The Definitions
Terminology for these two groups can vary by professional society. The European Alliance of Associations for Rheumatology (EULAR) published a definition for “difficult-to-treat” rheumatoid arthritis (RA) that includes cases with “both inflammatory activity and/or noninflammatory complaints.”
The definition includes three criteria:
1) Treatment according to EULAR recommendation and failure of at least two biologic DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated)
2) Signs suggestive of active/progressive disease, including at least one of the following:
- Moderate disease activity (according to validated composite measures including joint counts)
- Signs (including acute phase reactants and imaging) and/or symptoms suggestive of active disease, whether joint-related or other
- Inability to taper glucocorticoid treatment
- Rapid radiographic progression (with or without signs of active disease)
- RA symptoms that are causing a reduction in quality of life
3) Symptom/sign management perceived as problematic by the rheumatologist or the patient
All three criteria must be met.
Both GRAPPA and ASAS plan to use the term “difficult-to-treat” or “treatment refractory” to describe true biologically refractory inflammatory disease and are categorizing the larger, heterogeneous group of nonresponders as “difficult-to-manage” (ASAS) or “complex-to-manage” (GRAPPA).
According to Dr. Poddubnyy, the agreed ASAS definition of difficult-to-manage has several similarities with EULAR’s RA definition, including three pillars:
- Treatment according to existing recommendations and failure of at least two different bDMARDs or tsDMARDs with different mechanisms
- Having signs and symptoms of disease (measured by high disease activity by certain disease activity indexes, persistently elevated C-reactive protein, inflammation on MRI, or rapid radiographic spinal progression)
- Symptoms/signs of disease that are considered problematic by the provider or patient
The definition was approved in January, and the manuscript is in the works, Dr. Poddubnyy said.
The GRAPPA project on PsA is still in its early stages, which so far has included a comprehensive literature review as well as a survey of GRAPPA members across 47 countries. The group is generally in agreement that two separate definitions for nonresponse to treatment are necessary, and that the “difficult-to-treat” definition — which identifies true refractory disease — should include objective signs of inflammation, Dr. Singla said.
Looking Forward
The next step of the ASAS project is to “define the pathway” from difficult-to-manage axSpA to treatment refractory disease, Dr. Poddubnyy said.
“What should be ruled out in order to exclude so-called noninflammatory causes of pain?” he continued. “It will require some Delphi exercises and [a] consensus approach.”
Proft anticipates that this treatment refractory definition in both axSpA and PsA will be most useful in research, rather than clinical practice.
“It is really important to have unified definition criteria to shape as homogeneous a cohort as possible,” he said, for future clinical trials in this population.
On the other hand, the complex/difficult-to-manage definition may be more useful for clinical practice, Dr. Proft thought.
“If you see a patient not responding to treatment, the easiest thing you can do would be to change treatment,” like swapping one biologic for another, Dr. Poddubnyy added, “but this would not be the right approach in every patient.” One goal of these initiatives is to give guidance on “what things should be looked after or excluded before you conclude this is biological [nonresponse],” he said.
Dr. Singla consults for AbbVie, Janssen, and UCB and received research funding from Eli Lilly. Dr. Poddubnyy disclosed serving as a speaker, consultant, and/or research grant recipient for multiple companies including AbbVie, Lilly, Merck Sharp and Dohme, Novartis, Pfizer, GlaxoSmithKline, Novartis, and UCB. Dr. Proft reported receiving research grants, consultant fees, or support for attending meetings and/or travel from Amgen, AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, UCB, Medscape Medical News, Galapagos, and Hexal. Dr. Proft also participants on a data safety monitoring board or advisory board for AbbVie, Celgene, Janssen, Novartis, and UCB.
A version of this article appeared on Medscape.com.