two in infliximab-treated groups not further specified). Overall in the EXPRESS II study, one case of peripheral neuropathy was reported with an unspecified dose of infliximab [37]. From the aforementioned study by Gottlieb et al., one case (1/99) of sepsis was reported in a patient receiving 5 mg/kg infliximab [38]. Infliximab Anti-Drug Antibodies In EXPRESS II, anti-infliximab antibodies were detected in 69/ 145 (51.5%) patients in the 3 mg/kg every-8-week treatment group, 60/148 (46.2%) in the 3 mg/kg interrupted treatment group, 49/ 148 (35.8%) in the 5 mg/kg every-8-week group, and 59/149 (41.5%) in the 5 mg/kg interrupted treatment group [37]. The investigators reported that a majority (61.1%) of titers were ,1:40 [37]. Gottlieb et al. reported that 21/76 (27.6%) in the 3 mg/kg patients had antibodies to infliximab, compared to 17/87 (19.5%) in the 5 mg/kg group [38]. Infusion reactions were reported in 9/38 (24%) patients with antibodies through week 26, compared to 25/ 116 (22%) patients with no detectable antibodies [38]. Ustekinumab FDA-Approved Dosing Regimen In 2009, ustekinumab, a fully human monoclonal antibody that binds p40 subunit of IL-12 and IL-23 was approved for the treatment of moderate-to-severe psoriasis [40]. Ustekinumab is administered based on weight at 45 mg (#100 kg) or 90 mg (.100 kg) by SC injection at weeks 0 and 4, and then every 12 weeks thereafter [40]. Outcomes for off-label dosing regimens with ustekinumab in two trials are presented in Table S4. Efficacy of Ustekinumab Off-Label Dosing Regimens Efficacy of Ustekinumab Dose Escalation. In a dose escalation study, Papp et al. investigated the effect of dose intensification with ustekinumab in partial responders [21]. Specifically, patients achieving between PASI 50 and PASI 75 response at week 28 of standard dose ustekinumab (158/821) were re-randomized to continue dosing at 45 mg or 90 mg every 12 weeks or shorten the dosing interval to every 8 weeks [21]. Between weeks 40 and 52, all patients underwent four study visits. The mean number of visits that patients achieved PASI 75 was used as an outcomes measure. In patients receiving every-8-week dosing of 45 mg or 90 mg ustekinumab, the mean number of visits with PASI 75 was 1.75 visits, compared to 1.56 visits in patients dosed every 12 weeks (p = 0.468) [21]. Specifically, in the 45 mg group, the mean number of visits with patients achieving PASI 75 was 1.13 in the every-8-week dosing compared to 1.54 in the every-12-week dosing group (p = 0.21). In the 90 mg group, the mean number of visits with patients achieving PASI 75 was 2.63 in the every-8-week dosing compared to 1.58 in the every-12-week dosing group (p = 0.014) .[21]. Efficacy of Ustekinumab Withdrawal and Retreat- ment. One study investigated ustekinumab withdrawal and retreatment upon loss of responder status [20]. Leonardi et al. studied 76 weeks of treatment comparing maintenance therapy to interrupted treatment to determine time to loss of response [20]. Patients were randomly assigned to receive ustekinumab 45 mg or 90 mg at standard dosing intervals until week 40. At week 40, the patients who achieved PASI 75 were re-randomized to maintenance treatment or withdrawal of ustekinumab. Retreatment for the withdrawal group was administered upon loss of PASI 75 response. The median time to loss of response in the withdrawal group was 15 weeks or nearly 4 months [20]. Of the 195 patients who reinitiated ustekinumab after the withdrawal period, 167 (85.6%) achieved PASI 75 within 12 weeks of reinitiating therapy [20]. Off-Label Biologic Regimens in Psoriasis Ustekinumab Safety Data Safety data from the off-label ustekinumab regimens were examined whenever available and can be found in Table S9. During the dose escalation phase by Papp et al., one (1/77) cutaneous malignancy and one (1/77) non-cutaneous malignancy were reported in the every-8-week dosing group without specified dose [21]. Two (2/77) serious AEs were reported in the every-8- week dosing group without specified dose. One (1/81) serious infection and six (6/81) serious AEs were reported in the every-12- week dosing group without specified dose [21]. During the withdrawal phase of the study by Leonardi et al., one (1/160) non-cutaneous cancer was reported in the interrupted treatment group and two (2/161) cutaneous cancers were reported in the maintenance therapy group [20]. The authors also reported two (2/160) serious infections and seven (7/160) serious AEs in the interrupted treatment group and one (1/161) serious AE in the maintenance group during the randomized withdrawal phase [20]. Ustekinumab Anti-Drug Antibodies In the dose intensification study by Papp et al., anti-drug antibodies were found in 12.7% (20/158) of partial responders and 2.0% (12/589) of PASI 75 responders. The authors determined that most antibodies were neutralizing [21]. Overall, 5.4% (65/ 1202) of all patients receiving ustekinumab in the study developed antibodies [21]. In the study containing withdrawal-retreatment phases, anti-ustekinumab antibodies were found in 5.1% (38/746) of patients_ENREF_20 [20]. The majority of patients had low titers of less than 1:320 [20]. Alefacept FDA-Approved Dosing Regimen Alefacept is a recombinant dimeric fusion protein that consists of the extracellular CD2-binding portion of the human leukocyte function antigen-3 (LFA-3) linked to the Fc portion of the human IgG1 [41]. In psoriasis, activation of T lymphocytes involves interaction between LFA-3 on the antigen-presenting cells and CD2 on T lymphocytes. Alefacept binds to CD2 on lymphocytes, thereby inhibiting the LFA-3/CD2 interaction. Alefacept inter- feres with the activation and proliferation of memory effector T lymphocytes [41]. Alefacept is approved for dosing at 15 mg by once weekly intramuscular (IM) injection for a course of 12 weeks [41]. Repeated rounds of 12-week treatment periods are considered for patients only after a 12-week drug holiday provided that CD4+ T lymphocyte counts are within the normal range [41]. We will define a retreatment cycle as 12 weeks of treatment with alefacept, followed by 12 weeks of drug-free observation. Table S5 summarizes the outcome data for off-label dosing regimens with alefacept from seven clinical studies. Efficacy of Alefacept Off-Label Dosing Regimens Efficacy of Alefacept Dose Escalation. Two trials that studied dose escalation regimens with alefacept were identified in a search of the literature [42,43]. Gribetz et al. compared efficacy and safety of standard 12-week versus extended 16-week therapy with 15 mg IM alefacept in 20 patients [42]. After an initial 12 weekly dosing of alefacept, cohort 1 received 4 weekly doses of placebo (standard dosing), whereas cohort 2 received 4 additional weekly doses of alefacept (extended 16-week group). The mean percentage change in PASI from baseline during weeks 12 to 24 was 2% for cohort 1 compared to 26% for cohort 2 (p = ,0.05) [42]. PASI 75 and PASI 50 were achieved by 10% and 60% of patients in cohort 1, respectively, and 30% and 60% of patients in cohort 2 at any time during weeks 12 and 24 [42]. At week 24, PGA ‘‘clear’’ or ‘‘almost clear’’ was achieved in 0/10 (0%) of those PLoS ONE | www.plosone.org 6 April 2012 | Volume 7 | Issue 4 | e33486