Elsevier

The Lancet

Volume 389, Issue 10086, 10–16 June 2017, Pages 2328-2337
The Lancet

Series
Pathogenetic insights from the treatment of rheumatoid arthritis

https://doi.org/10.1016/S0140-6736(17)31472-1Get rights and content

Summary

Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular damage, functional loss, and comorbidity. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved clinical outcomes. Just as understanding of pathogenesis has led in large part to the development of drugs, so have mode-of-action studies of these specific immune-targeted agents revealed which immune pathways drive articular inflammation and related comorbidities. Cytokine inhibitors have definitively proven a critical role for tumour necrosis factor α and interleukin 6 in disease pathogenesis and possibly also for granulocyte–macrophage colony-stimulating factor. More recently, clinical trials with Janus kinase (JAK) inhibitors have shown that cytokine receptors that signal through the JAK/STAT signalling pathway are important for disease, informing the pathogenetic function of additional cytokines (such as the interferons). Finally, successful use of costimulatory blockade and B-cell depletion in the clinic has revealed that the adaptive immune response and the downstream events initiated by these cells participate directly in synovial inflammation. Taken together, it becomes apparent that understanding the effects of specific immune interventions can elucidate definitive molecular or cellular nodes that are essential to maintain complex inflammatory networks that subserve diseases like 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

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.

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