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A REGULAR CASE-BASED SERIES ON PRACTICAL PATHOLOGY FOR GPs


NOVEMBER 2008

Common Sense Pathology


CONTENTS
Appropriate screening for immune disorders Case study

Arthritis which tests to choose,


and which to avoid
A JOINT INITIATIVE OF
The Royal College of Pathologists of Australasia

Arthritis - which tests to choose, and which to avoid


Dr Theo de Malmanche, Staff Specialist in Immunology, Hunter Area Pathology Service and John Hunter Hospital, Newcastle, NSW. Associate Professor Glenn Reeves, Senior Staff Specialist in Immunology, John Hunter Hospital, Newcastle, and Director of Immunology, Hunter Area Pathology Service, NSW.

Introduction
Assessment of a patient with aching joints follows the usual lines of best medical practice, using thorough history-taking and examination to arrive at a provisional diagnosis. This is further refined through the selective ordering of appropriate pathology tests. This article uses a typical clinical case scenario to discuss some commonly encountered issues arising during this process, with emphasis on rational use of pathology testing.

Case study
Mrs AL is a 50-year-old-woman who presents with swelling of the right wrist that has been present for less than a week. She admits to reduced grip strength in both hands on most mornings for about an hour and sore balls of her feet in the evenings, both of which have been present for some weeks. Her wrists (right more than left) are swollen and tender to touch. Although fatigued, she denies fever or chills. She also mentions that her hands become very sore after prolonged activities such as knitting. What are the likely diagnoses? What should be done?
This issue of Common Sense Pathology is a joint initiative of Australian Doctor and the Royal College of Pathologists of Australasia. It is published by Reed Business Information Tower 2, 475 Victoria Ave, Locked Bag 2999 Chatswood DC NSW 2067. Ph: (02) 9422 2999 Fax: (02) 9422 2800 E-mail: mail@australiandoctor.com.au Web site: www.australiandoctor.com.au (Inc. in NSW) ACN 000 146 921 ABN 47 000 146 921 ISSN 1039-7116 2008 by the Royal College of Pathologists of Australasia www.rcpa.edu.au CEO Dr Debra Graves E-mail: debrag@rcpa.edu.au While the views expressed are those of the authors, modified by expert reviewers, they are not necessarily held by the College. Common Sense Pathology editor: Associate Professor Huy A Tran E-mail: huy.tran@hnehealth.nsw.gov.au Australian Doctor Editor: Dr Kerri Parnell E-mail: kerri.parnell@reedbusiness.com.au GP editor: Dr Wendy Morgan E-mail: wendy.morgan@reedbusiness.com.au Commercial director: Suzanne Coutinho E-mail: suzanne.coutinho@reedbusiness.com.au Sub-editor: Shahiron Sahari E-mail: shahiron.sahari@reedbusiness.com.au Graphic designer: Edison Bartolome E-mail: edison.bartolome@reedbusiness.com.au Production manager: Ray Gibbs E-mail: ray.gibbs@reedbusiness.com.au

Cover: Coloured X-ray of hands with rheumatoid arthritis. Science Photo Library.

For an electronic version of this and previous articles, you can visit www.australiandoctor.com.au Click on Clinical and Library, then Common Sense Pathology. You can also visit the Royal College of Pathologists of Australasias web site at www.rcpa.edu.au Click on Publications and Forms, then Common Sense Pathology. This publication is supported by financial assistance from the Australian Government Department of Health and Ageing.

