Introduction

The rare genodermatosis known as Hailey-Hailey disease(HHD), or benign familial pemphigus, was first reported by the Hailey brothers in 1939.¹ Though symptoms can appear at any age, this chronic ailment mostly appears after puberty, usually in the third or fourth decade of life.² The calcium pump protein encoded by the ATP2C1 gene, which is necessary for healthy skin cell adhesion, is mutated in HHD.³ The ATP2C1 gene codes for a protein that functions in cells as a pump for calcium and magnesium, especially in the Golgi apparatus.² Mutations in this gene cause the pump to malfunction, which impairs cell adhesion between cells and causes the impacted skin layers to break down, known as acantholysis.²

A single mutant copy of the gene is sufficient to induce the disease because the pattern of inheritance for the disease is autosomal dominant.⁴ There is a 50% risk that the mutant gene will be inherited by each kid of an affected parent. Similar effects are seen in men and women, and the general population is thought to be affected by HHD in 1 in 50,000 cases.⁴ 

The chronic, recurrent character of Hailey-Hailey disease and the fluctuating severity of its symptoms make care difficult in several ways. Depending on the severity of the condition, the frequency of flare-ups, and the patient's reaction to treatment, treatment strategies are highly customised.⁵ The medicines aid in lowering inflammation and avoiding recurrent. infections. However, they don't treat the underlying genetic issue, and using corticosteroids for a long time comes with hazards like resistance and skin thinning.¹ Patients' HHDs range greatly in severity from moderate discomfort to widespread, chronic lesions that have a major negative influence on their quality of life. There is an increasing recognition that systemic medications are necessary in more severe cases of HHD, even though many people with the condition can be managed with local therapy.⁶

In cases of severe, extensive, or resistant HHD to topical therapy, systemic medications are required. Oral antibiotics to prevent secondary infections, systemic corticosteroids to treat severe flare-ups temporarily, and immunomodulators such as methotrexate or cyclosporine for long-term therapy are a few examples of these.¹

Mechanism of the disease and Therapeutic targets:

An essential component of cell-to-cell adhesion is calcium. In HHD, the formation of desmosomes—structures that link neighbouring keratinocytes - is hampered by the malfunctioning calcium pump. This causes the epidermis of HHD patients to have the distinctive "dilapidated brick wall" look.⁷ When the integrity of the epidermis is compromised, inflammation results. Inflammation aggravates symptoms and adds to the chronic character of HHD lesions, while it is not the main cause.^1,8 Pathogens and environmental irritants can enter the body more easily due to the impaired epidermal barrier in HHD patients. Secondary infections and increased immunological activation may result from this.^1,2

Current systemic Therapeutic options

Immunosuppressants

When HHD flares up suddenly, oral corticosteroids have strong anti-inflammatory properties and can help quickly. However, because of possible adverse effects such as osteoporosis, diabetes, and adrenal suppression, its long-term use is restricted.⁹ The antimetabolite methotrexate, which has immunosuppressive qualities, has demonstrated effectiveness in the treatment of HHD.² By blocking dihydrofolate reductase, it suppresses the production of DNA and the growth of new cells. A regular assessment of blood counts and liver function is necessary because of the possibility of hepatotoxicity and bone marrow suppression.²

Biologic agents

Tumor necrosis factor-alpha (TNF-α) inhibitors have become a viable treatment for HHD that is refractory.¹⁰ TNF-α, a pro-inflammatory cytokine thought to be involved in the pathophysiology of HHD, is blocked by these medicines. Case studies have shown that etanercept and infliximab are effective treatments for recalcitrant HHD.¹⁰ However, the risk of infections and potential long-term side effects necessitates careful patient selection and monitoring.

Systemic therapies

One of the best ways to manage HHD is to use topical calcineurin inhibitors such as Tacrolimus and Pimecrolimus twice a day in the afflicted areas. To prevent steroid-induced skin shrinkage, it can be suggested as a long-term maintenance or second-line treatment.^11,12 Since tacrolimus and corticosteroids can control IL-8 and IL-6 levels, as well as indirectly ATP2C1 expression, they may be useful in treating HHD. Furthermore, ATP2C1 mRNA suppression generated by UVB can be promptly reversed by retinoids and oral corticosteroids.¹³ 

A second-generation retinoid that has shown promise in treating HHD is acitretin. It works by modifying keratinocyte development.¹⁴ Acitretin may worsen acantholysis when used in higher dosages.⁹ Mucocutaneous dryness and lipid irregularities are side effects that need to be regularly monitored. 

