Laboratory Tests

A good history and detailed clinical examination of patient are extremely important for proper diagnosis of over 100 types of arthritis. Recognition of patterns of joint involvement (topography) as well as those of disease presentation and progression is essential for correct clinical diagnosis. In rheumatology practice, a working diagnosis can usually be made on proper examination of the patient. Laboratory tests including X-Rays are ordered later for confirmation of diagnosis, ruling out other possible causes, estimating level of disease activity or monitoring drug toxicity. As with any other investigations, these must be obtained from a reliable laboratory and the results should always be interpreted in view of clinical picture. These tests are costly and must not be used indiscriminately. Laboratory studies are useful in arthritis only if ordered in an appropriate clinical situation and interpreted accordingly. Measurement errors, laboratory variations due to various factors and inherent limitations must always be born in mind. A positive test in absence of appropriate clinical setting can generally be overlooked.

Commonly used laboratory investigations are discussed below:

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  • Haemogram (Complete Blood Count - CBC)

    This simple and inexpensive test gives valuable information about anaemia (low haemoglobin concentration) and status of bone marrow which manufactures various blood cells. Morphology of red cells and other observations give a clue to the cause of anaemia. Bone marrow suppression is a common adverse effect of some drugs such as methotrexate and cyclophosphamide. Counts of white cells and platelets are also important in diseases like systemic lupus erythematosus (SLE) for diagnosis and follow up.

  • Erythrocyte sedimentation rate (ESR)

    Liver produces acute phase reactants such as fibrinogen, haptoglobin, alpha-1-antitrypsin, C-reactive and other proteins in response to inflammation. This production is stimulated by Interleukin-1, an inflammatory cytokine. Normal age-adjusted upper limit of ESR is age/2 for males and (age+10)/2 for females. Westergreen method is more accurate for ESR levels of more than 50 mm/hr as it uses longer tube. Wintrobe method is more accurate for borderline elevations. Sample for ESR must be obtained in a fasting state and examined immediately. ESR is nonspecific for disease process. Aging, obesity and pregnancy elevate ESR. Anaemia and polycythemia also give higher readings. ESR can be markedly elevated in various infections, malignancies, systemic lupus and vasculitides. Significant and persistent elevation of ESR in a case of arthritis indicates inflammatory process such as rheumatoid arthritis. It can also be used for monitoring efficacy of treatment in controlling disease activity. It must be noted that ESR remains elevated for longer time (falls by 50% per week) after inflammation subsides.

  • C-reactive protein (CRP)

    CRP, a glycoprotein, is an acute phase reactant by itself and, though costlier than ESR, is a more specific marker of acute inflammation. It elevates within 4 hours of injury and peaks within 24-72 hours. Half life of CRP is about 18 hours and it disappears rapidly when the inflammation subsides. It can be estimated from a fridge-stored sample. Estimation of CRP can also be used to monitor disease process. CRP is usually moderately elevated in connective tissue disorders. Markedly elevated levels indicate acute bacterial infection, trauma and systemic vasculitis. Discrepancies between ESR and CRP can be found in systemic lupus and other conditions wherein ESR is elevated whereas CRP remains normal.

  • Rheumatoid Factor

    Rheumatoid factors are autoantibodies directed against Fc portion of IgG immunoglobulin. Development of rheumatoid factor is a mechanism to help removal of immune complexes from circulation. Many inflammatory conditions including hepatic and pulmonary diseases, infections, sarcoid, neoplasia and others show positive rheumatoid factor. About 3% of general population is positive for rheumatoid factor and the prevalence increases with increasing age. Rheumatoid factor positivity is one of the seven classification criteria for diagnosis of rheumatoid arthritis (RA). It has a sensitivity of 80% and specificity of 95%. Its negative predictive value is 95% whereas positive predictive value is only about 20-30%. RA is a clinical diagnosis and positive predictive value increases if this test is used in selected cases. Quantitative readings must be obtained and levels above 40 IU/ml can be considered as significant. Rheumatoid factor positivity indicates poorer prognosis and higher incidence of systemic and extra-articular features.