This patient has arthritis, as demonstrated by the swelling and tenderness of the wrists. The hand and foot symptoms suggest several joints may be involved (polyarthritis) and the presence of swelling and tenderness on examination of the wrists reinforces this suspicion. There are two major types of arthritic pain non-inflammatory and inflammatory which, in addition to the clinical company they keep, provide clues to the underlying pathogenesis. Non-inflammatory pain, often due to osteoarthritis, is made worse by activity and often improves with rest. It may be associated with characteristic structural changes (Heberdens nodes: small nodules over the distal interphalangeal joints of the hands), and is often associated with involvement of other joints (particularly carpometacarpal joints and knees). Inflammatory pain refers to pain that is most pronounced after a period of rest (often associated with early morning stiffness), and duration of stiffness after rest can be used as a rough marker of inflammatory severity. In contrast to degenerative joint pain, inflammatory pain often improves with movement, and associated features suggestive of local inflammation (eg, redness, synovial swelling) or, occasionally, systemic inflammation (eg, fevers, weight loss) may coexist. Mrs AL has an inflammatory arthritis in the wrists, metatarsalgia, and hand pain suggestive of non-inflammatory arthritis. A patient such as Mrs AL has an undifferentiated polyarthritis, or early arthritis, with mixed features. Bacterial infection causing septic arthritis often presents with a sudden onset of arthritis involving only a few joints, in the setting of a febrile illness, although most patients with septic arthritis feel quite unwell. This is the most important possibility to address, as delayed introduction of appropriate antibiotics can cause permanent joint damage and dysfunction.

where culture and sensitivity testing of causative microbial pathogens (usually Staphylococcus species) allows appropriate targeted therapy. It should be noted however, that the use of prior antibiotics and other technical factors limit the sensitivity of synovial fluid analysis to about 70% depending on the pathogen. Ultrasound confirms fluid in the joint, ruling out soft tissue infection. Inability to detect crystals for gout (sodium urate) or pseudogout (calcium pyrophosphate) does not exclude these diagnoses. Small joint arthritis may be the presenting feature of viral arthritis, in which event a skin rash is sometimes also seen. An urgent request for ultrasound-guided aspiration shows there is fluid in Mrs ALs left wrist joint, and microscopy demonstrates 10,000 leucocytes/mm3 without bacteria or crystals.

Arthritis with inflammatory pain


Inflammatory arthritis is largely defined on clinical grounds by the presence of inflammatorytype joint pain, and suggests an autoimmune or infection-related aetiology. In this case, the modest degree of synovial white cell elevation and lack of identifiable bacteria argue against a septic process. Serological markers of inflammation (C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR], see below) are an insensitive tool for defining the presence of joint inflammation, and normal levels of inflammatory markers should not argue against such a process if there is a high clinical likelihood of infection (not the case with this patient).

Arthritis with non-inflammatory pain


Osteoarthritis is the most common cause of arthritis associated with non-inflammatory joint pain, and Mrs ALs hand pains are suggestive of such a process. Serological investigations including inflammatory and autoimmune markers are usually normal. It should be noted, however, that 10% of healthy individuals display positive antinuclear antibodies (ANA) [see below], with the proportion rising with age, and the attribution of non-inflammatory hand pain to an autoimmune aetiology in these circumstances would be inap-

Infective arthritis
Infective arthritis often affects larger joints, with particular predilection for joints prone to degenerative (eg, osteoarthritic) pathology. Diagnosis is best refined with synovial fluid analysis,

propriate. Also, osteoarthritis may sometimes display an inflammatory component, and in such circumstances low-level elevation of inflammatory markers (eg, CRP) may be seen. In advanced disease, X-rays show characteristic changes, eg, joint space reduction with osteophytes. Mrs ALs symptoms persist despite naproxen 750mg per day. In guiding diagnosis and management of arthritis, is CRP superior to ESR?

ulcerative colitis) can cause inflammation in the absence of CRP elevation, so in these circumstances ESR testing can be requested. Many clinicians request both CRP and ESR, at least in initial screening, and choose one to follow as a guide to treatment success. While normal ESR and/or CRP do not exclude an autoimmune disease, they do suggest a milder disease course. Pathology testing is rarely definitive it can only be considered as evidence for or against a clinical diagnosis.

Tests to guide diagnosis and management: CRP or ESR?


