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Familial pityriasis rubra pilaris is caused by mutations in CARD14.

ABSTRACT: Pityriasis rubra pilaris (PRP) is a papulosquamous disorder phenotypically related to psoriasis. The disease has been occasionally shown to be inherited in an autosomal-dominant fashion. To identify the genetic cause of familial PRP, we ascertained four unrelated families affected by autosomal-dominant PRP. We initially mapped PRP to 17q25.3, a region overlapping with psoriasis susceptibility locus 2 (PSORS2 [MIM 602723]). Using a combination of linkage analysis followed by targeted whole-exome sequencing and candidate-gene screening, we identified three different heterozygous mutations in CARD14, which encodes caspase recruitment domain family, member 14. CARD14 was found to be specifically expressed in the skin. CARD14 is a known activator of nuclear factor kappa B signaling, which has been implicated in inflammatory disorders. Accordingly, CARD14 levels were increased, and p65 was found to be activated in the skin of PRP-affected individuals. The present data demonstrate that autosomal-dominant PRP is allelic to familial psoriasis, which was recently shown to also be caused by mutations in CARD14.

SUBMITTER: Fuchs-Telem D

PROVIDER: S-EPMC3397268 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Familial pityriasis rubra pilaris is caused by mutations in CARD14.

Fuchs-Telem Dana D Sarig Ofer O van Steensel Maurice A M MA Isakov Ofer O Israeli Shirli S Nousbeck Janna J Richard Katharina K Winnepenninckx Veronique V Vernooij Marigje M Shomron Noam N Uitto Jouni J Fleckman Philip P Richard Gabriele G Sprecher Eli E

American journal of human genetics 20120614 1

Pityriasis rubra pilaris (PRP) is a papulosquamous disorder phenotypically related to psoriasis. The disease has been occasionally shown to be inherited in an autosomal-dominant fashion. To identify the genetic cause of familial PRP, we ascertained four unrelated families affected by autosomal-dominant PRP. We initially mapped PRP to 17q25.3, a region overlapping with psoriasis susceptibility locus 2 (PSORS2 [MIM 602723]). Using a combination of linkage analysis followed by targeted whole-exome ...[more]

PMID: 22703878

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Project description:ImportancePityriasis rubra pilaris is a rare and disabling cutaneous disease that is frequently recalcitrant to conventional therapies and appears to involve interleukin (IL)-17 overexpression.ObjectiveTo investigate the clinical response and safety of ixekizumab in treating pityriasis rubra pilaris.Design, setting, and participantsSingle-arm, investigator-initiated trial conducted in adult patients with moderate to severe pityriasis rubra pilaris at a single-center academic university from June 2018 to January 2020. A total of 41 patients were screened, 12 were enrolled, and 11 completed the full duration of therapy. A referred, consecutive sample was used during participant selection. The treatment period and primary outcome occurred over 24 weeks with additional patient follow-up through 36 weeks.InterventionSubcutaneous administration of ixekizumab, a humanized IgG4 antibody that binds IL-17A, at the US Food and Drug Administration-approved dosing schedule for treatment of psoriasis for 24 weeks.Main outcomes and measuresThe primary outcome was the mean change in Psoriasis Area and Severity Index at 24 weeks. Secondary outcomes included change in affected body surface area, quality of life, induction of sustained remission, and association of improvement with CARD14 genetic variations and cutaneous cytokine expression.ResultsA total of 12 white patients (mean [SD] age, 49.8 [15.1] years; 8 male [67%]) were enrolled between June 2018 and April 2019, with 11 completing the full course of intervention. The mean (SEM) improvements in Psoriasis Area and Severity Index, affected body surface area, and Dermatology Life Quality Index were 15.2 (2.1) (P < .0001), 29.8% (9.3%) (P = .009), and 9.5 (2.5) (P = .004), respectively. The 4 participants with the most improvement in Psoriasis Area and Severity Index at week 24 stayed in remission at week 36 (defined as lack of increase in Psoriasis Area and Severity Index from week 24 through week 36), off therapy. Relative dermal IL-17A expression decreased by a 1.9 log-fold change. No participants had known pathogenic CARD14 variations. There were no serious adverse events.Conclusions and relevanceIn this single-armed trial, ixekizumab was associated with reduced clinical signs and symptoms of pityriasis rubra pilaris in a subset of patients, including those in whom other systemic therapies have failed.Trial registrationClinicalTrials.gov Identifier: NCT03485976.

