.72; 0.039). UPA also achieved higher endoscopic remission at week 16 and 52 compared to UST (16w: OR 2.47; p = 0.036; 52w: OR 5.95; p &amp;lt; 0.001) and TOFA (16w: OR 5.42; p = 0.001; 52w: OR 2.64; p = 0.049). Post-hoc comparisons from the linear mixed-effects model showed that UPA achieved a higher reduction in faecal calprotectin than UST (p &amp;lt; 0.001) and TOFA (p = 0.044). In the subanalysis, UPA was superior to both UST (OR 3.00; p = 0.009) and TOFA (OR 6.11; p = 0.005) in achieving the primary outcome. Conclusion Even though all three medication demonstrated high efficacy in bio-exposed UC patients, UPA achieved better results at week 16 and 52 in this real-world study. Reference: Singh, Siddharth, et al. “AGA living clinical practice guideline on pharmacological management of moderate-to-severe ulcerative colitis.” Gastroenterology 167.7 (2024): 1307-1343. Conflict of interest: Ms. Camões Neves, Joana: No conflict of interest Costa, Dalila Amélia Amorim: No conflict of interest Cristiano, Margarida: No conflict of interest Portela, Francisco: consulting fees and support from the following companies: Abbvie, Falk, Ferring, Janssen, Lilly, Pfizer, Pharmakern, Takeda and Tillots. Fernandes, Ana Rita: No conflict of interest Fernandes, Samuel Raimundo: No conflict of interest Portugal, Margarida: No conflict of interest Gututui, Madalina: No conflict of interest Paulo, João Pedro: No conflict of interest Gonçalves, Nuno: No conflict of interest Fernandes, Daniela: No conflict of interest Costa, Catarina: No conflict of interest Madureira, Ana Rita: No conflict of interest Vaz Conde, Patrícia: No conflict of interest Damasceno, José: No conflict of interest Guimaraes, Andreia: No conflict of interest Arroja, Bruno: No conflict of interest Goncalves, Raquel: No conflict of interest Leal, Tiago Filipe: No conflict of interest

Abstract Background The effectiveness of tofacitinib (TOFA) and cyclosporine (CsA) as rescue therapy has already been proven, but there are no studies directly comparing the two agents in patients with steroid-refractory, acute severe ulcerative colitis (ASUC). Methods We conducted a single-center, real-life retrospective cohort study to assess and compare the short-term effectiveness of TOFA and CsA in ASUC patients. The co-primary outcomes were week 2 and 8 clinical remission rates defined as partial Mayo score &amp;lt;2 with a rectal bleeding subscore of 0 and C-reactive protein ≤5 mg/L. The secondary outcomes were colectomy and relapse rates within 24 weeks of rescue therapy. Relapse was defined as the need for treatment modification or escalation, IBD-related hospitalization, and/or colectomy. Inverse probability weighting analysis (IPTW) was performed for age, disease extent, baseline pMayo, baseline CRP, as well as concomitant local and/or systemic corticosteroid use between the two treatment groups. Results A total of 198 patients (106 TOFA, 92 CsA; mean age: 34.9 + 14.5 years; 43.9% male) were enrolled in the study. After IPTW analysis, there was no statistically significant difference between TOFA and CsA treated patients regarding the probability of achieving clinical remission at weeks 2 (OR:0.63, 95% CI: 0.39-1.04, p = 0.07) and 8 (OR:1.1, 95% CI: 0.72-1.67, p = 0.66). However, the risk of relapse within 24 weeks of rescue therapy was more than twofold higher in patients receiving CsA compared to those receiving TOFA (OR:2.10, 95% CI: 1.21-3.66, p = 0.01). Furthermore, the risk of early colectomy was also significantly higher among CsA-treated patients than in the TOFA-treated group (OR:2.78, 95% CI: 1.22-6.34, p = 0.02). No new safety signal was noted. Conclusion Based on our real-life data, TOFA rescue treatment might be more effective than CsA in preventing urgent colectomy and early relapse in patients with steroid-refractory ASUC. Conflict of interest: Dr. Farkas, Bernadett: No conflict of interest Resál, Tamás: No conflict of interest Bacsur, Péter: No conflict of interest Ivány, Emese: No conflict of interest Gálfalvi, Noémi: No conflict of interest. Pápista, Máté: I have no Conflict of interest to declare. Farkas, Klaudia: No conflict of interest Molnár, Tamás: Conflict of interest: Tamás Molnár has received speaker’s honoraria from MSD, AbbVie, Egis, Goodwill Pharma, Takeda, Pfizer, Janssen, Sandoz, Phytotec, Roche, Fresenius, Teva, Celltrion, Stada, BMS, Ferring, EwoPharma and SOBI