CRP is increasingly preferred to ESR as an inflammatory marker because of its ease of measurement, faster response to inflammatory change, greater specificity for inflammation and lack of artefactual change 1 in paraproteinaemic states. However, ESR is a useful disease marker in giant cell arteritis/polymylagia rheumatica and certain conditions (including SLE and

Appropriate screening for immune disorders


A systems review is highly recommended before ordering pathology tests. Some key symptoms can highlight potential diagnoses. Fever, weight loss and hypertension are important. One approach to the systems review is from head to toe, with examples of potentially useful tests listed in Table 1.

Table 1: Screening for immune disorders


Symptom or sign Hair loss Scalp pain and/or headache Dry eyes (and/or mouth) Rash (face or other) Jaw or tongue cramping Lymphadenopathy Myalgia (shoulder/hip girdle) Inflammatory small joint arthritis Weakness without pain Stiffness of limbs Change of colour of digits Chest pain Shortness of breath Back stiffness (not pain) Abdominal pain and/or change in bowel habit Tingling and/or numbness Condition to consider Chronic illness, including SLE Temporal arteritis Sjgren's syndrome SLE Temporal arteritis Lymphoma or recent infection RA and polymyalgia rheumatica RA or SLE Inflammatory myositis Inflammatory arthritis Limited scleroderma Serositis from SLE Pulmonary fibrosis Ankylosing spondylitis Potentially helpful tests ANA, ENA ESR, CRP ENA (especially SSA, SSB) ANA, ENA ESR, CRP Flow cytometry CCP, ESR, CRP ANA, CCP, RF CK, CRP CCP, CRP, ESR ANA, ENA ANA, ENA Lung function, ANA, ENA, CCP CRP [HLA-B27]

Inflammatory bowel disease, Urinalysis, CRP, [ANCA] Henoch-Schnlein purpura, vasculitis Neuropathy, including vasculitic CRP, ANA, ANCA

CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; ANA = antinuclear antibody; ENA = (antibodies to) extractable nuclear antigens; CCP = (antibodies to) cyclic citrullinated peptide; SSA = (antibodies to) Sjgrens syndrome A; SSB = (antibodies to) Sjgrens syndrome B; RF = rheumatoid factor; CK = creatine kinase; ANCA = antineutrophil cytoplasmic antibodies; SLE = systemic lupus erythematosus; RA = rheumatoid arthritis

Appropriate initial testing for the patient described would include those assays listed in Table 2, while Table 3 lists some assays of lower yield.

Rheumatoid factor or antibodies to cyclic citrullinated peptide?


Rheumatoid arthritis (RA) is one of the most common autoimmune conditions affecting the community, with a prevalence of about 1%.

It classically causes symmetrical small joint inflammatory pain (eg, hands, feet) which, with long-term illness, is often associated with deforming changes and radiological evidence of erosive arthritis. Where RA is a possibility (as with Mrs AL), testing for both rheumatoid factor (RF) and antibodies to cyclic citrullinated peptide (CCP) is recommended, as some patients with RA may be 2,3 positive for one and not the other. Multiple

Table 2: Appropriate initial testing for patient with arthritis


Test Electrolytes and creatinine Liver function testing CRP (+/- ESR) ANA ENA RF CCP Hold serum Urine dipstick for protein and blood. Reason Exclude advanced renal disease Check for infective (eg, hepatitis B and C, EBV, CMV) or immune-complex associated pathology Diagnostic and prognostic SLE unlikely if negative Diagnose condition if positive Screen for RA, SS Screen for RA Later (?viral) serology if necessary Screen for glomerulonephritis

CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; ANA = antinuclear antibody; ENA = (antibodies to) extractable nuclear antigens; CCP = (antibodies to) cyclic citrullinated peptide; RF = rheumatoid factor; SLE = systemic lupus erythematosus; SS = Sjgren's syndrome; EBV = Epstein-Barr virus; CMV = cytomegalovirus; RA = rheumatoid arthritis

