Retinol-binding protein 4 (RBP4) may serve as a biomarker for predicting and monitoring patient response to adalimumab in ankylosing spondylitis (AS), with those who have dysregulated serum protein profiles, according to research results published in Frontiers in Pharmacology.

Researchers sought to identify the proteins and pathways involved in AS, as well as to optimize the use of adalimumab treatment by identifying the proteins that might serve as biomarkers to predict and monitor treatment response in AS.

Participants were enrolled in the study in 2 phases: The discovery cohort included 39 patients with AS (82.05% men; mean age, 30.13±9.51 years) and 20 age- and sex-matched healthy control participants (80% men, age, 29.95±9.15 years); and the validation cohort included 43 patients with AS and 39 healthy control participants.

During the discovery phase, investigators detected and analyzed 1000 proteins, from which 53 differentially expressed proteins [DEPs] were identified, including 33 proteins with higher expression and 20 proteins with lower expression in patients with AS. The top 5 canonical pathways identified included coagulation-related pathways, liver X receptor/retinoid X receptor activation, and acute phase response signaling. Investigators used upstream regulator analysis to predict which molecules were potentially responsible for differential protein expression; they found that these regulators play prominent roles in inflammation and the immune system.

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Researchers also analyzed differential protein expression in samples from patients with AS before and after treatment with adalimumab for 24 weeks. In total, 42 DEPs were identified, with 32 upregulated and 10 downregulated proteins. The top 5 canonical pathways identified acted primarily on bone metabolism and inflammatory response. Three of these 5 pathways were not significantly related to adalimumab.

During the discovery phase, 7 of the 53 identified AS-related DEPs were also found to be adalimumab-related. These proteins included serum amyloid A-1, interferon regulatory factor 6, RBP4, tyrosine-protein kinase transmembrane receptor, osteocalcin, platelet-derived growth factor receptor beta, and A disintegrin and metalloproteinase with thrombospondin motifs 10. Significant differences in protein levels were noted at baseline between healthy control participants and the 16 patients treated with adalimumab.

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Serum levels of RBP4 were further tested in the validation cohort, with results showing that RBP4 levels were upregulated after adalimumab treatment — consistent with the results from the discovery cohort. No significant difference was noted at baseline between the AS and healthy control cohorts in terms of RBP4 levels. Further subgroup analyses did not identify any other significant differences, although patients who achieved major improvements after 24 weeks of adalimumab treatment generally had lower baseline levels of RBP4 compared with healthy control participants and patients who did not achieve major improvements.

“In our data, most AS-related pathways and upstream regulators were associated with [adalimumab] treatment,” the researchers concluded. “Coagulation pathways seemed to be crucial…but not to be altered by [adalimumab].…RBP4 was demonstrated to be a candidate biomarker for predicting and monitoring the response to [adalimumab] treatment.”


Wu J, Wu X, Chen Z, et al. Circulating retinol-binding protein 4 as a possible biomarker of treatment response for ankylosing spondylitis: an array-based comparative study [published online March 10, 2020]. Front Pharmacol. doi:10.3389/fphar.2020.00231