Off-Label Biologic Regimens in Psoriasis: A Systematic Review of Efficacy and Safety of Dose Escalation, Reduction, and Interrupted Biologic Therapy Elizabeth A. Brezinski2, April W. Armstrong 1 * 1 Department of Dermatology, University of California Davis, Sacramento, California, United States of America, 2 School of Medicine, University of California Davis, Sacramento, California, United States of America Abstract Objectives: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment) with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment. Data Sources and Study Selection: We searched OVID Medline from January 1, 1990 through August 1, 2011 for prospective clinical trials that studied biologic therapy for psoriasis treatment in adults. Individual articles were screened for studies that examined escalated, reduced, or interrupted therapy with etanercept, adalimumab, infliximab, ustekinumab, or alefacept. Data Synthesis: A total of 23 articles with 12,617 patients matched the inclusion and exclusion criteria for the systematic review. Data were examined for primary and secondary efficacy outcomes and adverse events including infections, malignancies, cardiovascular events, and anti-drug antibodies. The preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent was necessary for maintenance of disease control. Among non- responders, dose escalation with etanercept, adalimumab, ustekinumab, and alefacept typically resulted in greater efficacy than standard dosing. Dose reduction with etanercept and alefacept resulted in reduced efficacy. Withdrawal of the examined biologics led to an increase in disease activity; efficacy from retreatment did not result in equivalent initial response rates for most biologics. Safety data on off-label dosing regimens are limited. Conclusion: Dose escalation in non-responders generally resulted in increased efficacy in the examined biologics used to treat moderate-to-severe psoriasis. Continuous treatment with anti-TNF agents and anti-IL12/23 agent results in superior efficacy over interrupted therapy. The decision to use off-label dosing needs to account for both benefits and risks and be individualized to patients’ disease severity, quality of life, and existence of comorbidities. Citation: Brezinski EA, Armstrong AW (2012) Off-Label Biologic Regimens in Psoriasis: A Systematic Review of Efficacy and Safety of Dose Escalation, Reduction, and Interrupted Biologic Therapy. PLoS ONE 7(4): e33486. doi:10.1371/journal.pone.0033486 Editor: Maurice A. M. van Steensel, Maastricht University Medical Center, The Netherlands Received December 20, 2011; Accepted February 15, 2012; Published April 11, 2012 Copyright: 2012 Brezinski and Armstrong. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have read the journal’s policy and have the following conflicts: AWA has received research support and consultant honoraria from Abbott, Amgen, and Janssen. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: aprilarmstrong@post.harvard.edu Introduction Psoriasis is a chronic, inflammatory skin disease associated with comorbidities, psychosocial impairment, and markedly reduced quality of life [1,2]. The condition has an estimated prevalence of 2–3% of the population worldwide, including more than 4.5 million people in the US as of 2004 [3–5]. Psoriasis is considered an immune-mediated disorder involving T-cell activa- tion and cytokine elaboration [6]. Recent characterization of psoriasis immuno-pathophysiology showed that cytokines, in particular tumor necrosis factor (TNF), interleukin-12 (IL-12) and interleukin-23 (IL-23) represent therapeutic targets [7–11]. Biologic therapies that alter these fundamentally important immunologic pathways in psoriasis have been developed [12]. Further, biologic drugs serve as welcomed alternatives to traditional systemic treatments such as methotrexate and cyclo- sporine that can be associated with cumulative, dose-dependent toxicities [13,14]. Biologic Drugs Introduction The safety and efficacy of etanercept, adalimumab, infliximab, ustekinumab, and alefacept for the long-term treatment of adults with moderate-to-severe plaque psoriasis have been previously established in large randomized, double blind, placebo-controlled clinical trials [15–22]. Of particular interest are the health benefits and risks for tapering psoriasis patients off the biologic drugs etanercept, adalimumab, infliximab, ustekinumab, and alefacept. It is important to identify how long patients will stay in remission following treatment cessation and to understand the clinical characteristics associated with biologic therapy withdrawal, PLoS ONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e33486