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Naltrexone for the Treatment of Darier and Hailey-Hailey Diseases

Authors:
Abdulhadi Jfri at King Saud bin Abdulaziz University for Health Sciences
Abdulhadi Jfri
  • King Saud bin Abdulaziz University for Health Sciences
Ivan V Litvinov at McGill University
Ivan V Litvinov
Elena Netchiporouk at McGill University
Elena Netchiporouk
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https://doi.org/10.1177/1203475419843122
Journal of Cutaneous Medicine and Surgery
2019, Vol. 23(4) 453 –454
© The Author(s) 2019
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DOI: 10.1177/1203475419843122
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Introduction
Darier (DD) and Hailey-Hailey (HHD) diseases are both
genodermatoses caused by defective calcium transport and
homeostasis. DD is caused by a mutation of the ATPA2A
gene and HHD by a mutation of the ATP2C1 gene. Clinically,
the former is characterized by itchy, painful macerations
with red-brownish papules in a seborrheic distribution; the
latter manifests with painful blisters that rupture, leaving
erosions in intertriginous areas. Treatment options for both
conditions are limited and include topical steroids, systemic
steroids, retinoids, antibiotics, topical aminoglycosides, as
well as dapsone and immunosuppressive therapies.1-3 One
additional promising and novel therapeutic option for these
diseases is naltrexone.
Naltrexone is a long-lasting opiate receptor antagonist. In
dermatology it is used in recalcitrant chronic pruritis or neu-
rodermatoses such as prurigo nodularis. The exact mecha-
nism of action in these conditions is unknown, but it is
thought to be due to its anti-inflammatory and antianalgesic
effects.4 Naltrexone is a known Toll-like receptor 4 antago-
nist, which leads to decreased amounts of TNF-alpha, IL-6,
and nitric oxide. These effects are involved in calcium
homeostasis.1
Low-dose naltrexone (LDN) initiated at 3 mg nightly and
then maintained on 4.5 mg nightly showed significant
improvement in 3 patients with refractory HHD. These
patients previously failed topical, intralesional, and intra-
muscular steroids, along with failing oral and topical antibi-
otics. One of the 3 patients periodically discontinued and
then restarted the medication multiple times. Each time he
would develop lesions a few days after stopping and they
would resolve shortly after resuming naltrexone.1
Another set of 3 patients with HHD was treated with LDN:
Two showed a significant improvement with naltrexone alone
or in combination with topical regimens of tacrolimus and
corticosteroids. The third patient had mild improvement.
Interestingly, 1 of the patients who had significant improve-
ment was on 12.5 mg of naltrexone at that time and reported
slower healing of lesions than on the 4.5 mg dose.5
Another refractory patient with HHD had a dramatic
response to LDN at 4.5 mg daily. This patient failed topical
and oral steroids, prophylactic acyclovir and doxycycline,
dapsone, acitretin, and cyclosporine. In the report, 4 other
members of the same family responded well to LDN.1
Given the therapeutic success of naltrexone in HHD case
series, Boehmer et al recently explored the use of LDN in a
series of biopsy-proven DD patients. In this study, patients
were treated with LDN 4.5 mg and magnesium 200 mg once
daily. Authors supplemented the LDN with magnesium,
given that dysfunction of the SERCA2 calcium pump is
known to be magnesium dependent. Patients were followed
monthly for 12 weeks. Of 6 patients included in the study, 4
had a severe disease defined by a Physician Global
Assessment (PGA) score of 4, while 2 had mild-to-moderate
disease. Only those with mild-to-moderate disease demon-
strated clinical improvement. Of the 2 responders, 1 received
a concurrent treatment with oral acitretin, while the other
was not on any additional treatments.2
The use of LDN at 4.5 mg once daily in patients with HHD
has shown promise in early observational studies. In contrast
to the classic doses of 50-100 mg, LDN does not need any
laboratory monitoring and has a favourable safety profile,
with common side effects of vivid dreams and headache.1
Prior to LDN therapy, patients should be carefully screened
for recent use and/or prior dependence of opioids.1 Further
studies to assess the efficacy of naltrexone in low-dose or
higher doses in these 2 diseases are needed.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Medical Letter
843122CMSXXX10.1177/1203475419843122Journal of Cutaneous Medicine and SurgeryJfri et al
research-article2019
1Division of Dermatology, McGill University Health Centre, Montreal
General Hospital, QC, Canada
Corresponding Author:
Elena Netchiporouk, Montreal General Hospital, McGill University Health
Centre, Department of Medicine, Division of Dermatology, 1650 Cedar
Ave, Montreal, QC H3G 1A4, Canada.
