Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2024;14(3):e2024160 1 Hailey-Hailey Disease: Case Series and Review of Systemic Medications Kamran Balighi1, Zahra Razavi1, Maryam Daneshpazhooh1, Vahide Lajevardi1, Kambiz Kamyab-Hesari1, Kimia Ghafouri2 1 Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran 2 School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Key words: Hailey-Hailey disease, Blistering skin disorder, Systemic medications, Dermatology, Chronic inflammatory disease Citation: Balighi K, Razavi Z, Daneshpazhooh M, Lajevardi V, Kamyab-Hesari K, Ghafouri K. Hailey-Hailey Disease: Case Series and Review of Systemic Medications. Dermatol Pract Concept. 2024;14(3):e2024160. DOI: https://doi.org/10.5826/dpc.1403a160 Accepted: February 28, 2024; Published: July 2024 Copyright: ©2024 Balighi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Kimia Ghafouri, MD, School of Medicine, Tehran University of Medical Sciences, Poursina Street, Ghods Street, Keshavarz Boulevard, Tehran, 14155-6559, Iran. Tel: +1(201)-856-7370 Email: ghafouri.kim@gmail.com Introduction: Hailey-Hailey disease (HHD) is a rare inherited blistering skin disorder characterized by a chronic relapsing course. While it does not pose a serious threat to the patient’s health, the quality of life can change. Unfortunately, there is currently no standard treatment for this condition. Objectives: In this observational retrospective cohort study, our aim was to discover the demographic characteristics and treatment strategies for managing HHD. Methods: In this retrospective cohort study, we documented the demographic, clinical, and histo- pathological characteristics beside various treatment employed options of patients diagnosed with HHD at Razi Hospital over the past 14 years. Results: A total of 32 patients with HHD were enrolled in the study (15 male and 17 female). The mean age of patients was 50.41 ± 13.15 (22-77) years. The average age of disease onset was 37.31 ± 11.88 (15-60) years. Among the participants, 16 individuals (50%) affirm a positive family history of some kind of pemphigoid blisters. The most common site of disease activity was the inguinal area, observed in 14 patients (33.33%). Histopathological examination discovered the existence of suprabasal acanthol- ysis in all of the specimens. Worthily, direct immunofluorescence analysis showed negative results in all skin biopsies. All patients received topical steroids and either topical or systemic antimicrobial agents. In cases of flares, systemic steroids were the most popular and favorable treatment choice during flares. Conclusion: Indeed, Hailey-Hailey disease, characterized by its chronic inflammatory and rare nature with a relapsing and remitting course, poses a significant challenge for dermatologists. The treatment of HHD has been less than satisfactory and it often presents a challenge and could be misdiagnosed. Among the available treatment options, topical steroids and antimicrobial agents are the most administered therapies. ABSTRACT 2 Review | Dermatol Pract Concept. 2024;14(3):e2024160 Introduction Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare blistering skin disorder. This genodermatosis follows an autosomal dominant inheritance pattern with complete penetrance and variable expression. While the precise prevalence of HHD remains unknown, it is estimated to affect approximately 1 in 50000 individuals [1,2]. Notably, about 70% of patients may have a positive family history of the condition. Typically, the disease occurs during the second to fourth decade of life [1,3]. One of the challenging aspects of HHD is the vast and unpredictable severity of skin manifestations it may present [2]. The key pathological events in HHD are initiated by a single mutation occurring in one copy of the ATP2C1 gene located on chromosome 3. This gene encodes the P-type Ca2+- transporter ATPase, a protein pump responsible for transporting both calcium (Ca) and manganese (Mn) ions from the cytosol into the Golgi apparatus during each cycle. Consequently, only half of the required Golgi apparatus Ca transporter pumps are produced. As a result of the mutation, the altered protein which inadequately functions in the des- mosome causes epidermal acantholysis. Ultimately, this genetic mutation manifests as blisters and inflamed lesions on the skin mostly on the folds or even on a large area of the body [4-10]. Clinically, Painful blisters frequently rupture, occasionally become infected, resulting in an unpleasant malodor. In some