We searched Medline with the terms “rheumatoid arthritis” and “diagnosis”, “pathology”, “pathogenesis”, and “treatment”, and other specific terms when needed, and included all reports published between March, 1968, and March, 2008. We reviewed abstracts and selected relevant papers. All types of articles were included (original work, review, case report, letter, etc). We tried to select the most recent publications and to refer to the original description (that means first publication on
SeminarRheumatoid arthritis
Introduction
Rheumatoid arthritis is a disorder in rapid transition. It has evolved from a syndrome of unknown cause to one for which distinct subsets of disease are emerging, and growing knowledge of risk factors calls for preventive strategies. Instead of being regarded as a disease of uncertain pathogenesis, rheumatoid arthritis has become a prototype for application of knowledge of molecular pathogenesis for development of new treatments. Previously, resources were used mainly for care and rehabilitation of accrued handicaps; now the disorder has become a modern-day medical dilemma, whereby early treatment can prevent disability in many patients but the most effective new drugs can be too expensive to administer to all people who might benefit. In this Seminar, we describe some of these developments and their results, which, we believe, extend beyond care and cure for the patient with rheumatoid arthritis.
Section snippets
Clinical expression and sub-classification
From Garrod's initial definition of rheumatoid arthritis as a disease in 1859, current classification criteria were developed by American rheumatologists in the mid 1980s (panel).1 These criteria, which have served so well in selecting patients for clinical trials, are now becoming less relevant, partly because of the success of these same trials. At least two of the seven criteria (nodules and erosions) are generally not present at the best time for early diagnosis and initiation of treatment (
Cause and pathogenesis
Rheumatoid arthritis is called a complex genetic disease, meaning that several genes, environmental factors, and stochastic (chance) factors act in concert to cause pathological events. Findings of twin studies have estimated the relative contribution of genetic factors to be about 50% for the entire syndrome of rheumatoid arthritis, leaving the remaining part to environment and chance.9 In an elegant twin study published more than 10 years ago, the power of a causal approach was shown, whereby
Joint inflammation
The causal factors described above emphasise differences between two major subsets of rheumatoid arthritis and suggest a role for adaptive immunity in the initiation of at least ACPA-positive disease. However, findings of direct studies of inflammation in the joints have, for a long time, shown how a series of inflammatory cascades are active, in many cases probably triggered by adaptive immunity. Current data also indicate that similar inflammatory mechanisms could be at work, both in patients
Outcomes
Fatigue—defined as low energy and constant tiredness—was some years ago assumed to be part of a so-called rheumatoid arthritis personality. We now know that fatigue is a physiological state caused by direct action of proinflammatory cytokines—in particular interleukins 6 and 1—on cytokine receptors on brain endothelial cells, which in turn use prostaglandin signalling pathways to affect central parts of the brain.72 Fatigue is, thus, a state that can and should be measured as part of a
Disease progression and treatment
A major key to advances in both assessment and best use of disease-modifying anti-rheumatic drugs (DMARDs) has been development of valid and responsive methods that measure disease activity, functional status, and joint damage. Effects of treatment on disease activity can be measured either as relative improvement or in terms of the absolute value of disease activity that is reached. ACR response criteria89 measure relative changes, whereas the disease activity score (DAS) is a compound index
Treatment strategies
Strategies for treatment of rheumatoid arthritis have changed greatly over the past decade. Three ideas have driven the alteration. First, early and consistent reduction of inflammation is key—ie, if no inflammation, there is little joint damage. Second, specific molecular mechanisms implicated in pathogenesis of the disorder should be targeted. Third, rheumatoid arthritis is a diverse and dynamic disease, for which different treatments work for individual patients and at various timepoints.
Concluding remarks
Despite making major progress in rheumatoid arthritis research, important work still lies ahead of us. Already, new insights into the various molecular pathways have been used to develop new and very efficient treatment approaches for patients. However, we still need to find out how to best target these drugs to the right individuals at the right time. Some environmental risk factors for rheumatoid arthritis have been identified—mainly smoking—but we have not used this knowledge enough in
Search strategy and selection criteria
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