The approval of tumor necrosis factor inhibitors (TNFis) for the treatment of ankylosing spondylitis (AS) significantly changed the clinical trajectory of this aggressive chronic inflammatory disease. Traditionally, physical therapy, nonsteroidal anti-inflammatory drugs, and non-biologic disease-modifying agents were the only treatment options. These agents, while effective in alleviating the physical symptoms of AS, have not demonstrated efficacy in changing the disease course in patients with axial involvement.1 In contrast, TNFis have been shown to produce dramatic improvements in disease activity and physical function, controlling inflammation, and slowing down ossification of the axial skeleton.2 These benefits are, however, only demonstrated in patients who respond to TNFis.

Between 40% and 50% of patients with AS do not respond to TNFis, and in  patients who do, long-term efficacy with disease remission is rarely achieved. In fact, most patients flare after stopping TNFi treatment,2 although recent data from the Swiss Clinical Quality Management cohort suggest that TNFis can inhibit spinal radiographic progression.3 The non-responders to TNFis suggest that other pathways are involved in AS pathogenesis. The search for new therapeutic targets has presented an opportunity for an improved understanding of disease mechanisms in axial spondyloarthritis (SpA).

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Interleukin-17 (IL-17), an inflammatory cytokine involved in host defense against bacterial and fungal infections, has emerged as a pivotal player in AS pathogenesis. Focus on the key drivers of spondyloarthropathies is now on the IL23/IL-17 axis, supported by genetic studies and functional data.2,4, It has been postulated that IL-17 triggers the release of proinflammatory cytokines and chemokines by stimulating macrophages, fibroblasts, and epithelial and endothelial cells. Of the 6 isoforms of IL-17 (IL-17A to F), IL-17A has specifically been implicated in promoting bone formation and regeneration by facilitating osteoblast differentiation and proliferation.6 Therefore, inhibition of IL-17A has been identified as a therapeutic target that may halt AS radiographic progression. Supported by  IL-17 inhibition efficacy in psoriasis and psoriatic arthritis, several agents targeting the IL-17/IL-23 pathway have been evaluated for safety and efficacy in the treatment of AS.2,7 Specifically, agents targeting IL-17A include secukinumab and ixekizumab. Other investigational agents for AS include brodalumab (an IL-17 receptor blocker), and ustekinumab (an anti-IL-12/IL-23 agent).2,4,5,7 Of these agents, secukinumab is the most widely studied, and to date the first and only IL-17A inhibitor approved for the treatment of AS.8 The approval of secukinumab is a confirmation of the role of IL-17 in AS disease and offers an opportunity for other agents in this class beyond TNFis.

The approval of secukinumab was based on its demonstrated safety and efficacy, which was evaluated in a series of 4 randomized double-blind phase 3 clinical trials (MEASURE 1-4), which are summarized in a review by Dubash and colleagues.9 Overall, these studies showed a significant 20% improvement in Assessment of Spondyloarthritis International Society criteria  (ASAS20) with secukinumab treatment compared with placebo. A significantly improved ASAS20 response was also noted in patients who suboptimally responded to TNFis; long-term clinical response was maintained and secukinumab was well tolerated.9 Results with secukinumab are also encouraging with regard to the inhibition of radiographic progression, peripheral dactylitis, and enthesopathy; however, there is limited data to support a conclusive effect of secukinumab on the associated risk for Crohn disease and uveitis. While the risk for infection with secukinumab is comparable to TNFis, unlike TNFis, secukinumab to date has not been associated with a risk for tuberculosis infection or reactivation. In contrast to TNFi, there has been no report of demyelinating disease.10,11

Ixekizumab, a humanized IL-17A inhibitor approved for the treatment of psoriasis and psoriatic arthritis,12 has also been evaluated in two phase 3 trials for the treatment of AS. COAST-V, a trial including biologic-naïve patients and COAST-W, which included patients with inadequate response or intolerant to TNFis, have shown efficacy and safety data similar to secukinumab.13,14 These studies provide further support for the role of IL-17A in AS pathogenesis and a potential new treatment for AS.

With the approval of secukinumab, clinicians must decide whether to use a TNFi or an IL-17A inhibitor. Although there is an established clinical history with TNFis and, according to current guidelines it is the treatment of choice in patients with active axial SpA, switching to an IL-17A inhibitor or to another TNFi can be effective if there is a primary or secondary non-response.15 However, an IL-17A inhibitor may be considered the treatment of choice over a TNFi in special circumstances, such as in patients in whom a TNFi is contraindicated or patients with a higher risk for tuberculosis or in patients with psoriasis with a high burden of peripheral arthritis.

“[Rheumatologists] understand that secukinumab for treating patients with AS is a fully human monoclonal antibody, its safety profile looks better than that of TNF inhibitors, and there is no black box warning,” stated Muhammad Asim Khan, MD, FRCP, MACP, MACR, professor emeritus of medicine at Case Western Reserve University, in Cleveland, Ohio. “Updated guidelines are soon to be published for axial spondyloarthritis.”

Clearly, further research is needed before definitive recommendations can be made, particularly for individuals with a history of inflammatory bowel disease or anterior uveitis. However, with the approval of secukinumab and the promising clinical studies with ixekizumab, IL-17A inhibitors offers new options for AS beyond TNFi agents.

References

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  12. Highlights of Prescribing Information: TALTZ (ixekizumab). Eli Lilly and Company. https://pi.lilly.com/us/taltz-uspi.pdf. Updated May, 2018. Accessed March 4, 2019.
  13. van der Heijde D, Cheng-Chung Wei J, Dougados M, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392(10163):2441-2451.
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