Loss-of-function mutations in Keratin 32 gene disrupt skin immune homeostasis in pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is an inflammatory papulosquamous dermatosis, characterized by hyperkeratotic follicular papules and erythematous desquamative plaques. The precise pathogenic mechanism underlying PRP remains incompletely understood. Herein, we conduct a case-control study involving a cohort of 102 patients with sporadic PRP and 800 healthy controls of Han Chinese population and identify significant associations (P = 1.73 × 10-6) between PRP and heterozygous mutations in the Keratin 32 gene (KRT32). KRT32 is found to be predominantly localized in basal keratinocytes and exhibits an inhibitory effect on skin inflammation by antagonizing the NF-κB pathway. Mechanistically, KRT32 binds to NEMO, promoting excessive K48-linked polyubiquitination and NEMO degradation, which hinders IKK complex formation. Conversely, loss-of-function mutations in KRT32 among PRP patients result in NF-κB hyperactivation. Importantly, Krt32 knockout mice exhibit a PRP-like dermatitis phenotype, suggesting compromised anti-inflammatory function of keratinocytes in response to external pro-inflammatory stimuli. This study proposes a role for KRT32 in regulating inflammatory immune responses, with damaging variants in KRT32 being an important driver in PRP development. These findings offer insights into the regulation of skin immune homeostasis by keratin and open up the possibility of using KRT32 as a therapeutic target for PRP.

Pityriasis Rubra Pilaris - a difficult path to optimal treatment. Case report.

Pityriasis Rubra Pilaris is a rare, chronic inflammatory dermatosis of unknown etiology, presenting with erythema and papular eruptions. Treatment is difficult due to the lack of causal therapy, guidelines and requires an individualized approach. The most common treatments are systemic retinoids, immunosuppressants, phototherapy and biological therapy. This article presents the case of a 73-year-old man suffering from type 1 pityriasis rubra pilaris. The patient was initially treated with acitretin, which was discontinued due to hypogammaglobulinemia. This rare side effect of acitretin has not been previously published. As a second-line treatment, the patient received methotrexate, but with no clinical improvement after 3 months and an increase in skin pruritus. Finally, the use of isotretinoin resulted in significant clinical improvement and was well tolerated.

Targeting IL-1 controls refractory pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1ß as a key mediator, orchestrating an NF-κB-mediated IL-1ß-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1ß. With the central role of IL-1ß underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1ß antagonists in PRP.

Post-infectious pityriasis rubra pilaris in pediatric patients. / Pitiriasis rubra pilaris posinfecciosa en pacientes pediátricos.

Pityriasis rubra pilaris (PRP) is a rare skin condition. The etiology of PRP is unknown; however, it has been associated with infections, autoimmune diseases, and neoplasms. Here we describe the cases of 2 pediatric patients with PRP triggered by a respiratory syncytial virus infection concurrently with obstructive bronchial syndrome. PRP resolved after treatment with topical emollients, topical corticosteroids, and calcineurin inhibitors.

La pitiriasis rubra pilaris (PRP) es una enfermedad dermatológica poco frecuente. Se desconoce su etiología, sin embargo, se ha asociado a infecciones, enfermedades autoinmunes y neoplasias. Se describen los casos de dos pacientes pediátricos que presentaron PRP gatillada por una infección por virus sincicial respiratorio mientras cursaban un síndrome bronquial obstructivo. Los cuadros de PRP remitieron luego del tratamiento tópico con emolientes, corticoesteroides tópicos e inhibidores de la calcineurina.

Role of IL-23 inhibitors including risankizumab and guselkumab in the treatment of pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare and chronic inflammatory dermatologic condition characterized by hyperkeratotic salmon-colored plaques and palmoplantar keratoderma. Traditional therapeutic modalities have shown limited efficacy and often entail potential adverse effects, highlighting the need for alternative treatment options. Our review aims to summarize the current evidence on the off-label use of IL-23 inhibitors, risankizumab and guselkumab, in the treatment of PRP. These biologic agents have been approved for psoriasis, and their potential role in managing PRP has recently garnered interest. We conducted a comprehensive literature search on PubMed and Scopus databases, identifying relevant studies published in English up to June 2023 following PRISMA guidelines. A total of 10 studies were selected for data extraction and review. Results from the selected studies demonstrated encouraging outcomes with both risankizumab and guselkumab in managing PRP. Among 11 patients treated with risankizumab, 10 showed notable improvements in various disease manifestations, including pruritus, erythema, and affected body surface area. DLQI scores and BSA percentages reported a significant improvement before and after risankizumab treatment (p = 0.0322; p = 0.0216). However, two cases also reported symptom aggravation or even disease worsening. Patients treated with guselkumab exhibited ultimate improvement in all five cases, with complete clearance in three out of five cases. DLQI and BSA percentages also reported significant improvement with treatment with guselkumab (p = 0.0172; p < 0.0001). While most cases demonstrated positive outcomes, there were isolated instances of worsening symptoms, emphasizing the need for caution and further investigation. Further research with larger sample sizes and longer follow-up periods is necessary to establish the efficacy, optimal dosing, and long-term safety of risankizumab and guselkumab in treating PRP. Overall, we provide valuable insights into the potential use of IL-23 inhibitors, risankizumab, and guselkumab, as promising treatment options for PRP. These biologics have shown efficacy in improving symptoms in treatment-resistant cases, offering new avenues for clinicians to explore in the treatment of PRP.

