Secukinumab in Refractory Generalized Darier’s Disease with a 40-Year Disease Duration: A Case Report

Abstract

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.

Introduction

Darier’s disease (DD), also known as keratosis follicularis, is a rare autosomal dominant genodermatosis characterized by dyskeratosis. It typically affects seborrheic areas (scalp, forehead, chest, back, postauricular regions) with keratotic papules that may coalesce into verrucous plaques, often covered with greasy crusts. Nail changes are the initial presenting symptom in 20% of patients.¹ The estimated prevalence ranges from 1:30,000 to 1:100,000, with no gender predilection.^2,3 Lesions are frequently associated with pruritus, burning, or pain, significantly impairing quality of life.⁴ Factors such as summer heat, UV exposure, friction, sweating, and psychological stress can trigger or exacerbate the condition.⁵ According to the review,⁶ Darier disease is classified into classical lesions (keratotic papules, pits, wart-like lesions, mucosal cobblestoning, and nail abnormalities) and non-classical lesions (acral keratoderma, leukodermic macules, giant comedones, keloid-like vegetations, and acral hemorrhagic blisters). Patients with severe Darier disease demonstrated a tenfold higher risk of genital involvement relative to mild cases (P = 0.01). The hallmark histopathological features include suprabasal acantholysis forming clefts and the presence of distinctive dyskeratotic cells (corps ronds and grains).⁷ Over 320 familial and sporadic mutations in the ATP2A2 gene have been identified, scattered throughout the gene, with no clear genotype-phenotype correlation established.³ Mutations in ATP2A2 lead to dysfunction of sarco/endoplasmic reticulum Ca²⁺-ATPase type 2 (SERCA2), impairing keratinocyte adhesion and differentiation, which underlies the characteristic dyskeratosis and acantholysis in DD.

Treatment modalities primarily include oral retinoids, systemic therapies (eg, antibiotics, immunomodulators), topical agents (eg, retinoids, corticosteroids), and physical therapies (eg, laser, photodynamic therapy). However, efficacy remains suboptimal for some patients with severe disease.³ For generalized cases, therapeutic challenges are prominent due to a chronic relapsing course, epidermal barrier defects, and Th17-mediated inflammation, which predispose patients to severe superinfections, while current therapies remain largely symptomatic with unsatisfactory long-term outcomes.⁶ Recent studies have identified aberrant activation of the Th17 cell pathway and the IL-17/IL-23 axis in DD lesions, with IL-17A being a key pro-inflammatory cytokine driving local inflammation. Case series have demonstrated clinical improvement with monoclonal antibodies targeting IL-17 or IL-23, suggesting new potential therapeutic targets.^8,9 In patients with extensive skin involvement and refractory disease, targeting the IL-23/IL-17 axis with monoclonal antibodies represents a feasible therapeutic strategy. Ettinger et al demonstrated that the IL-23/IL-17 axis is markedly upregulated in the inflamed skin of Darier disease patients, and targeting this pathway with monoclonal antibodies (guselkumab or secukinumab) represents an effective and safe therapeutic strategy for treatment-refractory cases.⁸ Di Domizio et al demonstrated that Darier’s disease exhibits a dominant Th17 immune module, characterized by a prominent IL-17A signaling signature. This molecular profiling provides a mechanistic rationale for targeting the IL-17/IL-23 axis in the treatment of Darier’s disease, although variable therapeutic responses have been observed, potentially due to compensatory inflammatory pathways.¹⁰ Barajas Mendez et al first reported the efficacy of secukinumab in a 16-year-old patient with refractory Darier disease, with DLQI improving from 14 to 3 and IGA from 3 to 1, suggesting IL-17A inhibitors as a viable therapeutic option for pediatric patients.⁴ Warren et al Provided the first clinical proof of concept for oral IL-17 inhibitor DC-806 in mild-to-moderate psoriasis. At 28 days, the 800 mg BID group showed significantly greater PASI reduction versus placebo (43.7% vs 13.3%, P = 0.0008) with no serious adverse events, supporting the feasibility of oral small-molecule IL-17 inhibition.¹¹ Giorgio et al reported that IL-17 inhibition with brodalumab represents a potential therapeutic approach for Darier disease.¹²

Against this background, we herein report a case of severe, generalized DD with a disease duration of more than 40 years and a confirmed ATP2A2 mutation, and analyze its clinical response to secukinumab monotherapy.

