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Atopic dermatitis (AD) is a common inflammatory skin disorder, and its prevalence in the pediatric population has tripled in the past several decades alone.1 Atopic dermatitis is characterized by xerotic or scaly patches of skin with intense pruritus, resulting in eczematous lesions.2 Loss-of-function (LOF) mutations for the skin gene filaggrin (FLG [OMIM 135940]) are the most significant and widely replicated risk factors for AD.3 Immunologically, AD is characterized by type 2 inflammation through type 2 interleukin 4 (IL4), IL-5, and IL-13 cytokine production. Together, the evidence supports a prevailing paradigm of AD pathogenesis originating with a skin barrier deficiency that results in downstream immune dysregulation and triggers a chronic and relapsing inflammatory cascade. Commonly prescribed treatments for AD start with nonspecific, topical anti-inflammatory agents, such as topical corticosteroids and topical calcineurin inhibitors (TCI). Targeted biologic therapies, such as dupilumab, block IL-4Rα and have been effective in adult clinical trials.4 Nevertheless, patient responses to treatments are highly variable. Like other diseases, AD is a prime example that has motivated the presidential Precision Medicine Initiative to achieve individualized treatment of disease to realize this potential. A true understanding of the pharmacogenetic link between patients’ genetic risk factors for disease and their response to treatment is warranted. In this issue of JAMA Dermatology, Chang et al5 addressed this challenge in AD by investigating the associations between the genetic variants for filaggrin and thymic stromal lymphopoietin (TSLP), a potent regulator of type 2 immune responses, and each of the 2 commonly prescribed topical corticosteroids and TCI treatments in pediatric AD. The discovery of FLG LOF mutations shifted the paradigm in support of epidermal barrier deficiency in the etiology of AD.6 To date, FLG mutations reportedly account for as many as 50% of moderate-to-severe cases.2 The FLG LOF mutations commonly represent gains in stop mutations that result in a decrease in mature filaggrin. A reduction in filaggrin monomers results in decreased filaggrin monomer metabolites that contribute to the natural moisturizing factor of the skin.7 Increasing numbers of filaggrin monomers decrease the risk for AD.8 Despite these findings, the association of FLG variants to treatment outcomes in patients with AD is poorly understood. A pathomechanistic clue linking skin barrier deficiency to type 2 helper T (TH2) cell activation in AD resulted from the discovery of the epithelial-derived TSLP cytokine.9 Thymic stromal lymphopoietin is a key upstream activator of type 2 cytokine responses known to underlie AD. The role of TSLP has been linked to the activation of TH2 cells and specific innate immune cells that are strongly associated with allergic disorders.9-11 Expression of the TSLP gene (OMIM 607003) was induced in FLG knockdown experiments on human keratinocytes in isolation, suggesting a direct keratinocyte-specific regulatory-axis between FLG and TSLP for a pathologic type 2 immunological response.12 A screen for TSLP variants involved in AD modulation identified an intronic rs1898671 single-nucleotide polymorphism and demonstrated that patients with an FLG LOF mutation and TSLP rs1898671 were 5 times less likely to have persistent AD compared with patients with the FLG LOF allele alone.13 This protective effect of TSLP rs1898671 against AD was interpreted to result from reduced TSLP expression (although not functionally demonstrated), presumably minimizing the allergic immune response even in the context of FLG LOF–associated AD. Chang et al5 brought the field a step closer toward achieving precision medicine in the dermatology clinic. They sought to directly identify the associations between each of the FLG LOF and TSLP variants and the treatment response in children. To examine this association, they leveraged the longitudinal data of the Pediatric Eczema Elective Registry (PEER), a postmarketing registry for patients treated with pimecrolimus cream, 1%. The authors surveyed patients’ report of AD clearance and AD treatment with topical corticosteroid and/or TCI prescriptions. These patients underwent concurrent genotyping for the 4 most common European FLG LOF mutations and TSLP rs1898671. Overall, the study reports 2 key findings with respect to FLG LOF variants in AD. First, patients who were compound heterozygous or mutant for FLG LOF mutations were less likely to report skin clearance than their counterparts with wildtype or heterozygous mutations. Second, although the use of TCI was essentially equal among patients with all 4 tested FLG LOF genotypes, patients with 2 LOF mutations were more likely to report corticosteroid use and more frequent use. The decision to opt for more frequent corticosteroid use suggests that higher-potency treatments are more effective than TCIs for patients with FLG LOF mutations. Moreover, these findings provide pivotal knowledge highlighting the chronicity and seRelated article Opinion