Psoriatic arthritis is a chronic inflammatory disease associated with peripheral joint inflammation, enthesitis, dactylitis, axial disease, and cutaneous and nail involvement, all of which can substantially limit physical function and impair quality of life. Although the introduction of biologics (eg, tumor necrosis factor-α [TNF] inhibitors, ustekinumab, interleukin-17A [IL-17A] inhibitors, and abatacept) and oral drugs (eg, apremilast and tofacitinib) has increased the extent and duration of achievable clinical responses, new therapies are needed to treat the diverse manifestations of psoriatic arthritis while maintaining a favourable benefit–risk profile.1
The origins of the varying clinical manifestations of psoriatic arthritis remain under study. The IL-23/T-helper cell 17 (Th17) pathway—via downstream IL-17 expression—appears crucial to skin manifestations. IL-23 can also induce IL-22, a cytokine implicated in enthesitis and bone formation,2 and, in part via IL-17A and TNF induction, elicit the joint symptoms and damage that are hallmarks of psoriatic arthritis. IL-23 is a heterodimer formed by pairing p19 and p40 subunits, the latter of which is shared with IL-12. Although IL-12 and IL-23 share the p40 subunit, they also encompass unique subunits (p35 for IL-12 and p19 for IL-23).3, 4 IL-23 has been established to be a predominant driver of autoimmune-mediated articular inflammation, whereas IL-12 is more likely to facilitate protection from autoimmune inflammation and T-cell exhaustion.4, 5, 6, 7 The divergent roles of these closely related cytokines are highlighted by differential skin effects, whereby abnormal differentiation of keratinocytes is triggered by IL-23 but not IL-12,6 and differing roles in the body's response to bacterial and viral infections, as well as tumour control via their regulation of T-cell function.5 Targeting the p19 subunit of IL-23, and thus sparing IL-12, has demonstrated robust efficacy in psoriasis,7, 8, 9, 10 suggesting a prominent upstream position of the cytokine in the inflammatory hierarchy across the psoriatic disease spectrum, and thereby meriting analysis of selective IL-23 inhibition via IL-23 p19 binding in psoriatic arthritis.
Research in context
Evidence before this study
We searched PubMed on Oct 7–8, 2019, for original research and review articles published in English since Jan 1, 2000, with the following search terms: “biologic”, “cytokine”, “dactylitis”, “enthesitis”, “interleukin”, “outcome”, “psoriasis”, “psoriatic arthritis”, “radiograph”, “structural damage”, and “treatment”. Current literature indicates that IL-23 is instrumental in driving the chronic inflammation associated with several immune-mediated diseases, including psoriasis and psoriatic arthritis. Guselkumab is a high-affinity, anti-IL-23 human monoclonal antibody that specifically binds the cytokine's p19 subunit and is approved to treat moderate-to-severe psoriasis. In a phase 2 study, selective blockade of IL-23 by guselkumab significantly improved signs and symptoms of active psoriatic arthritis and was well tolerated during 1 year of exposure.
Added value of this study
Results of DISCOVER-2, the larger of two trials comprising the first phase 3 programme investigating a novel mechanism of action to treat psoriatic arthritis, confirm that targeting the p19 subunit of IL-23 effectively treats the diverse manifestations across psoriatic arthritis domains. Specifically, in patients with active disease despite standard treatments, but no previous exposure to biologics, subcutaneous guselkumab 100 mg significantly improved joint symptoms, dactylitis, enthesitis, psoriasis, physical function, and health-related quality of life when administered every 4 or 8 weeks. Guselkumab given every 4 weeks afforded significantly less progression of structural damage up to week 24 than did placebo, providing evidence of inhibition of radiographic progression by an IL-23 inhibitor that targets the p19 subunit. The overall safety profile of guselkumab in psoriatic arthritis patients was similar to that observed in patients with psoriasis treated with guselkumab.
Implications of all the available evidence
Consistent with previous findings of a proof-of-concept study confirming that IL-23 plays a crucial role in the pathogenesis of psoriatic arthritis, data from this phase 3 trial provide pivotal evidence that guselkumab offers a novel mechanism of action to treat the diverse clinical manifestations and inhibit the structural damage progression of psoriatic arthritis.
Guselkumab (Janssen Biotech, Horsham, PA, USA), a high-affinity, human monoclonal antibody that binds specifically to the p19 subunit of IL-23, is approved to treat patients with moderate-to-severe psoriasis who are candidates for systemic or phototherapy. In a randomised, placebo-controlled, phase 2 trial in patients with psoriatic arthritis, guselkumab demonstrated efficacy across all endpoints related to joint signs and symptoms, physical function, skin disease, enthesitis, dactylitis, and health-related quality of life.11
Here, we report 24-week results from one of two phase 3 trials (DISCOVER-2), conducted to assess guselkumab in biologic-naive patients with active psoriatic arthritis. DISCOVER-2 assessed patient outcomes related to joint and skin manifestations as well as structural damage. Results from the other registrational trial of guselkumab in psoriatic arthritis (DISCOVER-1), which aimed to enrol patients with a broader range of baseline levels of disease activity, some of whom were previously treated with one or two TNF inhibitors, are reported separately.12