  • Anticyclic Citrullinated Peptide Antibodies (ACPA)

    ACPA are newer antibodies found to be associated with RA. They are reported to be highly specific (98%) and moderately sensitive (70%) for RA. They predict an erosive disease. These antibodies can become positive 3 to 6 years prior to clinical onset of RA. They can also be used to differentiate RA from other rheumatoid factor positive conditions such as hepatitis C associated arthritis, other viral arthritis and fibromyalgia. High titers of these antibodies indicate aggressive disease as well as need for more aggressive therapy.. Rheumatoid factor positivity in addition to ACPA antibody positivity, however, does not help in prognostication of RA.

  • Anti-Streptolysin O (ASO)titre

    This test is directed against extra cellular products found in supernatant broth of culture of bacteria called streptococci. ASO titer test should be ordered only when diagnosis of acute rheumatic fever (ARF) is suspected. ARF is a childhood (4-15 year age) disease and joint involvement is characterized by migratory polyarthritis of large joints. Clinical diagnosis established by evidence of adequate Jones criteria. A positive ASO titer indicates nonspecific immune stimulation due to past exposure of streptococci. A four-fold rise (320 Todd units in children) is diagnostically significant. These titers start rising about 7 days after infection, peak at 3-5 weeks and gradually return to baseline over next 6-12 months. These titers also rise in infections caused by other streptococci (e.g. soar throat, skin infections, scarlet fever) and also other species of bacteria producing ASO-like products. ASO titers are of no value in nonmigratory arthritis especially in adults. It can be normal in about 20% cases of ARF. The sensitivity can be further improved up to 95% by testing other streptococcal products viz. antiDNase-B and antistreptokinase.

  • Uric acid

    Gout is the most common cause of inflammatory arthritis in men over 40 year age. It usually affects joint at the base of great toe. The onset of arthritis is abrupt with exquisite pain, warmth and redness and may spread around. This is an inflammatory reaction to deposition of urate crystals in joint. Demonstration of urate crystals in synovial fluid by polarized microscopy is needed to confirm diagnosis. A favourable response to colchicin used in initial 24 hours can provide a clue to diagnosis. Insteps, ankles, heels, knees, wrists, fingers and elbows are other joints that can be affected due to cooler peripheral temperature. Nonarticular sites can also be involved. Vague aches and pains as also monoarthritis without classical history of acute attack should never be labeled as gout unless synovial fluid shows urate crystals. Serum uric acid is raised in conditions of fast cell turnover or slowed renal excretion. Most hyperuricaemias are idiopathic or primary. Many drugs such as low dose aspirin, diuretic (except spironolactone), glucose, steroids, rifampicin, ethambutol, gentamycin, levodopa, theophyllin, methyldopa and propranolol cause hyperuricaemia. Premenopausal females do not develop gout because oestrogens lead to excretion of uric acid through urine. Ordering uric acid estimations in these females is a waste of money and insult to their feminity. Hyperuricaemia is a part of metabolic syndrome along with diabetes mellitus, hypertension, obesity, atherosclerosis and stress. Uric acid is the strongest antioxidant that body produces. Hyperuricaemia without crystal deposition should not be treated as reduction to less than 8 mg/dl has been shown to increase risk of coronary artery disease.

  • LE cell phenomenon

    LE cell phenomenon is an outdated test and should not be asked for.

  • Anti-nuclear antibodies (ANA)

    ANA are diverse group of auto antibodies positive in about 30% cases of RA. These patients have more severe disease and poorer prognosis. Arthritis due to other systemic autoimmune diseases such as SLE, Sjogren’s syndrome and scleroderma shows positive ANA. ANA test must be done by indirect immunofluorescence (IIF) method and positivity reported in terms of intensity and pattern of immunofluorescence. ELISA method is less sensitive as it gives frequent false positive as well as negative reports. A negative IIF ANA test excludes diagnosis of an autoimmune disease and further testing such as ANA blot test (for differentiating antibodies) is not warranted. ANA positivity can be seen in autoimmune rheumatic diseases as well as some other conditions such as chronic active hepatitis.

