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Testing in the Rheumatic Diseases

Testing in the Rheumatic Diseases. Salahuddin Kazi, M.D. Questions to Answer When Applying a Valid Diagnostic Test to a Specific Patient*. Is the test available, affordable, accurate and precise in our setting?

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Testing in the Rheumatic Diseases

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  1. Testing in the Rheumatic Diseases Salahuddin Kazi, M.D.

  2. Questions to Answer When Applying a Valid Diagnostic Test to a Specific Patient* • Is the test available, affordable, accurate and precise in our setting? • Can we generate a clinically sensible estimate of our patient’s pre-test probability? • Will the resulting post-test probability affect our management and help our patient? *Evidence Based Medicine: 2nd Edition, Sacket et al, 2000

  3. Test Statistics - A Review • Sensitivity - The proportion of affected individuals with a positive test • Specificity - The proportion of unaffected individuals with a negative test • Utility lies at the extremes - SpPin “High specificity; positive test rules in” and SnNout “High sensitivity; negative test rules out”

  4. Gold Standard Positive Negative True Pos False Pos Positive Predictive Value = a/ a+b Positive a b Test Result c d Negative Predictive Value = d/ c+d Negative False Neg True Neg Prevalence = a+c/ a+b+c+d Sensitivity = a/ a+c Specificity = d/ b+d

  5. Likelihood Ratios • The likelihood that a given test result would be expected in a patient with the target disorder compared with the likelihood that the same result would be expected in a patient without the target disorder • +LR = sensitivity/(1-specificity) • -LR = (1-sensitivity)/specificity

  6. 0.1 99 0.2 0.5 1000 95 1 90 500 2 200 80 100 70 50 5 60 20 50 10 10 40 5 30 20 2 1 20 30 0.5 40 0.2 10 50 0.1 60 5 0.05 70 0.02 80 0.01 2 0.005 0.002 90 1 95 0.5 0.001 0.2 99 0.1 Pre-test probability Post-test probability Likelihood ratio Likelihood Ratio Normogram

  7. Case #1 • A 32 y/o woman describes a 6 week history of pain and stiffness in her hands • No history of fever, rash, dysuria, conjunctivitis, travel or exposure. No prior renal disease, seizures, or serositis. Her mother has deforming arthritis. • On exam there is warmth and soft-tissue swelling of the 2nd and 3rd MCPs bilaterally, the 3rd right PIP, and the left wrist. There seems to be a small effusion in the left knee. • Labs: SMA6 and U/A - normal; mild anemia; CRP 2.7; ANA - 1:40, diffuse; Rheumatoid Factor - 320

  8. Rheumatoid Factor • Anti-IgG - can be all Ig classes • Specific for Fc portion of IgG • Can be polyclonal (typical of autoimmunity) or monoclonal (typical of lymphoid malignancy) • Causes immune complex damage • Reported as “units” or titer

  9. RF Test Characteristics • Sensitivity for RA is ~80% • Specificity is 85-95% • +LR of 5-16 depending on population studied • High titer is associated with more severe RA with extra-articular manifestations • Monitoring titer as an indicator of disease activity is not appropriate

  10. Conditions Associated with RF • Normal individuals (5%), especially with age (15%) • Rheumatoid arthritis (85%), Sjögren’s Syndrome, SLE (25-50%) • Viral Infections: Hepatitis C (25-50%), mononucleosis, HIV, influenza • Bacterial Infections: IE (25-50%), TB (10-25%), leprosy, syphilis, brucellosis • Parasites: Typanosomiasis, malaria, schistosomiasis, etc. • Other: Sarcoidosis, pulmonary fibrosis (10-25%), chronic liver disease

  11. Case #1 – Using the Test Results • Chronic, inflammatory, symmetrical polyarthritis of the hands in a young woman • What’s your pre-test probability that this patient has RA?

  12. 0.1 99 0.2 0.5 1000 95 1 90 500 2 200 80 100 70 50 5 60 20 50 10 10 40 5 30 20 2 1 20 30 0.5 40 0.2 10 50 0.1 60 5 0.05 70 0.02 80 0.01 2 0.005 0.002 90 1 95 0.5 0.001 0.2 99 0.1 Pre-test probability Post-test probability Likelihood ratio Highly positive RF takes a 50% pre-test probability to a >95% post-test probability In this case, a test with a moderate +LR makes the diagnosis almost certain in a patient with a high pre-test probability