Ophthalmic complication of pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare dermatological condition which may present with ocular manifestations. We report a case of recurrent cicatricial ectropion (CE) with topical beta-blocker use in the rare dermatological condition PRP. The patient underwent release of scar tissue, lateral tarsal strip and full-thickness supraclavicular skin graft for CE following immunosuppression with methotrexate for 3 months. Postoperatively, CE recurred, with skin graft shrinkage and resumption of periocular disease activity, 8 weeks following the introduction of topical timolol. The patient was referred for further immunosuppression and substitution of timolol before consideration for further surgery. PRP has a variety of potential ocular complications. Surgery has a high risk of recurrence and should be performed when the overall disease is quiescent and drugs, which could trigger reactivation, have been discontinued and/or substituted. Skin grafts should be oversized to off-set shrinkage.

Guselkumab for Pityriasis Rubra Pilaris and Dysregulation of IL-23/IL-17 and NFkB Signaling: A Nonrandomized Trial.

Importance: There is no US Food and Drug Administration-approved treatment for pityriasis rubra pilaris (PRP), and it is common for patients to fail to experience improvement with several systemic options. Involvement of interleukin (IL) 23 suggests a potential therapeutic target. Objective: To determine whether guselkumab, an IL-23p19 inhibitor, provides clinical improvement for participants with PRP and better understand gene and protein dysregulation in PRP. Design, Setting, and Participants: This single-arm, investigator-initiated nonrandomized trial was conducted from October 2019 to August 2022 at a single-center academic university with participants from 8 states in the US. In total, 14 adults with moderate to severe PRP were enrolled; 12 completed the trial. Age-matched and sex-matched healthy controls provided skin and blood for proteomic and transcriptomic studies. The primary outcome was observed at 24 weeks, and additional follow-up occurred at 36 weeks. Intervention: Guselkumab is a fully human immunoglobulin G1 λ monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23. Subcutaneous injections were given at the US Food and Drug Administration-approved dosing schedule for psoriasis over a 24-week period. Main Outcomes and Measures: The primary outcome was the mean change in the Psoriasis Area Severity Index (PASI) score at week 24. Secondary outcomes included pruritus, Dermatology Life Quality Index score, clinical response at week 36, and association with transcriptomics and proteomics expression. Results: A per-protocol analysis was performed for the cohort of 4 female and 8 male patients who had a mean (SD) age of 56.5 (18.7) years. The mean improvement in PASI score, pruritus, and Dermatology Life Quality Index score was 61.8% (P < .001), 62.3% (P = .001), and 60.2% (P < .001), respectively. Nine participants (75%) achieved a 50% improvement in PASI. Among these clinical responders, at week 36, 8 of 9 achieved PASI75, and 6 of 9 achieved PASI90. No participants had pathogenic CARD14 gene variations. There was 1 serious adverse event that was not associated with the study drug. Proteomics and gene expression profiles identified dysregulation of a predominance of inflammatory pathways (such as T helper 17 and nuclear factor κ B) in participants with PRP who later responded well to treatment with guselkumab and stronger dysregulation of keratinocyte development pathways in individuals who did not respond to guselkumab. Conclusion and Relevance: The results of this nonrandomized trial suggest that guselkumab has efficacy in treating refractory moderate to severe adult PRP. Trial Registration: ClinicalTrials.gov Identifier: NCT03975153.

Biologics for Treatment of Pityriasis Rubra Pilaris: A Literature Review.

OBJECTIVE: To describe the published efficacy and adverse event rates associated with existing biologics for the treatment of pityriasis rubra pilaris (PRP). DATA SOURCES: A literature review using the PubMed database (January 1990-July 2023) was conducted. Multiple search combinations were conducted using "pityriasis rubra pilaris" and various biologics as keywords to identify relevant articles. STUDY SELECTION AND DATA EXTRACTION: Inclusion criteria included all study types that were published within the past 30 years in English and mentioned at least one biologic and PRP. A preliminary search yielded a total of 499 results. After screening using inclusion and exclusion criteria, 77 relevant articles (69 case reports, 5 case series, 2 clinical trials, and 1 retrospective analysis) were analyzed. DATA SYNTHESIS: TNF-α inhibitors have been evaluated and are effective in treating PRP. However, recent treatment with anti-interleukin (IL)-17 and anti-IL-23 therapies such as ustekinumab, secukinumab, and ixekizumab are emerging as new treatment options with a mean improvement in PRP Area and Severity Index scores, change in severity of erythema, scaling, and thickness of PRP lesions. From initial clinical trials, secukinumab and ixekizumab are promising treatment options for achieving remission. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review compares the efficacy for numerous biologics and a discussion to guide clinicians on benefits and risks in choosing a biologic for PRP patients. CONCLUSIONS: Biologics may be a favourable treatment option leading to greater patient adherence due to reduced dosing frequencies, improvement in quality of life, and reduction in frequency and severity of flares.

