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Hailey-Hailey disease (HHD) is a rare autosomal dominant genodermatoses caused by mutations in the ATP2C1 gene that encodes a calcium pump of the Golgi apparatus. HHD is characterized by ruptured vesicles and blisters that tend to form eroded, erythematous plaques with painful “rhagades” in flexural areas. Histologically, acantholysis throughout the epidermis is a hallmark of HHD. There is no curative treatment. In mild cases, management is based on intermittent topical anti-inflammatory treatments and antiseptics applications. This activity reviews the pathophysiology, clinical presentation, evaluation, and management of patients with HHD and highlights the role of the interprofessional team in improving care for patients with this condition. Objectives: Describe the pathophysiology of Hailey-Hailey disease. Explain the histopathological findings that characterize Hailey-Hailey disease. Outline the management and treatment options for Hailey-Hailey disease. Review the role of the interprofessional team in enhancing clinical outcomes in patients with Hailey-Hailey disease. Access free multiple choice questions on this topic.

Hailey-Hailey disease (HHD; OMIM 169600), also known as benign familial pemphigus, is a rare genodermatoses firstly described in 1939 by the Hailey brothers.[1] HHD is characterized by impaired keratinocyte adhesion resulting in widespread intraepidermal acantholysis. Clinically, lesions appear as vesicles and bullae forming upon rupture, painful erosions, and rhagades in flexural areas. HHD is a chronic disease with a relapsing-remitting clinical course.  Exacerbations are mainly triggered by sweating, minor trauma, and secondary infections. No curative treatment is available. Patient management can be challenging. Mild cases can be controlled successfully with intermittent courses of topical corticosteroids and antibiotics.

Hailey-Hailey disease is an autosomal dominant genodermatoses with complete penetrance and variable expressivity amongst affected family members. There is no positive family history in approximately 15 to 30% of cases. These cases are due to either sporadic genetic mutations or undiagnosed mild diseases of other family members.[2] Mutations in the ATP2C1 gene (ATP2C1; OMIM 604384), localized at 3q21-q24, encode the human secretory-pathway Ca2+/Mn2+-ATPase isoform 1 (hSPCA1) of the Golgi apparatus is responsible for HHD.[3][4] More than 214 mutations have been identified scattered along the ATP2C1 gene without any hotspot or clustering.[5] The majority are loss-of-function mutations.[6][7] The hSPCA1 pump supplies the Golgi lumen with Ca2+ and Mn2+ and helps to maintain normal Ca2+/Mn2+ intracellular concentrations. In keratinocytes cultured from lesional and non-lesional skin of HHD patients, the regulation of cytosolic Ca2+ was found deficient, resulting in increased intracellular levels of Ca2+ and decreased levels of Ca2+ within Golgi bodies.[4] HHD is characterized by extensive interfamilial and intrafamilial phenotypic variability, suggesting that environmental factors and genetic modifiers may affect the clinical expression of this disease.[6] A direct correlation of genotype/phenotype (age of onset, severity, progression) has not been possible yet. However, some specific mutations correlate with a genitoperineal involvement or milder phenotypes.[8][9]

The prevalence of HHD is unknown, but it is estimated to be similar to that of Darier disease, and thus, it is calculated at around 1/50.000.[10] The female-to-male ratio is equal to one. There is no apparent predilection for any ethnic group. The onset of the disease occurs in the late teenage years or the third and fourth decades of life. A case of a 5-year-old infant with diffuse lesions carrying an ATP2C1 mutation has been reported.[11] In almost 50% of cases, lesions appear initially in the neck area, followed by the inguinal and axillary folds.[2]

