Introduction

Anti-tumor necrosis factor (TNF)-α are the first target therapies approved for the treatment of steroid-dependent or -refractory ulcerative colitis (UC). Drugs with different mechanisms of action have recently entered the market, but data on the optimal management of UC after failure of first-line anti-TNF-α are lacking.

Aims & Methods

The PODIUM study is a multicentre, retrospective, observational study that aims to compare the real-life effectiveness and safety of second-line vedolizumab (VDZ), ustekinumab (UST) and tofacitinib (TOF) in patients with UC. Consecutive patients with UC who had failed at least one anti-TNF-α and were never exposed to other target therapies were enrolled from 12 centres across Europe. Sociodemographic data, data on clinical activity and adverse events of interest (AEIs, defined as AE requiring temporary/permanent drug discontinuation or medical intervention) were retrospectively extracted from medical records, from the initiation of second-line therapy until one year of observation/drug discontinuation/last available follow-up. The primary outcome was the cumulative probability of achieving steroid-free clinical remission (SFCR), defined as stool frequency=0-1 and rectal bleeding=0 and no concomitant steroids, over the first year of treatment; inverse probability of treatment weighting (IPTW), calculated as the inverse of the probability of receiving each drug (IPTW=1/Propensity Score), was applied to the primary outcome to account for imbalances in cohorts’ characteristics. We performed an interim analysis including all data collected up to March 15^th 2024; data collection is still ongoing at the submission of this Abstract.

Results

Data on 303 patients (172 VDZ, 63 UST, 68 TOF) were included in the analysis. The main baseline characteristics are presented in Table 1. After IPTW, the cumulative probability of achieving SFCR during the first year was 51.0%, 59.1% and 64.1% for VDZ, UST and TOF, respectively; both UST and TOF were superior to VDZ at Log-rank test (p<0.001), with no differences between the two. At weighted logistic regression, female sex (adjusted Odds Ratio, aOR, 0.06, Confidence Interval, CI, 95% 0.41-0.73, p<0.001) and higher Charlosn Comorbidity Index calculated without considering age (aOR 0.73, 95% CI 95% 0.60-0.88, p=0.001) were independently associated with a lower probability of achieving SFCR during the first year. Recorded AEIs were 16 (4 infections) in the VDZ group (9.3% of VDZ-treated patients), 6 (1 infection) in the UST group (9.5% of UST-treated patients), and 15 (5 infections, including 1 Zoster reactivation) in the TOF group (22.1% of TOF-treated patients).
Table 1

Conclusion

This preliminary analysis suggests that both UST and TOF might have superior effectiveness, compared to VDZ, as second-line agents in patients with UC after anti-TNF-α. Confirmatory analysis with a larger sample size will be performed. A slightly higher rate of AEIs was observed in the TOF group.