Email: elena.netchiporouk@mail.mcgill.ca
Naltrexone for the Treatment of Darier
and Hailey-Hailey Diseases
Abdulhadi Jfri1, Ivan V. Litvinov1,
and Elena Netchiporouk1
Keywords
Darier disease (DD), Hailey-Hailey disease (HHD), low-dose naltrexone (LDN), naltrexone
454 Journal of Cutaneous Medicine and Surgery 23(4)
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Abdulhadi Jfri https://orcid.org/0000-0003-3866-1421
References
1. Lee B, Elston D. The uses of naltrexone in dermatological con-
ditions [published online ahead of print December 21, 2018]. J
Am Acad Dermatol. doi:10.1016/j.jaad.2018.12.031
2. Boehmer D, Eyerich K, Darsow U, Biedermann T, Zink A.
Variable response to low-dose naltrexone in patients with
Darier disease: a case series [published online ahead of print
February 3, 2019]. J Eur Acad Dermatol Venereol. doi:10.1111/
jdv.15457
3. Kellermayer R, Szigeti R, Keeling KM, Bedekovics T, Bedwell
DM. Aminoglycosides as potential pharmacogenetic agents
in the treatment of Hailey-Hailey disease. J Invest Dermatol.
2006;126(1):229-231. doi:10.1038/sj.jid.5700031
4. Younger J, Parkitny L, McLain D. The use of low-dose naltrex-
one (LDN) as a novel anti-inflammatory treatment for chronic
pain. Clin Rheumatol. 2014;33(4):451-459. doi:10.1007/
s10067-014-2517-2
5. Cao S, Lilly E, Chen ST. Variable response to naltrexone
in patients with Hailey-Hailey disease. JAMA Dermatol.
2018;154(3):362-363. doi:10.1001/jamadermatol.2017.5463
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... Emerging therapies focus on targeting specific molecules that may be involved in the inflammatory pathway of this disease. These medications include naltrexone, apremilast, dupilumab, and tumor necrosis factor (TNF)-α inhibitors [2][3][4][5][6][7][8]. Two reports have documented successful treatment of severe HHD after the administration of a TNF-alpha inhibitor [7,8]. ...
... The downregulation of CXCL10 decreases proinflammatory cytokines, including TNF-α [19,20]. Another drug that has been used to treat recalcitrant HHD is naltrexone, a toll-like receptor 4 antagonist that leads to a decrease in TNF-α, IL-6, and nitric oxide [2]. ...
Hailey-Hailey Disease Successfully Treated With Adalimumab: A Case Series
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Hailey-Hailey disease is an autosomal dominant disorder caused by a mutation in the ATP2C1 gene and characterized by recurrent blisters, erosions, and crust in intertriginous areas. Currently, there are no curative treatments for Hailey-Hailey disease, and therapeutic strategies are focused on controlling skin microbial colonization, infection, and inflammation. Recent efforts have aimed to find therapies that target the biochemical pathway involved in the pathogenesis of this disease. Several case reports indicate the use of different biological agents to achieve long-term remission in patients with recalcitrant Hailey-Hailey disease. Tumor necrosis factor-alpha inhibitors have been used to treat and maintain remission in recalcitrant Hailey-Hailey disease patients, but additional reporting and studies are required. In this case series, we report three cases of recalcitrant Hailey-Hailey disease whose lesions were successfully controlled with adalimumab.
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... 56 There have been several cases of successful treatment of DD by utilizing naltrexone, an antagonist of opioids that binds and blocks opioid receptors and reduces and suppresses opioid cravings. 57,58 The mechanism is unknown, however blockade of μ-receptors and δ-receptors with naltrexone may normalize cellular proliferation and improve adhesion. 58 Additionally, this blockade may reduce P2X7 ...
... 57,58 The mechanism is unknown, however blockade of μ-receptors and δ-receptors with naltrexone may normalize cellular proliferation and improve adhesion. 58 Additionally, this blockade may reduce P2X7 ...
