BACKGROUND:Overactivation of the alternative complement pathway contributes to IgA nephropathy and glomerular inflammation. In the 9-month interim analysis of this phase 3 trial, iptacopan, a complement factor B inhibitor, led to a significant reduction of 38.3% in the 24-hour urinary protein-to-creatinine ratio as compared with placebo and had an acceptable safety profile. METHODS:In this phase 3 trial, we enrolled adults who had IgA nephropathy, an estimated glomerular filtration rate (eGFR) of at least 30 ml per minute per 1.73 m2 of body-surface area, and a 24-hour urinary protein-to-creatinine ratio of 1 or higher (with protein and creatinine both measured in grams) despite supportive care. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily. The primary end point for the final analysis was the annualized total eGFR slope as estimated over a 24-month period. Secondary end points included a composite kidney-failure end point (i.e., a sustained decline in eGFR of ≥30%, a sustained eGFR of <15 ml per minute per 1.73 m2, the initiation of maintenance dialysis, receipt of kidney transplant, or death from kidney failure), assessed in a time-to-event analysis. Safety was also assessed. RESULTS:Among 477 patients included in the final analysis, 238 had been randomly assigned to iptacopan and 239 to placebo. The annualized total eGFR slope was -3.10 ml per minute per 1.73 m2 per year with iptacopan, as compared with -6.12 ml per minute per 1.73 m2 per year with placebo (difference, 3.02 ml per minute per 1.73 m2 per year; 95% confidence interval [CI], 2.02 to 4.01; adjusted P<0.001). A composite kidney-failure end-point event occurred in 21.4% of the patients in the iptacopan group, as compared with 33.5% of those in the placebo group (hazard ratio, 0.57; 95% CI, 0.40 to 0.81; adjusted P = 0.003). The incidence of adverse events was 87.0% in the iptacopan group and 89.1% in the placebo group. Serious adverse events occurred in 12.2% of the patients who received iptacopan and in 11.7% of those who received placebo, and serious infections in 6.7% and 2.1%, respectively. No deaths occurred. CONCLUSIONS:Iptacopan therapy led to a significantly slower decline in kidney function than placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.).
PORCSE studygroup: Anneline Cremer (Erasme University Hospital Department of Gastroenterology Brussels Belgium) João A. Cunha Neves (ULS-Algarve Department of Gastroenterology Portimão Portugal) Andreas Kapsoritakis (University Hospital of Larissa IBD unit- Department of Gastroenterology Larissa Greece) Mircea Diculescu (Faculty of Medicine- Carol Davila University of Medicine and Pharmacy- Fundeni Clinical Institute Department of Gastroenterology Bucharest Romania) Lieven Pouillon (Imelda Hospital Bonheiden Department of Gastroenterology and Hepatology Bonheiden Belgium) Ioannis E. Koutroubakis (University Hospital Heraklion Department of Gastroenterology Heraklion- Crete Greece) Laura Nieto (Hospital Clinico Universitario de Santiago de Compostela- Health Research Institute of Santiago de Compostela IDIS Gastroenterology Compostela Spain) Sophie Claeys (AZ Sint-Lucas Department of Gastroenterology Ghent Belgium) Iago Rodríguez-Lago (Hospital Universitario de Galdakao- Biobizkaia Health Research Institute Department of Gastroenterology Galdakao Spain) Pauline Rivière (Bordeaux University Hospitals Department of Gastroenterology Bordeaux France) Serkan Dumanli (Gazi University Department of Gastroenterology Ankara Turkey) Francisco Portela (ULS de Coimbra Department of Gastroenterology Coimbra Portugal) Ian Arnott (Western General Hospital IBD unit Edinburgh United Kingdom) Pinelopi Nikolaou (Venizeleio General Hospital Department of Gastroenterology Heraklion Greece) Joana Revés (Hospital Beatriz Ângelo Division of Gastroenterology- ULS Loures-Odivelas Loures Portugal) Inês Botto (Unidade local de saúde de santa maria- Clinica Universitária de Gastroenterologia- Faculdade de Medicina de Lisboa Servico Gastroenterologia e Hpatologia Lisbon Portugal) Margalida Calafat (Hospital Universitari Germans Trias i Pujol and