Abstract Background Although several therapeutic strategies exist for the treatment of Ulcerative colitis (UC), their efficacy is still far from optimal. The JAK/STAT signalling pathway has emerged as a promising therapeutic target. Tofacitinib (TOFA), an oral JAK inhibitor, is the first approved small molecule for the induction and maintenance of remission in moderate-severe UC. However, potential predictive markers for therapeutic response to TOFA are currently lacking. Therefore, we aimed to assess the mucosal expression of JAK/STAT and cytokine levels in UC patients treated with TOFA to identify potential predictive markers of therapeutic response. Methods This prospective study included patients with UC who initiated TOFA therapy. Clinical indices, laboratory parameters, and colonoscopy were evaluated at baseline and after a 12-week treatment period. RNA and total protein were isolated from colonic biopsies. qRT-PCR was applied for the investigation of the JAK/STAT signalling pathway. Mucosal protein levels of TNF-a, IL-6, IL-1b, IL-4, IL-17A, IFN-g, and PAI-1 were determined by multiplex ELISA. Results A total of 49 patients with UC were enrolled, with 75.5% completing the 12-week follow-up. Among these, 63.3% responded to TOFA. The clinical and endoscopic remission rates were 69.4% and 32.6%, respectively. Primary non-response was identified in 24.5% of patients, while 36.7% experienced loss of response. In responders, serum CRP levels as well as pMayo and eMayo scores decreased significantly. TOFA responders also showed significant downregulation of STAT1 and JAK2 gene expression. Mucosal protein levels of IL-6, IL-1β, IFN-γ, IL-17A, and PAI-1 were markedly reduced in these patients. Baseline concentrations of IL-6, IL-4, and PAI-1 were significantly lower among responders. Patients achieving steroid-free remission exhibited lower baseline levels of IL-1β, IL-4, and PAI-1, whereas elevated IL-1β levels were significantly associated with loss of response. Moderate correlations were detected between pMayo scores and levels of TNF-α, IL-6, IL-1β, and IL-17A, while weaker correlations were observed with eMayo scores. The strongest associations were found between mucosal PAI-1 levels and both pMayo (r = 0.55) and eMayo (r = 0.52) scores. Serum CRP levels showed moderate correlations with cytokine concentrations. Conclusion TOFA treatment proved effective in over 60% of patients, with nearly 70% achieving clinical remission. Lower baseline mucosal protein levels of IL-1b, IL-6, IL-4, and particularly PAI-1, may serve as potential predictors of treatment response. Among these markers, PAI-1 showed the strongest association with both clinical and endoscopic disease activity, highlighting its value as a predictive and monitoring biomarker in UC. Conflict of interest: Dr. Jójárt, Boldizsár: I have no conflict of interest. Resál, Tamás: No conflict of interest Kajári, Lilian: No conflict of interest Bacsur, Péter: No conflict of interest Molnár, Tünde: No conflict of interest Ivány, Emese: No conflict of interest Gémes, Nikolett: No conflict of interest Kemény, Ágnes: No conflict of interest Szebeni, Gábor: No conflict of interest Pallagi, Petra: No conflict of interest Farkas, Klaudia: No conflict of interest Maléth, József: No conflict of interest Molnár, Tamás: Conflict of interest: Tamás Molnár has received speaker’s honoraria from MSD, AbbVie, Egis, Goodwill Pharma, Takeda, Pfizer, Janssen, Sandoz, Phytotec, Roche, Fresenius, Teva, Celltrion, Stada, BMS, Ferring, EwoPharma and SOBI

