Clinical Reference / Therapeutic Strategies / Hailey-Hailey Disease

Hailey-Hailey Disease


Key Points

  • Hailey-Hailey disease is an autosomal dominantly inherited genodermatosis caused by dysregulation of calcium hemostasis in the keratinocyte that leads to acantholysis (loss of cell-cell adhesion) in the epidermis.
  • Clinically, it manifests with macerated, eroded plaques primarily in the intertriginous areas.
  • Bacterial and fungal superinfection is a frequent complication.
  • First-line treatment consists of high potency topical corticosteroids, often accompanied by topical antibiotics and/or antifungals as well as adjuvant treatments such as astringents and absorbent powders. Newer maintenance treatment options include topical immunomodulators.
  • For refractory disease, treatment options include ablative lasers, botulinum toxin, glycopyrrolate, and surgical excision. For more extensive disease, systemic antibiotics as well as systemic immunomodulators may be employed.

Introduction

Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare autosomal dominantly inherited genodermatosis with complete penetrance in adulthood but variable expressivity (some cases are very subtle and therefore never diagnosed). Approximately two thirds of affected patients report a family history of the disorder. HHD is caused by loss-of-function mutations (of which over 100 have been described) in the ATP2C1 gene on chromosome 3q21 that encodes the ATPase hSPCA1 which pumps calcium into the Golgi apparatus of keratinocytes. The ensuing derangement of calcium homeostasis leads to acantholysis (loss of cell-cell adhesion), clinically manifesting with vesiculation, erosions, and moist-macerated plaques primarily in the intertriginous regions (lateral neck, axillary, inframammary, perineal and inguinal folds). The plaques are frequently pruritic, and may become crusted and malodorous, particularly as they are highly prone to overgrowth of candida and bacteria. There may also be genital involvement, with possible increased risk for development of squamous cell carcinoma at these sites. Characteristic nail changes, consisting of longitudinal white banding of the nail plate, have also been well described.

While the disease causes discomfort (sometimes severe) and emotional distress secondary to its cosmetic effects, it is not life threatening. The disease tends to follow a waxing and waning course, and the lesions typically resolve with post-inflammatory hyperpigmentation. Exacerbating factors include heat, sweating, friction, skin infections, and ultraviolet exposure. The disease affects men and women equally. Peak incidence occurs between the ages of 20-40. No particular geographic or ethnic predilections are observed.

The diagnosis is confirmed by histopathologic examination of lesional skin. Biopsy specimens demonstrate acantholysis of intraepidermal keratinocytes extending down to the suprabasal level, producing the characteristic “dilapidated brick wall” appearance in the epidermis. Dyskeratosis is not a prominent feature, in contrast to the findings seen in Darier’s disease. As HHD is not an antibody-mediated condition, both direct and indirect immunofluorescence are negative (in contrast to pemphigus vulgaris and foliaceus as well as IgA pemphigus).

Treatment of HHD should be undertaken in consultation with a dermatologist, and includes both topical and systemic therapies depending on extent and severity of disease. Additionally, physical treatment modalities including laser, photodynamic therapy and surgical excision have been used with mixed success.

Initial Evaluation

Patients with suspicion of HHD should be referred to a dermatologist for an initial evaluation. Patients undergo a complete skin exam including examination of mucosal surfaces and nails.

Any lesions with significant crusting (or other signs of infection such as surrounding/spreading erythema, tenderness, or purulent exudates) are swabbed for bacterial culture.

A skin biopsy from lesional skin is performed and submitted for H&E, and a perilesional specimen may be submitted for direct immunofluorescence (DIF) if an autoimmune condition (e.g., pemphigus vulgaris or foliaceus) is strongly considered in the differential diagnosis.

Hailey-Hailey disease

Differential Diagnosis

Tinea cruris

Inverse psoriasis

Pemphigus vulgaris

Pemphigus foliaceus

Extramammary Paget’s disease

Darier’s disease

Also:

Erythrasma
Subcorneal pustular dermatosis / IgA pemphigus / Intertrigo
Dowling-Degos / Galli-Galli disease

Treatment

First-line therapy:

First steps

Skin care regimen for affected intertriginous areas:

  • Apply an astringent, either aluminum chloride 6% in a roll-on preparation twice daily or for more severe cases, aluminum chloride 20% solution once daily.
  • Immediately after application of astringent, apply clindamycin 1% solution or lotion (note that solutions are in alcohol vehicles and will cause a burning sensation if there is extensive fissuring of the lesions). Other topical antibiotics, such as mupirocin, are sometimes used.
  • After both astringent and topical antibiotic applications, apply an absorbent powder (such as talc or miconazole powder).
  • Finally, during flares, apply a superpotent topical steroid in a cream or foam base twice daily. This should be used for a limited time period under supervision by a dermatologist.
  • For maintenance treatment, a low- to mid-potency topical steroid in a cream or foam base may be applied.
  • A more recently available maintenance treatment option that avoids long-term steroid side effects is the use of tacrolimus 0.1% ointment or pimecrolimus 1% cream. This may be safely used for long periods in the groin and axilla, with intermittent pulses of potent topical steroids for breakthroughs. Patients should be counseled that a burning sensation may occur initially (first few days to weeks) with use of this treatment, which usually resolves on its own with continued use.
  • Most acute flares are associated with secondary infection with aureus. If secondary infection is apparent and/or if cultures reveal the presence of pathogenic bacteria, administer oral antibiotics, based on the results of bacterial sensitivities (cephalexin 500 mg 3 times daily, doxycycline 100 mg twice daily, TMP/SMX DS twice daily, and clindamycin 300 mg twice daily are all options). Erythromycin was used more commonly in the past. The duration of treatment should be at least 7-10 days, and often must be longer.
  • Nystatin or an azole (such a econazole or clotrimazole) cream or ointment may be applied to control candidal overgrowth, which may be a contributing factor.

