Abstract Background The clinical course of inflammatory bowel disease (IBD) is highly heterogeneous. Previously we identified a protein-based prognostic signature in serum using the proximity extension assay (PEA). To enable clinical translation, further assay development is required, including the establishment of standard curves and clinically actionable cut-offs. Therefore, we aimed to develop, optimise and validate a serum-based assay that quantifies absolute protein concentrations at diagnosis to identify individuals at higher risk of an aggressive course of IBD. Methods Proteins were selected from the commercially available Olink inflammation and oncology II panels as well as from five custom-made multiplex panels comprising 460 proteins based on genes in 163 IBD-risk loci (the IBD Character project1). Serum from 71 newly diagnosed IBD patients (Crohn’s disease, n = 29; ulcerative colitis, n = 42) (SIC-IBD) was analysed. Proteins associated with an aggressive course: I) need for biologics, ciclosporin, or surgery for flare after initial induction or II) hospitalisation, refractoriness to targeted therapy, excessive corticosteroid use or surgery within one year, were identified using penalised logistic regression. From these proteins a focused prognostic panel was developed and analytically optimized for absolute quantification. Model performance was evaluated by nested cross-validation (area under the curve AUC) and externally validated in 329 treatment-naïve IBD patients from the population-based IBSEN III cohort. Time to the composite outcome was analysed by estimating hazard rations (HR) using Cox regression. Results Thirteen proteins (CCL19, XPNPEP2, TGFα, VGFA, DLL1, PSGL1, OSM, CSF1, FURIN, IL-18, EpCAM, and TNFRSF9) met the pre-defined criteria and formed the final prognostic signature. In the discovery cohort, the model achieved an AUC of 0.76, with no interaction with age, sex or IBD subtype. External validation in the IBSEN III cohort yielded an AUC of 0.66 (95%CI 0.57-0.75), sensitivity 49% and specificity 70% at the discovery cohort derived optimal cut-off. Among patients classified as high risk, compared to low risk, the HR for the composite endpoint of aggressive disease course was 1.81 (P = 0.0002, Figure 1). Conclusion We developed and validated the first PEA-based serum panel enabling absolute quantitation of prognostic proteins for clinical use. At diagnosis, IBD-patients classified as high risk based on the 13-protein signature had an 81% higher relative risk of an aggressive disease course, supporting further evaluation. Reference: Kalla, A. T. Adams, D. Bergemalm et al. Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease. Journal of Crohn’s and Colitis, 2021, 699–708. doi:10.1093/ecco-jcc/jjaa2301 The p-value in the figure here below is from the KM log-rank test (not from the Cox regression). Conflict of interest: Germanopoulos, Antonios: No conflict of interest Dr. Bergemalm, Daniel: DB has received fees for lectures and/or advisory board from Abbvie, Bristol Mayers Squibb, Johnson and Johnson, Pharmacosmos, Pfizer, Takeda, Tillots Pharma and Sandoz. Grännö, Olle: No conflict of interest Salomon, Benita: No conflict of interest Eriksson, Carl: Grant support from Takeda Kruse, Robert: No conflict of interest Hedin, Charlotte Rose: C. R. H. Hedin served as a speaker and/or advisory board member for AstraZeneca, Abbvie, Celltrion, Dr Falk Pharma and the Falk Foundation, Galapagos, Janssen, Lilly, Pfizer, Ferring, Takeda, Tillotts Pharma, and received grant support from Tillotts and Takeda. Carlson, Marie: Dr Carlson has received speaker’s fees from ViforPharma and AbbVie. She is the national PI for clinical trials for AstraZeneca. None of these activities have any relation to the present study. Rejller, Martin: No conflict of interest Füchtbauer, David: travel grants from Tillotts Pharma Davíðsdóttir, Loa: No conflict of interest Fejrskov, Anja: No conflict of interest Andersen, Vibeke Charlotte: Grant support: The Region of Southern Denmark “Fri og Strategisk Forskning” (J.nr.: 20/44012 and 17/18561), Innovation Fund Denmark (90569 NORDTREAT: grant number 8114-00026B). Sundhedsdonationer (2024-0379). Presenting and/or advisory board fees from: MSD/Merck and Eli Lilly Bache-Wiig Mathisen, Charlotte: No conflict of interest Bengtson, May-Bente: No conflict of interest Aabrekk, Tone Bergene: No conflict of interest Detlie, Trond Espen: Served as aspeaker, consultant, or advisory board member for AbbVie,Ferring, Janssen-Cilag AS, Pfizer, Pharmacosmos, Takeda,Tillotts, and Vifor Pharma. He has received unrestrictedresearch grants from AbbVie and Pharmacosmos. Opheim, Randi: No conflict of interest Kristensen, Vendel: Served as a consultant or advisory board member for Janssen Cilag, Takeda, andTillotts Pharma Salihovic, Samira: No conflict of interest Öhman, Lena: No conflict of interest Söderholm, Johan D.: No conflict of interest Lindqvist, Carl Mårten: No conflict of interest Jahnsen, Jørgen: No conflict of interest Satsangi, Jack: Grant: Grants to Oxford University from Helmsley Trust & European Community. Kalla, Rahul: grant funding from JNJ, Crohn’s and colitis uk, UKRI and CSO. I have speaker fees from dr Falk Gomollón Garcia, Fernando: Grant: MSD, Abbvie, Janssen Personal Fees: Janssen, Abbvie, Takeda Non-financial Support: Janssen, Takeda, Falk,Pfizer Ricanek, Petr: No conflict of interest D’Amato, Mauro: No conflict of interest Kjeldsen, Jens: No conflict of interest Høivik, Marte: Investigator-initiated research grants from Takeda, Pfizer,Tillotts, Ferring, and Janssen. Received speaker honorariafrom Takeda, Tillotts, Ferring, AbbVie, Galapagos, and Meda.Advisory board affiliations with Takeda, Galapagos, MSD,Lilly, Celltrion, and AbbVie Repsilber, Dirk: No conflict of interest Halfvarson, Jonas: Grant support: Swedish Foundation for Strategic Research (RB13-0160 to J.H.), the Swedish Research Council (2020-02021 to J.H.), the Örebro University Hospital research foundation (OLL-890291 to J.H.), NordForsk (90569 to J.H.) and Vinnova ( 2019-01185 to JH and 2024-01155 co-applicant), IHI, EU, INTERCEPT (Grant agreement number 101194780, co-applicant), miGut-Health, HORIZON-HLTH-2022, EU (Grant Agreement 101095470, Co-applicant), 3TR, IMI 2, EU, (Grant agreement number 831434, Co-applicant), Janssen, MSD, and Takeda. Consulting and/or advisory board fees from: AbbVie, Alfasigma, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Hospira, Index Pharmaceuticals, Janssen, Johnson & Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and speaker’s fees from: AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma and research grant support from Janssen, Merck Sharp & Dohme and Takeda.
Germanopoulos et al. (Thu,) studied this question.