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Rheumatology

Rheumatology is an ever-changing field ­ Dr Benazir Saleem and Professor Paul Emery outline five key developments in treating rheumatoid arthritis

1. New scoring system

to evaluate severity

New treatments have placed greater importance on the need for standardised monitoring techniques to provide objective criteria to increase therapy and improve disease outcome.

Response to treatment in rheumatoid arthritis (RA) is assessed using Disease Activity Scores: a validated measure of disease activity that incorporates clinical (the number of swollen and tender joints) and biochemical (ESR or CRP) disease markers along with quality-of-life measures. The DAS was developed in Europe and uses a scoring system based on a total of 28 joints to calculate a numerical value for disease severity (www.das-score.nl/index.html). A DAS28 score of >5.1 indicates highly active disease eligible for further treatment. Most importantly it has provided us with objective criteria from which we can make decisions about increasing therapy. Parallel scoring systems have been developed for other inflammatory joint conditions such as the Bath Ankylosing Spondylitis Disease Activity Index. These scores are used in an outpatient setting and can be time-consuming.

2. Ultrasound:

the joint stethoscope

Radiographic progression is considered one of the most important outcome measures in RA. This is because it assesses the potential of anti-rheumatic drugs to prevent structural damage or slow its occurrence. RA causes inflammation of the synovium. Synovitis leads to bone oedema and subsequent erosions (discrete periarticular bony defects associated with active synovitis) and joint damage. Radiographically demonstrable damage of the joints is increasingly associated with a significant and irreversible loss of function.

The availability of ultrasound has enabled the detection of structural joint damage with greater sensitivity than clinical examination and X-ray in early inflammatory disease. Importantly ultrasound has the ability to simultaneously image both soft tissue and bone. This enables accurate diagnosis and sensitive measures of outcome. Ultrasound examination has become an integral part of a rheumatological assessment; other advantages include:

· low cost

· absence of ionising radiation

· short procedure time

· relative ease of access

Despite the obvious benefits it also has limitations, mainly its operator dependence and the limitations in its use for imaging deep joints.

With the integration of ultrasound into clinical services we could begin to see 'one stop clinics' ­ a complete clinical and radiological assessment and accurate diagnosis are all done in a single visit.

3. Diagnosing early inflammatory arthritis

With the recognition that erosive irreversible disease can occur in the first few months, early diagnosis is receiving increasing emphasis in RA. There are, however, inherent difficulties in making an accurate diagnosis of RA in the very early stages.

The American College of Rheumatology criteria have been shown to be less valid in early disease, as they describe features of RA that take time to develop. For example, in patients who eventually develop RA up to 60 per cent may have a normal acute phase response, 70 per cent have normal joint X-rays

and 50 per cent do not have

a positive rheumatoid factor.

The labelling of a patient with a diagnosis of RA in the early stages may not be the important step for a patient. It may be more relevant to establish the

presence of synovitis and determine the likelihood of persistent disease activity, that has been shown to have a disease duration of >12 weeks.

For the optimal management of patients with early inflammatory arthritis early referral to a specialist is crucial and should be based on appropriate history and presence of clinical features suggestive of inflammatory disease.

4. Spondyloarthropathies

Spondylo-arthropathies are distinct from RA, characteristically affecting the sacroiliac joint, spine and entheses. In addition they are seronegative for IgM rheumatoid factor, have distinct extra-articular features and some are associated with HLA B27.

Perception of these diseases is changing. Ankylosing spondylitis (AS), the prototype of this group, has traditionally been considered a rare disease with few therapeutic options and diagnosis was often delayed. But the advent of new imaging methods, especially MRI, has facilitated the possibility of early diagnosis of AS.

The biggest advance has been with evidence of the efficacy of tumour necrosis factor blocking agents, which have revolutionised the approach to managing spondyloarthropathies.

Advantages to these treatments include significant improvement in efficacy and quality of life compared with traditional treatments. This is offset by increased cost and the risk of adverse events related to the use of biologic therapy. There is an international consensus about the use of antiTNF for treating patients with AS developed by Assessments in AS Working Group (ASAS).

5. New treatments for rheumatoid arthritis

Overexpression of cytokines in inflamed joints plays a central role in joint inflammation and tissue damage.

The National Institute for Clinical Excellence has approved the use of two TNF antagonists for the treatment of RA. Infliximab is a chimeric monoclonal mouse antibody against TNF alpha. Etanercept is a soluble TNF receptor fusion protein whose profile has been raised by the much publicised 'TEMPO' study. This trial showed that the combination of etanercept and methotrexate was significantly better at reducing disease activity, improving functional disability, and retarding radiographic progression compared with methotrexate alone. The 'ATTRACT' trial published three years before provided the evidence for infliximab and methotrexate compared with methotraxate alone. Adalimubab, a fully human version, is licensed but not yet approved by NICE.

There is also interest and continuing research in products that target the activation of T cells (CTLA4Ig), B cells (rituximab) and interleukin 1 (anakinra). Although, contrary to expectations, interleukin 1 blockade is not effective for patients who fail antiTNF (it was thought that IL-1 might be a separate pathway).

And on its way....

five things that the

future holds

1 Remission: This is the ideal outcome in patients with RA and it represents absence of inflammation. Although previously thought of as rare, the concept is becoming a reality because of new therapeutic approaches and more effective therapies. For patients with RA this means less joint deformity, better quality of life and prolonged ability to work.

2 Screening for RA: The use of new antibodies, for example cyclic citrulinated peptides (CCP), that have high specificity may prove more useful in early diagnosis of RA. Interestingly these antibodies may appear in the serum years before onset of clinical disease. In the future they could be used to predict RA in patients at high risk, for example those with a positive family history.

3 Suppression of early inflammatory arthritis: 'Undifferentiated inflammatory arthritis' represents a neglected group of patients who do not satisfy the American College of Rheumatology criteria for RA. These patients are in trials involving early treatment with powerful biologic agents. The aim is that patients will achieve and remain in drug-free remission or require minimal additional disease-modifying therapy.

4 TNF resistant RA: RA has been thought of as

a T cell mediated disease. There is, however,

a cohort of patients that appears to be resistant to standard antiTNF treatment. Encouraging results are emerging from patients who have been treated with B cell therapy in the form of anti CD20-rituximab. Also providing an alternative in TNF failures is CTLA4Ig, a fusion protein, which reduces synovial inflammation by blocking T cell

co-stimulation, thereby decreasing CD4 T cell activation and results in the subsequent inactivation of B cells.

5 The future of imaging: New ultrasound and MRI machines that are specially designed to image small joints will allow patients to be seen as outpatients in 'one-stop clinics'. Their primary function will be to allow rapid and accurate diagnosis of early inflammatory arthritis allowing identification of patients with RA at an early stage. Such patients would be appropriate for early intervention.

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