cases, allergic blisters may also present in the involved area. Non-healing erosions grad- ually progress to scar formation or post-inflammatory hy- perpigmentation. Rarely, there is also a risk of squamous cell carcinoma developing within the affected region [1,11-12]. Histologically, HHD often exhibits suprabasal acanthol- ysis, which can be likened to a disrupted brick wall. Dysker- atosis may also be observed. Typically, the dermis remains unaffected; however, there may be lymphatic infiltration around the blood vessels. It is important to note that, un- like pemphigus vulgaris (an autoimmune blistering disorder) anti-desmosome antibodies are not present in HHD [13]. Patients with HHD generally enjoy a normal life span and retain their reproductive capacity. This condition generally affects the skin and follows a chronic relapsing course with flares becoming less frequent as individuals age. While HHD does not pose a serious risk to the patient health, can change the quality of life. Certain factors such as specific foods, hor- monal cycles, infection, medication and stress may trigger symptom outbreaks. Additionally, heat and sweating can ex- acerbate or trigger the condition, while sun exposure may either worsen or improve skin lesions [1]. Despite several studies describing effective treatments, the absence of a standard treatment modality is likely due to the rarity of the disease and the lack of large-scale clinical trials. Objectives Due to the scarcity of comprehensive studies focusing on the demographic characteristics of Hailey-Hailey disease, this study pursued to explore the demographic characteristics and treatment approaches employed in patients with HHD who were referred to Razi Hospital over the last 12 years. Methods Study Design This retrospective, observational cohort study received ap- proval from the Ethics Committee of Tehran University of Medical Science (approval ID 9223101036). Study Population and Outcomes All patients referred to Razi Hospital with a confirmed diag- nosis of HHD through skin biopsy between 2008 till 2022 were included in this survey. Verbal or written informed con- sent was obtained from each patient before inclusion in the study. The inclusion criteria confirmed a clinicopathologic di- agnosis of HHD and the patients agreement for participation. The following data were collected: (1) age of onset, (2) gender, (3) family history, (4) involvement area, (5) histopathological findings and (6) results of direct immunofluorescence (DIF) tests. Patients with missing required data were excluded from the study. The necessary information was retrieved from re- cords available in the dermatology outpatient clinic and the dermato-pathological department. In addition, some data were obtained by contacting or visiting the patients. Statistical Analysis All collected data were analyzed using IBM SPSS statistical software version 23. Continuous variables were reported as mean with standard deviation (SD). While categorical vari- ables were described in terms of frequencies. The differences between study groups were examined using the Chi-square test and T-test as appropriate. A significance level of P < 0.05 was considered statistically significant. Results Patients Characteristics and Clinical Findings A total of 32 patients with HHD were enrolled in the study (15 male and 17 female). The mean age of patients was 50.41 ± 13.15, ranging from 22 to 77 years. The average age of disease onset was 37.31 ± 11.88 years with an onset range from 15 to 60 years. Notably, 16 patients (50%) reported a positive family history of similar blistering conditions with seven attributing it to their fathers, six to their siblings and four to their mothers. Review | Dermatol Pract Concept. 2024;14(3):e2024160 3 Regarding the initial areas of presentation, the study detected the following distribution among patients: 19 (45.23%) in the axillary region, 18 (42.85%) in the ingui- nal region, 2 (4.8%) in the lateral neck region and 3 different patients each presented involvement of the inframammary fold, genital area and perianal area. However, at the time of data collection, the disease activ- ity was primarily concentrated in the inguinal area, affect- ing 14 (33.33%) patients. The second most common sites of involvement were the axillary and abdominal regions, each with 7 (16.67%) patients experiencing disease activity. Less frequently, the disease was active in the inframammary re- gion for 5 (11.90%) patients, the genital area for 4 (9.52%) patients, the lumbar and