RARE DISEASE
Darier disease
Darier disease
Darier disease
Synonyms: Darier-White disease, Keratosis follicularis
Synonyms: Darier-White disease, Keratosis follicularis
Synonyms: Darier-White disease, Keratosis follicularis
Drug discovery
0
drugs
With orphan designations
Overview
Darier disease is an autosomal dominant genodermatosis caused by ATP2A2 gene mutations impairing calcium transport (SERCA2), leading to keratinocyte adhesion defects. It presents with hyperkeratotic papules in seborrheic areas, nail dystrophy, and mucosal lesions, exacerbated by heat, UV exposure, and friction [1][2][5]. Chronic with relapsing-remitting course, it correlates with bacterial/viral infections and psychosocial burden [6][9][12].
Burden
Physical: Chronic skin breakdown, recurrent infections (bacterial, HSV), nail/mucosal involvement [6][9][18].
Psychosocial: Depression, anxiety, and reduced quality of life due to disfigurement and odor [1][6][12].
Economic: Frequent healthcare visits, hospitalization for severe flares/complications [6][18].
Therapies
Topical: Retinoids (tretinoin, adapalene), 5-fluorouracil, corticosteroids [4][7][10].
Systemic: Oral retinoids (acitretin, isotretinoin) for severe cases; antimicrobials for infections [4][5][10].
Emerging: MEK inhibitors (trametinib), biologics (dupilumab, tralokinumab) targeting type 2 inflammation [13][18].
Categories: rare genetic diseases, rare skin diseases
Research Papers
321 drug discovery papers about Darier disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
321 drug discovery papers about Darier disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-05 | Failed metabolic adaptation to stress contributes to epidermal cell adhesion defects in Darier disease.
Congenital pathogenic gene variants may not elicit symptoms until later in life, highlighting the importance of identifying extra-genetic factors influencing the onset and severity of heritable diseases. We explored this in Darier disease (DD or ATP2A2-nEDD), an autosomal dominant skin disorder arising from heterozygous ATP2A2 variants leading to haploinsufficiency of the endoplasmic reticulum (ER) calcium pump, SERCA2. Metabolic analysis of epidermal keratinocytes from confirmed patients with DD revealed abnormalities in the pentose phosphate pathway responsible for regenerating antioxidants like glutathione, accompanied by diminished free glutathione and increased glutathione-based, oxidative modifications of SERCA2. Induction of oxidative stress weakened intercellular adhesion, a defining characteristic of DD, which antioxidant treatment improved. Treatment with antioxidants or SERCA activators also diminished glutathionylation, consistent with SERCA2 haploinsufficiency giving rise to oxidative stress and placing residual SERCA2 at risk of oxidation. We posit that partial loss of protein activity primes cells for stress-induced loss of the remaining activity, a mechanism that may drive disease flares in other haploinsufficiencies.
2026-07-15 | Consensus Recommendations for Management of Darier Disease: A Practical Approach.
Darier disease (DD) is a rare, autosomal dominant genodermatosis caused by pathogenic variants in the ATP2A2 gene, encoding the sarco/endoplasmic reticulum calcium ATPase. DD is characterized by chronic, recurrent cutaneous lesions and variable extracutaneous manifestations, resulting in significant impairment of quality of life. Disease onset typically occurs after puberty, with environmental triggers and variable expressivity. The aim of this study was to provide practical, evidence- and consensus-based recommendations for the management of patients with DD, particularly for healthcare professionals in non-expert centers, and to highlight emerging therapeutic avenues. Recommendations were formulated on the basis of a systematic review of the literature and expert consensus from the European Reference Network for Rare and Undiagnosed Skin Disorders (ERN-Skin). Evidence from case reports, case series, and mechanistic studies was considered to provide guidance on symptomatic and advanced targeted therapies. The panel agreed on a total of 68 recommendations. Diagnosis is primarily clinical, supported by family history, histopathology, cytodiagnosis, and, whenever possible, ATP2A2 genetic testing. Genetic counseling should be offered to patients and at-risk relatives. First-line management entails trigger avoidance, skin care using topical antiseptics, emollients, and anti-inflammatory agents, alongside symptomatic control. Topical treatments include corticosteroids, retinoids, and calcineurin inhibitors; systemic therapies (oral retinoids, immunomodulators) are indicated for moderate-to-severe or refractory disease. Physical treatments (ablative lasers, cryotherapy, photodynamic therapy) are reserved for localized treatment-resistant lesions. Targeted therapies (JAK/IL-17/IL-23/IL-4-13/MEK inhibitors), and topical gene therapy, are under evaluation or development. Multidisciplinary management is recommended (neuropsychiatric, ocular, dental, and obstetric). Long-term outcomes remain limited, and durable remission is currently unattainable; treatments must be individualized. DD is a chronic, genetic disorder that significantly impairs quality of life. These practical recommendations provide a framework for diagnosis, management, and follow-up, and highlight the need for clinical trials, registries, and biomarker-driven research to advance therapeutic strategies and explore novel, mechanism-based treatments.
