OP0094 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-Naive Participants with Active Psoriatic Arthritis Treated with Guselkumab

Background: Previous research has shown that women with psoriatic arthritis (PsA) often have lower rates of clinical response to medication but less severe radiographic joint damage [1,2]. Despite this, few randomized controlled trials (RCTs) in PsA report sex-disaggregated results. In a previous analysis of a large, pooled cohort of PsA participants (pts) from three Phase 3 RCTs of guselkumab (GUS), no differences in clinical efficacy across PsA domains were observed between sexes after adjusting for baseline demographics and clinical features [3]. Objectives: To assess sex-disaggregated radiographic progression in a Phase 3 study of biologic-naïve PsA pts treated with GUS, considering sex differences in structural damage and whether this is associated with early improvements in clinical assessments of joint disease activity. Methods: DISCOVER-2 (NCT03158285) included biologic-naïve pts with active PsA (≥5 swollen and ≥5 tender joint counts [SJC, TJC]; C-reactive protein [CRP] ≥0.6 mg/dL) randomized (1:1:1) to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at Week (W)0, W4, then Q8W; or placebo with crossover to GUS 100 mg Q4W at W24. Early (W8) response in joint disease activity, defined as achievement of low disease activity based on the clinical Disease Activity Index for PsA [cDAPSA LDA; ≤13], was descriptively assessed among pts with cDAPSA >13 at baseline, without adjustment for sex-specific differences at baseline. cDAPSA is calculated by summing TJC [0–68], SJC [0–66], patient global assessment of arthritis using a visual analog scale [VAS; 0–10 cm], and patient assessment of pain [VAS 0–10 cm]). In these post hoc analyses, multivariate repeated measures mixed models assessed associations between biological sex and changes in total PsAmodified van der Heijde-Sharp [vdH-S] score through W100 (Figure 1) and the association between early response in joint disease activity and radiographic progression when stratified by sex (Figure 2); time-averaged (i.e. parameter estimate for the effect of time variable) and visit-specific (at W52 and W100) least squares mean (LSM) changes were derived from these models. Results: Among 739 PsA pts enrolled in DISCOVER-2, 47.5% were female. At baseline, female vs male pts were more likely to be older (29.3% vs 21.9% ≥55 years of age; p=0.0204) and have dactylitis (60.6% vs 50.3%; p=0.0049), and on average had higher body mass index (BMI) (29.5 vs 28.4 kg/m 2 ; p=0.0144), lower CRP levels (1.6 vs 2.3; p<0.0001), less extensive/severe psoriasis (Psoriasis Area and Severity Index [PASI] score: 7.5 vs 12.1; p<0.0001), more functional disability (Health Assessment Questionnaire-Disability Index [HAQ-DI] score: 1.4 vs 1.2; p<0.0001), and worse fatigue (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue score: 28.5 vs 30.9; p=0.0007). Joint-specific variables at baseline such as the 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 known risk factors of radiographic progression (including baseline age, CRP levels, and PsA-modifed vdH-S score), baseline characteristics with sex-specific differences in the pooled cohort (including BMI and presence of dactylitis), and PsA disease duration and non-biologic DMARD use at baseline, the difference between sexes in radiographic progression decreased but remained statistically significant (ΔLSM=0.90; p=0.0406), with corresponding LSM changes from baseline in PsA-modified vdH-S scores in males vs females of 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% (51/270) of men and 15.3% (34/222) of women treated with GUS. In men, this was associated with significantly less radiographic progression through W100 (time-averaged change in PsA-modifed vdH-S scores from baseline through W100 in cDAPSA LDA responders vs nonresponders: 0.39 vs 2.24; p=0.0288), while in females only numerical differences were observed (-0.15 vs 0.91; p=0.1732) (Figure 2). Conclusion: Results reported here confirm the known independent association of male sex with more rapid radiographic progression. The previously reported relationship between early improvement in joint disease activity and diminished radiographic progression [4] was found to be stronger in males than females, which may be due to the lower rate of radiographic progression in female PsA pts. REFERENCES: [1] Eder L, et al. Ann Rheum Dis. 2013;72(4):578-82. [2] Eder L, et al. Lancet Rheumatol. 2023;5(12):e716-e727. [3] Eder L, et al. Arthritis Rheumatol. 2024;76(suppl 9). [4] Mease PJ, et al. Clin Rheumatol. 2024;43(1):241-249. Acknowledgements: NIL . Disclosure of Interests: Dafna D. Gladman: Consultant - AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB, Grants - AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer and UCB, Lihi Eder: Consultant - AbbVie, Eli Lilly, Janssen, Bristol Myers Squibb, Moolake, Novartis, Pfizer, and UCB, Grants - AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, Fresenius Kabi, and UCB, Carlo Selmi: Speaker - AbbVie, Alfa-Wassermann, Amgen, Biogen, Eli Lilly, EUSA, Galapagos, Janssen, Novartis, and SOBI, Consultant - AbbVie, Alfa-Wassermann, Amgen, Biogen, Eli Lilly, EUSA, Galapagos, Janssen, Novartis, and SOBI, Grants - AbbVie, Amgen, and Pfizer, Philip J. Mease: Speaker - AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant - AbbVie, Acelyrin, Amgen, Bristol Myers Squibb, Eli Lilly, Immagene, Janssen, Novartis, Pfizer, UCB, and Ventyx, Grants - AbbVie, Acelyrin, Amgen, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, and UCB, Alexis Ogdie: Consultant - AbbVie, Amgen, Bristol Myers Squibb, Celgene, CorEvitas, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB, Grants - AbbVie to Penn, Amgen to Forward/NDB, Novartis to Penn, Pfizer to Penn, National Psoriasis Foundation, NIAMS, Rheumatology Research Foundation, and University of Pennsylvania, Karissa Lozenski: Shareholder - Johnson & Johnson and Bristol Myers Squibb, Employee - Immunology Global Medical Affairs, Janssen Pharmaceutical Companies of Johnson & Johnson, Mohamed Sharaf: Shareholder - Johnson & Johnson, Employee - EMEA Medical Affairs, Johnson & Johnson Middle East FZ LLC, Dubai United Arab Emirates, Emmanouil Rampakakis: Employee - JSS Medical Research, Consultant - Janssen Pharmaceuticals, LLC, a Johnson & Johnson Company, Laura Pina Vegas: Grants - Support for attending meeting: Novartis, Laura C. Coates: Speaker - AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Medac, Novartis, Pfizer, and UCB, Grants - AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer and UCB; Consultant: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Moonlake, Novartis, Pfizer, and UCB. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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