Circulating Retinol-Binding Protein 4 as a Possible Biomarker of Treatment Response for Ankylosing Spondylitis: An Array-Based Comparative Study

Abstract

Objective: To explore proteins associated with ankylosing spondylitis (AS) and to investigate potential proteins that may predict treatment response of adalimumab (ADA) in AS patients. Methods: In the discovery cohort, 39 AS patients and 20 healthy controls (HCs) were included, and 16 AS patients received ADA treatment for 24 weeks after included. In the validation cohort, 43 AS patients and 39 HCs were enrolled, and all 43 patients received ADA treatment after enrollment. Blood samples and clinical information were collected from two cohorts at baseline from all participants and week 24 from patients received ADA treatment. A human antibody array containing 1,000 proteins was used in the discovery phase, and Elisa kits were used for protein validation. Results: Compared with HCs, we identified 53 differentially expressed proteins (DEPs) in AS patients. Bioinformatics analysis revealed they were mostly enriched in coagulation function-related pathways, acute response signaling, and LXR/RXR activation. Bone metabolism pathways were also associated. Comparison between samples of pre-and post-ADA treatment revealed 42 DEPs. They were mostly associated with bone metabolism and inflammation response pathways. Significant enrichment was also found in LXR/RXR activation but not the coagulation functionrelated pathways. Upstream regulator analysis suggested that most regulators also significantly functioned under usage of ADA. Precisely, seven proteins were abnormally expressed in AS and restored after ADA treatment. Retinol-binding protein 4 (RBP4), one of the seven proteins, was validated that its baseline levels were inversely correlated with improvements in Ankylosing Spondylitis Disease Activity Score-C-reactive protein (ASDAS-CRP). Likewise, percentage changes in RBP4 levels were inversely correlated with changes in ASDAS-CRP score. Conclusion: A dysregulated serum protein profile existed in AS. ADA exerted a considerable but not entire alteration toward the dysregulation. RBP4 could be a biomarker for predicting and monitoring ADA treatment response.

Measurement of pre‐treatment inflammatory cytokine levels is valuable for prediction of treatment efficacy to tumor necrosis factor inhibitor in axial spondyloarthritis patients

“…Previous studies have evaluated the value of cytokine levels in predicting the response of axSpA patients to TNF inhibitors 19,21–24 . For instance, one study showed that CRP and Jun N‐terminal kinase pathway‐associated phosphatase (JKAP) might predict the treatment response to TNF inhibitors 21 .…”

“…Previous studies have evaluated the value of cytokine levels in predicting the response of axSpA patients to TNF inhibitors. 19,[21][22][23][24] For instance, one study showed that CRP and Jun N-terminal kinase pathway-associated phosphatase (JKAP) might predict the treatment response to TNF inhibitors. 21 Another study exhibited that circulating baseline IL-6 and erythrocyte sedimentation rate might reflect the response to adalimumab in AS patients.…”

The Hepatokine RBP4 Links Metabolic Diseases to Articular Inflammation

“…High levels of RBP4 have been associated with inflammation in metabolic disorders like insulin resistance [9,13], metabolic syndrome [14,15], fatty liver [16], cardiovascular diseases like atherosclerosis [17], and chronic inflammatory diseases such as psoriasis [8]. Moreover, altered levels of RBP4 have been reported in patients with rheumatic diseases, including rheumatoid arthritis (RA) [18,19] and ankylosing spondylitis [20]. RBP4 was also specifically related to RA co-morbidities in RA patients [21,22].…”

Leukemia inhibitory factor is dysregulated in ankylosing spondylitis and contributes to bone formation

“…However, the pathogenesis of bone erosion and bone formation in AS is not completely understood 5 . In recent years, many studies have reported that cytokines play a vital role in disease pathology, 6‐9 and other studies have reported that the dysregulation of the immune system and bone metabolism may play a critical role in AS etiology 10,11 …”

“…However, the pathogenesis of bone erosion and bone formation in AS is not completely understood. 5 In recent years, many studies have reported that cytokines play a vital role in disease pathology, [6][7][8][9] and other studies have reported that the dysregulation of the immune system and bone metabolism may play a critical role in AS etiology. 10,11 Leukemia inhibitor factor (LIF), also known as differentiationstimulating factor and differentiation-inducing factor, is a member of the interleukin (IL)-6 family, which is widely expressed in multiple types of tissue and is a pleiotropic cytokine.…”