Multiple logistic regression analysis of remission using cytokine /chemokaine/soluble receptor levels.

<p>-: excluded from analysis</p><p>sgp130: soluble gp130, IP-10: Interferon gamma-induced protein 10, IL: Interleukin, sTNFRII: soluble tumor necrosis factor receptor two, TNF: Tumor necrosis factor</p><p>Multiple logistic regression analysis of remission using cytokine /chemokaine/soluble receptor levels.</p

Box plot of typical cytokine/chemokine/soluble receptor levels in healthy controls (HC), tocilizumab treated naïve patients (Naïve (TCZ)), tocilizumab treated non-naïve patients (Non-naïve (TCZ)) and etanercept treated naïve patients (Naïve (ETN)).

<p>Sgp130 is expressed in raw values (μg/ml); the other variables are expressed in log-transformed values. Box plots consist of the minimum, first quartile, median, third quartile, and maximum.</p

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

<div><p>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.</p><p>Trial Registration</p><p>UMIN-CTR Clinical Trial <a href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000018909&language=E" target="_blank">UMIN000016298</a></p></div

Multiple linear regression analysis of week 16 DAS28-CRP score using cytokine/chemokaine/soluble receptor levels.

<p>-: excluded from analysis</p><p>sgp130: soluble gp130, IP-10: interferon gamma-induced protein 10, IL: interleukin, sTNFRI: soluble tumor necrosis factor receptor one, sTNFRII: soluble tumor necrosis factor receptor two, VEGF: vascular endothelial growth factor, GM-CSF: granulocyte macrophage colony-stimulating factor, TNF: tumor necrosis factor</p><p>Multiple linear regression analysis of week 16 DAS28-CRP score using cytokine/chemokaine/soluble receptor levels.</p

Differential distributions of pretreatment serum soluble gp130 levels in biologic naïve patients (remission:black line, non-remission:gray line).

<p>Serum soluble gp130 levels (μg/ml) were determined before therapy and remission was considered as DAS28-CRP score of 2.3 and below after 16 weeks of therapy.</p

ROC curves for predicting remission in biologic naïve patients (A) and non-naïve patients (B) to tocilizumab therapy.

<p>ROC curve for sgp130 (gray line); ROC curve for sgp130, logsTNFR-II, logIP-10 and logIL-6 (black line).</p

Baseline profile of tocilizumab and etanercept patients.

<p>*Values are the mean ± SEM</p><p>WBC: white blood cells, RBC: red blood cells, Hb: hemoglobin, Ht: hematocrit, Plt: platelet count, CRP: C-reactive protein, DAS28-CRP: disease activity acore 28 C-reactive protein, RF: rheumatoid factor, VAS: visual analog scale, MMP-3: matrix metalloproteinase protein 3</p><p>Baseline profile of tocilizumab and etanercept patients.</p

Scatter plot and regression lines for baseline and week 16 DAS28-CRP score in RA patients administered with tocilizumab (A: naïve and B: non-naïve) or etanerecept (C: naïve) therapy.

<p>Black circle to the left of the 45° line in Fig 2B represents the only non-naïve tocilizumab patient with no improvement in their DAS28-CRP score at week 16. Three black circles to the left of the 45° line in Fig 2C represents etanerecept patients with no improvement in their DAS28-CRP score at week 16.</p

Sample profile and patient outcome to tocilizumab therapy.

<p>Patient’s final outcome was based on their DAS28-CRP score 16 weeks after the first tocilizumab or etanerecept treatment. Non-naïve patients are those who had prior anti-cytokine treatment one to three times.</p