IL-36 gene expression in GPP lesions reduced by spesolimab

Different patterns of gene expression were identified in lesional compared with non-lesional skin of patients with generalised pustular psoriasis (GPP). In the Effisayil 1 trial, various changes present in lesional skin were re-transformed after spesolimab treatment.

“It is known that the dysregulation of the IL-36 signalling pathway is involved in the GPP pathogenesis,” Dr Ahmed Farag (Boehringer Ingelheim, Germany) stated. Spesolimab is a monoclonal, anti-IL-36R antibody with proven efficacy as a treatment of flaring GPP in the phase 2 Effisayil 1 trial (NCT03782792) [1,2]. This study also included a gene analysis of skin biopsies taken from lesional and non-lesional sites at different time points.

The study comprised 53 GPP patients experiencing an acute flare, who were randomised 2:1 to receive 900 mg of spesolimab or placebo once [2]. The primary endpoint of ‘no visible pustules’ (defined as Generalised Pustular Psoriasis Physician Global Assessment=0) at day 8 was achieved by 54.3% of the participants (one-sided P<0.001 for the risk difference vs placebo). Baseline biopsies were taken from lesional and non-lesional skin; lesional skin samples were also taken on days 8 and 57. RNA-sequencing and immunohistochemistry were performed in the skin samples.

In the gene expression analysis of the study, researchers compared baseline findings of lesional with non-lesional skin (adjusted P<0.05) and found 5,208 differentially expressed gene transcripts, of which 2,347 were upregulated and 2,861 downregulated [1]. “The lesional skin biopsies versus baseline at week 1 had 940 genes differentially expressed, reaching 2,200 genes at week 8,” Dr Farag pointed out. He elaborated that there were significantly differentially expressed genes in treatment responders compared with patients who did not achieve pustular clearance at week 1.

A closer look at the top 50 differentially expressed genes in lesional and non-lesional skin revealed pronounced dissimilarities. The group of most upregulated genes included IL-36A, IL-36B, and IL-36G. Further, genes linked to skin inflammation (i.e. DEFB4a, S100A7, S100A8, S100A9), neutrophilic recruitment (i.e. CXCL1, CXCL6, CXCL8), and pro-inflammatory cytokines (i.e. IL-6, IL-19, IL-20) showed markedly different expressions when comparing lesional versus non-lesional skin. At 1 and 8 weeks after a single dose of spesolimab, many genes were modulated within the lesional skin. Primarily, significantly decreased expression was found for the before upregulated IL-36 ligands, as well as genes associated with neutrophil recruitment and mediators of inflammation.

In a particular analysis of the IL-36 pathway, an IL-36 gene set variation analysis (GSVA), scores were significantly reduced in the spesolimab arm at day 8 (P=0.0047 for the difference to baseline) with a more robust effect at week 8 (P=0.001 for the difference to baseline). Interestingly, the researchers also found upregulation in the epidermal differentiation complex gene set. “We see increases in the GSVA score of this gene set at day 8 that was stronger at week 8, and all in all we see that this reflects spesolimab’s effect on restoring skin homeostasis,” Dr Farag stressed and pointed to a spesolimab-induced reversal of the lesional skin gene expression pattern that is linked to GPP.

“Pathway analysis showed that spesolimab did suppress genes involved in GPP pathogenesis and IL-36 signalling with GSVA scores also showing the decreases in the scores in the IL-36 gene set and increases in epidermal differentiation gene set after spesolimab treatment,” Dr Farag summarised.

 

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   1. Farag A. Spesolimab alters the molecular profile of lesional skin in patients with generalised pustular psoriasis with a clinical response. FC4, Psoriasis from Gene to Clinic 2021, 9–11 December.
   2. Bachelez H, et al. N Engl J Med 2021;385(26):2431–2440.

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Posted on 2 February 2022