EASI p-EASI: Utilizing a combination of serum biomarkers offers an objective measurement tool for disease severity in atopic dermatitis patients

Abstract

Serological biomarkers offer an objective and reliable outcome measure of disease severity in atopic dermatitis (AD). A recent meta-analysis identified serum thymus and activation-regulated chemokine (TARC/CCL17) as the best biomarker currently available for assessing disease severity in AD.1Thijs J. Krastev T. Weidinger S. Buckens C.F. de Bruin-Weller M. Bruijnzeel-Koomen C. et al.Biomarkers for atopic dermatitis: a systematic review and meta-analysis.Curr Opin Allergy Clin Immunol. 2015; 15: 453-460Crossref PubMed Scopus (148) Google Scholar Although TARC strongly correlates with disease activity in individual patients during follow-up, TARC levels vary between patients within cross-sectional cohorts of patients who have similar disease severity scores.2Landheer J. de Bruin-Weller M. Boonacker C. Hijnen D. Bruijnzeel-Koomen C. Rockmann H. Utility of serum thymus and activation-regulated chemokine as a biomarker for monitoring of atopic dermatitis severity.J Am Acad Dermatol. 2014; 71: 1160-1166Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar The variation in TARC levels between patients may be the result of the large number of biologic pathways involved in the pathogenesis of AD. The use of a combination of biomarkers from different biologic pathways may overcome this problem. Indeed, we have recently shown that a combination of biomarkers, including serum TARC, pulmonary and activation-regulated chemokine (PARC/CCL18), IL-22, and sIL-2R, had a correlation coefficient of 0.86 with disease severity, whereas the correlation coefficient with disease severity for the individual biomarkers ranged from 0.42 to 0.74.3Thijs J.L. Nierkens S. Herath A. Bruijnzeel-Koomen C.A. Knol E.F. Giovannone B. et al.A panel of biomarkers for disease severity in atopic dermatitis.Clin Exp Allergy. 2015; 45: 698-701Crossref PubMed Scopus (30) Google Scholar The aim of the present study was to validate the use of a combination of biomarkers for disease severity in patients with AD. A total of 150 serum biomarkers were measured as described in this article's Methods section in the Online Repository at www.jacionline.org in 193 patients with AD (demographic data are presented in Table E1 in this article's Online Repository at www.jacionline.org). A significant correlation with six area, six sign atopic dermatitis (SASSAD) severity score was found for 32 out of 147 serum biomarkers (see Table E2 in this article's Online Repository at www.jacionline.org). Serum TARC levels showed the strongest correlation with disease severity (r = 0.42; P < .01). In addition to the panel of biomarkers (TARC, PARC, IL-22, sIL-2R) described in our pilot study,3Thijs J.L. Nierkens S. Herath A. Bruijnzeel-Koomen C.A. Knol E.F. Giovannone B. et al.A panel of biomarkers for disease severity in atopic dermatitis.Clin Exp Allergy. 2015; 45: 698-701Crossref PubMed Scopus (30) Google Scholar biomarkers that significantly correlated with disease severity, and had correlation coefficients higher than 0.30 (IL-18, I-309, macrophage derived chemokine [MDC], sE-selectin, and stromal cell-derived factor 1 [SDF1] α), were considered meaningful and therefore included in the prospective study. To validate the use of a combination of biomarkers as a surrogate measure for disease severity, 65 patients with AD were included in a prospective cohort study. At baseline (t0), patients with AD started with daily application of potent topical steroids (fluticasone furoate, mometasone furoate, or betamethasone dipropionate) for a median duration of 22 days (interquartile range [IQR], 13-42 days). Between t1 and t2, patients used topical steroid treatment intermittantly (see Fig E1 in this article's Online Repository at www.jacionline.org). Disease severity significantly decreased from a median Eczema Area and Severity Index (EASI) score of 17.4 (IQR, 10.0-25.7) to a median EASI score of 3.3 (IQR, 1.2-5.6) at t1 (P < .0001), and remained stable until t2 (median EASI score, 2.7; IQR, 1.0-4.6). Similarly, patient-oriented outcome measure (POEM) and visual analog scale (VAS) pruritus decreased significantly (P < .0001) during the first treatment period and remained stable until the end of the study (Fig 1, A; see Table E3 in this article's Online Repository at www.jacionline.org). In addition, 14 patients with psoriasis and 26 nonatopic controls were included in the study (see Table E1). At baseline, serum biomarkers—I-309, TARC, MDC, IL-22, and sE-selectin—were significantly higher in patients with AD than in patients with psoriasis and healthy controls (P < .01; see Fig E2 in this article's Online Repository at www.jacionline.org). Linear mixed model analysis was used to model the biomarker changes over time after treatment initiation. Serum I-309, TARC, PARC, MDC, IL-18, IL-22, sE-selectin, and sIL-2R showed a significant decrease during daily treatment with topical steroids (P < .001) and remained stable between t1 and t2 when patients used topical steroid treatment intermittantly (Fig 1, B; see Table E4 in this article's Online Repository at www.jacionline.org). After adjusting for sex and age, results remained unchanged. We then aimed to model changes in EASI scores over time by using a combination of