Introduction

Mucosa protective effects can be mediated by physical as well as by anti-inflammatory mechanisms of action. For the root extract of marshmallow (Althaea officinalis L., REAo), known to cure mild irritation of stomach/gut mucosa [1], only a physical action had been considered. Recent studies have shown that it also induces regeneration of irritated mucosa [2,3]. Mucosal wound healing depends on the recruitment of several cell types, e.g., endothelial cells, fibroblasts, and macrophages (MΦ). Reactive oxygen species (ROS)-induced damage is associated with mucosal infiltration of activated leukocytes, such as MΦ, which produce excessive ROS and pro-inflammatory cytokines that may overwhelm the antioxidant and immune defenses of the cells and exacerbate mucosal inflammation. Additionally, fibroblasts exhibit a metabolic adaptation to control inflammation-related oxidative stress.

Aims & Methods

We aimed to investigate whether REAo has, on top of its physical effects, also anti-inflammatory/-oxidative properties in human dermal fibroblasts (NHDF), human umbilical vein endothelial cells (HUVEC), and human acute monocytic leukemia (THP-1) differentiated MΦ, critical cellular components of the gastrointestinal and oral mucosa.

The cells were pre-treated with REAo or its final formulation STW 42, containing REAo and selected excipients, followed by incubation with H₂O (pro-oxidative) or lipopolysaccharide (LPS, pro-inflammatory). Intracellular ROS were quantified with DCFDA. The releases of IL-6 and TNF-α were determined by ELISA. THP-1 cells were differentiated into MΦ with 0.1 μg/ml phorbol-12-myristate-13-acetatefor 3–5 days.

Results

Pre-treatment (24 h) of HUVEC, NHDF or THP-1-MΦ with STW 42 or REAo (100-1000 μg/ml) significantly inhibited the H₂O-induced intracellular ROS production by 30.0% to 58.7%. Whereas 24h(HUVEC, NHDF) or 48 h (THP-1-MΦ) pre-treatment with STW 42 or REAo (100-1000 μg/ml) inhibited the LPS-activated IL6 release by 25.0-67.0%. Additionally, 48 h pre-treatment of THP-1-MΦ with 50-500 μg/ml STW 42 or REAo significantly inhibited LPS-induced TNF-α release by 21.5% (50 μg/ml) to 52.0% (500 μg/ml), in comparison with LPS-treated MΦ. The observed effects of STW 42 or REAo were similar to 25-100 μM Diclofenac, which was used as an anti-inflammatory control.

Conclusion

These anti-inflammatory and antioxidant properties may support the benefit of STW 42 and its constituent REAo in patients with mucosal irritation with subsequent irritative cough or gastric complaints due to its protective/reparative effects on the mucosa.

References

1. HMPC of EMA 2016. European Union herbal monograph on Althaea officinalis L., radix. EMA/HMPC/436679/2015
2. Deters A, Zippel J, Hellenbrand N, Pappai D, Possemeyer C, Hensel A. 2010. Aqueous extracts and polysaccharides from Marshmallow roots (Althea officinalis L.): Cellular internalisation and stimulation of cell physiology of human epithelial cells in vitro. J Ethnopharmacol. 127: 62-9. doi: 10.1016/j.jep.2009.09.050.
3. Bonaterra GA, Schmitt J, Schneider K, Schwarzbach H, Aziz-Kalbhenn H, Kelber O, Müller J, Kinscherf R. Phytohustil^® and root extract of Althaea officinalis L. exert anti-inflammatory and anti-oxidative properties and improve the migratory capacity of endothelial cells in vitro. Front Pharmacol. 2022 Dec 8;13:948248.
   

Disclosure

JS and NS have nothing to disclose. GAB and RK received project support from Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany. OK, HAK and KB are employees of Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany.

Introduction

The LIR!C trial demonstrated that laparoscopic ileocaecal resection (ICR) is a cost-effective alternative to infliximab therapy (IFX) in patients with uncomplicated ileocaecal Crohn’s disease (CD), with comparable quality of life outcomes. The aim of this study was to assess the 10-year follow-up of patients enrolled in the LIR!C trial.

