were three malignancies (3/50) in the 40 mg QW group compared to two malignancies (2/97) in the 40 mg EOW group [31]. Menter et al. reported aggregate safety data for the 52-week study period and did not attribute AEs specifically to the withdrawal-retreatment phases [17]. During the 16 week retreat- ment period with 285 patients, Papp et al. reported one malignant melanoma in situ, two serious infections (pneumonia and hepatitis C), and seven serious AEs [32]. Specifically, the serious AEs were coronary artery disease, abdominal adhesions, umbilical hernia, chest discomfort, nephrolithiasis, and fracture of humerus [32]. Adalimumab Anti-Drug Antibodies No anti-adalimumab antibody (AAA) analyses were reported for adalimumab dose escalation trials. Although withdrawal-retreat- ment phases were included in the Menter et al. study, the authors reported aggregate AAA data for the 52-week study period and did not specify AAA in the withdrawal-retreatment phase [17]. During the 52-week period, 8.8% (73/825) of patients treated with at least one dose of adalimumab had detectable AAAs at least once [17]. A subanalysis showed that 3/7 positive AAA patients compared with 65/233 (27.9%) negative AAA patients lost adequate response during adalimumab withdrawal [17]. Papp et al. reported that after a median period of 141 days of withdrawal, 6% (17/275) of patients tested positive for AAAs [32]. During retreatment, positive AAA samples decreased to 1% (3/ 264) after 12 weeks and increased to 2% (4/262) at 16 weeks. A sub-analysis of patients who relapsed during the withdrawal period showed that, among those who achieved a PGA score of ‘‘clear’’ or ‘‘almost clear’’ during retreatment, 4% (5/119) had positive AAAs; in comparison, in those who failed to achieve a PGA score of ‘‘clear’’ or ‘‘almost clear’’ during retreatment, 15% (8/55) had positive AAA [32]. The authors concluded that the presence of AAAs is associated with increased risk of failure to re-achieve efficacy following treatment discontinuation and relapse [32]. In a prospective observational cohort study (n = 29), Lecluse et al. similarly observed that AAAs in psoriasis patients are associated with lower serum adalimumab trough concentrations and lack of adequate response [33]. Of note, in rheumatoid arthritis patients, the development of AAAs is associated with lower serum adalimumab concentrations, discontinued treatment, higher disease activity during treatment, and fewer instances of disease remission during 3 years of follow-up [34]. Infliximab FDA-Approved Dosing Regimen Infliximab is a chimeric monoclonal antibody to TNF-a that acts to neutralize soluble TNF-a and block membrane bound TNF-a [35]. This TNF-a inhibitor is administered by intravenous (IV) infusion. Infliximab is indicated for the treatment of psoriasis in a weight-based dosing regimen of 5 mg/kg at weeks 0, 2 and 6, then every 8 weeks [35]. Table S3 presents the compiled outcome data for off-label dosing regimens with infliximab from four publications. Efficacy of Infliximab Off-Label Dosing Regimens Efficacy of Infliximab Dose Escalation. One clinical trial specifically investigated dose intensification with infliximab in 33 patients [36]. In a controlled trial comparing an escalated dose of 10 mg/kg IV infliximab versus the standard dose of 5 mg/kg IV infliximab administered at weeks 0, 2, and 6, Chaudhari et al found that PASI 75 was achieved by 73% of patients dosed at 10 mg/kg compared to 82% of those dosed at 5 mg/kg at week 10 [36]. Efficacy of Infliximab Withdrawal and Retreatment. A review of the literature identified three controlled trials that investigated infliximab withdrawal and retreatment in adult psoriasis patients [37–39]. Gottlieb et al. conducted a 16 week Off-Label Biologic Regimens in Psoriasis open-label study at the conclusion to the aforementioned