The exact mechanism of acantholysis in benign familial pemphigus (Hailey Hailey disease) is complex and remains uncertain. The identification of mutations in the ATP2C1 gene suggested a role of a Ca2+-dependent signaling pathway in regulating cell-to-cell adhesion and epidermal differentiation. Desmosomes, tight and adherens junctions are responsible for keratinocyte adhesion in the epidermis. Cadherins, significant components of desmosomes and adherens junctions, are well-studied transmembrane glycoproteins that promote cell-cell adhesion in a Ca2+-dependent manner. In HHD keratinocytes, increased cytosolic Ca2+ could impair post-translational modifications (proteolytic processing, glycosylation, trafficking, or sorting) of cadherins and other structural proteins.[10] Leinonen et al. identified a lower Ca2+ content in the basal epidermal layers of lesional skin of HHD patients compared to nonlesional and normal control skin.[12] The disturbed Ca2+ gradient was linked to abnormal tissue distribution and diminished functionality of ATP receptors. These alterations promoted a defect in the keratinocyte differentiation process.[12] Furthermore, adherens junctions couple intercellular adhesion to the actin cytoskeleton. Impaired actin reorganization was identified in HHD and correlated with a marked decrease in cellular ATP, in vitro and in vivo, reflecting insufficient cellular ATP stores.[13] This defective ATP production could be related to a mitochondrial calcium overload.[14] A recent study analyzing proteomic changes in skin lesions of HHD revealed dysregulation of extracellular matrix and cell cytoskeleton components.[15] Finally, two studies highlighted the role of complex multi-pathway alterations and oxidative stress in the pathogenesis of HHD.[16][17] Notch1 and p63 are part of a regulatory signaling controlling keratinocyte proliferation and differentiation. HHD-derived keratinocytes undergo oxidative stress and subsequently exhibit downregulation of both Notch1 and Itch expression and differential regulation of different p63 isoforms.[16] Oxidative stress-mediated induction of miR-125b expression, a specific microRNA that modulates gene expression post-transcriptionally, may be responsible for the suppression of Notch1 and p63 expression in HHD.[17]

Finally, two studies highlighted the role of complex multi-pathway alterations and oxidative stress in the pathogenesis of HHD.[16][17] Notch1 and p63 are part of a regulatory signaling controlling keratinocyte proliferation and differentiation. HHD-derived keratinocytes undergo oxidative stress and subsequently exhibit downregulation of both Notch1 and Itch expression and differential regulation of different p63 isoforms.[16] Oxidative stress-mediated induction of miR-125b expression, a specific microRNA that modulates gene expression post-transcriptionally, may be responsible for the suppression of Notch1 and p63 expression in HHD.[17] ATP2C1 is ubiquitously expressed in human tissues, but HHD manifestations are limited to the intertriginous skin areas. A possible explanation is that epidermal keratinocytes express highly ATP2C1 and are less capable of compensating for the inactivation of hSPCA1 compared to other tissues.[18][19]

Histologically, Hailey-Hailey disease shows widespread keratinocyte acantholysis appearing as a "dilapidated brick wall" with suprabasal clefting (lacunae). Dyskeratosis, when present, is mild, but dyskeratotic keratinocytes have a well-defined nucleus and preserved cytoplasm. Elongated dermal papillae "villi" extend into the lacunae, lined with a single layer of basal cells. Suprabasal clefting in HHD spares the adnexal structures. The superficial dermis can contain focal perivascular lymphohistiocytic infiltrate. Chronic lesions present epidermal hyperplasia with ortho- and parakeratosis. The parakeratotic crust sometimes contains neutrophils and bacteria. Direct immunofluorescence is negative and helps differentiate from pemphigus vulgaris.

