Discussion
PsA, skin disease, PsA disease, PsA.
DISORDER, SKIN DISEASE, DISEASE, JOINT DISEASE, PATHOGENESIS
These results provide further support for the important role of the IL-23/IL-17 pathway in PsA pathogenesis and expand our knowledge of guselkumab pharmacodynamic effects in patients with TNFi-IR PsA. Baseline levels of IL-6, IL-10, IL-17A, IL-17F, IL-22, TNFα, and IFNγ were higher in participants with TNFi-IR PsA compared with healthy controls. These findings were generally consistent with results from an exploratory biomarker analysis [This study further demonstrates serum biomarker levels are likely associated with disease activity assessed using PsA-specific composite indices. For example, CRP levels positively correlated with PASDAS, which includes CRP level as a component. Further, IL-6, SAA, and IL-17A levels showed a trend towards correlation with PASDAS, suggesting their important roles in PsA disease activity. Also of note, a correlation between CRP and DAPSA was not observed despite DAPSA including CRP as a measure; the reason for this is unclear. In both the prior and current studies, the association between the serum biomarkers analyzed and SJC or TJC was limited and may indicate that tissue-specific variations in cytokine levels and/or other systemic factors also play a role in this complex disorder. Similar results were seen in analyses from the two phase 3 PSUMMIT studies of ustekinumab, which reported that serum levels of IL-23, IL-17A, and IL-17F correlated with baseline skin disease in participants with PsA, but did not find a clear association of these cytokines with joint disease [Similar to the DISCOVER-1 and -2 biomarker results in participants who were mostly biologic-naïve [Similar exploratory analyses have been performed in clinical studies with other classes of PsA treatments, including TNFi, IL-17i, and Janus kinase inhibitors [Results of analyses reported herein are limited by the potential incongruence between serum and tissue (e.g., joint and skin) levels of cytokines and acute phase proteins. 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 [We have now consistently observed correlations between serum biomarker levels and PsA disease activity in the DISCOVER-1 and -2 and COSMOS trials that reinforce the important role of serum inflammatory factors and cytokines in PsA pathogenesis. Additional research is needed to confirm these findings in a TNFi-IR population and more fully contrast with bio-naïve PsA patients. Further research will also be needed to strengthen the potential of using serum inflammatory biomarker levels to guide therapeutic selection for patients with PsA.