Transient responses to biologic therapy in Darier disease: consider the role of dysbiosis‐driven inflammation

Darier disease (DD) is a non-syndromal epidermal differentiation disorder (nEDD) caused by pathogenic variants in the ATP2A2 gene (ATP2A2-nEDD), encoding the sarcoendoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2). Disruption of SERCA2 in keratinocytes leads to impaired intracellular calcium signalling, abnormal cell–cell adhesion, and dyskeratosis.1 This elicits a chronic and relapsing disease course characterized by hyperkeratotic papules and plaques predominantly in seborrheic and intertriginous areas. Previously, skin inflammation in DD was mainly attributed to impaired epidermal barrier function and microbiomic dysbiosis.2 However, more recent studies found increased levels of cytokines of the IL-17 axis in lesional skin as well as upregulated presence of tissue-resident Th17 cells in both lesional skin and systemic circulation of DD patients, comparable to levels seen in psoriasis.3 As in other EDD, the improved insights into the underlying pathophysiological mechanisms have caused a shift to new biologic treatments, often targeting the TNF/IL-23/IL-17 or IL-4/IL-13 axes.4 Previously, Ettinger et al. reported clinical improvement in three DD patients treated with secukinumab (anti-IL-17A) and one with guselkumab (anti-IL-23A) with benefits lasting up to 13 months.3 The updated case series by Ettinger et al. now documents five patients with DD treated with biologics for up to 34 months and provides granular longitudinal cytokine data. Their observations underline a recurrent pattern: initial clinical improvement followed by variable and transient responses, ultimately leading to treatment discontinuation in all cases.5 Several aspects of the cohort are remarkable. First, the cytokine profiles in lesional biopsies displayed marked heterogeneity, with variable IL-17A or IL-23A predominance. The temporal discordance between clinical trajectory and cytokine expression in several cases is intriguing, suggesting dynamic compensatory responses. The authors interpret this as evidence that blocking a single inflammatory target may be insufficient when broader inflammatory circuitries become activated. This concept has been previously discussed in congenital ichthyoses receiving biologics.4 A major difference between DD and psoriasis is the extensive bacterial and fungal dysbiosis inducing inflammatory responses. Despite superficial overlap in cytokine profiles, the primary defect in DD lies in ATP2A2 loss-of-function, which disturbs keratinocyte calcium homeostasis and disrupts desmosomal adhesion.1 This structural failure results in acantholysis, dyskeratosis, barrier impairment, and pronounced susceptibility to bacterial and fungal colonization.2 This differs from Th17-induced skin morphology such as hyperkeratosis and sterile pustules. Several types of staphylococci, streptococci, and corynebacteria strains strongly correlate with disease severity in DD.2 As colonization induces IL-17 production, biologic therapy may initially suppress inflammation driven by dysbiosis, producing the early gains seen in four of the five patients. However, IL-17 signalling is central to cutaneous antimicrobial defence. Sustained blockade may impair microbial control, thereby worsening colonization and re-amplifying inflammation. The rebounds generally coincided with rising IL-17 family transcripts in qPCR, consistent with this interpretation. Biologic therapy may require concurrent management of dysbiosis. Prospective protocols integrating skin microbiome profiling before and during IL-17 or IL-23 blockade would clarify whether shifts in microbial composition predict the observed loss of response. Calcium-dependent desmosomal pathways activate stress signalling that converge on NF-κB and MAPK pathways.3 This raises the question of whether targeting upstream stress pathways or keratinocyte calcium handling may complement cytokine inhibition more effectively than cytokine blockade alone. In addition, combining biologics with retinoids or phosphodiesterase inhibitors can reduce the required cytokine blockade intensity, potentially lowering infection risk, as illustrated in one patient.5 This study provides valuable long-term evidence that biologics yield reproducible but often non-durable benefit in DD. The rebound pattern suggests temporary suppression of dysbiosis-driven inflammation, followed by rebounds as antimicrobial defence pathways reassert themselves (Figure 1). This article received no funding. The authors have no conflict of interest to declare. Data sharing is not applicable to this article as no new data were created or analysed in this study.