Successful Treatment of Recalcitrant Hailey-Hailey Disease

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Hailey-Hailey Disease (HHD), otherwise known as benign familial pemphigus, is an autosomal dominant, relapsing and remitting, genetic skin condition that results in blistering and maceration, often affecting the intertriginous areas of the skin.^1,2 These areas often progress to irritated erythematous plaques and pruritic painful fissures, which can be physically and mentally detrimental to patients. HHD can be exacerbated by menstruation, pregnancy, skin infections, physical trauma, excessive sweating, and exposure to ultraviolet radiation. HHD is due to an ATP2 C1 gene mutation causing a defect in keratinocyte adhesion, which results in characteristic suprabasal acantholysis seen on histopathology.¹ Certain mRNAs and oxidative stress may contribute to the pathogenesis of HHD.¹ There is a wide array of available treatment options, including topical, systemic, and surgical therapies. However, the efficacy of many of these treatments is limited.² Topical Janus kinase inhibitors (JAKs) have recently become treatment options for many dermatologic diseases, including atopic dermatitis (AD), vitiligo, and alopecia areata.

In this article, we present a patient with a history of recalcitrant HHD who had clearance of her current disease flare with the topical JAK inhibitor ruxolitinib.

Case Report

A 48-year-old woman presented with painful erythematous plaques, with maceration and fissuring in her axilla (Figure 1). She was diagnosed in 2015 with biopsy proven HHD affecting her bilateral axilla. Previous failed therapies included clindamycin 1% lotion, topical tofacitinib, glycopyrrolate, topical steroids, topical calcineurin inhibitors, calcipotriene, and systemic corticosteroids. In 2022, the patient was prescribed ruxolitinib 1% cream to be applied to the affected areas once daily and oral naltrexone 7 mg once daily for an 11-month duration. At the follow-up visit, she had resolution of her flare without recurrence (Figure 2). This was the longest period of time the patient had gone without flaring.

Discussion

The exact pathogenesis of HHD is unknown, but it is thought to consist of loss of function variants in the ATP2C1 gene on chromosome 3 at the 3q21-q24 region. This gene is responsible for the expression of the ATP-powered, magnesium-dependent calcium protein pump hSPCA1.¹ When functioning properly, this calcium pump helps regulate the intracellular concentrations of free Ca2+ by sequestering Ca2+ into the Golgi apparatus, which maintains calcium homeostasis in keratinocytes.¹ When calcium homeostasis is disrupted, acantholysis occurs and results in the painful blistering, plaques, and fissuring seen in HHD.¹

Systemic treatments include erythromycin, penicillin, doxycycline, erythromycin plus topical tacrolimus, oral dapsone, retinoids, and disease-modifying antirheumatic drugs.² Laser, light, and surgical therapies may also be used, including dermabrasion and excision with split-thickness skin grafting.² Reports of vitamin D supplementation, apremilast, dupilumab, and low-dose naltrexone being used for treatment have been seen as well.^4-6

Low-dose naltrexone was effective in this case report, as well as other case series.⁷ One case series involving 3 patients with recalcitrant HHD showed clinical resolution within 2 months, with the patient’s lesions flaring when stopping low-dose naltrexone and clearing once again a few days after resuming the treatment.³ Although systemic treatments may be effective, they may not be sufficient on their own or may have undesirable systemic side effects. Therefore, topical treatments can also be used.

Suspected bacterial colonization can be treated with topical clindamycin 1% lotion or cream, gentamicin 0.1% cream, or mupirocin 2% cream, along with chlorhexidine gluconate 4% wash. Fungal colonization can be treated with ketoconazole 2% cream or another azole cream, according to experts. Topical corticosteroids are used to combat inflammation but should only be used for acute exacerbations to avoid skin atrophy. One study of 58 patients with biopsy proven HHD found that 86% of patients averted the development of lesions by applying topical corticosteroids very early in the disease course when only pruritus was present. Topical calcineurin inhibitors are a nonsteroidal anti-inflammatory approach that can be used for sensitive areas such as skin folds. In case studies, topical application of 0.1% tacrolimus ointment resolved lesions after approximately 2 weeks of treatment.³ Other topical treatments include topical pimecrolimus, bleach baths, topical compress of diluted aluminum acetate, topical calcitriol, tacalcitol, topical 5-fluorouracil, topical cadexomer, intralesional steroids, and botulinum toxin type A injections.^2,8

Utilized either systemically or locally, JAK inhibitors are a developing skin treatment. They suppress the effects of cytokines, activating the JAK-STAT signaling pathway in inflammatory and autoimmune diseases.⁹ Oral and topical JAK inhibitors are small molecules, have a short-half life, and can be used as a steroid-sparing approach.⁹ Topical JAK inhibitors have proven valuable in the treatment of AD. For example, in a randomized double-blind study of 307 adult patients with AD, ruxolitinib cream rapidly and persistently improved AD symptoms, including pruritus, with no clinically significant application site adverse reactions observed.¹⁰

The mechanism behind the dramatic clearance of our patient’s HHD is unclear, but it may be due to inhibition of cytokine release that occurs with inflammation resulting from the acantholysis of HHD. JAK inhibitors are also thought to improve skin barrier function by improving the expression of the filaggrin protein, which could also decrease HHD symptoms.²

Conclusion

Although this new potential treatment modality is exciting, it is important to ensure that the benefits outweigh the risks. The adverse effects of JAK inhibitors include infections, but side effects may be less severe with the topical form of the drug because the medication is applied locally instead of systemically. More studies are necessary to explore the safe treatment of HHD with the topical JAK inhibitor ruxolitinib.

At the University of Oklahoma College of Medicine in Oklahoma City, OK, Kelsey Johnson is a fourth-year medical student, Dr Harrell is a graduate resident, and Jarad Levin is an assistant professor and serves as the medical student director and assistant program director.

Disclosure: The authors report no relevant financial relationships.

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