Pretreatment Prediction of Individual Rheumatoid Arthritis Patients’ Response to Anti-Cytokine Therapy Using Serum Cytokine/Chemokine/Soluble Receptor Biomarkers

Abstract

The inability to match rheumatoid arthritis (RA) patients with the anti-cytokine agent most efficacious for them is a major hindrance to patients’ speedy recovery and to the clinical use of anti-cytokine therapy. Identifying predictive biomarkers that can assist in matching RA patients with more suitable anti-cytokine treatment was our aim in this report. The sample consisted of 138 RA patients (naïve and non-naïve) who were administered tocilizumab or etanercept for a minimum of 16 weeks as a prescribed RA treatment. Pretreatment serum samples were obtained from patients and clinical measures of their disease activity were evaluated at baseline and 16 weeks after treatment commenced. Using patients’ pretreatment serum, we measured 31 cytokines/chemokines/soluble receptors and used multiple linear regression analysis to identify biomarkers that correlated with patients’ symptom levels (DAS28-CRP score) at week 16 and multiple logistic analyses for biomarkers that correlated with patients’ final outcome. The results revealed that sgp130, logIL-6, logIL-8, logEotaxin, logIP-10, logVEGF, logsTNFR-I and logsTNFR-II pretreatment serum levels were predictive of the week 16 DAS28-CRP score in naïve tocilizumab patients while sgp130, logGM-CSF and logIP-10 were predictive in non-naïve patients. Additionally, we found logIL-9, logVEGF and logTNF-α to be less reliable at predicting the week 16 DAS28-CRP score in naïve etanercept patients. Multiple linear regression and multiple logistic regression analyses identified biomarkers that were predictive of remission/non-remission in tocilizumab and etanercept therapy. Although less reliable than those for tocilizumab, we identified a few possible biomarkers for etanercept therapy. The biomarkers for these two therapies differ suggesting that their efficacy will vary for individual patients. We discovered biomarkers in RA pretreatment serum that predicted their week 16 DAS28-CRP score and clinical outcome to tocilizumab therapy. Most of these biomarkers, especially sgp130, are involved in RA pathogenesis and IL-6 signal transduction, which further suggests that they are highly reliable.Trial RegistrationUMIN-CTR Clinical Trial UMIN000016298

Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia

“…Thus, we believe the high levels of sgp130 that are seen in our patients prior to treatment with tocilizumab are clinically and biologically relevant; however, future work investigating the importance and function of trans-IL6 signaling is needed. (25)…”

Association of High Serum Interleukin‐6 Levels With Severe Progression of Rheumatoid Arthritis and Increased Treatment Response Differentiating Sarilumab From Adalimumab or Methotrexate in a Post Hoc Analysis

“…Studies of circulating IL-6 concentrations in patients with RA treated with tocilizumab have reported conflicting findings. Some found that responses to treatment improved in patients with low IL-6 levels (30,31), while others identified patients with high IL-6 levels as better responders (13,32,33). A comprehensive study conducted by Wang et al (13) evaluated the impact on change in DAS28-ESR with tocilizumab for every 3-fold increase in baseline IL-6 level.…”

Proteomics to predict the response to tumour necrosis factor-α inhibitors in rheumatoid arthritis using a supervised cluster-analysis based protein score

“…It is therefore not expected that patients with a low DAS28 and high HAQ will have a better response to any non-TNFi. Proteomic approaches to the prediction of response have been studied before (14)(15)(16)(17)(18)(19)(20)(21)). An overview of these studies and reported results is presented in Table 5.…”