Topical cinacalcet efficacious in Hailey-Hailey Disease- JAMA study

Topical cinacalcet efficacious in Hailey-Hailey Disease- JAMA study

Hailey-Hailey disease (HHD) is a rare inherited acantholytic disorder secondary to dysregulated intracellular calcium handling. There are only few treatments which have been found to be effective in HHD. Recently a report of HHD improving with topical cinacalcet was published in JAMA Dermatology.

A 50 year old woman with biopsy-proven HHD presented with a 2-week history of a painful large, crusted, erythematous plaque on the right chest area on the right lateral chest. She was on prednisone, 10mg, daily and had not used any topical medications. Previous flares had been treated unsuccessfully with methotrexate, mycophenolate mofetil, cyclosporine, glycopyrrolate, oral antibiotics, topical corticosteroids, topical calcineurin inhibitors, and topical antibiotics.

This time the patient was treated with a compounded topical ointment comprising cinacalcet, 3%, in a petrolatum-based vehicle. After applying 0.25 g twice daily for 5 days, complete resolution of the lesion occurred with residual hyperpigmentation. Two weeks later, she developed new areas of HHD on the left arm and left chest. She applied between 0.25 to 0.5 g of the ointment twice daily, stopping after 12 days when she ran out of the medication. During treatment, rapid improvement on the left chest and gradual improvement on the left arm was observed. No local or systemic adverse effects were present. Baseline and post treatment laboratory values were within normal limits for intact parathyroid hormone, ionized calcium, and phosphorus.

Hailey-Hailey disease is a a relapsing remitting course with only few effective treatments. The underlying pathophysiology of HHD is a variant of theATP2C1 gene, which encodes the SPCA1 calcium pump on the Golgi complex. The resultant dysregulated intracellular calcium handling manifests histologically as poor cell-to-cell adhesion and acantholysis. The epidermal calcium-sensing receptor (CaSR) represents a novel target for pathogenesis-directed therapy for HHD. The CaSR is best known for its presence in parathyroid tissue. Calcimimetics like oral cinacalcet have been used in hyperparathyroidism, for which they act as positive allosteric modulators of the parathyroid CaSR to decrease serum parathyroid hormone and calcium levels. CaSR is also distributed on the keratinocyte plasma membrane, Golgi and endoplasmic reticulum where it regulates intracellular calcium signaling and keratinocyte differentiation. Additionally, the epidermal CaSR forms a complex with calcium-regulating proteins and the SPCA1 pump on the Golgi, which is defective in HHD.

Immunoelectron microscopy of HHD keratinocytes demonstrates cytoplasmic dissolution of components of the adherens junction (E-cadherin, β-catenin) and desmosomes (desmoglein, plakoglobin). Prominent actin stress fibers, which transmit mechanical tension, have been observed with confocal laser scanning microscopy of affected keratinocytes. Research suggests that the epidermal CaSR promotes E-cadherin–mediated assembly of the aforementioned adherens junction, reorganization of actin cytoskeletal networks, and promotion of keratinocyte differentiation and proliferation via the mitogen-activated protein kinase pathway. E-cadherin signaling has also been implicated in desmosome assembly. Altogether, these events promote cell-to-cell adhesion and wound healing.

The authors hypothesize that this patient’s improvement with topical cinacalcet is due to stimulation of the epidermal CaSR signaling pathway, thereby restoring the ability of keratinocytes to organize intercellular junctions. Interactions between cinacalcet-bound CaSR on the Golgi membrane and defective SPCA1 may also alter the dysfunctional calcium signaling in HHD keratinocytes.

To conclude targeting the epidermal CaSR with topical cinacalcet is a therapeutic approach that merits further investigation into its use for HHD, Darier disease, wound healing and other dermatologic conditions.

Source- Edminister JR, Patel HA, Pixley JN, Huang WW, Jorizzo JL. Improvement of Hailey-Hailey Disease With Topical Cinacalcet, 3%, Ointment. JAMA Dermatol. 2023 Apr 12. doi: 10.1001/jamadermatol.2023.0435. Epub ahead of print. PMID: 37043228.