Background/Purpose: Guselkumab (GUS), an IL-23 inhibitor monoclonal antibody (MAb) that specifically binds the IL-23p19 subunit, demonstrated efficacy compared to placebo (PBO) in reducing skin & musculoskeletal signs & symptoms in patients (pts) with active PsA in two Ph3 studies, DISCOVER 1 & 2.^1,2 Results from a GUS PsA Ph2 trial³ & Ustekinumab (UST, anti-IL12/23p40 MAb) PsA Ph3 trials (PSUMMIT 1 & 2)⁴ showed associations of baseline IL-17A, IL-17F, & CRP with baseline disease characteristics, & associations of GUS-induced cytokine reductions with clinical responses. We investigated cytokine expression in PsA & changes post GUS therapy.

Methods: In DISCOVER 1 & 2, pts received GUS 100 mg at Week (Wk) 0, 4, then every 8Wks (q8w); GUS 100 mg q4w; or matching PBO. 21 serum biomarkers were measured in 300 PsA pts from DISCOVER at Wks 0, 4, & 24, & in 34 healthy controls matched for age, sex, & ethnicity. Serum proteins measured were acute phase reactants: CRP & SAA & inflammatory cytokines/chemokines: Th17 effector cytokines IL-17A, IL-17F, IL-22, soluble ICAM-1, soluble VCAM-1, IL-6, CXCL-8, IL-10, IL-13, IL-12p70, CCL22, IFN-γ, CCL2, CCL4, TNF-α, IL-1β, IL-2, IL-4 (MSD), & YKL-40. Serum IL-17A, IL-17B, & CRP measured in PSUMMIT⁴ were compared with GUS.

Results: Baseline serum levels of CRP, SAA, IL-6, IL-17A, & IL-17F were elevated in PsA pts vs healthy controls (p< 0.05, geometric mean [GM] ≥40% higher, FIG 1). No significant dysregulation in other cytokines in PsA pts vs healthy controls. Baseline IL-17A, IL-17F, IL-22, & CCL22 were significantly associated with baseline psoriasis disease activity (Body Surface Area & Psoriatic Area & Severity Index, Spearman Signed Rank p< 0.05, r >0.25). Baseline CRP, SAA, IL-6, & YKL40 were significantly associated with baseline joint disease (Disease Activity Score 28-CRP, Spearman p< 0.05, r >0.25). Baseline SAA, IL-6, IL-17A, & IL-17F were higher in pts with prior TNF inhibitor exposure than without (p< 0.05, GM ≥40% higher), although PsA pts with/without prior TNF inhibitor had higher levels vs healthy controls. GUS treatment resulted in decreases in serum CRP, SAA, IL-6, IL-17A, IL-17F, & IL-22 that were significantly greater than PBO as early as Wk 4 (FIG 1). These protein levels continued to decrease through Wk 24 in GUS-treated pts with both regimens (p< 0.05, GM decrease from baseline ≥ 33%). No significant difference in Wk 24 IL-17A & IL-17F levels for GUS vs healthy controls suggests a normalization of peripheral effector cytokines associated with the IL-23/Th17 axis post GUS treatment. Effects on IL-17A/IL-17F were greater in GUS vs UST treated pts, while CRP levels were similar in both programs (FIG 2).

Conclusion: Comprising a strong pharmacodynamic effect, GUS reduced serum protein levels of acute phase & Th17-effector cytokines (whose elevations at baseline were associated with PsA disease characteristics) & achieved comparable levels to those in healthy controls. In PsA pts, reductions of IL-17A & IL-17F by GUS were of greater magnitude than those by UST.

References:

1. Deodhar et al. Arth Rheumatol 2019;71 S10: 1386
2. Mease et al. Arth Rheumatol 2019;71 S10:5247
3. Siebert et al. Ann Rheum Dis 2019;78 S2:293
4. Siebert et al. Arth Rheumatol 2019;71:1660

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/guselkumab-induces-sustained-reduction-in-acute-phase-proteins-and-th17-effector-cytokines-in-active-psoriatic-arthritis-in-two-phase-3-clinical-trials-discover-1-and-discover-2/