Hailey-Hailey disease: the role of azathioprine an immunomodulator

Hailey-Hailey disease (HHD) is a rare autosomal dominant hereditary blistering and erosions disorder affecting the intertriginous regions of the body. There is still no treatment protocol for this disease thus clinicians are highly advised to draw up individualized treatment plan. In this case report, we discuss a case of HHD in a 58-year-old Chinese man who was successfully treated with azathioprine in Hubei province.


Introduction
Hailey-Hailey disease (HHD), named after the two brothers Howard and Hugh Hailey who first described this still rare autosomal dominant hereditary blistering and erosious disorder affecting the intertriginous regions of the body in 1939 [1]. HHD is synonym as benign chronic familial pemphigus, benign chronic pemphigus or familial benign pemphigus [2]. It is not an autoimmune disorder and thus there are no autoantibodies. The first onset of HHD generally occurs between 20 years and 40 years of age. Xu et al. in 2017, approximate that the prevalence of HHD is 1: 50,000 worldwide [3,4]. The onset of symptoms usually occurs around puberty or middle age and may be exacerbated by perspiration, weight gain, infection, trauma, pregnancy and ultraviolet radiation [5]. This rare disease is due to a heterozygous autosomal dominant mutation in the ATP2C1 gene [2] on chromosome 3, which encodes for secretory pathway of adenosine triphosphate-dependent calcium/manganese pump (Ca2+/Mn2+ ATP-ase protein (SPCA1)) in the Golgi apparatus whose function is to maintain intercellular calcium homeostasis thus leading to alterations in Ca2+-dependent intracellular signaling and resulting in the loss of cellular adhesion in the epidermis [6,7]. Clinically patients with HHD presents with a long history of wax and wanes of symptoms; these include but not limited to the following dermatosis characterized by chronic, recurrent vesicles, erosions, and maceration in flexural areas friction areas, mainly in the axillae, submammary folds, groin, perineum and neck. However, lesions also can occur in non-skin-fold areas [8]. The other associated features are itchiness, burning sensation, pain and fever which are mainly complications of the primary pathology. Chiaravalloti and Payette, 2014 record that nail changes are part of a criteria to diagnose HHD. The duo documents that about 71% of patients have asymptomatic linear, white bands in the nail plates. According to them, nail changes has been the presenting feature in many cases [4,5,9]. In this case review, we shall discuss a case of HHD, review the commonest triggers and the role of azathioprine, an immunosuppressive agent in the management of the disease.

Patient and observation
A 50-year-old Asian male was referred to our outpatient department from a local clinic with a diagnosis of familial benign pemphigus for 10 years and well controlled hypertension for 20 years now. With the current hospital visit, he had been complaining of waxing and waning lesions under armpit and groin which where dark-reddish in colour with many papular-vesicles which could easily break and leave erosions and ulcers in these regions and later on form scab. They were associated with lots of pain which was initially itchy and fever for the past five days' prior presentation to our hospital. This presentation limited his normal daily chaos. He has not received much improvement from the usual topical and oral medication which he has been taking from since past the illness started. The patient showed much improvement after day 5 on azathioprine and he was treated as outpatient on the same cocktail with a 2 weekly supply of the immunomodulator as indicated in Figure 3, Figure 4.

Management of genetically influenced diseases like HHD can always
be very challenging because most of them rarely have a cure but they can be managed clinically as and when symptoms evolve. HHD is such a disease which requires patient education on their illness, its possible triggers or precipitants, how to both avoid and manage flares. They also require special education on the various kinds of drugs used for their condition. Our patient prior being referred to us, used a series of both topical and oral antibiotics which were becoming less effective for his condition. During our first contact, he was put on anti-allergic treatment (compound glycyrrhizin and calcium aspartate intravenously), topical antibiotic (cefoperazone tazobactam topical drug) for both symptomatic and disease modification treatment. Day three post admission, the disease was still active evidenced by laboratory and clinical evaluation and a consensus to add an immunosuppressive agent was reached, azathioprine was included on the drug list. The use of azathioprine in management of HHD has been reported although in combination with other drugs [10,11].
For instance, dermatologists have been using azathioprine to successfully treat immunobullous diseases for nearly 35 years.
Consequently, this application has become well recognized, and azathioprine has thus been ''grandfathered'' into the dermatologic armamentarium despite the lack of multiple prospective randomized, double-blinded controlled trials to support its use [12]. Symptoms are exacerbated by factors including sun exposure, heat, sweat and friction [5] as was with our patient. Burge S.M, 1992, notes that exacerbations have also been observed with patch testing and herpes simplex virus type 1, with possible evolution into herpetic eczema [13]. As for our client viral screen for herpes simplex virus type 1 was unsatisfactory. HHD is an autosomal dominant skin disorder characterized by abnormal keratinocyte adhesion in the suprabasal layer of the epidermis.
On histology, suprabasilar acantholysis is often described as "a row of tombstones" or a "dilapidated brick wall" -the "tombstones" or "bricks" referring to the basilar keratinocytes [4]. Dyskeratosis may be present, and the dermis is rarely affected, though perivascular lymphocytic infiltrate may be found [13]. Furthermore, unlike in bullous diseases such as pemphigus vulgaris, antidesmosomal autoantibodies might not be detected as described by Chiaravalloti and Payette, 2014 [4].  [13]. One of the complications watch out for is the transformation of squamous cell carcinoma especially in patients on immunomodulators [14,15].