2026-06-23 | P01 Modulation of the µ-opioid pathway for the treatment of pruritus: a systematic review of 1146 patients across dermatological and systemic conditions
Abstract Introduction and aims Pruritus is a debilitating symptom across dermatological and systemic diseases, and conventional therapies often provide incomplete relief. The µ-opioid receptor pathway is a key regulator of itch. A range of µ-pathway-modulating agents are used off-label for refractory pruritus. This review aimed to systematically evaluate the efficacy, safety, and real-world use of µ-opioid pathway modulators for pruritus of dermatological and systemic origin. Methods We conducted a systematic review following PRISMA guidelines (PROSPERO CRD420251207101), with a comprehensive search of four databases. Results were narratively synthesized owing to heterogeneity. Results Of 3274 records identified, 69 studies met inclusion criteria: 14 randomized controlled trials (RCTs) (n = 795) and 55 nonrandomized studies (n = 351). Five RCTs evaluated dermatological conditions (atopic dermatitis, prurigo nodularis, chronic urticaria, and lichen planopilaris), while 9 RCTs evaluated systemic pruritus, predominantly cholestatic pruritus and uraemic pruritus. RCTs (1980–2023) assessed oral or topical naltrexone, intravenous naloxone, nalmefene and nalbuphine extended release. Most RCTs demonstrated clinically meaningful reductions in pruritus severity, measured using validated itch scales [visual analogue scale, numeric rating scale (NRS) or worst itch NRS], with the strongest evidence observed in atopic dermatitis, cholestatic pruritus, and uraemic pruritus. Nonrandomized studies (1979–2024) included 199 dermatological and 152 systemic cases, reporting improvement across conditions such as Hailey–Hailey disease, Darier disease, psoriasis, dermatomyositis, chronic pruritus, postburn pruritus, systemic sclerosis and cholestatic disease. Adverse events were mostly mild and tolerated. Conclusions µ-Opioid pathway modulators demonstrate promising efficacy with acceptable short-term safety across a broad spectrum of pruritic conditions. Evidence from randomized trials is strongest for naltrexone and nalmefene in cholestatic pruritus, naltrexone in atopic dermatitis and chronic urticaria, and nalbuphine in uraemic pruritus. In addition, signals of benefit from nonrandomized and real-world studies suggest potential utility across a wider range of dermatological and systemic conditions. Larger, high-quality RCTs are needed to define optimal dosing and support further clinical translation.
2026-06-23 | SERCA2b loss of function drives pigmentation by inducing adaptive ER stress and enhancing mitochondrial calcium uptake: significance in pathological hyperpigmentation associated with Darier’s Disease
Abstract Pigmentation is a critical protective mechanism that safeguards the skin against UV-induced damage, whereas dysregulated pigmentation predisposes to pigmentary disorders and skin malignancies. Although calcium signaling has emerged as an important regulator of melanogenesis, the identity of the calcium-handling proteins and the molecular mechanisms linking calcium dynamics to pigmentation remain poorly understood. Here, we identify the ER calcium pump SERCA2b as a negative regulator of pigmentation through modulation of ER stress and mitochondrial calcium uptake. We demonstrate that SERCA2b expression inversely correlates with pigmentation levels, and gain- and loss-of-function studies establish SERCA2b as a suppressor of melanogenesis. Mechanistically, SERCA2b depletion induces adaptive ER stress, enhances ER–mitochondrial proximity, and promotes mitochondrial calcium uptake. Notably, mutations in SERCA2b are associated with Darier disease, a condition characterized by hyperpigmented skin lesions, although the underlying mechanism remains unknown. To address this, we generated SERCA2b mutants corresponding to variants identified in Indian Darier’s disease patients and examined their effects on pigmentation, ER stress, and mitochondrial calcium dynamics. The mutant phenotypes closely recapitulated SERCA2b loss-of-function effects, demonstrating that adaptive ER stress and enhanced mitochondrial calcium signaling underlie hyperpigmentation associated with Darier’s disease. Importantly, treatment with 4-phenylbutyrate (4-PBA), an FDA-approved ER stress alleviator, rescued mutant-induced hyperpigmentation, reduced ER stress, and normalized mitochondrial calcium uptake. Collectively, our findings uncover a previously unrecognized role of SERCA2b in skin pigmentation, establish a mechanistic link between SERCA2b mutations and hyperpigmentation, and identify adaptive ER stress pathways as potential therapeutic target for pigmentary disorders.
2026-05-27 | Computational dissection of sarco/endoplasmic reticulum Ca²⁺-ATPase 2b C-Terminal extension autoinhibition and its therapeutic potential in Darier's disease.
The sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) maintains cellular calcium homeostasis by pumping Ca²⁺ from the cytoplasm into the endoplasmic reticulum. Among SERCA isoforms, SERCA2b is unique in possessing a C-terminal extension (CTE) composed of loop L10/11, transmembrane helix M11, and a luminal extension (LE). The CTE inhibits activity, but the mechanism remains unclear because the L10/11 structure is unresolved. Based on SERCA2b cryo-EM structures, we used integrative structural modeling and molecular dynamics simulations to show that L10/11 contains a short helix (Helix1003) that docks into a native cleft formed by loops L6/7 and L8/9 at the pump neck and remains engaged across transport intermediates. This interaction stabilizes specific conformations and slows transitions required for Ca²⁺ transport through a dual "pull-and-block" mechanism. When Helix1003 docking is disrupted by mutation, the helix unwinds, and the L10/11 segment instead engages the phosphorylation (P) domain. These interactions impede the P-domain tilting motion required for effective Ca²⁺ transport. This mechanistic shift explains several previously unresolved experimental observations for SERCA2b. We further show that the LE anchors M11, stabilizing L10/11 so that Helix1003 wedges between L6/7 and L8/9, restricts central-core tilting, and hinders conformational transitions throughout the transport cycle, defining elements of a CTE-mediated autoinhibitory mechanism. Finally, our findings suggest that relieving CTE-mediated autoinhibition may offer a therapeutic strategy for ATP2A2-linked Darier's disease. Together, this work defines the structural basis of SERCA2b CTE autoinhibition and identifies the L10/11 and L6/7-L8/9 cleft as promising therapeutic targets.
cell therapies
2022-03-01 | The Potential of CRISPR-Guided Therapies in the Dermatology Clinic
Over the past decade, CRISPR has rapidly made its way from the bench to the bedside, providing a newfound therapeutic avenue to not only treat genetic diseases but also permanently cure them. Although there are several clinical trials in early stages, there are so far no CRISPR-based clinical trials for cutaneous disease. In this review, we describe multiple cutaneous diseases that represent ideal targets for CRISPR-based therapeutics owing to known single gene‒causing mutations. We also explore the potential of CRISPR nucleases to treat inflammatory disorders such as eczema and psoriasis, which are not classically categorized as genodermatoses. We describe the therapeutic solutions for these diseases that are guided by various CRISPR-associated (Cas) effector proteins, for example, using Cas9 to permanently edit the DNA of somatic cells, Cas3 to target foreign DNA to combat viral/bacterial skin infections, and Cas13 to edit mutated RNA transcripts in diseases where permanent DNA editing is untenable. Furthermore, we discuss various drug delivery modalities for CRISPR therapeutics, including transdermal patches and microneedles, which are uniquely suited for dermatological diseases. In summary, we highlight the potential of CRISPR-based therapeutics to revolutionize the treatment of cutaneous disease with a goal of being accessible to the practicing dermatologist. Over the past decade, CRISPR has rapidly made its way from the bench to the bedside, providing a newfound therapeutic avenue to not only treat genetic diseases but also permanently cure them. Although there are several clinical trials in early stages, there are so far no CRISPR-based clinical trials for cutaneous disease. In this review, we describe multiple cutaneous diseases that represent ideal targets for CRISPR-based therapeutics owing to known single gene‒causing mutations. We also explore the potential of CRISPR nucleases to treat inflammatory disorders such as eczema and psoriasis, which are not classically categorized as genodermatoses. We describe the therapeutic solutions for these diseases that are guided by various CRISPR-associated (Cas) effector proteins, for example, using Cas9 to permanently edit the DNA of somatic cells, Cas3 to target foreign DNA to combat viral/bacterial skin infections, and Cas13 to edit mutated RNA transcripts in diseases where permanent DNA editing is untenable. Furthermore, we discuss various drug delivery modalities for CRISPR therapeutics, including transdermal patches and microneedles, which are uniquely suited for dermatological diseases. In summary, we highlight the potential of CRISPR-based therapeutics to revolutionize the treatment of cutaneous disease with a goal of being accessible to the practicing dermatologist.
2018-06-28 | Preliminary observations of a new approach to tissue repair: Peripheral blood mononuclear cells in platelet-rich plasma injected into skin graft area
Abstract Our purpose was accelerating the physiologic wound healing, stimulating tissue regeneration and the reparative tissue processes in resistant skin ulcers as in a case of an erosive lichen planus of the soles and after a surgical treatment as for severe Darier disease. The challenge was to establish an effective therapy to enhance tissue healing by the injection of a mixture of peripheral blood mononuclear cells (PB‐MNCs) and platelet‐rich plasma (PRP) into a skin autograft area. This new perioperative biotechnological approach enriches PRP with the effects of PB‐MNCs. It offers a novel advanced strategy that could become an ideal biologic blood‐derived therapy, whose components are entirely autologous and produced by a protocol independent by the operator.
1999-03-01 | Management of Darier's disease
Darier's disease is an uncommon inherited cutaneous disease which is difficult to manage, especially in adolescence. The warty keratotic papules irritate, smell and look unsightly. Histologically, the condition is characterized by the presence of focal acantholytic dyskeratosis. Treatment is unsatisfactory, particularly in patients with erosive flexural disease, but retinoids reduce the hyperkeratosis. Now the mutation causing Darier's disease has been identified, there is a real possibility of more effective treatment in the future.
