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Rheumatoid arthritis (RA) is a complex autoimmune inflammatory disease with systemic sequelae. Like most other diseases there are both environmental and genetic factors which contribute to development of the disease. The history of RA is debated, with some seeing it as a disease of modern times (possibly precipitated by environmental toxins such as cigarette smoke), 1 while other sources claim that it has existed since antiquity at least. 2 Over the course of the last century, the drugs used in the treatment of RA have become increasingly sophisticated, with the drugs of today targeting specific immunopathogenic pathways which are involved in the development of the disease. These new-age treatments have led to better clinical outcomes, namely an improvement in symptom control and a reduction in radiographic progression of the disease. As a result, patients suffering from RA in the 21st century have a better quality of life than their ancestors. However, even today, we are still not entirely certain of the exact cause of RA and this presents us with a challenge when trying to make best use of the sophisticated therapies which are now on the market. This editorial will discuss the evolution of RA management from the peculiar trials of the 1940s to the complex biological therapies available today as well as the potential for personalized medicine in the future. However, first we will contemplate the history of the disease. The history of RA is a long and complex one. There is evidence of rheumatological disease in the Ebers Papyrus – a historically significant medical text from ancient Egypt dating back to 1500 BC. The papyrus describes what is probably RA, and examination of Egyptian mummies has pointed toward the existence of RA at this time. In 400 BC, Hippocrates (the father of modern medicine) also described arthritis, although at this time there was no differentiation between the various forms of arthritis. It was proposed that rheumatic disorders were the result of imbalance of the four humors (from the Greek meaning ‘juice’ and rheum meaning ‘current’ or ‘stream’) and that these humors would flow into the joint and cause the symptoms of rheumatic disease. 2, 3 In contrast, some groups believe that RA is strictly a disease of modern times and acknowledge the first medical report of RA to be in the year 1800 by the French surgeon Augustin Jacob Landre-Beauvais. (However, it was not until 1890 that the English physician Alfred Garrod coined the term “rheumatoid arthritis”). 1 There may be truth in both of the theories regarding the history of RA: whilst a small number of humans may have had the condition in ancient times (and therefore the potential to develop the disease has been present for thousands of years at least), life expectancy in antiquity was poor and so it is likely that only a small number actually lived long enough to develop the disease, making it hard to find documented evidence of the disease at this time. (RA typically presents in patients when they are aged between 30 and 65. 4) As the global population is now living longer, a greater number of people are being diagnosed with RA and so effective treatment which slows disease progression is more important now than ever before. In the 1950s, corticosteroids were introduced for the treatment of RA. Prior to this, treatment of RA was largely limited to non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin. While these classes of drugs reduce inflammation and provide symptomatic relief, they do not slow disease progression. Although disease-modifying antirheumatic drugs (DMARDs) have been in use since 1929 (intramuscular gold injections), this treatment was reserved only for those with severe disease5 and so patients and their doctors were crying out for novel new therapies which could achieve better disease control. These desperate times called for desperate measures. Indeed, in 1947, a study published in the British Medical Journal (BMJ) described trials of injections with the blood of pregnant women in 28 patients with RA for whom “scientific treatment had so far yielded no result”. The study claimed that the results were comparable to other contemporary treatments (such as gold injections and other “vaccinations”) with 64% of patients improving or recovering, while 36% remained unchanged. 6 New treatments were very much needed; however, the approval of the low molecular weight DMARDs methotrexate (MTX) and sulfasalazine (SSZ) did not come until 1988 and 1990 respectively. 5 These DMARDs changed the face of modern RA treatment and remain key players in the treatment of RA today. Sixty years after the BMJ article was published, another world-leading journal, The Lancet, published an article of a similar name: “New therapies for treatment of rheumatoid arthritis”. This article discusses the new classes of RA drugs which are beginning to be used clinically. Unsurprisingly, they are a world away from the primitive treatments of the pre-1950s, providing better symptom control and slowing disease progression. One such class of drugs are tumor necrosis factor (TNF) inhibitors (e. g. , etanercept). TNF receptors are found in most tissues and, when activated by TNF in response to a stimulus, set off an inflammatory chain reaction in the form of an immune response. TNF is involved in the inflammatory pathway of RA and etanercept is one of several anti-TNF drugs used to treat the disease. Etanercept inhibits binding of both TNF-alpha and lymphotoxin-alpha to cell surface TNF receptors, thus dampening the inflammatory response. 7 These drugs are typically used in patients who are unresponsive to at least two traditional DMARDs, usually one of which is MTX. Other new agents include T-cell blockers (e. g. , abatacept), B-cell depletors (e. g. , rituximab) and anti-interleukin 6 receptors (e. g. , tocilizumab) which are typically only used if there has been an insufficient response to TNF inhibitors. 8 There have been numerous studies which have tried to identify the gene polymorphism which is associated with a good response to anti-TNF drugs but these have not yet been successful. 9 This may be down to the associated difficulty in quantifying what marks a good response to treatment. The advent of these drugs has revolutionized the treatment of RA by offering a wide variety of treatments to patients who fail on other drugs. Indeed, this may be viewed as the first step toward providing personalized medicine for RA. Personalized medicine is the art of tailoring treatments to an individual based on their genetic profile. It has the potential to revolutionize the way that clinical decisions are made by providing the best treatment for a particular individual. This could lead to better use of drugs already in use or which failed in trial stage or it could even lead to the development of new drugs tailored to a particular group of people with common features in their genotype. It is hoped that we will be able to class TNF inhibitors as personalized medicine if we are able to find biomarkers which safely and reliably predict response to these drugs in an individual; however, studies to date have been unable to find a single marker which predicts response to TNF inhibitors. 10 If we are able to accurately predict response to biologics then we may be able to achieve better control of RA in a more cost-effective manner11 as the minimal required drug dose for disease control could be calculated from biomarker levels. The treatments used in RA have changed dramatically over the past 100 years. Whether the disease originated in ancient or modern times has no bearing on the choice of treatment and fortunately future research into new treatments for RA will no longer involve the blood of child-bearing women. Many of the initial treatments for RA are no longer first-line; however, the literature suggests that MTX will be likely to continue as a key player in the management of RA. 5 New biological therapies have been shown to yield good results; however, the associated cost means that they are unlikely to become first-line treatment in the near future (etanercept currently costs approximately 14, 000 annually12). The Lancet review showed that etanercept, abatacept, rituximab and tocilizumab all yielded better results with MTX than when used alone8 and this provides further evidence that MTX may continue to have a use in RA, even when biologics become more affordable. Biologics are not without their side effects and this may limit which patient groups are suitable for the drugs. Until we have a better understanding of the exact mechanisms of these drugs, traditional DMARDs will continue to form the mainstay of drug treatment for RA.
Iain Hyndman (Thu,) studied this question.