New Definitions Refine Difficult-to-Treat PsA

BOGOTÁ, Colombia — After a 2-year process involving a systematic literature review, surveys of more than 200 member clinicians, and feedback from some 600 patients worldwide, investigators with the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) have announced consensus-based definitions of complex-to-manage (C2M) and treatment-refractory (TR) psoriatic arthritis (PsA) — two different but overlapping concepts of treatment failure. 

At the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2025 Annual Meeting and Trainee Symposium, Fabian Proft, MD, head of the rheumatology section at Charité-Universitätsmedizin Berlin, Berlin, Germany, presented what he and his colleagues described as a more nuanced and precise approach to what has been described as difficult-to-treat (D2T) PsA. 

The new definitions, which have yet to be published, clearly separate objectively measured TR inflammation from other types of treatment failure. They are expected to help in clinical decision-making and to inform inclusion and exclusion criteria for trials and disease registries.

C2M-PsA, TR-PSA Defined

C2M-PsA is defined by GRAPPA as “characterized by persistent symptoms despite at least one adequate trial of a ts- or bDMARD [t argeted synthetic- or biologic disease-modifying antirheumatic drug ] recommended for PsA treatment.” The category extends beyond biologic nonresponse to include factors such as comorbidities, overlapping conditions, psychosocial factors, and treatment-related challenges. 

With C2M-PsA, the impact of symptoms on quality of life and complexity of disease management may be determined by the patient, the treating clinician, or both.

TR-PsA is defined as “the failure to respond to three or more previous treatments for PsA with different modes of action (including two or more ts or bDMARDs) and persistent symptoms perceived as problematic by both the treating clinician and the patient” as well as objective evidence of ongoing inflammation. TR-PsA comprises a smaller patient group within the rubric of C2M disease and is expected to improve patient selection for research and clinical trials.

Proft called the new definitions “only a starting point,” noting that researchers plan to re-evaluate their utility within 3 years of their publication. It will be important to determine how often the definitions are used in different registries or cohorts, included in guidelines, and cited, as well as whether they prove applicable to translational research. “We have metrics [in place] to see if they were successful or not,” he said.

In an interview at the conference, Philip Mease, MD, director, rheumatology research, Providence Swedish Medical Center, and clinical professor of rheumatology, University of Washington, Seattle, commented that the definitions represent an advance on concepts of D2T PsA. Though criteria vary, D2T usually implies the failure of least two targeted therapies along with objective evidence of disease. 

“But with C2M, we have also had a clause that allows a patient to say ‘I feel terrible,’” said Mease, who co-led the task force with Proft. “Objective evidence [of inflammation] isn’t absolutely required. They may have fibromyalgia or concomitant osteoarthritis or obesity or other comorbidities. So we decided to split C2M into two concepts.”

The shift in terminology from “difficult-to-treat” to “complex-to-manage” was patient-driven, with patients objecting to the use of the word “difficult.” Chris Lindsay, PharmD, who represented the patient research partner network on the task force, noted in an interview that the definitions contain another patient-centric feature: Both patient and physician perspectives are used to define PsA as TR. “This incorporates shared decision-making and allows patient voices to be represented,” she said. “It was an important advance.” 

The GRAPPA definitions, once published and disseminated, “will get used by all kinds of stakeholders,” Mease told Medscape Medical News. Defining treatment resistance is especially important for clinical trials investigating dual therapies, such as a biologic DMARD paired with a targeted synthetic DMARD, or two biologics used in combination. 

The FDA “might argue that it’s a safety problem,” to try these drugs in tandem, Mease said. “But the data collected from the registries over the years show that between 10% and 30% of patients fall into the treatment-refractory category — so it’s an unmet need.” Likewise, he said, insurers are more likely to cover multiple therapeutics if treatment resistance is better defined. 

Proft disclosed speaking and/or consulting fees from AbbVie, Amgen, BMS, Celgene, Eli Lilly, Hexal, Janssen, Medscape, MSD, Novartis, Pfizer, Roche and UCB. Mease disclosed research funding, consultation fees, and/or speaker fees from AbbVie, Amgen, Astra Zeneca, Bristol Myers Squibb, Century, Cullinan, Inmagene, Janssen, Eli Lilly, Moonlake, Novartis, Pfizer, Spyre, Takeda, and UCB. Lindsay disclosed consulting for Tonix and holding stock in Amgen and Arcutis.