Correction: Effect of guselkumab on serum biomarkers in patients with active psoriatic arthritis and inadequate response to tumor necrosis factor inhibitors: results from the COSMOS phase 3b study

Methods Adults with active PsA ( ≥ 3 swollen joints, ≥ 3 tender joints) and IR to one or two TNFi (TNFi-IR) were randomized 2:1 to guselkumab at Weeks 0, 4, then every 8 weeks (Q8W) or placebo ➔ guselkumab Q8W at Week 24 with possible early escape at Week 16. Levels of serum cytokines, including interferon γ (IFN γ ), IL-10, and tumor necrosis factor α (TNFα); T helper 17 (Th17) effector cytokines IL-17A, IL-17F, and IL-22; and acute phase proteins C-reactive protein (CRP), IL-6, and serum amyloid A (SAA), were assessed and compared with demographically matched healthy controls; guselkumab pharmacodynamics through Week 24 were also assessed.

…Guselkumab-treated participants achieving ACR20 response at Week 24 exhibited higher baseline IL-22 and IFNγ levels versus nonresponders… Keywords Serum biomarkers, IL-23/IL-17 pathway, Guselkumab, Psoriatic arthritis Background … Treatment recommendations from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis have highlighted interleukin (IL)-23 inhibitors (IL-23i), along with TNFi, IL-17i, and IL-12/IL-23i, as appropriate for use in both biologic-naive and biologicexperienced patients with peripheral joint symptoms… …The objectives of this analysis were to evaluate baseline serum levels of proinflammatory biomarkers in participants with TNFi-IR PsA in the COSMOS trial in comparison with healthy controls and the relationship of these biomarker levels with… Clinical assessments …ACR20 response was used to assess efficacy in the joints at Week 24.Skin responses were assessed among participants with ≥ 3% BSA and Investigator's Global Assessment (IGA) score ≥ 2 [22] at…To assess consistency of response in the biomarker cohort versus the overall COSMOS population, additional efficacy outcomes at Week 24 determined in the biomarker cohort were ≥ 50% improvement by ACR criteria (ACR50) response, ≥ 75% improvement in PASI (PASI75), change…

Biomarker sample collection
In COSMOS, blood samples for biomarker analyses were collected from all participants at Weeks 0, 4, 16, 24, and 48 into standard serum separation tubes… Serum samples from 24 healthy control volunteers (defined as those with no signs of active inflammation,…

Statistical analyses
This analysis included participants with available baseline values and follow-up biomarker and clinical data over time.All analyses were post hoc; thus, reported p values are nominal….

Analysis of baseline serum biomarker levels and correlation with disease activity
…Differences in baseline serum cytokine levels between participants with PsA and healthy controls were assessed using log2-transformed data with a general linear model… …Correlations between baseline serum biomarker levels and baseline disease activity (i.e., DAPSA scores, PASDAS, and PASI scores) were assessed using Spearman linear regression, with a Spearman correlation (rho) > 0.25 and p < 0.05 considered significant…

Analysis of association between biomarker levels and clinical response
…Differences in baseline biomarker levels by clinical response at Week 24 (i.e., response versus nonresponse for ACR20/50, IGA 0/1, and PASI75)….

Baseline serum levels and correlation with baseline disease activity
…Baseline CRP, SAA, and IL-6 levels were positively associated with baseline joint disease severity as measured by the DAS28-CRP (p ≤ 0.0001 for each biomarker)….
…IL-17A levels showed a trend towards a correlation with PASDAS.No statistically significant correlations were observed between baseline levels of other biomarkers evaluated and measures of baseline disease activity assessed (Table 1)…

Effect of treatment on biomarker levels
In participants randomized to guselkumab, reductions from baseline in the levels of… Th17 effector cytokines IL-17A, IL-17F,….. …biomarkers at Week 48 were similar to those observed in participants receiving guselkumab Q8W from baseline (Fig. 2)….

Discussion
…These findings were generally consistent with results from an exploratory biomarker analysis [16] in patients with active PsA from the DISCOVER-1 and -2 trials [13, 14]….
…The present study extends these findings by demonstrating that the pharmacodynamic effect of guselkumab is sustained through Week 48 in the COS-MOS TNFi-IR population, with levels of IL-17F, IL-22, CRP, and SAA approximating the levels seen in healthy controls at Week 48….
…The current limited data on predictors of response across biomarker studies make it difficult to incorporate precision medicine in the management of PsA at this stage….
…While analysis of serum levels allows for collection of serial samples in the clinic, evaluation of tissue would further our knowledge of disease pathogenesis and could potentially help further elucidate the mechanism(s) of action of guselkumab in joints, as preclinical evidence suggests that IL-17 is a key mediator of PsA joint pathogenesis [40]….