Abstract
Psoriasis relapse may involve compensatory T-cell activation pathways in the presence of CD28-CD80/CD86 blockade with abatacept. To determine whether costimulatory signaling blockade with abatacept prevents psoriasis relapse after ustekinumab withdrawal. Psoriasis Treatment with Abatacept and Ustekinumab: a Study of Efficacy (PAUSE), a parallel-design, double-blind, placebo-controlled randomized clinical trial, was conducted at 10 sites in the US and Canada. Participant enrollment opened on March 19, 2014, and concluded on April 11, 2016. Participants were adults with moderate to severe plaque psoriasis and received ustekinumab in a lead-in phase. Those who responded to ustekinumab at week 12 were randomized 1:1 to either the continued with ustekinumab group (ustekinumab group) or the switched to abatacept group (abatacept group). Treatment was discontinued at week 39, and participants were followed up for psoriasis relapse until week 88. Statistical analyses were performed in the intention-to-treat (ITT) and safety samples from May 3, 2018, to July 6, 2021. Participants received subcutaneous ustekinumab at weeks 0 and 4 (45 mg per dose for those ≤100 kg; 90 mg per dose for those >100 kg). Participants randomized to the abatacept group at week 12 received subcutaneous abatacept, 125 mg weekly, from weeks 12 to 39 and ustekinumab placebo at weeks 16 and 28. Participants randomized to the ustekinumab group received ustekinumab at weeks 16 and 28 and abatacept placebo weekly from weeks 12 to 39. The primary end point was the proportion of participants with psoriasis relapse (loss of ≥50% of the initial Psoriasis Area and Severity Index improvement) between weeks 12 and 88. Secondary end points included time to psoriasis relapse, proportion of participants with psoriasis relapse between weeks 12 and 40, and adverse events. The psoriasis transcriptome and serum cytokines were evaluated. A total of 108 participants (mean [SD] age, 46.1 [12.1] years; 73 [67.6%] men) were treated with open-label ustekinumab; 91 were randomized to blinded treatment. Similar proportions of participants in the abatacept group and the ustekinumab group relapsed between weeks 12 and 88 (41 of 45 [91.1%] vs 40 of 46 [87.0%]; P = .41). Median time to relapse from the last dose of ustekinumab was similar between groups as well: 36 weeks (95% CI, 36-48 weeks) in the abatacept group vs 32 weeks (95% CI, 28-40 weeks) in the ustekinumab group. Similar numbers and rates of adverse events occurred. Abatacept did not maintain suppression of the pathogenic IL-23-mediated psoriasis molecular signature in lesions after ustekinumab withdrawal, and serum IL-19 levels increased. This parallel-design, double-blind randomized clinical trial found that abatacept did not prevent psoriasis relapse that occurred after ustekinumab withdrawal because it did not completely block the pathogenic psoriasis molecular pathways that led to relapse. ClinicalTrials.gov Identifier: NCT01999868.
Highlights
Study Design PAUSE was a multicenter parallel-design, double-blind, placebo-controlled randomized clinical trial that was conducted at 10 investigational sites in the United States and Canada (US: Dermatology Research Associates, Los Angeles, California; Northwestern University, Chicago, Illinois; Tulane University School of Medicine, New Orleans, Louisiana; University of Michigan, Ann Arbor; The Rockefeller University, New York, New York; Wake Forest University, WinstonSalem, North Carolina; Case Western University, Cleveland, Ohio; and University of Utah, Salt Lake City; Canada: Kirk Barber Research, Calgary, Alberta, and Innovaderm Research Inc, Montreal, Quebec)
Reduction of Serum Cytokines Associated With Regulatory T Cells by Abatacept Given that ustekinumab downregulated molecular targets of abatacept in resolving lesions and that sequential treatment with abatacept did not prevent psoriasis relapse or maintain improvement in clinically relevant biomarkers, we investigated other immunological effects in the abatacept group
This result likely reflects a reduction in the pathogenic T cell–mediated pathways in resolving lesions that were modulated by abatacept in the context of active disease.[12,36]
Summary
Study Design PAUSE was a multicenter parallel-design, double-blind, placebo-controlled randomized clinical trial that was conducted at 10 investigational sites in the United States and Canada (US: Dermatology Research Associates, Los Angeles, California; Northwestern University, Chicago, Illinois; Tulane University School of Medicine, New Orleans, Louisiana; University of Michigan, Ann Arbor; The Rockefeller University, New York, New York; Wake Forest University, WinstonSalem, North Carolina; Case Western University, Cleveland, Ohio; and University of Utah, Salt Lake City; Canada: Kirk Barber Research, Calgary, Alberta, and Innovaderm Research Inc, Montreal, Quebec). Enrollment opened on March 19, 2014, and concluded on April 11, 2016. The trial was conducted in compliance with the Declaration of Helsinki[14] and was approved by the institutional review boards at all of the investigational sites. We followed the Consolidated Standards of Reporting Trials
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