Pityriasis Rubra Pilaris

Altered epidermal differentiation along with increased keratinocyte proliferation is a characteristic feature of psoriasis and pityriasis rubra pilaris (PRP). However, despite this large degree of overlapping clinical and histologic features, the molecular signatures these skin disorders share are unknown. Using global transcriptomic profiling, we demonstrate that plaque psoriasis and PRP skin lesions have high overlap, with all differentially expressed genes in PRP relative to normal skin having complete overlap with those in psoriasis. The major common pathway shared between psoriasis and PRP involves the phospholipases PLA2G2F, PLA2G4D, and PLA2G4E, which were found to be primarily expressed in the epidermis. Gene silencing each of the 3 PLA2s led to reduction in immune responses and epidermal thickness both in vitro and in vivo in a mouse model of psoriasis, establishing their proinflammatory roles. Lipidomic analyses demonstrated that PLA2s affect mobilization of a phospholipid-eicosanoid pool, which is altered in psoriatic lesions and functions to promote immune responses in keratinocytes. Taken together, our results highlight the important role of PLA2s as regulators of epidermal barrier homeostasis and inflammation, identify PLA2s as a shared pathogenic mechanism between PRP and psoriasis, and as potential therapeutic targets for both diseases.

BackgroundChanarin Dorfman Syndrome (CDS) is a rare autosomal recessive disorder characterized by the multisytemic accumulation of neutral lipids inside the cytoplasmic lipid droplets. This condition is caused by mutations in the abhydrolase domain containing 5 gene (ABHD5). In CDS the skin involvement is the prevalent and always observed clinical feature, consisting of a non-bullous congenital ichthyosiform erythroderma (NCIE). Moreover, a variable involvement of the liver and neuromuscular system can be also observed. In this report, we aimed to perform the clinical and genetic characterization of a patient affected by CDS with atypical dermatological findings, considering this rare inborn error of neutral lipid metabolism.MethodsGenomic DNA samples obtained from patient and his parents were used to perform the sequencing of the ABHD5 exons and their intron/exon boundaries. Bioinformatic analyses were performed to investigate the possible effect of the identified mutation on protein structure.ResultsHere we present the case of a 29-year-old male patient with CDS, who, for long time, has been misdiagnosed as pityriasis rubra pilaris (PRP). He has a history of increasing hyperlipidemia; hepatomegaly associated with hepatosteatosis was also detected. ABHD5 molecular analysis revealed a novel missense mutation, the c.811G > A (p.G271R). Bioinformatic investigations showed that the variant has a deleterious effect on ABHD5 function, probably causing an incorrect folding of the mutant protein.ConclusionsThese results highlihts the importance of genetic testing for ABHD5 in unresolved cases of patients presenting unusual skin lesions, that resemble PRP, associated with a history of hyperlipidemia and nonalcoholic fatty liver.

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 (PRP) is a rare inflammatory skin disease characterized by hyperkeratotic follicular papules, palmoplantar hyperkeratosis, and associated normal "islands of unaffected skin". Its pathogenesis has not been fully elucidated, and treatment poses significant challenges. Conventional therapies include oral retinoids and topical emollients. In recent years, although biological agents have been used in treatment, they are associated with side effects such as an increased risk of infection, and some patients show no response to treatment, thus necessitating the exploration of new therapeutic approaches.This case represents the first reported use of a TYK2 inhibitor (deucravacitinib) for the treatment of PRP. The patient was a 39-year-old male who developed extensive erythema in December 2024. The erythema gradually increased and progressed to red punctate eruptions accompanied by mild desquamation, slight pruritus with a stinging sensation, and "islands of unaffected skin". Initial treatment with topical dinoprostone and mometasone furoate cream was ineffective. In March 2025, the patient received deucravacitinib (6 mg daily) in combination with topical halometasone cream. At the 1-month follow-up, significant improvements were observed in erythema, desquamation, and pruritus. At the final 6-month follow-up, the skin lesions almost resolved, leaving only mild erythema and a small amount of desquamation. Both the disease severity and the patient's quality of life were significantly improved. This case suggests that deucravacitinib exhibits favorable efficacy and safety in the treatment of PRP. However, due to the low incidence of PRP, which makes large-scale controlled trials difficult, and the lack of recognized treatment guidelines, more clinical studies are needed in the future to further verify the potential of deucravacitinib in the treatment of PRP.