What Have We Learned about the Pathogenesis of Rheumatoid Arthritis from TNF-Targeted Therapy?

Abstract

Studies of cytokine regulation in rheumatoid arthritis led to the development of TNFαinhibitors which are now used for a number of indications, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, and ankylosing spondylitis. The widespread use of biologics in the clinic offers unique opportunities for probing disease pathogenesis and this paper provides an overview of rheumatoid arthritis, with a particular emphasis on the impact of anti-TNFαtherapy on pathogenetic mechanisms. An overview is also provided on the most commonly used animal models that mimic RA, including adjuvant-induced arthritis, collagen-induced arthritis, TNFα-transgenic mice, and the K/BxN and SKG models. These models have led to significant discoveries relating to the importance of pro-inflammatory cytokines in the pathogenesis of rheumatoid arthritis, resulting from disregulation of the normally finely tuned balance of pro- and anti-inflammatory cytokine signalling. In addition, experimental evidence is discussed suggesting how genetic and environmental factors can contribute to disease susceptibility. The role of effector and regulatory T cells is discussed in the light of the relatively disappointing therapeutic effects of T cell modifying agents such as anti-CD4 antibody and cyclosporin. It is concluded that comprehensive analyses of mechanisms of action of biologics and other drugs entering the clinic will be essential to optimise therapy, with the ultimate aim of providing a cure.

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

“…In the second model, collagen-induced or anti-collagen antibody-induced arthritis results in an autoimmune response against collagen and subsequent joint damage. These are generally used as models of rheumatoid arthritis, resulting in pathology similar to that of the human disease (Williams, 2012). A range of P2X7 antagonists has resulted in improved experimental outcomes in models of inflammatory arthritis (Table 7).…”

Integrated Multi-Omics Techniques and Network Pharmacology Analysis to Explore the Material Basis and Mechanism of Simiao Pill in the Treatment of Rheumatoid Arthritis

“… 1 , 2 RA is a worldwide public health problem with a prevalence of 1% abroad and is one of the leading causes of disability and incapacity. 3 In China, the prevalence is approximately 0.37%. 4 Patients with RA may experience extra-articular signs and symptoms such as joint swelling, pain, pressure, deformity, stiffness and swelling, rheumatoid nodules, vasculitis, and damage to various systems, 5 which often cause great physical and psychological damage to patients due to its long course and easy recurrence.…”

“…Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease that manifests mainly as chronic symmetrical progressive polyarthritis with chronic inflammation of the synovial membrane, proliferation forming vascular opacities, and invasion of the articular cartilage, leading to joint destruction, deformity, and loss of function. , RA is a worldwide public health problem with a prevalence of 1% abroad and is one of the leading causes of disability and incapacity . In China, the prevalence is approximately 0.37% .…”

Resolution of Th/Tc17‐driven inflammation during anti‐TNFα treatment of rheumatoid arthritis reveals a unique immune biomarker profiling pattern

“…In addition, RA immunopathogenesis is strongly linked to the secretion of the rheumatoid factor (RF) and anti‐citrullinated protein antibodies (ACPA), which can be successfully treated by targeting B cells with rituximab, for example 1,6,8,9 . Despite these therapeutic efforts, only a small fraction of RA patients achieve disease remission using current biologic treatments 1,7,10 . Thus, further studies on immunopathogenesis—particularly on the resolution of inflammation phase—during biological treatments, such as the administration of infliximab, are warranted 8 .…”