Interpreting rheumatology tests

Antibody tests help in arthritis diagnoses but can be misleading.

Antibody tests are useful for confirming a rheumatological diagnosis. However, there are major pitfalls in relying on them to diagnose or rule out a disease.

Most antibody tests are reported either as absolute values in international units or as a titre. A titre gives a value for the number of dilutions before activity is lost. The higher the titre, the greater the concentration of the antibody.

To avoid pitfalls when referring a patient with inflammatory arthritis, suspected connective tissue disease or vasculitis, it is important to know exactly which tests to request to confirm or exclude a specific diagnosis.

Inflammatory arthritis
Blood tests are of limited use in the diagnosis of specific forms of inflammatory arthritis.

Many patients with early inflammatory arthritis who go on to develop severe chronic inflammatory rheumatic disease, such as rheumatoid arthritis (RA), psoriatic arthritis or ankylosing spondylitis, have normal blood tests when first seen.

There is clear evidence that the earlier the arthritis is treated, the better the outcome. Therefore rapid referral to rheumatology services is recommended for patients with inflammatory joint swelling, regardless of blood test results.

Referral should be made on the basis of the signs and symptoms of inflamed joints including pain, swelling and stiffness, particularly prolonged early morning stiffness, and the pattern of affected joints together with other clinical features.

Rheumatoid factor test
A rheumatoid factor (RhF) test cannot be used to exclude RA, and is of only limited use in its diagnosis, because of its poor sensitivity.

In patients with synovitis seen within 12 weeks of symptom onset, RhF has a sensitivity of only 68 per cent in predicting the future development of RA. This means that 32 per cent of patients who go on to develop RA have a negative RhF result when first tested.

RhF testing can be useful to specialists because in patients who have evident signs of RA it identifies a population at greater risk of joint damage and systemic complications.

Anti-CCP test
The anti-cyclic citrullinated peptide (CCP) antibody test is available in some areas. It has better specificity than RhF for predicting a diagnosis of RA but it has similarly poor sensitivity.

As with the RhF test, the anti-CCP test should not be used to make an initial RA diagnosis, but it does provide extra information to the specialist managing a patient with RA because a positive result is associated with more severe disease.

Several groups are investigating a model combining the results of RhF and anti-CCP testing, together with clinical features, to see if it can predict the development of RA in patients with very early synovitis. The results of these studies are awaited.

Inflammatory markers
Tests for inflammatory markers can be useful in patients with RA. They include the ESR and CRP blood test. These tests are frequently normal in the seronegative spondyloarthropathies such as psoriatic arthritis and ankylosing spondylitis, and can also be normal in patients in the early stages of RA.

Multisystem disease
Inflammatory joint symptoms also occur in connective tissue diseases such as systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, scleroderma and Sjogren's syndrome as well as in vasculitis, infection and malignancy. Features suggestive of a connective tissue disease or vasculitis should prompt urgent referral to specialist services (see box, left).

A common organ and life-threatening complications of multisystem diseases, such as SLE, is renal involvement.

At early stages, when it is most easily controlled by immunosuppressive therapy, the disease can often be detected using urinalysis. Any patient with a history suggestive of multisystem disease should have their urine tested by dipstick.

The prevalence of SLE, which is the most common of the connective tissue diseases, varies from 0.2 to 2 per 1,000 depending on local ethnic mix, so it is important to be aware of it, and be able screen for its symptoms.

ANA test
The antinuclear antibody (ANA) test can be used to aid clinical assessment of patients with connective tissue disease. It lacks specificity, but is commonly positive in connective tissue diseases, including 98 per cent of those with SLE and systemic sclerosis and 80 per cent of Sjogren's disease patients.

A negative ANA result should not rule out a specialist referral if connective tissue disease is suspected on clinical grounds, but a positive result in association with clinical features of connective tissue disease should prompt early referral.

It is important to be aware that there is a false positive rate of around 15 per cent at low titres. This rate increases with age.

The anti-double stranded DNA antibody test has a high specificity for SLE, but is not positive in all patients.

Its titres can vary over time and with disease activity. If positive it is useful from a diagnostic point of view, but cannot be used to rule out SLE.

ANCA test
Positivity for the anti-neutrophil cytoplasmic antibody (ANCA) is associated with certain types of systemic vasculitis, particularly Wegener's granulomatosis and microscopic polyarteritis.

The sensitivity of the test is not high and many forms of vasculitis, including giant cell arteritis, are typically ANCA negative.

These diseases are very rare as a group, however, sick patients with inflammatory joint symptoms, rashes and unexplained symptoms particularly involving the nervous system or chest should be urgently referred for assessment with the result of urinalysis.

Reports of ANCA test results may also include proteinase 3 or myeloperoxidase antibody levels. These are the antibodies to the two specific cellular targets of ANCA.

In some patients these antibody levels increase when disease is more active.

Anti-ENA test
The anti extractable nuclear antigen (anti-ENA) screen can be carried out by most immunology laboratories.

It can be an aid in the diagnosis and differentiation of various connective tissue diseases (see box, below).

Although they are useful in confirming diagnosis and predicting potential complications of disease, these antibodies have poor sensitivity, and should therefore not be used to rule out connective tissue disease.

Dr Filer is a clinical lecturer and Dr Raza a senior lecturer at Sandwell and West Birmingham Hospitals NHS Trust

Connective tissue disease and vasculitis
Suggestive features should prompt urgent referral:
  • Pleuritic chest pain. Hair loss.
  • Pericarditis.
  • Oral and ocular dryness.
  • Rashes and photosensitivity.
  • Proteinuria or haematuria.
  • Thickening of the skin.
  • Arthritis.
  • Raynaud's phenomenon.
  • Leukopenias.
  • Neurological symptoms.
  • Thrombocytopenia.
  • Severe oral ulceration.
  • Muscle weakness.
  • Ocular inflammation.
  • Unexplained thrombosis

 

ENAs with connective tissue disease
Anti-ENA antibody Associated connective tissue disease
Ro (SSA) SLE, Sjogren's disease
La (SSB)SLE, Sjogren's disease
Sm (anti Smith) SLE
RNP SLE, mixed connective tissue disease
Scl70 Diffuse scleroderma, systemic sclerosis
Centromere
Limited cutaneous scleroderma (formerly CREST)

Jo1, Ku, Mi2

Polymyositis, dermatomyositis

 

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