Depending on the severity of skin lesions, topical or oral antimicrobial medicines may be used.¹ Treatment should be guided by cultures of bacteria and fungi. Oral and topical antibiotic use over time may lead to acquired resistance.¹ Doxycycline at a half-dose may be given as maintenance in patients who are suffering recurrence.¹⁵ In one patient, minocycline at a dose of 100 mg twice a day for two weeks and a maintenance dose of 100 mg daily for two months has been linked to total clearance.¹⁵ In addition to their ability to act as antibiotics, tetracyclines have anti-inflammatory qualities that are mediated via their inhibition of neutrophil chemotaxis, control over keratinocyte production of inflammatory cytokines, and inhibition of matrix metalloproteases.¹⁶ Photosensitivity and gastrointestinal intolerance (esophagitis) are the most frequent side effects.¹⁷ The use of minocycline in this indication should be restricted due to the possibility of skin hyperpigmentation and hypersensitivity reactions, such as ‘DRESS syndrome’. Dapsone has also been anecdotally utilised in HHD.¹⁷ 

Several immunosuppressive medications, including azathioprine, cyclosporine, and methotrexate, have been studied with differing degrees of success but have little application in clinical settings.¹⁸

Interventional treatments

A full-thickness excision followed by secondary intention healing, primary closure, or split-skin grafting has been suggested for extremely invalidating, confined lesions that are resistant to medical treatment.¹⁹ An intriguing therapy strategy for HHD is to destroy the epidermis down to the papillary dermis. Tissue re-epithelisation is made possible by the adnexal structures not having the defect.²⁰

Photodynamic Therapy may function by triggering mechanisms for tissue healing, which would then enhance the epithelium's mechanical integrity.²¹ Though its precise chemical mechanism of action in HHD is still unknown, PDT's inherent photooxidative qualities most likely play a role. 

One known cause of HHD exacerbations is perspiration.²² Botulinum toxin looks to be a promising treatment for hyperhidrosis by inhibiting the release of acetylcholine from sympathetic nerve fibres, hence reducing the output of eccrine sweat glands.

Each patient experiences UV light exposure differently. After being exposed to the sun, some patients may experience flare-ups even in areas of unaffected skin, while others may see a clinical improvement.²³ UVB radiation suppresses ATP2C1 mRNA in vitro. However, it is not a significant cellular stressor on its own to cause HHD lesions.^{13, 23}

Conclusion

HHD, while benign in terms of systemic health risks, often results in severe discomfort, reduced quality of life, and frequent episodes of infection. The disease’s unpredictable flare-ups and resistance to conventional treatments necessitate a multifaceted approach to management.

Despite advancements in dermatology, HHD remains difficult to treat effectively. While there is some relief from topical medications like calcineurin inhibitors and corticosteroids, their effectiveness tends to decrease in more severe cases. Thus, systemic medications become critical to the care of patients with refractory or severe illness. These alternatives do, however, present a unique set of difficulties, such as the possibility of immunosuppression and severe adverse effects.

Recent developments in immunomodulatory treatments have provided fresh optimism. Case studies and limited clinical trials have demonstrated the potential of biologic medicines, such as interleukin (IL) inhibitors and tumour necrosis factor (TNF)-α inhibitors, to avoid illness flare-ups and reduce inflammation in patients with HHD.

With the use of small molecule inhibitors and genetic therapy developments, future HHD treatments might profit from a more individualised strategy.²⁴ As hereditary, Huntington's disease (HHD) may be prevented from its underlying cause via gene therapy, which would fix the ATP2C1 gene mutation and stop the aberrant calcium regulation that causes skin disintegration. Future treatments that are less harmful and more successful are still a possibility because of ongoing research into tailored therapeutics for uncommon inherited skin disorders.