Table 3: Assays useful in a minority of patients with arthritis


Test Anti-dsDNA Urate ANCA HLA-B27 C3, C4 Vascular risk profile (HDL, LDL) CK Comment Virtually always negative if ANA negative Levels <0.4mmol/L argue against gout, but can fall during acute episodes. Less useful than joint aspirate microscopy Rarely positive without supportive clinical features; however, may be appropriate if above assays non-diagnostic Not specific for ankylosing spondylitis: positive in 9% of Caucasians Can be low in SLE and SS, but only mildly supportive of the diagnosis Important once a diagnosis is made, but not in the initial work-up Screen for myositis if weakness prominent

ANA = antinuclear antibody; anti-dsDNA = antibodies to double-stranded DNA; CCP = (antibodies to) cyclic citrullinated peptide; CK = creatine kinase; ANCA = antineutrophil cytoplasmic antibodies; SLE = systemic lupus erythematosus; SS = Sjgren's syndrome; C3 = complement component C3; C4 = complement component C4; HDL = high-density lipoprotein; LDL = low-density lipoprotein

Speckled pattern ANA using indirect immunofluorescence on HEp-2 substrate.

regression analyses of diagnostic testing for RA include both of these assays as independent predictors (see below). Mrs ALs blood results are ANA 1:80 speckled pattern; ENA: SSA-antibody positive; RF 40 IU/L (<20 IU/L); CRP 180mg/L (<12mg/L); ESR 80mm/hr and anti-CCP antibodies 80 EU (<20 EU). Her urinalysis and biochemistry are unremarkable. What should be done? Anti-CCP antibodies have emerged as the best single serological predictor for RA. Not all patients with RA are anti-CCP antibody positive,4 but those who are tend to display a more aggressive course, especially when anti-CCP antibody levels are high.5 Such patients are also at higher risk of vascular disease,6 particularly if inflammatory markers are also persistently elevated.7 If a patient with arthritis is anti-CCP antibody positive, they should be reviewed by a physician experienced in the management of RA, as early intensive treatment may be indicated to prevent joint damage.8 Anti-CCP antibodies have been reported in other disease states, but usually at low levels. Avoid testing for anti-CCP antibodies in patients without arthritis. The predictive value of anti-CCP antibodies is improved further if one also assesses RF, CRP and

the number of swollen joints. These four tests were shown to have performed better than the American College of Rheumatology criteria for RA,3 and current gene tests for RA risk.9 One series also included age, female gender, distribution of joint involvement, duration of joint stiffness and number of tender joints as markers of poorer prognosis.2 Patients with anti-CCP antibodies are more likely to have smoked tobacco.10 Smoking cessation will improve their significant cardiovascular risk but will not alter the course of the arthritis.

Antinuclear antibody testing what do the results mean?


ANA testing looks at how antibodies in the patient serum stick to cells which are attached to a microscope slide. These cells are of human origin, and so any antibodies sticking are autoantibodies. ANA results are often confusing, and sometimes frustrating while they are very sensitive markers of SLE, their specificity is poor. Positive ANA results are seen in up to 10% of normal individuals, as well as in the context of a range of infections (eg, Epstein-Barr virus infection), drug therapies (eg, hydralazine, TNF-inhibitors), and neoplasms (eg, lymphoma). The ANA pattern reflects which part(s) of the nucleus (and occasionally cytoplasm) the antibodies bind to: homogenous staining is a smooth staining

across the nucleus, as would be seen with antibodies to double-stranded DNA (anti-dsDNA); speckled staining of nuclear riboproteins is seen, for example, with the antibodies found in Sjgren's syndrome. A few principles can help with interpretation of ANA results: ANA testing is a useful screening test a negative ANA makes conditions such as SLE and scleroderma unlikely. High levels are more important, especially in youth. Most laboratories report results as dilutions. A titre of 1:1280 is clearly positive, while a titre of 1:40 is only relevant when the pre-test likelihood of SLE is quite high. A few patterns are well associated with particular disorders, such as centromere antibodies with limited scleroderma (CREST) and antibody to proliferating cell nuclear antigen (PCNA) with SLE, and guiding comments will usually reflect this. Most ANA results however, attract comments such as consistent with SLE or similar, and therefore are not highly specific for a clinical diagnosis. A doctors initial reaction to pathology results often reflects the clinical suspicion, and should not be ignored (see if the result does not fit below).

