Unmet Needs in Darier's Disease from a Patient's Perspective: Lessons Learnt from the German Registry.

The MDHHgermany registry was initiated to characterize the "real-life" situation of affected individuals with Darier's disease (DD; Morbus Darier, MD) and Hailey-Hailey disease (HH), including their treatment and healthcare. To gain deeper insights into medical care of patients with DD, various aspects such as demographics, subjective symptoms, patient satisfaction with medical care, past and current therapies were explored. Patients with diagnosed DD were included. Subjective symptoms such as itch, pain and burning sensation were assessed. Individual therapy goals were recorded and patients assessed previous/current therapies along with satisfaction of medical care and treatment. A total of 55 patients were recruited; 47 patients were eligible for the analysis. Pruritus was rated the most bothersome symptom. Some 42.6% had not received systemic treatment so far or systemic therapies were rated ineffective (32.6%). Most commonly oral retinoids were prescribed, followed by corticosteroids. Patient satisfaction with medical care and treatment proved to be mediocre. This "real-life" data show an alarming unmet need regarding patients' satisfaction with medical care and treatment, evidenced by the reported lack of disease control. Further studies and interventions are needed to improve the spectrum of available therapies. MDHHgermany provides a foundational platform for future clinical trials, epidemiological studies, and pathophysiological analyses.

Patients' perspective, quality of life and treatment goals in Hailey-Hailey disease: Lessons learned from the German National Registry.

BACKGROUND: Hailey-Hailey disease (HHD) remains a difficult-to-treat dermatosis and little is known about the patient's perception of the disease activity, the treatment success and its impact on quality-of-life (QoL). OBJECTIVE: To obtain better understanding of HHD patients' needs regarding their medical condition, financial burden, QoL, subjective well-being and treatment thereof as well as satisfaction to evaluate common treatments' 'real-life' relevance. METHODS: With initiation of the national registry for Darier's disease (DD; Morbus Darier, MD) and Hailey-Hailey disease (HH) MDHHgermany, patients with HHD diagnosis were included starting June 2020. To assess subjective symptoms, patients filled out questionnaires such as the DLQI (dermatological life quality index), numeric rating scale (NRS) for itch, pain and burning sensation, as well as the SWLS (satisfaction with life scale) questionnaire to quantify overall satisfaction in life. Additionally, data on therapies were collected along with the patients' satisfaction of those and their medical care. Furthermore, patients assessed financial aspects and work ability. RESULTS: One hundred and two patients were recruited from dermatology clinics, office-based dermatologists and self-help platforms across Germany between June 2020 and February 2023, 90 were eligible and analysed (mean: 49.91 years, 73.33% females, 26.67% males). 39.77% stated according to the DLQI their life is severely/very severely affected. Satisfaction with life was mediocre. Burning sensation was most pronounced among subjective symptoms (NRS 5.85 ± 2.80). Systemic treatments were rated as ineffective according to 56.92%, 25.56% had never received one. Most prescribed systemic treatments were corticosteroids (73.8%), followed by low-dose naltrexone (LDN) (26.2%), retinoids (15.4%) and antibiotics (13.8%). Satisfaction with medical care was generally low. CONCLUSION: Our 'real-life' data state a major disease burden and impact on the QoL for affected individuals, as well as limited disease control due to inadequate therapies. MDHHgermany can provide insights into improvement of healthcare support with this debilitating disease and improve QoL. In the long term, it aims to provide basis for further clinical trials, epidemiological studies and immunological investigations.

[Clinical, therapeutic and pathophysiological aspects of Darier's disease]. / Aspects physiopathologiques cliniques et thérapeutiques de la maladie de Darier.

Darier Disease is a rare autosomal dominant inherited skin disorder classified as an acantholytic dermatosis. It manifests around puberty as brownish keratotic papules of skin folds and seborrheic areas, associated with onychopathy and mucosal involvementand have a chronic relapsing-remitting course with frequent exacerbations triggered by sun exposure, heat, friction, or infections. Darier patients have an increased risk of neuropsychiatric disorders, type 1 diabetes and heart failure. Short-term management relies on antibiotics/antiviral, topical corticosteroids and/or retinoids. Moisturizers, sun protection and avoiding triggers are essential for long-term management. Conventional long-term treatment is not standardized and many topical treatments, physical and surgical measures and systemic treatments are described in the literature.

