Low-Dose Naltrexone Treatment of Familial Benign Pemphigus (Hailey-Hailey Disease)

Key Points

Question

Is low-dose naltrexone hydrochloride effective in the treatment of familial benign pemphigus (Hailey-Hailey disease)?

Findings

This case series presents 3 patients who exhibited at least an 80% reduction in extent of Hailey-Hailey disease after treatment with low-dose naltrexone.

Meaning

Low-dose naltrexone may represent a low-cost and low-risk alternative or adjunct in the treatment of Hailey-Hailey disease.

Abstract

Importance

Familial benign pemphigus, or Hailey-Hailey disease (HHD), is a rare and debilitating genetic dermatosis characterized by chronic, recurrent vesicles, erosions, and maceration in flexural areas. Despite the reported therapeutic modalities, such as topical and systemic corticosteroids, systemic immunomodulators, topical and systemic retinoids, and laser, HHD can still be markedly difficult to control.

Objective

To assess low-dose naltrexone hydrochloride in the treatment of recalcitrant HHD.

Design, Setting, and Participants

In this case series, 3 patients with biopsy-proven recalcitrant HHD were evaluated in the outpatient dermatology clinic at the Cleveland Clinic. Each patient was treated with low-dose naltrexone hydrochloride at a dosage of 1.5 to 3.0 mg per day. No laboratory monitoring was necessary. Clinical response (healing of erosions, improvement in erythema, and alleviation of pain), adverse effects, and subjective quality of life were monitored throughout the treatment. The study dates were January 2016 to January 2017.

Main Outcomes and Measures

Objective clinical response as assessed by the treating dermatologist, subjective quality of life as reported by the patient, and recorded adverse effects were monitored throughout the treatment at intervals of 2 to 3 months.

Results

The 3 patients included a woman in her 40s and 2 men in their 60s. Each patient exhibited at least an 80% improvement in extent of disease, with one patient demonstrating 90% clearance. All 3 patients had substantial improvement in quality of life, with one patient reporting improvement in his depression. No adverse effects were recorded.

Conclusions and Relevance

Low-dose naltrexone may represent a low-cost and low-risk alternative or adjunct in the treatment of HHD.

This case series evaluates whether low-dose naltrexone is efficacious and safe in the treatment of recalcitrant familial benign pemphigus (Hailey-Hailey disease).

Introduction

Familial benign pemphigus, or Hailey-Hailey disease (HHD), is a rare autosomal dominant genetic dermatosis characterized by chronic, recurrent vesicles, erosions, and maceration in flexural areas. It results from mutations in the ATP2C1 gene (UniProt P98194) that lead to defective calcium homeostasis in the Golgi apparatus and ultimately loss of adhesion between keratinocytes. Hailey-Hailey disease is often challenging to treat. Herein, we present a novel treatment option for HHD.

Methods

Patients with biopsy-proven recalcitrant HHD were evaluated in the outpatient dermatology clinic at the Cleveland Clinic and treated with low-dose naltrexone hydrochloride (1.5-3.0 mg/d). Because reported dosages in the literature for low-dose naltrexone hydrochloride range from 1.5 to 4.5 mg per day, patients were started on 1.5 mg/d and titrated monthly as needed; concomitant topical and systemic medications were ceased. The same physician (one of us, A.P.F.) administered all treatments to all patients and assessed response. Patients were followed up every 2 to 3 months. Clinical response, adverse effects, and subjective quality of life were monitored throughout the treatment. The study dates were January 2016 to January 2017. Because no standardized rating scale exists for HHD to date, response was judged and quantified by taking into account healing of areas of cutaneous breakdown, improvement in erythema, and decrease in patients’ reported symptoms or pain and discomfort. No laboratory monitoring was necessary.

The department of dermatology determined that institutional review board approval was not necessary for the reporting of this case series. Each patient was treated in the outpatient setting after giving verbal consent.

Report of Cases

Case 1

A woman in her 40s was seen at our clinic with a 13-year history of erythematous, macerated, and eroded plaques under the pannus, below the breasts, in the axillae, and in the groin. Biopsy of the inframammary area revealed an acanthotic epidermis with intact granular layer and diffuse acantholysis at multiple levels of the epidermis without substantial dyskeratosis, consistent with a diagnosis of familial benign pemphigus, or HHD.

After failing topical corticosteroid and antifungal therapies, the patient stated that she had learned through online lay sources, including HHD support groups, that low-dose naltrexone had been anecdotally reported as effective for HHD. After confirming these anecdotal reports and carefully considering the risks associated with the use of this medication, the patient was started on treatment with naltrexone hydrochloride (1.5 mg/d) and titrated to 3.0 mg/d within 4 weeks; all other topical and systemic therapy was stopped. With this treatment regimen, the patient exhibited 80% clearance of her disease by 3 months, noting resolution of erosions and ulcerations, improvement in pain, and decrease in erythema. The patient continues to have sustained results 9 months into treatment, with mild intermittent flares every 3 to 4 months. She reports no adverse effects.

