Nocebo effects in systemic therapies for adult plaque psoriasis: A systematic review and meta-analysis

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 I-2 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, I-2 = 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.