Abstract Background Tofacitinib (TOFA), an oral Janus kinase inhibitor, is approved for moderate to severe ulcerative colitis (UC). The aim of this study was to evaluate the effectiveness and safety of dose escalation and de-escalation of TOFA in clinical practice. Methods In this retrospective cohort study, we included UC patients treated with TOFA between January 2018 and July 2023 in the Capital Region of Denmark (≈ 33% of the Danish population). The primary outcome was clinical remission (SCCAI ≤2) and secondary outcomes were steroid-free clinical remission (SFR), secondary loss of response (SLR) and safety. Outcomes were assessed at weeks 8 (W8), 16, 28, and 52 (W52). Logistic regression analyses examined predictors of clinical response/remission at W8 and SFR at W52, while Cox proportional-hazards models evaluated predictors of SLR and SFR, with emphasis on the impact of dose modifications on the clinical outcomes. Results A total of 85 patients were included (Table 1). Clinical remission and SFR were achieved in 43.4% and 34.9% at W8, and 35.3% and 29.4% at W52, respectively. One-third (N = 26 [30.6%]) were unable to de-escalate dosing after induction; however, 60.0% (N = 6) of the patients who were without prior clinical remission achieved so within four months and de-escalated TOFA dosing. Among patients requiring dose escalation due to SLR (N = 16 [18.8%]), seven (43.8%) recaptured clinical remission. In Cox analyses, TOFA dosing did not significantly influence SLR (HR 1.86 [95% CI 0.82–4.25]) nor SFR at 52 weeks (continued high-dose 57.1% vs. de-escalation 47.8%, p = 0.71; HR 1.13 [95% CI 0.53–4.45]). Early clinical response and remission at W8 was the only clinical factor associated with SFR at W52 (OR 46.3, 95% CI 8.78–856.61, p &amp;lt; 0.001). No serious adverse events occurred; however, 40 patients (47.1%) experienced adverse events, with no significant association with dosing escalations, most commonly including hypercholesterolemia, anaemia, nausea, and few cases of herpes zoster reactivation (N = 3 (3.5%)). Conclusion This real-world multicentre study demonstrates that TOFA is effective and safe for inducing and maintaining clinical remission in bio-exposed patients with refractory UC. Dose de-escalation after induction and escalation for SLR were feasible, with no clear long-term efficacy difference between strategies and no new safety concerns. Individualized dosing of TOFA dependent on induction response to improve long-term outcome was in this study safe. Conflict of interest: Ms. Mirza, Hina: No conflict of interest Toma, Maria Bassam Mati: No conflict of interest Rasmussen, Michelle Bjørnshauge: No conflict of interest Seidelin, Jakob Benedict: has received research grants from Takeda, Janssen, the Danish Research Council, and the Capital Region Denmark, and is national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim. Attauabi, Mohamed: Research grants from Novo Nordisk Fonden and Lundbeck Foundation. Personal fees from Eli Lilly, Celltrion, and Lundcbeck foundation, outside the submitted work.

Abstract Background Tofacitinib (TOFA) and Upadacitinib (UPA) are inhibitors of Janus Kinases (JAKi) with different target specificities, as TOFA inhibits JAK1 and JAK3, while UPA primarily targets JAK1. Aim of the present study was to record the efficacy of UPA in patients with active ulcerative colitis (UC), who had previously been treated with TOFA. Methods This prospective cohort study included patients with active moderate-to-severe UC, who initiated UPA after 1/1/2024 and who had previously been treated with TOFA. Each patient was treated with 45mg daily for the 8-week induction period, followed by 45, 30 or 15mg as maintenance dose. Our primary end-point was clinical remission (Clin-Rem) [PRO-Rectal bleeding = 0 and PRO-bowel movement = 0] at week 24. Secondary end-points were clinical response (Clin-Resp) [drop of at least 50% of the baseline PROs], Clin-Rem and corticosteroid-free clinical remission (Cs-F-Rem) at week 8, Clin-Resp, Cs-F-Rem, endoscopic improvement and mucosal healing [endoscopic MAYO = 0] at week 24, maintenance dose of UPA and adverse events on treatment. Data were analyzed using SPSSv23. Results We have included 32 patients [23 male, mean age:39.4 years (SD = 13.7), median disease duration:5.9 years (IQR:4.1-10.3)]. The majority of the patients (59.4%) were exposed to ≥ 3 advanced treatments and 8 (25%) to ≥ 4. TOFA was discontinued in 15 (46.9%) patients due to primary non-response and in 17 (53.1%) due to secondary loss of response with a median treatment duration of 10 months (IQR:4.3-18.4). At week 8, 24 (75%) patients achieved Clin-Resp and 11 (34.4%) Clin-Rem. Twenty-three patients commenced maintenance treatment with 30mg daily, one with 15mg and 6 patients required extended induction with 45mg daily. At week 24 Clin-Rem was achieved by 13 (40.6%) patients. Detailed rates for the secondary end-points are presented in the Figure. Clin-Rem at week 24 significantly correlated with older age (OR = 1.06, 95%CI:1.00-1.13) and showed a tendency for association with E3 Montreal classification (OR = 0.22, 95%CI:0.05-1.06), PRO-”bowel movement” (OR = 0.40, 95%CI:0.15-1.07) and baseline endoscopic MAYO score (OR = 0.26, 95%CI:0.07-1.00). Clin-Resp at week 4 (11/18 vs 0/11, P = 0.001), as well as Clin-Resp (13/24 vs 0/8, P = 0.007) and Clin-Rem (9/11 vs 4/21, P = 0.001) at week 8 were predictive of Clin-Rem at week 24. Adverse events occurred in 10 (31.3%) patients with hyperlipidemia being the most prevalent in 7 patients. Conclusion In this cohort of refractory patients who were exposed to tofacitinib, Upadacitinib showed remarkably good response rates. Younger age and higher disease burden at initiation decrease the probability of clinical remission, while early clinical response and remission appear to predict persistence of clinical remission. Conflict of interest: Dr. Kokkotis, Georgios: No conflict of interest Kitsou, Vasiliki: No conflict of interest Ioannou, Alexandros: No conflict of interest Striki, Athanasia: No conflict of interest Lakiotaki, Dimitra: No conflict of interest Mousourakis, Konstantinos: No conflict of interest Kyriakos, Nikolaos: No conflict of interest Fousekis, Fotios: No conflict of interest Athanasiadou, Eftychia: No conflict of interest Vlachou, Evangelina: No conflict of interest Viazis, Nikolaos: No conflict of interest Zampeli, Evanthia: I have received honor-aria and speaker fees from Abbvie, Janssen, Pfizer,Takeda, MSD, AMGEN, Genesis, Ferring, Mylan, BMS, Galenica Liatsos, Christos: No conflict of interest Michalopoulos, George: speaker fees TAKEDA, ABBVIE, MSD, GALENICA, ENORASIS, AMGEM PFEIZER Karatzas, Pantelis: No conflict of interest Karmiris, Konstantinos: Personal Fees: Speaker fees from Abbvie, BMS, Eli-Lilly, Genesis, Innovis, Johnson &amp; Johnson, Pfizer and consultancy or advisory board member fees from Abbvie, BMS, Faran, Ferring, Genesis, Johnson &amp; Johnson, Pfizer, Roche and Takeda Theodoropoulou, Angeliki: No conflict of interest Soufleris, Konstantinos: No conflict of interest Koutroubakis, Ioannis E.: No conflict of interest Tzouvala, Maria: No conflict of interest Katsanos, Konstantinos: AbbVie, Amgen, Athos, Αenorasis, Biocon,Biogaia, Drugssales Ltd, Epsilon Health, Falk, Faran, Ferring, Genesis, Grifols S.A., Hospital line, Johnson &amp; Johnson, COPER, MSD, Biocon, Pfizer, Potamitis Medicare, Rafarm, Petsiavas, Shire,Takeda, Vianex, Lilly Giouleme, Olga: No conflict of interest Bamias, Giorgos: Grants: Grants from Takeda, AbbVie, Mylan/Viatris/Biocon, Genesis Pharma, Ferring, Vianex, and Aenorasis Consulting Fees and Speaker Honoraria: AbbVie, Adacyte Therapeutics, Amgen, Bristol Myers Squibb, Faran, Ferring, Galenica, Genesis Pharma, J &amp; J, Lilly, MSD, Mylan/Viatris/Biocon, Pfizer, Shattuck Labs, Takeda, Vianex

Abstract Background As therapeutic options for ulcerative colitis (UC) expand, real-world data are needed to understand durability of different advanced therapies (ADV) beyond initial treatment lines. Longer-term outcomes in bio-experienced individuals remain poorly characterised. We evaluated persistence—a pragmatic measure of ongoing effectiveness across six ADVs—in bio experienced people with UC and assessed predictors of persistence. Methods Prospectively collected routine-care data from the Crohn’s Colitis Care (CCCare) registry were analysed. Adults with UC and prior ADV exposure who commenced a subsequent maintenance course (standard