Hailey-hailey disease responding to thalidomide.

Familial benign chronic pemphigus or Hailey-Hailey disease (HHD) is a rare autosomal dominant disorder characterized by the development of recurrent blisters and erosions in the intertriginous areas. Various topical and systemic treatment options include corticosteroids, topical 5-fluorouracil, topical vitamin D analogs, topical zinc oxide, dapsone, psoralen plus ultraviolet A, systemic retinoids, cyclosporine, methotrexate, and photodynamic therapy. In recalcitrant cases, further options including, invasive methods such as grenz ray therapy, carbon dioxide laser abrasion, and erbium: YAG laser ablation, dermabrasion, electron beam therapy, botulinum toxin, and full-thickness excision of affected skin with repair by split-thickness grafting have been reported as useful in treatment of HHD. We describe a case of HHD who was treated with several treatment modalities including antibiotics, corticosteroids, and dapsone earlier and when presented to us had a severe recalcitrant disease. Thalidomide, as a modality of treatment has been successfully used in few cases earlier. Our patient responded well to thalidomide.

What was known?

Hailey-Hailey disease is a rare genodermatosis. Thalidomide has been used in very few cases earlier.

Introduction

Hailey-Hailey disease (HHD) or familial benign chronic pemphigus first described in 1939, is a rare autosomal dominant genodermatosis, which presents with recurrent vesicles, erythematous crusts and erosions in the areas subjected to friction, including, the neck and intertriginous areas. Abnormalities in the tonofilament–desmosome–keratin complex results in marked acantholysis, giving the histological appearance of a dilapidated brick wall, which is pathognomonic of the disease. Ultra violet B rays provokes acantholysis and can be used to detect carriers.[12] The treatment is often not satisfactory and hence, various modalities of treatment have been tried. There are very few case reports of HHD responding to thalidomide in the literature. We describe a case of HHD with a positive family history, in which various treatment modalities were tried without any benefit but responded well to thalidomide.

Case Report

A 30-year-old unmarried male presented with a history of recurrent painful fluid and pus filled lesions followed by painful erosions over the neck, axillae, trunk and groins of 15 years duration exacerbated over the past 10-15 days. The lesions were mildly pruritic and the discharge was foul-smelling. The lesions aggravated on sun exposure with exacerbation in summer season. He gave family history of similar disease in his father, paternal grandmother and paternal uncles. Before coming to us, he was diagnosed as a case of HHD, which was confirmed histopathologically. He had been treated with dapsone following which he developed agranulocytosis and dapsone was discontinued. Several other treatment modalities including oral and topical antibiotics, corticosteroids were tried but resulted in only partial or temporary improvement. His condition had been steadily deteriorating.

On examination, he was febrile. Large macerated plaques studded with foul-smelling pus along with erosions, fissures, and crusts were present on the anterior and the lateral aspect of the neck, axillae, back, lower abdomen, pubic area, gluteal cleft, groins, upper medial thighs and scrotum [Figure 1]. Surrounding skin was friable and erythematous. Nikolsky's sign was positive perilesionally. Few types of erosion with slough were seen on the tongue dorsum and throat. Erosions and crusts were seen on the glans with purulent foul smelling discharge in the prepucial sac, sparing rest of the penis. Nails showed longitudinal ridging. The skin biopsy specimen for histopathological reconfirmation of the diagnosis revealed focal suprabasilar clefting, few acantholytic cells, intercellular edema with dilapidated brick wall appearance which confirmed our diagnosis [Figures 2 and 3].

Figure 1

Macerated plaques with erosions and crusts over the scrotum, glans penis and upper medial thighs

Figure 2

Focal suprabasal clefting and lacunae (H and E, ×10)

Figure 3

Suprabasalar clefting with few acantholytic cells, intercellular edema and dilapidated brick wall appearance (H and E, ×40)

Patient was started on intravenous (IV) betamethasone 4 mg, 8th h which was tapered off with the introduction of 40 mg of oral prednisolone, IV ceftriaxone 1 mg twice daily and later IV piperacillin-tazobactam based on pus culture and sensitivity reports along with a combination of fusidic acid and betamethasone for topical application.

He continued to develop new lesions with the deterioration of his general condition and was febrile throughout. In spite of controlling the secondary infection, the vesicular eruptions persisted. Therefore, he was started on oral thalidomide 100 mg three times a day and a combination of betamethasone and gentamycin for topical application. Marked improvement was seen within a week of starting thalidomide [Figure 4] and hence we discontinued corticosteroid after rapid tapering of its dose and continued treating him with oral thalidomide 100 mg three times a day for one more week, which was then tapered off in 3-4 weeks and maintained on 50 mg daily. After 6 months of receiving 50 mg thalidomide, the drug was stopped in view of no recurrence of the lesions. He has improved well and comes to us for regular follow-up.

Figure 4

Post-treatment photograph after a week of starting the thalidomide

Discussion

Mucosal involvement is unusual in HHD and has been very rarely reported and can involve oral, conjunctival, vaginal, or in very rare instances esophageal mucosa.[13] Our patient had oral, pharyngeal, and genital mucosal involvement, which were resistant to the symptomatic treatment.

Apart from the symptomatic therapy, drugs such as corticosteroids, dapsone, etretinate, methotrexate, cyclosporine, topical 5-fluorouracil, topical vitamin D analogs, topical zinc oxide, alefacept, psoralen plus ultraviolet A therapy and photodynamic therapy have been tried with varying results. As HHD is often recalcitrant to treatment, further options including invasive methods such as grenz ray therapy, carbon dioxide laser abrasion, erbium: YAG laser ablation, dermabrasion, electron beam therapy, botulinum toxin and full-thickness excision of affected skin with repair by split-thickness grafting have been reported as useful in treatment of HHD.[145678910]

In the study conducted by Galimberti et al., the majority of the patients responded to topical treatment with corticosteroids and antibiotics. The most efficacious treatment was the combination of betamethasone dipropionate and gentamicin.[5] HHD is linked to mutations in the Calcium-transporting ATPase type 2C member 1 gene encoding the human secretory pathway Ca2+/Mn2+ ATPase. Topical aminoglycosides can induce read through of premature stop mutations in the epidermis. Topical gentamicin was found to be very effective in inducing remission in a HHD patient carrying a premature stop mutation.[11]

Thalidomide, as a modality of treatment has been successfully used in few cases.[23] It may be an important alternative in the treatment of HHD in patients not responding to the other modalities of treatment or when the conventional drugs are contraindicated. Our patient developed agranulocytosis to Dapsone and hence was discontinued. He did not respond to high-dose steroids. He responded well to thalidomide. However, its mechanism of action in HHD has not been extensively studied.

What is new?

Mucosal involvement is unusual in Hailey-Hailey disease (HHD) and has been very rarely reported. Our patient had oral, pharyngeal, and genital mucosal involvement.

Thalidomide may be an important alternative in the treatment of HHD in patients not responding to the other modalities of treatment or when the conventional drugs are contraindicated.