Introduction

Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass. Primary sarcopenia is associated with aging, while secondary sarcopenia is caused by various factors, including inflammatory conditions such as inflammatory bowel disease (IBD). The complex interaction between inflammation, intestinal dysbiosis, and malnutrition in IBD patients is referred to as the gut-muscle axis. High levels of cytokines and intestinal dysbiosis in IBD activate pathways that disrupt muscle protein synthesis. However, molecular and microbial mechanisms of sarcopenia in IBD are not extensively studied as well as therapeutic approaches.

Aims & Methods

A murine model of DSS-induced colitis was used. To detect sarcopenia, physical performance assessment on a rotarod was conducted. In this model, muscle was studied using immunohistochemistry, fiber counting per field, and cross-sectional area evaluation. Subsequently, intestinal microbiota and serum LPS detection were assessed. Additionally, an in vitro model of muscle cells was created using the immortalized murine cell line C2C12. Cells were exposed for 30 Min and 6 h to treatments including exposure to pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6), lipopolysaccharides (LPS), drugs (Infliximab, Upadacitinib, Tofacitinib), and probiotics (L. plantarum, L. rhamnosus).

Results

The murine model showed decreased body weight and muscle function alongside increased expression of muscle atrophy markers (myostatin and Murf-1) in colitic mouse muscle. Furthermore, there was an upregulation of the STAT3-pSTAT3 pathway associated with muscle wasting and a decrease in pAKT, a pathway associated with muscle growth. Surprisingly, DSS-induced colitis in mice resulted in intestinal dysbiosis characterized by reduced Roseburia genus and increased Sutterella, Turicibacter, and Bacteroides in the DSS group, as well as increased serum LPS levels.
In vitro, Upadacitinib and Tofacitinib, in the presence of inflammatory cytokines, reduced the expression of pathways associated with muscle atrophy (STAT3, pSTAT3, and NFκB) and increased pAKT expression, a protein associated with muscle synthesis. When cells were treated with LPS, NFκB expression did not decrease with the addition of the drugs, suggesting that LPS can activate NFκB independently of the JAK/STAT pathway.
Treatment with probiotics reduced STAT3 and pSTAT3 signals, suggesting potential positive modulation by all probiotics.

Conclusion

These data open new avenues for the gut-muscle axis as a promising research area for managing sarcopenia in IBD. Considering microbiota and LPS along with inflammatory cytokines may provide a more comprehensive understanding, especially as LPS-induced signaling appears to be only partially controlled by drugs and potentially positively influenced by probiotics.

Introduction

Mirikizumab (MIRI) has shown promising results in ulcerative colitis (UC) based on the data from the pivotal clinical trials (LUCENT). However, these results still need to be validated in clinical practice.

Aims & Methods

This study aims to assess the short-term real-world effectiveness and safety of MIRI in patients with UC.
All patients with UC who received MIRI and without previous colectomy included in the prospectively-maintained ENEIDA registry were included. Clinical disease activity was assessed by partial Mayo score (pMS). The primary outcome was clinical remission (defined as pMS ≤2 with no subscore >1 and no rectal bleeding) at week 8 and 12, alongside its safety profile.

Results

A total of 171 patients from 43 Spanish hospitals were included (mean age of 49.5 years [SD 18], 54% male, median disease duration of 128 months [SD 97], 55% non-smokers, 62% extensive colitis. Concomitant therapy at baseline included 44% with steroids and 7.6% with immunosuppressants. Prior advanced therapies exposure was: 89% Anti-TNF, 69% vedolizumab, 54% ustekinumab, and 40% JAK inhibitors, with 54% exposed to > 2 mechanisms of action (MoA). At baseline patients had a median pMS 5 (IQR, 4-7) and faecal calprotectin of 557 ug/g (IQR, 120-1000). All but one patient started MIRI 300 mg iv every 4 weeks. Mean follow-up was 5.3 (SD 4.4) months. Clinical response and clinical remission at week 8 were 44% and 26%, respectively, and this increased up to 45% and 30% at week 12. Clinical remission rate at week 12 was higher among those with prior exposure to 1 MoA vs 2 or more than 2 (65%, 25%, 27% respectively, p=0.04, p=0.02). Previous exposure to ustekinumab was associated with a numerically lower, not statistically significant, rate of clinical remission at week 12 (28% vs. 38%, p=0.4). Faecal calprotectin significantly decreased at week 12 (160 ug/g [IQR, 54-852], p=0.001). The overall hospitalization and colectomy rates were 5.8% and 1.7% respectively. MIRI was generally well tolerated, with 10% of patients reporting at least one adverse event, but only one of them categorized as severe.

