No abstract

Rheumatoid arthritis is the most common inflammatory arthritis and is a major cause of disability. It existed in early Native American populations several thousand years ago but might not have appeared in Europe until the 17th century. Early theories on the pathogenesis of rheumatoid arthritis focused on autoantibodies and immune complexes. T-cell-mediated antigen-specific responses, T-cell-independent cytokine networks, and aggressive tumour-like behaviour of rheumatoid synovium have also been implicated. More recently, the contribution of autoantibodies has returned to the forefront. Based on the pathogenic mechanisms, specific therapeutic interventions can be designed to suppress synovial inflammation and joint destruction in rheumatoid arthritis.

Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1alpha, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. Loss of VHL leads to a large increase in acute inflammatory responses. Our results show that HIF-1alpha is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1alpha is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. This role for HIF-1alpha demonstrates its direct regulation of survival and function in the inflammatory microenvironment.

SummaryRheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints and is associated with autoantibodies that target various molecules including modified self-epitopes. The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability, and permit improved follow-up. In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades. Current strategies strive for early referral, early diagnosis and early start of effective therapy aimed at remission or, at the least, low disease activity, with rapid adaptation of treatment if this target is not reached. This treat-to-target approach prevents progression of joint damage and optimizes physical functioning, work and social participation. In this Primer, we discuss the epidemiology, pathophysiology, diagnosis and management of RA.