Gribetz et al. reported that an additional four weeks of alefacept resulted in greater efficacy as measured by PASI 75 and PGA than the standard 12-week dosing [42]. Larger studies are necessary to further characterize the degree of efficacy gained through the varying dose escalation regimens and duration of dose escalation. Dose Reduction Considerations All dose reduction studies found that decreased doses of biologic therapy resulted in worse outcomes compared to standard biologic treatment [16,44,45]. Reduction of etanercept induction and maintenance treatment to 25 mg QW and 25 mg BIW resulted in decreased PASI improvement compared to standard dosing [16]. Alefacept dose reduction from 15 mg IM to 10 mg IM resulted in smaller proportion of patients achieving PASI 75 [44,45]. Overall, treatment with FDA-approved dosing regimens resulted in superior efficacy compared to dose reduction regimens. Withdrawal and Retreatment Considerations The preponderance of data in Tables S1, S2, S3, S4, S5 suggests that continuous therapy is recommended for all biologics reviewed here with the exception of alefacept. In most studies, only responders (usually defined as patients achieving PASI 75 or PGA ‘‘clear’’ or ‘‘almost clear’’) were eligible to enter the withdrawal and retreatment periods. Thus, much of the withdrawal-retreat- ment data cannot be directly extrapolated to non-responders. Studies also used different definitions for disease relapse as well as efficacy outcome measures for retreatment. Specifically, for patients on etanercept, it took a median of 85 days for responders to relapse (loss of PASI 75), and 52% of the initial responders regained PASI 75 with retreatment [27]. For those on adalimu- mab, nearly 5 months of treatment withdrawal was necessary for responders to relapse to at least moderate disease, and 87% of patients regained PASI 75 after retreatment [32]. Due to the significant concern with anti-drug antibody formation, continuous infliximab therapy was necessary to maintain psoriasis control. While some clinicians add methotrexate to infliximab to prevent the formation of anti-drug antibody and to increase efficacy, large RCTs are necessary to determine potential additive efficacy from methotrexate addition. Patients on ustekinumab lost PASI 50 response after a median of 15 weeks of withdrawal, and 85.6% of initial responders regained PASI 75 [20]. Alefacept is approved as intermittent treatment where treatment cycles lasting 12-weeks are punctuated with a 12-weeks of drug-free period [22,46–48]. Safety Considerations Safety considerations are important in assessing benefit-risk profile of administering biologic therapy to eligible psoriasis patients. Challenges in assessing safety issues include low event rates, lack of a comparison group for some open-label extension studies, inconsistent reporting methods, and long lead-time expected for certain types of adverse events (such as malignancy). For standard dosing regimen of anti-TNF agents, a meta-analysis studying the association of short-term use of anti-TNF agents with infections and malignancies showed that there was a small risk of overall infection and no increased risk of serious infection or malignancy [49]. A recent meta-analysis studying adverse cardiovascular events found no significant differences in the MACE in psoriasis patients receiving etanercept, adalimumab, infliximab, or ustekinumab [50]. Most studies involving off-label dosing regimens of biologic agents enrolled a smaller number of participants, and therefore adverse event rates were small and difficult to interpret. Furthermore, the aforementioned challenges in reporting safety events likely exist to a greater degree in off-label dosing studies. Off-Label Biologic Regimens in Psoriasis While this systematic review synthesized detailed rates of adverse events for the off-label dosing regimen, further large studies are necessary to understand whether safety issues exist with dose intensification, reduction, or withdrawal-retreatment. Summary Off-label dosing of biologics for the treatment of moderate-to- severe psoriasis is a clinically relevant and important issue in real- world practice settings. This is the first systematic review to date that examined off-label dosing regimens of the FDA-approved biologic agents etanercept, adalimumab, infliximab, ustekinumab, and alefacept for moderate-to-severe psoriasis. In general, the preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent are necessary for maintenance of disease control. Among non-responders, dose escalation with etanercept, adalimumab, and ustekinumab usually results in greater efficacy than standard dosing. Safety data on off- label dosing regimens are limited in the examined biologics, and larger studies are necessary to determine risks associated with varying dosing regimens. In patients where interrupted therapy is considered, such as those experiencing active infections, undergoing invasive surgeries, or desiring to discontinue treatment in pregnancy, the clinician needs to carefully weigh the benefit-risk ratio of interrupted therapy. Clinicians need to consider whether an interruption is necessary, how the duration of interruption may affect subsequent treatment efficacy, and possible disease exacerbation during interruption. Therefore, 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. Supporting Information Table S1 Etanercept Off-label Regimens: Study Char- acteristics and Outcomes. (DOCX) Table S2 Adalimumab Off-label Regimens: Study Char- acteristics and Outcomes. (DOCX) Table S3 Infliximab Off-label Regimens: Study Char- acteristics and Outcomes. (DOCX) Regimens: Study Table S4 Ustekinumab Off-label Characteristics and Outcomes. (DOCX) Table S5 Alefacept Off-label Regimens: Study Charac- teristics and Outcomes. (DOCX) Table S6 mens. (DOCX) Table S7 mens. (DOCX) Table S8 mens. (DOCX) Table S9 imens. (DOCX) Safety Data for Etanercept Off-Label Regi- Safety Data for Adalimumab Off-Label Regi- Safety Data for Infliximab Off-Label Regi- Safety Data for Ustekinumab Off-Label Reg- PLoS ONE | www.plosone.org 8 April 2012 | Volume 7 | Issue 4 | e33486