Toward Overcoming Treatment Failure in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by inflammation and bone erosion. The exact mechanism of RA is still unknown, but various immune cytokines, signaling pathways and effector cells are involved. Disease-modifying antirheumatic drugs (DMARDs) are commonly used in RA treatment and classified into different categories. Nevertheless, RA treatment is based on a “trial-and-error” approach, and a substantial proportion of patients show failed therapy for each DMARD. Over the past decades, great efforts have been made to overcome treatment failure, including identification of biomarkers, exploration of the reasons for loss of efficacy, development of sequential or combinational DMARDs strategies and approval of new DMARDs. Here, we summarize these efforts, which would provide valuable insights for accurate RA clinical medication. While gratifying, researchers realize that these efforts are still far from enough to recommend specific DMARDs for individual patients. Precision medicine is an emerging medical model that proposes a highly individualized and tailored approach for disease management. In this review, we also discuss the potential of precision medicine for overcoming RA treatment failure, with the introduction of various cutting-edge technologies and big data.

Immune checkpoint molecules in prevention and development of asthma

“…Owing to their success in cancer therapy, ICIs have gained considerable interest as treatments for other immune-related diseases ( 162 ). However, it is controversial ICI therapy would be beneficial in treatment of such diseases due to a lack of knowledge about exact compensatory mechanisms in different immune checkpoint signaling pathways.…”

Low-dose IL-2 improved clinical symptoms by restoring reduced regulatory T cells in patients with refractory rheumatoid arthritis: A randomized controlled trial

“…Moreover, long-term immunosuppressive therapies also lead to drug resistance ( 35 , 36 ), which may be another cause of refractory RA. Therapeutic unresponsiveness may be caused by various mechanisms, such as the rapid degradation of corticosteroids (CCS), the release of neutralizing antibodies against biological agents such as infliximab, or other factors ( 37 , 38 ). Moreover, long-term immunosuppressants downregulated the level of effector T cells, leading to a higher risk of infection and malignancy ( 39 , 40 ).…”

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

“…Although animal models have undoubtedly contributed to our understanding of the fundamental immunological mechanisms of RA, concerns about low clinical development success rates for investigational drugs, 137–141 coupled with increasing awareness of the ethical issues surrounding the use of pain-inducing animal models, have led many to question their utility in the study of complex human conditions, as well as their effectiveness in drug target identification. 142–146…”

“…For example, non-steroidal anti-inflammatory drugs are remarkably effective in rat adjuvant arthritis but provide only modest relief for RA patients. 135,136 Although animal models have undoubtedly contributed to our understanding of the fundamental immunological mechanisms of RA, concerns about low clinical development success rates for investigational drugs, [137][138][139][140][141] coupled with increasing awareness of the ethical issues surrounding the use of pain-inducing animal models, have led many to question their utility in the study of complex human conditions, as well as their effectiveness in drug target identification. [142][143][144][145][146] Human-based advanced approaches for RA research…”