Methotrexate for Cutaneous Sarcoidosis: A Dermatology-Based Case Series of 23 Patients

Hrin, Matthew L.; Williams, Josiah; Bowers, Nathan L.; Jorizzo, Joseph L.; Feldman, Steven R.; Huang, William W.

doi:10.1177/12034754221101361

Cited by 3 publications

(1 citation statement)

References 6 publications

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“…Current therapy of GD is based on case series and expert opinion as it lacks any treatment proven in prospective trials (7,8,52). Retinoids, which regulate the differentiation of keratinocytes, have been used in observational studies for GD (7,8,(53)(54)(55), but they confer a high risk of toxicity with long-term use and are potent teratogens (56,57). Other conventional, but off-label, therapies for GD include topical corticosteroids and repeated narrow-band ultraviolet light treatment, which is burdensome for patients (7,8).…”

Section: Discussionmentioning

confidence: 99%

ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology

Simpson,

Tiwaa,

Zaver

et al. 2024

Preprint

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Grover disease is an acquired dermatologic disorder characterized by pruritic vesicular and eroded skin lesions. While its pathologic features are well-defined, including impaired cohesion of epidermal keratinocytes, the etiology of Grover disease remains unclear and it lacks any FDA-approved therapy. Interestingly, drug-induced Grover disease occurs in patients treated with B-RAF inhibitors that can paradoxically activate C-RAF and the downstream kinase MEK. We recently identified hyperactivation of MEK and ERK as key drivers of Darier disease, which is histologically identical to Grover disease, supporting our hypothesis that they share a pathogenic mechanism. To model drug-induced Grover disease, we treated human keratinocytes with clinically utilized B-RAF inhibitors dabrafenib or vemurafenib and leveraged a fluorescent biosensor to confirm they activated ERK, which disrupted intercellular junctions and compromised keratinocyte sheet integrity. Consistent with clinical data showing concomitant MEK blockade prevents Grover disease in patients receiving B-RAF inhibitors, we found that MEK inhibition suppressed excess ERK activity to rescue cohesion of B-RAF-inhibited keratinocytes. Validating these results, we demonstrated ERK hyperactivation in skin biopsies of vemurafenib-induced Grover disease, but also in spontaneous Grover disease. In sum, our data define a pathogenic role for ERK hyperactivation in Grover disease and support MEK inhibition as a therapeutic strategy.

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