Impaired calcium signalling and neuropsychiatric disorders in Darier disease: An exploratory review
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Darier (Darier‐White) disease (DD) is an autosomal dominant skin disorder caused by pathogenic mutations in the ATP2A2 gene which encodes a calcium ATPase in the sarco‐endoplasmic reticulum (SERCA2). Defects in the SERCA2 protein lead to an impairment of cellular calcium homeostasis, which in turn, triggers cell death pathways. There is a high prevalence of neuropsychiatric disorders in patients affected by this condition, namely intellectual disability, bipolar disorder, schizophrenia, and suicidality. Though these associations have been well‐documented over the years, little has been discussed or investigated regarding the pathophysiological mechanisms. The goal of this article is to review the literature related to the most commonly associated neuropsychiatric disorders found in patients with DD, highlight the pathophysiological mechanisms underlying each condition, and examine potential interventions that may be of interest for future development. A literature search was performed using PubMed to access and review relevant articles published in the last 40 years. Keywords searched included Darier disease neuropsychiatric, Darier disease pathophysiology, SERCA2 central nervous system, SERCA 2 skin, ATP2A2 central nervous system, ATP2A2 skin, sphingosine‐1‐phosphate signalling skin, sphingosine‐1‐phosphate signalling central nervous system, P2X7 receptor skin, and P2X7 receptor central nervous system. Our search resulted in 2692 articles, of which 61 articles were ultimately included in this review.
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... Although the clinical literature harbors numerous reports of improvement using agents such as oral or topical corticosteroids, topical calcineurin inhibitors, the antiopioid naltrexone, or immunologic modulators approved for atopic dermatitis (dupilumab, Jak inhibitors) or psoriasis (apremilast), it remains unclear whether these drugs alter the primary pathology of acantholytic disorders or the secondary inflammation that can result from a breach in the epidermal barrier (Aldana and Khachemoune, 2020;Ben Lagha et al, 2020;Hanna et al, 2022;Jfri et al, 2019;Porro et al, 2024;Rogner et al, 2024). However, repurposing of such FDAapproved drugs for new indications may prove more tenable for rare disorders such as DD and HHD. ...
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... La eficacia de la naltrexona está mejor documentada en la enfermedad de Hailey-Hailey, el liquen plano pilar y la esclerosis sistémica. En la enfermedad de Hailey-Hailey, con la mayor cantidad de informes de casos y series de casos publicadas hasta el momento, las dosis bajas de naltrexona han mejorado la intensidad y duración de los brotes y los síntomas de la enfermedad en los pacientes con clínica refractaria a múltiples tratamientos de primera línea 3,4 . En el liquen plano pilar, una serie de 4 casos de pacientes con síntomas persistentes luego de 3 a 5 años de tratamientos fallidos de primera línea fueron tratados con dosis bajas de naltrexona, con disminución de la inflamación y el prurito asociado 5 . ...
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... 5 Naltrexone, another novel agent used in the treatment of HHD, is thought to modulate dysfunction of calcium transportation by inhibiting Toll-like receptor 4, leading to a subsequent reduction in the levels of nitric oxide, interleukin (IL) 6, and TNF-a. 6 Collectively, these mechanisms introduce the biological plausibility of targeting TNF-a for the treatment of HHD. ...
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Genetics of Darier’s Disease: New Insights into Pathogenic Mechanisms
Article
  • May 2025
Darier′s disease (DD) is a rare, autosomal dominant genodermatosis caused by pathogenic variants in the ATP2A2 gene, which encodes the SERCA2 protein, an endoplasmic reticulum ATPase Ca2+ transporter. These mutations impair the intracellular calcium homeostasis leading to increased protein misfolding, endoplasmic reticulum (ER) stress response, and the activation of the unfolded protein response (UPR), culminating in keratinocyte apoptosis and anomalies in interfollicular epidermal stratification. Clinically, the disease is characterized by the presence of skin lesions with hyperkeratotic papules and an increased susceptibility to inflammatory reactions, bacterial and viral infections. The histological hallmarks include acantholysis, dyskeratosis, and increased apoptotic keratinocytes, referred to as “corp ronds”. The SERCA2b isoform is expressed not only in the epidermis but it is present ubiquitously in all tissues, suggesting that its alteration may have multi-organ effects. The review aims to provide a broad overview of the pathology, from intracellular dysfunction to the clinical manifestations, elucidating the molecular effects of SERCA2 variants found in DD patients and exploring the potential cell signaling pathways that may contribute to disease progression. Beginning with an examination of the cellular alterations, our work then shifts to exploring their impact in an organ-specific context, providing insights into new potential therapeutic strategies tailored to clinical manifestations.