Case Report

Clinical Data

A 59-year-old unmarried male presented on February 20, 2024, with a chief complaint of “papules, plaques, and greasy crusts on the head, face, trunk, and limbs accompanied by pruritus for over 40 years.” The condition began at age 13 with erythema and papules on the scalp, dorsa of hands, and chest. The disease progressed slowly but relentlessly, with lesions gradually becoming generalized over the entire body, accompanied by exudation, thick, greasy yellow crusts, persistent non-healing, significant pruritus, and a foul odor. The course followed a pattern of worsening in summer and improving in winter. He had received multiple symptomatic treatments with both Chinese and Western medicine (specific regimens unknown) with poor results. The patient had no intellectual disability or neurological manifestations such as epilepsy or schizophrenia. He was born full-term via normal delivery. His parents were non-consanguineous. There was no history of a similar disease in his parents, elder brother, or other relatives, and he denied any family history of genetic disorders.

Physical Examination

Dermatological examination revealed diffuse hyperpigmentation of the skin. Multiple red and brown firm papules and nodules were observed on the head, face, neck, trunk, limbs, nipples, and perineum. Some lesions had coalesced into irregular verrucous plaques covered with thick, yellow, sticky crusts. Fissures were noted on the nose, facial skin, and pretibial areas of the legs. Several fingernails displayed characteristic distal “V”-shaped notching. No significant abnormalities were noted in mucous membranes or hair (Figure 1Ai–Fi).

Figure 1.

Clinical photographs before (Ai–Fi) and after (Aii–Fii) secukinumab treatment. Before treatment, widespread red-brown papules, nodules, and plaques with greasy crusts involved the head, face, neck, trunk, extremities, nipples, and perineum. After 9 months, partial improvement with thinning of plaques and reduced crusting was observed. Arrows indicate skin biopsy sites.

Auxiliary Examinations

Histopathological Examination

A biopsy from a lesion on the chest revealed hyperkeratosis, suprabasal cleft formation with acantholytic cells within the clefts, and dyskeratotic cells (“corps ronds” and “grains”) in areas of acantholysis (Figure 2). These findings were consistent with Darier’s disease.

Figure 2.

Histopathological examination results of the patient. Histopathological examination revealed suprabasal acantholysis with the presence of mature corps ronds (green arrows) and grains (blue arrows) (HE, ×100).

Genetic Testing

After obtaining written informed consent, peripheral blood was collected. Testing identified a heterozygous c.479C>T (p.P160L) mutation in the ATP2A2 gene (Figure 3).

Figure 3.

The patient’s genetic test results. A heterozygous c.479C>T mutation was detected in the ATP2A2 gene. The red arrow marks the position of the identified c.479C>T heterozygous mutation site.

Other Examinations

Complete blood count, liver and kidney function tests, blood glucose, lipids, tumor markers, antinuclear antibodies, interferon-gamma release assay, chest CT, electrocardiogram, and urinalysis were performed. All results were within normal reference ranges.

Treatment and Outcome

Considering the patient’s long disease duration, severe generalized lesions, and poor response to traditional therapies, and after thorough discussion and obtaining informed consent, treatment with secukinumab was initiated. The regimen consisted of subcutaneous injections of secukinumab 300 mg. The initial loading phase involved administration at weeks 0, 1, 2, 3, and 4, followed by a maintenance phase with injections every 4 weeks. Signs of infection and liver/kidney function were monitored regularly.

After 9 months of treatment, the patient subjectively reported alleviation of pruritus. The generalized greasy yellow crusted lesions were reduced, and some plaques on the chest had become thinner (Figure 1Aii–Fii). However, due to inability to bear the long-term treatment costs, the patient self-discontinued treatment after 9 months. Long-term follow-up after discontinuation was not conducted; therefore, the long-term efficacy and recurrence status remain unknown.