or dose-escalated) of adalimumab (ADA), infliximab (IFX), ustekinumab (UST), vedolizumab (VDZ), upadacitinib (UPA) or tofacitinib (TOF) were included. All courses up to 30 October 2025 were eligible. The primary outcome was treatment persistence, assessed with Kaplan–Meier curves; predictors of persistence were evaluated using univariate and multivariable Cox models. Results A total of 402 maintenance courses were analysed in 280 individuals. Median age at course commencement was 35.5 years; 52.0% were in males. Median disease duration was 7.7 years and follow-up 4.9 years. Most had left-sided or extensive colitis. Courses were predominantly second-line (66.4%), and 41.8% were dose-escalated from initiation, most commonly with UPA (61.2%, p &amp;lt; 0.001). UPA and UST were the most common second-line agents (22.8% and 23.2%) while later lines were increasingly dominated by UPA (47.4% third-line; 37.5% fourth-line). Concomitant 5-ASA use in UPA (24%) was significantly lower than IFX (45%), VDZ (47.7%) and ADA (55.6%; p &amp;lt; 0.001). Concomitant IMS use in UPA (4.1%) was the lowest across therapies, though not significantly different from TOF (12.0%). In the bio-experienced cohort, 24-month persistence ranged from 43.6% (ADA) to 69.7% (VDZ), without a significant difference between therapies (p = 0.16). In pairwise Cox analyses, subsequent therapy with VDZ showed a consistent trend toward lower discontinuation risk versus other ADVs (HRs 0.51–0.61), although none reached statistical significance. In multivariable modelling, independent predictors of discontinuation were dose escalation (HR 1.84, 95% CI 1.10–3.11) and concomitant systemic steroid use (HR 1.71, 1.14–2.55). Conclusion In this large, multicentre real-world UC cohort, no ADV as second or subsequent choice demonstrated superior persistence, although VDZ had a non-significant trend toward greater persistence. Dose escalation at initiation and systemic steroid use were strong predictors of shorter persistence, identifying individuals with more severe or higher-risk disease who may benefit from proactive monitoring and treatment optimisation. Conflict of interest: Wu, Rodger: No conflicts Ghali, Mark: No conflicts. Wilson, William: No conflict of interest Caquilpan, Victor: No conflict of interest Rivas, Consuelo: No conflict of interest Lynch, Kate: Kate Lynch has received speaker honoraria, advisory board fees, and/or conferencetravel/registration support from AbbVie, Bristol-Myers Squibb (BMS), Chiesi, Dr. Falk, Ferring, Gilead, Guidepoint, Intercept Pharmaceuticals, Janssen-Cilag, Merck Sharp &amp; Dohme (MSD), Norgine, Pfizer, Pliant, Sandoz, Takeda, and the Royal Adelaide Hospital (RAH) Research Fund. Haifer, Craig: Grant: Grants from St Vincent’s Clinic Foundation, Gastroenterological Society of Australia, Gutsy Group, Royal Australasian College of Physicians and Ferring. Personal Fees: CH has received speaker fees and educational support from Janssen, Pfizer, Takeda, Ferring and Abbvie. Walker, Gareth: In the last 24 months, Dr Walker has received investigator grants or served as a speaker, a consultant or an advisory board member for: Janssen AbbVie Takeda Ferring Dr Falk Pharma Georgiamune Radford-Smith, Graham Lindsay: No conflict of interest Lawrance, Ian Craig: No conflict of interest Begun, Jakob: I have received honoraria or consulting fees from Abbvie, Janssen, Takeda, Pfizer, Ferring, Bristol Myers Squibb, Gilead, Tillott’s, Sandoz, Celltrion, Chiesi, Dr Falk, Microba, Glaxo Smith Klein, Antara, Suono, Therpeutic Guidelines, Research Review,Grants: NHMRC, US Department of Defence, The Gutsy Foundation, The Gastroenterological Society of Australia, The University of Queensland, The Viertel Foundation, and The Mater Foundation Wark, Gabrielle: Conference travel/registration support from Dr Falk Verdon, Christine: No conflict of interest Andrews, Jane Mary: Grant: The work I will present was funded svia CCCure. CCCure’s funding sources include grants for research and payments for data reports from Pharma including AbbVie, J &amp; J, Takeda, Celltrion, Falk, Ferring, BMS, Janssen, Pfizer, Sandoz 