1994-11-01 | Genetically Modified Skin to Treat Disease: Potential and Limitations
Molecular definition of disease at the level of the gene and advances in recombinant DNA technology suggest that many diseases are amenable to correction by genes not bearing the defective elements that result in disease. Many questions must be answered before this therapy can be used to correct chronic diseases. These questions fall into safety and efficacy categories. Experience with transplanting cellular elements of skin or skin substitutes (defined as skin that possess the cell types and a dermal structure to develop into a functioning skin) to athymic rodents is considerable and is seen as a system where these questions can be answered. This paper reviews these questions and presents our early analysis of genetically modified cells in skin substitutes in vivo and in vitro. Experimental data demonstrate that both a matrix of woven nylon, housing a fibroblast generated collage, and dead dermis can be utilized to shuttle genetically modified human fibroblasts from the laboratory to an in vivo setting. Genetically modified fibroblasts do not migrate from the shuttle to the surrounding tissue. The survival of significant numbers, approximately 70%, of genetically modified fibroblasts for at least 6 weeks in these shuttles, supports this general approach as having clinical utility. It is also concluded that skin substitute systems can be used to generate a genetically modified skin in vitro that has the capacity to develop into functional skin in vivo. Further, as genetically modified keratinocytes differentiate there is increased production by the transgene, supporting the concept that keratinocytes have true potential as shuttles for therapeutic genes. This work demonstrates that transplantation of systems containing genetically modified cells of the skin can be used to experimentally define many aspects of gene therapy using skin before this technology is taken to the clinic. Examples include determining the effect of gene transduction and expression on structure and function of the genetically modified skin as well as on distant skin and an assessment of the translational capacity of the transgene as function of time and cell number.
antibodies
2026-08-01 | Secukinumab in Refractory Generalized Darier’s Disease with a 40-Year Disease Duration: A Case Report
Objective: To report a rare case of refractory generalized Darier’s disease (DD), also known as keratosis follicularis, with a disease duration exceeding 40 years and to explore the therapeutic effect of the interleukin-17A inhibitor secukinumab. Methods: Clinical data were collected. Skin histopathological examination was performed using hematoxylin-eosin (HE) staining, and ATP2A2 gene mutation testing was conducted via whole-exome high-throughput sequencing. The patient was treated with secukinumab. The patient received subcutaneous secukinumab 300 mg once weekly for the first 5 weeks (loading phase), followed by 300 mg every 4 weeks as maintenance therapy. Results: The patient presented with generalized hyperpigmentation, widespread keratotic papules and plaques, some with an oyster-shell appearance, covered with greasy crusts. Histopathology examination further revealed characteristic suprabasal clefts, acantholysis, and dyskeratotic cells (corps ronds and grains). Genetic testing subsequently identified a heterozygous c.479C>T (p.P160L) mutation in the ATP2A2 gene. Following 9 months of secukinumab treatment, the patient experienced partial improvement in pruritus and skin lesions. Conclusion: This case represents a severe form of generalized Darier’s disease with well-defined clinical, pathological, and genetic features. Secukinumab treatment suggested partial clinical improvement, although complete clearance was not achieved. However, the patient discontinued treatment due to financial constraints, and long-term follow-up data are lacking, warranting further investigation. This report provides preliminary experience with biologic therapy for this condition, and the findings require confirmation through controlled studies. Keywords: Darier’s disease, keratosis follicularis, ATP2A2 gene, IL-17A inhibitor, secukinumab, case report, biologic therapy
2026-07-14 | Dupilumab Add‐On Therapy in Severe Refractory Darier Disease
The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2026-06-10 | Effect of Anti-IL-23 and Anti-IL-17 Therapy on Darier Disease: A Case Series.
Darier disease is a rare ATP2A2-related genodermatosis for which therapeutic options remain limited, as acitretin is often constrained by toxicity and teratogenicity. In this retrospective real-world case series of eight patients, anti-IL-17 therapy showed a more consistent early signal of clinical benefit than anti-IL-23 therapy, with greater improvement in disease severity and patient-reported outcomes and no reported adverse events. Although limited by the small sample size and attrition over time, these findings support further prospective evaluation of biologic therapies in Darier disease.
2026-04-23 | Markedly improved disease control in Darier disease ( ATP2A2 -nonsyndromic epidermal differentiation disorder) with ustekinumab versus other biologics: a case series
Abstract In this case series, we report six patients with severe, treatment-refractory Darier disease, or dyskeratosis follicularis, also known as ATP2A2-nEDD (nonsyndromic epidermal differentiation disorder), treated with off-label biologic therapy, including dupilumab (n = 3), secukinumab followed by guselkumab (n = 1), and ustekinumab (n = 2). All patients had longstanding disease with recurrent flares, frequent infections and substantial impairment of quality of life, despite multiple conventional treatments. All biologic treatments were well tolerated, with no serious adverse events. Dupilumab consistently improved pruritus but had limited effects on skin lesions. Secukinumab and guselkumab provided only transient or partial disease control. In contrast, both patients treated with ustekinumab achieved pronounced and sustained clinical improvement, with markedly reduced disease severity and pruritus, and considerable improved quality of life. The pronounced and sustained responses observed with ustekinumab support its prioritization for future studies in Darier disease.