La maladie de Darier est une génodermatose rare à transmission autosomique dominante. Elle se manifeste autour de la puberté par des papules kératosiques brunâtres des plis et des zones séborrhéiques, associées à une onychopathie et une atteinte muqueuse, et évolue par poussées déclenchées par les UV, la chaleur, les frottements ou les infections. Les patients atteints présentent un risque accru de diabète de type 1, d'insuffisance cardiaque et de troubles neuropsychiatriques. La prise en charge à court terme consiste en des antibiotiques/antiviraux, des corticostéroïdes topiques et/ou des rétinoïdes. Celle à long terme repose sur les émollients et l'éviction des facteurs déclenchants. Le traitement à long terme n'étant pas codifié, de nombreux traitements locaux et sytémiques, mesures physiques et chirurgicales sont décrits dans la littérature.

Exacerbation of Darier disease with lithium therapy.

Darier disease is an autosomal dominant blistering disorder linked to mutation of the endoplasmic reticulum calcium pump, SERCA2, which compromises keratinocyte adhesion and differentiation. Beyond the typical keratotic and eroded skin lesions, patients with Darier disease often present with psychiatric co-morbidities. Herein, we present a biopsy-confirmed case of Darier disease in a patient with bipolar disorder, whose cutaneous disease dramatically worsened upon initiation of lithium therapy. In consultation with the patient's psychiatrist, lithium was tapered, leading to rapid improvement in her skin. This case highlights the potential for lithium to complicate management of Darier disease and underscores the need for dermatologists to collaborate with psychiatrists to optimize both cutaneous and mental health in patients.

A detailed regimen of isotretinoin for the successful treatment of severe keratosis pilaris.

Although a well-known recommended treatment option, there are currently no studies that describe the detailed regimen of isotretinoin for the treatment of primary keratosis pilaris. Based on previous studies involving other hyperkeratotic disorders, this report describes a safe and effective treatment course of isotretinoin for severe keratosis pilaris.

Keratosis pilaris rubra successfully treated with topical sirolimus: Report of a case and review of the literature.

Keratosis pilaris rubra (KPR) is a subtype of keratosis pilaris (KP) presenting with numerous "grainlike" follicular papules in a background of confluent erythema most often affecting the face and upper extremities with persistence beyond puberty. Treatment has remained challenging with inconsistent benefit from topical therapies such as emollients, keratolytics, corticosteroids, and retinoids, though case reports documenting success with pulsed dye laser therapy have been found. We present a case of KPR in a 15-year-old boy who was successfully treated with topical sirolimus 1% cream.

Therapeutic Options for the Treatment of Darier's Disease: A Comprehensive Review of the Literature.

Darier's disease (also known as keratosis follicularis or dyskeratosis follicularis) is an autosomal dominant inherited disorder which manifests as hyperkeratotic greasy papules in the first or second decade of life. Aside from symptom management and behavioral modifications to avoid triggers, there are currently no validated treatments for Darier's disease (DD). However, a variety of treatments have been proposed in the literature including retinoids, steroids, vitamin D analogs, photodynamic therapy, and surgical excision. The purpose of this review article is to identify therapeutic options for treating DD and to outline the evidence underlying these interventions. A search was conducted in Medline for English language articles from inception to July 4, 2020. Our search identified a total of 474 nonduplicate studies, which were screened by title and abstract. Of these, 155 full text articles were screened against inclusion/exclusion criteria, and 113 studies were included in our review. We identified Grade B evidence for the following treatments of DD: oral acitretin, oral isotretinoin, systemic Vitamin A, topical tretinoin, topical isotretinoin, topical adapalene gel, topical 5-flououracil, topical calciptriol and tacalcitol (with sunscreen), grenz ray radiation, and x-ray radiation. All other evidence for treatments of DD consisted of case reports or case series, which is considered grade C evidence. Considering the quality and quantity of evidence, clinicians may consider initiating a trial of select topical or oral retinoids first in patients with localized or generalized DD, respectively.

Darier and Hailey-Hailey disease: update 2021.