Conclusion

MIRI demonstrated its real-life effectiveness in the short-term, even in a highly-refractory cohort. Prior advanced therapy exposure to more than one MoA significantly impacts the effectiveness of MIRI during the induction. Safety was consistent with the known profile of this drug.

Introduction

Upadacitinib (UPA) is an oral, reversible Janus kinase inhibitor (JAKi) approved for the treatment of patients with moderate-to-severe ulcerative colitis (UC).^1-2 Despite substantial evidence from clinical trials supporting the use of UPA for treating UC, real-world (RW) data on its effectiveness and safety remain limited.³ The Prospective Real-World Study of UPA in UC (PROFUNDUS) is an ongoing multi-country, open-label, noninterventional, observational study aimed to evaluate the effectiveness and safety of UPA in patients with moderate-to-severe UC in RW practice (initiated 15 Aug 2022).

Aims & Methods

PROFUNDUS recruited 785 adult patients (18 to 75 years [yrs] of age) with moderate-to-severe UC initiating UPA in 16 countries worldwide. UPA was administered in accordance with the terms of the local marketing authorization, with patient treatment determined by the investigator, and patients followed for up to 3 yrs (156 weeks [wk]). This analysis represents data available after the first 500 patients completed 6 months of treatment or discontinued before 6 months, with a data cut-off of 28 Feb 2025. Of the first 500 patients who provided informed consent and met the inclusion criteria, the full analysis set (FAS) included 490 patients who initiated a once-daily UPA dosing regimen. This analysis reported baseline demographics and disease characteristics among FAS; the time to achievement of first clinical response per daily Partial Adapted Mayo Score (pAMS) and the percentage of patients achieving clinical response per pAMS at the end of UPA induction (wk 8) or extended induction (wk 16) were reported among evaluable patients who took at least 1 dose of UPA and had available scores to define the outcomes, a subset of FAS. Safety outcomes were analysed through week 26 (6 months), with treatment-emergent adverse events (TEAEs) presented as patient numbers and percentages.

Results

Among FAS, the patient age range was 18 to 79 yrs; 43.3% were female. At baseline (defined as the last available assessment on or before the first dose date of UPA), pAMS were as follows: < 2: 26.5%; 2-4: 48.1%; > 4-5: 18.8%; > 5-6: 6.6%; with score 0 indicative of inactive disease, while a score of 6 indicates active disease and spontaneous bleeding.⁴ At baseline, 51.3% of patients had a history of intolerance or inadequate response (IR) to advanced therapies (AT-IR), with 13.1% of patients who failed ≥ 1 JAKi. Among evaluable patients, the median (IQR) time to achieve the first clinical response per daily pAMS was 4 (3.0-8.0) days (N = 373; Table). By the end of induction treatment (wk 8 or 16), 79.6% (258/324) of the evaluable UPA-treated patients achieved clinical response per pAMS (Table). Among UPA-treated patients, the occurrence rates of any treatment-emergent adverse events (TEAEs) and TEAEs possibly related to the study treatment were as follows: any adverse event (AE) (51.2%; 34.9%), serious AEs (5.5%; 2.2%), and severe AEs (5.1%; 2.2%) (Table).

Conclusion

In this interim analysis of the PROFUNDUS study, UPA demonstrated rapid effectiveness in achieving clinical response in patients with moderate-to-severe UC in RW practice, in a wide variety of age ranges, consistent with the efficacy observed in the UPA UC clinical trials.¹ Overall, UPA was well-tolerated, with few serious AEs reported, and most of these were assessed as unrelated to UPA by the investigator.