intergluteal regions for 2 (4.76%) patients each and the perianal area for 2 (4.76%) patients. Histopathological Findings Histopathological findings were documented for all patients. In the histopathological examination, suprabasal acanthol- ysis was a consistent finding in all patients. Additionally, dyskeratosis was observed in 10 (31.25%) patients, and a brick wall appearance was reported in the specimens of 8 (25%) patients. DIF analysis was conducted on all pa- tients and the results were consistently negative. Anti-IgG was assessed in all patients, Anti-C3 in 92.86% of patients, Anti-IgA in 42.85% of patients, Anti-IgM in 14.28% of pa- tients, Anti-fibrinogen in 7.14% and Anti-total-Ig in 7.14% of patients. In all these assessments, the results were reported as negative. Treatment All patients received a treatment regimen consisting of topical corticosteroids (triamcinolone acetonide cream, mometasone cream), topical antifungals (clotrimazole or sertaconazole) and topical antibacterial agents (mupirocin, gentamicin, fusidic acid). In cases where complications such as eczema herpeticum arose, oral acyclovir was added to the therapeutic regimen. It is worth noting that all patients experienced multiple flares of their condition throughout their lives. For severe flares, treatment included oral prednisolone with doses ranging up to 0.5mg/kg or 0.75mg/kg as required. Follow- ing the remission of the flare condition, a gradual tapering of systemic corticosteroids was initiated and typically con- tinued for a duration of 4-6 months. The specific duration of the tapering regimen depended on the severity of HHD in each patient. One of our patients, a 45-year-old male with a known history of HHD for the past 10 years, had been us- ing topical steroids and antifungal agents with only partial improvement. Approximately one year ago, he experienced a severe flare-up of HHD affecting his axillary and ingui- nal areas. The patient continued to use topical steroids and anti- fungal agents concurrently. Within a span of two months, a dramatic response was observed (Figure 1), and after four months, the lesions had completely cleared (Figure 2). Conclusions HHD is a rare blistering disorder known for its chronic re- lapsing feature. In our study, the average age of patients with HHD was 50.41 ± 13.15 (22-77) years. The mean age of onset was 37.31 ± 11.88 (15-60) years. Similarly, in a ret- rospective study conducted by Zhao et al, on 26 patients with HHD the mean time of disease onset was 35 years [14]. These findings show that HHD tends to present in adulthood Figure 1. Partial improvement with oral methotrexate with few remaining inguinal ulcers. 4 Review | Dermatol Pract Concept. 2024;14(3):e2024160 In severe cases of HHD or during flare-ups, use of topical and systemic medications as well as interventional therapies have successful outcomes [1,16-18]. Oral systemic medications are commonly administered for cases of HHD with recalcitrant and widespread skin involvement [1,17,18]. There is substantial supportive evi- dence for the efficacy of oral antibiotics, particularly tetracy- cline, improving skin lesions associated with HHD. These antibiotics are favored due to their anti-inflammatory properties and safety profiles, making them a first-line choice among systemic medications. How- ever, exacerbation during treatment and relapsing upon dis- continuation or failure to respond, have been reported with Tetracycline. In such cases, dermatologists may consider a low maintenance dose or explore alternative medications to manage the condition more effectively. Systemic corticosteroid can control severe HHD. How- ever, their use is typically limited to short-term periods due to the potential long-term side effects associated with pro- longed therapy. Among the emerging medications for HHD, low-dose naltrexone (LDN) and systemic retinoids have been sup- ported most by the previous case reports and case series [1]. LDN has the potential to modulate the immune system, promote wound healing and alter the cell migration pattern through inhibition of opioid receptors and increasing the levels of enkephalin and endorphin in the body [19]. Strong evidence supports the use of low dose oral acitretin (10-30 mg daily) for managing HHD, due to their role in regulating epidermal proliferation and maintaining calcium homeo- stasis. There have been some unresponsive cases with oral retinoids though [1,17,18]. Other systemic agents (cyclospo- rine, thalidomide, glycopyrrolate, azathioprine and biologics such