4 Investigations
Cases relevant to this chapter
1–4, 12–13, 18, 23–32, 34, 68, 72, 74–77, 79–80, 82–91, 93–94, 96–97, 99
Essential facts
1. Investigations are useful to support a diagnosis, but should not be performed in the absence of a clinical indication; remember that false-positive tests for autoantibodies are common, especially for rheumatoid factor and anti-nuclear antibody (ANA).
2. A number of drugs can induce the development of autoantibodies, and only occasionally does this lead to clinical disease.
3. Anti-cyclic citrullinated peptide antibody (ACPA) testing for rheumatoid arthritis (RA) is very specific in early disease, but lacks sensitivity.
4. Many rheumatic diseases and their treatments can result in systemic abnormalities including anaemia, low white cell count, thrombocytopenia and abnormal liver function.
5. The ‘ALARA’ principle (‘as low as reasonably achievable’) underpins the use of ionizing radiation.
After a thorough history and clinical examination, further investigations can help to confirm or exclude a diagnosis. Important factors to consider are age, sex, family history of rheumatic disease, medication, pregnancy, infection, malignancy, and liver, pulmonary, haematological, endocrine or skin diseases. Laboratory or imaging investigations used in isolation will not usually provide a diagnosis and the result will depend on the pre-test probability of the diagnosis being present, which in turn is influenced significantly by the clinical findings. This principle is a very important one to follow. It can prevent unnecessary and sometimes costly tests being performed and potentially causing distress to patients. Laboratory tests are important in monitoring drug toxicity, especially for patients being treated with disease-modifying anti-rheumatic drug therapy, and can be used to monitor disease progress or to identify complications of disease. Further specialist investigations may be required in some circumstances, especially in patients with multi-system disease (such as echocardiography, lung function testing, high-resolution computed tomography (CT), positron emission tomography (PET)), but these are beyond the remit of this book. Their use is indicated in the relevant disease area.
Immunology testing
RF and ACPA
Rheumatoid factors are autoantibodies, usually of the IgM class, directed against the Fc portion of normal IgG molecules, and are the commonest autoantibodies in humans. They are present in polyclonal form in a large number of autoimmune disorders as well as in some inflammatory states (Table 4.1). In monoclonal form, they are produced by proliferating B cells (for example in Waldenström’s macroglobulinaemia and chronic lymphoid leukaemia). In addition, RFs are part of the normal antibody repertoire, especially in the fetal and neonatal periods, suggesting that they may play a role in the development of the immune system. Healthy individuals are capable of making RF, but not usually in large amounts. Some 70% of patients with RA have increased levels of RF. The presence of RF is associated with a worse prognosis and a higher incidence of systemic manifestations of the disease. Early in the course of RA, however, RF may not be detectable, and it is worth repeating the test some months later in patients who have clinical features of RA. RF is also produced in other autoimmune rheumatic diseases, chronic infection and vasculitis, resulting in low specificity for RA. Anti-filaggrin antibodies, anti-keratin antibody (AKA) and anti-perinuclear factor (APF) are more specific than RF and may be detected in early RA. However, the assays are not standardized. Cyclic citrullinated peptides (CCPs) of filaggrin are the target of those antibodies and a more specific enzyme-linked immunosorbent assay (ELISA) has been developed. In established disease, ACPAs have a specificity greater than 90% and a sensitivity of 70%, and may replace RF testing in future. However, in patients with clinical evidence of early RA, although the specificity of RF and ACPA testing is very high (above 95%), around 20–30% of patients are negative for RF and/or ACPA.
Normal health | Normal population, especially the elderly |
Autoimmune rheumatic disease | High prevalence in rheumatoid arthritis, but also seen in Sjögren syndrome, systemic lupus erythematosus and hepatitis C-associated mixed cryoglobulinaemia; chronic inflammatory lung disease |
Juvenile arthritis | Found in a small number of children with polyarticular juvenile idiopathic arthritis |
Infectious diseases | Chronic bacterial infections, including sub-acute bacterial endocarditis, infective exacerbations of cystic fibrosis, tuberculosis, leprosy, trypanosomiasis, visceral larva migrans, infectious mononucleosis, influenza A, hepatitis A and cytomegalovirus infections |
Endocrine diseases | Graves’ disease and hypothyroidism |
Liver disease | Chronic liver disease, autoimmune hepatitis |
Malignancy | Some malignancies including B-cell proliferative diseases, adenocarcinoma of the bladder |
ANA, double-stranded DNA antibodies and ENA
Over 85% of patients with SLE will be positive for ANA, and in the correct clinical setting this is a very useful test in diagnosis. The ANA test is sensitive, but not specific (Table 4.2). Healthy people often have positive results. The test should not be used to evaluate vague symptoms, but to support a diagnosis of a autoimmune rheumatic disease if a patient has appropriate symptoms or signs. The final diagnosis is based on clinical findings, although test results may support the diagnosis, or prompt further specific investigation.
Normal health | Normal population, especially the elderly, transient during pregnancy |
Autoimmune rheumatic disease | High prevalence in systemic lupus erythematosus, but also seen in scleroderma, dermatomyositis, Sjögren syndrome, mixed connective tissue disease and long-standing rheumatoid arthritis |
Juvenile arthritis | Highest prevalence in girls with oligoarticular juvenile arthritis, but also seen in polyarticular and systemic disease |
Infectious disease | Malaria, bacterial infections, transient rise during many viral infections |
Endocrine disease | Type 1 diabetes, autoimmune thyroiditis |
Liver disease | Chronic liver disease, autoimmune hepatitis |
Malignancy | Breast cancer, squamous cell carcinoma of the lung and hepatocellular carcinoma |
Haematological disease | Autoimmune thrombocytopenic purpura and haemolytic anaemia |
Drugs | Many reported including minocycline, penicillamine, hydralazine, procainamide, isoniazid, methyldopa and quinidine |