Pityriasis Rubra Pilaris: A Multicentric Case Series of 65 Spanish Patients.

INTRODUCTION: PRP is a rare entity of unknown etiopathogenesis. Lack of management guidelines makes it a challenge for clinicians. OBJECTIVE: To add our experience to increase evidence about PRP. METHODS: We performed a retrospective, descriptive and multicentric study of 65 patients with PRP, being the largest European case series of patients with PRP. RESULTS: PRP was more frequent in male patients with an average age of 51 years, but erythrodermic forms presented in older patients (average age 61 years). Six (75%) paediatric patients and ten (60%) non-erythrodermic adults controlled their disease with topical corticosteroids. On the contrary, 26 (68%) erythrodermic patients required biologic therapy as last and effective therapy line requiring an average of 6.5 months to achieve complete response. CONCLUSION: Our study showed a statistical difference in terms of outcome and response to treatment between children or patients with limited disease and patients who develop erythroderma.

Updates on Pityriasis Rubra Pilaris: A Scoping Review.

Pityriasis rubra pilaris (PRP) is a rare, inflammatory papulosquamous skin disease with unknown exact etiology. Historically, PRP has been challenging to diagnose, especially during the acute phase, and to treat, due to its unclear pathogenesis. To better inform clinical practice, a literature review was conducted employing a broad search strategy to capture PRP-related published studies between January 1, 2012 to October 31, 2022. Two hundred twenty-one studies were identified, which were categorized into 9 themes: (1) potential causes and triggering factors, (2) comorbidities, (3) diagnostic difficulties, (4) genetics, (5) clinical manifestations and laboratory values, (6) treatment, (7) treatment-related adverse events, (8) quality of life, and (9) other. COVID-19 infection, COVID-19 vaccination, and malignancy were the most commonly reported potential triggering factors. Misdiagnosis is very common during the early acute stages. Pathogenesis and genetic studies have further implicated caspase recruitment domain family member 14 (CARD14) mutations in the development of familial PRP (Type V) and have underlined the overlap between psoriasis and PRP. To date, there are currently no specific and validated scoring systems or tools to assess the severity of PRP. While large, randomized trials are still lacking, biologic agents remain the most effective therapy.

Patients with keratinization disorders due to ABCA12 variants showing pityriasis rubra pilaris phenotypes.

Pathogenic variants in ABCA12 are important causative genetic defects for autosomal recessive congenital ichthyoses (ARCI), which include congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis, and lamellar ichthyosis. In addition, pathogenic variants in ABCA12 are known to cause a localized nevoid form of CIE due to recessive mosaicism. We previously reported siblings who carried an ABCA12 variant but did not show a "congenital" phenotype. They were considered to have pityriasis rubra pilaris (PRP). Here, we present a further patient with ABCA12 variants whose phenotype was not congenital ichthyosis, in an independent family. Notably, these three patients had geographic unaffected areas. Such areas are not usually found in patients with ARCI who have ABCA12 variants, suggesting mild phenotypes for these patients. Interestingly, the histological features of the ichthyotic lesions in these patients resembled those of PRP. All three patients had homozygous pathogenic missense variants in ABCA12. Our findings expand the phenotypic spectrum of patients with ABCA12 variants.

Pityriasis Rubra Pilaris: An Updated Review of Clinical Presentation, Etiopathogenesis, and Treatment Options.

Pityriasis rubra pilaris (PRP) is a rare papulosquamous reaction pattern with a significant impact on quality of life. Type I PRP is the most common PRP variant, presenting as erythematous papules emerging in a follicular distribution and later coalescing into plaques with characteristic islands of sparing; histologically, an alternating pattern of orthokeratosis and parakeratosis is considered the hallmark of PRP (checkerboard hyperkeratosis). Other PRP variants (types II-V) differ in their age of onset and clinical presentation. Type VI PRP is a rare PRP subtype associated with human immunodeficiency virus infection and is occasionally associated with diseases of the follicular occlusion tetrad. Caspase recruitment domain family, member 14 (CARD14)-associated papulosquamous eruption and facial discoid dermatitis are newly described disease states that have an important clinical overlap with PRP, creating shared conundrums with respect to diagnosis and treatment. The etiology inciting PRP often remains uncertain; PRP has been suggested to be associated with infection, malignancy, or drug/vaccine administration in some cases, although these are based on case reports and causality has not been established. Type V PRP is often due to inborn CARD14 mutations. Furthermore, recent literature has identified interleukin-23/T-helper-17 cell axis dysregulation to be a major mediator of PRP pathogenesis, paving the way for mechanism-directed therapy. At present, high-dose isotretinoin, ixekizumab, and secukinumab are systemic agents supported by single-arm prospective studies; numerous other agents have also been trialed for PRP, with variable success rates. Here, we discuss updates on clinical manifestations, present new insights into etiopathogenesis, and offer a survey of recently described therapeutic options.