as etanercept) have different efficacy in the manage- ment of HHD. and predominantly affects middle-aged individuals. Accord- ing to our results, half of our patients had a negative family history of this disease. This inconsistency could possibly be attributed to the variable penetrance of the mutated gene re- sponsible for HHD or the occurrence of de novo mutations in the responsible gene. In contrast, in a survey performed by Zhao et al, positive family history of the disease was stated in nearly all patients [14]. Similarly, in the study by Gisondi, half of the patients had positive family history [15]. The dif- ferences in the family history may reflect variations in the genetic inheritance patterns and the presence of mutations in different populations of patients with HHD. Our findings showed that HHD mostly affected the inguinal and axil- lary areas, which is parallel with the results reported in the survey conducted by Zhao et al [14]. The study performed by Gisondi, lesions were also observed on the back, shoul- ders and trunk [15]. These differences in lesion distribution among HHD patients may possibly reflect both genetic and environmental factors influencing the various presentation of HHD. The treatment of HHD relies heavily on informa- tion derived from case reports and case series. The absence of randomized clinical studies and chronic relapsing course of the disease cause challenges in managing HHD. There is not any gold standard treatment and it remains difficult to directly compare the efficacy of various therapeutic ap- proaches [1,16-18]. First step is certain lifestyle modifica- tions. They are believed to improve the condition. These modifications include: Heat, sweating and friction avoidance as potential exac- erbating factors. Weight loss is recommended to eliminate the friction of the skin. Personal hygiene and frequent bathing are important to prevent bacterial, fungal and viral superinfections which po- tentially can worsen HHD lesions. Figure 2. Complete improvement with oral methotrexate after 5 months. Review | Dermatol Pract Concept. 2024;14(3):e2024160 5 8. Marsch WC, Stüttgen G. Generalized Hailey-Hailey disease. Br J Dermatol. 1978;99(5):553-560. doi:10.1111/j.1365-2133.1978. tb01968.x 9. Dhitavat J, Fairclough RJ, Hovnanian A, Burge SM. Calcium pumps and keratinocytes: lessons from Darier’s disease and Hailey-Hailey disease. Br J Dermatol. 2004;150(5):821-828. doi:10.1111/j.1365-2133.2004.05839.x 10. Engin B, Kutlubay Z, Erkan E, Tüzün Y. Hailey-Hailey disease: A fold (intertriginous) dermatosis. Clin Dermatol. 2015;33(4): 452-455. doi:10.1016/j.clindermatol.2015.04.010 11. Chiaravalloti A, Payette M. Hailey-Hailey disease and review of management. J Drugs Dermatol. 2014;13(10):1254-1257. 12. Gottlieb SK, Lutzner MA. Hailey-Hailey disease—an electron microscopic study. J Invest Dermatol. 1970;54(5):368-376. doi:10.1111/1523-1747.ep12258260 13. Arora H, Bray FN, Cervantes J, Aizpurua LAF. Management of familial benign chronic pemphigus. Clin Cosmet Investig Derma- tol. 2016;9:281-286. doi:10.2147/CCID.S100518 14. Zhao QF, Song ZQ, Shi W, et al. Hailey-Hailey disease: A review of clinical features in 26 cases with special reference to the sec- ondary infections and their control. Dermatol Sin. 2017;35(1): 7-11. doi:10.1016/j.dsi.2017.01.002 15. Gisondi P, Veller Fornasa C, Girolomoni G. Severe Impairment of Quality of Life in Hailey‐Hailey Disease. Acta Derm Venereol. 2005;85(2):132-133. doi:10.1080/00015550410024471 16. Farahnik B, Blattner CM, Mortazie MB, Perry BM, Lear W, Elston DM. Interventional treatments for Hailey-Hailey dis- ease. J Am Acad Dermatol. 2017;76(3):551-558. doi:10.1016 /j.jaad.2016.08.019 17. Rogner DF, Lammer J, Zink A, Hamm H. Darier and Hailey‐Hailey disease: update 2021. J Dtsch Dermatol Ges. 2021;19(10):1478-1501. doi:10.1111/ddg.14564 18. Arora H, Bray FN, Cervantes J, Aizpurua LAF. Management of familial benign chronic pemphigus. Clin Cosmet Investig Derma- tol. 2016;9:281-286. doi:10.2147/CCID.S100518 19. Izquierdo D, Renvoise B, LaPoint K, et al. Could low-dose nal- trexone be an effective treatment for Hailey-Hailey disease? Mol Med Lett. 2016;1(1):5-9. 20. Arjona-Aguilera C, Jiménez-Gallo D, Villegas-Romero I, Valenzuela-Ubiña S, Linares-Barrios M. Subcutaneous methotrex- ate for Hailey-Hailey disease: two case reports and review of the lit- erature. J Dtsch Dermatol Ges. 2021;19(2):278-281. doi:10.1111 /ddg.14344 Treatment of HHD is less than satisfying. 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