The typical skin lesions of Hailey-Hailey disease usually occur in friction or intertriginous areas, including the sides and back of the neck, axillary, inguinal, and perineal folds (scrotum, vulva). The sub-mammary area affects as much as 50% of female patients with HHD. Isolated vulvar disease is possible. Primary lesions are grouped, flaccid vesicles and blisters on an erythematous base or normal skin. A foul-smelling exudate is produced upon rupture, and crusted erosions are formed. Lesions develop peripherally in a serpiginous pattern with an active vesico-pustular border. When central resolution occurs, expanding lesions can obtain a circinate form. Chronic lesions, especially in the intertriginous areas, tend to form erythematous plaques with worm-eaten erosions and painful "rhagades" or moist vegetations.[2] Lesions present a symmetrical, bilateral distribution. Dissemination is rare and often secondary to a staphylococcal, viral, or yeast infection.[20] Approximately 70% of HHD patients have longitudinal white bands in their fingernails (longitudinal leukonychia).[21] Oral, esophageal, vaginal, and conjunctival involvements have been reported but remain uncommon.[22][23][24] There are no other known extracutaneous manifestations of HHD. Two distinct segmental HHD patterns have been described, reflecting mosaicism. These patients show a band-like distribution of lesions following the Blaschko lines. Type 1 HHD patients present a segmental distribution of lesions with no family history. It is due to a de novo post-zygotic mutation occurring at the first stages of embryogenesis.[25] These patients risk transmitting non-segmental HHD to their children if the mutation affects the germline (gonadal mosaicism), and preconception genetic counseling is advised. In type 2 segmental HHD, severely affected segmental lesions and "classical" non-segmental HHD lesions are superimposed. The deeper portions of the adnexal structures express the genetic defect in the affected segment. Type 2 segmental HHD is due to a germinal mutation with associated loss of heterozygosity.[26] Affected family members have non-segmental HHD, and the risk of transmission from the affected parent to the offspring is 50%.[27]

These patients risk transmitting non-segmental HHD to their children if the mutation affects the germline (gonadal mosaicism), and preconception genetic counseling is advised. In type 2 segmental HHD, severely affected segmental lesions and "classical" non-segmental HHD lesions are superimposed. The deeper portions of the adnexal structures express the genetic defect in the affected segment. Type 2 segmental HHD is due to a germinal mutation with associated loss of heterozygosity.[26] Affected family members have non-segmental HHD, and the risk of transmission from the affected parent to the offspring is 50%.[27] Acute exacerbations of the disease are often triggered by minor trauma, friction, heating, humidity irradiation, and secondary infections. These disease-modifying factors can be responsible for the induction of acantholysis and skin lesions even in non-flexural sites within 24 hours of exposure. Staphylococcal infections, in particular, may aggravate acantholysis by producing exfoliative toxins leading to severe flares. An infection should be suspected when lesions are malodorous or vegetating, and topical or/and oral anti-infective agents should be prescribed. HDD can severely impact the quality of life of patients. More precisely, patients describe severe debilitating symptoms such as itch, pain, burning sensation, and body malodor. HDD is associated with crucial psychological distress and significantly impacts social functioning.[28] The mean Dermatology Life Quality Index (DLQI) is comparable to other severe dermatoses such as psoriasis.[29] There can be a lack of correlation between the physicians' assessment of disease severity and the degree of handicap experienced by the patient, as in other chronic dermatoses leading to undertreatment in some cases.[30]

Diagnosis of Hailey-Hailey disease can be made clinically, with a follow-up confirmation using skin histopathology. Dermoscopy and reflectance confocal microscopy may also contribute to an early diagnosis of HHD. HHD's most common dermoscopic features include polymorphous vessels such as glomerular and linear-looped vessels within a pink-whitish background. In reflectance confocal microscopy, suprabasal partial acantholysis and clefting are the main findings associated with crusts, dilated papillae with tortuous vessels, and inflammatory cells.[31] Adnexal sparing is also observed. A search of mutations in the ATP2C1 gene by molecular biology is not routinely performed but can be helpful in difficult-to-diagnose cases.

