Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis

Mease, Philip J.; Hall, Stephen; FitzGerald, Oliver; Heijde, Desirée van der; Merola, Joseph F.; Ávila‐Zapata, Francisco; Cieślak, D.; Graham, Daniela; Wang, Cunshan; Menon, Sujatha; Hendrikx, Thijs; Kanik, Keith S.

doi:10.1056/nejmoa1615975

Cited by 483 publications

(581 citation statements)

References 19 publications

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“…Psoriatic arthritis is an autoimmune disease that affects both joints and the skin. Tofacitinib was found to be superior to placebo in patients with psoriatic arthritis who had previously had an inadequate response to conventional disease modifying agents and TNF inhibitors . Tofacitinib is now approved for this indication (Table ).…”

Section: A Brief Survey Of Approved and Late Phase Jakinibsmentioning

confidence: 99%

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

130

100

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In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.

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Section: A Brief Survey Of Approved and Late Phase Jakinibsmentioning

confidence: 99%

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

130

100

View full text Add to dashboard Cite

show abstract

“…A report showed that tofacitinib may lead to the inhibition of the functional effects of IL‐23 on memory T‐cells and suppresses the expression of IL‐23 receptor during the stimulation of lymphocytes . Different studies have reported the effect of tofacitinib on enthesitis in PsA . Although this may not be primary or exclusively driven by affecting IL‐23 secretion, yet we believe that JAKi are unique in their mechanism of action by affecting the production of several cytokine and, in this case, also IL‐23.…”

Section: Pathogenic Role Of Il‐23 In Enthesitis From Clinical Datamentioning

confidence: 82%

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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“…Example In this hypothetical example targeting at a real clinical trial scenario, we consider designing a two‐arm superiority Phase 3 trial for a new oral drug in a Janus kinase inhibitor class to treat patients with psoriatic arthritis. The design is based on the recently published data from a Tofacitinib (Tofa), a Janus kinase inhibitor compound, psoriatic arthritis Phase 3 study . The primary efficacy endpoint of the trial was the composite binary endpoint ACR20, a measurement of patients' improvement in signs and symptoms, at the three‐month time point.…”

Section: Implementation Examplesmentioning

confidence: 99%

On the efficiency of adaptive sample size design

Zhang

2018

Statistics in Medicine

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Adaptive sample size designs, including group sequential designs, have been used as alternatives to fixed sample size designs to achieve more robust statistical power and better trial efficiency. This work investigates the efficiency of adaptive sample size designs as compared to group sequential designs. We show that given a group sequential design, a uniformly more efficient adaptive sample size design based on the same maximum sample size and rejection boundary can be constructed. While maintaining stable statistical power at the required level, the expected sample size of the obtained adaptive sample size design is uniformly smaller than that of the group sequential design with respect to a range of the true treatment difference. The finding provides further insights into the efficiency of adaptive sample size designs and challenges the popular belief of better efficiency associated with group sequential designs. Good adaptive performance plus easy implementation and other desirable operational features make adaptive sample size designs more attractive and applicable to modern clinical trials.

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Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis

Cited by 483 publications

References 19 publications

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

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

On the efficiency of adaptive sample size design

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