Difficult-to-treat rheumatoid arthritis: Current concept and unsolved problems

Abstract

Over the past several decades, the treatment of rheumatoid arthritis (RA) has advanced significantly, and clinical, structural, and functional remission are achievable therapeutic goals. However, a substantial number of patients show resistance to multiple drugs. In particular, patients whose disease activity cannot be controlled despite the use of two or more biological disease-modifying antirheumatic drugs (DMARDs) or targeted synthetic DMARDs (tsDMARDs) with different mechanisms of action (MOA) have recently been referred to as having difficult-to-treat RA (D2T RA). D2T RA is a heterogeneous and multifactorial disease state, and the major problems are uncontrolled disease activity and decreased quality of life, as well as the economic burden due to frequent healthcare utilization and multiple admissions. Since the concept of D2T RA is relatively new and publication regarding D2T RA is limited, the mechanism underlying DMARD inefficacy and which factors form a "difficult-to-treat" state in such patients are not yet fully understood. It is also possible that factors contributing to D2T RA may differ by patient, sex, country, and race. The present Mini Review introduces the current concept and unsolved problems of D2T RA, including the definition, prevalence, and factors contributing to D2T RA. We then discuss the management and therapeutic strategies for D2T RA. Finally, we explore a clinical approach to prevent patients from developing D2T RA.

Keywords: difficult-to-treat; disease-modifying antirheumatic drugs; drug resistance; methotrexate; pulmonary involvement.

FIGURE 1

EULAR definition of difficult-to-treat RA. b/tsDMARDs, biological or targeted synthetic disease-modifying antirheumatic drug; CDAI, clinical disease activity index; CS, conventional synthetic; DAS28-ESR, disease activity score assessing 28 joints using erythrocyte sedimentation rate; D2T RA, difficult-to-treat rheumatoid arthritis; EULAR, European League Against Rheumatism; RA, rheumatoid arthritis.

FIGURE 2

Factors that contribute to the development of difficult-to-treat RA. A wide variety of factors contribute to difficult-to-treat rheumatoid arthritis (D2T RA). We propose that high baseline disease activity, seropositivity for rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA), and pulmonary involvement are the major causes of D2T RA, particularly in Asian countries. In addition, (1) aging-related factors, such as fracture/sarcopenia, cellular/immune senescence, a history of/coexisting malignancy, and cognitive disorders; (2) organ damage, such as cardiovascular disease, chronic kidney disease, liver disease, and pain syndrome/fibromyalgia; (3) environmental factors, such as smoking, periodontitis, infectious diseases; and (4) other factors, such as obesity, non-adherence, and a history of thrombosis also participate in the development of D2T RA. It should be noted that these factors may vary by patient, sex, country, and race.