Psoriasis vulgaris is a common skin disorder characterised by focal formation of inflamed, raised plaques that constantly shed scales derived from excessive growth of skin epithelial cells. The ...disease is defined by a series of linked cellular changes in the skin: hyperplasia of epidermal keratinocytes, vascular hyperplasia and ectasia, and infiltration of T lymphocytes, neutrophils, and other types of leucocyte in affected skin. In a relatively short period, psoriasis vulgaris has been conceptualised as a T lymphocyte mediated autoimmune disease and new biological therapies that target T cells have just entered routine clinical practice. Similarly, rapid progress has been made towards dissecting cellular and molecular pathways of inflammation that contribute to disease pathogenesis. This short review presents current pathogenic concepts that have emerged from genetic, genomic, and cellular information obtained in basic studies and from clinical studies of selective immune targeting drugs.
Summary
Background
The interleukin‐17 cytokine family plays a central role in psoriasis pathogenesis.
Objectives
To evaluate the efficacy and safety of brodalumab, a human anti‐interleukin‐17 ...receptor antibody, in treating patients with moderate‐to‐severe plaque psoriasis.
Methods
In this phase III, double‐blind, placebo‐controlled study (NCT01708590; AMAGINE‐1), adult patients in the U.S.A., Canada and Europe were randomized to brodalumab (140 or 210 mg) or placebo every 2 weeks (Q2W), with an additional dose at week 1, for a 12‐week induction phase. At week 12, patients receiving brodalumab who achieved static Physician's Global Assessment 0 or 1 (sPGA success) were rerandomized to the placebo or induction dose. After week 16, patients with sPGA ≥ 3 were re‐treated with the induction dose. After ≥ 12 weeks of retreatment, patients with sPGA 2 for ≥ 4 weeks or sPGA ≥ 3 were rescued with brodalumab 210 mg Q2W. At week 12, patients randomized to brodalumab with sPGA ≥ 2 or placebo received brodalumab 210 mg Q2W. Coprimary end points were the percentage of patients with ≥ 75% improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA success at week 12.
Results
There were 661 patients randomized: 220 placebo, 219 brodalumab 140 mg and 222 brodalumab 210 mg. At week 12, 60% (140 mg) and 83% (210 mg) vs. 3% (placebo) achieved PASI 75, and 54% (140 mg) and 76% (210 mg) vs. 1% (placebo) achieved sPGA success. The safety profile was considered acceptable.
Conclusions
Brodalumab therapy resulted in significant clinical benefit and an acceptable safety profile in patients with moderate‐to‐severe plaque psoriasis.
What's already known about this topic?
Anti‐interleukin (anti‐IL)‐17 receptor A and anti‐IL‐17A antibodies have been shown to be efficacious in treating patients with moderate‐to‐severe plaque psoriasis.
What does this study add?
This study further demonstrates that brodalumab therapy in patients with moderate‐to‐severe plaque psoriasis results in a high degree of complete skin clearance.
This study also further elucidates the safety profile of brodalumab.
Linked Comment: Ormerod. Br J Dermatol 2016; 175:243–244
Plain language summary available online
Summary
Background
There is a need for valid and reliable biomarkers in hidradenitis suppurativa (HS) for diagnosis and disease activity monitoring. Imaging‐based biomarkers have the potential to ...fulfil this unmet need but no evaluation of analytical or clinical validity has yet been undertaken.
Objectives
To evaluate the analytical and clinical validity of sonographic epidermal thickness, Doppler ultrasound and dermal tunnel diameter in patients with HS.
Methods
Twenty‐two participants with HS were recruited and underwent a total of 65 matched ultrasound and skin biopsies of lesional, perilesional and unaffected tissue. Ultrasound measurements were performed in triplicate with mean values used. Skin biopsies underwent immunohistochemistry as per previously published methods. Analytical validity was assessed in individual ultrasound–biopsy pairs (n = 65) by comparisons of sonographic variables with histological correlates. Clinical validity was assessed in individual patients (n = 22) by comparing measures of overall disease activity with sonographic outcomes.
Results
Epidermal thickness, dermal tunnel diameter and power Doppler intensity were assessed. Sonographic epidermal thickness and dermal tunnel diameter have high analytical validity with corresponding histological measurements. Power Doppler intensity demonstrated high correlation with dermal CD3+ and CD11c+ cell counts but not neutrophil elastase‐positive cells. Power Doppler ultrasound has significant correlation with pain scores, abscess and nodule count, International HS Severity Scoring System score and number of draining tunnels.