HHD is a chronic disease with no curative treatment. Current therapeutic strategies aim to control disease flares, improve patients’ quality of life, and provide prolonged remissions. The management of HHD is based on anecdotal data from the off-label use of various topical, systemic and interventional treatments. Since HHD is a relapsing-remitting disease and lesions can present spontaneous remission, data from individual case reports and small case series with no control group are of limited value (Level of evidence 5). Randomized, prospective studies are lacking. General Measures Avoiding triggering factors such as mechanical stress, heat, sun exposure, and sweating are essential measures to prevent disease exacerbations. Overall, lifestyle modifications are necessary, and patients’ education can be helpful. Patients are advised to lose weight and wear loose clothing and underwear to avoid friction in the intertriginous areas. Physical activity involving friction should be limited. Adhesive and occlusive dressings should be avoided. Personal hygiene and mild daily cleansing with non-soap-based surfactants and synthetic detergents are recommended. Applications of antiseptics are essential (octenidine, chlorhexidine).[32] Bathing in dilute bleach (1/2 cup of 5% bleach in a full bathtub for a final concentration of 0.005%) for 10 minutes twice weekly can be proposed by analogy with atopic dermatitis.[33] Antiseptic treatments can decrease bacterial colonization without the risk of bacterial resistance induction. Topical Treatments Topical treatments are the mainstay of HHD management. Antiseptics and topical anti-inflammatory treatments applied during disease flares are often enough to control mild cases of HHD.[32] Zinc Paste Zinc oxide paste protects the skin against friction and humidity by forming a barrier. Zinc oxide paste 50% applied twice daily alone was found to be more effective than topical tacrolimus.[34] Zinc oxide can prevent the colonization of skin lesions and has been reported to increase in vitro levels of intracellular calcium.[35] Topical Corticosteroids

Zinc oxide paste protects the skin against friction and humidity by forming a barrier. Zinc oxide paste 50% applied twice daily alone was found to be more effective than topical tacrolimus.[34] Zinc oxide can prevent the colonization of skin lesions and has been reported to increase in vitro levels of intracellular calcium.[35] Topical Corticosteroids Moderate to high-intensity topical steroids are often proposed during disease outbreaks as a first-line treatment, with continuous daily applications until clinical remission is obtained.[32][36] Prolonged treatment courses are limited by the risk of steroid-induced atrophy and striae, especially in flexural areas. Topical Calcineurin Inhibitors (Tacrolimus, Pimecrolimus) Applying topical calcineurin inhibitors twice a day to affected areas is an excellent way to control HHD. It can be proposed as a second-line or long-term maintenance treatment to avoid steroid-induced skin atrophy.[37][38][39] Lesion resolution typically occurs after two weeks.[40][41] Tacrolimus 0.1% is available as an ointment, and pimecrolimus 1% as a cream. Alternative topical agents anecdotally include calcitriol, 5-fluorouracil, and cadexomer iodine.[42][43][44] Antibiotics Colonization and infection with Staphylococcus, Streptococcus, dermatophytes, herpes simplex virus, and Candida species may exacerbate lesions. The use of topical or oral antimicrobial agents depends on the extent of skin lesions. Bacterial and fungal cultures should guide treatment. Long-term use of topical and oral antibiotics can induce acquired resistance. In a case series of 58 patients, 43% improved with oral erythromycin or penicillin antibiotics. Doxycycline and minocycline belong to the class of tetracyclines. Doxycycline at a dose of 100 mg daily for up to 3 months has been associated with good clinical outcomes in a case series of 6 patients with HHD and 2 case reports.[45][46][47]

In a case series of 58 patients, 43% improved with oral erythromycin or penicillin antibiotics. Doxycycline and minocycline belong to the class of tetracyclines. Doxycycline at a dose of 100 mg daily for up to 3 months has been associated with good clinical outcomes in a case series of 6 patients with HHD and 2 case reports.[45][46][47] In patients experiencing recurrence, doxycycline could be used as maintenance at half-dose. Minocycline at 100 mg twice daily for two weeks and a maintenance dose of 100 mg daily for two months has been associated with complete clearance in one patient.[48] Besides their antibiotic potential, tetracyclines exert anti-inflammatory properties mediated by the inhibition of neutrophil chemotaxis, the regulation of inflammatory cytokines production by keratinocytes, and the inhibition of matrix metalloproteases.[49] The most common side effects are gastrointestinal intolerance (esophagitis) and photosensitivity. The minocycline-related risk of skin hyperpigmentation and hypersensitivity reactions such as DRESS syndrome should limit its use in this indication. Dapsone has been used anecdotally in HHD as well.[50] Almost 20% of mutations in HHD are base substitutions resulting in a premature stop codon. They are responsible for synthesizing a truncated form of hSPCA1[10]. In several case reports, topical gentamicin 0.1% has successfully been used for treating HHD.[51][52][51] In a patient with HHD carrying a stop mutation, topical gentamicin 0.1% applied for 7-10 days was more effective than topical 5% boric acid despite their similar antimicrobial spectrum of action.[51] In a Saccharomyces cerevisiae model of HHD, the authors further showed that topical paromomycin, another aminoglycoside, can induce read-through of a premature nonsense mutation of ATP2C1.[51] Systemic Therapies Even though acantholysis is the primary event in HHD, the main target of available systemic treatments is cutaneous inflammation. The development of skin lesions in HHD requires a reduction in the ATP2C1 gene expression from the intact allele and a heterozygous mutation of the ATP2C1 gene.[53]

