Modulation of Interleukin‐23 Signaling With Guselkumab in Biologic‐Naive Patients Versus Tumor Necrosis Factor Inhibitor–Inadequate Responders With Active Psoriatic Arthritis

Abstract

ObjectiveAssess and compare immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)‐23p19‐subunit inhibitor, in participants with active PsA who were biologic‐naïve or had inadequate response to tumor necrosis factor inhibitors (TNFi‐IR).MethodsSerum biomarker levels at baseline and following treatment with guselkumab 100 mg Q8W were compared between biologic‐naïve (N=251) and TNFi‐IR (N=93) subgroups identified in the pooled DISCOVER‐1/DISCOVER‐2/COSMOS dataset. Baseline biomarker levels determined by achievement of Week‐24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2‐point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between subgroups.ResultsBaseline IL‐22, TNFα, and beta defensin (BD)‐2 levels were significantly lower in biologic‐naïve than in TNFi‐IR participants. With guselkumab, Week‐24 IL‐17A, IL‐17F, IL‐22, serum amyloid A, C‐reactive protein, IL‐6, and BD‐2 levels were significantly reduced from baseline in biologic‐naïve and TNFi‐IR participants (≥1.4‐fold difference, nominal P<0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL‐17A, IL‐17F, BD‐2 in biologic‐naïve PASI 90 responders; IL‐17A, BD‐2 in TNFi‐IR IGA 0/1 responders; IL‐22, BD‐2 in TNFi‐IR PASI 90 responders [nominal P<0.05]) and trended higher in TNFi‐IR ACR20 responders.ConclusionGuselkumab modulates IL‐23 signaling and provides consistent pharmacodynamic effects in both biologic‐naïve and TNFi‐IR PsA patients. Significantly elevated baseline IL‐22, TNFα, and BD‐2 levels and associations between baseline IL‐22, IL‐17A, and BD‐2 levels and skin responses with guselkumab suggest greater dysregulation of IL‐23/Th17 signaling in TNFi‐IR patients.