proportion of patients who were PASI 75 responders during the initial 24 week treatment cycle that achieved PASI 75 at week 12 of the retreatment cycle, was reported to be 52% [27]. A second study by Moore et al. compared continuous versus interrupted treatment with 50 mg QW etanercept from weeks 12 to 24 [28]. Patients identified as responders (n = 917, 72.0%) were discontinued from initial etanercept therapy at week 12 and retreated with the original dose upon disease relapse. At week 24, a PGA score 0 to 2, and improvement from baseline was achieved by 71.0% of patients in the group receiving continuous therapy and 59.5% of patients who received interrupted treatment (p,0.0001), compared to 71.3% and 72.0% for each group, respectively, at week 12 [28]. The investigators also found that a PGA ‘‘clear’’ (0) or ‘‘almost clear’’ (1) status at week 12 and 24 was achieved by 48.9% and 47.2% of patients in the continuous treatment group, respectively, and 47.6% and 32.2% of patients in the interrupted treatment group, at the same time intervals [28]. The mean (median) time to relapse in the interrupted group was 36.9(33.0) days and the mean (median) time to regain responder status in patients who relapsed was 35.0(29.0) days [28]. Ortonne et al. studied etanercept retreatment in responders to therapy after a withdrawal period [29]. At week 12 of treatment with 50 mg BIW etanercept, responders to the regimen were withdrawn from treatment, and administered a reduced induction dose of 25 mg BIW etanercept upon disease relapse [29]. The mean (SD) time to relapse was 72(46) days or about 2 months. The authors found that 83% of responders recaptured a PGA score of 0 to 2 upon retreatment [29]. The mean time to response after retreatment was 15 weeks, compared to 11 weeks for the initial standard dose (p = 0.001) [29]. Etanercept Safety Data Safety data from the off-label etanercept regimens were examined whenever available and can be found in Table S6. A dose escalation study by Leonardi et al. showed a serious infections rate of 1.9 events per 100 patient-years in the 50 mg BIW compared to 0.9 events per 100 patient-years in the 50 mg QW group [25]. Leonardi et al. also reported two (2/591) myocardial infarctions in the 50 mg BIW group compared to zero (0/321) in the 50 mg QW group [25]. Safety data for withdrawal-retreatment studies were also analyzed. After a median of 85 days of etanercept withdrawal, one case (1/85) of rebound was reported in a patient receiving 25 mg etanercept QW, which was later reversed after 4 weeks of treatment re-initiation [27]. During the retreatment period, two serious infections (2/103) in patients receiving etanercept 50 mg BIW and seven unspecified serious AEs were reported [27]. Another etanercept withdrawal study reported one serious infection (1/363) during the withdrawal period [29]. During the retreatment period with 50 mg QW, Moore et al. reported three internal malignancies and nine non-melanoma skin cancers among 1,274 patients [28]. They also reported three unspecified cases of congestive heart failure and two cases of coronary artery disease in the interrupted treatment group [28]. Etanercept Anti-Drug Antibodies During one dose escalation study, Leonardi et al. reported non- neutralizing antibodies in 15.2% of patients, and the authors noted that antibodies developed to a similar degree in both the 50 mg BIW dose escalation group and the 50 mg QW group [25]. In a dose reduction study by Leonardi et al., the investigators found that 1.2% (8/652) of patients treated with etanercept at an unspecified dose developed antibodies [16]. After a median of 85 days of withdrawal, Gordon et al. reported that 4.7% of Off-Label Biologic Regimens in Psoriasis patients displayed low titer, non-neutralizing antibodies during the retreatment phase [27]. Adalimumab FDA-Approved Dosing Regimen Adalimumab is a fully human monoclonal antibody that binds specifically to TNF-a but not TNF-b. It lyses cells that express TNF-a on their surface in vitro [30]. Adalimumab is approved as a SC injection for the treatment of moderate-to-severe psoriasis. The FDA-approved standard dosing regimen for adalimumab is an initial dose of 80 mg at week 0 that is followed by 40 mg every other week (EOW) starting at week 1 [30]. Table S2 presents the outcome data for off-label dosing regimens with adalimumab from three studies. Efficacy of Adalimumab Off-Label Dosing Regimens Efficacy of Adalimumab Dose Escalation. One study investigated dose escalation therapy by administering adalimumab 40 mg QW to 30 patients who achieved ,PASI 50 during the initial 24-week study period [31]. After 36 weeks of treatment (from week 24 through week 60) at 40 mg QW, 17% achieved PASI 75 and 40% achieved PASI 50 [31]. Efficacy of Adalimumab Withdrawal and Retreatment. Two trials examined withdrawal and retreatment with adalimumab [17,32]. Menter et al. investigated withdrawal from treatment by re-randomizing 490 patients who had achieved PASI 75 previously to adalimumab 40 mg EOW or placebo at week 33 of the study. A patient was determined to have ‘‘lost adequate response’’ if he/she experienced ,PASI 50 response and at least 6-point increase in PASI score relative to week 33 score. Approximately 19 weeks after randomization, 28% (68/240) of patients who were withdrawn from adalimumab lost adequate response compared with 5% (12/250) of participants who were continued to adalimumab 40 mg EOW [17]. A second study evaluated the efficacy of adalimumab for retreatment after open-label treatment and withdrawal periods [32]. Patients who achieved stable psoriasis control during the open- label treatment period were withdrawn from therapy and monitored for relapse for up to 40 weeks. Retreatment began when a patient relapsed or had achieved week 40 without relapse. Papp et al. found that the median time to relapse was 141 days (IQR 93–202 days), or almost 5 months [32]. After the withdrawal period, patients entered 16 weeks of retreatment with adalimumab 80 mg initially followed by 40 mg EOW. Among patients who had relapsed prior to week 40, 69% (123/178) achieved PGA ‘‘clear’’ or ‘‘minimal’’ by the end of the retreatment period compared to 89% (95/107) of patients who did not relapse during the withdrawal period [32]. Using PASI 75 as a secondary endpoint, the investigators found that 83% of patients who had relapsed during the withdrawal period achieved PASI 75 by the end of the retreatment period, compared to 93% of those who did not relapse [32]. Adalimumab Safety Data Safety data from the off-label adalimumab regimens were recorded whenever available and are can be found in Table S7. In the aforementioned studies, there were no reports of rebound after withdrawal of adalimumab and no cases of non-melanoma skin cancer, demyelinating disease, or lupus-like syndrome through 60 weeks of investigation [17,31,32]. After dose escalation to 40 mg QW adalimumab therapy, Gordon et al. reported one case (1/50) of recent-onset latent TB infection and one death (1/50) due to cerebrovascular accident in the 40 mg QW group and one case of coccidiomycosis (1/97) in the 40 mg EOW group [31]. With regard to malignancies, there PLoS ONE | www.plosone.org 4 April 2012 | Volume 7 | Issue 4 | e33486