Baseline CXCL10 and CXCL13 levels are predictive biomarkers for tumor necrosis factor inhibitor therapy in patients with moderate to severe rheumatoid arthritis: a pilot, prospective study

Abstract

BackgroundTNF inhibitors have been used as a treatment for moderate to severe RA patients. However, reliable biomarkers that predict therapeutic response to TNF inhibitors are lacking. In this study, we investigated whether chemokines may represent useful biomarkers to predict the response to TNF inhibitor therapy in RA.MethodsRA patients (n = 29) who were initiating adalimumab or etanercept were recruited from the rheumatology clinics at Cooper University Hospital. RA patients were evaluated at baseline and 14 weeks after TNF inhibitor therapy, and serum levels of CXCL10, CXCL13, and CCL20 were measured by ELISA. Responders (n = 16) were defined as patients who had good or moderate response at week 14 by EULAR response criteria, and nonresponders (n = 13) were defined as having no response.ResultsResponders had higher levels of baseline CXCL10 and CXCL13 compared to nonresponders (p = 0.03 and 0.002 respectively). There was no difference in CCL20 levels. CXCL10 and CXCL13 were highly correlated with each other, and were higher in seropositive RA patients. CXCL10 and CXCL13 levels were decreased after TNF inhibitor therapy in responders. Baseline additive levels of CXCL10 + 13 were correlated with changes in DAS score at 14 weeks after TNF inhibitor therapy (r = 0.42, p = 0.03), and ROC curve analyses for predictive ability of CXCL10 + 13 showed an AUC of 0.83.ConclusionsElevated baseline levels of CXCL10 and CXCL13 were associated with favorable response to TNF inhibitor therapy in RA. Subjects with high CXCL10 and high CXCL13 may represent a subset of RA patients whose inflammatory reactions are primarily driven by TNF.

Pathogenic role of endogenous TNF-α in the development of Sjögren's-like sialadenitis and secretory dysfunction in non-obese diabetic mice

“…Whether the induction of CXCL9 by TNF-α requires cooperation of other factors, such as IFN-γ, during the development of SS will be addressed in our future investigations. In addition to CXCR3 ligands, CXCL13 is a critical chemokine directing B cell recruitment to target organs in inflammatory conditions 44 and the decrease in CXCL13 expression resulting from the anti-TNF therapy is considered a potential predictive biomarker in rheumatic arthritis patients 45 . In line with these findings, we demonstrated that neutralization of TNF-α leads to down-regulation of CXCL13 expression also in SS disease settings.…”

08.07 Blood chemokine profile in untreated early rheumatoid arthritis: cxcl10 as a disease activity marker

“…Similarly, higher serum levels of CCL22 in patients with RA compared to healthy controls have been reported previously; however, in that study, the majority of the patients were treated with DMARD and there was no information concerning the disease duration [22]. Various treatments have been shown to affect the levels of chemokines in the circulation [15][16][17][18], which suggests that evaluation of chemokines in untreated patients might be advantageous.…”

“…Similarly, in another cohort with pre-patients and early RA patients in which blood chemokines were investigated, 39% of the patients were treated with prednisolone [14]. Treatment with biological and non-biological DMARD in RA have been shown to alter the chemokine levels in the blood [15][16][17][18], suggesting a need to evaluate chemokines in a pure group of DMARD-naive ueRA patients.…”

Filgotinib, a JAK1 Inhibitor, Modulates Disease-Related Biomarkers in Rheumatoid Arthritis: Results from Two Randomized, Controlled Phase 2b Trials

“…Immune effects of filgotinib were also captured with key T-cell, B-cell, and innate cell cytokines and their recruiting chemokines, together with a cell-based biomarker readout of major immune cell subsets in the blood by flow cytometry immunophenotyping. Pathogenic effectors of tissue matrix damage and cross-talk between synovial fibroblasts, endothelial cells, cartilage, and bone were founded on a clinically validated panel of soluble biomarkers that associate with RA disease activity [1,11]. Finally, several biomarkers that have been implicated in predicting clinical therapeutic response were also included [11,12].…”

“…Pathogenic effectors of tissue matrix damage and cross-talk between synovial fibroblasts, endothelial cells, cartilage, and bone were founded on a clinically validated panel of soluble biomarkers that associate with RA disease activity [1,11]. Finally, several biomarkers that have been implicated in predicting clinical therapeutic response were also included [11,12]. By using highly sensitive multiplex immunoassays that minimized sample blood volume burden to patients, we could profile serial time points for an extensive characterization of a new molecular entity in the next generation of targeted RA therapeutics.…”