Calcitriol, 1±25-dihydroxyvitamin D3, can induce differentiation of epidermal keratinocytes into squamous and denucleated horny cells by regulating inter- and intra-cellular calcium concentration. Cytoplasmic calcium homeostasis is known to be impaired in keratinocytes from Hailey-Hailey disease (HHD) and the normal epidermal calcium gradient is weakened in HHD patients. These observations and our previous published study on the effectiveness of systemic calcitriol in HHD, led us to a topical formulation of this compound in an HHD patient.Calcitriol, 1±25-dihydroxyvitamin D3, can induce differentiation of epidermal keratinocytes into squamous and denucleated horny cells by regulating inter- and intra-cellular calcium concentration. Cytoplasmic calcium homeostasis is known to be impaired in keratinocytes from Hailey-Hailey disease (HHD) and the normal epidermal calcium gradient is weakened in HHD patients. These observations and our previous published study on the effectiveness of systemic calcitriol in HHD, led us to a topical formulation of this compound in an HHD patient.
A 25 year-old woman with a 10-year history of biopsy-proven Hailey-Hailey Disease, mostly involving the chest, was referred to our clinic because of substantial discomfort and ineffective response to several therapies. Her father was also affected. She complained of a large reddened, superficial, crusted erosion on the front of the chest. After informed consent had been obtained, she started twice-daily treatment with calcitrol 3 mg g¹ ointment (Silkis ointment, Galderma Laboratories) for one month. Local skin irritation was not reported. The patient experienced complete clearing of the lesion. After 3 months of follow-up, the clinical result is still maintained.
Hailey-Hailey disease, or benign familial pemphigus, is a rare inherited skin condition in which there is a problem with keratinocyte adhesion. The disorder, which is transmitted as an irregular autosomal dominant trait, causes significant symptoms. The skin in such areas as the genital area, neck, armpits, and behind the knees is affected with red, scaly areas that may itch and blister. HHD has a chronic, relapsing-remitting course, which is made worse by sweat, moisture, ultraviolet radiation, and friction, or by bacterial, fungal, and parasitic infections. It can be relieved by several surgical and medical treatments. Our previous report has already documented the effectiveness of systemic calcitriol on HHD at the daily dosage of 0.25 mg. More recently, another compound derived from vitamin D3, tacalcitol, was also topically effective on HHD lesions. Recent studies have revealed that the HHD region is localized to 3q21-q24 and that the disorder is caused by mutations in the ATP2C1 gene encoding a Ca²` pump. Ca²` pumps are thought to play an important role in maintaining cytoplasmic Ca²` homeostasis. Extracellular calcium plays a critical role in regulating differentiation and adhesion of cultured keratinocytes. Low levels of Ca²` induce keratinocyte proliferation, while normal levels of Ca²` induce cell-to-cell adhesion and cell differentiation. HHD appears to represent a defect in keratinocyte adhesion due to dysfunction of desmosomal proteins. Experimental studies have demonstrated that HHD keratinocytes, ATP2C1 mutated, are deficient in intracellular Ca²` regulation. Furthermore, the inhibitory effect of calcitriol on T cells and on some inflammatory mediators could also participate in the healing process. Our experience and the previous report with tacalcitol seem to indicate that topical vitamin D3 derivatives, mostly affecting the calcium gradient in differentiating keratinocytes, could regulate and preserve the desmosome assembly and integrity, which is genetically altered in HHD. One month, twice daily, application cleared the lesion and the remission continued at three months observation.
In conclusion, we believe that calcitriol could be considered a therapeutic option for treating this inherited disorder and for maintaining, with occasional application, a disease-free condition
Luca Bianchi, MD, Department of Dermatology, Tor Vergata, University of Rome, Italy Maria Sole Chimenti, MD, Department of Rheumatology, La Sapienza, Univerity of Rome, Italy Alessandro Giunta, MD, Department of Dermatology, Tor Vergata, University of Rome, Italy Reprinted from the Journal of the American Academy of Dermatology, Sept. 2004; 51(3): 475-476, with permission from Elsevier. Please contact Maureen in the Foundation office for a complete copy of this article with the accompanying references, 1-800-545-3286, or click here to send an email.
Definitions of terms, in order of appearance:
Differentiation-the process by which cells and tissues in the body develop the characteristics they need to carry out their specific functions.
Epidermal keratinocytes-the cells of the skin that synthesize proteins that make up the cellular layers of the skin.
Squamous cells/denucleated horny cells-the flat dead skin cells that make up the outer layer of the epidermis.
Intracellular-within cells.
Intercellular-between cells.
Cytoplasmic calcium homoestasis-the relatively constant concentration of calcium within a cell.
Calcium gradient-the balance of calcium concentration within and between cells.
Systemic-through out the whole body. In this instance, taking the medication by mouth in a pill or other form.
Autosomal dominant trait-the gene for the disorder is carried on one of the 22 human chromosomes that do not determine sex and is dominant over the gene for normal skin.
Topical/ topically-applied to the skin.
Extracellular - outside the cell.
Keratinocyte proliferation - the reproduction or multiplication of the skin cells.
Desmosomal proteins - structural proteins that help hold the cells of the skin together.
T cells / inflammatory mediators - the cells and biochemicals that move to the site of an infection or injury, which work to destroy the infection and wall off the injured tissue.
