Three Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Studies Evaluating the Efficacy and Safety of Ustekinumab in Axial Spondyloarthritis

Deodhar, Atul; Gensler, Lianne S.; Sieper, Joachim; Clark, Michael B.; Calderón, César; Wang, Yuhua; Zhou, Yiying; Leu, Jocelyn H; Campbell, Kim; Sweet, Kristen; Harrison, Diane D.; Hsia, Elizabeth C.; Heijde, Desirée van der

doi:10.1002/art.40728

Cited by 256 publications

(167 citation statements)

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“…In the spine, the paradigm was reversed with ustekinumab being reported as ineffective in the treatment of AS, and similarly, selective targeting of IL‐23p19 with risankizumab had no clinical effect for the treatment of established AS . However, inhibition of IL‐17A has shown clinical benefit for the treatment of AS .…”

Section: The Concept Of Il‐23–independent Il‐17 Productionmentioning

confidence: 99%

“…Furthermore, the TNF blockers are universally effective in the therapy of peripheral enthesitis involving the limbs but also the polyenthesitis that effects the spine . The highly surprising observation that IL‐23 blockers do not appear to be effective for spinal enthesitis but show efficacy for peripheral enthesitis has been an unexpected finding . It has been established that the spinal enthesis has a resident population of gamma delta T‐cells that can make IL‐17A independently of IL‐23 signaling .…”

Section: Animal Models Showing a Role For Il‐23 In Enthesitismentioning

confidence: 99%

“…114,115 In the spine, the paradigm was reversed with ustekinumab being reported as ineffective in the treatment of AS, and similarly, selective targeting of IL-23p19 with risankizumab had no clinical effect for the treatment of established AS. 116,117 However, inhibition of IL-17A has shown clinical benefit for the treatment of AS. 111,118,119 The fact that IL-23 inhibition is ineffective in the spine, whereas inhibition of the downstream effector molecule IL-17A is, strongly suggests an IL-23-independent mechanism for the production of IL-17A.…”

Section: The Con Cep T Of Il-23-independent Il-17 Produc Tionmentioning

confidence: 99%

“…239,240 The highly surprising observation that IL-23 blockers do not appear to be effective for spinal enthesitis but show efficacy for peripheral enthesitis has been an unexpected finding. 116,117 It has been established that the spinal enthesis has a resident population of gamma delta T-cells that can make IL-17A independently of IL-23 signaling. 93 However, no data are thus far available on the peripheral skeleton.…”

Section: Unraveling Role Of Il-23 In Enthesis Biologymentioning

confidence: 99%

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Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

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Section: The Concept Of Il‐23–independent Il‐17 Productionmentioning

confidence: 99%

Section: Animal Models Showing a Role For Il‐23 In Enthesitismentioning

confidence: 99%

Section: The Con Cep T Of Il-23-independent Il-17 Produc Tionmentioning

confidence: 99%

Section: Unraveling Role Of Il-23 In Enthesis Biologymentioning

confidence: 99%

See 2 more Smart Citations

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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“…In this issue of Arthritis & Rheumatology , Deodhar et al report negative phase III study results for ustekinumab in axial spondyloarthritis (SpA) . Ustekinumab is an interleukin‐12 (IL‐12)/IL‐23 inhibitor approved for the treatment of psoriasis, psoriatic arthritis (PsA), and Crohn's disease.…”

mentioning

confidence: 99%

Ustekinumab Fails to Show Efficacy in a Phase III Axial Spondyloarthritis Program: The Importance of Negative Results

Mease

2019

Arthritis & Rheumatology

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In this issue of Arthritis & Rheumatology, Deodhar et al report negative phase III study results for ustekinumab in axial spondyloarthritis (SpA) (1). Ustekinumab is an interleukin-12 (IL-12)/IL-23 inhibitor approved for the treatment of psoriasis, psoriatic arthritis (PsA), and Crohn's disease. PsA has close clinical and genetic associations with axial SpA, including genetic association with variants in the IL-23 receptor signaling pathway. In addition, ustekinumab demonstrated promising results in a phase II open-label proof-of-concept study among 20 patients with ankylosing spondylitis (AS). In this previous study, ustekinumab at 90 mg was given subcutaneously (SC) at baseline and at weeks 4 and 16, and 65% of patients met the Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (achieved an ASAS40 response) at 24 weeks (2). Many other outcomes also favored ustekinumab, including reduced evidence of inflammation on magnetic resonance imaging (MRI). These results suggested that ustekinumab's benefits may be comparable to those of tumor necrosis factor (TNF) and IL-17 antagonists, 2 classes of agents approved for use in AS. Thus, the negative results of the phase III trial came as a real surprise, notwithstanding that the earlier study was not placebo controlled.The phase III program for ustekinumab was well designed and comprehensive. Three different studies were undertaken: one in patients with radiographic axial SpA (otherwise known as AS) who were naive to biologic therapy; a second in patients with radiographic axial SpA who were intolerant of (or whose disease was refractory to) a single TNF inhibitor (TNFi); and a third in patients with nonradiographic axial SpA who had an inadequate response to nonsteroidal antiinflammatory drugs and could have been exposed to a single TNFi. These are now standard populations for a phase III program in axial SpA. Patients were randomized to receive either 45 mg or 90 mg ustekinumab or placebo administered SC. Sample size estimates for all 3 studies were chosen to achieve 90% power to detect treatment differences between ustekinu mab and placebo for the primary end point at a significance level of 0.05. Estimates of 40% achieving an ASAS40 response in the treatment group and 20% in the placebo group were used for power calculation.What was demonstrated? At 24 weeks in study 1, the ASAS40 responses in the placebo, 45 mg ustekinumab, and 90 mg ustekinumab arms were 28.4%, 31.0%, and 28.1%, respectively, showing no separation between treatment arms and placebo. Other measures, including spine MRI, showed no significant separation between the treatment arms and placebo. Based on these negative results, the decision was made to stop the whole phase III study program; thus, studies 2 and 3 were not completed. Results for patients in those studies who did complete 24 weeks showed a similar lack of difference between placebo and treatment arms.Did biomarker analysis shed any light on the results? In study 1, several analytes at ba...

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Measuring Outcomes in Axial Spondyloarthritis

Ogdie

Duarte‐García

Hwang

et al. 2020

Arthritis Care & Research

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Three Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Studies Evaluating the Efficacy and Safety of Ustekinumab in Axial Spondyloarthritis

Abstract: In these 3 placebo-controlled trials, efficacy of ustekinumab in the treatment of axSpA was not demonstrated. The safety profile was consistent with that of studies in other indications. This article is protected by copyright. All rights reserved.

Cited by 256 publications

References 40 publications

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Ustekinumab Fails to Show Efficacy in a Phase III Axial Spondyloarthritis Program: The Importance of Negative Results

Measuring Outcomes in Axial Spondyloarthritis

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