In a patient with HHD carrying a stop mutation, topical gentamicin 0.1% applied for 7-10 days was more effective than topical 5% boric acid despite their similar antimicrobial spectrum of action.[51] In a Saccharomyces cerevisiae model of HHD, the authors further showed that topical paromomycin, another aminoglycoside, can induce read-through of a premature nonsense mutation of ATP2C1.[51] Systemic Therapies Even though acantholysis is the primary event in HHD, the main target of available systemic treatments is cutaneous inflammation. The development of skin lesions in HHD requires a reduction in the ATP2C1 gene expression from the intact allele and a heterozygous mutation of the ATP2C1 gene.[53] The pro-inflammatory cytokines IL-6 and IL-8 could play an essential role in regulating ATP2C1 expression. Thus, corticosteroids, cyclosporine A and tacrolimus could be effective in HHD due to their ability to regulate IL-6 and IL-8 levels and indirectly ATP2C1 expression. Additionally, retinoids and oral corticosteroids can act by directly reversing UVB-induced ATP2C1 mRNA suppression.[53] Oral corticosteroids such as prednisolone at daily doses of 0.5 mg/kg can control severe flares in selected cases. Still, rebounds can be expected at the end of treatment.[54] Oral corticosteroids are not suitable for long-term therapy. Several case reports have been published on the use of oral retinoids in HHD (acitretin, isotretinoin, alitretinoin, etretinate). The more robust evidence is available for acitretin at a dose of 10 to 25 mg daily, but the clinical efficacy is not constant.[55][56][57][58] At higher doses, acitretin can exacerbate acantholysis.[32] For females of childbearing age, isotretinoin should be preferred. A synergistic effect of 25 mg acitretin and narrowband ultraviolet B (nbUVB) phototherapy has also been reported.[58] Other immunosuppressive agents such as methotrexate, cyclosporine, and azathioprine have been tested with varying efficacy results but are of limited value in clinical practice.[59][60] Further studies are needed to validate their use for recalcitrant and extended cases. Interventional Treatments Surgery

Several case reports have been published on the use of oral retinoids in HHD (acitretin, isotretinoin, alitretinoin, etretinate). The more robust evidence is available for acitretin at a dose of 10 to 25 mg daily, but the clinical efficacy is not constant.[55][56][57][58] At higher doses, acitretin can exacerbate acantholysis.[32] For females of childbearing age, isotretinoin should be preferred. A synergistic effect of 25 mg acitretin and narrowband ultraviolet B (nbUVB) phototherapy has also been reported.[58] Other immunosuppressive agents such as methotrexate, cyclosporine, and azathioprine have been tested with varying efficacy results but are of limited value in clinical practice.[59][60] Further studies are needed to validate their use for recalcitrant and extended cases. Interventional Treatments Surgery In highly invalidating, localized lesions, resisting medical treatment, full-thickness excision, followed by secondary intention healing, primary closure, or split-skin grafting, has been proposed.[61] For some authors, primary closure presents an increased risk of recurrence and morbidity and should not be preferred.[62] Currently, ablative techniques have progressively replaced surgical excision with the advantages of shorter downtime and lower complication rates. Ablative Techniques Destruction of the epidermis until the level of the papillary dermis is an interesting treatment option for HHD. The adnexal structures do not bear the defect, allowing tissue reepithelization.[63] Different ablative techniques are used to treat HHD, including laser (CO2, erbium-doped yttrium aluminum garnet [Er: YAG], diode laser), electrodesiccation, mechanical dermabrasion, and photodynamic therapy.[64] Ablative techniques are preferred in cases of recalcitrant, localized disease. It is noteworthy that the severe involvement of deep adnexal structures in type 2 segmental HHD makes these patients bad candidates for ablative treatments.[65]

