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

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

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

Image_2_Prompt Reduction in CRP, IL-6, IFN-γ, IP-10, and MCP-1 and a Relatively Low Basal Ratio of Ferritin/CRP Is Possibly Associated With the Efficacy of Tocilizumab Monotherapy in Severely to Critically Ill Patients With COVID-19.jpg

Background and Aim: Tocilizumab, a humanized anti-IL-6 receptor antibody, has been used to treat severely to critically ill patients with COVID-19. A living systematic review with meta-analysis of recent RCTs indicates that the combination therapy of corticosteroids and tocilizumab produce better outcomes, while previous observational studies suggest that tocilizumab monotherapy is beneficial for substantial numbers of patients. However, what patients could respond to tocilizumab monotherapy remained unknown.Methods: In this retrospective study we evaluated the effects of tocilizumab monotherapy on the clinical characteristics, serum biomediator levels, viral elimination, and specific IgG antibody induction in 13 severely to critically ill patients and compared with those of dexamethasone monotherapy and dexamethasone plus tocilizumab.Results: A single tocilizumab administration led to a rapid improvement in clinical characteristics, inflammatory findings, and oxygen supply in 7 of 11 patients with severe COVID-19, and could recover from mechanical ventilation management (MVM) in 2 patients with critically ill COVID-19. Four patients exhibited rapidly worsening even after tocilizumab administration and required MVM and additional methylprednisolone treatment. Tocilizumab did not delay viral elimination or inhibit IgG production specific for the virus, whereas dexamethasone inhibited IgG induction. A multiplex cytokine array system revealed a significant increase in the serum expression of 54 out of 80 biomediators in patients with COVID-19 compared with that in healthy controls. Compared with those who promptly recovered in response to tocilizumab, patients requiring MVM showed a significantly higher ratio of basal level of ferritin/CRP and a persistent increase in the levels of CRP and specific cytokines and chemokines including IL-6, IFN-γ, IP-10, and MCP-1. The basal high ratio of ferritin/CRP was also associated with clinical deterioration even in patients treated with dexamethasone and tocilizumab.Conclusion: Tocilizumab as monotherapy has substantial beneficial effects in some patients with severe COVID-19, who showed a relatively low level of the ratio of ferritin/CRP and prompt reduction in CRP, IL-6, IFN-γ, IP-10, and MCP-1. The high ratio of ferritin/CRP is associated with rapid worsening of pneumonia. Further evaluation is warranted to clarify whether tocilizumab monotherapy or its combination with corticosteroid is preferred for severely to critically ill patients with COVID-19.</p