From Empirical to Pathogenesis-Based Treatments for Psoriasis

Kerkhof, Peter C M van de

doi:10.1016/j.jid.2022.01.014

Cited by 39 publications

(31 citation statements)

References 86 publications

(83 reference statements)

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“…We next aimed to establish if PCSK9 expression was linked to any well-known mediator of psoriasis. Examining PCSK9 expression in cultured keratinocytes revealed that SNP rs662145 C > T was associated with differential expression of IL36 , an IL-1 family member and psoriasis-defining cytokine ( 15 , 16 ). Comparing IL36 expression in primary human keratinocytes homozygous and heterozygous for PCSK9 SNP rs662145 C > T revealed that homozygosity for rs662145 C > T was associated with lower expression levels of PCSK9 ( Figure 3A ) and higher levels of IL36B and IL36G ( Figure 4, A and B ).…”

Section: Resultsmentioning

confidence: 99%

Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G

Merleev¹,

Ji‐Xu²,

Toussi³

et al. 2022

JCI Insight

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Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a posttranslational regulator of the LDL receptor (LDLR). Recent studies have proposed a role for PCSK9 in regulating immune responses. Using RNA-Seq–based variant discovery, we identified a possible psoriasis-susceptibility locus at 1p32.3, located within PCSK9 (rs662145 C > T). This finding was verified in independently acquired genomic and RNA-Seq data sets. Single-cell RNA-Seq (scRNA-Seq) identified keratinocytes as the primary source of PCSK9 in human skin. PCSK9 expression, however, was not uniform across keratinocyte subpopulations. scRNA-Seq and IHC demonstrated an epidermal gradient of PCSK9, with expression being highest in basal and early spinous layer keratinocytes and lowest in granular layer keratinocytes. IL36G expression followed the opposite pattern, with expression highest in granular layer keratinocytes. PCSK9 siRNA knockdown experiments confirmed this inverse relationship between PCSK9 and IL36G expression. Other immune genes were also linked to PCSK9 expression, including IL27RA , IL1RL1 , ISG20 , and STX3 . In both cultured keratinocytes and nonlesional human skin, homozygosity for PCSK9 SNP rs662145 C > T was associated with lower PCSK9 expression and higher IL36G expression, when compared with heterozygous skin or cell lines. Together, these results support PCSK9 as a psoriasis-susceptibility locus and establish a putative link between PCSK9 and inflammatory cytokine expression.

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Section: Resultsmentioning

confidence: 99%

Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G

Merleev¹,

Ji‐Xu²,

Toussi³

et al. 2022

JCI Insight

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“…Other non-biologic agents that have been used for the treatment of GPP, also with limited evidence, include mycophenolate mofetil, hydroxyurea, apremilast, and colchicine. Considering the acute lifethreatening characteristics of GPP flares, cyclosporine sometimes is preferred due to its rapid onset of action [7,8,33,[35][36][37][38]40].…”

Section: Gpp Treatmentmentioning

confidence: 99%

“…In Japan and other Asian countries, several biologics are approved for treatment the disease, including TNF inhibitors (infliximab, adalimumab, and certolizumab pegol), IL-17/IL-17R inhibitors (secukinumab, brodalumab, and ixekizumab), and IL-23 inhibitors (risankizumab and guselkumab) [7,8,33,[35][36][37][38]40]. Although these therapies are approved for GPP in Japan, all of them present uncertainties in terms of safety and efficacy in GPP treatment [36].…”

Section: Gpp Treatmentmentioning

confidence: 99%

Generalized Pustular Psoriasis: A Review on Clinical Characteristics, Diagnosis, and Treatment

Díaz

Daudén

Carrascosa

et al. 2023

Dermatol Ther (Heidelb)

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Generalized pustular psoriasis (GPP) is a rare, chronic, and severe inflammatory skin disorder characterized by sudden eruption of sterile pustules, often accompanied by systemic inflammation. GPP flares can be life-threatening if untreated, owing to potential serious complications such as sepsis and cardiovascular failure. Diagnosis and clinical measurement of disease severity in GPP are often difficult. Lack of standardized criteria in the international guidelines and the heterogeneity of cutaneous and extracutaneous symptoms make the diagnosis of GPP difficult. Clinical criteria for description and diagnosis of pustular conditions, including GPP, are variable and there is no specific agreement on commonly sustained concepts. Differentiation of GPP from other similar conditions/diseases is important and requires careful assessments. The evidence that supports current topical or systemic therapies is largely based on case reports and small studies. Some biologic agents that target key cytokines involved in the activation of inflammatory pathways have been used as treatments for GPP. Recently, spesolimab, an IL-36R antagonist, has been approved in the USA and Japan for the treatment of GPP flares in adults, but there are no currently approved treatments for GPP in Europe. The IL-36 pathway has recently emerged as a central axis driving the pathogenic inflammatory mechanisms of GPP. Biologic agents that inhibit the IL-36 pathway have shown efficacy and safety in patients with GPP, addressing a generally considered unmet medical need.

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“…66 The long-term existence and resilience of TRMs despite treatment supports the notion of TRMs as potential biomarkers for deep long-term remission and residual disease activity. [67][68][69] Though much research has recently been focused on TRMs other potential causes of disease memory in skin have been proposed. Langerhans cells have reduced mobility in the lesional psoriatic skin, can produce IL-23, and can modulate the pathogenicity of TRMs.…”

Section: Clinical Studiesmentioning

confidence: 99%

Early intervention and disease memory in psoriasis: A literature review

Abdallah

Emmanuel

Bregnhøj

et al. 2022

JEADV Clinical Practice

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Psoriasis is a chronic inflammatory skin disease, in which molecular and cellular changes retain following clinical resolution of psoriatic lesions, a form of disease memory (‘molecular scar’) that may reestablish the psoriatic inflammation. The increasing evidence of the benefits from early intervention in other immune‐mediated diseases prompts the question of whether early systemic intervention, such as biologics, in new‐onset cutaneous psoriasis may lead to improved clinical response and sustained remission by averting an inflammatory disease memory. Herein, we review the current evidence on early intervention and disease memory in psoriasis. The evidence is sparse and inconsistent, although an early intervention within 2 years of disease‐onset may provide a more favourable long‐term prognosis in psoriasis. However, ongoing randomised clinical trials will explore whether early intervention with biologics in new‐onset psoriasis will be an effective treatment strategy, and whether it prevents the molecular and cellular changes potentially underlying the inflammatory disease memory.

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From Empirical to Pathogenesis-Based Treatments for Psoriasis

Cited by 39 publications

References 86 publications

Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G

Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G

Generalized Pustular Psoriasis: A Review on Clinical Characteristics, Diagnosis, and Treatment

Early intervention and disease memory in psoriasis: A literature review

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