  • Anti ds-DNA Antibodies

    This test is useful in confirmation of diagnosis of systemic lupus erythematosus. It also indicates activity of SLE as well as kidney disease in SLE. It should ideally be done by Farr assay method and expressed as IU/ml. ELISA method can give false positive results.

  • HLA B27

    HLA B27, a commonly misused test, is a genetic marker normally present in 8-10% of normal population. The diagnosis of ankylosing spondylitis (AS) and other spondarthritides needs to be considered in cases of asymmetric large joint arthritis associated with inflammatory backache. 83-94% of Indian patients of AS are HAL B27 positive. It cannot be a diagnostic test for AS in absence of typical features of back pain; because of high prevalence in population. HLA-B27 positive patients are more likely to have spine, eye and heart disease. HLA-B27 is a costly test and must be used in selected patients with incomplete manifestations of the disease. AS affects less than 0.1% population and indiscriminate ordering of this test can lead to a false positive result

  • Liver Function Tests

    These are often ordered to assess preliminary status and monitoring toxicity due to drugs like methotrexate, sulphasalazine and azathioprine. Serum protein estimation indicates appropriate functioning of liver cells; raised SGPT (ALT) and SGOT (AST) indicate inflammation of liver cells whereas raised alkaline phosphatase indicates disease of bile-collecting system of liver or bone diseases.

  • Kidney function Tests

    These are ordered to assess preliminary status and monitoring toxicity or dose adjustments of some drugs such as pain killers. Simple tests such as urine examination, blood urea and serum creatinine can indicate kidney involvement at an early stage. Kidney derangement is usually asymptomatic during initial stages. These tests are invaluable in detecting kidney involvement in various rheumatic diseases such as SLE and vasculitis. They are also useful in following up these diseases as therapy can be modified on their basis.

  • Synovial fluid examination

    Examination of fluid aspirated from a swollen joint is invaluable in diagnosis of inflammatory, septic and crystal-induced arthritis as well as haemarthrosis (blood in a joint). Fluid must be examined immediately after aspiration and cultured for isolation of pathogenic organisms. Synovial biopsy is usually required for diagnosis of monoarthritis. Arthroscopic biopsy has better chances of positive results.

  • Imaging Techniques

    X-Rays are necessary for detecting bone erosions and other changes for diagnosis of arthritis. There are many other situations where X-Rays of various body parts may be required. Obtaining proper films and reading of X-Rays requires properly trained personnel. Indiscriminate use of X-rays should be avoided as there is a possibility of radiation hazard. Natural background radiation to Indian population is estimated to be 2.299 millisievert per year. X-Ray of spine, extremities and chest has radiation exposure of 1.5 mSv, 0.001 mSv and 0.1 mSv respectively. X-Rays should, therefore, be ordered only if required. Pregnant patients must avoid X-Ray and CT examinations.
    Computed tomography (CT scan) is a useful investigation for knowing more about bones in and around joints. CT scan has higher radiation exposure.
    Magnetic Resonance Imaging (MRI), a costly test, is useful for various soft tissues in and around joints. MRI often over reads the situation and requires a trained observer for correct interpretation. Physicians and family practitioners are not trained in reading these sophisticated investigations.
    Ultrasound examination of joints is a simpler and cheaper test for assessment of soft tissues but requires a trained sinologist.
    Isotope bone scan is never required for assessment of arthritic joints as better tests are available and the reports can be fallacious and misleading. Diagnosis of ankylosing spondylitis should never be based on sacroiliitis seen on an isotope scan.

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