Effect of Costimulatory Blockade with Abatacept after Ustekinumab Withdrawal in Patients with Moderate to Severe Plaque Psoriasis: The PAUSE Randomized Clinical Trial

Kristina M. Harris*, Dawn E. Smilek, Margie Byron, Noha Lim, William T. Barry, James McNamara, Sandra Garcet, Robert J. Konrad, Martin Stengelin, Pradeepthi Bathala, Neil J. Korman, Steven R. Feldman, Erin E. Boh, Kirk Barber, Anne E. Laumann, Yolanda Rosi Helfrich, Gerald G. Krueger, Howard Sofen, Robert Bissonnette, James G. Krueger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Importance: Psoriasis relapse may involve compensatory T-cell activation pathways in the presence of CD28-CD80/CD86 blockade with abatacept. Objective: To determine whether costimulatory signaling blockade with abatacept prevents psoriasis relapse after ustekinumab withdrawal. Design, Setting, and Participants: 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. Interventions: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01999868.

Original languageEnglish (US)
Pages (from-to)1306-1315
Number of pages10
JournalJAMA dermatology
Volume157
Issue number11
DOIs
StatePublished - Nov 2021

Funding

All authors. Drafting of the manuscript: Harris, Smilek, Byron, Lim, Barry, Barber, J. G. Krueger. Critical revision of the manuscript for important intellectual content: Harris, Smilek, Lim, Barry, McNamara, Garcet, Konrad, Stengelin, Bathala, Korman, Feldman, Boh, Barber, Laumann, Helfrich, G. G. Krueger, Sofen, Bissonnette, J. G. Krueger. Statistical analysis: Harris, Byron, Lim, Barry, Garcet, Stengelin. Obtained funding: Stengelin. Administrative, technical, or material support: McNamara, Konrad, Stengelin, Boh, Laumann, G. G. Krueger, J. G. Krueger. Supervision: Harris, Konrad, Stengelin, Boh, Sofen, J. G. Krueger. ConflictofInterestDisclosures:DrKormanreported receivinggrantsandpersonalfeesfromAbbVie,EliLilly, Leo Pharma, Principia, and Trevi; grants from Amgen, Celgene,Chemocentryx,Dermira,MenloTherapeutics, Syntimmune, and XBiotech; and personal fees from Genentech,Janssen,Novartis,Regeneron,SunPharma, and UCB. Dr Feldman reported receiving grants from AbbVie, Amgen, Janssen, Lilly, and UCB and personal feesfromAbbVie,Amgen,Janssen,Lilly,Novartis,Sun, andUCBoutsidethesubmittedwork.DrBohreported receivinggrantsfromJanssenduringtheconductofthe study;personalfeesfromSunandUCB;andgrantsfrom AbbVie,Janssen,andIncyteoutsidethesubmittedwork. Dr Helfrich reported receiving grants from Immune ToleranceNetworkduringtheconductofthestudyand grantsfromAbbVie,BoehringerIngelheim,EliLilly,and Novartisoutsidethesubmittedwork.DrSofenreported receiving grants from Janssen outside the submitted work. Dr Bissonnette reported receiving grants from AbbVie, AnaptysBio, Arcutis, Aristea, Bausch Health, BoehringerIngelheim,BristolMyersSquibb,Dermavant, Eli Lilly, Escalier, Janssen, Leo Pharma, Nimbus, Regeneron, Sienna, and UCB outside the submitted work; personal fees from AbbVie, Almirall, Amgen, Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant,EliLilly,Janssen,KyowaKirin,LeoPharma, and Pfizer; and being a shareholder with Innovaderm Research.DrJ.G.Kruegerreportedreceivinggrantsfrom Immune Tolerance Network during the conduct of the study; money for his institution from Novartis, Pfizer, Amgen, Lilly, Boehringer Ingelheim, Innovaderm, Bristol Myers Squibb, Janssen, AbbVie, Paraxel, Regeneron, Allergan, Novan, Biogen MA, Sienna, UCB, Botanix, Incyte, Avillion, Execure, Nimbus, and Arista; personal fees from Novartis, Pfizer, Amgen, Lilly, BoehringerIngelheim,AbbVie,LeoPharma,BiogenIdec, Valeant,Aurigne,Allergan,Asana,UCB,Siena,Celgene, Nimbus, Sanofi, Sun Pharma, Allmiral, Arena, Bristol MyersSquibb,Ventyx,Aclaris,andGalapagosoutsidethe submitted work. No other disclosures were reported. Funding/Support: This trial was conducted by the Immune Tolerance Network and supported by grant UM1-AI-109565fromtheNationalInstituteofAllergyand InfectiousDiseases(NIAID)oftheNationalInstitutesof Health (NIH). Abatacept and abatacept placebo were provided by Bristol Myers Squibb. Multiplex serum cytokine analysis was conducted by Meso Scale DiagnosticsLLCandsupportedbygrantU24-AI-118663 from the NIAID/NIH. IL-19 serum assay was conducted and supported by Eli Lilly and Co. Role of the Funder/Sponsor: Immune Tolerance Network and Rho Inc had a role in analysis of the data. The other funders and supporters had no role in the design and conduct of the study; collection, management, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The views expressed herein are those of the authors and do not reflect the official policy or position of the NIH. Data Sharing Statement: See Supplement 5. AdditionalContributions:WethankthePAUSEteam andthetrialparticipants.WethankBrianJ.Nickoloff,MD, PhD,LillyResearchLaboratories,EliLillyandCompany, for his contribution to the design, performance, and interpretation of the IL-19 immunoassay; George Rodgers, BS, Lilly Research Laboratories, Eli Lilly and Company, for performing the IL-19 immunoassay; and ShraddhaKale,MS,andParidhiGupta,PhD,MesoScale DiagnosticsLLC,fortheircontributionstothemultiplex serumcytokineassay.WealsothankE.WilliamSt.Clair, MD, Division of Rheumatology and Immunology, Duke UniversitySchoolofMedicine,andGeraldNepom,MD, PhD, Immune Tolerance Network, Benaroya Research InstituteatVirginiaMason,fortheircriticalreviewofthe manuscript and for their advice. These individuals received no additional compensation, outside of their usual salary, for their contributions. Additional Information: Data sets and the clinical protocol are accessible through TrialShare, a public website managed by the Immune Tolerance Network (https://www.itntrialshare.org).

ASJC Scopus subject areas

  • Dermatology

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