We searched PubMed using terms “rheumatoid”, “arthritis”, “biologic”, “mode of action”, “synovial biopsy”, “inflammatory synovitis”. Our search included all articles published in English until Feb 1, 2017. We prioritised articles about therapeutics for rheumatoid arthritis and their mode of action.
SeriesPathogenetic insights from the treatment of rheumatoid arthritis
Introduction
Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular destruction and associated comorbidities in vascular, metabolic, bone, and psychological domains. Rheumatoid arthritis affects about 1% of the population, can present at any age, and is more prevalent in women than in men. The primary aetiopathogenesis is thought to be caused by auto-immune dysfunction that develops in notional phases. A pre-rheumatoid arthritis phase, during which systemic immune mediators (eg, autoantibodies and cytokines) can usually be detected, precedes the onset of clinically evident articular disease during the early rheumatoid arthritis phase. This usually evolves into established rheumatoid arthritis that is characterised by chronic inflammation and associated tissue remodelling and damage. Advances in specific immune-targeted therapeutics, including biologics and kinase inhibitors, have revolutionised clinical care and improved outcomes remarkably. These drugs have also helped unravel the crucial molecular and cellular nodes within the complex inflammatory networks that propagate and perpetuate the disease.
Thus, the successes and failures of specific targeted immune therapies for patients with rheumatoid arthritis offer an invaluable opportunity to dissect mechanisms of disease.
Section snippets
Rheumatoid arthritis pathogenesis
The pathogenesis of rheumatoid arthritis has been extensively reviewed1, 2, 3 and will be summarised only briefly in this Review. The genetic architecture of the disease has been well characterised through conventional and genome-wide approaches. More than 100 loci are associated with disease risk and progression, most of which implicate immune effector or regulatory gene products.4 Prominent among these loci are genes encoding MHC class II molecules, especially HLADR01/04, which is implicated
TNF and interleukin 6
TNF inhibition with antibodies or soluble receptors has been used for patients with rheumatoid arthritis for many years. In consequence, TNF biology in rheumatoid arthritis has been investigated in most detail. In early studies of rheumatoid arthritis, a rapid reduction of circulating interleukin 6 was detected following TNF blockade, which is consistent with the existence of a functional cytokine hierarchy that in turn regulates the acute phase response.11 Subsequently, in a series of elegant
Adaptive immune pathways
Although implicated for many years at a theoretical level in the origins of rheumatoid arthritis, the direct contribution of adaptive immune pathways to disease state has been confirmed primarily via clinical intervention studies.36 The role of T cells in disease pathogenesis has long been debated. The strong genetic clues from MHC class II and costimulatory pathway associations in patients with rheumatoid arthritis, the important functions of T cells in animal arthritis models, and a plausible
Constituent articular cell lineages
Rheumatoid arthritis is characterised by a resident tissue response associated with the formation of a hyperplastic synovial membrane, which acts as a cytokine-producing tissue, facilitates the development of structural damage, and most likely mediates the chronicity of the disease that leads to high relapse rates upon treatment cessation.66 This process is based on sustained activation of synovial fibroblasts, which proliferate and develop resistance to apoptosis. Epigenetic modifications by
Mechanisms of structural damage
Progressive tissue damage results from continuous and direct exposure of bone and cartilage to an inflammatory microenvironment. Bone loss starts very early in the disease course.74 In the pre-disease phase, structural changes are initially driven by the induction of bone-resorbing osteoclasts by autoantibodies and then further aggravated by the action of proinflammatory cytokines.75, 76 Structural damage is determined by exposure time to inflammatory cytokines. Therapeutic strategies to block
Mechanisms driving major comorbidities
Rheumatoid arthritis increases the risk of myocardial infarction and stroke independent of classical risk factors for atherogenesis.80 The intrinsic increase in cardiovascular risk might result from systemic immune activation and inflammation. Chronically elevated serum concentrations of acute phase reactants, such as C-reactive protein, and proinflammatory cytokines, such as TNF and interleukin 6, are associated with enhanced atherogenesis and cardiovascular events.81 Cardiovascular risk
To the future: amelioration or prevention of disease via tolerance induction?
Modification of established inflammatory processes by immune modulatory cells, including those designed to re-establish tolerance, has always been an attractive vision to treat autoimmune diseases, but has so far not progressed to clinical application in rheumatoid arthritis. Pathogenetic understanding obtained from the foregoing clinical experiments and mode-of-action studies now offers this intriguing possibility. The lag in the development of cellular therapies to induce tolerance relates to
Search strategy and selection criteria
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