Biological Sex–Related Differences in Radiographic Progression and Relationship with Early Clinical Response: Post Hoc Analysis of a Phase 3, Randomized, Double-Blind, Placebo Controlled Study in Biologic-Naïve Participants with Active Psoriatic Arthritis Treated with Guselkumab

Objectives Previous research has shown women with psoriatic arthritis (PsA) often have lower rates of clinical response but less severe radiographic damage. Few randomized controlled trials (RCTs) in PsA report sex-disaggregated results. We assessed sex-disaggregated radiographic progression (RP) in DISCOVER-2 ( NCT03158285 ) considering sex differences in structural damage and whether this is associated with early improvements in joint disease activity (DA). Methods Biologic-naïve pts with active PsA were randomized (1:1:1) to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then Q8W; or placebo with crossover to GUS 100 mg Q4W at W24. Early (W8) response in joint DA, (based on clinical DA Index for PsA [cDAPSA LDA; ≤13]), was assessed among pts with cDAPSA >13 at BL, without adjustment for sex-specific differences at BL. Multivariate repeated measures mixed models assessed associations between sex and changes in total PsAmodified van der Heijde-Sharp [vdH-S] score through W100 (Figure 1). Results Of 739 PsA pts enrolled, 47.5% were female. At BL, female vs male pts were more likely to have dactylitis (60.6% vs 50.3%; p=0.0049), and on average had higher BMI (29.5 vs 28.4 kg/m 2 ; p=0.0144), lower CRP levels (1.6 vs 2.3; p<0.0001), less severe psoriasis (Psoriasis Area and Severity Index [PASI] score: 7.5 vs 12.1; p<0.0001), and more functional disability (Health Assessment Questionnaire–Disability Index [HAQ-DI] score: 1.4 vs 1.2; p<0.0001). BL cDAPSA (46.1 vs 46.4) and PsA-modified vdH-S (26.2 vs 25.5) scores were similar (p>0.05) between sexes. In unadjusted analyses of GUS-treated pts, male sex was associated with greater progression of structural damage through W100 (ΔLSM=1.02; p=0.0260). After adjusting for risk factors of RP, BL characteristics with sex-specific differences in the pooled cohort, disease duration and non-biologic DMARD use at BL, the difference between sexes in RP decreased but remained significant (ΔLSM=0.90; p=0.0406); LSM changes from BL in PsA-modified vdH-S scores in males vs females were 1.36 vs 0.69 (p=0.0502) at W52 and 2.22 vs 1.10 (p=0.0475) at W100 (Figure 1). Early (W8) cDAPSA LDA was achieved by 18.9% of men vs 15.3% of women. In men, this was associated with significantly less RP through W100; in females only, numerical differences were observed. Conclusion These results confirm the independent association of male sex with more rapid RP. The previously reported relationship between early improvement in joint DA and diminished RP,[1] was found to be stronger in males than females, which may be due to the lower rate of RP in females. References [1.] Mease PJ. Clin Rheumatol 2024;43(1):241-9.