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 as a systemic disease.

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disorder of unknown etiology, initially described in 1835. It is characterized by keratotic follicular papules, well-demarcated salmon-colored erythematous scaly plaques interspersed with distinct islands of uninvolved skin, and palmoplantar keratoderma. Is PRP a systemic disease? Skin is mainly affected in PRP. Despite its clinical heterogeneity, PRP could be associated with a variety of rheumatologic, infectious, neoplastic, and other extracutaneous manifestations. We accept the hypothesis of not only an association but also a causative relation between skin and systemic manifestations with possible common underlying pathomechanisms such as systemic immunologic processes and superantigen mimicry.

Case of pityriasis rubra pilaris progressed to generalized erythroderma following blockade of interleukin-17A, but improved after blockade of interleukin-12/23 p40.

We report herein a case of a 72-year-old man with pityriasis rubra pilaris (PRP) that was refractory to conventional therapies. His skin lesions progressed to generalized erythroderma despite anti-interleukin (IL)-17A antibody therapy. Topical corticosteroids, emollients, systemic retinoid, methotrexate, cyclosporin and phototherapy yielded no therapeutic response. However, blockade of IL-12/23 p40 dramatically improved his cutaneous lesions. Complete remission was achieved 4 weeks after the first injection of ustekinumab and maintained for more than 48 weeks. Our data indicate that IL-12 was associated with the onset of PRP in this patient, rather than IL-23. IL-12 is critical for the differentiation of T-helper (Th)1 cells. Thus, the Th1 pathway may be associated with the onset of PRP.

Refractory pityriasis rubra pilaris treated with etanercept, adalimumab, or ustekinumab: A retrospective investigation.

Pityriasis rubra pilaris (PRP) is a rare, difficult to treat papulosquamous disorder that responds variably to retinoids and immunosuppression. Successful use of biologics for treating PRP has been described in the literature by case reports and a limited number of case series. To provide additional data, we retrospectively analyzed cases of PRP treated with biologics at our institution. We identified seven patients with a clear diagnosis of PRP treated with adalimumab, etanercept, and/or ustekinumab at our institution from January 1, 2014 to April 1, 2017. Six of seven patients had type I, adult acquired PRP, and one had type V atypical juvenile PRP. In response to tumor necrosis factor (TNF)-α inhibition, two patients had marked responses (>75% improvement in involved body surface area), while three patients failed to show any improvement on a TNF-α inhibitor. In two cases of PRP refractory to TNF-α inhibition, ustekinumab resulted in a partial response (<75% improvement) in one patient and no response in the other. Compared to other published data, our cohort was substantially more resistant to treatment with biologics, a finding which may provide valuable perspective for dermatologists managing refractory PRP in the future.

Severe, Disfiguring, Pityriasis Rubra Pilaris in a Woman in the Dominican Republic: Histopathologic Diagnosis and Response to Antiretroviral Therapy.

Pityriasis rubra pilaris (PRP) is a poorly understood dermatologic condition usually accompanied by keratoderma and intense erythroderma with islands of unaffected skin. The PRP categories include HIV-associated PRP VI. A 23-year-old HIV-infected, dark-skinned woman in the Dominican Republic developed an extremely severe, disfiguring process characterized first by a dry scaly rash involving her face, trunk, and extremities with hyperpigmentation and islands of spared skin and minimal erythroderma, followed by alopecia and development of a thick horny layer on the scalp and face. The condition, histologically proven to be PRP, was accompanied by fever, wasting, and decline in CD4 count. Initiation of combination antiretroviral therapy (cART) was followed by rapid and sustained resolution of PRP. Nine years after ART initiation, she remains well, with viral suppression and immune recovery, without PRP recurrence but with sparse hair regrowth and facial scarring. In some dark-skinned patients, severe PRP may not feature characteristic erythroderma but will respond to combination ART.

[Acute postinfectious pityriasis rubra pilaris: a superantigen-mediated dermatosis]. / Pitiriasis rubra pilaris aguda postinfecciosa: una dermatosis mediada por superantígenos.

Acute postinfectious pityriasis rubra pilaris (PRP) is a variant of juvenile PRP (Griffiths type III) characterized by no family history, an acute course associated with a prior fever, and good prognosis. Clinical features may resemble other superantigen-mediated diseases, such as scarlatiniform rash or staphylococcal scalded skin syndrome, but its histology and treatment are different. We present 4 cases of acute postinfectious PRP that illustrate the clinical features of this uncommon disease and we review possible underlying pathogenic mechanisms.

