In this study, children and adolescents with AD showed significantly higher serum levels of SCCA1 and SCCA2 compared with healthy volunteers. The levels were not elevated in those with BA or AR without AD, indicating that SCCAs are specific markers for AD in allergic children. Their levels were higher in AD group 2 (patients with severe AD) than in AD group 1 (volunteers with AD, presumably mild disease). We also found that the serum levels of SCCAs in AD group 2 correlated significantly with the SCORAD index, and decreases in their levels during treatment correlated well with decreases in the SCORAD index. The correlation indices were highest for SCCA2 compared with SCCA1 and TARC. These results indicate that SCCAs are reliable biomarkers for AD, and that the serum levels of SCCAs, especially SCCA2, predict the disease severity and treatment response.
TARC has been regarded as the most reliable biomarker of the severity of AD . TARC is a ligand for CC chemokine receptor 4, which is selectively expressed on Th2 type cells. It is produced by dendritic cells, endothelial cells and keratinocytes, and its overproduction leads to Th2 type cell accumulation at inflammation sites . In contrast, SCCAs are induced by Th2 type cytokines such as IL-4 and IL-13 . Therefore, SCCAs may reflect the “down-stream” of the immune response, which might lead to superiority of SCCAs in our study. The reason for the stronger correlation of the SCCA2 level with disease severity remains unclear. An earlier study showed that keratinocytes produced mainly SCCA2 upon stimulation with IL-4 or IL-13 . This result may in part explain the superiority of SCCA2 over SCCA1 for disease activity.
In addition, serum TARC levels are high in children, especially infants . Thus, it is necessary to have different reference and cut-off values for TARC in different age groups for clinical use. On the contrary, the serum levels of SCCAs in healthy children were similar among the different age groups in our study. Although the levels were slightly higher in the 2 younger groups, the differences were not statistically significant and were much smaller than those found for TARC . In our previous report , we demonstrated the validity of a single cut-off at 1.6 ng/ml for SCCA2. We also determined the normal ranges and cut-off levels of SCCA1 and SCCA2, irrespective of age, which may be helpful in clinical application. Because different subject groups were recruited for determination of cut-off levels, i.e., only mild AD in this study and more severe AD in the previous study, the cut-off levels of SCCA2 were different. However, the cut-off level at 95% specificity was 1.5 ng/ml in this studyis close tothe 1.6 ng/ml in the previous study.
An important finding in this study was that the serum levels of SCCAs correlated with the severity of AD. It is sometimes difficult to assess the severity and evaluate the outcome of a certain treatment because physicians’ visual examinations are not always accurate . Various instruments have been developed to measure the symptoms of AD, and several have been recommended as core outcome sets . However, the main objective of the recommendation was to define the core outcome sets that should be used in clinical trials. These instruments are not suitable for use in daily clinical practice because their scoring systems are complex . Accordingly, a simple and reliable biomarker for assessing disease severity would be a great breakthrough.
The serum levels of SCCAs were similar between healthy volunteers and those with BA or AR. In a study that included children with acute asthma, serum SCCA levels increased only in the acute phase of asthma exacerbation, while in the recovery phase they were similar to those in age-matched healthy children . Another study found the SCCA levels to be elevated in BA patients compared with controls, but the difference was only 1 ng/mL . Furthermore, serum SCCA levels in adult patients with AR caused by cedar pollen were similar to those in healthy adult volunteers, and the median level in patients with AR caused by Dermatophagoides farinaen was only 0.20 ng/mL higher than that in healthy volunteers . Our present findings are consistent with those earlier results. However, serum levels of SCCAs were reported to be elevated in patients with psoriasis , so special attention needs to be paid to differential diagnosis of AD from psoriasis.
This study has several limitations. First, we used the SCORAD index as a severity scale, but that is not considered to be a gold-standard severity scale . Second, we did not assess the relationship between the disease severity and the serum levels of biomarkers in patients with mild or moderate AD. However, we previously reported the SCCA2 levels in that population of AD patients , and one of the purposes of this study was to clarify utility of SCCAs in AD children with comorbidities
In conclusion, the serum levels of SCCA1 and SCCA2 were elevated in children and adolescents with AD. In addition, the SCCA2 level correlated more strongly with the SCORAD index than the TARC or SCCA1 level. We think that SCCA2 has potential as a useful and reliable biomarker for assessing the severity of AD in children and adolescents and their responses to treatment.