Complex-, Difficult-To-Manage, and Treatment-Refractory Psoriatic Arthritis: Insights from a Prospective Cohort Study

Objectives Complex/Difficult-to-Manage (C2M/D2M) and Treatment-Refractory (TR) psoriatic arthritis (PsA) represent patient subgroups with substantial residual disease burden despite optimal use of current therapeutic strategies. GRAPPA and EULAR have recently proposed classification frameworks for these challenging phenotypes.[1,2] This study aimed to determine the frequency and characteristics of D2M/C2M and TR PsA in a large, prospectively followed cohort. Methods This analysis was conducted on PsA patients evaluated in the Gladman Krembil Psoriatic Arthritis Program between July 1, 2024, and July 1, 2025. Patients were classified into C2M/D2M and TR categories according to GRAPPA and EULAR criteria.[1,2] Demographic, clinical, radiographic variables as well as treatment, and comorbidity data were analyzed to characterize the C2M/D2M and TR groups. C2M/D2M patients were compared to non-C2M/D2M, and TR patients compared to C2M/D2M patients who did not meet TR criteria, using both GRAPPA and EULAR classification frameworks. Results Of 630 patients assessed, GRAPPA criteria identified 225 (35.7%) as C2M and 81 (12.9%) as TR, while EULAR criteria identified 122 (19.4%) as D2M and 79 (12.5%) as TR. Patients fulfilling C2M/D2M definitions, including TR, showed significantly higher disease activity and treatment intensity compared with non-C2M/D2M groups. These patients had higher patient and physician global assessment scores, increased tender and swollen joint counts (TJC/SJC), higher Psoriasis Area and Severity Index (PASI) scores, and higher entheisitis (tender) point count. C-reactive protein (CRP) and Disease Activity index for Psoriatic Arthritis (DAPSA) were also markedly elevated, accompanied by greater biologic use and a higher number of biologic DMARDs (bDMARDs). The TR subset demonstrated more severe articular involvement (higher TJC/SJC), elevated CRP, and substantially greater treatment exposure, reflected by higher bDMARD use (Figure 1). Female sex and higher BMI were associated with C2M/D2M but not consistently with TR disease. Conclusion GRAPPA and EULAR criteria both effectively identify PsA patients with high disease burden but differ in sensitivity and thresholds. GRAPPA captured a broader subset, whereas EULAR applied more stringent definitions. C2M/D2M disease appears multifactorial, potentially driven by non-PsA and comorbidity-related factors such as elevated BMI, while TR disease primarily reflects persistent, objectively active inflammation despite adequate therapeutic exposure. References [1.] Marzo-Ortega H. Ann Rheum Dis 2025;84:e220. [2.] Proft F. Ann Rheum Dis 2025;84(Suppl 1):143–5.