LAUSR

Despite nearly three decades of advances in the management of rheumatoid arthritis (RA), a substantial minority of patients are exposed to multiple DMARDs without necessarily benefitting from them; a group of patients variously designated as having ‘difficult to treat’, ‘treatment-resistant’ or ‘refractory’ RA. This Review of refractory RA focuses on two types of patients: those for whom multiple targeted therapies lack efficacy and who have persistent inflammatory pathology, which we designate as persistent inflammatory refractory RA (PIRRA); and those with supposed refractory RA who have continued disease activity that is predominantly independent of objective evidence of inflammation, which we designate as non-inflammatory refractory RA (NIRRA). These two types of disease are not mutually exclusive, but identifying those individuals with predominant PIRRA or NIRRA is important, as it informs distinct treatment and management approaches. This Review outlines the clinical differences between PIRRA and NIRRA, the genetic and epigenetic mechanisms and immune pathways that might contribute to the immunopathogenesis of recalcitrant synovitis in PIRRA, and a possible basis for non-inflammatory symptomatology in NIRRA. Future approaches towards the definition of refractory RA and the application of single-cell and integrated omics technologies to the identification of refractory RA endotypes are also discussed. Refractory rheumatoid arthritis (RA) can present with or without signs of ongoing inflammation. A better understanding of the mechanisms behind refractory RA in the presence and absence of inflammation could help to improve the treatment of this condition. The term refractory rheumatoid arthritis (RA) implies treatment-resistant persistent joint and/or systemic inflammation; however, it is often used interchangeably with broader definitions such as ‘difficult to treat’ RA. Refractory RA could be stratified into two major categories; persistent inflammatory refractory RA (PIRRA), in which unabated inflammation is evident, and non-inflammatory refractory RA (NIRRA), which lacks discernible inflammation. Within the category of PIRRA, serological status and HLA associations can provide meaningful stratification that can inform potential therapeutic avenues. Epigenetic modifiers, including methylation, microRNAs and long non-coding RNAs, can influence the course of RA and could provide a basis for the emergence of refractory RA. NIRRA is typically mediated by ongoing pain and patient-reported outcomes; pain mechanisms might include autoimmune and neuroinflammatory pathways that are independent of joint synovitis. The classification of RA and other diseases along an innate-to-adaptive immunological axis can be applied to refractory RA to help discover targets that might be of therapeutic benefit.