Treatment of Severe Hailey-Hailey Disease With Apremilast

Key Points

Question

Is apremilast, a phosphodiesterase-4 antagonist approved for the treatment of psoriasis, effective in the treatment of Hailey-Hailey disease?

Findings

This case series presents 4 patients with treatment-resistant Hailey-Hailey disease whose symptoms showed improvement after 1 month with use of apremilast, 30 mg, twice daily.

Meaning

In severe cases of Hailey-Hailey disease resistant to conventional treatments, apremilast appears to be a good, low-risk therapeutic alternative.

Abstract

Importance

Hailey-Hailey disease (HHD) is a rare, autosomal-dominant acantholytic dermatosis characterized clinically by development of recurrent blisters and erosions in friction areas. Despite progression in our understanding of the molecular genetics of HHD, therapy remains suboptimal and there is no known cure.

Objective

To determine whether the novel phosphodiesterase-4 inhibitor apremilast is effective in the treatment of HHD.

Design, Setting, and Participants

Clinical case series of 4 patients with severe, treatment-resistant HHD at an outpatient clinic in the Department of Dermatology of Nice University Hospital, Nice, France. The patients were treated with apremilast; after the initial titration, the dose was 30 mg, twice daily.

Main Outcomes and Measures

Objective clinical response was assessed by the treating dermatologist using the physician global assessment score; recorded adverse effects were monitored throughout the treatment at intervals of 2 to 3 months.

Results

Three women and 1 man, with a mean age of 56 years, were treated and followed up for 6 to 10 months. Family history of the disease was noted in 3 (75%) of the cases. The lesions affected the axillary regions (75%), submammary regions (75%), inguinal regions (100%), and back and neck areas (50%). An improvement in the symptoms was reported by all of the patients after a treatment period of 1 month. After 6 months, the improvement of HHD lesions was reported as moderate to almost cleared among the patients. However, 2 patients developed some flares after 6 to 10 months of treatment and stopped apremilast therapy. One of the patients developed uncontrolled diffuse lesions and apremilast was reintroduced, resulting in partial control of her disease.

Conclusions and Relevance

Apremilast appears to offer a low-risk therapeutic alternative or adjunct in resistant and severe forms of HHD. A prospective controlled trial with long-term follow-up is required to confirm these preliminary observations.

This case series describes 4 adult patients who received apremilast (a phosphodiesterase-4 inhibitor) for treatment-resistant Hailey-Hailey disease.

Introduction

Chronic Hailey-Hailey disease (HHD) (benign familial pemphigus) is a rare, autosomal-dominant genodermatosis characterized clinically by recurrent blisters and erosions occurring in intertriginous sites in a symmetrical pattern. Hailey-Hailey disease results from ATP2C1 gene mutation,¹ which encodes a Golgi apparatus calcium adenosine triphosphatase protein and leads to inappropriate processing of desmosomal proteins and abnormal keratinocyte adhesion. Despite progression in our understanding of the molecular genetics of HHD, therapy remains suboptimal and there is no known cure. Treatment is aimed at reducing inflammation and preventing flare-ups. Although the primary event of HHD is acantholysis, the standard treatment relies on topical corticosteroids that reduce localized inflammation. Isolated successes have also been reported with cyclosporine,^2,3,4,5 methotrexate,^6,7 and thalidomide,⁸ suggesting that immunomodulatory drugs could be helpful for severe cases. Apremilast is a small molecule, approved for use in the treatment of psoriasis, that specifically inhibits the activity of cyclic adenosine monophosphate phosphodiesterase-4 decreasing T_h1 and T_h17 activation and CXCL10 release. We describe 4 patients (mean age, 56 years) with severe and resistant HHD treated with apremilast. All patients gave informed written consent for their information to be published.

Case Reports

Case 1

A woman in her 50s was diagnosed with HHD 30 years ago, with no family history of the disease. Her axillary and lumbar areas were affected (Figure 1). Her various treatments include high-potency topical corticosteroids, antiviral oral drugs, methotrexate, carbon dioxide, and erbium laser. Owing to the severity of the disease and the persistent lesions despite topical treatment, we decided to start apremilast treatment after verbal consent was given by the patient in March 2017. A physical global assessment (PGA) scale was used to assess the efficacy of the treatment, with 0 indicating clear; 1, almost clear; 2, moderate improvement; 3, slight improvement; 4, no change; and 5, worsening of the disease. After 1 month, the PGA level was 2 and decreased to 1 at 6 months. Tolerance was good with no adverse effects reported.

Figure 1. Clinical Presentation of Patient 1.

Baseline presentation (A and B) and evolution after 6 months of apremilast treatment (C and D) of the back and axillary areas.

One month later she had familial stress and experienced a flare of HHD with the PGA level increasing to 4. She decided to stop the treatment. Two weeks after the medication was discontinued, the lesions were worse compared with the baseline level (PGA 5). We tried to treat the disease with twice-daily, high-potency topical corticosteroids, but with minimal efficacy. Finally, apremilast was reintroduced and, 1 month later, the PGA level was 3. At the time of writing, she was still receiving treatment.