Destruction of the epidermis until the level of the papillary dermis is an interesting treatment option for HHD. The adnexal structures do not bear the defect, allowing tissue reepithelization.[63] Different ablative techniques are used to treat HHD, including laser (CO2, erbium-doped yttrium aluminum garnet [Er: YAG], diode laser), electrodesiccation, mechanical dermabrasion, and photodynamic therapy.[64] Ablative techniques are preferred in cases of recalcitrant, localized disease. It is noteworthy that the severe involvement of deep adnexal structures in type 2 segmental HHD makes these patients bad candidates for ablative treatments.[65] Mechanical dermabrasion was initially proposed as an alternative to surgical excision.[63][66][67] In a retrospective series of 10 patients treated successfully with dermabrasion, the recurrence rate by treated area was only 17% after a median follow-up of 42 months. Relapsing patients were treated with another session with no subsequent relapse.[66] Mechanical dermabrasion is nevertheless less and less used nowadays as it is more hemorrhagic than laser treatments. Among laser treatments, CO2 laser is better evaluated. In most studies, CO2 laser has been used in continuous, defocused mode with power settings ranging from 5 to 25 W and 1 to 5 passes.[68][69][70] In a retrospective series of 13 patients with patient-reported outcomes, CO2 laser allowed a substantial improvement in the quality of life in 69% of cases. The mean time to heal was 6.3 weeks.[68] No recurrence was noted within the treated area. Post-inflammatory hypopigmentation or hyperpigmentation occurred in almost 85% of cases and scarring in 30%. In another series of 8 patients, four achieved more than 75% clinical improvement and two 50 to 75%.[68] Recurrences at the border of previously treated areas are well described after ablative treatments and respond to additional laser sessions. Pulse dye laser at 595-nm has been evaluated in a series of 7 patients using subpurpuric settings (pulse duration of 6 to 10 msec, spot size 7 to 10 mm, fluence 7-10 J/cm). Six patients achieved mild-to-complete clearance after an average of 5 sessions.[71] The lesions resolution time ranged from 2 weeks to 2 months. Four patients relapsed prematurely at the end of treatment.

Pulse dye laser at 595-nm has been evaluated in a series of 7 patients using subpurpuric settings (pulse duration of 6 to 10 msec, spot size 7 to 10 mm, fluence 7-10 J/cm). Six patients achieved mild-to-complete clearance after an average of 5 sessions.[71] The lesions resolution time ranged from 2 weeks to 2 months. Four patients relapsed prematurely at the end of treatment. Er: YAG and Alexandrite laser efficacy has been evaluated in isolated case reports with variable outcomes.[70] In the only reported case of HHD treated with diode laser at 1450 nm, a reduction in malodor and sweating was noted without clinical improvement of lesions.[72] Photodynamic Therapy (PDT) In a case series of 8 patients with long-lasting, recalcitrant HHD lesions, PDT with methyl-amino levulinate achieved complete or partial response for all treated lesions and no recurrence after a follow-up of 3 to 36 months.[73] A standard protocol of 3 sessions with 3-week intervals was used. In another recent retrospective study, ten patients with difficult-to-treat HHD received PDT with 5-aminolevulinic acid (5-ALA).[74] All patients achieved complete remission after 1 to 12 weekly sessions. Three patients experienced a relapse that responded well to further sessions. Tolerability was excellent since 5-ALA is a second-generation photosensitizer that penetrates deeper into the skin, beyond the nerve endings, and is associated with reduced perioperative pain. The exact molecular mechanism behind the efficacy of PDT in HHD remains elusive but is probably related to its intrinsic photooxidative properties. PDT could act by the induction of tissue repair mechanisms and the subsequent improvement of the mechanical integrity of the epithelium.[75] Botulinum Toxin Injection Sweating is a well-identified factor of HHD exacerbations. Reducing the production of eccrine sweat glands by blocking the release of acetylcholine from the sympathetic nerve fibers with botulinum toxin appears to be a promising treatment for HHD.[76]