2026-02-06 | Interleukin (IL)-17A Inhibitor as a Treatment for Darier Disease in the Pediatric Population.
Darier disease is a genodermatosis that significantly affects patients' quality of life. We present the case of a 16-year-old patient whose quality of life remained markedly impaired despite systemic treatment. The patient experienced substantial clinical improvement in cutaneous lesions and quality of life following treatment with an interleukin (IL)-17A inhibitor. IL-17A inhibitors have demonstrated benefit in adults with Darier disease. In this case, we also observed therapeutic efficacy in a pediatric patient, supporting the relevance of this treatment approach in younger individuals. IL-17A inhibitors may play an important role in the management of Darier disease and represent a promising therapeutic option for pediatric patients, particularly in cases refractory to conventional therapies.
small molecules
2026-08-05 | Failed metabolic adaptation to stress contributes to epidermal cell adhesion defects in Darier disease.
Congenital pathogenic gene variants may not elicit symptoms until later in life, highlighting the importance of identifying extra-genetic factors influencing the onset and severity of heritable diseases. We explored this in Darier disease (DD or ATP2A2-nEDD), an autosomal dominant skin disorder arising from heterozygous ATP2A2 variants leading to haploinsufficiency of the endoplasmic reticulum (ER) calcium pump, SERCA2. Metabolic analysis of epidermal keratinocytes from confirmed patients with DD revealed abnormalities in the pentose phosphate pathway responsible for regenerating antioxidants like glutathione, accompanied by diminished free glutathione and increased glutathione-based, oxidative modifications of SERCA2. Induction of oxidative stress weakened intercellular adhesion, a defining characteristic of DD, which antioxidant treatment improved. Treatment with antioxidants or SERCA activators also diminished glutathionylation, consistent with SERCA2 haploinsufficiency giving rise to oxidative stress and placing residual SERCA2 at risk of oxidation. We posit that partial loss of protein activity primes cells for stress-induced loss of the remaining activity, a mechanism that may drive disease flares in other haploinsufficiencies.
2026-07-15 | Consensus Recommendations for Management of Darier Disease: A Practical Approach.
Darier disease (DD) is a rare, autosomal dominant genodermatosis caused by pathogenic variants in the ATP2A2 gene, encoding the sarco/endoplasmic reticulum calcium ATPase. DD is characterized by chronic, recurrent cutaneous lesions and variable extracutaneous manifestations, resulting in significant impairment of quality of life. Disease onset typically occurs after puberty, with environmental triggers and variable expressivity. The aim of this study was to provide practical, evidence- and consensus-based recommendations for the management of patients with DD, particularly for healthcare professionals in non-expert centers, and to highlight emerging therapeutic avenues. Recommendations were formulated on the basis of a systematic review of the literature and expert consensus from the European Reference Network for Rare and Undiagnosed Skin Disorders (ERN-Skin). Evidence from case reports, case series, and mechanistic studies was considered to provide guidance on symptomatic and advanced targeted therapies. The panel agreed on a total of 68 recommendations. Diagnosis is primarily clinical, supported by family history, histopathology, cytodiagnosis, and, whenever possible, ATP2A2 genetic testing. Genetic counseling should be offered to patients and at-risk relatives. First-line management entails trigger avoidance, skin care using topical antiseptics, emollients, and anti-inflammatory agents, alongside symptomatic control. Topical treatments include corticosteroids, retinoids, and calcineurin inhibitors; systemic therapies (oral retinoids, immunomodulators) are indicated for moderate-to-severe or refractory disease. Physical treatments (ablative lasers, cryotherapy, photodynamic therapy) are reserved for localized treatment-resistant lesions. Targeted therapies (JAK/IL-17/IL-23/IL-4-13/MEK inhibitors), and topical gene therapy, are under evaluation or development. Multidisciplinary management is recommended (neuropsychiatric, ocular, dental, and obstetric). Long-term outcomes remain limited, and durable remission is currently unattainable; treatments must be individualized. DD is a chronic, genetic disorder that significantly impairs quality of life. These practical recommendations provide a framework for diagnosis, management, and follow-up, and highlight the need for clinical trials, registries, and biomarker-driven research to advance therapeutic strategies and explore novel, mechanism-based treatments.