Conclusions
Sonographic epidermal thickness and dermal tunnel diameter have acceptable levels of analytical validity in the assessment of HS lesions. Power Doppler intensity demonstrates acceptable clinical and analytical validity, suggesting it is a valid imaging‐based biomarker in HS.
What is already known about this topic?
Image‐based biomarkers have potential for monitoring of hidradenitis suppurativa disease, but no evaluation of the analytical or clinical validity of image‐based biomarkers currently exists.
What does this study add?
Power Doppler intensity has greater analytical and clinical validity than epidermal thickness and dermal tunnel thickness.
What are the clinical implications of this work?
Power Doppler intensity is a valid imaging biomarker for disease activity in hidradenitis suppurativa.
Linked Comment: Wortsman. Br J Dermatol 2021; 184:591–592.
Summary
Background
Tildrakizumab is a high‐affinity, humanized, IgG1/κ, anti‐interleukin (IL)‐23p19 monoclonal antibody that does not bind human IL‐12 or p40 is being developed for the treatment of ...chronic plaque psoriasis.
Objectives
To evaluate the safety and efficacy of subcutaneous tildrakizumab in patients with moderate‐to‐severe chronic plaque psoriasis.
Methods
A three‐part, randomized, double‐blind, phase IIb trial was conducted in 355 adults with chronic plaque psoriasis. Participants were randomized to receive subcutaneous tildrakizumab (5, 25, 100, 200 mg) or placebo at weeks 0 and 4 (part I) and every 12 weeks thereafter until week 52 (part II). Study drug was discontinued at week 52 and participants were followed through week 72 (part III). Primary efficacy end point was Psoriasis Area and Severity Index (PASI) 75 response at week 16. Adverse events (AEs) and vital signs were monitored throughout the study.
Results
At week 16, PASI 75 responses were 33·3% (n = 14), 64·4% (n = 58), 66·3% (n = 59), 74·4% (n = 64) and 4·4% (n = 2) in the 5‐, 25‐, 100‐ and 200‐mg tildrakizumab and placebo groups, respectively (P ≤ 0·001 for each tildrakizumab dose vs. placebo). PASI 75 response was generally maintained through week 52; only eight of 222 participants who achieved PASI 75 response at week 52 and continued to part III relapsed following discontinuation up to week 72. Possible drug‐related serious AEs included bacterial arthritis and lymphoedema (part I), and melanoma, stroke, epiglottitis and knee infection (part II).
Conclusions
Tildrakizumab had treatment effects that were superior to placebo, maintained for 52 weeks of treatment, and persisted for 20 weeks after cessation. Tildrakizumab was generally safe and well tolerated. These results suggest that IL‐23p19 is a key target for suppressing psoriasis.
What's already known about this topic?
Immune mechanism‐specific targeted biological treatments have successfully demonstrated improvements in clinical outcomes in patients with chronic plaque psoriasis.
Selective interleukin (IL)‐23 inhibition has been a recent target for novel therapies and small initial phase I trials have confirmed safety and preliminary efficacy in humans.
What does this study add?
This is the first large‐scale phase II trial to evaluate a monoclonal antibody that selectively inhibits IL‐23 in patients with chronic plaque psoriasis
.
Linked Comment: Strober, Br J Dermatol 2015; 173: 887–888.
Summary
Background Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines, yet the relative contribution of interferon (IFN)‐γ, interleukin (IL)‐17 and IL‐22 on ...disease pathogenesis is still unknown.
Objectives In this study, we sought to identify the cytokines produced by skin‐resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors.
Methods We used intracellular cytokine staining and flow cytometry to evaluate T cell cytokine production, and immunohistochemistry and double‐label immunofluorescence to localize cytokine receptors in skin. Gene array analysis of cytokine‐treated keratinocytes was performed using moderated paired t‐test controlling for false discovery rate using the Benjamini–Hochberg procedure.
Results We demonstrate that T‐helper cells producing IL‐17, IL‐22 and/or IFN‐γ, as well as the cells bearing cognate cytokine receptors, are present in normal human skin. Keratinocytes stimulated with IL‐17 expressed chemokines that were different from those induced by IFN‐γ, probably contributing to the influx of neutrophils, dendritic cells and memory T cells into the psoriatic lesion. In contrast, IL‐22 downregulated genes associated with keratinocyte differentiation and caused epidermal alterations in an organotypic skin model.
Conclusions Our results suggest that the Th17 cytokines IL‐17 and IL‐22 mediate distinct downstream pathways that contribute to the psoriatic phenotype: IL‐17 is more proinflammatory, while IL‐22 retards keratinocyte differentiation.
