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P019 Differential effects of first-line IFX and conventional treatment on inflammatory serum proteins of paediatric moderate- to-severe Crohn’s disease patients.

JongsmaMSc, M.(1);Costes, L.M.M.(2);Tindemans, I.(2);Cozijnsen, M.A.(1);Raatgeep, R.H.C.(2);van Pieterson, M.(1);Li, Y.(3);Escher, J.C.(1);de Ridder, L.(1);Samsom, J.N.(2);

(1)Erasmus MC - Sophia Children's hospital, Department of Pediatric Gastroenterology, Rotterdam, The Netherlands;(2)Erasmus MC - Sophia Children's hospital, Laboratory of Paediatrics- division Gastroenterology and Nutrition, Rotterdam, The Netherlands;(3)Erasmus University Medical Centre/Erasmus MC Cancer Institute, Department of Pathology & Clinical Bioinformatics, Rotterdam, The Netherlands

Background

Recently, we established that First-line infliximab (FL-IFX) was superior to conventional treatment (CONV) in achieving and maintaining clinical remission in newly diagnosed paediatric patients with moderate-to-severe Crohn’s disease (CD) (PMID: 33384335). Selection of patients eligible for FL-IFX can be corroborated by combining clinical criteria with immunological biomarkers relating to the patients’ underlying immunopathology. Therefore, we investigated differential effects of FL-IFX and CONV induction treatment on serum inflammatory protein concentrations and assessed whether stratification of CD patients according to baseline serum profiles of IFX-modulated proteins relates to maintaining remission at week 52.

Methods

In the TISKIDS randomised controlled trial, newly diagnosed therapy-naïve CD patients with a weighted paediatric CD activity index (wPCDAI) >40 were included. FL-IFX consisted of 5 IFX infusions (5 mg/kg) combined with azathioprine (AZA) maintenance treatment. CONV treatment consisted of induction therapy with Exclusive Enteral Nutrition or oral prednisolone combined with AZA maintenance. Serum samples of 48 FL-IFX and 43 CONV patients, collected at time of diagnosis and after 10-14 weeks of induction treatment, were available. Concentrations of 92 inflammatory proteins were determined with Olink Proteomics® proximity extension technology. Hierarchical clustering was performed to stratify patients according to their serum immune profiles. Clinical disease remission was defined as wPCDAI<12.5.

Results

At baseline, prior to therapy, clinical disease characteristics and serum inflammatory protein concentrations did not significantly differ between FL-IFX and CONV treated patients. After 10-14 weeks, FL-IFX reduced 28 proteins and enhanced 2 proteins while CONV treatment reduced 13 proteins and enhanced 1 protein. Eighteen proteins were differentially regulated by FL-IFX only.

Hierarchical clustering of patients based on their baseline profiles of the 30 IFX-modulated proteins revealed 2 patient clusters. The CD-hi cluster had an increased abundance of 24/30 proteins amongst which Oncostatin-M, TNFSF14, HGF and TGF-alpha and higher clinical inflammatory parameters compared to the CD-lo cluster.

Crucially, both baseline inflammatory protein profile and type of induction therapy significantly determined whether patients reached clinical disease remission without treatment escalation at week 52; with CD-hi patients having the lowest change.

Conclusion

FL-IFX achieves stronger reduction and modulates more proteins than CONV treatment. Stratification of patients according to profiles of IFX-modulated proteins discerns patients with a lower chance of reaching clinical remission without treatment escalation at week 52.

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