including the risk of disease rebound and development of anti-drug antibodies. Furthermore, it is of interest to determine whether control of psoriasis can be recaptured with retreatment following disease relapse. Defining Non-Standard, Off-Label Dosing Regimens In this systematic review, ‘‘off-label’’ or ‘‘non-standard’’ dosing of biologics refers to any dosing regimens that are not the current FDA-approved regimens for psoriasis treatment. The non- standard dosing regimens are broadly categorized into (1) dose escalation or intensification, (2) dose reduction, (3) interrupted therapy followed by retreatment, and (4) intermittent therapy. Specifically, dose escalation includes shortening the dosing interval and/or increasing the amount of medication per single dose. Similarly, dose reduction includes both lengthening of the dosing interval and/or reduction in the amount of medication per single dose. Interrupted treatment is defined as a withdrawal period followed by a retreatment period with a biologic agent; the retreatment period typically begins either at the time of disease relapse or after a predetermined period of medication interrup- tion. In intermittent therapy, multiple treatment cycles occur punctuated by regular periods of non-retreatment. Clinicians consider using non-standard dosing regimens to treat psoriasis patients for various reasons, including patients’ unsatis- factory response to approved regimen, changing or discontinuing health insurance coverage, or preparing for surgeries with significant infectious risks. Therefore, understanding the literature on efficacy and safety of non-standard biologics dosing regimens is crucial to clinical decision-making and care for psoriasis patients. Aims of Systematic Review The aims of this systematic review are (1) to determine efficacy of off-label dosing regimens of biologic treatments in adults with psoriasis, including dosing escalation, reduction, interruption with retreatment, and intermittent therapy, and (2) to assess safety of these off-label dosing regimens by examination of serious adverse events (AEs), psoriasis rebound, and anti-drug antibodies. Methods Data Sources A systematic search was performed using Ovid MEDLINE In- Process and Ovid MEDLINE Daily from January 1, 1990 through August 1, 2011. We searched for prospective clinical trials, which included non-phase I/II randomized controlled clinical trials (RCTs) and open-label extension studies that evaluated a non- standard dosing regimen with a single biologic drug for the treatment of moderate-to-severe plaque psoriasis in adults. Initial identification of studies were performed using the search terms ‘‘psoriasis,’’ ‘‘etanercept,’’ ‘‘adalimumab,’’ ‘‘infliximab,’’ ‘‘usteki- numab,’’ and ‘‘alefacept.’’ Five searches with the term ‘‘psoriasis AND’’ each of the five biologic drugs were then conducted. These five searches were then combined with ‘‘OR’’ in a final search. Next, exclusion criteria were applied. Exclusion criteria included studies that were not in English, review articles, and pediatric evaluations. Then inclusion criteria was defined as ‘‘adults (19 plus years),’’ ‘‘clinical trials,’’ and ‘‘randomized controlled trials.’’ Titles and abstracts obtained from this systematic search were screened for trials that studied biologic therapy in non-standard regimens, which include dose escalation, dose reduction, interrupted therapy with retreatment, or intermittent therapy. Off-Label Biologic Regimens in Psoriasis Study Selection Publications were selected based on five criteria: study design (randomized controlled clinical trials, randomized trials, and prospective open-label extension studies) study population (adults with moderate-to-severe plaque psoriasis), intervention (non- standard biologic drug dosing regimens as a single therapy), data available for the primary outcomes (PASI score, PGA score, or median time to relapse), and data available for adverse events (serious infections, malignancy, major adverse cardiovascular events [MACE], or anti-drug antibodies). Studies that combined biologic treatment with other medications, such as methotrexate, were not included in this systematic review. Methodological Quality of Studies We recorded several aspects of study design including randomization, allocation concealment, groups similar at baseline, blinding (double, single, open), inclusion of all randomized participants, completeness of follow-up, and funding source. Data Abstraction Data were extracted independently by two authors (EAB and AWA) and any disagreements were resolved by consensus. Studies were also graded using the Grading of Recommendations Assessment, Development and Evaluation Working Group guidelines to provide treatment recommendations based on quality of evidence and clinical outcomes [23]. Results Study Selection An initial review of the databases generated 143 publications that matched the search criteria. After reading the abstracts of the relevant studies, we included 23 publications with 12,617 participants in this article (Figure 1). Study characteristics and primary and secondary outcomes for each drug are found in Tables S1, S2, S3, S4, S5. For each trial, safety data and anti- drug antibody data are recorded in Tables S6, S7, S8, S9, S10. Etanercept FDA-Approved Dosing Regimen Etanercept is a fully human dimeric fusion protein in the class of TNF-alpha (TNF-a) inhibitors that binds both the soluble and membrane bound TNF-a and TNF-beta (TNF-b), preventing the cytokine from binding cell surface receptors [24]. The biologic drug is FDA-approved as a subcutaneous (SC) injection dosed at 50 mg twice weekly (BIW) for 3 months, followed by 50 mg once weekly (QW) for an unspecified amount of time [24]. Table S1 summarizes the outcome data for off-label dosing regimens with etanercept from six clinical studies. Efficacy of Etanercept Off-Label Dosing Regimens Efficacy of Etanercept Dose Escalation. From the literature review, two studies examined the efficacy of etanercept dose escalation [25,26]. Cassano et al. studied dose escalation to 50 mg BIW etanercept in eight patients who did not achieve PASI 50 after 12 weeks of 50 mg QW etanercept [26]. At week 24, 75% (6/8) of patients dosed at 50 mg BIW etanercept achieved PASI 50 and were then discontinued from etanercept treatment. At week 36, PASI 50 was maintained by four out of these six patients [26]. Another study investigated dose escalation to 50 mg BIW after 12 weeks of maintenance dose at 50 mg QW etanercept if participants satisfied 1 of 3 criteria: (1) did not achieve PASI 75 from baseline, (2) achieved PASI 75 but had significant residual disease overall, or (3) achieved PASI 75 but had a clinically PLoS ONE | www.plosone.org 2 April 2012 | Volume 7 | Issue 4 | e33486