Aims & Methods

This retrospective follow-up study included patients from the original LIR!C trial, a multicentre randomized controlled trial comparing ICR to IFX treatment in patients with ileal CD. Long term follow-up data were collected between February 3 and April 14, 2025. Data extraction was focused on initiation or switch of IBD treatments (corticosteroids, immunomodulators and/or advanced medical therapies) and (re)-resections. The follow-up period ranged from trial enrolment to the last visit with the gastroenterologist or surgeon. Primary outcomes were: (1) proportion of patients in clinical remission without therapy switch (no medical therapy or re-resection in the ICR group, and continuation or the cessation of IFX in case of remission in the IFX group), and (2) therapy-free remission, defined as clinical remission without IBD medication and (re)resections.

Results

Follow-up data were available from 60 ICR patients and 57 IFX patients (87% of 134 patients originally included). The median follow-up time was 12 years (IQR 9-14). The clinical remission rate without therapy switch was 40% in the ICR group compared to 26.3% in the IFX group (p=0.117). Of the 60 ICR patients, 24 (40%) had no additional therapy, 13 (21.7%) received an immunomodulator, 18 (30%) biological therapy and 5 (8.3%) underwent a second resection after biological treatment. In the IFX group, 33 (57.9%) required an ICR of whom 25 (75.8%) had previously received second-line biological treatment. Additionally, 7/57 patients (12.3%) were therapy free, 8 (14%) continued IFX treatment, 6 (10.5%) received other biological treatment, and 3 (5.3%) switched to an immunomodulator. Therapy-free remission was significantly higher in the ICR group when compared to the IFX group (40% vs 12%, p < 0.001).

Conclusion

After 10 years of follow-up, the clinical remission rate without therapy switch was comparable between both groups, highlighting the long-term durability of both treatment approaches. The majority of IFX patients needed ICR within 10 years of follow-up. 40% of the ICR group did not require any additional therapy further supporting ICR as first-line treatment option in ileal CD.

References

Ponsioen, C. Y., de Groof, E. J., Eshuis, E. J., Gardenbroek, T. J., Bossuyt, P. M. M., Hart, A., Warusavitarne, J., Buskens, C. J., van Bodegraven, A. A., Brink, M. A., Consten, E. C. J., van Wagensveld, B. A., Rijk, M. C. M., Crolla, R. M. P. H., Noomen, C. G., Houdijk, A. P. J., Mallant, R. C., Boom, M., Marsman, W. A., Stockmann, H. B., … LIR!C study group (2017). Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial. The lancet. Gastroenterology & hepatology, 2(11), 785–792. https://doi.org/10.1016/S2468-1253(17)30248-0

Disclosure

GD'H served as a consultant for AbbVie, Alimentiv, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Exeliom Biosciences, Johnson & Johnson, Pfizer, and Takeda; and has received speakers bureau fees from AbbVie, Eli Lilly, Pfizer, Bristol Myers Squibb, and Takeda.

Introduction

Ulcerative colitis (UC) is associated with debilitating symptoms that impair the quality of life (QoL) of patients; restoration of QoL is an important long-term treatment goal.¹ Upadacitinib (UPA), an oral, reversible Janus kinase inhibitor approved for the treatment of UC, improves health-related QoL (HRQoL) and patient-reported outcomes (PROs) with 1 year (yr) of maintenance therapy.^2-4 This post hoc analysis of the U-ACTIVATE long-term extension (LTE) study evaluated the long-term efficacy of UPA in sustaining PROs and HRQoL outcomes in patients who had received up to a total of 4 years (yrs) of UPA maintenance therapy.

