Ixekizumab and complete resolution of enthesitis and dactylitis: integrated analysis of two phase 3 randomized trials in psoriatic arthritis

Abstract

Background: Ixekizumab improves signs/symptoms of psoriatic arthritis (PsA). We present an integrated analysis of baseline disease burden and post-baseline outcomes in ixekizumab-treated patients with enthesitis or dactylitis.

Methods: Data from SPIRIT-P1 and SPIRIT-P2 were integrated. Patients with PsA were randomized to 80-mg ixekizumab every 4 weeks (IXEQ4W) or 2 weeks (IXEQ2W), after a 160-mg starting dose, or to placebo. Inadequate responders at week 16 received rescue therapy. Among patients with baseline enthesitis (Leeds Enthesitis Index [LEI] > 0) or dactylitis (Leeds Dactylitis Index-Basic [LDI-B] > 0), baseline characteristics and disease burden were reported. At week 24, LEI and LDI-B (percentage of patients with resolution [LEI = 0, LDI-B = 0]) were assessed. In pooled treatment groups, the impact of enthesitis or dactylitis resolution on health-related quality of life (HRQoL) (EuroQol-5 Dimensions Visual Analogue Scale [EQ-5D VAS]), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and pain was assessed.

Results: The integrated analysis set comprised 679 patients; of these, 60% (n = 403 of 675) had baseline enthesitis (LEI > 0) and 23% (n = 155 of 676) had baseline dactylitis (LDI > 0). At week 24, ixekizumab-treated patients experienced significantly more resolution than placebo of enthesitis (39% IXEQ4W, 35% IXEQ2W, 21% placebo) and dactylitis (78% IXEQ4W, 65% IXEQ2W, 24% placebo). Furthermore, at entheseal points measured by the LEI, ixekizumab-treated patients had significantly higher resolution of enthesitis compared to placebo. At week 24, among all placebo- and ixekizumab-treated patients, resolution of enthesitis was associated with improvements in function and HRQoL whereas dactylitis resolution was associated with more limited improvements. The least squares mean HAQ-DI improvements from baseline were - 0.44 and - 0.25 for patients who did/did not resolve enthesitis, and - 0.41 and - 0.31 for patients who did/did not resolve dactylitis. EQ-5D VAS improvements were 12.3 and 5.8 for patients who did/did not resolve enthesitis, and 10.8 and 9.8 for patients who did/did not resolve dactylitis.

Conclusions: Among patients with pre-existing enthesitis or dactylitis, IXEQ2W- and IXEQ4W-treatment resulted in significant improvements in enthesitis and dactylitis. Enthesitis resolution was associated with improvements in patients' function, pain, and HRQoL.

Trial registration: ClinicalTrials.gov, NCT01695239 , registered on September 25, 2012, and NCT02349295 , registered on October 10, 2014.

Keywords: Dactylitis; Enthesitis; Ixekizumab; Psoriatic arthritis.

Conflict of interest statement

Ethics approval

SPIRIT-P1 and SPIRIT-P2 were conducted in accordance with Good Clinical Practice, the principles of the Declaration of Helsinki, and local laws and regulations. Both SPIRIT-P1 and SPIRIT-P2 were registered at https://ichgcp.net/clinical-trials-registry/NCT01695239); SPIRIT-P2 was registered as NCT02349295 on 10-October-2014 (https://ichgcp.net/clinical-trials-registry/NCT02349295).

SPIRIT-P1 was approved by the Western Institutional Review Board (approval #1-838258-1) and SPIRIT-P2 was approved by the Bellberry Human Research Ethics Committee (Application #2015-01-049-AA). For both studies, approval was also obtained from each additional site. All patients in both studies gave written informed consent.

Consent for publication

Not applicable

Competing interests

D. D. Gladman is a consultant for AbbVie, Amgen, BMS, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, and UCB, and has received grant/research support from AbbVie, Amgen, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, and UCB.

A.-M. Orbai is a consultant for Eli Lilly and Company, Novartis, and has received grant/research support from AbbVie, Celgene, Eli Lilly and Company, Horizon, Janssen, and Novartis.

U. Kiltz has received grant and research support and consultancy fees from AbbVie, Biogen, Chugai, Grünenthal, Janssen, MSD, Novartis, Pfizer, Roche, and UCB.

J.C.-C. Wei has been consulted for Pfizer, Celgene, Chugai, UCB, and TSH (Taiwan); has received research grants from BMS, Janssen, Pfizer, Sanofi-Aventis, and Novartis; and has served on speakers bureaus for Abbott, BMS, Chugai, Eisai, Janssen, and Pfizer.

H. Marzo-Ortega has received grant/research support from Janssen and is on the speaker bureau for AbbVie, Celgene, Janssen, MSD, Novartis, Pfizer, and UCB.

G. Gallo, J. Birt, S. Rathmann, and D. Shrom are current employees and minor shareholders of Eli Lilly and Company.

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Figures

Fig. 1

Patients reporting no enthesitis (a) and no dactylitis (b) at week 24. Integrated analysis set with baseline enthesitis and dactylitis are shown as the percentages of responders (95% CI, NRI). *P vs PBO < 0.05; **P vs PBO < 0.001. Abbreviations: Achill tend insert, Achilles tendon insertion; CI, confidence interval; IXEQ2W, ixekizumab 80 mg every 2 weeks; IXEQ4W, ixekizumab 80 mg every 4 weeks; Lat epicond, lateral epicondyle; LEI, Leeds Enthesitis Index; LDI-B, Leeds Dactylitis Index-Basic; Med fem cond, medial femoral condyle; NRI, nonresponder imputation; PBO, placebo

Fig. 2

Impact of enthesitis or dactylitis resolution at week 24. Data are from integrated analysis sets of patients with baseline enthesitis and dactylitis. LS mean change from baseline (SE) of EQ-5D VAS (a) and HAQ-DI (b) scores in patients with enthesitis or dactylitis resolution. c Percentages of patients (NRI) with enthesitis or dactylitis resolution reporting improvement meeting or exceeding the MCID of the HAQ-DI (≥ 0.35). d Mean change from baseline (LOCF) (SD) of pain VAS. Only one side of the error bar is shown. Abbreviations: EQ-5D VAS, EuroQol-5 Dimensions Visual Analogue Scale; HAQ-DI, Health Assessment Questionnaire-Disability Index; LDI-B, Leeds Dactylitis Index-Basic; LEI, Leeds Enthesitis Index; LOCF, last observation carried forward; LSM, least squares mean; MCID, minimal clinically important difference; N, population size; n, number in group; NRI, nonresponder imputation; SD, standard deviation; SE, standard error; VAS, visual analogue scale