Three systematic reviews, two randomized-controlled trials (RCTs), and nine non-randomized studies of safety outcomes formed the evidence base for this review. The systematic reviews and RCTs assessed outcomes at 12-16 weeks, while the non-randomized studies provided follow-up of several years. Few studies conducted head-to-head comparisons of cyclosporine with traditional systemic treatments or biologics. Only one RCT had a head-to-head comparison between cyclosporine and biologics.A well conducted systematic review and network meta-analysis found no difference between cyclosporine and methotrexate (direct comparison) in Psoriasis Area and Severity Index (PASI) 90, PASI 75, or Physician Global Assessment (PGA) of 0 or 1. In the network meta-analysis, cyclosporine was inferior to some biologics on these outcomes. In two RCTs not included in the systematic reviews, no statistically significant differences were observed in PASI score with cyclosporine versus methotrexate, or cyclosporine versus etanercept or ustekinumab. These studies had a sample size of 34 and 150 respectively, and may have been underpowered.In a network meta-analysis, no statistically significant differences in adverse events were observed between cyclosporine and biologics or traditional systemic treatments. The same was observed for serious adverse events, although this data must be interpreted with caution due to small event rates.9 The non-randomized studies provided insights into long-term safety outcomes, such as infections, cardiovascular events, and discontinuation. All non-randomized studies were conducted in European centers and the generalizability to Canadian settings is unclear. The choice of the optimal initial treatment modality for moderate to severe plaque psoriasis remains uncertain. Given the lack of long-term efficacy data, safety data in the Canadian context, and head-to-head comparisons for cyclosporine and biologics, the evidence base is limited.