in cohort 1 and 3/10 (30%) in cohort 2 [42]. Cafardi et al. investigated treatment escalation in two off-label regimens [43]. Cohort 1 received 30 mg IM alefacept for 6 weeks followed by 6 weeks of 15 mg IM alefacept, and cohort 2 received 30 mg IM alefacept for 12 weeks. At week 14 of the study, 1/8 (12.5%) patients in cohort 1 and 1/8 (12.5%) in cohort 2 achieved PASI 75 [43]. Efficacy of Alefacept Dose Reduction. Ortonne et al. and Lebwohl et al. compared alefacept 15 mg IM once weekly, 10 mg IM once weekly, or placebo in 507 adult psoriasis patients [44,45]. At week 2 of the drug holiday, after 12-weeks of treatment, PASI 75 was achieved by 21% of patients receiving 15 mg alefacept, 12% of those on 10 mg alefacept, and 5% of those receiving placebo [44]. Efficacy of Alefacept Intermittent Treatment. Four studies investigated intermittent treatment with alefacept defined as drug withdrawal and retreatment in consecutive cycles [22,46–48]. Krueger et al. compared two cycles of 7.5 mg IV alefacept, defined as cohort 1, to one cycle of 7.5 mg IV alefacept followed by one cycle of placebo, defined as cohort 2 [22]. PASI 75 at week 2 of withdrawal during the second treatment cycle was achieved by 23% of cohort 1 compared to 7% of cohort 2 [22]. Overall response rates (ORRs) were defined as achieving PASI 75, PASI 50, or a PGA score of ‘‘clear’’ or ‘‘almost clear’’ during any time in a 24-week treatment and follow-up cycle. After one treatment cycle, members of cohorts 1 and 2 reported ORRs to be 28% (PASI 75), 56% (PASI 50), and 23% (PGA ‘‘clear’’ or ‘‘almost clear’’) [22]. After two cycles, cohort 1 achieved higher ORRs, 37% (PASI 75), 64% (PASI 50), and 30% (PGA ‘‘clear’’ or ‘‘almost clear’’), compared to cohort 2 who achieved ORRs of 19%, 49%, and 18% after 12 weeks of placebo (p = 0.035 for PGA score ‘‘clear’’ or ‘‘almost clear’’) [22]. The median duration of PASI 50 maintenance in cohort 2 patients who achieved PASI 75 anytime during the initial treatment cycle was 216 days, or over 7 months [22]. Three open-label studies evaluated retreatment cycles with alefacept for up to three treatment cycles [46–48]. Each study enrolled patients who had previously received treatment with one or two cycles of alefacept in Phase II or III drug trials and who presented with disease severity investigators determined required systemic therapy. Lowe et al. administered 7.5 mg IV alefacept to 174 patients who had previously received alefacept in a Phase II RCT [46]. Two weeks after completion of the 12-week alefacept administration, PASI 75 was achieved by 16% of patients in cycle 1 compared to 18% of patients at the same point during treatment cycle 2 [46]. Of note, almost half (50/107) patients experienced superior ORRs during cycle 2 compared to cycle 1 [46]. Gordon et al. examined the median duration to loss of response, defined as PGA ‘‘mild’’ or more severe, in patients treated with 15 mg IM alefacept [48]. The authors found that patients who achieved PASI 75 during initial treatment maintained PASI 50 for a median duration of 209 days or approximately 7 months. Upon loss of response, patients were retreated with 15 mg IM alefacept for 12 weeks. At the conclusion of the 24 week study, 43% of patients had achieved PASI 75 upon retreatment with alefacept [48]. Roberts et al. investigated retreatment cycles with 15 mg IM alefacept in patients who did not receive PGA ‘‘clear’’ after each cycle of treatment [47]. PGA ‘‘clear’’ or ‘‘almost clear’’ was achieved by 16%, 22%, and 19% of patients at week 2 after the 12-week treatment completion for cycles 1, 2, and 3 respectively [47]. Alefacept Safety Data Safety data from the off-label alefacept regimens were examined whenever available and can be found in Table S10. In a dose Off-Label Biologic Regimens in Psoriasis escalation trial, Gribetz et al. reported two (2/10) serious infections in cohort 1, including one case of cellulitis and one case of Helicobacter pylori, and no (0/10) serious infections in cohort 2 [42]. In the second dose escalation study, Cafardi et al. reported two cases (2/8) of morphological change from plaque psoriasis to erythroderma in cohort 1 [43]. One patient with erythroderma was hospitalized during the 15 mg IM alefacept phase [43]. One intermittent treatment study reported five internal and cutaneous malignancies (5/174) in unspecified treatment cycles [46] and another reported 16 (16/183) internal and cutaneous malignancies in unspecified treatment cycles [47]. Specifically, Lowe et al. stated that there were no excess malignancies in alefacept-treated patients than untreated individuals [46]. Lowe et al. reported two serious infections, including one case (1/174) of pneumonia in retreatment cycle 1 and one case (1/107) of herpes zoster in retreatment cycle 2 [46]. Roberts et al. reported 15 serious infections, including one case of mycoplasmal tracheobronchitis and 14 cases of herpes simplex: four cases (4/175) in cycle 1, six cases (6/121) in cycle 2, and four cases (4/88) in cycle 3 [47]. Alefacept Anti-Drug Antibodies Anti-alefacept antibodies were detected in ,1% to 6% of patients receiving the study drug for up to 5 retreatment cycles with no significant increase in antibodies reported with retreat- ment [22,45–48]. One study reported decreases in anti-drug antibodies with retreatment [46]. Low titers were observed with anti-drug antibodies [22,45–48] and were not associated with hypersensitivity reactions [22,45]. Discussion Psoriasis is a chronic, relapsing and remitting disease that necessitates long-term treatment. In clinical practice, off-label dosing regimens are relevant and central to individualized therapy. For example, patients that exhibit sub-optimal response to standard biologic therapy may require dose intensification, whereas invasive surgery, infectious episodes, or changes in healthcare coverage may require temporary cessation of a biologic therapy. Therefore, it is important to synthesize the highest-quality available evidence for off-label regimens to inform real-world clinical practice. No guidelines exist to date for off-label use of biologic therapy in dose escalated, reduced, interrupted, or intermittent regimens. Through a systematic review, we synthe- sized data from 23 trials that investigated non-standard treatments with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for moderate-to-severe plaque psoriasis in adults. Dose Escalation Considerations Most dose escalation trials were performed in patients who did not exhibit full response to standard biologic dosing regimens. For etanercept dose escalation, data support that dose escalation to 50 mg BIW among non-responders improves PASI 50 response after 12 weeks of dose intensification [26] and improves PASI 75 response for at least 60 weeks of treatment [25]. With regard to adalimumab dose escalation, in non-responders to standard therapy, dose escalation to 40 mg QW improves clinical response from 0% achieving PASI 50 to 40% achieving PASI 50 after 36 weeks of treatment [31]. Dose escalation with infliximab at 10 mg/kg did not produce superior results to standard therapy, with 73% of patients on 10 mg/kg achieving PASI 75 compared to 82% of patients on 5 mg/kg [36]. Data from one ustekinumab dose escalation study suggests that partial responders who escalate dosing to every 8 weeks experience greater psoriasis control for at least 28 weeks [21]. With regard to alefacept dose escalation, PLoS ONE | www.plosone.org 7 April 2012 | Volume 7 | Issue 4 | e33486