biomarkers in a linear mixed model approach as described in this article's Methods section. We developed the following signature to predict EASI scores before treatment: EASI = −36.12 + 18.49 × logTARC + 0.009 × IL-22 − 0.009 × sIL-2R, and the following signature to predict EASI scores during topical steroid treatment: EASI = −5.82 + 4.04 × logTARC + 0.003 × IL-22 − 0.003 × sIL-2R (Fig 1, C; see Table E5 in this article's Online Repository at www.jacionline.org). The predicted formula-derived EASI score showed a sensitivity of 100% and a specificity of 88.9% (see the Methods section and Tables E5 and E6 in this article's Online Repository at www.jacionline.org). To test the robustness of our findings, the analysis was repeated 5 times: by random selection of 55 patients with AD to build the model and using the 10 remaining patients for validation. The predictive capacity of our model showed a sensitivity ranging from 83.3% to 100.0% and a specificity ranging from 88.5% to 95.2%. The biomarkers included in our signature are involved in inflammation and have been previously described in the pathogenesis of AD. TARC, a member of the CC chemokine family, is produced by dendritic cells and involved in the recruitment of T cells into the skin.4Imai T. Nagira M. Takagi S. Kakizaki M. Nishimura M. Wang J. et al.Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine.Int Immunol. 1999; 11: 81-88Crossref PubMed Scopus (604) Google Scholar IL-2R is expressed on the T-cell surface after stimulation with IL-2.5Gaulton G.N. Williamson P. Interleukin-2 and the interleukin-2 receptor complex.Chem Immunol. 1994; 59: 91-114Crossref PubMed Google Scholar sIL-2R is released into the serum, and sIL-2R levels have been found to reflect the activation state of the T cells in skin.6Walker C. Kagi M.K. Ingold P. Braun P. Blaser K. Bruijnzeel-Koomen C.A. et al.Atopic dermatitis: correlation of peripheral blood T cell activation, eosinophilia and serum factors with clinical severity.Clin Exp Allergy. 1993; 23: 145-153Crossref PubMed Scopus (105) Google Scholar IL-22 is less well known as a biomarker for disease severity in AD, although it has been recognized to play a role in the pathogenesis of AD.7Gutowska-Owsiak D. Schaupp A.L. Salimi M. Taylor S. Ogg G.S. Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes.Br J Dermatol. 2011; 165: 492-498Crossref PubMed Scopus (112) Google Scholar, 8Nograles K.E. Zaba L.C. Shemer A. Fuentes-Duculan J. Cardinale I. Kikuchi T. et al.IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells.J Allergy Clin Immunol. 2009; 123: 1244-1252.e2Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar, 9Hijnen D. Knol E.F. Gent Y.Y. Giovannone B. Beijn S.J. Kupper T.S. et al.CD8(+) T cells in the lesional skin of atopic dermatitis and psoriasis patients are an important source of IFN-gamma, IL-13, IL-17, and IL-22.J Invest Dermatol. 2013; 133: 973-979Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar IL-22 has previously been reported to induce keratinocyte proliferation, and downregulate filaggrin expression, in a similar way to IL-4 and IL-13, thereby contributing to epidermal barrier dysfunction.7Gutowska-Owsiak D. Schaupp A.L. Salimi M. Taylor S. Ogg G.S. Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes.Br J Dermatol. 2011; 165: 492-498Crossref PubMed Scopus (112) Google Scholar To make a combination of biomarkers suitable for clinical use, simplicity and ease of interpretation is key. Levels of TARC, IL-22, and sIL-2R should not be interpreted separately; rather, it is the combination of these biomarkers as a signature that reflects the disease activity. Combining levels of biomarkers in an algorithm provides a single, easy-to-interpret value. Because the algorithm was developed to predict EASI scores, we named this outcome measure the predicted-EASI (p-EASI). In contrast to EASI, the p-EASI provides an objective outcome measure that is not subjected to intrarater and interrater variability. A core strength of the present study is its design, including a retrospective cohort for the discovery of new biomarkers and a prospective cohort to validate our findings. Although correlation of serum biomarkers with disease severity has been investigated in many studies, most of these studies included biomarker measurements only on a single time point.1Thijs J. Krastev T. Weidinger S. Buckens C.F. de Bruin-Weller M. Bruijnzeel-Koomen C. et al.Biomarkers for atopic dermatitis: a systematic review and meta-analysis.Curr Opin Allergy Clin Immunol. 2015; 15: 453-460Crossref PubMed Scopus (148) Google Scholar By including multiple time points in the present study, we were able to investigate the changes in biomarkers during treatment. In conclusion, we have invented a biomarker signature (p-EASI) consisting of TARC, IL-22, and sIL-2R that provides a reliable and objective measure of disease severity in patients with AD. With the increasing number of clinical trials evaluating new biological agents for the treatment of AD, the comparability of study outcomes is of major importance. We believe that the use of a combination of serum biomarkers will highly improve precision measurement of outcomes and improve comparability of current and future treatments in AD. Download .docx (.09 MB) Help with docx files Online Repository textFig E2View Large Image Figure ViewerDownload Hi-res image Download (PPT)