Discussion

Diagnostic Analysis

The diagnosis in this case is clear and well-supported: 1) Typical Clinical Presentation: The patient had onset in childhood, with lesions distributed in seborrheic areas (scalp, face, neck, trunk), manifesting as keratotic papules, plaques, greasy crusts, and distal “V”-shaped nail notching, with a characteristic summer-worsening pattern. 2) Histopathological Confirmation: Pathology showed suprabasal clefts, acantholysis, and the characteristic “corps ronds” and “grains”, the diagnostic gold standard for DD. 3) Molecular Genetic Evidence: A heterozygous c.479C>T mutation in the ATP2A2 gene was detected. The ATP2A2 gene encodes the sarco/endoplasmic reticulum calcium ATPase (SERCA2). Mutations disrupt intracellular calcium homeostasis, affecting keratinocyte adhesion.³ The c.479C>T mutation site has been reported previously.^13,14 This case represents a sporadic form with no family history, consistent with a de novo mutation.

Therapeutic Exploration and Considerations

The treatment goals for DD are to control symptoms, reduce recurrence, prevent secondary infection, and improve quality of life. For extensive, persistent lesions, oral retinoids remain a primary treatment option.¹⁵ This patient had a prolonged disease course with severe lesions and poor past treatment response, classifying him as refractory. Recent studies have found upregulation of inflammatory cytokines such as IL-17 and IL-23 in DD lesions, suggesting immune-inflammatory mechanisms may contribute to its pathogenesis.^8,15 Therefore, biologic agents targeting these pathways represent a potential therapeutic option.

Multiple studies have indicated that in Darier disease, keratinocyte dysfunction resulting from ATP2A2 mutations - characterized by calcium homeostasis imbalance and impaired cell adhesion-may trigger adaptive immune responses through mechanisms such as the release of damage-associated molecular patterns (DAMPs) or microbiome dysbiosis, ultimately leading to Th17 polarization. Therefore, IL-17 serves as the core effector molecule driving chronic inflammation in DD.

Secukinumab is a fully human monoclonal antibody that selectively neutralizes IL-17A and has shown efficacy in Th17-mediated inflammatory skin diseases like psoriasis. In this case, secukinumab treatment over 9 months led to reductions in pruritus and partial lesion improvement, suggesting IL-17A may play a role in DD-associated inflammation and pruritus.

However, several key limitations warrant consideration. First, efficacy was only partial, failing to achieve complete clearance, indicating that DD’s pathogenesis involves not only inflammation but, more fundamentally, the keratinocyte differentiation disorder caused by the ATP2A2 mutation. Biologics may primarily ameliorate the inflammatory component. Second, the clinical assessment relied primarily on subjective reporting rather than objective, quantifiable outcome measures, and the 9-month treatment period from February to November spanned autumn and winter, during which DD tends to improve spontaneously, introducing a potential confounding effect of natural seasonal fluctuation that cannot be excluded. Third, the patient discontinued treatment due to financial constraints, highlighting the practical challenge of long-term use of expensive biologic agents for rare diseases. Importantly, as this report is based on a single case with an exceptionally prolonged disease course spanning over 40 years, our findings are inherently exploratory and should not be generalized to the broader DD population, particularly those with mild-to-moderate or early-onset disease. Future prospective studies with larger cohorts, objective outcome measures, seasonal adjustment, and extended post-discontinuation follow-up are warranted to validate the efficacy and safety of secukinumab in DD.

Conclusion

This report describes a case of severe, generalized Darier’s disease confirmed by clinical, histopathological, and genetic testing. The case exhibited typical clinical manifestations and histopathological features, and was driven by an ATP2A2 gene mutation. Treatment with the IL-17A inhibitor secukinumab yielded partial efficacy, suggesting that immunomodulation may serve as a supplementary option for patients refractory to conventional therapies. This case report aims to enhance clinicians’ awareness of this rare disease and accumulate practical experience for exploring treatment strategies.

Funding Statement

This work was supported by the Science and Technology Project of Sichuan Provincial Administration of Traditional Chinese Medicine (25MSZX340).

Data Sharing Statement

Data generated during the current study are available from the corresponding author, Li Cheng (chengli15183034801@163.com), upon reasonable request.

Ethics Statement

This case report required formal institutional ethical approval prior to publication. Ethical approval was retrospectively granted by the Ethics Committee of Suining Central Hospital (Approval number: KYLLMC20260016) for the purpose of publication. All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments. Written informed consent was obtained from the patient for publication of clinical data and images.

Informed Consent

Written informed consent was provided by the patient for publication of images and information.

Disclosure

All authors declare no conflicts of interest.