All patients achieved complete remission after 1 to 12 weekly sessions. Three patients experienced a relapse that responded well to further sessions. Tolerability was excellent since 5-ALA is a second-generation photosensitizer that penetrates deeper into the skin, beyond the nerve endings, and is associated with reduced perioperative pain. The exact molecular mechanism behind the efficacy of PDT in HHD remains elusive but is probably related to its intrinsic photooxidative properties. PDT could act by the induction of tissue repair mechanisms and the subsequent improvement of the mechanical integrity of the epithelium.[75] Botulinum Toxin Injection Sweating is a well-identified factor of HHD exacerbations. Reducing the production of eccrine sweat glands by blocking the release of acetylcholine from the sympathetic nerve fibers with botulinum toxin appears to be a promising treatment for HHD.[76] In a prospective, single-center, interventional study, 26 patients with HHD were injected with botulinum toxin type A (BtxA) at a dose of 50 IU per 100 cm(2.5 IU/0.1 ml every 2 cm). BtxA was effective with an 85% reduction of the treated area at six months. However, the cost of this intervention has to be taken into consideration. BtxA can be proposed as a first-line approach for mild-to-moderate axillary and inguinal lesions of HHD.[76][60] Narrowband Ultraviolet B Phototherapy The effect of ultraviolet light exposure differs between patients. Some patients can present flares even in unaffected skin after sun exposure, while others experience clinical improvement. In vitro, UVB light induces the suppression of ATP2C1 mRNA but is an insufficient cellular stress factor alone for the induction of HHD lesions.[53][77] Several case reports have suggested the efficacy of nbUVB therapy either in monotherapy or synergistically with retinoids in HHD.[78] In selected patients, NbUVB phototherapy could be an interesting treatment option for HHD. The use of other interventional treatments such as radiofrequency and electron beam radiotherapy (cumulative dose of 20 Gy in 10 fractions) has been reported in isolated cases.[79][80] Novel Therapies Emerging therapies for HHD include oral anticholinergic drugs (oxybutynin, glycopyrrolate), afamelanotide, oral magnesium chloride, oral naltrexone, apremilast, and dupilumab.

The use of other interventional treatments such as radiofrequency and electron beam radiotherapy (cumulative dose of 20 Gy in 10 fractions) has been reported in isolated cases.[79][80] Novel Therapies Emerging therapies for HHD include oral anticholinergic drugs (oxybutynin, glycopyrrolate), afamelanotide, oral magnesium chloride, oral naltrexone, apremilast, and dupilumab. Glycopyrrolate and other anticholinergics such as oxybutynin are thought to work in HHD by controlling sweating. Glycopyrrolate is an anticholinergic agent that is safe and effective in hyperhidrosis with the advantage of fewer central nervous system adverse events since it does not cross the blood-brain barrier. Two case reports noted the efficacy of low-dose oral and topical glycopyrrolate, respectively, in HHD.[81][82] Naltrexone is an orally active opioid antagonist that blocks µ- and δ-opioid receptors. At doses ranging from 50 to 100 mg daily, naltrexone is approved to treat opioid addiction. At low doses, naltrexone seems to influence various systemic pathways with paradoxical analgesic and systemic anti-inflammatory effects.[83] In 2017, two small case series reported the efficacy of low-dose naltrexone in HHD for the first time. All six patients reached complete to almost complete clearance after 1 to 3 months of treatment with doses varying from 3 to 4.5 mg per day. Treatment was well tolerated.[83][84] Apremilast at a dose of 30 mg twice daily has been used off-label in HHD in several case reports with good results.[85] On the other hand, Riquelme-Mc Loughlin et al. reported a lack of response or premature treatment cessation due to intolerance in 5 consecutive cases of resistant HHD.[86] A combined treatment of apremilast and dermabrasion or botulinum toxin has also been reported.[87][88] Two small case series of 5 patients report the efficacy of dupilumab, a fully human IgG4 monoclonal antibody that inhibits the signaling of IL-4 and IL-13 in HHD but again, large-scale, long-term data are lacking.[89][90]

