Response to secukinumab on synovitis using Power Doppler ultrasound in psoriatic arthritis: 12-week results from a phase III study, ULTIMATE

Abstract

Objectives: To investigate the dynamics of response of synovitis to IL-17A inhibition with secukinumab in patients with active PsA using Power Doppler ultrasound.

Methods: The randomized, placebo-controlled, Phase III ULTIMATE study enrolled PsA patients with active ultrasound synovitis and clinical synovitis and enthesitis having an inadequate response to conventional DMARDs and naïve to biologic DMARDs. Patients were randomly assigned to receive either weekly subcutaneous secukinumab (300 or 150 mg according to the severity of psoriasis) or placebo followed by 4-weekly dosing thereafter. The primary outcome was the mean change in the ultrasound Global EULAR and OMERACT Synovitis Score (GLOESS) from baseline to week 12. Key secondary endpoints included ACR 20 and 50 responses.

Results: Of the 166 patients enrolled, 97% completed 12 weeks of treatment (secukinumab, 99%; placebo, 95%). The primary end point was met, and the adjusted mean change in GLOESS was higher with secukinumab than placebo [-9 (0.9) vs -6 (0.9), difference (95% CI): -3 (-6, -1); one-sided P=0.004] at week 12. The difference in GLOESS between secukinumab and placebo was significant as early as one week after initiation of treatment. All key secondary endpoints were met. No new or unexpected safety findings were reported.

Conclusion: This unique ultrasound study shows that apart from improving the signs and symptoms of PsA, IL-17A inhibition with secukinumab leads to a rapid and significant reduction of synovitis in PsA patients.

Trial registration: ClinicalTrials.gov; NCT02662985.

Keywords: GLOESS; OMERACT; Power Doppler ultrasound; PsA; biological DMARDs; clinical outcome; joints; responsiveness; secukinumab; synovitis.

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

Figures

Fig. 1

Patient disposition through week 12 Screen failures are those who were screened but failed to meet the inclusion or met the exclusion criteria or met eligibility but did not move into treatment period 1 (i.e. the patient was not randomized; percentage is computed using the number of screened patients as the denominator). n: total number of patients.

Fig. 2

Distribution of synovitis detected by ultrasound and tender and swollen joints detected by clinical assessment at baseline The distribution of synovitis detected by ultrasound and distribution of tender and swollen joint detected by clinical examination at baseline side by side. Frequency of distribution varies from 0 to 80% (highest proportion of patients with ultrasound detected synovitis on wrist) and is visualized by a code of colour from yellow to red shown on the right bar. Grey colour means ultrasound did not assess synovitis of these joints. CMC: carpometacarpal; DIP: distal interphalangeal; MCP: metacarpophalangeal; MTP: metatarsophalangeal; PIP: proximal interphalangeal.

Fig. 3

PDUS efficacy outcomes through week 12 *P < 0.05 vs placebo. (A) primary endpoint GLOESS [MMRM, difference (95% CI): –3 (–6, –1),P =0.004] at Week 12; (B) GLOESS SH [MMRM, difference (95% CI): –3 (–6, –1), P =0.004]; and (C) GLOESS PD [MMRM, difference (95% CI): –2 (–3, –1), P =0.001]. The ‘null zone’ presented GLOESS scores was derived from the CI around the difference, which was obtained from the MMRM. It shows the area where the means are located when there is no significant difference between the groups at the P <0.05 level. GLOESS: Global OMERACT-EULAR Synovitis Score; LS: least squares; MMRM: mixed-effect model repeated measures; N: total number of randomized patients;n: number of evaluable patients; PD: Power Doppler; SEC: secukinumab; SH: synovial hypertrophy.

Fig. 4

Clinical efficacy outcomes through week 12 *P < 0.05 vs placebo. (A) ACR20 response [NRI, odds ratio (95% CI): 5 (2, 9), P <0.0001, relative risk: 2]; (B) ACR50 response [NRI, odds ratio (95% CI): 10 (4, 24), P <0.0001, relative risk: 5]; (C) ACR70 response [NRI, odds ratio (95% CI): 23 (3, 178), P =0.0013, relative risk: 18]; and (D) HAQ-DI score [MMRM, difference: ‒0.5 (‒0.6, ‒0.3); P <0.0001]. The ‘null zone’ presented HAQ-DI score was derived from the CI around the difference, which was obtained from the MMRM. It shows the area where the means are located when there is no significant difference between the groups at the P <0.05 level. HAQ-DI: Health Assessment Questioner Disability Index; LS: least squares; MMRM: mixed-effect model repeated measures; N: total number of randomized patients; n: number of evaluable patients; NRI: non-responder imputation; SEC: secukinumab.