OBJECTIVES:  Moderate-to-severe psoriasis is associated with great impairment in activity and work productivity. However, the causal pathways involving treatment and psoriasis-related symptoms on work productivity and activity impairment (WPAI) are unknown. This analysis examined the differential direct and indirect effects of secukinumab vs. ustekinumab on psoriasis symptoms and patient-reported WPAI at 52 weeks. METHODS:  Clinical and patient-reported outcomes from CLEAR, a head-to-head, phase 3b study comparing the efficacy and safety of secukinumab vs. ustekinumab in moderate-to-severe psoriasis patients, were examined. Key variables in the analysis included Psoriasis Area and Severity Index (PASI) 50/75/90/100 response (percent improvement from baseline), patient-reported symptoms (pain, itching, scaling), and the WPAI at Week 52. Structural equation modelling (SEM) was used to demonstrate that treatment and selected disease covariates affect WPAI indirectly by first improving symptoms. Model fit was evaluated for each PASI response. Standardized coefficients (β ranging -1 to +1) compared the strength of relationships between covariates. RESULTS:  Fit of all models to the data was excellent (comparative fit index=0.98). The greater likelihood for secukinumab to achieve PASI 50/75/90/100 response directly resulted in less activity impairment (β=-0.37, -0.35, -0.22, -0.15, respectively) and work impairment (β=-0.37, -0.33, -0.24, -0.15, respectively) than ustekinumab (all P<0.05). Secukinumab directly improved scaling, and indirectly improved pain and itching, which directly resulted in lower activity impairment and work impairment and indirectly resulted in lower absenteeism. The indirect effects on WPAI resulted from the correlation of absenteeism with activity impairment and work impairment, and correlation of pain and itch with scaling. Results were similar for all PASI levels. CONCLUSIONS:  SEM allows a detailed understanding of the differential direct and indirect effects of secukinumab vs. ustekinumab on multiple patient-relevant outcomes simultaneously. Secukinumab treatment results in lower activity impairment and work impairment through greater improvements in psoriasis symptoms and greater PASI response vs. ustekinumab.