Case 2

A man in his 60s with biopsy-proven HHD was initially seen with recalcitrant disease unresponsive to topical and systemic corticosteroids, antifungals, antibiotics, and dapsone. Carbon dioxide laser excision to a limited area years prior was helpful, but recovery time and cost precluded further treatment. The patient was started on a regimen of low-dose naltrexone hydrochloride (1.5 mg/d), with cessation of other topical and systemic medications, and titrated to 3.0 mg/d within 1 month. After 3 months of treatment, the patient exhibited a sustained 80% improvement in extent of disease characterized by resolution of erosions, improvement in erythema, and alleviation of pain (Figure). He reports overall improvement in his quality of life and no medication-related adverse effects.

Figure. Familial Benign Pemphigus (Hailey-Hailey Disease) of the Right Axilla and Response to Low-Dose Naltrexone in Case 2.

A, Shown are extensive erosions and macerations involving the axilla. B, Three months of low-dose naltrexone hydrochloride resulted in 80% clearance of the disease in the axilla, with resolution of erosions, alleviation of pain, and some improvement in erythema.

Case 3

A man in his 60s with biopsy-proven HHD was seen with severe disease refractory to topical and intralesional corticosteroids, systemic antibiotics, and topical calcineurin inhibitors. Treatment with topical and systemic medications was stopped, and he was treated with low-dose naltrexone hydrochloride (1.5 mg/d) and instructed to increase his dosage to 3.0 mg/d during flares. After 4 months of therapy, the patient demonstrates 90% clearance in extent of disease, as noted by resolution of erosions, improvement in erythema, and decrease in tenderness and discomfort. He reports improvement in his depression, better quality of life, and no adverse effects from the use of the medication.

Discussion

Hailey-Hailey disease is often refractory to many treatments, including topical and intralesional corticosteroids, topical and systemic retinoids, immunomodulators (eg, methotrexate and cyclosporine), and energy-based therapy (eg, narrowband UV-B light and carbon dioxide laser). To our knowledge, low-dose naltrexone has never been described in the peer-reviewed medical literature as an effective treatment for HHD.

Naltrexone was synthesized in 1963 as an orally active opioid receptor antagonist and was approved by the US Food and Drug Administration in 1984 for the treatment of opioid addiction. The typical dose for opioid addiction ranges from 50 to 100 mg daily. However, reported low-dose naltrexone hydrochloride dosages range from 1.5 to 4.5 mg daily, with some fluctuation above or below this range depending on the disease and the investigator. In the United States, low-dose naltrexone capsules must be prepared by a compounding pharmacy because such low doses are not yet commercially available.

Low-dose naltrexone may be an effective treatment for several inflammatory disorders. Fibromyalgia is now considered an inflammatory chronic pain disorder characterized by diffuse musculoskeletal pain and nerve hyperesthesia. Low-dose naltrexone has been reported as an effective treatment for fibromyalgia. Also, low-dose naltrexone may show promise in the treatment of Crohn disease, reducing flares, aiding in mucosal healing, and diminishing systemic inflammatory markers. However, owing to insufficient data, lack of randomized clinical trials, and variability in treatment regimens, the efficacy of low-dose naltrexone in treating Crohn disease has not yet been firmly confirmed. Other inflammatory conditions in which low-dose naltrexone may show potential include complex regional pain syndrome, chronic pruritus, and multiple sclerosis.

At low doses, naltrexone appears to have paradoxical analgesic and anti-inflammatory systemic effects. At typical doses, naltrexone blocks µ- and δ-opioid receptors, thereby blocking β-endorphins at those receptors; however, at low doses, naltrexone seems to have a paradoxical effect. Some investigators hypothesize that partial blockade of those receptors causes the body to compensate by producing more endogenous opioids and opioid receptors, thus explaining the analgesic effects of low-dose naltrexone. In addition, naltrexone antagonizes Toll-like receptors found on microglia in the central nervous system, thereby decreasing central production of proinflammatory cytokines, substance P, reactive oxygen species, and excitatory amino acids. The anti-inflammatory effect also seems to extend to peripheral macrophages, as evidenced by diminished release of tumor necrosis factor, interleukin 6, and other proinflammatory cytokines. The mechanism of action of low-dose naltrexone specifically leading to improvement in our patients with HHD is unknown but may be attributed to its central and peripheral anti-inflammatory effects, as well as some other influence on intracellular calcium homeostasis. Formal in vitro studies on the effect of naltrexone on keratinocytes are needed to elucidate this conjecture further.

In contrast to full-dose naltrexone hydrochloride (50-100 mg daily), which can cause suicidality, depression, hypersensitivity reactions, gastrointestinal tract distress, and hepatotoxicity, reported adverse effects related to the use of low-dose naltrexone are rare. In the literature, some patients reported more vivid dreams or headaches. No organ system toxicities, medication withdrawals, or abuse of low-dose naltrexone have been reported to date.

Conclusions

Herein, we present the first reported cases to our knowledge of successful treatment of HHD with low-dose naltrexone. Although off-label and not approved by the Food and Drug Administration, low-dose naltrexone may represent a low-cost and low-risk alternative or adjunct in the treatment of HHD. To mitigate possible confounders, concurrent therapy was not administered to our patients, and we hypothesize that greater improvement may have been possible with the use of concomitant therapies. Further studies and reports are needed to truly assess the efficacy and long-term safety of this medication in treating HHD.