Secukinumab for the treatment of adult-onset pityriasis rubra pilaris: a single-arm clinical trial with transcriptomic analysis
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PROVIDER: PRJNA1094992 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR28519503_1.fastq.gz | Fastqsanger.gz | |||
| SRR28519503_2.fastq.gz | Fastqsanger.gz | |||
| SRR28519504_1.fastq.gz | Fastqsanger.gz | |||
| SRR28519504_2.fastq.gz | Fastqsanger.gz | |||
| SRR28519505_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: The pathogenesis of pityriasis rubra pilaris (PRP) is not completely understood, but interleukin (IL)-17 has been shown to play a critical role. There are no reliable immunomodulatory agents to treat PRP. We conducted an open-label, single-arm clinical trial of secukinumab, a monoclonal antibody that inhibits IL-17A, for the treatment of PRP. Objectives: To evaluate the clinical efficacy of secukinumab and define the transcriptomic landscape of PRP and its response to IL-17A blockade. Methods: Twelve patients with PRP were recruited for an open-label trial of secukinumab. Patients received a 24-week course of secukinumab. The primary endpoint was a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) from baseline to week 28. Secondary endpoints included PASI 90, change in Physician's Global Assessment (PGA), and change in Dermatology Life Quality Index (DLQI). RNA sequencing was performed on lesional and nonlesional skin biopsies obtained at baseline and week 2. Sample groups were compared to identify differential gene expression and pathway enrichment. This trial was registered with ClinicalTrials.gov: 'Cosentyx (secukinumab) for the treatment of adult onset pityriasis rubra pilaris' - NCT03342573. Results: At week 28, six of 11 patients (55%) achieved PASI 75, and three patients (27%) achieved PASI 90. PGA (P = 0.008) and DLQI scores (P = 0.010) showed significant improvement with treatment. No serious treatment-related adverse events were encountered. Treatment with secukinumab normalized transcriptional differences between lesional and nonlesional skin. Transcriptomic data from nonresponsive patients suggest that overactivity of innate immune pathways may be driving resistance to secukinumab. Conclusions: Secukinumab appears to be an effective treatment for PRP and warrants further investigation. PRP is a transcriptionally heterogeneous disease, reflecting its variable response to therapy. Agents targeting other IL-17 isoforms and innate immune mediators should be considered for future clinical trials. What is already known about this topic? The pathogenesis of pityriasis rubra pilaris is incompletely understood. Successful treatment has been reported with a variety of immunomodulatory agents, but disease is often refractory to therapy. Interleukin (IL)-17 is thought to drive keratinocyte proliferation and vascular dysfunction in this disease. A previous trial demonstrated efficacy of the anti-IL-17A drug ixekizumab for pityriasis rubra pilaris. What does this study add? Herein we describe the findings of a clinical trial of secukinumab, an anti-IL-17A monoclonal antibody, for the treatment of pityriasis rubra pilaris. Secukinumab was effective in treating pityriasis rubra pilaris. Our transcriptomic data give new insight into the expressional changes that occur in response to secukinumab and suggest mechanisms of treatment resistance.
2024-04-23 | GSE262954 | GEO
Project description:Importance: There is no FDA-approved treatment for pityriasis rubra pilaris and it is common for patients to fail several systemic options. Involvement of IL-23 pathway suggests a potential therapeutic target. Objective: To determine whether guselkumab, an IL-23p19 inhibitor, provides clinical improvement for subjects with PRP. Design: Single-arm, investigator-initiated trial from October, 2019 to August, 2022. Primary outcome was observed at 24 weeks, and additional patient follow-up occurred at 36 weeks. Participants: 14 adult subjects with moderate-to-severe pityriasis rubra pilaris were enrolled; 12 completed the trial. Age- and sex-matched healthy controls provided skin and blood for proteomic and transcriptomic studies. Intervention: Guselkumab is a humanized IgG1 lambda antibody that selectively binds and inhibits the p19 subunit of interleukin-23. Subcutaneous injections were performed at the FDA-approved dosing schedule for psoriasis over a 24-week period. Main Outcomes and Measures: The primary outcome was mean change in psoriasis area and severity index (PASI) at week 24. Secondary outcomes included improvement in body surface area, quality of life, time to improvement, sustained remission at 36 weeks, and correlation to germline mutations and cytokine expression. Results: An intention-to-treat analysis was performed for our cohort of ten males and six females, with a median age of 59.5 years. The mean improvement in psoriasis area and severity index, body surface area, and dermatology life quality index (DLQI) were 18.9 ± 12.5 (p<0.001), 40.5 ± 36.5 (p=0.003), and 12.2 ± 7.8 (p<0.001), respectively. 11 subjects showed sustained remission off therapy, evidenced by decreased PASI scores between week-24 and week-36. No subjects had CARD14 gene variations. There was one serious adverse event, unrelated to study drug. Proteomics and gene expression profiles improved with clinical improvement. Conclusion and Relevance: Guselkumab appears to be efficacious in the treatment of refractory PRP.
2024-03-31 | GSE235570 | GEO
Project description:Transcriptomic profiling of Pityriasis Rubra Pilaris (PRP) and Psoriasis
| PRJNA759245 | ENA
Project description: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 we identified IL-1β as a key mediator, orchestrating an NF-κB-mediated IL-1β-CCL20 axis. Treatment with the IL-1-antagonists anakinra and canakinumab in patients resulted in rapid clinical improvement. Here we show by spatial profiling that in skin samples after treatment the molecular signature of the PRP was reversed: positive DEGs before treatment showed significant negative enrichment after treatment; the same accounts for GSEA analysis of selected pathways of interest, such as TNF-alpha signaling via NF-kB; predicted activation scores of IPA annotations for disease, pathways, and upstream regulator exhibited a significant negative correlation between active PRP and after treatment; and finally IPA mechanistic network analysis showed that gene regulation arising from IL1B was reversed with treatment.
2024-08-01 | GSE264192 | GEO
Project description:A single-arm trial of guselkumab in the treatment of adults with pityriasis rubra pilaris (PRP)
| PRJNA986483 | ENA
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.
2023-07-28 | GSE209981 | GEO
Project description:Pityriasis rubra pilaris transcriptomics implicate IL-17 signaling and correlate with response to IL-17A inhibition
| PRJNA863260 | ENA
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.
| S-EPMC7160757 | biostudies-literature
Project description:Comparison of skin spatial transciptomics before and after IL-1-targeted biological treatment in Pityriasis rubra pilaris
| PRJNA1101431 | ENA
Project description:Hyperactivation of the IL-17 axis and IL-36 signaling in Card14-mutant pityriasis rubra pilaris model mice
| PRJNA842018 | ENA