Methotrexate Versus Acitretin for Grover’s Disease Refractory to Topical Therapies

To the Editor,

Grover’s disease (GD) is a rare papular/papulovesicular disorder with a poorly characterized etiology. GD (transient and persistent acantholytic dermatosis) can take a chronic course, and recalcitrant symptomatic cases may warrant systemic therapy. Corticosteroids yield resolution in roughly 64% of patients; however, rapid relapses often occur upon tapering. ¹ There is a dearth of evidence for use of steroid-sparing immunosuppressive agents such as methotrexate (MTX) for GD. ² Systemic retinoids are supported by a 100% response rate in a four-patient case series (75% complete clearance). ³ We retrospectively review outcomes obtained in 15 GD patients who underwent either MTX or acitretin therapy.

Upon Institutional Review Board approval, a retrospective review of patients who received MTX and acitretin for GD between 2013-2020 was performed. Patients without biopsy-proven disease and patients without follow-up evaluation were excluded. Outcomes were classified as: complete clearance, partial response (reduced pruritus, fewer/flatter papules, less erythema), no response.

MTX and acitretin patients had comparable demographics: white (100% MTX, 100% acitretin), males (90% MTX, 100% acitretin), with mean ages 78 ± 7 years (MTX) and 70 ± 9 years (acitretin) (Supplemental Tables 1 and 2). Several patients had associated co-morbid skin conditions: papular atopic dermatitis (40% MTX, 20% acitretin), xerosis cutis (20% MTX, 20% acitretin), allergic contact dermatitis (20% MTX, 0% acitretin), and irritant contact dermatitis (0% MTX, 20% acitretin). ⁴ No patients presented with malignancies, histories of transplantation, bullous pemphigoid, viral infections, or prolonged immobilization. While the association between GD disease activity and time of year is debated, there was no clear predilection for the season of disease inception in the 15 patients (4 summer, 3 winter, 2 fall, 2 spring, 4 unknown). ⁵ Severely pruritic (100%) erythematous papules (100%) presented on the trunk (100%) and upper extremities (67%), with occasional burning pain (13%). Disease existed a mean 33 months before MTX initiation (median dose 8.75 mg weekly, median duration 13 months), and a mean 6 months before acitretin initiation (median dose 25 mg daily, median duration 5 months). Medications attempted before MTX and acitretin most commonly included topical corticosteroids (100% MTX, 100% acitretin) and oral antihistamines (60% MTX, 40% acitretin).

Comparable proportions of improvements occurred (90% MTX, 80% acitretin) within comparable timeframes (median 2 months MTX, median 2 months acitretin). More MTX patients completely cleared (70%, 20% acitretin). Two MTX responders flared during therapy (1 associated with a dose reduction trial); both did not respond to subsequent MTX therapy. Four MTX responders flared upon discontinuation (median 6.5 months post-MTX cessation; median follow-up evaluation period 26 months). No acitretin responders flared (median follow-up evaluation period 3 months).

Many patients (80% MTX, 80% acitretin) concomitantly applied topical corticosteroids. MTX and acitretin were well tolerated; one MTX patient (10%) complained of fatigue, and one acitretin patient (20%) experienced dry lips.

Although this study is limited by a small sample size, non-standardized outcome measures, and flares which may occur as natural fluctuation of the disease, it appears MTX and acitretin may provide some disease control for patients with severe, persistent, and/or recalcitrant GD.

Supplemental Material

Table S1 - Supplemental material for Methotrexate Versus Acitretin for Grover’s Disease Refractory to Topical Therapies

Supplemental material, Table S1, for Methotrexate Versus Acitretin for Grover’s Disease Refractory to Topical Therapies by Matthew L. Hrin, Palak V. Patel, Joseph L. Jorizzo, Steven R. Feldman and William W. Huang in Journal of Cutaneous Medicine and Surgery