ABSTRACT
Introduction: The nocebo effect is defined as adverse outcomes secondary to negative patient expectations rather than the pharmacologic activity of an intervention. Nocebo effects can reduce treatment adherence and/or persistence. Therefore, nocebo effects in psoriasis need to be defined. Methods: A Cochrane systematic review was updated with a search of MEDLINE, Embase, and the CENTRAL Register of Controlled Trials for phase II - IV RCTs comparing systemic therapy versus placebo for patients with moderate-to-severe plaque psoriasis. Estimates were pooled using a random effects model, and heterogeneity was evaluated using the I2 statistic. The primary outcome was the pooled proportion of any adverse event (AE) and corresponding risk difference (RD) in patients randomized to placebo versus systemic therapy. Results: A total of 103 unique trials were identified enrolling 43,189 patients. The overall pooled AE rate in patients randomized to systemic therapy was 57.1% [95% CI: 54.7-59.5%] compared to 49.8% [95% CI: 47.1-52.4%] for placebo [RD 6.7% (95% CI: 4.6-8.9%), p < 0.00001, I2 = 75%]. Both biologic and non-biologic systemic therapy groups had a higher proportion of infectious AEs compared to placebo. No statistically significant RD in serious AEs or AEs leading to discontinuation was identified between systemic therapy and placebo groups. Discussion: Half of patients exposed to inert placebo in clinical trials of systemic psoriasis therapies experienced AEs, which may be explained by nocebo effects. These findings have important implications when counseling patients and designing future studies.
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.
