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OP003 Temporal changes in immune pathways with consecutive biological therapies as measured by serum proteomics

M. de Bruyn1,2*, V. Ballet3, S. Verstockt4, B. Verstockt1,3, G. Van Assche1,3, M. Ferrante1,3, K. Machiels1, S. Vermeire1,3

1Translational Research Center for GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism and Ageing (CHROMETA), Leuven, Belgium, 2Rega Institute for Medical Research, Microbiology and Immunology, Leuven, Belgium, 3University Hospitals Leuven, Gastroenterology and Hepatology, Leuven, Belgium, 4Laboratory of Complex Genetics, Human Genetics, Leuven, Belgium

Background

The last decade, anti-α4β7 (vedolizumab/VDZ) and anti-p40 (ustekinumab/UST) antibodies became available on top of anti-TNF agents (infliximab/IFX, adalimumab/ADM) for patients with inflammatory bowel disease. Biological-naïve patients consistently had better outcomes compared with exposed patients. It is unclear whether this is due to more refractory disease or alterations in immune pathways triggered by biological exposure. Using serum proteomics, we evaluated differences in immune profiles at start and after switch of different types of biologicals.

Methods

Consecutive serum samples were collected at start of biological treatment (Time point/T1) and at time of switch to another biological (T2, T3) from 176 anti-TNF-treated patients (137 IFX, 39 ADM), 41 VDZ-treated patients, 5 UST-treated patients, 40 patients treated with IFX, ADM, and VDZ, and 13 patients treated with anti-TNF, VDZ, and UST. All patients starting anti-TNF were biological-naïve. With the proximity extension assay technology, 79 inflammatory markers were measured (OLINK). RNA sequencing on matched baseline mucosal biopsies (n = 54) was performed with Illumina HiSeq 4000NGS. Significance was reported after multiple testing correction (false discovery rate).

Results

In patients failing IFX, 34 serum markers involved in cell migration and immune response were significantly higher at T2 compared with T1. In contrast, patients failing ADM had significantly lower levels of 23 markers involved in immune process stimulation and chemotaxis at T2. IL-17A was significantly higher at T2 after both IFX and ADM. At ADM T1 vs. IFX T1, 9 markers involved in cell migration were significantly different, regardless of disease activity. In patients failing VDZ, five markers involved in cytokine signalling were lower at T2. Similar trends were observed at mRNA level (Table 1). In patients failing UST, 14 markers involved in immune regulation (e.g. TNF, CCL25) were lower at T2. Patients switching from IFX–>ADM(T2)–>VDZ(T3) had significantly higher levels of 21 cell migration markers (e.g. CCL7) at T2 and most of these decreased at T3. Patients switching from anti-TNF–>VDZ(T2)–>UST(T3) had higher levels of apoptotic markers at T2, and altered levels of lymphocyte differentiation markers (e.g. IL-12B) at T3.

Table 1. Overview of dysregulated inflammatory markers as measured by serum proteomics and mucosal transcriptomics.

Conclusion

Exposure to different types of biological treatments is associated with specific changes in immune profiles. Future studies should now prospectively characterise these profiles on a larger scale to see whether they can aid clinicians in personalised therapeutic decision-making.