2026-06-23 | P01 Modulation of the µ-opioid pathway for the treatment of pruritus: a systematic review of 1146 patients across dermatological and systemic conditions
Abstract Introduction and aims Pruritus is a debilitating symptom across dermatological and systemic diseases, and conventional therapies often provide incomplete relief. The µ-opioid receptor pathway is a key regulator of itch. A range of µ-pathway-modulating agents are used off-label for refractory pruritus. This review aimed to systematically evaluate the efficacy, safety, and real-world use of µ-opioid pathway modulators for pruritus of dermatological and systemic origin. Methods We conducted a systematic review following PRISMA guidelines (PROSPERO CRD420251207101), with a comprehensive search of four databases. Results were narratively synthesized owing to heterogeneity. Results Of 3274 records identified, 69 studies met inclusion criteria: 14 randomized controlled trials (RCTs) (n = 795) and 55 nonrandomized studies (n = 351). Five RCTs evaluated dermatological conditions (atopic dermatitis, prurigo nodularis, chronic urticaria, and lichen planopilaris), while 9 RCTs evaluated systemic pruritus, predominantly cholestatic pruritus and uraemic pruritus. RCTs (1980–2023) assessed oral or topical naltrexone, intravenous naloxone, nalmefene and nalbuphine extended release. Most RCTs demonstrated clinically meaningful reductions in pruritus severity, measured using validated itch scales [visual analogue scale, numeric rating scale (NRS) or worst itch NRS], with the strongest evidence observed in atopic dermatitis, cholestatic pruritus, and uraemic pruritus. Nonrandomized studies (1979–2024) included 199 dermatological and 152 systemic cases, reporting improvement across conditions such as Hailey–Hailey disease, Darier disease, psoriasis, dermatomyositis, chronic pruritus, postburn pruritus, systemic sclerosis and cholestatic disease. Adverse events were mostly mild and tolerated. Conclusions µ-Opioid pathway modulators demonstrate promising efficacy with acceptable short-term safety across a broad spectrum of pruritic conditions. Evidence from randomized trials is strongest for naltrexone and nalmefene in cholestatic pruritus, naltrexone in atopic dermatitis and chronic urticaria, and nalbuphine in uraemic pruritus. In addition, signals of benefit from nonrandomized and real-world studies suggest potential utility across a wider range of dermatological and systemic conditions. Larger, high-quality RCTs are needed to define optimal dosing and support further clinical translation.
2026-06-23 | SERCA2b loss of function drives pigmentation by inducing adaptive ER stress and enhancing mitochondrial calcium uptake: significance in pathological hyperpigmentation associated with Darier’s Disease
Abstract Pigmentation is a critical protective mechanism that safeguards the skin against UV-induced damage, whereas dysregulated pigmentation predisposes to pigmentary disorders and skin malignancies. Although calcium signaling has emerged as an important regulator of melanogenesis, the identity of the calcium-handling proteins and the molecular mechanisms linking calcium dynamics to pigmentation remain poorly understood. Here, we identify the ER calcium pump SERCA2b as a negative regulator of pigmentation through modulation of ER stress and mitochondrial calcium uptake. We demonstrate that SERCA2b expression inversely correlates with pigmentation levels, and gain- and loss-of-function studies establish SERCA2b as a suppressor of melanogenesis. Mechanistically, SERCA2b depletion induces adaptive ER stress, enhances ER–mitochondrial proximity, and promotes mitochondrial calcium uptake. Notably, mutations in SERCA2b are associated with Darier disease, a condition characterized by hyperpigmented skin lesions, although the underlying mechanism remains unknown. To address this, we generated SERCA2b mutants corresponding to variants identified in Indian Darier’s disease patients and examined their effects on pigmentation, ER stress, and mitochondrial calcium dynamics. The mutant phenotypes closely recapitulated SERCA2b loss-of-function effects, demonstrating that adaptive ER stress and enhanced mitochondrial calcium signaling underlie hyperpigmentation associated with Darier’s disease. Importantly, treatment with 4-phenylbutyrate (4-PBA), an FDA-approved ER stress alleviator, rescued mutant-induced hyperpigmentation, reduced ER stress, and normalized mitochondrial calcium uptake. Collectively, our findings uncover a previously unrecognized role of SERCA2b in skin pigmentation, establish a mechanistic link between SERCA2b mutations and hyperpigmentation, and identify adaptive ER stress pathways as potential therapeutic target for pigmentary disorders.
2026-05-27 | Computational dissection of sarco/endoplasmic reticulum Ca²⁺-ATPase 2b C-Terminal extension autoinhibition and its therapeutic potential in Darier's disease.
The sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) maintains cellular calcium homeostasis by pumping Ca²⁺ from the cytoplasm into the endoplasmic reticulum. Among SERCA isoforms, SERCA2b is unique in possessing a C-terminal extension (CTE) composed of loop L10/11, transmembrane helix M11, and a luminal extension (LE). The CTE inhibits activity, but the mechanism remains unclear because the L10/11 structure is unresolved. Based on SERCA2b cryo-EM structures, we used integrative structural modeling and molecular dynamics simulations to show that L10/11 contains a short helix (Helix1003) that docks into a native cleft formed by loops L6/7 and L8/9 at the pump neck and remains engaged across transport intermediates. This interaction stabilizes specific conformations and slows transitions required for Ca²⁺ transport through a dual "pull-and-block" mechanism. When Helix1003 docking is disrupted by mutation, the helix unwinds, and the L10/11 segment instead engages the phosphorylation (P) domain. These interactions impede the P-domain tilting motion required for effective Ca²⁺ transport. This mechanistic shift explains several previously unresolved experimental observations for SERCA2b. We further show that the LE anchors M11, stabilizing L10/11 so that Helix1003 wedges between L6/7 and L8/9, restricts central-core tilting, and hinders conformational transitions throughout the transport cycle, defining elements of a CTE-mediated autoinhibitory mechanism. Finally, our findings suggest that relieving CTE-mediated autoinhibition may offer a therapeutic strategy for ATP2A2-linked Darier's disease. Together, this work defines the structural basis of SERCA2b CTE autoinhibition and identifies the L10/11 and L6/7-L8/9 cleft as promising therapeutic targets.