The differential diagnosis of Hailey-Hailey disease includes: Darier disease Grover disease Pemphigus vulgaris/vegetans Psoriasis inversa Tinea cruris Intertriginous candidiasis Erythrasma Galli-Galli disease

Hailey-Hailey disease has a chronic fluctuating course. Patients with HHD can undergo recurrent flares and remissions lasting months to years. In some cases, the severity of HHD tends to improve with age, but lack of improvement or deterioration is also possible.[2]

Secondary infections are quite common, especially on erosive and macerated plaques of Hailey-Hailey disease, and can trigger the exacerbation or even acute dissemination of lesions.[20] Bacterial (Staphylococcus aureus, Streptococcus pyogenes), fungal (Candida species), and viral (herpes simplex, poxvirus, human papillomavirus) infections require prompt initiation of antimicrobial treatment for disease control. Staphylococci and other microbes may induce IL-6 and IL-8 production in keratinocytes, decreasing hSPCA1 expression in an autocrine fashion.[91][53] Chronic inflammation of long-lasting, recalcitrant lesions of HHD can lead to malignant transformation to squamous cell carcinoma.[92] This transformation has been mainly described in the literature for genital lesions and was associated, in some cases, with a human papillomavirus infection.[93]

Avoiding triggering factors is of paramount importance in preventing exacerbations of Hailey-Hailey disease. Overall, patients’ education on precipitating factors can help them to apply the necessary lifestyle modifications. Preventative measures include proper hygiene practices such as daily cleaning with a gentle cleanser and an antiseptic solution to limit secondary infections and avoidance of sun exposure. Flares are common during summer due to heat and humidity. Patients should also avoid any physical activity involving friction and tight-fitting clothing. In patients with obesity, weight loss can help to reduce friction in flexural areas and is highly recommended. Non-segmental and type 2 segmental HHD are inherited in an autosomal dominant fashion. Patients with type 1 segmental HHD have a risk of transmitting non-segmental HHD to their children in case of gonadal mosaicism. Thus, patients with HHD should be offered genetic counseling.

HHD is a rare autosomal dominant genodermatoses with complete penetrance and variable expressivity. HHD is a chronic disease with a remitting-relapsing course. Mutations in the ATP2C1 gene, localized at 3q21-q24 that encodes the human secretory-pathway Ca/Mn-ATPase isoform 1 of the Golgi apparatus, are responsible for HHD. The typical skin lesions usually occur in friction or intertriginous areas. Clinically, ruptured vesicles and blisters tend to form erythematous plaques with worm-eaten erosions and painful "rhagades." Acantholysis throughout the spinous layer, appearing as a "dilapidated brick wall'' is a hallmark of HHD histology. Avoiding triggering factors such as mechanical stress, heat, sun exposure, and sweating are essential measures to prevent disease flares. There is no curative treatment for Hailey-Hailey disease. Antiseptics and intermittent topical anti-inflammatory therapies can help control mild cases of HHD.

Hailey-Hailey disease follows a chronic course with lesions tending to wax and wane. In chronic, poorly controlled lesions, there is a risk of malignant transformation, especially in the vulvar area. Thus, a regular follow-up with a dermatologist is essential. Considering the burdensome symptoms of HHD and the complexity of clinical management, an integrated interprofessional approach coordinated by a dermatologist and specialty-trained dermatology nurses is recommended. [Level 5] An interprofessional team dedicated to HHD management should include a specialist in genetic counseling, a psychologist and mental health specialists, a dietician, and a pharmacist. Genetic counseling upon diagnosis and pre-conceptually should be proposed. A psychologist and a mental health consult may be necessary in case of disease-related anxiety and depression. Patient education regarding photoprotection, proper hygiene practices, and adequate lifestyle modifications by specialty-trained dermatology nurses are essential. Furthermore, patients should learn with the help of dedicated patient education consults to recognize early signs of disease flares and secondary infections for prompt initiation of adequate treatment. The role of the primary care provider in long-term patient activation and engagement in self-management is central.