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. Connor, Susan Jane: Grant: Research Support: Abbvie, Agency for Clinical Innovation, Amgen, BMS, Chiesi, Celltrion, Dr Falk, Ferring, Janssen, Medical Research Future Fund, Pfizer, South Western Sydney Local Health District, Sydney Partnership for Health, Research and Enterprise, Takeda and The Leona M and Harry B Helmsley Charitable Trust Personal Fees: Ad Boards: Abbvie, Amgen, BMS, Celltrion, Eli Lilly, Ferring, GSK, Janssen, Organon, Pfizer, Takeda Speaker Fees: Abbvie, Cornerstones Health, Dr Falk, Ferring, Janssen, Pfizer, Sandoz, Sydney IBD School, Takeda Educational Support: DrFalk, Sandoz, Takeda

ObjectivesTo compare the 2-year clinical effectiveness of the four globally approved Janus kinase inhibitors (JAKis; tofacitinib (TOF), baricitinib (BAR), upadacitinib (UPA) and filgotinib (FIL)) in patients with rheumatoid arthritis (RA) in real-world settings.MethodsThis retrospective cohort study used data from FIRST registry, a multicentre registry of patients with RA. The primary endpoint was the change in Clinical Disease Activity Index (CDAI) score at year 2. Secondary endpoints included changes in individual CDAI components, patient-reported outcomes (PROs) and reasons for JAKi discontinuation. Multivariable mixed-effects models adjusted for baseline characteristics were used to compare the four JAKis.ResultsA total of 607 treatment courses with JAKis (TOF: 159, BAR: 262, UPA: 122, FIL: 64) were included. Baseline characteristics differed notably among treatment groups: UPA and FIL were frequently used as the second-line JAKis for older patients with comorbidities. The 2-year overall retention rate was 78%. The most common reason for discontinuation was insufficient effectiveness, with 6.5/100 person-years (py), followed by adverse events of 4.2/100 py. As-observed analysis demonstrated the slower improvement in the UPA and FIL groups. However, multivariable analysis revealed no significant differences in CDAI or PROs. The UPA group demonstrated greater improvement in two CDAI components: tender joint count and evaluator’s global assessment.ConclusionThis real-world study found no clinically meaningful differences in 2-year effectiveness among four JAKis, although the study was not powerful enough to detect differences in safety. Further long-term, real-world data are needed to evaluate the safety of these agents and refine their risk-benefit profiles.

Background and aim: Tofacitinib (TOF), filgotinib (FIL), and upadacitinib (UPA) are approved Janus kinase inhibitors (JAKis) for ulcerative colitis (UC), but real-world comparative data remain limited. This study assessed their efficacy, persistence, and safety in regional Japanese hospitals.Methods: We retrospectively analyzed 148 UC treatment sessions (TOF, 60; FIL, 53; UPA, 35). The primary outcome was clinical remission (partial Mayo score ≤1 with rectal bleeding score 0). Secondary outcomes included clinical response, steroid-free remission, and treatment persistence. Adverse events and biologics (Bio)/JAKi subgroup data were collected.Results: At week 8, clinical remission rates were similar for TOF (46%), FIL (44%), and UPA (46%). At week 24, FIL had the highest remission rate (61%) vs. TOF (46%) and UPA (41%), a trend that continued at week 48 (59%, 41%, 44%). FIL also showed the highest remission in both Bio/JAKi-naïve and failure sessions at weeks 24 and 48. UPA had the highest clinical response at week 8 (67%). TOF showed stable remission over time (46%, 46%, 41%). Steroid-free remission was more frequent with FIL at weeks 24 (61%) and 48 (59%) than with TOF (46%, 41%) or UPA (35%, 33%). Persistence was similar across agents through week 24. Safety profiles aligned with prior data, though rare events such as Pneumocystis jirovecii pneumonia and interstitial pneumonia were noted.Conclusions: FIL showed favorable remission rates, especially in Bio/JAKi-naïve patients, and remained effective after prior failures, suggesting broad applicability. UPA and TOF showed similar remission rates in our cohort.