Introduction

Hailey-Hailey disease (HHD) is an autosomal-dominant skin disorder caused by mutations in the ATP2C1 gene, which encodes the calcium pump protein and is involved in maintaining normal cell-cell interactions in the epidermis. This skin disorder is initially present from the third decade of life; it is often excoriated and humid due to the continuous tearing of the skin. The susceptibility to OHLADS from an early age can be significantly relieved by combining topical steroids and antibiotics to prolong the drug's curative effect.

Recently, it has been reported that cyclosporine can be used to treat HHD; however, long-term use can negatively affect organs such as the kidneys, liver, and gastrointestinal system, resulting in the beneficial outcome of photodynamic therapy. In another report, the beneficial effects of photodynamic therapy for patients with ATP2C1 gene expression after ATP2C1 siRNA were observed, further elucidating the quenching effect of photosynthesis on its genetic expression.^1,2

The literature reports that a middle-aged patient suffers from OHLADS, evolving into ELM, and still cannot be effectively treated with many other drugs but does see improvement through photodynamic therapy, showing that PDT is a highly effective treatment for HHD and that the success rate of one-time complete cure is free of recurrence for one year.

In recent years, several studies have suggested that PDT is an effective treatment for HHD. It uses lasers irradiated with defined wavelengths to activate exogenous photosensitizer drugs, generating oxygen ions that can kill cells under specific temporary conditions without the risk of photosynthetic oxidative damage. Overall, this is a treatment with broad application prospects. However, since a combination of dye sensitisers, light treatment, and drugs is required, very few reports have been published.^3-5

What is Hailey-Hailey disease?

Hailey-Hailey disease (HHD) is a genetic disorder with an autosomal dominant pattern. This means only one of the two inherited doses of the gene is enough to be affected. It is caused by mutations in the ATP2C1 gene, located at the 3q21-q24 chromosome, encoding calcium-ATPase. It alters the functioning of specific types of epidermal cells, specifically impairing those that are held together employing a molecular apparatus called desmosomes. This results in recurrent multi-vesicular secretion, acantholysis, neutrophilic spongiosis, and superficial inflammation, creating great pain in the affected areas.

Although it is a rare disorder, it systematically demands tenacious therapies that can be applied systemically or involve complex medical procedures. Several local treatments have been proposed, such as anti-inflammatory drugs, including topical corticosteroids applied once or twice a day, and nicotinamide cream. These drugs relieve some of the symptoms during infection, enhancing patients' quality of life. However, these treatments are not a definitive solution to the health problem.

For this reason, novel therapies have been proposed using which dermatologists can use to improve the patient's quality of life with a lower burden of medications or cycle therapy with different mechanisms of action. In particular, we evaluated the use of photodynamic therapy, an advanced antineoplastic treatment already used with success in different kinds of keratinocyte tumours, in the everyday treatment of Hailey-Hailey disease. The results seem to be satisfactory.¹

What are the current Treatment Challenges?

The primary method of preventing blistering is hydration of the skin through frequent application of steroidal lotions, systemic treatment with oral antibiotics and their combination, as well as treatment with the immunomodulatory drug calcineurin inhibitor. Among all the medications, the most effective way to stop the period of exacerbation is the systemic use of antibiotics. The advantage of drug use is known only for certain groups and should be used in the first or second week after the formation of vesicles.⁶

Different options for stand-alone treatment of Hailey-Hailey disease are described, including phototherapy, strands incubated with botulinum toxin, and, in combination with other methods, topical photodynamic therapy. Currently, numerous new topical cytostatic, anti-inflammatory, and dermo-epidermal drugs continue to appear, and traditional antiseptics show limited effect and destroy cells near the focus. Unfortunately, it is still difficult to prevent recurrences. Alternate treatments, such as electrocoagulation, small doses of radiotherapy, or photochemotherapy, are often used, usually combined with other treatments.⁶

What is Photodynamic Therapy?

The principle of photodynamic therapy (PDT) is defined by light-induced cell death. It is an innovative form of therapy that has been successfully used since the 1980s to treat a variety of medical problems in dermatology and oncology using naturally occurring porphyrins in organisms or exogenously applied porphyrin derivatives as photosensitizers.

