IntroductIon

Autoimmune rheumatic diseases: an introductiondavid A Isenberg

Abstractrecently, diseases of the immune system have become better understood

and immunosuppressive therapy is now available to treat a wider range

of conditions. In addition, the advancement of biological therapy offers

the possibility of treating autoimmune disorders with fewer side effects.

this contribution provides a general introduction to the Medicine issue

dedicated to autoimmune disorders. It summarizes the developments

that have occurred in the area of autoimmune diseases over the past few

years, including advances in the treat.

Keywords autoimmune diseases; biological agents; B cell depletion;

immunosuppressive drugs; tnF-α blockers

We are entering a very exciting time in human history as dis-eases of the immune system which have plagued mankind for centuries are becoming much better understood and amenable to more targeted therapies. Although not all autoimmune diseases require immunosuppressive therapy (autoimmune hypothyroid-ism is a good example where replacement of the missing hor-mone, thyroxine, is a safe and effective treatment), a wide range of conditions from chronic active hepatitis (which affects a single organ or system) to systemic lupus erythematosus (which affects virtually all organs or systems) are increasingly being treated by monoclonal antibodies. This so-called biological therapy offers the tantalizing prospect of effective treatment with far fewer side effects. The classic immunosuppressive drugs, from corticoste-roids to cyclophosphamide, were a major advance on what went before (which was virtually nothing!) and have also contributed significantly to both the morbidity and mortality of the autoim-mune diseases. However, the capacity for biological agents to induce serious side effects, as was observed recently at North-wick Park Hospital, cannot be ignored. It may be that the biologi-cal agent used in this case, which aimed to stimulate a T cell (via the CD28 receptor), will prove highly exceptional but great care will be needed with new approaches in the future.

David A Isenberg MD FRCP is Arthritis Research Campaign Professor of

Rheumatology at University College London, UK. His research interests

are clinical assessment and the structure, function and origin of

autoantibodies. Competing interests: none declared.

MEdIcInE 34:11 43

About 1 in 20 individuals will develop an autoimmune con-dition during their lifetime, and autoimmune rheumatic dis-eases, which this volume of Medicine focuses on, are prominent amongst them. The burden of these diseases both to the indi-vidual and to society cannot be underestimated. In economic terms, for example, it is estimated that rheumatoid arthritis costs the UK health system over £1 billion per annum due to both the costs of looking after the patients per se and the loss of productivity, as so many of them have been unable to continue working.

Studies in rheumatoid arthritis

In the past decade it has become widely acknowledged that biological therapies which block TNF-α have a significant role to play in patients who fail to improve on conventional drugs, such as methotrexate and sulphasalazine. A Biologics Regis-ter established by the British Society for Rheumatology will shortly ‘close its books’, registering 4,000 patients each treated with etanercept, infliximab and adalimumab. There are also 4,000 controls who have rheumatoid arthritis but who are not being treated with the TNF-α blockers. From an analysis of over 13,000 patients already registered it is clear that about 70−75% of patients given any TNF-α blocker will show a use-ful clinical and serological response. Intriguingly, a very simi-lar figure is being seen for patients who have failed a single TNF-α blocker (because of lack of effects or presence of side effects) and are switched to a second such agent. Furthermore, it is increasingly likely that there is going to be a role for ritux-imab, which blocks the CD20 antigen present on many B cells, and CT4LAIg (abatacept) which interferes with a so-called ‘second signal’ between the antigen presenting cells and the T lymphocytes.

Waiting not far behind ‘in the wings’ are a host of other potential therapeutic agents including monoclonal antibodies which block interleukin 6 receptor, interleukin 10 and interleu-kin 15. It remains to be seen which of these drugs will, in the end, be the winners or losers but the sense of excitement is truly palpable.

Other diseases

The use of B cell depletion, employing rituximab either alone or together with steroids and cyclophosphamide, has already been shown to be of value, albeit in open label studies, in patients with lupus, Wegener’s granulomatosus, dermatomyositis and Sjögren’s syndrome. TNF-α blockade using infliximab has shown to be of benefit in patients with lupus and some forms of TNF-α blockade also help patients with Crohn’s disease. A variety of agents are being tried in multiple sclerosis and it is possible to say with confidence that within the next decade, certainly for patients with more severe autoimmune diseases, major changes in ‘standard therapy’ are going to occur.

Clinical trials

In the past few years it has clearly been established that the prospective double blind placebo controlled clinical trial is an essential tool in demonstrating the effectiveness of the biological

9 © 2006 Elsevier Ltd. All rights reserved.

IntroductIon

agents. For many autoimmune diseases international efforts have focused on developing the three types of essential tools which are needed to capture the totality of the effect of one of these diseases on a patient: • a disease activity index (which captures potentially reversible

change) • a damage index (which captures those clinical features that

are permanent) • a health perception index (the SF36 index has been widely

used for this purpose).

MEdIcInE 34:11 440

 These tools are available for use in many autoimmune rheumatic diseases and are being applied for use in clinical trials.

Conclusion

This volume of Medicine will, I hope, demonstrate that not only do we have a much better understanding of autoimmune diseases in general, and autoimmune rheumatic diseases in particular, but also that more targeted therapy using biological agents has really arrived at the bedside having ‘escaped’ from the laboratory! ◆

© 2006 Elsevier Ltd. All rights reserved.