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The course of established rheumatoid arthritis

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Rheumatoid arthritis (RA) varies over time in individual patients and there are marked differences between patients in its impact and progression. The course of RA is therefore unique to each individual patient and is affected by the overall pattern of disease; many patients have classical polyarticular disease but there is also a range of subtypes, such as fibromyalgic and polymyalgic disease. Some patients with RA enter a period of sustained remission; this varies between 10% and 36% of cases; its frequency is mainly influenced by the different approaches to studying RA patients over time, and does not represent a true difference in disease outcome. Most patients have persisting synovial inflammation and disease activity scores average between 3 and 4; there is some evidence that inflammation is less marked in late RA. Persisting synovitis results in increasing disability – this worsens by an average of 0.6% each year – and in joint damage, which increases by an average of 2% each year. Comorbidities and extra-articular features are commonplace: about one-third of patients, respectively, have associated cardiovascular disease, lung disease or extra-articular features, although severe extra-articular problems like vasculitis affect only about 10% of patients. Some aspects of the course of RA are influenced by genetic risks; currently these are only weak predictors but it is anticipated their value will increase with time.

Introduction

In 1992, an article in this series of reviews summarised existing opinions on the course of rheumatoid arthritis (RA).1 There have been many developments in the intervening period, including new diagnostic tests, novel imaging modalities, better understanding and assessment of disability and quality of life, and many therapeutic innovations. Yet not everything has changed; patients with RA continue to have a disabling and often severe disease and much remains to be done before the disease can be considered to have been cured. Consequently, it is both timely and relevant to look once again at the course of RA from the perspective of current clinical practice, and to consider what has changed in the last couple of decades.

Studying the course of a disease is only of major relevance in long-term medical conditions. Acute self-limiting diseases or disorders that are rapidly fatal are not usually considered from such a viewpoint. The course of a chronic disease is synonymous with the concept of its natural history. This approach to medical practice can be traced back to Pliny the Elder and classical Rome, which was the source of the concept of ‘natural history’. In modern day terms, the natural history of RA falls into a number of areas, which although broadly inter-related, are nevertheless relatively independent.

Three general themes define the course of RA and contribute to its understanding. The first theme is the impact of joint inflammation; the extent and severity of these inflammatory changes varies, depending on both factors caused by the disease itself and by the impact of anti-rheumatic drugs. The second theme is the effect of RA on general health, including both extra-articular disease and associated comorbidities. The third theme is its effect on joint damage. These different aspects of RA combine and cause disability and reduce quality of life.

Cutting across these general themes are three other issues, which are important but somewhat different. One of these is the effect of RA on subsets of patients, such as different age groups and different racial groups. A second is the existence of variants of rheumatoid arthritis, an example being fibromyalgic RA. Third, there are issues related to prognostic factors; in particular identifying patients with RA who will do well or badly based on pre-existing genetic risks.

This multiplicity of factors means that there is no single or simple way to summarise the natural history of RA in an individual patient or even in a group of patients. The overall natural history of RA remains complex and its different components need to be described independently. A consequence of the variability in the clinical features of RA is that some clinicians believe it is not a single disease but a collection of separate disorders collected under a ‘flag of convenience’. Heterogeneity in both the genotypes and phenotypes of RA might favour the presence of such disease diversity, but the arguments favouring disease splitting or disease lumping are probably true for most chronic disorders.

Virtually no patients with RA are untreated nowadays, although many choose not to take all the treatments recommended to them. It is very difficult to assess the impacts of different forms of treatment in the long term, beyond the impacts identified in randomised controlled trials. Consequently, in this chapter we will not consider the impact or effects of specific forms of therapy in RA. Clearly, this restriction has limitations. For example, patients treated before the current era of biologics received very different patterns of therapy from those that are now widely used, making it difficult to compare treatment across different eras. Nevertheless, the experiences of these earlier years still have some valuable lessons for current times.

