Guselkumab, a Selective Interleukin‐23 p19 Subunit Inhibitor, Resolves Dactylitis in Patients With Active Psoriatic Arthritis: Pooled Results Through Week 52 From Two Phase 3 Studies

Abstract

Objective Previous analyses of pooled DISCOVER‐1 and DISCOVER‐2 data through Week 24 showed significantly higher rates of dactylitis resolution in patients treated with guselkumab compared with placebo. Here, we investigate associations between dactylitis resolution and other outcomes through 1 year. Methods Patients were randomized 1:1:1 to receive subcutaneous injections of guselkumab 100 mg at Week 0, Week 4, and then every 4 or 8 weeks, or placebo with crossover to guselkumab at Week 24. Independent assessors determined dactylitis severity score (DSS; 0‐3/digit; total = 0‐60). Dactylitis resolution (DSS = 0) (prespecified) and at least 20%, at least 50%, and at least 70% DSS improvement from baseline (post hoc) were determined through Week 52 (nonresponder imputation for treatment failure through Week 24 and for missing data through Week 52). ACR50, tender/swollen joints, low disease activity (LDA) as assessed by composite indices, and radiographic progression (DISCOVER‐2 only) were assessed in patients with dactylitis versus without dactylitis resolution at Week 24 and Week 52. Results Patients with dactylitis at baseline (473 of 1118) had more severe joint and skin disease than those without dactylitis (645 of 1118). At Week 52, approximately 75% of guselkumab‐randomized patients with dactylitis at baseline had complete resolution; approximately 80% had at least 70% DSS improvement. Through Week 52, new‐onset dactylitis (DSS ≥1) was uncommon among patients with a DSS of 0 at baseline. Guselkumab‐randomized patients with dactylitis resolution were more likely to achieve ACR50, at least 50% reduction in tender and swollen joints, and LDA at Week 24 and Week 52 than those without resolution. At Week 52, patients with dactylitis resolution had numerically less radiographic progression from baseline (DISCOVER‐2). Conclusion Through 1 year, approximately 75% of guselkumab‐randomized patients had complete resolution of dactylitis; patients exhibiting resolution were more likely to achieve other important clinical outcomes. Given the high burden of dactylitis, resolution may be associated with better long‐term patient outcomes.

Association between enthesitis/dactylitis resolution and patient-reported outcomes in guselkumab-treated patients with psoriatic arthritis

“…Specifically, a greater proportion of guselkumab-randomized patients achieved such improvements compared with placebo at week 24 and demonstrated a clinically meaningful improvement in fatigue at week 52 across studies. We found that DR was associated with an increased likelihood of achieving fatigue response among biologic-naïve patients enrolled in DISCOVER-2, which is consistent with the findings from analyses previously conducted in the larger population of both biologic-naïve and -experienced patients with dactylitis in the pooled DISCOVER-1 and -2 population [ 22 ]. In that report, mediation analyses demonstrated the substantial direct effect of guselkumab on fatigue beyond its impact on achievement of MDA or 20% improvement in ACR response criteria or on changes in CRP levels.…”

“…Through the last efficacy assessment (week 100), two-thirds of guselkumab-treated patients achieved ER and three-quarters achieved DR. These results are similar to those based on pooled analyses through 1 year in subpopulations with enthesitis and/or dactylitis in both DISCOVER studies as well as the phase 2 study of guselkumab in PsA, which included patients with and without prior biologic experience [ 22 , 23 , 40 ]. The robust efficacy of guselkumab reported here further highlights the central role of the IL-23/IL-17 immune axis in the pathogenesis of PsA.…”

“…It also validates the p19 subunit of IL-23 as a relevant target for therapeutic intervention in patients with enthesitis and dactylitis. Results from other studies of patients treated with guselkumab and other biologic agents targeting pro-inflammatory cytokines in the IL-12, IL-23 or IL-17 pathways also confirm the appropriate use of guselkumab to treat these specific disease domains [ 22 , 23 , 41 ].…”

“…Only biologic-naïve patients were included, which may limit the generalizability of the results for patients treated previously with other biologic agents; however, studies of pooled DISCOVER-1 and DISCOVER-2 data support some of the same associations [ 22 , 23 ]. While analyses were not performed to evaluate the consistency of the relationships across subgroups defined by demographic or disease characteristics, in previous analyses from DISCOVER-2, rates of achieving resolution of dactylitis and enthesitis were largely consistent across such subgroups through 2 years [ 43 ].…”

Enthesitis and Dactylitis Resolution with Risankizumab for Active Psoriatic Arthritis: Integrated Analysis of the Randomized KEEPsAKE 1 and 2 Trials

“…In the phase 3 PSUMMIT-1 and PSUMMIT-2 studies of the IL-12/23 inhibitor ustekinumab, significantly greater improvements in enthesitis and dactylitis were observed in ustekinumab-treated patients compared with those patients who received placebo [ 22 , 23 ]. In the phase 3 DISCOVER-1 and DISCOVER-2 studies, the IL-23 inhibitor guselkumab demonstrated higher rates of enthesitis and dactylitis resolution compared with placebo [ 24 , 25 ]. These results indicate that IL-23 inhibition is efficacious in improving and resolving enthesitis and/or dactylitis in patients with PsA.…”