References

1. 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.
2. 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.
3. Seidelin J, et al. J Crohn’s Colitis. 2025;19(1):i1260-i1262. [Abstract].
4. Louis E, et al. JAMA. 2024;332(11):881-897.

Disclosure

Funding: AbbVie funded this study (PROFUNDUS; NCT05494606) 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.
Disclosures: 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.
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.
Mathurin Fumery has received lecture and consulting fees from AbbVie, Amgen, Biogen, BI, BMS, Celgene, Celltrion, CTMA, Ferring, Fresenius, Galapagos, Gilead, Janssen, Pfizer, Lilly, MSD, Sandoz, Takeda, Tillots, and Viatris.
Dominik Bettenworth is on the advisory board or consultant for Amgen, AbbVie, Dr. Falk Foundation, Ferring, MSD, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts Pharma, and Vifor. Silvio Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grünenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor.
Pierre A Morisset, Madhuja Mallick, Shirley H. Chen, and Smitha Suravaram are employees of AbbVie and may own stock options.

Introduction

Upadacitinib (UPA) has shown promising results in the pivotal trials, which require validation in clinical practice. Primary aim: To assess the durability of UPA treatment in patients with ulcerative colitis (UC). Secondary aims: To assess the short and long-term effectiveness, dose optimization and response to dosage adjustments, the impact of extraintestinal manifestations (EIM) and immunomediated diseases (IMIDs), and the tolerability of UPA in UC in a real-world setting.

Aims & Methods

Adult patients who started UPA for UC treatment at least 8 weeks prior to data collection and were part of the prospectively maintained ENEIDA registry of GETECCU were included. Patients on concomitant biologic agents or with a history of colectomy were excluded. Patients were followed-up from the first UPA dose until treatment discontinuation or the last visit. Effectiveness analysis was restricted to patients with active disease [Partial Mayo Score (PMS)>2] at UPA initiation. Clinical effectiveness was measured using PMS, and concomitant steroid use was assessed at each visit. Patients who discontinued UPA before their last visit were considered not in remission at subsequent time points (negative imputation).

Results

The study included 168 patients, 89% with active disease; 48% had been previously exposed to JAK inhibitors (JAKi), and 31% to all approved therapeutic targets. Mean time of follow-up was 5.6 months (interquartile range = 2.7-11 months). The proportion of patients under 45 mg/day of UPA was 77% at week 8 and 40% at week 16. A total of 29 patients discontinued treatment during a median follow-up time of 4.3 months. The incidence rate of UPA discontinuation was 27% per patient-year of follow-up, with no significant differences related to prior JAKi exposure (log-rank p-value > 0.05). The main reason for UPA discontinuation was loss of response (34%), with colectomy being the main subsequent treatment (21%). No predictive factors for UPA discontinuation were identified (including severity, number of previous advanced therapies, and prior JAKi exposure). Proportions of patients in steroid-free clinical remission (SFCR) were 67%, 71%, 65%, 60% and 75% at week 8, week 16, month 6, month 12 and month 18, respectively. In multivariate analysis, PMS at baseline [Odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.63-0.98] and previous exposure to JAKi (OR = 0.29, 95%CI = 0.14-0.61) were associated with lower probability of SFCR at week 8. Among 100 patients in SFCR at week 8, 13 (13%) lost response (31% per patient-year), and 10 (77%) of these had dose escalation, with 9 (90%) regaining SFCR. Of 31 patients (18%) with active EIM/IMIDs at the start of UPA, 15 (48%) showed improvement. Adverse events occurred in 45 patients (27%), with hypercholesterolemia being the most common, but no major cardiovascular or thromboembolic events were reported.

Conclusion

This study, the largest of its kind in clinical practice, confirms the short- and long-term benefits and the safety profile of UPA for UC. Although prior JAKi exposure reduced short-term effectiveness, it did not impact drug survival, indicating that UPA could be a viable option even for patients who have experienced JAKi failure.