Disclosure

Giuseppe Privitera received consultancy fees from Alphasigma and Janssen. Cristina Bezzio received lecture fees and served as a consultant for Takeda, MSD, Ferring, Abbvie, Galapagos and Janssen. Edoardo Vincenzo Savarino has served as speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr. Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, MayolyBiohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, and Unifarco; has served as a consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, DiademaFarmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Takeda, and Unifarco; he has received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, Zeta Farmaceutici. Daniela Pugliese received speaker fees and/or advisory board from AbbVie, Galapagos, MSD, Takeda and Janssen, Pfizer. Iago Rodriguez-Lago has received financial support for traveling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Celltrion, Chiesi, Danone, Ferring, Faes Farma, Janssen, Galapagos, MSD, Pfizer, Roche, Takeda, and Tillotts Pharma. Financial support for research: Tillotts Pharma. Manuel Barreiro-de Acosta has served as a speaker, consultant and advisory member for and has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gilead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma. Sara Onali has received speaker fees from AbbVie, Takeda, Janssen, Amgen, Galapagos and Norgine. Massimo Claudio Fantini has received speaker and consultancy fees from AbbVie, Takeda, Janssen-Cilag, Pfizer, Sandoz, Biogen, Galapagos, Bristol-Myers Squibb, and MSD; and research grants from Pfizer and Janssen-Cilag. Karmiris K has served as speaker, consultant, and advisory member for Abbvie, Amgen, Enorasis, Ferring, Galenica, Genesis, Janssen, MSD, Pfizer, Takeda and Vianex. Henit Yanai has received consulting fees Abbvie, Ferring, Janssen, Neopharm Ltd., Pfizer, Takeda; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Abbvie, Janssen, Pfizer, Takeda, Neopharm Ltd.; Participation on a Data Safety Monitoring Board or Advisory Board Abbvie, Neopharm Ltd., Pfizer, Takeda. Ana Gutierrez has served as speaker, consultant and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Tillotts Pharma, Chiesi and Otsuka Pharmaceutical. Luca Pastorelli has received consultant and/or speaker fees from Giuliani, Ferring, Janssen, Takeda. María Chaparro has served as a speaker and consultant for and has received research or education funding from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Biogen, Gilead and Lilly. Yamile Zabana has received speaker and/or consultant fees from AbbVie, Adacyte, Almirall, Amgen, Dr Falk Pharma, FAES Pharma, Ferring, Janssen, MSD, Otsuka, Pfizer, Shire, Takeda, Galapagos, Boehringer Ingelheim and Tillots. Alessandro Armuzzi: consulting and/or advisory board fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda; lecture and/or speaker bureau fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mitsubishi-Tanabe, Novartis, Pfizer, Roche, Sandoz, Samsung Bioepis, Takeda; and research grants from MSD, Pfizer, Takeda and Biogen. The remaining authors declare no competing interests. The remaining Authors declare no competing interests.

Introduction

Targeted therapies have revolutionized the management of immune-mediated inflammatory diseases (IMIDs), however, there is a substantial number of patients who respond poorly to a given drug. There is a big need to understand the factors that are associated with this heterogeneity.

Aims & Methods

The DoCTIS project (1) aims to characterize molecular variation both at the disease and drug response levels across six different IMIDs. We applied single cell RNA sequencing to 360 peripheral blood mononuclear cell (PBMC) samples from 176 patients from six prevalent IMIDs –psoriasis (PS), psoriatic arthritis (PsA), Crohn’s Disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE)- treated with five different drugs targeting TNF, IL12p40, IL6R, BLySS, IL17 and JAK pathways. All patients were analyzed at two time points including baseline and at the week of clinical response creating an immune landscape of more than two million peripheral immune cells.

Results

We found large inter-disease differences both at the compositional and genetic regulatory programs. ScRNA-Seq analysis revealed large differences at the systemic level between the six IMIDs. Compositional analyses demonstrated that the circulating immune cell profiles of UC and CD were more similar to each other than to the rest of IMIDs, and also identified differences in pDC, MAIT, NK CD16- and T CD4+ Memory subsets between both diseases. At the transcriptional level, we found the expected upregulated interferon response signature affecting multiple cell types in SLE, but also novel findings like strong regulatory differences in B and CD14+ monocyte compartments between UC and CD, two diseases with a highly shared genetic risk. The impact of each drug was found to be largely disease-specific. Furthermore, we found multiple regulatory features associated with the effect of each drug as well the association to response.

Conclusion

The scRNA-Seq atlas developed in DoCTIS provides a unique resource for the understanding of drug response and disease heterogeneity across immune-mediated inflammatory diseases.