cell therapies
2022-03-01 | The Potential of CRISPR-Guided Therapies in the Dermatology Clinic
Over the past decade, CRISPR has rapidly made its way from the bench to the bedside, providing a newfound therapeutic avenue to not only treat genetic diseases but also permanently cure them. Although there are several clinical trials in early stages, there are so far no CRISPR-based clinical trials for cutaneous disease. In this review, we describe multiple cutaneous diseases that represent ideal targets for CRISPR-based therapeutics owing to known single gene‒causing mutations. We also explore the potential of CRISPR nucleases to treat inflammatory disorders such as eczema and psoriasis, which are not classically categorized as genodermatoses. We describe the therapeutic solutions for these diseases that are guided by various CRISPR-associated (Cas) effector proteins, for example, using Cas9 to permanently edit the DNA of somatic cells, Cas3 to target foreign DNA to combat viral/bacterial skin infections, and Cas13 to edit mutated RNA transcripts in diseases where permanent DNA editing is untenable. Furthermore, we discuss various drug delivery modalities for CRISPR therapeutics, including transdermal patches and microneedles, which are uniquely suited for dermatological diseases. In summary, we highlight the potential of CRISPR-based therapeutics to revolutionize the treatment of cutaneous disease with a goal of being accessible to the practicing dermatologist. Over the past decade, CRISPR has rapidly made its way from the bench to the bedside, providing a newfound therapeutic avenue to not only treat genetic diseases but also permanently cure them. Although there are several clinical trials in early stages, there are so far no CRISPR-based clinical trials for cutaneous disease. In this review, we describe multiple cutaneous diseases that represent ideal targets for CRISPR-based therapeutics owing to known single gene‒causing mutations. We also explore the potential of CRISPR nucleases to treat inflammatory disorders such as eczema and psoriasis, which are not classically categorized as genodermatoses. We describe the therapeutic solutions for these diseases that are guided by various CRISPR-associated (Cas) effector proteins, for example, using Cas9 to permanently edit the DNA of somatic cells, Cas3 to target foreign DNA to combat viral/bacterial skin infections, and Cas13 to edit mutated RNA transcripts in diseases where permanent DNA editing is untenable. Furthermore, we discuss various drug delivery modalities for CRISPR therapeutics, including transdermal patches and microneedles, which are uniquely suited for dermatological diseases. In summary, we highlight the potential of CRISPR-based therapeutics to revolutionize the treatment of cutaneous disease with a goal of being accessible to the practicing dermatologist.
2018-06-28 | Preliminary observations of a new approach to tissue repair: Peripheral blood mononuclear cells in platelet-rich plasma injected into skin graft area
Abstract Our purpose was accelerating the physiologic wound healing, stimulating tissue regeneration and the reparative tissue processes in resistant skin ulcers as in a case of an erosive lichen planus of the soles and after a surgical treatment as for severe Darier disease. The challenge was to establish an effective therapy to enhance tissue healing by the injection of a mixture of peripheral blood mononuclear cells (PB‐MNCs) and platelet‐rich plasma (PRP) into a skin autograft area. This new perioperative biotechnological approach enriches PRP with the effects of PB‐MNCs. It offers a novel advanced strategy that could become an ideal biologic blood‐derived therapy, whose components are entirely autologous and produced by a protocol independent by the operator.
1999-03-01 | Management of Darier's disease
Darier's disease is an uncommon inherited cutaneous disease which is difficult to manage, especially in adolescence. The warty keratotic papules irritate, smell and look unsightly. Histologically, the condition is characterized by the presence of focal acantholytic dyskeratosis. Treatment is unsatisfactory, particularly in patients with erosive flexural disease, but retinoids reduce the hyperkeratosis. Now the mutation causing Darier's disease has been identified, there is a real possibility of more effective treatment in the future.
1994-11-01 | Genetically Modified Skin to Treat Disease: Potential and Limitations
Molecular definition of disease at the level of the gene and advances in recombinant DNA technology suggest that many diseases are amenable to correction by genes not bearing the defective elements that result in disease. Many questions must be answered before this therapy can be used to correct chronic diseases. These questions fall into safety and efficacy categories. Experience with transplanting cellular elements of skin or skin substitutes (defined as skin that possess the cell types and a dermal structure to develop into a functioning skin) to athymic rodents is considerable and is seen as a system where these questions can be answered. This paper reviews these questions and presents our early analysis of genetically modified cells in skin substitutes in vivo and in vitro. Experimental data demonstrate that both a matrix of woven nylon, housing a fibroblast generated collage, and dead dermis can be utilized to shuttle genetically modified human fibroblasts from the laboratory to an in vivo setting. Genetically modified fibroblasts do not migrate from the shuttle to the surrounding tissue. The survival of significant numbers, approximately 70%, of genetically modified fibroblasts for at least 6 weeks in these shuttles, supports this general approach as having clinical utility. It is also concluded that skin substitute systems can be used to generate a genetically modified skin in vitro that has the capacity to develop into functional skin in vivo. Further, as genetically modified keratinocytes differentiate there is increased production by the transgene, supporting the concept that keratinocytes have true potential as shuttles for therapeutic genes. This work demonstrates that transplantation of systems containing genetically modified cells of the skin can be used to experimentally define many aspects of gene therapy using skin before this technology is taken to the clinic. Examples include determining the effect of gene transduction and expression on structure and function of the genetically modified skin as well as on distant skin and an assessment of the translational capacity of the transgene as function of time and cell number.
