OP12 Blood proteins related to immunoregulation or cellular junctions reveal distinct biological profiles associated with the risk of short-term versus mid/long-term relapse in Crohn’s Disease patients stopping infliximab

Abstract

Abstract Background In Crohn’s disease (CD), biologics can induce mucosal healing and stable remission. After reaching this target, treatment de-escalation could be considered but the risk of relapse needs to be estimated. Current biomarkers used to predict relapse (C-reactive protein: CRP, faecal calprotectin) offer a limited prognostic capacity. Furthermore, they only monitor inflammation while we recently highlighted various and distinct pathological processes associated with the risk of short-term (<6 months) and mid/long-term (>6 months) relapse in CD patients stopping infliximab. Herein, the aim of our study was to further characterise this distinction. Methods Serum abundance of 92 proteins were measured by proximity extension assay (immune response panel, Olink) at baseline of the STORI cohort (infliximab diScon-Tinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors, n=102). Association of markers with the risk of relapse was determined by univariable Cox model in stratified (relapse <6 months or >6 months) and non-stratified datasets. Study of protein characteristics and enrichment analyses were performed to find biological patterns differentiating short-term from mid/long-term relapsers. To evaluate the predictive capacity of markers, we combined them systematically by pairs (‘AND’ or ‘OR’ logical operators) and used log-rank statistics with false discovery rate (FDR) correction (Benjamini-Hochberg). Results The risk of mid/long-term relapse was associated with a decreased circulating level of anti-inflammatory effectors while the risk of short-term relapse was associated with an increased circulating level of pro-inflammatory effectors (Fig. 1A, 1B). The risk associated with the downstream signalling of cytokine and pattern recognition receptors showed an opposite pattern in the short-term versus mid/long-term relapsers (Fig. 1D, 1E). The risk of short-term relapse was characterised by a perturbed circulating level of proteins inducing tolerance and immunity in antigen presenting cells (Fig. 2A, 2B). The risk of mid/long-term relapse was characterised by an increased circulating level of proteins promoting lymphocyte tolerance (Fig. 2D, 2E) and a decreased circulating level of cellular junction proteins (Fig. 3). We found 1223 (short-term relapse dataset), 233 (mid/long-term relapse dataset) and 101 (non-stratified dataset) novel marker combinations with FDR<0.05 and higher Z-scores than CRP and faecal calprotectin. The best combinations are showed in Fig. 4. Conclusion In CD patients stopping infliximab, blood proteins linked to immunoregulation or cellular junctions support the distinct profiles of short-term and mid/long-term relapsers. These proteins showed a capacity to predict the relapse.