Serum protein profile of Crohn's disease treated with infliximab

Abstract

The infliximab (IFX) has dramatically improved the treatment of Crohn's disease (CD). However, the need for predictive factors, indicative of patients' response to IFX, has yet to be met. In the current study, proteomics technologies were employed in order to monitor for differences in protein expression in a cohort of patients following IFX administration, aiming at identifying a panel of candidate protein biomarkers of CD, symptomatic of response to treatment. We enrolled 18 patients, who either had achieved clinical and serological remission (Rm, n=6), or response (Rs, n=6) and/or were PNRs (n=6), to IFX. Serum samples were subjected to two-dimensional Gel Electrophoresis. Following evaluation of densitometrical data, protein spots exhibiting differential expression among the groups, were further characterized by MALDI-TOF-MS. Identified proteins where evaluated by immunoblot analysis while functional network association was carried out to asses significance. Proteins apolipoprotein A-I (APOA1), apolipoprotein E (APOE), complement C4-B (CO4B), plasminogen (PLMN), serotransferrin (TRFE), beta-2-glycoprotein 1 (APOH), and clusterin (CLUS) were found to be up-regulated in the PNR and Rs groups whereas their levels displayed no changes in the Rm group when compared to baseline samples. Additionally, leucine-rich alpha-2-glycoprotein (A2GL), vitamin D-binding protein (VTDB), alpha-1B-glycoprotein (A1BG) and complement C1r subcomponent (C1R) were significantly increased in the serum of the Rm group. Through the incorporation of proteomics technologies, novel serum marker-molecules demonstrating high sensitivity and specificity are introduced, hence offering an innovative approach regarding the evaluation of CD patients' response to IFX therapy.

Validation of Biomarkers in Gene Expression Datasets of Inflammatory Bowel Disease: IL13RA2, PTGS2 and WNT5A as Predictors of Responsiveness to Infliximab Therapy

“…Although there are no data available whether IBD patients non-responding to IFX therapy are at an increased risk for colon cancer, an animal study indicated that IBD animals treated with IFX are protected from colon cancer [22][23][24][25][26][27][28][29]. Therefore, one may also speculate that patients having high Wnt5a gene expression may be subjected to IFX non-responsiveness and, also, are at a higher risk of cancer.…”

Biomarkers of Inflammatory Bowel Disease

“…The authors successfully identified 15 proteins that were differentially accumulated in the sera of infliximab-responsive and -non-responsive CD patients. Among them, apolipoprotein A-I, apolipoprotein E, basic complement C4, plasminogen, serotransferrin, beta-2-glycoprotein 1, and clusterin were found to be more abundant in the primary non-responder and clinical/serological responder groups compared to the clinical/serological remission group, whereas leucine-rich alpha-2-glycoprotein, vitamin D-binding protein, alpha-1B glycoprotein and complement C1r subcomponent were more abundant in the latter group (84). This study thus showed the feasibility of identifying serum biomarkers capable of predicting treatment outcomes.…”

“…The authors verified the four previously identified biomarkers (81), generated a model for predicting the treatment response, and selected relevant potential biomarkers (including platelet aggregation factor 4, which was associated with non-response to infliximab) (83). In an effort to identify a panel of candidate protein biomarkers of CD that might predict the response to infliximab therapy, Gazouli et al recently measured changes in serum protein levels in a small cohort of 18 CD patients, including six primary non-responders (meaning that they did not respond to classical induction therapy), six patients who had responded clinically and serologically to infliximab, and six patients who had achieved clinical and serological remission on infliximab (84). Serum samples were analyzed using 2D polyacrylamide gel electrophoresis (PAGE), and 240 protein spots were selected for in-gel digestion and MALDI-TOF-MS.…”

Current application of proteomics in biomarker discovery for inflammatory bowel disease

“…Meuwis et al [37] published a second report which identified a serum protein profile which correlated with infliximab response. Gazouli et al [38] performed a similar study using MALDI TOF MS, identifying 15 proteins that were differentially expressed amongst patients that responded differently to infliximab. They were however, unable to confirm the findings by Meuwis et al [37] .…”

“…This issue holds true across the aforementioned studies in IBD as out of 19 biosample based discovery experiments, 8 studies used ≤ 6 cases and controls [33,34,38,5659] . In an effort to address this issue, Skates et al [55] designed a statistical model that estimates the statistical power of discovery and verification studies in tissue and plasma.…”