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Inherited Acantholytic Disorders
Chapter
  • Feb 2024
Darier disease (DD) and Hailey–Hailey disease (HHD) are autosomal dominant disorders characterised by epidermal acantholysis. They have a similar molecular pathogenesis, with mutations in intracellular calcium pumps of the endoplasmic reticulum ( SERCA2 ) and Golgi ( SPCA1 ), respectively. DD presents with persistent, hyperkeratotic papules in a seborrhoeic distribution, associated with nail changes and palmar pitting. HHD presents with painful, mainly flexural, erosions. In both, secondary infection is common and hypertrophic flexural disease can be disabling. Histologically, both are characterised by loss of epidermal intercellular adhesion (acantholysis). DD may be accompanied by neuropsychiatric symptoms such as depression, epilepsy, learning disabilities or bipolar disease. First line topical treatment is with emollients, antimicrobials and corticosteroids. Oral antibiotics are often necessary for exacerbations; other systemic options include retinoids and ciclosporin. Physical measures such as laser resurfacing, photodynamic therapy, botulinum toxin and surgical interventions can be considered in refractory cases.
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Hailey-Hailey Disease
Chapter
  • Oct 2023
Hailey-Hailey disease is a rare autosomal dominant genetic disease due to mutations in the ATP2C1 gene. The defective gene induces the production of altered desmosomal components in the Golgi apparatus. The clinical diagnosis of Hailey-Hailey disease is based on the recurrent erythematous plaques with vesicles and fissures occurred symmetrically in flexural areas. The lesions can become hypertrophic and malodorous. The histopathological elements are characteristic acantholytic vesicles and a “dilapidated brick wall” structure of the epidermis. The Hailey-Hailey disease has no specific treatment, and the patients have a poor quality of life. Local and systemic treatment includes: antibiotics, antifungals, naltrexone, magnesium chloride, and corticosteroids. Other treatments include: botulinum toxin injections, retinoids, laser ablation (CO2, Er:YAG), PDT, and cryotherapy.
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Estudio de la prevalencia del síndrome metabólico en pacientes con hidradenitis supurativa: Estudio retrospectivo de los últimos 2 años en el Hospital Alejandro Posadas
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Antecedentes: La hidradenitis supurativa (HS) es una enfermedad inflamatoria crónica relacionada con el síndrome metabólico(SM), con un mayor riesgo de comorbilidades cardiovasculares; por lo tanto, se debe mantener un alto grado de sospecha clínica frente al hallazgo de alguno de sus componentes. Objetivo: Evaluar la prevalencia del SM en los pacientes con diagnóstico de HS en comparación con la población general. Diseño: Estudio retrospectivo descriptivo. Métodos: Se revisaron las historias clínicas y el archivo fotográfico de los pacientes con diagnóstico de HS que consultaron entre el 1/9/2017 y el 31/8/2019. Se analizaron las variables: sexo, edad, antecedentes familiares, tiempo de evolución, índice de masa corporal, obesidad abdominal, laboratorio (glucemia y perfil lipídico), presión arterial, tabaquismo, número y localización de las lesiones, gravedad clinicoecográfica, respuesta al tratamiento y evolución clínica. Resultados: Se evaluaron 30 pacientes con HS valorados en nuestro servicio en los últimos 2 años; 23 mujeres y 7 varones. Predominó el grupo etario de 31-40 años. De ellos, 19 pacientes (63,3%) cumplieron con los criterios necesarios para diagnosticar el SM, hallazgo que no se relacionó con el grado de severidad de la HS. Conclusiones: La prevalencia del SM en nuestros pacientes con HS fue del 63,3% con respecto al 27,5% de la población general. La importancia de este hallazgo radica en detectar de forma temprana y oportuna la presencia de este síndrome en los pacientes con HS para evitar el riesgo de comorbilidades cardiovasculares a futuro.
