The Role of Tumour Necrosis Factor-α in the Treatment of Rheumatoid Arthritis – A Review

Muhammad K Nisar, Andrew JK Östör
European Musculoskeletal Review, 2011;6(3):174-8
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Abstract

Since the discovery that tumour necrosis factor-α (TNF-α) plays a pivotal role in the immunopathogenesis of rheumatoid arthritis (RA), a revolution has occurred in the management of the condition. This has been spearheaded by the introduction of anti-TNF-α biological agents, leading to unprecedented improvements in multiple aspects of the disorder including signs and symptoms, radiographic damage, disability and quality of life. As a consequence we now consider disease remission a realistic goal. Over a decade of experience with these drugs has revealed that they are both effective and have an acceptable safety profile, although vigilance for side effects is mandatory. This article focuses on the current knowledge regarding TNF-α antagonists, including their efficacy and safety, and where the field is moving in order to optimise outcomes for this previously crippling disease.
Keywords
Rheumatoid arthritis, tumour necrosis factor-α (TNF-α), anti-TNF-α drugs, infliximab, etanercept, adalimumab, certolizumab, golimumab
Disclosure Muhammad Nisar has no conflicts of interest to declare. Andrew JK Östör has received support from (including attendance at conferences), undertakes clinical trials for and acts as a consultant to Roche, Chugai, Schering-Plough/MSD, Abbott, Wyeth, BMS, GSK, MerckSorono and UCB.
Received: March 04, 2011 Accepted June 02, 2011
Correspondence: Muhammad Nisar, Rheumatology Clinical Research Unit, Box 194, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Rd, Cambridge, CB2 2QQ, UK. E: muhammad.nisar@addenbrookes.nhs.uk

Rheumatoid arthritis (RA) is a chronic, systemic, disabling disease of unknown aetiology affecting up to 1 % of the population.1 Females are affected three times more often than males and disease onset is most frequent between 50 and 70 years of age. Persistently active RA leads to a significantly reduced quality of life and premature mortality, chiefly as a consequence of increased cardiovascular disease. In addition, RA has major economic implications, with an estimated cost to the UK economy, in terms of lost productivity, of £8 billion per year not including the direct healthcare costs.2

The outcome of RA has altered dramatically over the last decade following the introduction of biological disease modifying anti-rheumatic drugs (DMARDs). Tumour necrosis factor-α (TNF-α) antagonists have spearheaded this therapeutic revolution, leading to unprecedented improvements not only in the signs and symptoms of disease but also in radiographic damage, function and mortality.3 Anti- TNF-α agents have been instrumental in shifting the goal of treatment of RA with disease remission now a realistic target.4 This article will focus on the role that anti-TNF-α medications play in the treatment of RA, including their efficacy and safety and how they may be best utilised in the future.

Tumour Necrosis Factor-α in the Pathogenesis of Rheumatoid Arthritis
The inflammatory response mounted by the immune system is a tightly regulated process, involving both pro- and anti-inflammatory mediators. However, in states of chronic inflammation, an imbalance occurs that may result in tissue damage. In the case of RA this manifests principally as destruction of cartilage and bone. Although the precise initiating insult in RA is unknown, both the innate and adaptive components of the immune system are involved. The CD4+ T cell holds primacy as the orchestrator of the cell-mediated immune response stimulating other cells such as monocytes, macrophages, B cells, T cells and synovial fibroblasts to produce cytokines including TNF-α (see below), interleukin-1 (IL-1) and IL-6.5 This inflammatory insult is borne predominantly by the synovial membrane in RA, which displays hyperplasia, increased vascularity and an infiltrate of inflammatory cells.

TNF-α is a pleotropic pro-inflammatory cytokine found in high concentrations in the serum and synovium of patients with active RA.6 TNF-α itself stimulates the production of other inflammatory cytokines, including IL1 and IL67–9 and stimulates fibroblasts to express adhesion molecules resulting in increased transport of leukocytes into sites of inflammation.10 TNF-α additionally promotes the release of tissue-destroying matrix metallo-proteinases11 and via an action on the RANK/RANK-L system stimulates osteoclasts, resulting in bone degradation.12

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