The autosomal-dominant genodermatoses Darier disease and Hailey-Hailey disease present special challenges to dermatologists. Despite their similar pathogenesis featuring impaired adhesion of suprabasal keratinocytes as a result of defective ATPases in epidermal calcium channels, the two diseases differ considerably in clinical presentation and therapeutic options. Darier disease is characterized by reddish brown, keratotic papules in seborrheic and intertriginous areas, which may coalesce into extensive lesions. Individuals affected with Hailey-Hailey disease primarily develop intertriginous papulovesicles and small blisters, which often evolve into erythematous plaques with erosions and painful fissures. Quality of life is significantly reduced because of complaints (itch, burning sensation, pain), body malodor and chronicity. Therapeutic options remain limited. Antiseptics and intermittent topical corticosteroids are a cornerstone of therapy, and systemic anti-infective treatment is often required in cases of superinfection. Ablative surgical interventions such as dermabrasion and CO2 laser surgery can lead to long-term remissions in intertriginous Hailey-Hailey disease, while temporary relief may also be achieved by intralesional injections of botulinum toxin. Of the systemic medications available for Darier disease, acitretin, which is approved for this purpose, has the best supporting evidence. The efficacy of immunosuppressants and immune modulators is inconsistent. Low-dose naltrexone produces more satisfactory results in Hailey-Hailey than Darier disease. The present CME article summarizes current knowledge of the two dermatoses, taking recent developments into account.

The treatment of Kyrle's disease: a systematic review.

Kyrle's disease (KD) is a cutaneous disease that develops in individuals with underlying systemic disease, particularly chronic renal failure and diabetes mellitus (DM), and is associated with a high burden of disease linked to itch. The intensely pruritic, hyperkeratotic papulonodular rash seen in KD dramatically impairs patients' quality of life and increases their risk of mortality. Unfortunately, no guidelines or evidence-based regimens have been specifically developed for KD, making the treatment of this disease particularly challenging for physicians. This article aims to provide the first comprehensive, up-to-date overview and analysis of treatment options employed for KD. A search of the PubMed/MEDLINE and Scopus databases was performed for articles regarding the treatment of KD, published in English between 1990 and 2019. Seventy-three articles were identified, of which eighteen met the inclusion criteria. We discovered that a wide variety of treatment regimens for KD have been reported in the literature, including oral antibiotics, immunosuppressants, phototherapy, topical/systemic retinoids, topical keratolytics and various combination therapies, which include some of the aforementioned treatments, in conjunction with oral/topical/injectable steroids, emollients and/or antihistamines. The use of a combination regimen is the most commonly practiced therapeutic approach to KD. Topical corticosteroids and depot corticosteroid injections repeatedly appeared in many of the regimens encountered during our search. While no definitive recommendations can be made based on existing literature, this article provides physicians with a summative outline that can help guide management and be referenced when other treatment efforts fail. The increasing prevalence of renal disease, DM and other chronic diseases will inevitably lead to rising rates of KD in the upcoming years. While randomized controlled trials are greatly needed, novel antipruritic immunomodulatory drugs targeting specific interleukin receptors (IL-4/13/31) and intracellular signalling (e.g. Janus kinase) pathways may have a potential role in the treatment of this disease.

Variable response to low-dose naltrexone in patients with Darier disease: a case series.

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.

Vesiculobullous Darier Disease Symptomatically Responsive to Cetirizine

Darier disease is an autosomal dominant genodermatosis of abnormal keratinization characterized by hyperkeratotic papules and plaques with a predilection for seborrheic areas. We report a case of a rare vesiculobullous variant of treatment-resistant Darier disease in a 55-year-old woman that failed topical tacrolimus and topical and oral glucocorticoids. Cetirizine was initiated at 10 mg daily and increased to 40 mg daily over four weeks, with resultant marked improvement of the patient's burning sensation. A punch biopsy revealed a perivascular infiltrate of eosinophils. This patient's symptomatic improvement with cetirizine, which has antagonizing properties against eosinophils, highlights the potential role of eosinophils in the pathogenesis of vesiculobullous Darier disease. We suggest that major basic protein secreted by eosinophils may propagate blister formation in vesiculobullous Darier disease by disrupting desmosomes. J Drugs Dermatol. 2019;18(2):213-214.

Chlorine Dioxide Complex Cleanser: A New Agent With Rapid Efficacy for Keratosis Pilaris.