CIBEREHD Gastroenterology Badalona Spain) The retrospective, multicentric, observational PORCSE study evaluated postoperative recurrence of Crohn’s disease after ileocaecal resection. Early medical prophylaxis (proactive strategy, cohort1) was found to have lower rates of endoscopic (Rutgeerts >i1) and clinical postoperative recurrence compared to expectant management (reactive strategy, cohort2) at first endoscopic evaluation. In this analysis from a subgroup of the PORCSE population, long term outcomes of these 2 strategies are explored. A subgroup analysis was performed in patients with extended follow-up beyond the timeframe of the original PORCSE study (Fig1). Primary endpoints were surgical (sPOR) and clinical (cPOR) recurrence. Endoscopic disease activity and progression were evaluated as secondary endpoints. Progression was defined as an increase in Rutgeerts score (>i1) and/or development of colon inflammation from first to consecutive postoperative endoscopies. Logistic regression models with propensity score matching were fitted to adjust for confounding factors in comparing the proactive and reactive strategy. For 92.2% of the 346 originally included patients, a mean additional follow-up duration of 38.5months (SD24.5) was available (mean total follow-up 110.9months, SD44.8). sPOR and cPOR rate was numerically higher with the reactive strategy. However these differences were not statistically significant (sPOR: cohort1:13.2%, cohort2:18.2%; OR1.78, 95%CI 0.73-4.34, P = 0.202 - cPOR: cohort1: 39.3%, cohort2:49.7%; OR1.73, 95%CI 0.92-3.24, P = 0.089). No difference was found in IBD-related hospitalisation rate (cohort1: 10.8%, cohort2: 10.1%; OR 1.48, 95%CI 0.53-4.18, P = 0.457). Survival analysis did not show a significant difference for time to sPOR (HR1.34, 95% CI 0.59-3.06, P = 0.485) nor in time to cPOR (HR1.28, 95%CI 0.35-4.66, P = 0.713). Rates of endoscopic disease activity (Rutgeerts>i1 and/or colonic inflammation) at consecutive endoscopies after initial postoperative endoscopy did not differ (cohort1:59.2%, cohort2:57.8%, OR0.70, 95%CI 0.31-1.57, P = 0.381). Univariate analysis revealed a higher rate of endoscopic progression with a proactive strategy (cohort1: 20.6%, cohort2: 10.6%, P = 0.041). However, after correction for confounders this difference was no longer significant (OR2.44, 95%CI 0.92-6.48, P = 0.073). In this large subgroup of patients with extended follow-up from the original PORCSE study, proactive medical prophylaxis after ileocaecal resection showed no statistically significant differences compared with a reactive approach in reducing the rate of surgical and clinical posoperative recurrence, despite a numerical trend. Further prospective studies and larger cohorts are required to confirm these findings. References: Geldof, J., Truyens, M., Hanssens, M., Van Gucht, E., Holvoet, T., Elorza, A., Bouillon, V., Barros, S., Martins, V., Argyriou, K., Potamianos, S., Diculescu, M., Stroie, T., Bossuyt, P., Moens, A., Theodoraki, E., Koutroubakis, I. E., Pedro, J., Fernandes, S., … Lobaton, T. (2024). Prophylactic Versus Endoscopy-driven Treatment of Crohn’s Postoperative Recurrence: A Retrospective, Multicentric, European Study [PORCSE Study]. Journal of Crohn’s and Colitis, 18(8), 1202–1214. https://doi.org/10.1093/ecco-jcc/jjae011 Conflict of interest: Dr. Geldof, Jeroen: JG received honoraria as speaker or advisory board member from Galapagos, Viatris, Abbvie, Pfizer, Janssen, Celltrion and Arena Pharmaceuticals. Truyens, Marie: No conflict of interest Van Gucht, Emily: No conflict of interest Argyriou, Konstantinos: No conflict of interest Bouchard, Isaure: No conflict of interest Abrantes, Daniela: No conflict of interest Roseira, Joana Selas: Advisory board fees from Abbvie and Janssen presenter fees from dr. Falk Nicholls, Jack: No conflict of interest. Elorza, Ainara: No conflict of interest Ferreiro Iglesias, Rocio: RF-I has served as a speaker, or has received research or education funding from AbbVie, Takeda, MSD, Pfizer, Janssen, Adacyte, Ferring, Casen Recordati, Palex, Tillotts Pharma, Dr. Falk, Chiesi, Faes