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
References (103)
- et al.
Novel approaches for the treatment of rheumatoid arthritis: lessons from the evaluation of synovial biomarkers in clinical trials
Best Pract Res Clin Rheumatol
(2008) - et al.
Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study
Lancet
(2017) - et al.
Is IL-1 a good therapeutic target in the treatment of arthritis?
Best Pract Res Clin Rheumatol
(2006) - et al.
Rheumatoid arthritis
Lancet
(2016) Cytokine-producing B lymphocytes—key regulators of immunity
Curr Opin Immunol
(2008)- et al.
Effects of DMARDs on citrullinated peptide autoantibody levels in RA patients— a longitudinal analysis
Semin Arthritis Rheum
(2017) - et al.
High risk of clinical cardiovascular events in rheumatoid arthritis: levels of associations of myocardial infarction and stroke through a systematic review and meta-analysis
Arch Cardiovasc Dis
(2010) - et al.
Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease
Am J Cardiol
(2011) - et al.
Immune suppression and immune activation in depression
Brain Behav Immun
(2011) - et al.
Mechanisms involved in triggering rheumatoid arthritis
Immunol Rev
(2016)
The pathogenesis of rheumatoid arthritis
N Engl J Med
Historical observations contributing insights on etiopathogenesis of rheumatoid arthritis and role of rheumatoid factor
J Exp Med
Genetics of rheumatoid arthritis contributes to biology and drug discovery
Nature
Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke
Ann Rheum Dis
Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis
Sci Transl Med
Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis
Elife
Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin
J Clin Invest
Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss
Ann Rheum Dis
Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease
Nat Immunol
Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti TNF-alpha therapy in rheumatoid arthritis
J Immunol
The relationship between synovial lymphocyte aggregates and the clinical response to infliximab in rheumatoid arthritis: a prospective study
Arthritis Rheum
The gene expression profile in the synovium as a predictor of the clinical response to infliximab treatment in rheumatoid arthritis
PLoS One
Monocyte migration to the synovium in rheumatoid arthritis patients treated with adalimumab
Ann Rheum Dis
The value of synovial cytokine expression in predicting the clinical response to TNF antagonist therapy (infliximab)
Rheumatology (Oxford)
Decrease in cellularity and expression of adhesion molecules by nanti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis
Arthritis Rheum
Immature blood vessels in rheumatoid synovium are selectively depleted in response to anti-TNF therapy
PLoS One
Clinical significance of synovial lymphoid neogenesis and its reversal after anti-tumour necrosis factor alpha therapy in rheumatoid arthritis
Ann Rheum Dis
Metabolic profiling predicts response to anti-tumor necrosis factor α therapy in patients with rheumatoid arthritis
Arthritis Rheum
Urinary proteomics can define distinct diagnostic inflammatory arthritis subgroups
Sci Rep
Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray
Arthritis Rheumatol
Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium
Arthritis Rheumatol
Synovial fluid IL-6 concentrations associated with positive response to tocilizumab in an RA patient with failed response to anti-TNF and rituximab
Rheumatology (Oxford)
Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases
Nat Rev Drug Discov
A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis
Ann Rheum Dis
The mechanism of action of tofacitinib—an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis
Clin Exp Rheumatol
The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-γ and interleukin-17 production by human CD4+ T cells
Arthritis Rheum
The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon
Ann Rheum Dis
The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis
Ann Rheum Dis
Anti-IL-17 therapy in treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials
Rheumatol Int
A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate
Ann Rheum Dis
Cytokines in rheumatoid arthritis—shaping the immunological landscape
Nat Rev Rheumatol
Abatacept (CTLA-4Ig) treatment reduces T cell apoptosis and regulatory T cell suppression in patients with rheumatoid arthritis
Rheumatology (Oxford)
CTLA-4 blockade in the treatment of rheumatoid arthritis: an update
Expert Rev Clin Immunol
Abatacept modulates proinflammatory macrophage responses upon cytokine-activated T cell and Toll-like receptor ligand stimulation
Ann Rheum Dis
Abatacept inhibition of T cell priming in mice by induction of a unique transcriptional profile that reduces their ability to activate antigen-presenting cells
Arthritis Rheumatol
Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study
Ann Rheum Dis
Immunohistological analysis of synovium treated with abatacept in rheumatoid arthritis
Rheumatol Int
The pathogenesis of rheumatoid arthritis
N Engl J Med
Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells
Arthritis Rheum
The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial
Arthritis Rheum
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