This is the first study demonstrating that the risk of keloids is strongly associated with AD in the Korean population. Our results also demonstrate that the risk of keloids increases with coexisting allergic diseases, such as asthma, AR, and ACD. Previous data on the prevalence of keloids is based mainly on Caucasians and Taiwanese in Asia [10, 11]. In Korea, where all citizens are obligated to subscribe to national medical insurance, big data research using electronic medical information is feasible. For the first time, our findings show that the prevalence of keloids increased in patients with AD in the Korean population. Hajdarbegovic et al. also suggested that keloids may be strongly associated with atopic asthma in European, African, and Asian populations [12]. The findings in this study are consistent with those of previous studies wherein the risk of keloids is higher in AD patients with allergic comorbidities.
The molecular pathophysiology of keloid formation and progression is poorly understood. However, fibroblasts, one of the main cells responsible for most of the collagen and extracellular matrix deposition in both normal and abnormal wound healing, have been identified to contribute to keloid formation and dermal structural changes in AD skin lesions [13]. Recently, Shin et al. reported that keloidal fibroblasts treated with thymic stromal lymphopoietin (TSLP) produced significantly increased collagen I, collagen III, and transforming growth factor β [14]. TSLP, an IL-7-like cytokine, is thought to induce upregulation of Th2-inflammatory cytokines, and there is increased expression of the TSLP gene in AD skin lesions [15].
Another molecule that contributes to the collagen production of dermal fibroblasts in AD is Oncostatin M (OSM), a T lymphocyte/macrophage-derived proinflammatory signaling molecule similar to the IL-6 cytokine family [16]. Fibroblasts are target cells for OSM. OSM stimulates collagen and glycosaminoglycan production in dermal fibroblasts, and this process can be observed in both keloidal formation and prurigo nodularis in patients with AD [17].
Other than upregulation of Th2 cytokines, effector memory CD8 + T cells and CD103 + CD8 + resident memory T (TRM) cells are increased in keloid tissue. Therefore, increased CD8 + TRM in keloid tissues might contribute to local inflammation [18]. TRM cells have been shown to contribute to the recurrence of AD; however, the exact roles of skin TRM are still unclear [19].
There have been a few reports on the association between allergic diseases and keloid development; however, these results are still debated. Hajdarbegovic et al., for example, revealed no association between AD and keloids in the adjusted model of a case-control study. Additionally, they suggested that asthma was significantly, consistently, and strongly associated with keloids. However, there were no consistent associations found on keloids with atopic eczema or hay fever [12]. In contrast, Lu et al. demonstrated that patients with AD had a greater possibility of developing keloids in a nationwide retrospective cohort study in Taiwan. According to this study, the AD cohort had significantly higher percentages of patients with asthma (25.41 vs. 12.91, p < 0.001), AR (54.78 vs. 35.92, p < 0.001), and allergic conjunctivitis (57.22 vs. 42.08, p < 0.001) compared with the non-AD cohort [11]. In our study, AD patients with ACD also had an increased prevalence of keloid risk, which is different from previous studies, suggesting that ACD may have the characteristic of AD-associated comorbidity. In the past, the higher permeation of contact allergens through the disrupted skin barrier was the main factor of ACD in patients with AD. Recently, potential shared immune pathways have been demonstrated for subsets of AD and ACD, including Th1, Th2, Th9, and/or Th17 [20, 21].
Han et al. demonstrated the relationship between a disintegrin and metalloprotease 33 (ADAM33) polymorphism and keloid scars in an East Asian population. Q-1 SNPs in blood were significantly associated with keloid scars. ADAM33 protein is a zinc-dependent endopeptidase, characterized by a pro-domain, metalloprotease domain, and disintegrin domain [22]. The ADAM33 gene was found to be associated with asthma and airway hyperresponsiveness [23]. It is thought that this may explain the increased keloid risk in AD associated with asthma. Considering the literature mentioned above, AD and keloid share various genetic and pathologic mechanisms.
One of the strengths of this study is the use of a large population-based claims dataset consisting of one ethnic group, which enabled the analysis of all cases of AD, keloids, and comorbid allergic diseases. Moreover, since the Korean NHID is one of the largest claims datasets including all age groups and the entire region, the possibility of selection bias is reduced to compare the relationships between the AD patients and control group. Second, it is the first time that big data analysis has demonstrated the result of an increase in the prevalence of keloids in AD patients with allergic diseases. However, this study has several limitations. First, because the analyzed medical records were originally collected for national insurance purposes, not for research purposes, additional demographic or social histories were unavailable. Second, due to the drawbacks of big data analysis regarding control variables such as age and sex, we used multiple logistic regression models to match those of the two groups. This systematic problem may result in confounding factors.
In conclusion, this study demonstrated that in the Korean population, patients with AD have a higher risk of keloid development, and the risk is even higher with coexisting allergic diseases. Nevertheless, further exploration of this association is needed to confirm these relationships and the pathophysiological mechanisms common to AD and keloids.