Farma, Alphasigma. Eder, Piotr Michał: Travel and educational grants: Takeda, Ferring, Abbvie, Janssen (J & J), Eli Lilly. Lecture and/or consultancy fees: Takeda, Abbvie, Ferring, Janssen (J & J), Eli Lilly, Bristol Myers Squibb, Pfizer, Recordati, Ibsen, Sandoz. Karakan, Tarkan: None Bossuyt, Peter: Grant support for research from AbbVie, EG Consulting fee from AbbVie, Bristol Meyers Squibb, CIRC, Galapagos, Janssen, Jeito capital, Lilly, Pentax, Pfizer, PSI-CRO, Roche, Takeda, Tetrameros Speakers fee from AbbVie, AMC ICP, Amgen, Bristol Myers Squibb, Celltrion, Dr Falk Benelux, EG, Galapagos, Globalport, Lilly, Medtalks, Materia Prima, Pentax, Springer Media Bouillon, Vincent: No conflict of interest Holvoet, Tom: No conflict of interest Peeters, Harald: Disclosures – conflicts of interest Financial support for research: Abbvie, Mylan, Amgen, Sandoz, Takeda Speaker fees: Janssen, Takeda, Abbvie Consultancy fees: Janssen, Fresenius-Kabi, Abbvie, Galapagos Baert, Filip J.: Grants: Abbvie, Amgen, Eurogenerics, J&J, Takeda Lecture fees/Speakers Bureau: AbbVie, Arena Pharmaceuticals, Celltrion, Ferring, Galapagos, J&J, Lilly, Merck Sharp & Dohme, Pfizer, and Takeda Consultancy: AbbVie, Abivax, Amgen, Arena Pharmaceuticals, Celgene, Celltrion, Ferring, Fresenius Kabi, J&J, Merck Sharp & Dohme, Pfizer, Sandoz Desmedt, Valérie: Speakers fee: AbbVie Jauregui-Amezaga, Aranzazu: I declare that I have no personal financial conflicts of interest related to my scientific activities. Any research funding received from Takeda, Johnson & Johnson, and AbbVie has been allocated to the research group to which I belong and has been used exclusively to support institutional or group-based research initiatives, with no personal financial benefit. Van Dyck, Evi: No conflict of interest Stroie, Tudor Gheorghe: No conflict of interest Theodoraki, Eirini: No conflict of interest Casanova, María José: María José Casanova, has received education funding from Pfizer, Takeda, Janssen, MSD, Dr. Falk, Shire, Ferring, Galápagos and Abbvie, and research funding from Lilly. Mañosa Ciria, Miriam: Personal Fees: Abbvie, FAES Pharma, Ferring, Jannsen, MSD, Pfizer, Tillots and Lilly Cristiano, Margarida: No conflict of interest Karmiris, Konstantinos: Personal Fees: Speaker fees from Abbvie, BMS, Eli-Lilly, Genesis, Innovis, Johnson & Johnson, Pfizer and consultancy or advisory board member fees from Abbvie, BMS, Faran, Ferring, Genesis, Johnson & Johnson, Pfizer, Roche and Takeda Fernandes, Samuel Raimundo: None to declare Márquez Mosquera, Lucía: None Mesonero Gismero, Francisco: I ve served as a speaker for and received consulting fees from MSD, AbbVie, Takeda, Janssen, Pfizer, Ferring Pharmaceuticals, Kern Pharma, Dr. Falk Pharma, Galapagos, Lilly, Chiesi Farmaceutici, and Faes Farma. Lobatón Ortega, Triana: No conflict of interest
AIM:This study aimed to evaluate the significance of a stepped nurse-led low anterior resection syndrome (LARS) clinic for patients. METHODS:A Nurse-Led Clinic (NLC) with a stepped intervention approach for patients with LARS was developed and implemented. An exploratory study was conducted in three hospitals to evaluate the nurse-led clinic. Adult rectal cancer patients experiencing LARS who attended the NLC were recruited via maximum variation sampling for semi-structured interviews. Thematic analysis was performed, employing researcher triangulation to enhance reliability. RESULTS:Seventeen participants were interviewed to evaluate the clinic. Participants described five characteristics: (1) presence of the nurse, (2) accessibility, (3) providing recognition, affirmation and understanding, (4) coordinating and (5) timing of the consultation. In addition, participants outlined four principal tasks: (1) providing information, (2) management of symptoms, (3) support and (4) follow-up and continuity of care. CONCLUSION:The NLC offered meaningful support by addressing patients' concerns comprehensively. It normalised the condition, empowered patients with tailored information and provided effective symptom management strategies. REPORTING METHOD:SRQR checklist.
