Collagen Turnover Biomarkers Associate with Active Psoriatic Arthritis and Decrease with Guselkumab Treatment in a Phase 3 Clinical Trial (DISCOVER-2)

Abstract

Introduction: Guselkumab, a novel interleukin-23p19 subunit monoclonal antibody, has been shown to effectively improve the diverse manifestations of active psoriatic arthritis (PsA) in two phase 3 trials (DISCOVER-1, DISCOVER-2). Serum concentrations of extracellular matrix (ECM) biomarkers at baseline and following treatment with guselkumab were evaluated in patients with active PsA, and the relationship of these biomarkers with baseline PsA characteristics and clinical response to guselkumab treatment was explored.

Methods: Serum samples were collected at weeks 0, 4, 24, and 52 from a selected subset (N = 260) of the 739 biologic-naïve patients with PsA treated with guselkumab 100 mg every 4 or 8 weeks or placebo in DISCOVER-2. Demographically matched healthy controls (N = 76) were used for comparison. The samples were analyzed for ECM biomarkers associated with collagen degradation (C1M, C2M, C3M, C4M, C6M, C10C) and collagen formation (PRO-C1, PRO-C2, PRO-C3, PRO-C4, PRO-C6).

Results: Baseline concentrations of collagen degradation biomarkers C1M, C3M, C4M, and C6M and collagen formation biomarkers PRO-C3 and PRO-C6 were significantly higher (i.e., ≥ 1.25-fold and false discovery rate adjusted p < 0.05) in PsA patients than in healthy controls. Serum C1M, C3M, C4M, and C6M levels declined from baseline in guselkumab-treated patients in both dosing regimens. In addition, guselkumab-treated ACR20 responders (≥ 20% improvement in American College of Rhematology response criteria) had significantly lower C1M levels than ACR20 nonresponders.

Conclusion: These data demonstrate that serum collagen biomarkers are elevated in patients with PsA compared with healthy controls and that treatment with guselkumab decreases levels of C1M, C3M, C4M, and C6M. Importantly, C1M serves as a biomarker that associates with improvement of joint signs and symptoms.

Trial registration: ClinicalTrials.gov identifier: NCT03158285.

Keywords: Biomarkers; Collagen turnover; Extracellular matrix; Guselkumab; Psoriatic arthritis.

Fig. 1

Upregulation of collagen degradation and formation biomarkers in the serum of PsA patients (PsA biomarker subset: N = 260) compared to healthy controls (healthy control subset: N = 76). Healthy controls were demographically matched (age and sex) to the PsA biomarker subset. Values are shown as the median (mean is shown as a (plus [+] sign). Boxes represent the interquartile range, while whiskers represent the minimum and maximum values. The asterisk indicates significance defined by a fold change ≥ 1.25 and adjusted (adj) p < 0.05. C1M, C3M, C4M, C6M collagen degradation biomarkers, PRO-C1, PRO-C3 collagen formation biomarkers, PsA psoriatic arthritis

Fig. 2

Collagen degradation biomarkers (C1M, C3M, C4M, and C6M) significantly decrease with GUS vs. PBO at week 24. GUS treatment Q4W or Q8W significantly reduced collagen degradation biomarkers C1M, C3M, C3M, and C6M compared to PBO at 24 weeks. Asterisk indicates significant difference vs. PBO at adj p_GUSvsPBO < 0.05. Dagger indicates signficant difference vs. placebo at p_GUSvsPBO < 0.07. Error bars represent 1 standard error. GUS Guselkumab, Q4W, Q8W every 4 weeks, every 8 weeks, PBO placebo

Fig. 3

Significantly lower C1M expression in ACR20 responders vs. nonresponders at baseline and weeks 4 and 24. Response was defined by ACR20 (≥ 20% improvement according to the American College of Rheumatology criteria) at week 24. Values are shown as the median (mean is shown as a (plus [+] sign). Boxes represent the interquartile range, while whiskers represent the minimum and maximum values. Asterisk indicates signficant difference at p = 0.0065 between responder and nonresponder defined by fold change ≥ 1.25 and adj p < 0.05