Section snippets

General description of the disease course

The classic descriptions of disease course by Short and Bauer, conceived over 50 years ago, suggested three broad patterns – progressive, intermittent and ‘malignant’ RA.2, 3, 4 In progressive disease, which occurred in 70% of cases, there was an invariable trend towards progression, with fluctuations in severity. In intermittent disease, which occurred in 25% of cases, attacks of arthritis were followed by intermissions for variable periods; in many cases, these remissions lasted for more than

Classic polyarticular disease

Our present understanding the natural history of classic polyarticular RA has been advanced by large, prospective, observational studies of early disease followed-up for prolonged periods. The best example is the Norfolk Arthritis Register (NOAR), which was set up in 1989 and has now enrolled over 3000 patients with early inflammatory arthritis.7 One important finding from NOAR is that the 1987 American College of Rheumatology (ACR) criteria for RA are not ideal.8 Some patients met the criteria

Definitions

Although remission is an important outcome of treatment, it is defined in many different ways and no single set of criteria is predominant. Many studies use the American Rheumatism Association (ARA) criteria; these are strict and require patients to satisfy five criteria on two consecutive months, including: morning stiffness lasting 15 minutes; no fatigue; no joint pain by history; no joint tenderness or pain on motion; no soft tissue swelling in joints or tendon sheaths; and ESR < 30 mm/h for men

Assessments

Disability can be measured using generic measures, like the SF-36 and Nottingham Health Profile (NHP), or disease-specific measures, like the Health Assessment Questionnaire (HAQ) or the Arthritis Impact Measurement Score (AIMS).52 Historically, simple classifications systems were used such as the Steinbrocker Functional Class.53 The most detailed information has come from studies using the HAQ. Disability increases with disease duration with an average annual increase of 1–2% in patients

Assessment

Outcome studies evaluate joint damage using plain X-rays and focus on joint-space loss and juxta-articular bone erosions, usually in the hands and feet. These X-rays are generally evaluated using semiquantitative methods, particular Larsen's and Sharp's scores, together with a number of variations in these approaches.82 As these methods have different scales, changes in damage have been expressed as percent maximal damage.

Changes in damage

We have identified 15 studies that have assessed changes in joint damage

Assessment

Disease activity can be assessed in terms of individual measures, such as joint counts, the ESR or as composite measures; the most well-known composite measure is the disease activity score (DAS). Joint counts can include an extended 66/68 joint count, the Ritchie articular index and the reduced 28-joint count. There is no advantage in examining large numbers of joints, and therefore the 28-joint count has been widely adopted.98 The DAS can be used with 28-joint counts.99 It is widely

Definitions

There are many different types of comorbidity in RA. Some of these, such as lung disease and vasculitis, are extra-articular manifestations of the disease process. Others, such as gastrointestinal ulcers and liver damage, might be a consequence of medication. A third group is disease-associated comorbidities, the best example of which is ischaemic heart disease. Finally, comorbidities might be unrelated to the disease process and could have occurred for other reasons. These various types of

Potential extent

Genetic polymorphisms have the potential to influence joint inflammation, joint damage and extra-articular disease, thus profoundly affecting the course of RA. Associated comorbidities such as cardiovascular disease are now well recognised as being complex diseases themselves, with specific genetic risk factors; these can affect the outcome of RA either directly or indirectly, via interactions with the rheumatoid disease process itself. To make matters more complicated, the effects of treatment

Conclusions

There is no single approach to assessing the course of RA. Patients can have problems in a variety of domains and although patients with severe disease are likely to fare less well overall, not all patients will do poorly in all areas. The variability of RA with time and across different aspects of patients' lives makes it very difficult to capture its overall course in a single individual.

One key issue is whether the various subtypes of RA, such as fibromyalgic and polymyalgic disease, are

Acknowledgements

The authors' ongoing research in rheumatoid arthritis is supported by the Arthritis Research Campaign and we are grateful for their continuing help.

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