Aims & Methods

This analysis included patients who completed 1 yr (52 weeks [wks]) in the U-ACHIEVE maintenance study and received UPA15 mg once-daily (QD) (UPA15) or UPA 30 mg QD (UPA30) maintenance treatment in the U-ACTIVATE LTE study. Patients receiving UPA15 or UPA30 who achieved clinical remission per Adapted Mayo score at maintenance wk 52 continued their double-blind treatment upon entering the LTE study. Nonremitters receiving UPA15 were escalated to UPA30, those receiving UPA30 continued UPA30, and those assigned to PBO were escalated to UPA15, all in a blinded manner. The UPA UC program was not designed to compare UPA15 and UPA30 doses. Efficacy was assessed at LTE wks 0, 96, and 144 (data cutoff date: 30 June 2024) and included the percentage of patients who achieved absence of abdominal pain, absence of bowel urgency, Inflammatory Bowel Disease Questionnaire (IBDQ) response, IBDQ remission, and a meaningful within-person change (MWPC) in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue; Short-Form Health Survey-36 version 2 Mental Component Score (SF-36v2 MCS), and SF-36v2 Physical Component Score (PCS). Data were reported using as-observed (AO) and modified nonresponder imputation (mNRI) methods (shown in Table). Safety was reported previously.²

Results

This analysis included 369 patients treated with UPA15 or UPA30 at wk 0 of LTE trial. In the AO analysis, patients treated with UPA15 or UPA30 achieved sustained improvements from LTE wk 0 to wk 144 in PROs and HRQoL assessments (Table), including the absence of abdominal pain, absence of bowel urgency, IBDQ response, IBDQ remission; and achieved MWPC in FACIT-Fatigue, SF-36v2 PCS, and SF-36v2 MCS. Similar results were observed for all endpoints with the more conservative mNRI analysis (Table).

Conclusion

Patients with UC who responded to induction therapy and received long-term UPA maintenance therapy showed a sustained absence of symptoms and improvements in HRQoL, suggesting that UPA maintains long-term improvements in patient-reported outcomes.

References

1. Turner D, Ricciuto A, Lewis A, D’Amico F, Dhaliwal J, et al. Gastroenterology. 2021;160:1570–83.
2. Panaccione R, et al. J Crohn’s Colitis. 2025;19(S1):i84-i86 [abstract].
3. AbbVie Inc. RINVOQ (Upadacitinib) [package insert] U.S. Food and Drug Administration website. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf. Revised May 2023. Accessed 25 Feb 2025.
4. AbbVie DG& CoK. RINVOQ. Summary of Product Characteristics. European Medicine Agency website. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf. Revised Feb 2025. Accessed 25 Feb 2025.

Disclosure

Funding: AbbVie funded this study (U-ACTIVATE; NCT03006068) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.

Acknowledgments: AbbVie and the authors thank the participants, study sites, and investigators who participated in this clinical trial. Paulette A. Krishack, PhD, of AbbVie, provided medical writing support; Angela T. Hadsell, BA, of AbbVie, provided editorial support.

Joana Torres has received grant funding/speaker fees from and/or has participated in advisory boards for AbbVie, Lilly, Takeda, Janssen, and Pfizer.

Corey A Siegel has served as a consultant, advisor, and/or speaker for CME activities and/or received grant funding from AbbVie, BMS, Celltrion, Fresenius, Janssen, Lilly, Napo, Pfizer, Prometheus, Prometheus Labs, Roivant, and Takeda.

Julian Panés received consultancy fees/honorarium from AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman, and has served on a data safety monitoring board for Alimentiv, Mirum, Sorriso, Sanofi, and Surrozen.

Edward V. Loftus Jr. has served as a consultant for AbbVie, Abivax, Amgen, Astellas, Avalo, Biocon, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Fresenius Kabi, Genentech, Gilead, Iota Biosciences, Iterative Health, Janssen, Morphic Therapeutics, Ono Pharma, Takeda, and TR1X Bio; has received research grants from AbbVie, Genentech, Gilead, Janssen, Merck, and Takeda; and is a share owner of Exact Sciences and Moderna.