Chlorine dioxide complex™ is a new molecule to dermatology that is a unique, non-toxic, broad spectrum anti-microbial and keratolytic compound. Chlorine dioxide has been used as an antiseptic in industrial settings for decades, primarily in water treatment facilities for municipal water supplies and food preparation. The compound has exceptional antiseptic properties with no known potential for development of resistance. It is a true keratolytic and anti-inflammatory, but is non-toxic to human tissue due to its unique mechanism of action. Chlorine dioxide's use in consumer products was previously limited because it is inherently an unstable molecule that had to be used quickly after it was produced. However, the recent development of a complexed form of chlorine dioxide that retains its antimicrobial and keratolytic activity has allowed the development of products (AsepticMD, Aseptic Plus, Nashville, TN) that take advantage of the properties of this unique molecule. Here we report a case series demonstrating its efficacy as a cleanser in keratosis pilaris. J Drugs Dermatol. 2018;17(5):554-556.

Dermal Microflora Restoration With Ammonia-Oxidizing Bacteria Nitrosomonas Eutropha in the Treatment of Keratosis Pilaris: A Randomized Clinical Trial.

Keratosis pilaris (KP) is a common skin finding that presents as follicular hyperkeratotic papules on the proximal extremities in patients with a propensity for atopy. Although often asymptomatic, the stippled appearance is cosmetically disturbing to patients and difficult to treat as current therapies are limited in availability and efficacy. Nitric oxide (NO) has been found to be essential in basic systemic and cutaneous physiologic function, specifically in terms of its anti-microbial and anti-inflammatory properties, which evolutionarily was maintained by ammonia-oxidizing bacteria (AOB). As modern hygiene practices have improved, there has been a gradual loss of cutaneous AOB and, therefore, the availability of an important source of human physiologic NO. We propose that restoring this dermal microflora with a purified strain of AOB, Nitrosomonas eutropha (D23), may reduce the overall cutaneous inflammatory state and, thus, be a potential therapeutic option for improving the cosmetic appearance of a skin condition such as KP which is often found in association with xerosis and atopic dermatitis. Clinical trial registry number: NCT03243617

J Drugs Dermatol. 2018;17(3):285-288.

A case of segmental Darier disease treated with doxycycline monotherapy.

Darier disease is a rare autosomal dominant disorder that results from a mutation in the gene coding for the endoplasmic reticulum membrane calcium pump Ca2+-ATPase type 2 (SERCA2), leading to compromised intercellular adhesion. Patients typically present in the first two decades of life with keratotic, greasy papules in a seborrheic distribution. Segmental Darier disease is a variant with localized disease that follows Blaschko lines. Treatment options include topical and systemic agents including corticosteroids, retinoids, and antibiotics. We present a 67-year-old woman who came to our clinic with segmental Darier disease recalcitrant to topical therapy. Owing to cost and side effect profile, the patient declined treatment with oral retinoids. Doxycycline 100mg daily was started with significant improvement. Tetracyclines both chelate and assist calcium to cross membranes. This mechanism may correct the cellular calcium imbalance present in Darier disease. In addition, tetracyclines have been shown to inhibit metalloproteinase 9, an important part of Darier disease pathogenesis. Owing to its favorable side effect profile, further investigation is warranted to establish doxycycline as a more widely utilized treatment option for Darier disease.

Acral Hemorrhagic Darier Disease. / Enfermedad de Darier acral hemorrágica.

Darier disease is an autosomal-dominant inherited condition caused by mutation of a gene, which produces a protein involved in calcium channel regulation. The disease has a variety of manifestations and lacks consistent genotype-phenotype correlations. Acral hemorrhagic Darier disease causes macules, papules, vesicles and/or hemorrhagic blisters on the extremities. Other classic signs of the disease may be present in the same patient or relatives. Histopathology reveals dyskeratosis and suprabasal acantholysis with hemorrhagic lacunae. We report 3 new cases of this type of Darier disease triggered by injuries. Response to retinoid therapy was good.

Primary cicatricial alopecia: Other lymphocytic primary cicatricial alopecias and neutrophilic and mixed primary cicatricial alopecias.

Primary cicatricial alopecias can be frustrating for both patients and physicians. Proper diagnosis guides more successful management of these challenging conditions. Part II will cover the remaining lymphocytic primary cicatricial alopecias, which include pseudopelade of Brocq, central centrifugal cicatricial alopecia, alopecia mucinosa, and keratosis follicularis spinulosa decalvans. It will also discuss the neutrophilic and mixed primary cicatricial alopecias, namely folliculitis decalvans, dissecting cellulitis, folliculitis keloidalis, folliculitis (acne) necrotica, and erosive pustular dermatosis.