Case 2

A woman in her 60s, with HHD diagnosed when she was aged 29 years, experienced axillary, submammary, abdominal, inguinal, and neck and back lesions (Figure 2). Five other members of her family also have HHD, including her mother, grandfather, 2 brothers, and her son. Her only comorbidity is hypertension. Over the years, she has tried topical medications, such as corticosteroids and tacrolimus, and botulinum toxin injections and has been hospitalized several times for HHD. She also received treatment with fractional, then continuous-wave carbon dioxide and erbium laser, as well as antiviral and antibiotic drugs, showing transient improvement on each occasion. Her usual treatment was valaciclovir once daily, along with topical corticosteroids.

Figure 2. Clinical Presentation of Patient 2.

Baseline presentation (A and B) and evolution after 6 months of apremilast treatment (C and D) of the submammary areas.

She started apremilast treatment in June 2017, completing a 6-day titration period before taking 30 mg twice daily. The only adverse effect was diarrhea, with no more than 3 stools per day. After 1 month the PGA level was 3; the PGA level remained between 1 and 2 for the following 5 months of treatment.

Case 3

A woman in her 50s received a histologic diagnosis of HHD in 1999; her mother also has this disease. The patient also has hypothyroidism. The disease is localized in the patient’s axillary, abdominal, neck, and back areas (Figure 3). She was treated successively with topical corticosteroids and tacrolimus, oral antivirals and antibiotics, injections of botulinum toxin, erbium laser, and methotrexate without success. She started apremilast after giving verbal consent in May 2017. The PGA level was 3 after 1 month, 2 after 3 months, and 1 after 6 months with no adverse effects reported. At the time of writing, she was still receiving apremilast and had almost stopped applying topical corticosteroids.

Figure 3. Clinical Presentation of Patient 3.

Baseline presentation (A and B) and evolution after 6 months of apremilast treatment (C and D) of the inguinal and back areas. Note the marked decrease of the inflammation.

Case 4

A man in his 50s with a family history of HHD (cousin and aunt) received the diagnosis in 1996; the lesions were present in his inguinal areas. He was treated with topical corticosteroids without success. He started apremilast in February 2017, with a positive level of effectiveness after 1 month (PGA 2). He experienced myalgia and diarrhea and therefore had to reduce the dosage to 30 mg once daily. With the decreased dose, some lesions became worse and the PGA level increased to 4. With probiotics and over time, diarrhea improved and, after 1 month, the apremilast dose was increased to 30 mg twice daily. The PGA progressively reached level 1 at 6 months. Between 6 and 10 months, he experienced new flare-ups and decided to stop the treatment.

Discussion

Hailey-Hailey disease has been treated with varying degrees of success using a variety of interventions aimed at reducing inflammation or triggering factors. The more severe forms of HHD are difficult to manage with only topical treatments or laser. Systemic approaches with cyclosporine,^2,3,4,5 methotrexate,^6,7 or thalidomide⁸ have been proposed and gave isolated success. There are increasing reports of data showing that keratinocytes are able to produce large amounts of chemokines, including CXCL10.^9,10 We can hypothesize that the genetic alteration of keratinocytes in HHD can trigger their production of chemokines on stress or maceration and contribute to the clinical inflammation observed in this disease. Apremilast induces specific inhibition of phosphodiesterase-4, leading to T_h1 and T_h17 inhibition and a decrease of CXCL10 release.^11,12 In the 4 patients described herein, apremilast showed a sustained improvement in symptoms during the 6 first months of treatment. The number and severity of lesions decreased and they were less inflammatory. As is always the case for HHD, recurrent flares occur. All of the patients experienced some recurrences during the follow-up period. During the first 6 months these recurrences were minimal and easily resolved with the use of topical corticosteroids. Two patients experienced a marked flare after 6 months of treatment and discontinued apremilast. The more severe flare developed after a familial stress event and did not respond to any treatment; however, the lesions improved significantly when apremilast was reintroduced. Owing to the severity of their disease, 2 patients had a history of treatment with methotrexate, but this approach failed to improve their condition. Adverse effects were mild, including transient diarrhea and myalgia; however, 1 patient required a decrease of the dose for 1 month.

Limitations

The limitations of this study are the low number of patients treated and the absence of controls in a disorder classically presenting alternative periods of flares and spontaneous improvements. However, we included adults with severe, active, diffuse, and chronic erosions despite the daily use of topical treatment.

Conclusions

All of the patients experienced significant improvement of their condition with a marked reduction in the number and intensity of their flares for a follow-up period of 6 to 10 months. The response after reintroduction of apremilast for the patient who experienced a relapse after discontinuation of treatment also emphasizes the potential usefulness of apremilast in this indication. Taken together, these results suggest that apremilast could be a safe option to consider for treatment of severe and diffuse HHD. A prospective controlled trial is required to confirm these preliminary observations.