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Genetic Conditions
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  • Jun 2022
Although rare, a number of genodermatoses may have vulval involvement which requires specific management such as in epidermolysis bullosa. Others may be incidental findings causing no symptoms. However, a knowledge of how genetic problems can present in the skin is important as occasionally the cutaneous features are the first clue to the diagnosis.
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Variable response to low‐dose naltrexone in patients with Darier disease: a case series
Article
Full-text available
Background Darier disease is a rare autosomal‐dominant genodermatosis with a loss of function of a Ca²⁺‐ATPase pump (SERCA2‐pump). Clinically, the disease is characterized by red–brown keratotic papules mainly in seborrhoeic areas and has only limited and unsatisfactory treatment options. Previously, low‐dose naltrexone was described as a successful treatment option in Hailey–Hailey disease, a genodermatosis with a genetic mutation coding for a similar loss of function of a Ca²⁺‐ATPase pump (hSPCA1‐pump). Objective To assess the efficacy of low‐dose naltrexone as a treatment option in Darier disease. Methods Six patients with biopsy‐proven Darier disease (four had severe, one had moderate and one mild clinical manifestations). The patients received off‐label therapy with naltrexone [5 mg per os (p.o.)] and magnesium [200 mg p.o.]. Patients were followed up every 4 weeks for minimally 12 weeks. Upon clinical presentation, the disease severity and subjective pain and itch scores were assessed, and standardized photographs were obtained. Results The clinical response to naltrexone varied after 12 weeks. The four patients with severe Darier disease showed worsening after initial improvement during the first 4 weeks, whereas the two patients with a mild to moderate clinical manifestation clearly improved, showing almost full remission after 12 weeks with complete flattening of the keratotic papules. Conclusion Low‐dose naltrexone did not have an effect on severe Darier disease compared to Hailey–Hailey disease, but it was beneficial in mild to moderate forms of the disease. Further studies are needed to confirm these observations of variable responses.
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The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain
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Full-text available
  • Feb 2014
  • CLIN RHEUMATOL
Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.
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Aminoglycosides as Potential Pharmacogenetic Agents in the Treatment of Hailey–Hailey Disease
Article
Full-text available
  • Feb 2006
HHD, Hailey–Hailey disease; hSPCA1, human secretory pathway Ca2+/Mn2+ ATPase
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The Uses of Naltrexone in Dermatological Conditions
Article
  • Dec 2018
  • J AM ACAD DERMATOL
Background: Naltrexone in standard and reduced doses is efficacious in many inflammatory and acantholytic disorders. Objective: We summarized the current data of naltrexone that are relevant to dermatologic practice. Methods: An English language PubMed literature search was performed using the terms naltrexone, low-dose naltrexone, Hailey-Hailey, psoriasis, lichen planopilaris, alopecia, opioid, opioid receptor, treatment, dermatology, monitoring, side effect, skin, pruritus, cutaneous, acantholytic, and Darier. Results: Opioid receptors are found throughout the skin and affect cell proliferation, migration, and adhesion. μ Opioid receptors have been found in all layers of the epidermis, while δ receptors are concentrated at cell junctions and can reduce desmoglein expression. Typical doses of naltrexone result in continuous binding to receptors. Low doses result in intermittent blockade with increased ligand and receptor expression, potentiating their effect. Limitations: Our review was restricted to the English language literature. Conclusion: Naltrexone affects inflammation, cell adhesion, and keratinocyte proliferation and migration. While low-dose naltrexone has demonstrated efficacy in treating patients with Hailey-Hailey disease, further dose-ranging studies are needed. Data suggest that naltrexone could be helpful in the treatment of pruritus and a variety of inflammatory and acantholytic skin diseases that are refractory to other treatments. At higher doses, liver function tests should be monitored on a periodic basis.
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Variable Response to Naltrexone in Patients With Hailey-Hailey Disease
Article
  • Jan 2018
Hailey-Hailey disease (HHD) is a genetic intraepidermal blistering disorder characterized by chronic macerated erosions in intertriginous areas.¹ The recent report of 2 case series²,3 demonstrating the efficacy of low-dose naltrexone in the treatment of HHD represents exciting progress in the management of a disease with limited therapeutic options. Herein we present 3 additional cases of HHD demonstrating varying responses to naltrexone.
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