Advances in the therapy of rheumatoid arthritis with biological agents

Abstract

Rheumatoid arthritis (RA) is the most common chronic systemic autoimmune inflammatory disease. The physiology of inflammation has been systemically studied and this has provided specific therapeutic targets for its modulation. The classical treatments of the disease, such as myocrisin and sulphasalazine, are not always effective at controlling the disease. This has necessitated the development of novel agents for treating RA, most of which are biological in nature and are targeted at specific sites of the inflammatory cascades. Advances in molecular biology have heralded the advent of bio-drugs (recombinant proteins) and gene therapy in which specific genes are introduced to locally enhance in vivo gene expression or suppress gene(s) of interest with a view to downregulating inflammation. Some bio-drugs, such as antitumour necrosis factor-α (TNF-α) antibodies and interleukin-1 receptor antagonists (IL-1Ra) have been tested, shown to be effective, and are licensed for clinical use. The clinical effects that have been observed are transient, necessitating repeated treatments and increasing the risk of vaccination effects. Anti-inflammatory cytokines, such as IL-4, IL-10, transforming growth factor-β (TGF-β) and interferon-β (IFN-β) are undergoing clinical trials. Many of these agents have to be administered parenterally and production costs are very high. Consequently, chemical entities which can be taken orally need to be developed. Since the immune system is very complex with pleiotropic cytokines and redundancy in some of the regulatory networks, it may be necessary to use multiple agents targeting different specific sites of the inflammatory cascade or different agents that could be given at different stages of the disease, in order to induce disease remission and maintain the response to it. Cytokines and other mediators play important physiological roles in the host’s defence systems against infections and malignancy. The chronic inhibition, exogenous administration or constitutive overexpression of some cytokines may therefore lead to the development of side effects. Thus, carefully controlled long-term studies will be required to assess the safety of selective targeting of processes involved in the physiology of inflammation. This review summarises the important developments in the biotherapy of RA.

• anti-TNF-α
• biotherapy
• gene therapy
• inflammation
• rheumatoid arthritis