Remo Panaccione has received consulting fees, speaker fees, and research support from Abbott, AbbVie, Abbivax, Alimentiv Amgen, AnaptysBio, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Janssen Pharmaceuticals, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Sanofi, Satisfai Health, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.

Si Xuan, Nidhi Shukla, Ari Stromberg, Sina Ogholikhan, Leah Rizzo, and Dolly Sharma, are employees of AbbVie and may own stock options.

Gareth Parkesreports personal payments, honoraria, speaker fees, travel grants and/or fellowships from AbbVie, Allergan, Bristol Myers Squibb, Celltrion, Ferring, Galapagos, Janssen, Napp, Takeda, and Tillotts, and directorship and shareholding with Ampersand Health. TR reports personal grants from AbbVie; personal consulting fees from AbbVie, Arena, Aslan, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, MonteRosa, Mylan, MSD, Novartis, Numab, Pfizer, Roche, Sandoz, Takeda, UCB and XAP; membership of the ECCO Scientific Committee, and membership in the UEG Scientific Committee; director of Endoread.

Introduction

Upadacitinib, a selective JAK inhibitor, has demonstrated efficacy in clinical trials for ulcerative colitis (UC), but real-world data in refractory populations remain limited. This study evaluates its effectiveness, safety, and differential response based on prior advanced therapy failures in a real-world cohort.

Aims & Methods

Ambispective analysis of 80 UC patients initiating upadacitinib across 13 centers. Clinical remission (CR: partial Mayo score <3), clinical-biochemical remission (CBR: Mayo <3 + CRP <5 mg/L + calprotectin <250 μg/g), and steroid-free remission (SFR) were assessed at weeks 8, 16, and 6 months. Subgroup analyses compared outcomes by prior biologic/small molecule exposure.

Results

A total of 80 patients with ulcerative colitis were included, with a mean age of 38 years (range 17–69) and a predominance of males (62.5%). Most patients had extensive colitis (57%), and the average disease duration was 9 years. Extraintestinal manifestations were present in 26.6% (mainly articular). The cohort was highly refractory, with a mean of 2.3 prior advanced therapies; 84.6% had previously received infliximab, 37.2% ustekinumab, and nearly one-third had tried tofacitinib. At induction, 54.5% received upadacitinib 45 mg for 8 weeks, and at 6 months, 69.7% were maintained on 30 mg, while 24.2% required 45 mg.
At week 8, a rapid improvement in disease activity was observed, with the mean partial Mayo score dropping from 5.8 at baseline to 2.0. Clinical remission was achieved in 62.3% of patients at this timepoint, and 23.2% reached combined clinical-biochemical remission. These benefits were largely maintained over time: at 6 months, 51.3% of patients remained in clinical remission, 23.1% in combined remission, and 28.2% achieved steroid-free remission. Inflammatory markers also improved, with CRP decreasing from 15.0 mg/L at baseline to 4.8 mg/L at 6 months, and calprotectin showing a downward trend. (Table 1)
When analyzing effectiveness by prior treatment exposure, patients with only one previous advanced therapy achieved higher rates of clinical remission at 6 months (64.3%) compared to those with two or more prior biologic failures (44.0%). A similar pattern was seen for steroid-free remission (35.7% vs. 24.0%). Nonetheless, even among multi-refractory patients, a substantial proportion achieved and maintained remission with upadacitinib.
Treatment was generally well tolerated. Ten patients (12.6%) discontinued upadacitinib before 6 months, mainly due to primary non-response. Adverse events were reported in 23.8% of patients, most commonly mild (acne, herpes zoster, mild infections). Only three discontinuations were attributed to adverse events (herpes zoster, pneumonia, and acne), and no serious safety signals were identified.

Table 1: Effectiveness Outcomes

Conclusion

Upadacitinib demonstrates rapid and sustained effectiveness in refractory UC, even in multi-refractory patients. While response rates diminish with prior treatment failures, clinically meaningful benefits persist, supporting its use in advanced therapy-experienced populations. The safety profile aligns with clinical trial data, with manageable adverse events.