AIMS:The natural history and response to tafamidis treatment in women with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) remain insufficiently characterised. Current study aimed to explore sex-differences in clinical presentation, natural course and tafamidis treatment efficacy, focusing on women with ATTRwt-CM. METHODS AND RESULTS:An international, multicentric cohort of ATTRwt-CM subjects was evaluated, including for all-cause mortality. In total 1454 patients were studied (mean age 81±7y), including 307 (21.1%) females. At presentation, females were ∼3 years older than males with slightly worse phenotype, including higher indexed left ventricular wall thickness and National Amyloidosis Centre (NAC) disease stage (p<0.050). Heart failure with preserved ejection fraction and hypertension coincided more often in women (p=0.001). Natural disease course was poor without sex-difference, even when age-corrected (p=0.210). Tafamidis was initiated in 1055 patients, 12% less in females (p<0.001), although reasons for non-initiation and discontinuation did not show heterogeneity by sex (p=0.116 and p=0.304, respectively), indicating structural undertreatment. After 1.9 (0.9-3.3) years of median follow-up, 409 (28.1%) patients died. Tafamidis related to lower mortality in the overall and propensity score-matched cohort (n=742, HR 0.44, 95%CI 0.32-0.61, p<0.001), without sex-difference (female HR 0.76, 95%CI 0.52-1.11, p=0.150) nor sex-based treatment efficacy interaction (p=0.381). NAC disease stages strongly related to mortality under tafamidis treatment (HR 2.13%, 95%, 1.81-2.50, p<0.001), but female sex did not (HR 0.82, 95%CI 0.53-1.27, p=0.365). CONCLUSIONS:Women with ATTRwt-CM are prone to underdiagnosis and undertreatment, despite similar poor natural course and tafamidis treatment efficacy. Initiatives to increase diagnostic awareness and disease modifying treatment initiation in women are urgently needed.
BACKGROUND & AIMS:Upadacitinib (UPA) is an oral, reversible Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We assessed the long-term safety of UPA in both inflammatory bowel disease (IBD) entities. METHODS:Safety from 6 UC/CD trials assessed UPA 45 mg (UPA45) once daily (QD) induction, UPA 15 mg and 30 mg (UPA 15/30 QD) maintenance/long-term extension (LTE) doses, and rescue therapy (UPA30 QD). Adverse events (AEs) were reported as events per 100 patient-years (E/100 PY). RESULTS:Overall, 2118 patients received placebo (PBO; n = 725) or UPA45 (n = 1393) induction; 1419 received PBO (n = 468), UPA15 (n = 471), or UPA30 (n = 480) maintenance/LTE. During maintenance/LTE, UPA cumulative exposure was 5149.3 patient-years (n = 1910). Median treatment duration was 8.7 weeks (interquartile range [IQR], 8.0-12.0 weeks) for UPA45 induction; median maintenance/LTE treatment duration was 58.1 weeks (IQR, 30.4-164.0 weeks) for UPA15, and 130.9 weeks (IQR, 39.4-175.1 weeks) for UPA30. AE incidence was comparable between UPA and PBO during induction and maintenance/LTE; AEs leading to study drug discontinuation and serious or severe AEs were lower with UPA. During maintenance/LTE, rates (UPA15/30 vs PBO) of venous thromboembolic events (0.3/0.4 vs 0 E/100 PY), gastrointestinal perforations (0.4/<0.1 vs 0.8 E/100 PY), and AEs leading to death (0.2/<0.1 vs 0 E/100 PY) were low. Herpes zoster, neutropenia, lymphopenia, creatine phosphokinase elevation, hepatic disorder, and COVID-19 were higher across UPA groups vs PBO; COVID-19 and herpes zoster were among the most common AEs during maintenance. CONCLUSIONS:Long-term, UPA was generally well-tolerated. This integrated analysis supports the favorable safety profile of UPA and treatment decisions for patients with IBD. CLINICALTRIALS:gov, Numbers: NCT02819635, NCT03653026, NCT03006068, NCT03345836, NCT03345849, and NCT03345823.