dose escalation study to investigate withdrawal and retreatment with 10 mg/kg IV infliximab and 5 mg/kg IV infliximab [39]. ‘‘Responders’’ to initial treatment (PGA ‘‘good,’’ ‘‘excellent,’’ or ‘‘clear’’) with 10 mg/kg or 5 mg/kg IV infliximab were withdrawn and monitored for disease relapse, defined as loss of at least half of the improvement in PASI at week 10. At the time of relapse, patients were treated with a single-dose infusion of their originally randomized dose. The authors reported that patients in the 5 mg/ kg group began to lose response after 8 weeks of drug withdrawal compared to 12 weeks for the 10 mg/kg group [39]. In EXPRESS II, Menter et al. evaluated continuous versus interrupted treatment with IV infliximab dosed at 3 mg/kg or 5 mg/kg [37]. All patients received infliximab 3 mg/kg or 5 mg/ kg at weeks 0, 2, and 6. From week 6 through week 14, all patients entered a withdrawal period. At week 14, the patients were re- randomized to continuous infusions of infliximab at 8-week intervals, or interruption with retreatment at the originally randomized dose upon loss of PASI 75. At week 10, during the withdrawal period, 70.3% of patients on 3 mg/kg and 75.5% of patients on 5 mg/kg achieved PASI 75. At week 50, PASI 75 was achieved by 43.8% of patients on 3 mg/kg every-8-weeks, 54.5% of those on 5 mg/kg every-8-weeks, 25.4% of patients on 3 mg/kg interrupted treatment, and 38.1% of those on 5 mg/kg interrupt- ed treatment [37]. Similar outcomes were observed using proportion of patients achieving PGA scores of ‘‘clear’’ (1) or ‘‘excellent’’ (2) at weeks 10 and 50. At week 10, 69.8% of patients receiving 3 mg/kg and 76.0% of patients receiving 5 mg/kg achieved a PGA score of 1 or 2. In comparison, at week 50, 46.9% of patients dosed at 3 mg/kg every-8-weeks, 58.2% of those at 5 mg/kg every-8-weeks, 31.7% on 3 mg/kg interrupted treat- ment, and 42.1% on 5 mg/kg interrupted treatment achieved a PGA score of 1 or 2 [37]. The authors reported that the most common time interval for intermittent infusions was 4 to 8 weeks [37]. Gottlieb et al. examined the effect of a single additional dose of infliximab after a 20-week withdrawal period [38]. At the study initiation, all patients were administered 3 mg/kg or 5 mg/kg IV infliximab at weeks 0, 2, and 6 [38]. From week 6 through week 26, all patients were withdrawn from infliximab treatment. During the withdrawal period at week 10, PASI 75 was achieved by 71.9% of patients on 3 mg/kg and 87.9% of patients on 5 mg/ kg. At week 26, patients with PGA of ‘‘moderate’’ or ‘‘severe’’ disease (114/198) were eligible for a single additional IV infusion of the originally assigned dose of infliximab. At week 30, a PGA score of ‘‘clear,’’ ‘‘minimal,’’ or ‘‘mild’’ was achieved by 38% of those retreated with one single 3 mg/kg infusion and 64% of those retreated with one single 5 mg/kg infusion of infliximab [38]. Infliximab Safety Data Safety data from the off-label infliximab regimens were examined whenever available and can be found in Table S8. In the dose escalation trial, one case (1/11) of pneumonia was reported in the 10 mg/kg group and one dental abscess (1/11) was reported in the 5 mg/kg group [36]. In the withdrawal and retreatment study by Gottlieb et al, serious infections were reported in three (3/11) patients in the 10 mg/kg group, two (2/11) patients in the 5 mg/kg group, and two (2/11) patients in the placebo group [39]. During the induction phase of EXPRESS II, one case (1/313) of TB was reported in the 3 mg/kg group. During the withdrawal-retreatment phase, another case of TB was reported in the 5 mg/kg interrupted treatment group [37]. In the same study, the authors noted three cases (3/835) of lupus-like syndrome during the 50-week study period (one in placebo and PLoS ONE | www.plosone.org 5 April 2012 | Volume 7 | Issue 4 | e33486