Acute juvenile pityriasis rubra pilaris: a superantigen mediated disease?

Juvenile acute pityriasis rubra pilaris (JAPRP) is a form of pityriasis rubra pilaris (PRP) with particular clinical characteristics and course. It is usually preceded by an infectious condition. We report a boy, initially thought to have Kawasaki disease, and subsequently diagnosed as having JAPRP, who made a satisfactory recovery. In this case, prior antibiotic treatment made it impossible to show the presence of any microorganism. However, the clinical characteristics of these patients and the similarities with other disorders involving the skin that are mediated by superantigens led us to think that these antigens may be involved in the development of this disease. Also, in view of the obvious differences between JAPRP and the other PRP, we suggest that, in the future this disorder may be considered a separate entity as a reactive exanthem.

Pitiriasis rubra pilaris asociada a artritis reumatoidea. Presentación de 1 caso / Pityriasis rubra pilaris associated with rheumatoid arthritis: a case report

Se presentó 1 caso de pitiriasis rubra pilaris eritrodérmica de 10 años de evolución en 1 paciente de 74 años de edad. Se observó que la enfermedad cutánea se asoció con artritis reumatoidea lo que hizo pensar a los autores en el posible papel etiológico de los factores inmunológicos en la pitiriasis rubra pilaris. Durante su evolución también se presentó un carcinoma papilar de vejiga, queratosis seborreicas múltiples, nódulo laríngeo benigno, carcinomas basales y un queratoacantoma. Se impuso tratamiento con methotrexate, pero no resultó satisfactorio para su PRP. Se obtuvo una buena respuesta con el etretinato (AU)

Pitiriasis rubra pilaris asociada a artritis reumatoidea. Presentación de 1 caso / Pityriasis rubra pilaris associated with rheumatoid arthritis: a case report

Se presentó 1 caso de pitiriasis rubra pilaris eritrodérmica de 10 años de evolución en 1 paciente de 74 años de edad. Se observó que la enfermedad cutánea se asoció con artritis reumatoidea lo que hizo pensar a los autores en el posible papel etiológico de los factores inmunológicos en la pitiriasis rubra pilaris. Durante su evolución también se presentó un carcinoma papilar de vejiga, queratosis seborreicas múltiples, nódulo laríngeo benigno, carcinomas basales y un queratoacantoma. Se impuso tratamiento con methotrexate, pero no resultó satisfactorio para su PRP. Se obtuvo una buena respuesta con el etretinato

HIV-associated pityriasis rubra pilaris responsive to triple antiretroviral therapy.

HIV-associated pityriasis rubra pilaris (PRP) or PRP type VI designates a new distinctive entity reported in HIV patients. It is characterized by cutaneous lesions of PRP and variable association with lesions of acne conglobata, hidradenitis suppurativa and lichen spinulosus. We report a patient with HIV-associated PRP which was treated by triple antiretroviral therapy (zidovudine, lamivudin and saquinavir) with complete response. The patient has remained free from symptoms for 20 months of follow-up. We review the clinical features, pathology, evolution, treatment and possible aetiology of this recently described entity.

Pityriasis rubra pilaris: an unusual cutaneous complication of AIDS.

Pityriasis rubra pilaris is an uncommon hyperkeratotic, papulosquamous disorder that has been reported in patients infected by HIV. We recount a case of pityriasis rubra pilaris in an HIV-seropositive man. A 36-year-old man with a history of ulcerative colitis and recurrent otitis externa had diffuse psoriaform erythroderma. He was treated initially with methotrexate and isoretinoin without clinical improvement. Skin examination showed large, erythematous, orange, scaly patches on the upper extremities and thickening of the nail beds. The palms and soles were hyperkeratotic. Skin biopsy revealed changes that were consistent with pityriasis rubra pilaris. Six months before the onset of symptoms, results of an enzyme-linked immunosorbent assay (ELISA) and Western Blot assay for HIV were negative. Six months after symptoms, results of repeat enzyme-linked immunosorbent assay and Western blots for HIV were positive (CD4+ T-cell count = 200 cells/ mm3). Clinical course had been complicated by episodes of Staphylococcus aureus bacteremia, mucocutaneous candidiasis, and development of localized squamous cell carcinoma of the skin. The increased severity of pityriasis rubra pilaris should prompt clinicians to consider coinfection with HIV in patients who have disease that is refractory to treatment. Clinicians also should remain vigilant for the development of squamous cell carcinoma.