Background/Purpose: Guselkumab (GUS) is a fully human monoclonal antibody that binds to the p19 subunit of IL23. In a recent Phase 2 study, GUS demonstrated clinical reduction of signs and symptoms of arthritis and improvement of psoriatic lesions in patients with active psoriatic arthritis (PsA). Longitudinal analysis on serum proteins was performed to evaluate the impact of IL23 blockade on effector cytokines associated with the IL23/Th17 axis and biomarkers that may be impacted by treatment or associated with clinical response to GUS over 16 weeks.

Methods: In a double-blind, placebo-controlled, multicenter study (CTA:2014-003697-17), patients with active PsA and ≥3% body surface area (BSA) of plaque psoriasis despite current or previous treatment with standard of care therapies, including those previously exposed to anti-TNFα agents, were randomized 2:1 to receive GUS 100 mg subcutaneously (SC) (n=97) or placebo (PBO) (n=45) at weeks 0, 4, and every 8 weeks (q8w) thereafter through week 44. The study included 149 patients fulfilling the American College of Rheumatology 2012 criteria for the classification of PsA. Serum samples were collected at week 0, week 4, and week 16. Acute phase (C-reactive protein (CRP), serum amyloid A (SAA), soluble cell adhesion molecules (sICAM1, sVCAM1)) (Meso Scale Discovery Platform) and Th17 effector cytokines (IL17A, IL17F, and IL22) (SMC Immunoassay platform) were measured in the serum samples. Baseline protein levels were fitted in Generalized linear model (anti-TNF usage as covariate) to test for association with treatment group, baseline demographic and clinical phenotypes of PsA, PsA medicine history, and clinical response for major study endpoints. Within-subject change from baseline levels were used to test the pharmacodynamic effect of GUS and association with clinical response.

Results: Acute phase proteins (CRP, SAA, sICAM, sVCAM) and Th17 effector cytokines (IL17A, IL17F, and IL22) were elevated at baseline in patients with PsA compared to healthy (Mean levels ≥50% higher than healthy, P < 0.05). Baseline IL17A, IL17F and IL22 levels were positively correlated with BSA (R > 0.4 and P < 0.05). No correlation was identified with other demographics and ACR component measures evaluated. GUS treatment significantly decreased all 7 analytes at week 16 (P < 0.05), with significant down-modulation of IL17A, IL17F, IL22, and SAA already observed by week 4, which is consistent with clinical observations. Week 24 ACR20 responders to GUS had a significantly larger down-modulation of IL17F, IL22, and CRP compared to non-responders (P < 0.05). Week 24 PASI75 responders to GUS had a significantly larger down-modulation of sVCAM1 and IL17A compared to non-responders (P < 0.05).

Conclusion: In patients with active PsA in this study, GUS significantly decreased the levels of acute phase inflammation proteins and Th17 effector cytokines. These decreases were significant by the week 4 visit, suggesting a rapid pharmacodynamic effect of GUS. Down-modulation of IL17F, IL22, and CRP was associated with benefit to joint symptoms, while down-modulation of IL17A and sVCAM1 was associated with improvement in plaque psoriasis activity.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/reduction-of-serum-il17f-and-il22-by-il23p19-blockade-with-guselkumab-is-associated-with-improvement-in-joint-symptoms-in-psoriatic-arthritis/