Resolution of enthesitis by guselkumab and relationships to disease burden: 1-year results of two phase 3 psoriatic arthritis studies

Dennis McGonagle, Iain B McInnes, Atul Deodhar, Georg Schett, May Shawi, Shelly Kafka, Chetan S Karyekar, Alexa P Kollmeier, Elizabeth C Hsia, Xie L Xu, Shihong Sheng, Prasheen Agarwal, Bei Zhou, Christopher T Ritchlin, Proton Rahman, Philip J Mease, Dennis McGonagle, Iain B McInnes, Atul Deodhar, Georg Schett, May Shawi, Shelly Kafka, Chetan S Karyekar, Alexa P Kollmeier, Elizabeth C Hsia, Xie L Xu, Shihong Sheng, Prasheen Agarwal, Bei Zhou, Christopher T Ritchlin, Proton Rahman, Philip J Mease

Abstract

Objective: To further characterize the effect of guselkumab, a selective IL-23p19-subunit inhibitor approved for PsA, on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes.

Methods: Adults with active PsA despite standard therapies in the phase 3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, Q8W; or placebo through week 20 followed by guselkumab 100 mg Q4W. Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0-6). Enthesitis findings through week 24 were pre-specified to be pooled across studies; post hoc and week 52 analyses also employed pooled data.

Results: Among 1118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1 LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at week 24 (45 and 50% vs 29%; both adjusted P = 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at week 52, including patients with mild (LEI = 1; 70-75%), moderate (LEI = 2; 69-73%) or severe (LEI = 3-6; 42-44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at week 24, 42% achieved minimal disease activity at week 52, vs 17% of patients with unresolved enthesitis.

Conclusion: Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by week 24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes.

Clinical trial registration: DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285).

Keywords: biologic; entheses; interleukin-23; p19 protein; psoriatic arthritis; spondyloarthritis.

© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.

Figures

Fig . 1
Fig. 1
Time to first enthesitis resolution through week 52 in PsA patients with enthesitis at baseline Observed resolution status pooled across DISCOVER-1 and DISCOVER-2. The intersections of the dashed lines represent the time points at which 50% of patients achieved resolution of enthesitis in the Q4W and Q8W groups (week 16) and in the placebo-crossover group (week 24). Enthesitis defined as LEI EC ≥ 1; enthesitis resolution defined as LEI EC = 0. Patients ‘at risk’ at each visit are those still with enthesitis. GUS: guselkumab; EC: enthesitis count; LEI: Leeds Enthesitis Index; PBO, placebo; Q4W/Q8W: every 4/8 weeks.
Fig . 2
Fig. 2
Enthesitis resolution at week 24 by baseline characteristics in PsA patients with enthesitis at baseline Data pooled across DISCOVER-1 and DISCOVER-2. Enthesitis defined as LEI EC ≥1; enthesitis resolution defined as LEI EC = 0 (patients meeting TF criteria were considered non-responders). Q4W, n = 243; Q8W, n = 230; PBO, n = 255. csDMARD: conventional synthetic DMARD; EC: enthesitis count; GUS: guselkumab; IGA: Investigator’s Global Assessment of psoriasis; LEI: Leeds Enthesitis Index; PASI: Psoriasis Area and Severity Index; PBO: placebo; Q4W/Q8W: every 4/8 weeks.
Fig . 3
Fig. 3
Heat-map of patient-level changes in enthesitis through week 52 in PsA patients with enthesitis at baseline Observed scores pooled across DISCOVER-1 and DISCOVER-2. Enthesitis defined as LEI score ≥1 (n = 720, excludes eight patients with assessment of only 4/6 LEI entheseal sites). Patients with missing data following discontinuation are shown as white. BL: baseline; GUS: guselkumab; LEI: Leeds Enthesitis Index; Q4W/Q8W: every 4/8 weeks.
Fig . 4
Fig. 4
Clinical response at weeks 24 and 52 by enthesitis resolution status Data pooled across DISCOVER-1 and DISCOVER-2. Enthesitis defined as LEI EC ≥1; enthesitis resolution defined as LEI EC = 0 (patients meeting treatment failure criteria were considered non-responders). ACR50: ≥50% improvement in ACR response criteria; EC: enthesitis count; ER: enthesitis resolution; GUS: guselkumab; LEI: Leeds Enthesitis Index; MDA: minimal disease activity; PBO: placebo; Q4W/Q8W: every 4/8 weeks; SJC: swollen joint count; TJC: tender joint count; Y/N: yes/no.

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