Project description:IMPORTANCE:Pityriasis rubra pilaris (PRP) is a rare papulosquamous disorder with limited epidemiologic and clinicopathologic data. Little information is available on long-term outcomes, comorbidities, and treatment efficacy. OBJECTIVE:To evaluate objective and subjective disease experience metrics from the perspectives of patients and clinicians. DESIGN, SETTING, AND PARTICIPANTS:One hundred patients with a putative diagnosis of PRP and who elected to participate completed a comprehensive survey, followed by acquisition of their medical records, including histopathology slides and reports. The data were analyzed separately from the health care clinician and the patient perspectives. Two academic dermatologists examined clinical notes, pathology reports, and photographs, confirming diagnoses via predetermined criteria. Patients were categorized into 4 levels of diagnostic certainty to allow stratification of the findings for subgroup analysis. Patients with a diagnosis of PRP were solicited through patient support organization websites. MAIN OUTCOMES AND MEASURES:Clinical outcomes, unexpected association of comorbidities, and efficacy (or lack of it) of various treatment modalities. RESULTS:Among the 100 patients, 50 were diagnosed as having classic, unquestionable PRP. The patients were a median of 61 years old (range, 5-87 years), and 46% were female. Fifty were categorized as level 1 diagnostic certainty, 15 as level 2, 30 as level 3, and 5 as level 4. Of the level 1 patients, 13 (26%) were correctly diagnosed at initial presentation; diagnosis was delayed, on average, by 29 months (range, 0.25-288 months; median, 2 months); and 27 (54%) having undergone 2 or more biopsies. At enrollment, PRP symptoms had persisted in 36 patients (72%) for an average of 58 months (range, 1-300 months; median, 30 months). Thirty-one patients (62%) had comorbidities, including hypothyroidism (20%). Nearly all patients (98%) received some form of therapy. Patients cited topical emollients, corticosteroids, and salicylic acid along with oral retinoids, methotrexate, and tumor necrosis factor inhibitors as most helpful. CONCLUSIONS AND RELEVANCE:Pityriasis rubra pilaris remains a challenging diagnosis without established and specific treatment. Our data highlight new potential avenues for research with therapeutic perspective.

Project description:Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disorder associated with significant patient morbidity. To further characterize the molecular landscape of PRP, we conducted a transcriptomic analysis of epidermis and dermis collected from patients with moderate-to-severe PRP compared to matched healthy controls, on no systemic therapy and then following 24 weeks of treatment with the IL17A inhibitor, ixekizumab. Patients with PRP not only experienced clinical improvements, but also correction of their cutaneous transcriptome dysregulation after therapy. Moreover, those who has >50% improvement in PASI score after treatment demonstrated distinct transcriptomic profiles when compared to those who failed to respond, despite the lack of a discernable phenotypic difference. Pathway enrichment was strongest among DEGs belonging to inflammatory processes for patients with PRP – in particular, enrichment of the Th17 immune response was seen both prior to and following treatment with IL17A inhibition. Positive regulation of natural killer cell chemotaxis was also seen pre- and post-treatment, however, the pathway’s odds of enrichment decreased following treatment in both epidermis and dermis. Additionally, negative regulation of IL-12 production was highly enriched following therapy, suggesting decreased activity of the Th1 axis. Several individual genes of interest similarly displayed marked differential expression by response status. In parallel with their overall normalization in gene expression, responders had a greater normalization toward healthy control skin than non-responders in the Th17 family genes IL17C, IL23A, CCL20, as well as IL36A and IL36F (implicated in pustular psoriasis), Phospholipase A2 group IVD, and the antimicrobial protein S100A7, all of which remained elevated in non-responders. Intriguingly, responders had higher baseline levels of IL17A and IL17F than non-responders. Whereas dermal IL17A/F levels improved in responders, epidermal expression remained high despite the clinical response to IL17A inhibition. In contrast, non-responder IL17A/F epidermal levels normalized and dermal levels were significantly suppressed compared to healthy controls, despite the lack of clinical improvement. This suggests alternative pathways such as specific targeting of IL17C or IL36 may be preferred in some subsets of PRP.

Dataset Information

Familial pityriasis rubra pilaris is caused by mutations in CARD14.

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Familial pityriasis rubra pilaris is caused by mutations in CARD14.

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