Light irradiation in the presence of a photosensitizer initiates three events. Energy transfer from the photosensitizer to molecular oxygen in the photoreactive range results in the formation of highly reactive singlet oxygen. Cell death in the target cells is induced by necrosis, apoptosis, and autophagy. Recent advances in vivo imaging technology and the development of molecular targeting tools have facilitated a better understanding of the complex biological processes that follow the interaction between the light and the photosensitizer in the tumour environment. The pre-plan of the light stimulation spot, the actual light stimulation, and the response process are connected. With photooxidation as a trigger, PDT can be used to treat tumours by initiating cell death.⁷

The major advantage of PDT is the ability to conduct highly tissue-selective treatment. An optimal treatment requires a sufficient oxygen supply to produce oxygen radicals and sufficient light to access the entire lesion. The damage caused by PDT is confined to the tissue layers treated with light. There is the added benefit of good aesthetic results for malignant skin tumours, as it avoids the need for invasive surgical procedures that scar and often lead to poor functional and aesthetic outcomes. The spectrum of side effects of PDT is broad. According to the principle of PS and photosensitization reaction, anti-photoaging antioxidants can also cause cell death in target cells when light with the characteristic wavelength of the photosensitizer is irradiated.⁷

How can PDT be applied to Hailey-Hailey Disease?

PDT has emerged as one of the promising treatments for HHD, a genetic skin disorder characterized by painful blistering eruptions that recurrently occur and cripple the life of patients. Dermatology clinics have tried PDT to manage HHD with certain success.⁸

One recently published work on the subject in the Archives of Dermatological Research from this year by the lead researcher, Dr. Jessica Kaffenberger et al., discussed the efficacy of PDT amongst HHD patients, where they noted marked improvements in symptoms related to reduced blistering and inflammation of the tissues.

Their study provided important insight into the practical use of PDT. Further, Dr. Olivia Ueltschi added that PDT offers a very focused approach to the treatment of HHD, which minimises the use of systemic medications and hence their side effects. Patients reported physical relief and improved quality of life following PDT.Success in PDT has drawn the attention of the whole world, with the expectation that this modality will be considered for inclusion in the standard management of HHD.⁸

Summary 

Hailey-Hailey disease is an autosomal-dominant genetic skin disorder caused by mutations in the gene encoding a calcium pump protein, ATP2C1. Mutations in this gene disrupt normal cell-to-cell interactions in the epidermis. HHD typically first manifests in the third decade of life with persistent blistering and inflammation of the skin. The conventional therapies for HHD include topical steroids, antibiotics, and immunomodulatory drugs, among which are calcineurin inhibitors. These symptomatic therapies generally afford temporary relief and do little to prevent recurrences.

Limitations of conventional therapies have opened new vistas for alternative modes of treatment. PDT has come out to be a very promising treatment for HHD. PDT involves the administration of light for the activation of photosensitizing agents that can produce reactive oxygen species, which selectively destroy the affected cells. The main advantages of the approach are as follows: high tissue selectivity, minimal invasiveness, and probably a better aesthetic outcome compared with surgical interventions.

Recent studies indeed have shown promising results in the use of PDT for treating HHD. Clinicians like Dr. Jessica Kaffenberger and Dr. Olivia Ueltschi report a significant gain in improvements in symptoms, with reduced blistering and inflammation in patients. The nature of PDT being focused, there is less reliance on systemic medications, thereby reducing the chances of drug side effects from its long-term usage.

PDT in the treatment of HHD is a novel approach to the management of the condition. PDT acts directly on lesional skin, thus offering better symptom control and improvement in the quality of life of patients. As research in this area continues to unfold, there is increased interest in integrating PDT into the standard protocol for the management of Hailey-Hailey disease. Although the PDT protocols in HHD need to be further optimised, the preliminary results seem promising. This new therapeutic modality could offer fresh hope to these patients who suffer from the persistent and debilitating symptoms of Hailey-Hailey disease.