Subsequent steps

  • Overgrowth with Candida albicans may complicate aggressive antibiotic treatment. Fluconazole 100-200 mg daily may be required to control this complication.
  • Relapses with recurrent colonization/infection with aureus may be prevented by including 5-10 days of rifampin 600 mg daily in addition to the antibiotic regimens outlined above. Note: rifampin should only be given in combination with another antibiotic, as resistance is common in rifampin monotherapy.

Alternative steps

  • Patients refractory to the above treatments should be re-evaluated by a dermatologist for consideration of second-line treatments.
  • Calcipotriene ointment 0.005% can be applied twice daily to plaques on the trunk. Irritation may limit use in intertriginous areas.
  • Botulinum toxin (BTX) injections will markedly reduce intertriginous sweating. This can lead to a prolonged remission (from a few months up to a year or more) of HHD. BTX is as effective as laser procedures for the short term (first year) and can be used repeatedly to maintain control.
  • A more recently described treatment is oral glycopyrrolate, an anticholinergic agent which blocks the production of eccrine sweat, thus having a similar effect to BTX. Unlike other anticholinergic medications, it does not cross the blood-brain barrier thus avoiding central nervous system effects. Side effects include xerostomia, decreased gastric motility, and in some cases tachycardia.
  • Laser ablation with erbium: YAG or short-pulsed CO2 laser can produce prolonged remissions (up to years) of refractory areas of HHD. This therapy is particularly useful for lesions in the axillae, gluteal cleft, and groin. Surgical excision and possibly photodynamic therapy can produce similar results.
  • A recent case series described the successful use of pulsed dye laser in seven female patients with refractory HHD—this non-ablative modality is appealing due to a milder side effect profile and faster recovery time as compared to ablative laser treatments, however multiple treatments are required.
  • For very severe cases, systemic corticosteroids can lead to improvement. Cyclosporine A is an alternative. These are not long-term management strategies, but they are useful to treat severe flares.
  • Systemic retinoids, methotrexate, and dapsone, will at times be useful in refractory disease, especially if generalized. Their use has largely been replaced by the use of BTX and cyclosporine.

Pitfalls

  • The use of prophylactic systemic antibiotics should be avoided if possible, to minimize the emergence of resistant strains.
  • Resident microflora also can develop resistance to topical antibiotics. Hence, if long-term topical antibiotics are employed, clindamycin resistance may occur.
  • Cyclosporine A and systemic steroids can have significant side effects when used for periods longer than several months. These prolonged courses should be avoided in HHD, as alternative treatments are available.
  • Dapsone can produce acute hemolysis in patients who are G6PD deficient; therefore, blood serum analysis for enzyme activity must be obtained prior to initiating therapy.
  • Do not use pure cornstarch powder. Cornstarch is a nutritious substrate for microbes; hence, pure cornstarch powder has no place in modern topical therapy (it may, however, be used as an inactive ingredient in powders containing antifungal medications).

Clinical Cases

Case 1

  • 42-year-old Middle Eastern man
  • Past medical history notable for impaired fasting glucose and hypertension
  • Review of systems negative
  • Social history is unremarkable
  • Presents for evaluation of six-month history of itchy rashes in armpits and groin that occasionally become malodorous. No response to over-the-counter 1% hydrocortisone cream.
  • Family history is notable for a father and brother with similar symptoms

Initial evaluation

  • Healthy appearing, slightly overweight man
  • Erythematous, macerated plaques with scant crusting symmetrically in bilateral axillary vaults and inguinal folds
  • Several nails with leukonychia striata

Diagnosis: Hailey-Hailey disease

  • Biopsy a representative skin lesion
  • Bacterial swab culture from crusted area

Follow-up evaluation

  • H&E demonstrates intraepidermal and suprabasal acantholysis without prominent dyskeratosis
  • Bacterial culture was negative
  • Initiate treatment with: aluminum chloride 20% solution, clindamycin 1%, solution, high potency topical steroid cream while flaring
  • For maintenance treatment, use tacrolimus 0.1% cream
  • Consider trial of botulinum toxin injections or oral glycopyrrolate if refractory to above measures

References

Bessa GR, Grazziotin TC, Manzoni AP, Weber MB, Bonamigo RR. Hailey-Hailey disease treatment with Botulinum toxin type A. An Bras Dermatol. 2010;85(5):717-722.

Chiaravalloti A, Payette M. Hailey-Hailey disease and review of management. J Drugs Dermatol. 2014;13(10):1254-1257.

Ho D, Jagdeo J. Successful botulinum toxin (onabotulinumtoxinA) treatment of Hailey-Hailey disease. J Drugs Dermatol. 2015;14(1):68-70.

Hunt KM, Jensen JD, Walsh SB, et al. Successful treatment of refractory Hailey-Hailey disease with a 595-nm pulsed dye laser: a series of 7 cases. J Am Acad Dermatol. 2015;72(4):735-737. doi: 10.1016/j.jaad.2014.12.023

Kaniszewska M, Rovner R, Arshanapalli A, Tung R. Oral glycopyrrolate for the treatment of Hailey-Hailey disease. JAMA Dermatol. 2015;151(3):328-329. doi: 10.1001/jamadermatol.2014.4578

Sudbrak R, Brown J, Dobson-Stone C, et al. Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump. Hum Mol Genet. 2000;9(7):1131-1140.

Tchernev G, Cardoso JC. Familial benign chronic pemphigus (Hailey-Hailey Disease): use of topical immunomodulators as a modern treatment option. Rev Med Chil. 2011;139(5):633-637. doi: /S0034-98872011000500011