A Case of Darier Disease With p.N767S Mutation in ATP2A2 Successfully Treated With Upadacitinib

To the Editor: Darier disease (DD) is an autosomal dominant genetic keratinization disorder with an estimated prevalence between 1/36,000 and 1/100,000. Most instances do not show any phenotypic manifestations of DD during infancy, because the condition tends to emerge in childhood or adolescence.1 Individuals affected by DD exhibit a range of cutaneous symptoms, including keratotic papules on the sebaceous regions and verrucous papules on hands and feet. Most DD cases stem from mutations in ATP2A2—a gene that encodes the cardiac muscle SERCA2a protein and the widely distributed SERCA2b protein and is expressed in both the skin and the brain.2 SERCA2 plays a crucial role as a calcium pump.2 It is believed that a genetic alteration in ATP2A2 gives rise to dyskeratosis and irregularities in intercellular adhesion.2 Although a range of pharmaceutical substances have been used for managing DD, no reliable treatment method has yet been developed. In addition to DD, 2 other acantholytic disorders, Grover disease and Hailey–Hailey disease (HHD), are also associated with ATP gene. Grover disease typically presents as pruritic papulovesicles on the trunk and is related to the somatic ATP2A2 variants.3 HHD had flaccid vesicles and blisters in intertriginous regions caused by autosomal dominant mutations in ATP2C1 gene.4 A recent case study has indicated that upadacitinib, a second-generation Janus kinase (JAK) inhibitor, might be effective in managing HHD.5 However, the clinical treatment of JAK inhibitors in patients with DD or Grover disease has never been reported previously. In this study, we describe a case involving a Chinese male patient with DD who was successfully treated with upadacitinib. A 31-year-old Chinese male presented to us with a 25-year history of numerous itchy, recurring, hyperkeratotic erythematous papules and merged plaques affecting his face, neck, trunk, flexural areas, genital region, perianal area, and limbs, with yellowish greasy serocrusts on the cephalofacial region (examples of pretreatment pictures are shown in Figs. 1A, C, E). In addition, a foul odor emanated from his entire body. He had no family history of DD or other severe concurrent conditions. A biopsy of lesional skin revealed epidermal abnormalities, including hyperkeratosis, acantholysis, cleft formation, as well as the presence of grains and corps ronds (Figs. 1H–J). Sanger sequencing analysis was performed using genomic DNA extracted from the patient's peripheral blood. Data analysis identified the heterozygous missense mutation as c.2300A>G (p.N767S) (Fig. 1G), which has also been reported by previous studies.6 These findings aligned with a DD diagnosis. Despite multiple visits to a dermatology clinic and using varied treatments, the condition of the patient remained unchanged. Given poor response to conventional treatments (topical mometasone furoate ointment once a day, oral olopatadine 5 mg twice a day, and oral acitretin 20 mg once a day for 4 months), we initiated treatment with upadacitinib at 15 mg daily according to standard titration. After 12 weeks of treatment, the lesions were reduced and itchiness was relieved (post-treatment pictures in Figs. 1B, D, F). Based on a numeric rating scale reported previously,7 this patient had a score of 1 (not at all itchy, sore, painful, or stinging) after the treatment, compared with a score of 4 (very much itchy, sore, painful, or stinging) before the treatment. He is currently continuing the treatment with upadacitinib for >6 months. No adverse events have so far been reported during the treatment. In addition, his hematologic parameters remained unchanged during and after the treatment.FIGURE 1.: Clinical features of the patient before treatment (A, C, E) and after 12 weeks of upadacitinib treatment (B, D, F). Sanger sequencing reveals a heterozygous mutation within ATP2A2, c.2300A>G (G). Skin biopsy obtained from the patient. The cells were stained using hematoxylin–eosin staining (magnification: H 10 ×; I 20 ×; J 40 ×, with the scale bar of 100, 50, 20 μm, respectively).HHD, also known as benign familial pemphigus, exhibits parallels with DD. Both are rare genetic disorders involving ATPases within the epidermal calcium channels, with specific association with ATP2C1 mutations. Clinically, HHD is marked by erosions and recurrent blisters localized to the neck, axillae, umbilicus, and inguinal regions. Owing to the reported efficacy of upadacitinib in the management of HHD, we selected it for the present case.5 Upadacitinib is a second-generation JAK inhibitor with selective activity against the JAK1 enzyme and has been approved by the US Food and Drug Administration for the management of psoriatic arthritis and atopic dermatitis.8 It has been suggested that the therapeutic efficacy of upadacitinib stems from its selective inhibition of JAK1, a key mediator in the signal transduction pathways of multiple proinflammatory cytokines, including IL-4, IL-13, IL-22, IL-31, and interferon-gamma, which potentially reduce Th1-, Th2-, and Th17-mediated inflammation responses. DD-associated skin barrier disruptions may induce the secondary Th2-driven inflammation.5 Prior studies have examined the potential involvement of IL-4 and IL-13 in modulating calcium mobilization within human keratinocytes.9 A previous report revealed that IL-4/IL-13 attenuates the calcium influx of epidermal differentiation while upregulating Th2 cytokines.9 In this case, the efficacy of upadacitinib likely stems from its selective JAK1 inhibition, which curtails cytokine signaling through the JAK/STAT pathway.5 However, the mode of action of upadacitinib on DD is also largely unknown, further researches are needed. This case is the first report of the utilization of upadacitinib for DD, with favorable therapeutic outcomes.