Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial

Abstract

ObjectiveAssess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents.MethodsIn this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients.ResultsMore ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change −0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change −0.13). No unexpected adverse events were observed through week 60.ConclusionsThe interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.

Performance of 3 Enthesitis Indices in Patients with Peripheral Spondyloarthritis During Treatment with Adalimumab

“…First, patients with nonpsoriatic pSpA and patients with PsA both belong to the SpA group with predominant peripheral manifestations sharing common clinical and genetic features 1,2 . Second, the degree of improvements in enthesitis burden (mean change from baseline or percentage improvement or resolution of enthesitis) observed in our trial is comparable with that observed in patients with PsA 19,21,23 . Third, an imaging study comparing magnetic resonance imaging (MRI) and clinical examination showed similar enthesitis patterns (similar frequencies of enthesitis on MRI compared with clinical examination) in patients with PsA and SpA 27 .…”

“…The MASES showed inconsistent performance in terms of discriminatory properties in 3 trials of apremilast in PsA; no clear dose response was evident, and only 1 of 6 dose arms showed significant improvement versus PBO 18 . The lack of clear, evidence-based recommendations for enthesitis tools may explain the use of a modified MASES in a phase III trial of ustekinumab in PsA; in this version, the insertions of the plantar fascia-peripheral enthesitis sites were included along with the original MASES sites 19 . Using this PsA-modified MASES, ustekinumab 90 mg significantly improved enthesitis at Week 24 compared with PBO (median percentage change 48% vs 0%, respectively, p < 0.01) 19 .…”

“…However, there is no consensus or a clear recommendation regarding which of these enthesitis indices should be used, especially in pSpA 16,17 . Interestingly, the MASES, which was developed to identify entheses specific for axial disease in ankylosing spondylitis (AS), has been used in several PsA clinical studies with varying levels of success 18,19 . More recently, the LEI and SPARCC indices were used in PsA trials, likely because they include more peripheral sites characteristic of PsA 20,21,22,23 .…”

Targeting IL-17 in psoriatic arthritis

“…In a phase III PSUMMIT 1 trial, similar improvements were shown in PsA patients who were anti-TNF-experienced (78). In a PSUMMIT-2 phase III trial, data through week 60 indicated that ustekinumab induces long-term significant improvement in the joint, enthesitis/dactylitis and skin symptoms of active PsA (79). These findings supported the FDA approval of ustekinumab in the treatment of active PsA as of September 2013.…”

Of Mice and Men: Defining the Role of Interleukin 17 in Rheumatoid Arthritis

“…Indeed, all 5 of the antibodies above have been demonstrated to be effective in skin psoriasis, and 2 (ustekinumab and secukinumab) have been approved in the United States for this indication 4,5,7,8,9 . Ustekinumab has also been approved for the treatment of PsA, and there have been studies demonstrating the effectiveness of brodalumab and secukinumab in this disease as well 10,11 .…”