Antibodies to extractable nuclear antigens


Each of the antibodies to extractable nuclear antigens (ENA) results is more strongly associated with particular clinical disorders (Table 4), in contrast to the screening ANA test above. It should be remembered that the assays performed when ENA is requested may vary between laboratories. Only a few currently include Pm-scl (antibodies in polymyositis-scleroderma overlap syndromes), and none include anti-dsDNA antibodies (see below). Anti-ribosomal-P antibodies, SSA(Ro)52 antibodies, and RNA polymerase-III antibodies can be requested separately or as 'addons' if considered relevant. Some assays for SSA(Ro) antibodies contain both SSA(Ro)60 and SSA(Ro)52 antigens. The clinical relevance of antibodies to SSA(Ro)52 is uncertain.

If the result does not fit


If a result does not support the provisional diagnosis then consider that: Antibodies can precede the clinical features; consider observing for such features on further review. Some recent improvements of assays maximise detection of antibodies, and will detect clinically irrel-

Table 4: Antibodies detected during ENA testing


ENA RNP* SSA(Ro)* SSB(La)* Scl-70* Jo-1* Sm* PM-scl** Ribo-P** RNA polymerase III** SSA(Ro)52** Association Mixed connective tissue disorder, SLE Sjgrens syndrome, SLE, cutaneous lupus, neonatal lupus As for Ro Scleroderma, perhaps with pulmonary fibrosis Myositis and pulmonary fibrosis SLE (rare in Caucasians) Myositis and/or scleroderma Specific for SLE, seen in about 20% of cases Scleroderma with renal crisis Less well associated than the above ANA pattern Speckled Speckled Speckled Speckled, nucleolar +/- homogenous Negative or nucleolar Speckled Nucleolar Cytoplasmic +/- nucleolar Nucleolar Speckled

RNP = ribonucleoprotein antibodies; SSA = Sjgrens syndrome A; SSB = Sjgrens syndrome B; Scl-70 = (antibodies to) 70kD scleroderma antigen (DNA topoisomerase); Jo-1 = (antibodies to) anti-histidyl tRNA synthetase; RNA = ribonucleic acid; Sm = (antibodies to) Smith antigen; Pm-scl = antibodies in polymyositisscleroderma overlap syndromes; Ribo-P = antibodies to ribosomal-P antigens; SLE= systemic lupus erythematosus *Usually part of routine assessment when ENA requested **Not done by all laboratories

evant antibodies. These may be negative on repeat testing. Try to avoid testing for disorders which are clearly irrelevant, and avoid the best of three cycle where repeated testing just confuses the diagnosis. If a doctor is unfamiliar with an assay, they will be unfamiliar with the significance of the results and may under- or over-estimate their relevance. Consider discussion with a pathologist or specialist. If in doubt, refer the patient to a specialist in the area.

New assays
Nucleosome and chromatin: Some laboratories consider antibodies to chromatin, nucleosome and native (double-stranded) DNA interchangeable, though definitive direct comparisons of assay utility are lacking. These new assays use structurally supporting histone proteins to maintain the natural DNA conformation. These antibodies are considered specific for SLE and potential renal involvement, though results are method dependent and some assay methods (eg, enzyme immunoassay versus radio immunoassay) yield false-positive results. RNA polymerase III antibodies: These antibodies are highly specific for scleroderma, and are associated with increased risk of renal disease and scleroderma renal crisis. Mrs AL mentions that her brother has ankylosing spondylitis and asks whether this could be relevant to her condition.

