Efficacy and Safety of Secukinumab in Patients With Spondyloarthritis and Enthesitis at the Achilles Tendon

Results From a Phase 3b Trial

Frank Behrens; Philipp Sewerin; Eugenio de Miguel; Yusuf Patel; Anastas Batalov; Eva Dokoupilova; Christine Kleinmond; Effie Pournara; Ankita Shekhawat; Claudia Jentzsch; Annette Wiedon; Xenofon Baraliakos

Disclosures

Rheumatology. 2022;61(7):2856-2866. 

In This Article

Abstract and Introduction

Abstract

Objective: ACHILLES aimed to demonstrate efficacy of secukinumab on Achilles' tendon enthesitis in spondyloarthritis (SpA) patients.

Methods: Patients ≥18 years (n = 204) with active PsA or axial SpA and heel enthesitis were randomized 1:1 to secukinumab 150/300 mg or placebo up to week 24, and thereafter placebo patients were switched to secukinumab.

Results: At week 24, a higher, yet statistically non-significant (P = 0.136), proportion of patients in secukinumab vs placebo reported resolution of Achilles tendon enthesitis in affected foot (42.2% vs 31.4%; odds ratio [OR] = 1.63; 95% CI: 0.87, 3.08). Proportion of patients reporting resolution of enthesitis based on Leeds Enthesitis Index was higher with secukinumab vs placebo (33.3% vs 23.5%; OR = 1.65; 95% CI: 0.85, 3.25) at week 24. Mean change from baseline in heel pain at week 24 was higher in secukinumab patients vs placebo (−2.8 [3.0] vs −1.9 [2.7]). Greater improvements with secukinumab were observed in heel enthesopathy activity and global assessment of disease activity. Imaging evaluation by local reading confirmed heel enthesitis on MRI at screening for all patients. Based on central reading, 56% presented with bone marrow oedema and/or tendinitis; according to Heel Enthesitis MRI Scoring System (HEMRIS) post hoc analysis, 76% had signs of entheseal inflammation while 86% had entheseal inflammation and/or structural changes.

Conclusion: A substantial proportion of patients showed no signs of inflammation on the centrally read MRIs despite a clinical diagnosis of heel enthesitis, thus highlighting that the discrepancy between the clinical and imaging assessments of enthesitis requires further investigation. Although ACHILLES did not meet the primary end point, the study reported clinically meaningful improvements in patient-related outcomes.

Trial Registration: clinicaltrials.gov, NCT02771210

Introduction

Enthesitis is the hallmark feature of a broad spectrum of conditions termed spondyloarthritis (SpA) and can be the first clinical sign in this group of chronic progressive autoimmune disease.[1–3] The prevalence of enthesitis in patients with non-radiographic axial SpA (nr-axSpA) is 36% and ankylosing spondylitis (also termed radiographic axial SpA, r-axSpA) is 32–74%, with Achilles tendon, plantar fascia and lateral epicondyles presenting as the most common sites.[4,5] The heel is frequently affected in patients with PsA[6] and axial SpA (axSpA)[7] at an estimated proportion of 35% and 8.5% for PsA and axSpA patients, respectively.[8] The two most common causes for posterior heel pain are plantar fasciitis and Achilles enthesitis.[9]

The key symptom of entheseal involvement substantially contributing to the overall burden of disease in patients with PsA and axSpA is pain resulting in higher disease activity and lower quality of life (QoL).[10–12] In patients with r-axSpA, QoL assessments, including physical function and general health, were related to entheseal involvement.[13] PsA patients with enthesitis also reported worse disease outcomes compared with those without.[14]

IL-17, IL-23, and TNF are the effector cytokines of enthesitis, and their inhibition has proved effective in the management of PsA and axSpA.[1,15,16] Secukinumab, a fully human monoclonal antibody that directly inhibits IL-17A, has consistently demonstrated significant and sustained improvements in the signs and symptoms of PsA[16,17] and axSpA.[18–21] Studies focusing on the underlying entheseal inflammation as a treatment target to relieve symptoms are limited.[22]

ACHILLES (NCT02771210) investigated the efficacy and safety of secukinumab on the resolution of Achilles tendon enthesitis and the improvement of enthesitis-driven disease burden in patients with SpA and is so far the largest randomized controlled trial (RCT) that assessed clinical and imaging endpoints up to 52 weeks.

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