Background/Purpose: Abatacept (ABA), a selective T-cell co-stimulation modulator, has been shown to improve disease activity in patients with psoriatic arthritis (PsA), but its effect on psoriatic inflammation at a molecular level has not been determined.

Methods: 40 patients received ABA and 38 received PBO in this substudy of a 24 week, Phase 3, randomized, double blind, placebo (PBO) controlled, multicenter study, followed by a 28 week open-label period in subjects with active PsA based on the Classification Criteria for Psoriatic Arthritis (CASPAR). 3mm punch skin biopsies were taken of lesional and non-lesional skin at Day 1 and of lesional skin at 24 weeks. Gene expression analysis was conducted using Affymetrix HGU133 2.0+ arrays. Differentially expressed genes (DEG) were evaluated with a cut-off of fold change >2.0 and FDR < 0.05. Results were validated with RT-PCR. To summarize per-patient differences across pathways, we also used gene set variation analysis (GSVA).

Results: Globally, gene expression of lesional skin (LS) in the ABA treatment group at week 24 more closely resembled non-lesional (NL) skin than did the placebo group at week 24. Comparing LS at week 24 to baseline NL skin, the placebo group had 38% more DEG (more transcriptionally abnormal). The ABA treated group had 48% fewer DEG (less transcriptionally abnormal). Improvement analysis showed significant normalization in curated gene sets representative of active psoriasis. Both the “PsA skin vs normal skin” gene set and the “PsA synovium vs normal synovium” gene set showed greater improvement in the ABA treated group than the placebo treated group. The improvement in many gene sets appeared to be amplified (50-90% improvement) for patients who achieved an ACR20, PASI75, and KRT16-75 responses vs those who did not regardless of treatment. Several cellular markers of epidermal growth and differentiation were reduced in both drug and PBO treated groups. This was significant in the ABA treated group for K16 and Ki67. There was a significantly greater % reduction in thickness, KRT16, Ki67, CD3 and CD11c in the ABA treated ACR20 and KRT16-75 responders group than in the ABA treatment group as a whole. In the ABA group, but not in PBO group, mRNA expression of IL22, IL17F, KRT16, CXCL1, CXCL8, IL1B, IL26, CCL18, iCOS, and CTLA4 was significantly decreased at Week 24 compared to Day 1 (p< 0.05). Changes in IL17A and IL23p19 mRNA in the skin were correlated with joint tenderness in all patients.

Conclusion: Abatacept modulates a wide range of inflammatory molecules in psoriasis skin lesions. At a molecular level, patients treated with ABA showed a reversion toward more transcriptionally normal gene patterns and markers of epidermal growth and differentiation. While the primary purpose of this study was to look at the effect of ABA on psoriatic inflammation, this was also an opportunity to evaluate any associations between the ACR20 components and changes in the skin at a molecular level over time. IL17A and IL23p19 in the skin were correlated with joint tenderness.  Cytokines produced in the skin might affect joints via diffusion through the blood.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/normalization-of-inflammatory-gene-expression-and-cellular-markers-by-abatacept-in-the-skin-lesions-of-psoriatic-arthritis-patients-a-biopsy-substudy-of-a-phase-iii-study/