Mrs AL is unlikely to have ankylosing spondylitis or another seronegative spondyloarthropathy on the basis of her story, as she has no axial stiffness (which suggests arthritis affecting the spine and sacroiliac joints) and no other symptoms or disorders to suggest other causes (psoriasis, inflammatory bowel disease, prior genitourinary infection). Where seronegative spondyloarthropathy is considered possible, demonstration of inflammation serologically and through joint imaging (particularly focusing upon sacroiliac joints in ankylosing spondylitis) is supportive of this diagnosis. HLAB27 testing can also be performed. HLA-B27 is a Class I major histo-compatibility (MHC) antigen involved in presentation of intracellular antigens (often microbial) to the immune system. While positive HLA-B27 results are seen in 9% of normal individuals, the prevalence rises to about 90% for those with ankylosing spondylitis, so a negative result may help to reduce the likelihood of ankylosing spondylitis, and a positive result in the appropriate clinical setting represents evidence in favour of ankylosing spondylitis. HLA-B27 results are more likely to be negative in other causes of seronegative spondyloarthropathy such as Reiter's syndrome (post-infective conjunctivitis, arthritis and urethritis), psoriatic arthritis and enteropathic (gut-associated) arthritis.

Summary
Clinical features (systems review) should guide testing in the diagnostic work up for arthritis. Recommended initial testing includes electrolytes, creatinine, liver function tests, CRP +/- ESR, ANA, ENA, RF, anti-CCP antibodies, urine dipstick and hold serum. ANA testing should be considered a screening test for lupus and related immune disorders. Anti-CCP antibody is the single most specific test for early RA, and anti-CCP-antibodypositive patients should be considered for specialist review.

Seronegative spondyloarthropathies
The seronegative spondyloarthropathies, of which ankylosing spondylitis is the prototype, are so named because they cause inflammatory joint pain but display no associated autoantibodies.

Arthritis which tests to choose,


and which to avoid
References
1. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. New England Journal of Medicine 1999; 340(6):448-54. 2. van der Helm-van Mil AH et al. Validation of a prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis. Arthritis & Rheumatism 2008; 58(8): 2241-47. 3. Yamane T et al. Easy and accurate diagnosis of rheumatoid arthritis using anti-cyclic citrullinated peptide 2 antibody, swollen joint count, and C-reactive protein/rheumatoid factor. Journal of Rheumatology 2008; 35:414-20. 4. Bukhari M et al. The performance of anti-cyclic citrullinated peptide antibodies in predicting the severity of radiologic damage in inflammatory polyarthritis: results from the Norfolk Arthritis Register. Arthritis & Rheumatism 2007; 56(9):2929-35. 5. Syversen SW et al. High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year long longitudinal study. Annals of Rheumatic Disease 2008; 67(2):212-17. 6. Farragher TM et al. Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis. Arthritis & Rheumatism 2008; 58(2):359-69. 7. Szekanecz Z et al. Accelerated atherosclerosis in rheumatoid arthritis. Annals of the New York Academy of Sciences 2007; 1108:349-58. 8. Saag KG et al. American College of Rheumatology 2008 Recommendations for the use of nonbiologic and biologic diseasemodifying antirheumatic drugs in rheumatoid arthritis. Arthritis & Rheumatism (Arthritis Care & Research) 2008; 59(6):762-84. 9. Karlson EW et al. Associations between human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study. Annals of Rheumatic Disease 2008; 67(3): 358-63. 10. Verpoort KN et al. Association of smoking with the constitution of the anti-cyclic citrullinated peptide response in the absence of HLA-DRB1 shared epitope alleles. Arthritis & Rheumatism, September 2007; 56(9):2913-18.

Further reading
Reeves, GEM. Update on the immunology, diagnosis and management of systemic lupus erythematosus. Journal of Internal Medicine 2004; 34:338-47.

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