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Clinical trials investigating biologic immune targeting therapeutics should deliver insight regardless of direction of the primary clinical outcome. Given the remarkable specificity of the ‘molecular scalpels’ now consequent upon the pharmacologic biologic revolution, it is imperative to learn lessons, particularly from those studies whose outcomes challenge pathogenetic wisdom. In this context, progress in understanding and treatment of the spondyloarthritides (SpA) and related extra-articular manifestations, especially psoriasis and inflammatory bowel disease (IBD), has been remarkable in the last decade. This group of phenotypically related, but still rather heterogeneous conditions share common genetic and pathogenetic features, leading to the notion that common clinical responses across the SpA spectrum should arise from specific immune-targeted interventions. This notion may shortly be disabused.
Whereas initial therapeutic advances in SpA comprised adoption of tumour necrosis factor (TNF) inhibitors from rheumatoid arthritis, major recent therapeutic breakthroughs followed identification of a substantial role for the IL-23/IL-17 pathway in pathogenesis. These studies integrated insights from a composite of genome-wide association studies (GWASs), postfunctional genomic studies, tissue analyses and a variety of preclinical models. Advances have been most marked in psoriasis with ‘PASI100’ response rates of around 50%–70% following IL-17A or IL-23p19 inhibition.1–5 Subsequently, IL-12/23p40, IL-23p19 and IL-17A inhibitors demonstrated efficacy in psoriatic arthritis (PsA), although this has been somewhat less penetrant in terms of high-hurdle responses.6–11 The IL-17A inhibitor, secukinumab, has recently also been shown to be efficacious in patients with active ankylosing spondylitis (AS).12 Studies of IL-23 inhibition for the treatment of AS were commenced based on this suggestive preclinical and human data resource.
In Annals of the Rheumatic Diseases, Baeten and colleagues present a phase II clinical trial evaluating risankizumab, a humanised monoclonal antibody targeting the p19 subunit of IL-23, in patients with active AS.13 The authors and editors should be congratulated for …
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