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2026-08-01 | Secukinumab in Refractory Generalized Darier’s Disease with a 40-Year Disease Duration: A Case Report
Objective: To report a rare case of refractory generalized Darier’s disease (DD), also known as keratosis follicularis, with a disease duration exceeding 40 years and to explore the therapeutic effect of the interleukin-17A inhibitor secukinumab. Methods: Clinical data were collected. Skin histopathological examination was performed using hematoxylin-eosin (HE) staining, and ATP2A2 gene mutation testing was conducted via whole-exome high-throughput sequencing. The patient was treated with secukinumab. The patient received subcutaneous secukinumab 300 mg once weekly for the first 5 weeks (loading phase), followed by 300 mg every 4 weeks as maintenance therapy. Results: The patient presented with generalized hyperpigmentation, widespread keratotic papules and plaques, some with an oyster-shell appearance, covered with greasy crusts. Histopathology examination further revealed characteristic suprabasal clefts, acantholysis, and dyskeratotic cells (corps ronds and grains). Genetic testing subsequently identified a heterozygous c.479C>T (p.P160L) mutation in the ATP2A2 gene. Following 9 months of secukinumab treatment, the patient experienced partial improvement in pruritus and skin lesions. Conclusion: This case represents a severe form of generalized Darier’s disease with well-defined clinical, pathological, and genetic features. Secukinumab treatment suggested partial clinical improvement, although complete clearance was not achieved. However, the patient discontinued treatment due to financial constraints, and long-term follow-up data are lacking, warranting further investigation. This report provides preliminary experience with biologic therapy for this condition, and the findings require confirmation through controlled studies. Keywords: Darier’s disease, keratosis follicularis, ATP2A2 gene, IL-17A inhibitor, secukinumab, case report, biologic therapy
2026-07-14 | Dupilumab Add‐On Therapy in Severe Refractory Darier Disease
The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2026-06-10 | Effect of Anti-IL-23 and Anti-IL-17 Therapy on Darier Disease: A Case Series.
Darier disease is a rare ATP2A2-related genodermatosis for which therapeutic options remain limited, as acitretin is often constrained by toxicity and teratogenicity. In this retrospective real-world case series of eight patients, anti-IL-17 therapy showed a more consistent early signal of clinical benefit than anti-IL-23 therapy, with greater improvement in disease severity and patient-reported outcomes and no reported adverse events. Although limited by the small sample size and attrition over time, these findings support further prospective evaluation of biologic therapies in Darier disease.
2026-04-23 | Markedly improved disease control in Darier disease ( ATP2A2 -nonsyndromic epidermal differentiation disorder) with ustekinumab versus other biologics: a case series
Abstract In this case series, we report six patients with severe, treatment-refractory Darier disease, or dyskeratosis follicularis, also known as ATP2A2-nEDD (nonsyndromic epidermal differentiation disorder), treated with off-label biologic therapy, including dupilumab (n = 3), secukinumab followed by guselkumab (n = 1), and ustekinumab (n = 2). All patients had longstanding disease with recurrent flares, frequent infections and substantial impairment of quality of life, despite multiple conventional treatments. All biologic treatments were well tolerated, with no serious adverse events. Dupilumab consistently improved pruritus but had limited effects on skin lesions. Secukinumab and guselkumab provided only transient or partial disease control. In contrast, both patients treated with ustekinumab achieved pronounced and sustained clinical improvement, with markedly reduced disease severity and pruritus, and considerable improved quality of life. The pronounced and sustained responses observed with ustekinumab support its prioritization for future studies in Darier disease.
2026-02-06 | Interleukin (IL)-17A Inhibitor as a Treatment for Darier Disease in the Pediatric Population.
Darier disease is a genodermatosis that significantly affects patients' quality of life. We present the case of a 16-year-old patient whose quality of life remained markedly impaired despite systemic treatment. The patient experienced substantial clinical improvement in cutaneous lesions and quality of life following treatment with an interleukin (IL)-17A inhibitor. IL-17A inhibitors have demonstrated benefit in adults with Darier disease. In this case, we also observed therapeutic efficacy in a pediatric patient, supporting the relevance of this treatment approach in younger individuals. IL-17A inhibitors may play an important role in the management of Darier disease and represent a promising therapeutic option for pediatric patients, particularly in cases refractory to conventional therapies.
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