GRAPPA vs. EULAR on Complex/Difficult-to-Manage Psoriatic Arthritis Save

Following the establishment of formal definitions for Difficult-to-Treat Rheumatoid Arthritis (D2T RA) by EULAR and Difficult-to-Manage axial Spondyloarthritis (D2M axSpA) by ASAS, the “Difficult” framework has now reached psoriatic arthritis (PsA).

At the EULAR 2025 Congress in Barcelona, two independent definitions were presented: one by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA; OP0175, Dr. Fabian Proft) and another by EULAR (Saturday recommendations session, Dr. Helena Marzo-Ortega).

This short review explores the similarities and differences between these definitions and discusses their potential implications for clinical practice and research, especially for the increasingly perplexed rheumatologist.

Title: GRAPPA characterised their effort as a consensus initiative, employing a rigorous methodology to develop consensus-based definitions. EULAR adhered to its 2014 standard operating procedures (SOP) for developing “Points to Consider” (PtC), an approach generally reserved when advice cannot be sufficiently data-driven.

Aim: GRAPPA aimed to develop consensus-based definitions addressing the reasons for treatment failure in PsA, while EULAR sought to facilitate clinical research by developing evidence-based PtC and consensus-based definitions to facilitate research in this area.

Methods: Both groups employed a structured methodology: Formulating research questions, literature review, multidisciplinary task force formation (rheumatologists, dermatologists, patients, methodologists, and young investigators) and consensus-building via Delphi rounds (GRAPPA) or voting on agreement levels (EULAR).

Format: GRAPPA presented 5 overarching principles (OP), encompassing multidisciplinarity, shared decision making, considering all disease domains, and the need to reevaluate the diagnosis in case of treatment failure. They defined a broader group labelled Complex to Manage (C2M) disease, and a narrower group with a more stringent definition (Treatment refractory (TR), also labelled D2T), with mandatory objective evidence of ongoing inflammation. Then they specified the definitions of C2M and TR/D2T PsA.

EULAR presented 4 OP encompassing unsatisfactory treatment response despite best care, its impact on patients, its multifactorial nature and the necessity of establishing the reasons for failure. They were followed by 6 core PtC, then the consensus-based definitions of D2M (the broader group) and TR PsA.

Both used, first, an umbrella term: C2M for GRAPPA, D2M for EULAR, a broad term capturing larger, heterogeneous patient profiles. While the term D2M is in line with the ASAS definition for axSpA, “C2M” was driven by the patients’ request of not being pejoratively labelled as “difficult”.

GRAPPA defined C2M-PsA as a disease state characterised by persistent symptoms despite at least one adequate trial of a b/tsDMARD recommended (by GRAPPA) for PsA treatment. This category extends beyond pure biological non-response to also include factors like comorbidities, overlapping conditions, and treatment-related challenges.

EULAR defined D2M based on 3 mandatory criteria: (1) failure to achieve or maintain a response to ≥2 b/tsDMARDs with ≥2 modes of action (MOAs) (as per the EULAR treatment recommendations), (2) the perception of this being problematic by the rheumatologist and/or the patient and (3) at least one of the 3 following point: (A) failure to achieve low disease activity (regardless of the cause: inflammation, comorbidities, or psychosocial factors), (B) active extra-musculoskeletal manifestations (EMMs), and (C) objective signs of inflammation (clinical, C-reactive protein and/or imaging).

They diverged on the perspective of defining the TR group, a more narrowly defined group requiring objective evidence of inflammation. GRAPPA used an additive approach and defined it as failure to respond to ≥3 treatments for PsA with different MOAs (including ≥2 b/tsDMARDs), AND persistent symptoms perceived as problematic by both the treating clinician and the patient,  AND presence of objective evidence of ongoing inflammation. EULAR used a subtractive approach, defining TR as the same above D2M definition with a stringent third criterion: (3) at least two (instead of one) of the 3 following point: (A) failure to achieve low disease activity, (B) active EMMs), and (C) objective signs of inflammation (clinical, C-reactive protein and/or imaging); C being mandatory, and adding a fourth obligatory criterion: exclusion of comorbidities and psychosocial factors.

Failure due to side effects, intolerability, or contraindication was included in D2M but excluded in the TR EULAR definition. It was mentioned in the C2M umbrella term as treatment-related challenges.

Neither mentioned the time frame definition for failure.

Final agreement

GRAPPA’s definitions were endorsed by 95% of its global membership, with 89–100% agreement across items.

EULAR’s PtC achieved 88–100% agreement among task force members.

Both definitions are pending formal publication, which might include modifications from what was presented by EULAR.

Implications for the perplexed rheumatologist

For the umbrella term, in C2M (GRAPPA) or D2M (EULAR) patients, management is problematic for heterogeneous factors, including inflammation, comorbidities, and other psychosocial factors, with the GRAPPA definition being less stringent (failure ≥1 b/tsDMARDs) than EULAR’s (failure ≥2 b/tsDMARDs with ≥2 MOAs), which, when applied to clinical studies, might identify a higher proportion of C2M patients.

For the more stringent definition of TR patients, the objective inflammation is mandatory for both GRAPPA and EULAR. However, GRAPPA stated the need for failure of ≥3 treatments for PsA with different MOAs (including ≥2 b/tsDMARDs), so conventional DMARDs might be implicitly included, while EULAR stated ≥2 b/tsDMARDs with ≥2 different MOAs, not mentioning conventional DMARDs. Also, EULAR excluded from this definition other comorbidities and psychosocial factors as drivers of the disease persistence, which might eventually exclude some patients with overlapping inflammation and comorbidities, and might result, again, in fewer patients being included in research based on the EULAR definition.

The distinction between these frameworks becomes especially critical in research contexts. Application of GRAPPA criteria may yield larger study cohorts, while EULAR’s more stringent requirements might support more mechanistic or intervention-specific trials.

The emergence of two parallel yet distinct definitions for complex or difficult-to-manage PsA underscores the multifaceted nature of this condition and the challenge of reconciling patient diversity with research rigour.

Ultimately, the “perplexed” rheumatologist and researcher must choose a framework that aligns with their clinical or research goals. Future studies comparing outcomes under both definitions will help refine PsA categorisation and future management.