Ratio of plasma IL-13/TNF- ∝ and CXCL10/CCL17 predicts mepolizumab and omalizumab response in asthma better than eosinophil count or immunoglobulin E level

Abstract

To date, most studies to identify biomarkers associated with response to the anti-interleukin 5 agent, mepolizumab, and to the anti-immunoglobulin E agent, omalizumab have focused on clinically available biomarkers, such as the peripheral blood eosinophil counts (BEC) and total immunoglobulin E (IgE). However, these biomarkers often have low predictive accuracy, with many patients with eosinophilic or allergic asthma failing to demonstrate clinical response to mepolizumab or omalizumab respectively. In this study, we evaluated the association of baseline pre-biologic plasma levels of 26 cytokines and chemokines, including T-helper 1 (Th1)-, Th2-, Th17-related cytokines, and their ratios with subsequent clinical response to mepolizumab or omalizumab. We defined clinical response as a reduction in the baseline annual exacerbation rate by half or more over the one-year period following initiation of the biologic. Baseline levels of plasma IL-13 were differentially elevated in responders versus non-responders to mepolizumab and plasma CXCL10 levels were differentially elevated in responders to omalizumab. The ratio of IL-13/TNF-α had the best sensitivity and specificity in predicting response to mepolizumab and CXCL10/CCL17 to omalizumab, and these performed better as predictive biomarkers of response than BEC and IgE. Cytokines and chemokines associated with airway eosinophilia, allergic inflammation, or Th2 inflammation, such as IL-13 and CXCL10, may be better predictors of clinical response to mepolizumab and omalizumab, than IL-5 or IgE, the targets of mepolizumab and omalizumab.

Figure 1

Differential expression analysis for 26 cytokines and response status in the mepolizumab group. Shows the results from limma analysis adjusted for pre-treatment annualized exacerbation rate. Cytokines with raw P-value < 0.05 were considered statistically significant. Effect sizes were presented as log2 of fold change where positive (negative) values indicated up-regulation in responders (non-responders). The vertical dashed line represents no difference. The horizontal dashed line represents P-value < 0.05. Green dot indicates levels of the cytokine are higher in responders; Gray dot ‘None’ indicates levels of that cytokine are not different between responders and nonresponders.

Figure 2

Differential expression analysis for ratios of cytokines/chemokines and response status in the mepolizumab group. Shows the results from limma analysis adjusted for pre-treatment annualized exacerbation rate. Cytokine ratios with raw P-value < 0.05 were considered statistically significant. Effect sizes are presented as log2 of fold change where positive (negative) values indicate up-regulation in responders (non-responders). The vertical dashed line represents no difference. The horizontal dashed line represents P-value < 0.05. Green dot indicates levels of the cytokine are higher in responders; Gray dot “None” indicates levels of that cytokine are not different between responders and nonresponders.

Figure 3

Differential expression analysis for 26 cytokines and response status in the omalizumab group. Shows the differential expression between omalizumab responders and non-responders from limma analysis adjusted for pre-treatment annualized exacerbation rate. Cytokines with raw P-value < 0.05 were considered statistically significant. Effect sizes are presented as log2 of fold change where positive (negative) values indicate up-regulation in responders (non-responders). The vertical dashed line represents no difference. The horizontal dashed line represents P-value < 0.05. Green dot indicates levels of the cytokine are higher in responders; Gray dot “None” indicates levels of that cytokine are not different between responders and nonresponders.

Figure 4

Differential expression analysis for ratios of cytokines/chemokines and response status in the omalizumab group. Shows the results from limma analysis adjusted for pre-treatment annualized exacerbation rate. Cytokine ratios with raw P-value < 0.05 were considered statistically significant. Effect sizes were presented as log2 of fold change where positive (negative) values indicated up-regulation responders (non-responders). The vertical dashed lines represented no difference. The horizontal dashed line represented P-value < 0.05. Green dot indicates levels of the cytokine are higher in responders; Red circle with triangle indicates levels of the cytokine are higher in nonresponders (or lower in responders); Gray dot “None” indicates levels of that cytokine are not different between responders and nonresponders.