Disclosure

María Chaparro has served as speaker, consultant or research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Biogen, Gilead and Lilly.
Luisa de Castro has received grants for conference attendance from Abbvie, Johnsson and Johnsson, Takeda, Falk and Pfizer. She has received grants or participated as a speaker for Johnsson and Johnsson, Falk and Tillots.
Iago Rodríguez Lago has received financial support for traveling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Biogen, Celltrion, Chiesi, Faes Farma, Ferring, Fresenius Kabi, Galapagos, Janssen, Lilly, Mirum Pharmaceuticals, MSD, Pfizer, Roche, Takeda, and Tillotts Pharma. Research support from AbbVie. Iago Rodriguez Lago is supported by a research grant from Gobierno Vasco-Eusko Jaurlaritza [Grant No 2020111061].
Carla J. Gargallo-Puyuelo Conflicts with Abbvie, Takeda, Janssen, Ferring, Lilly.
Marisa Iborra reports grants and personal fees from MSD, Janssen, Abbvie, Takeda, Kern and Pfizer, during the conduct of the study.
Manuel Barreiro has served as a speaker, consultant and advisory member for or have received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gillead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte, Vifor Pharma and Oncostellae.
Ruth de Francisco has received support for conference attendance, and research support from AbbVie, Faes Pharma, Ferring, Janssen, Pfizer, Takeda, and Galapagos.
R Pajares Villarroya has received financial support for educational activities from Takeda.
Trapero Martínez Ana María Conflict of interest; Abbvie, Jansen, Lilly, MSD.
Lara Arias García scientific advice, research support and/or training activities for Abbvie FAES Pharma, Kern Pharma, Ferring and MSD.
Raquel Camargo has received funding for different types of training activities from Johnson&Johnson, Avbbie, Pfizer, Ferring, Falk and Galapagos.
Margalida Calafat has served as a speaker or has received research or education funding or advisory fees from Takeda, Janssen, Faes Farma, Falk, Abbvie, Pfizer, Adacyte Therapeutics, Ferring, Gilead, Kern Pharma, and MSD.
MT Diz-Lois Palomares has received funding for training activities/congresses/lectures: Abbvie, Ferring, Johnson and Johnson, Lilly, Takeda.
F. Bermejo has been a speaker, consultant and advisory member or has received research funding from Abbvie, Takeda, Janssen, Pfizer, Lilly, MSD, Biogen, Amgen, Galapagos, Ferring, Faes Farma, Tillotts Pharma, Chiesi, Vifor Pharma.
Marta Calvo Moya has received support for conference attendance, speaker fees, research support, and consultancy fees from AbbVie, MSD, Takeda, Janssen, Pfizer, Lilly, Shire, Chiesi, DrFalk Pharma, Faes Pharma, Ferring, Kern Pharma, and Tillotts Pharma.
MJ Casanova, has received education funding from Pfizer, Takeda, Janssen, MSD, Dr. Falk, Shire, Ferring, Galápagos and Abbvie.
Francisco Mesonero has received funding for educational activities, conferences and scientific advice/consultations from MSD, AbbVie, Takeda, Janssen, Pfizer, Ferring, Kern Pharma, Dr. Falk Pharma, Celltrion Healthcare, Galapagos, Chiesi, Tillots Pharma and Faes Farma.
Yamile Zabana has received support for conference attendance, speaker fees, research support and consulting fees from: AbbVie, Adacyte, Alfa-Sigma, Almirall, Amgen, Boehringer Ingelheim, Dr Falk Pharma, FAES Pharma, Fresenius Kabi, Ferring, Galapagos, Janssen, J&J, Kern, Lilly, MSD, Otsuka, Pfizer, Sanofi, Shire, Takeda, Tillots.
Mónica Sierra has participated as a speaker and attended courses financed by MSD, Abbvie, Takeda, Pfizer, Lilly, Ferring, Sandoz.
B Caballol has received support for congress and conference attendance, speaker fees, research support or consulting fees from Abbvie, Ferring, Janssen, Pfizer, Takeda, Galapagos, Kern Pharma and Lilly.
Javier P. Gisbert has served as speaker, consultant, and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos, Lilly, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine and Vifor Pharma.