References

1. Decision on Optimal Combinatorial Therapies in IMIDS using Systems Approaches (DoCTIS). https://doctis.eu/

Disclosure

Antonio Julià: None declared, Yolanda Guillén: None declared, Paloma Vela Casasempere: None declared, Antonio Fernández Nebro: None declared, Carlos Marras: None declared, Santos Castañeda Bristol-Myers Squibb, Eli Lilly, Bristol-Myers Squibb, Jaime Calvo Alén: None declared, Jesús Tornero Molina: None declared, Juan de Dios Cañete Crespillo: None declared, Eugeni Domènech: None declared, Javier Gisbert: None declared, Jose M Carrascosa: None declared, Eduardo Fonseca: None declared, Luis Bujanda Fernández de Pierola: None declared, Valle García Sánchez: None declared, Britta Siegmund: AbbVie, AlfaSigma, BMS, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, MSD, Ferring, Galapagos, Janssen, Pfizer, and Takeda, Abivax, Boehringer Ingelheim, Endpoint Health, Gilead, Janssen, Landos, Materia Prima, PredictImmune, Giampiero Girolomoni: AbbVie, Almirall, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli-Lilly, Leo Pharma, Merck Serono, Novartis, Pfizer, Pierre Fabre, Samsung bioepis and Sanofi, Almirall, Amgen, Bristol-Myers Squibb, Eli-Lilly, Leo Pharma, Merck Serono, Novartis, Pfizer, Samsung bioepis and Sanofi, Pfizer, Holger Heyn: Mirxes, Moderna, Nanostring, Omniscope, Singularity, Laura Jimenez: None declared, Pere Santamaría: None declared, Edgar Angelats: None declared, Rick Myers: None declared, Sergio H. Martínez-Mateu: None declared, Juan Angel Patiño Galindo: None declared, Ernest Choy: AbbVie, Amgen, Biocon, Biogen, Chugai, Eli Lilly, Fresenus Kabi, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, RPharm, and Sanofi, Bio-Cancer, Biogen, Novartis, PFizer, and Sanofi, AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Fresenus Kabi, Galapagos, Gilead, Novartis, Pfizer, Regeneron, Roche, RPharm, Sanofi, and UCB Pharma, Sara Marsal: None declared

Introduction

The optimal surgical approach to reduce recurrence rates after laparoscopic repair of paraesophageal hernia (PEH) is yet to be defined. The crural repair is challenged by both axial and transverse-lateral tension, which may compromise durability. The aim of this double-blind randomized clinical trial was to investigate whether a left-sided diaphragmatic relaxing incision in addition to standard crural repair and fundoplication reduces anatomical recurrence rates at one year postoperatively.

Aims & Methods

This study was conducted at two high-volume Swedish centers—Ersta Hospital (Stockholm) and Sahlgrenska University Hospital (Gothenburg)—between August 2019 and August 2023. Adult patients undergoing surgery for PEH were randomized 1:1 to either standard crural repair with total (360°) fundoplication (control) or the same procedure with the addition of a left-sided diaphragmatic relaxing incision covered by synthetic mesh (intervention). Patients with prior hiatal surgery, ASA class IV or above, type I hernia, major esophageal motility disorders, or any contraindication to fundoplication were excluded. Blinding for patients and assessors was maintained throughout follow-up. Pre- and postoperative assessments included computed tomography (CT), symptom questionnaires (Dakkak dysphagia score, Gastrointestinal Symptom Rating Scale [GSRS]), and quality of life (QoL, RAND-36). The primary outcome was radiologically confirmed PEH recurrence at 12 months.

Results

Of 103 patients screened, 76 were randomized (38 per group). Baseline characteristics were well balanced. CT was completed in 72 patients (95%) at 12 months. The recurrence rate was 66% in the control group and 54% in the intervention group (p=0.313). Three patients in the intervention group had asymptomatic CT verified herniation at the site of the diaphragmatic incision. There were no differences in recurrence size distribution (<4 cm vs >4 cm) between groups. Postoperative symptom assessment revealed significant improvements in dysphagia, reflux, indigestion, and abdominal pain in both groups, without intergroup differences. Physical QoL (PCS) improved significantlywhereas mental QoL (MCS) remained unchanged. Two deaths occurred within 90 days postoperatively (1 per group), yielding a 90-day mortality of 2.6%. Other complications included mediastinal abscess (n=1, intervention group) and need for postoperative endoscopic dilatation (n=5 in total). Operation time tended to be longer in the intervention group (150 vs 133 min; p=ns).

Conclusion

In this randomized, double-blind trial, the addition of a left-sided diaphragmatic relaxing incision to standard laparoscopic PEH repair did not improve anatomical recurrence rates, symptom relief or QoL at 12 months after surgery and should not be recommended for routine use. Alternative strategies to improve recurrence rates after PEH need to be explored in the future.