Difficult‐To‐Treat Psoriatic Arthritis: An Evolving Clinical Construct

Psoriatic arthritis (PsA) is a complex disease with articular, extra-articular, and extra-musculoskeletal manifestations. Despite therapeutic advances, sustained remission remains elusive for a considerable proportion of patients. This editorial examines the multifaceted reasons behind treatment resistance, evolving definitions of difficult-to-treat (D2T) PsA, and emerging strategies that promise to reshape future management 1. The concept of difficult-to-treat (D2T) PsA is evolving, with frameworks being introduced by the Group for Research and Assessment in Psoriasis and Psoriatic Arthritis (GRAPPA) and the European Alliance of Associations for Rheumatology (EULAR) 3, 4. While both definitions were developed through expert consensus, they share common elements. However, there are differences in terminology, treatment thresholds, and inclusion of factors beyond inflammation. GRAPPA introduces a broader concept of Complex-to-Manage PsA (C2M), encompassing treatment intolerance, comorbidities and coexistent medical conditions, fibromyalgia, nociplastic pain, sex and gender constructs, treatment effects, and region-specific challenges such as access to care 3. D2T or treatment-refractory represents a subset of C2M, with objective signs of arthritis, enthesitis, dactylitis, or active skin or nail disease, or magnetic resonance imaging (MRI) evidence of axial PsA, despite one or more biologic or targeted synthetic Disease-Modifying Antirheumatic Drugs(b/tsDMARDs) with different mechanisms of action. EULAR, on the other hand, uses the term Difficult-to-Manage PsA (D2M) as an umbrella category, aligning with terminology used in axial spondyloarthritis 4. True treatment refractory state, which requires failure to respond to two or more b/tsDMARDs with different mechanisms of action, is defined by both the groups (Table 1). Comparing the D2T concept between GRAPPA and EULAR, GRAPPA C2M provides a broader inclusion of patients. The treatment resistance criteria in the EULAR definition, which exclude comorbidities, represent more stringent criteria for patient selection in intervention-specific clinical trials. a. Persistent symptoms despite ≥ 1 b/tsDMARD; includes comorbidities, treatment barriers, overlap syndromes b. Disease perceived as problematic by patient or physician a. Failure of ≥ 2 b/tsDMARDs with ≥ 2 modes of action (MOA), per EULAR recommendations, AND b. Impression of this being problematic per physician and/or patient, AND c. At least one of the following: * Failure to achieve low disease activity, regardless of the cause ** Active EMM *** Objective inflammation (clinical/c-reactive protein and/or imaging) Failure to respond to ≥ 3 treatments for PsA with different MOA (including ≥ 2 b/ts DMARDs) AND Persistent symptoms recognized as problematic by both the physician and the patient AND Presence of objective signs of inflammation Fulfillment of D2M criteria PLUS ≥ 2 of A) Failure to achieve a low disease activity state, B) Active EMMs C) Objective signs of inflammation (c-reactive protein and/or imaging) are mandatory D) Obligatory: Exclusion of comorbidities and psychosocial factors Nearly 1 in 6 patients with PsA met the D2T criteria in a multicentric real-world study, with female sex, obesity, extensive psoriasis, axial involvement, inflammatory bowel disease, fibromyalgia, and depression as risk factors 5. It is important to verify the diagnosis of PsA and ensure that the root cause of persistent symptoms is the disease rather than comorbidities. This also highlights the need for an in-depth discussion with the patients for drug compliance, investigation into the adverse effects of drugs, evaluation of comorbidities, and discussion of the management plan to maximize treat-to-target strategies. Integrating clinical, imaging, and biomarker data offers a path to personalized care in PsA. While several promising biomarkers have been identified, most lack clinical validation. Emerging predictors of treatment response include the presence of specific CD4+ T-cell subsets, such as Th1 and Th17 cells, genetic variants in the TNF/TNF receptor and NF-κB pathways, epigenetic changes like histone modifications, proteomic markers, autoantibodies, as well as insights derived from AI-driven multi-omic analytics 2. Until these tools are fully validated and implemented in clinical practice, comprehensive clinical assessment and imaging remain indispensable for guiding treatment decisions and evaluating disease activityssss 6. Drug Sequencing: After two b/tsDMARD failures, switching therapeutics with different mechanisms of action should be considered. Combination Therapy: Strategies for the use of combination b/tsDMARDs in PsA lack robust evidence. While the combination of csDMARDs with bDMARDs does not improve efficacy in randomized trials, observational data show heterogeneous, agent-specific effects on drug persistence, with no consistent benefit beyond TNF inhibitors. Added treatment burden and csDMARD-related toxicity limit the routine use of such combinations 7. Dual-targeted therapy (e.g., TNFi + IL-12/23 or IL-17) shows promise from real-world observational data, with remission rates approaching 60% in refractory cases of PsA or spondyloarthritis 8. Further research is needed to define the optimal combination therapy regimen in PsA. Antidrug Antibodies (ADA): Though the use of b/tsDMARDs in PsA is expanding, the loss of efficacy over time remains a challenge. ADAs can dampen pharmacokinetics and clinical response. The utility of ADA monitoring in clinical care, however, is challenged by the assay diversity and accessibility. Also, the presence of ADA does not correspond to clinical responses. Currently, there is more widespread use of ADA therapeutic monitoring in the management of inflammatory bowel disease, but not for PsA 9. Management of Comorbidities: Optimizing the management of comorbidities is vital in PsA as they may shape the inflammatory burden, pain mechanisms, and drug survival. Weight reduction and emerging microbiome-modulating approaches may further improve outcomes, as gut dysbiosis can influence TNF, IL-6, and IL-17 pathways, and potentially modify treatment response. Probiotics, prebiotics and phage therapy have been evaluated with varying results. Glucagon-like peptide-1 receptor agonists can show promise in patients with PsO/PsA and obesity by improving metabolic health and indirectly reducing inflammation, though more rigorous evaluation is required 10. Multidisciplinary care with shared decision-making supports adherence and alignment with patient priorities. Emerging Agents: TYK2 inhibitors, JAK1/STAT3 inhibitors, broader JAK inhibitors, and more drugs targeting IL-17, IL-23, and other mechanisms of action are under active investigation. Key challenges in D2T PsA include marked clinical and biological heterogeneity, the need for clearer phenotypic definition and classification, limited long-term data on novel therapies, insufficient understanding of residual symptoms such as pain and fatigue, and the lack of validated biomarkers. Priority areas for research include precision medicine to guide the prediction of therapeutic response, b/ts DMARDs combination therapies, and the development of new therapies. Managing D2T PsA remains complex due to its heterogeneous presentation and comorbidities. Comprehensive assessment of disease activity in all PsA domains and adherence to treat-to-target strategies remain fundamental. In addition, evaluating various comorbidities and their management through a multidisciplinary approach, as appropriate, is essential. Personalized treatment significantly enhances outcomes and quality of life in PsA. I.K.I. – Conceptualization, writing – original draft. Y.Y.L. – Supervision, review and editing. A.J.M. – Conceptualization, supervision, review and editing. All authors have read and approved the final manuscript. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.