Summary
Background
Genotype–phenotype correlation measures the correlation between the presence of a physical trait with a group of similar mutations but is dependent on reliable phenotyping. It can ...provide information on disease pathogenesis, future disease progression, severity or activity. Such indicators would be valuable in hidradenitis suppurativa (HS).
Objectives
To assess inter‐rater reliability (IRR) of HS clinical phenotypes and perform exploratory genotype–phenotype correlation in cases of HS with identified sequence variants.
Methods
Linkage disequilibrium between variants was assessed. Genotype–phenotype correlations were explored using Spearman correlation coefficients. IRR was calculated using Cohen's κ. Correlation between phenotype classifications was assessed using the χ2 statistic.
Results
Forty‐three sequence variants with clinical information were identified. Clinical phenotypes were classified as LC2 (n = 29; 67%), scarring folliculitis (n = 18; 42%), atypical (n = 38; 88%) and nodular (n = 26; 60%). LC1 phenotype was associated with regular (χ2 = 41·289, P < 0·001) and typical (χ2 = 29·013, P < 0·001) phenotypes. Cohen's κ was highest for van der Zee and Jemec (0·815), followed by Martorell‐Calatayud et al. (0·813), Naasan and Affleck (0·774) and Canoui‐Poitrine et al. (0·435) classifications. High linkage disequilibrium was seen between variants of Han Chinese pedigrees. No significant genotype–phenotype correlations were identified.
Conclusions
These findings may be influenced by selection, publication bias and the assumption that HS is a monogenic disorder. The poor IRR of existing phenotype measures suggests limited utility of existing measures. Further investigations into the correlation of clinical phenotypes with inflammatory biomarkers may aid in prognostic efforts for this disease.
What's already known about this topic?
Genotype–phenotype correlation can provide information regarding disease pathogenesis and predictions for future disease progression, severity or activity.
The identification of such indicators in hidradenitis suppurativa (HS) would be valuable for patients and clinicians alike, given the lack of biomarkers or clinical predictors of disease.
What does this study add?
Sixty‐five sequence variants across 20 separate genes were identified.
There was no significant correlation between phenotype classification in four separate classification schema and gene, mutation type or impact on Notch signalling.
Utility of current phenotype measurements are limited.
The lack of genotype–phenotype correlation in HS is suggestive that the underlying assumption of inherited HS as a monogenic disorder may need revision.
Linked Comment: Alavi and Piguet. Br J Dermatol 2019; 181:443–444.
Respond to this article
Summary
Background
Many immune‐mediated disorders, including psoriasis, involve cytokine signalling via Janus kinase (JAK) enzymes. ASP015K (also designated JNJ‐54781532), a novel oral JAK inhibitor, ...has shown moderate selectivity for JAK3 over JAK1 and JAK2 in enzyme assays.
Objectives
The objective of this study was to evaluate the efficacy and safety of escalating, sequentially grouped, doses of ASP015K vs. placebo in patients with moderate‐to‐severe psoriasis.
Methods
This phase 2a multicentre, double‐blind, randomized, placebo‐controlled study (NCT01096862) enrolled 124 patients with moderate‐to‐severe plaque psoriasis. Five sequential ASP015K cohorts were enrolled, consisting of four twice‐daily dosing groups (10, 25, 60, 100 mg) and one once‐daily dosing group (50 mg) for 6 weeks.
Results
The primary efficacy end point mean change in Psoriasis Area and Severity Index score from baseline to end of treatment (EOT; day 42) significantly favoured ASP015K (overall treatment effect; P < 0·001) vs. placebo, with greater improvements at higher doses. By EOT, the secondary end points Physician Static Global Assessment (PSGA) score, percentage of patients achieving PSGA success, and change in percentage, body surface area (BSA) also improved with ASP015K vs. placebo (P < 0·001 for PSGA score and BSA; P < 0·01 for PSGA success). Epidermal thickness and proliferation decreased from baseline with ASP015K vs. placebo. ASP015K was generally well tolerated, with no serious adverse events (AEs) reported.
Conclusions
In patients with moderate‐to‐severe psoriasis, ASP015K demonstrated dose‐dependent improvements in clinical and histological measures of severity over 6 weeks of treatment. At all doses, ASP015K was well tolerated, with no reported serious AEs.
What's already known about this topic?
Janus kinases (JAKs) mediate intracellular cytokine‐receptor signalling associated with plaque psoriasis.
What does this study add?
ASP015K is a novel JAK inhibitor with specificity for JAK3 and JAK1, which exhibits dose‐dependent reductions in psoriasis severity in patients with moderate‐to‐severe psoriasis, and was generally well tolerated in this phase 2a study.
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