Efficacy and Safety of IL-17 Inhibitors for the Treatment of Ankylosing Spondylitis

A Systematic Review and Meta-Analysis

Yufeng Yin; Mingjun Wang; Mengru Liu; Erye Zhou; Tian Ren; Xin Chang; Michun He; Keqin Zeng; Yufan Guo; Jian Wu

Disclosures

Arthritis Res Ther. 2020;22(111) 

In This Article

Abstract and Introduction

Abstract

Objectives: To systematically assess the efficacy and safety of IL-17 inhibitors in patients with active ankylosing spondylitis.

Methods: A systematic review of the literature was performed for randomized controlled trials (RCTs) concerning IL-17 inhibitors in patients with ankylosing spondylitis. Meta-analyses were used to determine the efficacy and safety of the IL-17 inhibitors in the treatment of these patients. The primary endpoint was predefined as the proportion of patients with at least 20% improvement in the Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16, and the secondary endpoint was defined as ASAS40 at week 16.

Results: Six phase III randomized, double-blind, placebo-controlled trials including 1733 patients (1153 patients received IL-17 inhibitors, including secukinumab or ixekizumab, whereas 580 patients received a placebo as comparators) were included. At week 16, the IL-17 inhibitor regimen produced a significant increase in the ASAS20 response rate (RR = 1.63, 95% CI 1.45 to 1.84, p = 0.00) and the secondary endpoint ASAS40 response rate (RR = 2.12, 95% CI 1.75 to 2.56, p = 0.00) versus those for the placebo. With respect to the safety profile, more treatment-emergent adverse events (RR = 1.11, 95% CI 1.01 to 1.22, p = 0.03) and non-severe infections (RR = 1.82, 95% CI 1.40 to 2.37, p < 0.001) were described after treatment with IL-17 inhibitors than after treatment with placebo, while no increased risk of other adverse events was indicated after IL-17 inhibitor therapy, including death, discontinuation due to adverse events, or serious adverse events.

Conclusions: IL-17 inhibitors produced favorable response rates but an increased risk of non-severe infections in the treatment of active ankylosing spondylitis.

Introduction

Ankylosing spondylitis is a chronic disease, with a prevalence ranging from 9 to 30 per 10,000 persons of the adult population worldwide.[1,2] Ankylosing spondylitis is generally characterized by irreversible and structural damage of the sacroiliac and spinal joints, and finally, progressive spinal ankylosis due to new bone formation.[3] Clinical presentations of these patients include chronic back pain, morning stiffness, and loss of spinal mobility, which primarily affect the pelvis and the lower back.[3] For the treatment of active ankylosing spondylitis, non-steroidal anti-inflammatory drugs (NSAIDs) are still the first-line recommended treatment approach in the current primary management recommendations.[4,5] On the other hand, there is no evidence that conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate and sulfasalazine, have any role in the treatment of axial manifestations, although these medications may slightly improve the peripheral symptoms that coexist with axial disease.[6] For patients who do not respond to or tolerate NSAIDs, biological disease-modifying antirheumatic drugs (bDMARDs), mainly tumor necrosis factor inhibitors (TNFis), have been recommended since the early 2000s.[4,5] However, approximately 30 to 40% of patients have disease that remains active after standardized treatment with NSAIDs and/or bDMARDs.[7–9] The emergence of interleukin (IL)-17 inhibitors has changed the treatment landscape of active ankylosing spondylitis.[10]

IL-17 is a pro-inflammatory cytokine that plays critical roles within a network of cytokines and is a key contributor to tissue repair on barrier surfaces, anti-infective immune responses, and the pathogenesis of various inflammatory diseases, especially ankylosing spondylitis.[3] This activity indicates that IL-17 blockade is a potential and efficient treatment option. During the past decade, there has been an increasing interest in the use of IL-17 inhibitors (such as secukinumab, ixekizumab, and brodalumab) in the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis.[11] Secukinumab is a fully recombinant human immunoglobulin G (IgG)1 kappa monoclonal antibody (mAb) that directly inhibits IL-17A. It is the first approved IL-17 inhibitor for the treatment of patients with ankylosing spondylitis.[12] Increasing studies have displayed the efficacy of secukinumab in the treatment of ankylosing spondylitis after the first randomized controlled trials (RCTs) that focused on IL-17 blockade in ankylosing spondylitis.[13] Ixekizumab is another mAb specific for IL-17A that is approved for the treatment of moderate-to-severe plaque psoriasis and active psoriatic arthritis.[14,15] Recently released results demonstrated that ixekizumab can also improve the clinical presentations of patients with ankylosing spondylitis.[16,17] Brodalumab is a human mAb that binds with high affinity to human IL-17 receptor A (IL-17RA) and can lead to a significantly efficacious therapeutic alternative for psoriasis and psoriatic arthritis.[18–20] However, a clinical trial in psoriasis was aborted after several cases of suicide attempts, even though the association between IL-17RA inhibitor and suicidal tendency is still not confirmed.[21] Clinical trials focusing on several other IL-17 inhibitors, including bimekizumab and netakimab, are underway to evaluate their therapeutic potential in ankylosing spondylitis.[10]

To date, a comprehensive overview of different IL-17 inhibitors as an entity in ankylosing spondylitis has not been satisfactorily explained. In the present study, we therefore assessed the efficacy and safety of IL-17 inhibitors in the treatment of ankylosing spondylitis via a systematic review and quantitative meta-analysis of data from the recently released RCTs.

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