Selective IL-23 inhibition normalises gene expression in active PsA

An analysis of gene expression profiles in blood of patients with active psoriatic arthritis (PsA) compared with healthy controls showed that genes related to neutrophils, monocytes, eosinophils, and macrophages are upregulated. Therapy with guselkumab starting after only 4 weeks led to a down-regulation of these genes towards a normalisation of whole blood transcriptomic signatures.

Based on the phase 3 trials results of DISCOVER-1 (NCT03162796) and DISCOVER-2 (NCT03158285), which together included over 1,000 patients with active PsA, the IL-23(p19)-blocker guselkumab has been approved for adults with moderate-to-severe psoriasis and active PsA [1,2]. Ms Michelle Miron (Janssen Research & Development, CA, USA) presented an analysis of gene expression in the blood of patients with PsA both at baseline and through week 24 of guselkumab treatment [3]. Their gene profiles were compared with demographically matched, healthy control subjects. Whole blood transcriptome profiling by RNA sequencing was performed using the NovaSeq 6000 System. “The cohort of PsA patients selected for the whole blood RNA sequencing was chosen to be representative of the overall DISCOVER-1 and -2 population,” Ms Miron explained.

The researchers found 355 upregulated genes and 314 downregulated genes in patients with PsA compared with the non-PsA control group. “Upregulated genes were associated with neutrophils, monocytes, and certain myeloid cells,” Ms Mirion said. This is consistent with the published literature. Downregulated genes were not specific to cell types.

“We then asked what is happening over time,” Ms Mirion continued. Therapy with guselkumab had a distinct effect on the disease-associated genes. Upregulated disease-associated genes were significantly decreased, and downregulated genes were significantly increased by guselkumab treatment versus placebo at week 4 and week 24. Changes from baseline with guselkumab showed directionality towards a normalisation of whole blood transcriptomic signatures. In contrast, there was no change in the placebo group. Moreover, in PsA patients who showed a good response to guselkumab treatment (defined as an American College of Rheumatology [ACR] 20 response), disease-associated genes were downregulated to a greater extent compared with non-responders at week 24.

These findings suggest a dysregulation of immune cell profiles in PsA. Most of these disease-associated genes can be modulated by guselkumab towards the direction of normalisation.

1. 
   
   1. Deodhar A, et al. Lancet 2020;395:1115–25.
   2. Mease P, et al. Lancet 2020:395:1126–36.
   3. Miron M, et al. Guselkumab, an anti-interleukin-23p19 monoclonal antibody, modulates core psoriatic arthritis gene expression in two phase 3 clinical trials (DISCOVER-1 and -2). FC24, Psoriasis from Gene to Clinic 2021, 9–11 December.

 

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Posted on 2 February, 2022