  13. Case #2 • A 64-year-old female was evaluated for generalized joint pain and muscle pain, fatigue, fever and chills for the past 6-8 weeks • No rash, Raynaud’s, weight loss • Graves’ disease 18 years ago - radioactive iodine • Family history: SLE, thyroid disease • PE: Tender joints but no joint swelling • Labs: • CBC, Chem 7, LFT’s, UA, TSH - all normal • ESR 18 mm/h, CRP <0.8, RF negative, ANA positive 1:80, homogeneous pattern

  14. Anti-Nuclear Antibodies • Began with the demonstration of the “LE cell” by Hargraves in 1948 • Includes antibodies to a number of antigens, including native DNA • Performed by indirect immunofluorescence • Reported as “negative” - usually less than a certain titer, or as a titer and pattern

  15. ANA - Characteristics • Sensitivity - 95-100% • Specificity - Depends on titer used as cut-off • 15-30% of normals have ANA of 1:40 • 5% have ANA of 1:160 • +LR is ~20; utility for SLE is based on prevalence: • General population 50/100,000 • Young, African-American women 400/100,000 • Children/elderly men 1/100,000

  16. Immunofluorescence Patterns of ANAs

  17. Homogeneous Rim or Peripheral Nucleolar Speckled

  18. Causes of a Positive ANA

  19. Interpreting a Positive ANA

  20. Non Rheumatic Disease Infections Inflammatory bowel disease Autoimmune hepatitis Pulmonary fibrosis Endocrine diseases Hematologic diseases Neoplastic diseases End-stage renal disease Post-transplant Healthy People Pregnancy Older people Family history of rheumatic disease Drug induced Other Causes of Positive ANA

  21. Case #2:Why is the ANA Positive? • History and PE: Does not suggest a CTD • Labs: normal except for positive ANA • Pretest probability of SLE is low • Posttest probability for SLE remains low • Look for an alternative explanation • Elderly female • Positive family history of rheumatic disease • Reassure: ANA result is a normal finding

  22. 0.1 99 0.2 0.5 1000 95 1 90 500 2 200 80 100 70 50 5 60 20 50 10 10 40 5 30 20 2 1 20 30 0.5 40 0.2 10 50 0.1 60 5 0.05 70 0.02 80 0.01 2 0.005 0.002 90 1 95 0.5 0.001 0.2 99 0.1 Pre-test probability Post-test probability Likelihood ratio Although an ANA >1:160 has a high +LR, it should not be used to screen patients without clinical evidence of autoimmune disease

  23. Ordering an ANA • To confirm the diagnosis of SLE when the clinical suspicion is high • To exclude SLE when the clinical suspicion is moderate (2 or 3 lupus criteria) • Avoid ordering it when the clinic suspicion for SLE is low - a positive result can cause diagnostic confusion and unnecessary anxiety

  24. Anti-DNA Antibodies • Detect antibodies to native (double stranded) DNA • Typical methods are ELISA and immunofluorescence on Crithidia • Can have both diagnostic and prognostic significance

  25. Anti-DNA - Characteristics • Sensitivity - 60% for SLE • Specificity - 97% • Low titers seen in 2-5% of RA, Sjögren’s, scleroderma, relatives of SLE pts., etc. • Average +LR of 16 and -LR of 0.49 means that a positive anti-DNA has a large impact, but lack of one doesn’t exclude SLE

  26. Anti-DNA - Prognosis • SLE Disease activity: Useful, but with small +LR (~4) • Nephritis: Associated, but with very small +LR (~1.7) • Rising titers may predict a flare of disease activity in some, but not all, patients • Clinical correlation is advised

  27. Anti-ENA • Small nuclear RNP • Sm: Seen in 15-30% of SLE; specific • U1-RNP: 30-40% of SLE; also RA, Sjögren's, scleroderma, and overlap syndromes • Anti-Ro and anti-La • Subacute cutaneous LE • Sjögren's syndrome • Neonatal lupus with congenital heart block

  28. “ENA”-Extractable Nuclear Antigens RNP Antigens Sm Antigens C 70kDa 28kDa (B) 28kDa (B’) G 16kDa (D) 33kDa (A) 3’ 5’ U1RNA E F

  29. Anti-Scl-70/Anti-Centromere • Scl-70 = Topoisomerase I; seen in 40-70% of patients with diffuse scleroderma; worse prognosis with more organ involvement • Centromere - 70-85% of patients with limited scleroderma; associated with Raynaud’s syndrome • Neither is diagnostic by themselves

  30. Case #3 • A 48-year-old male has chronic sinusitis with occasional bloody drainage • You order a c-ANCA • Positive at 1:80 • The chest radiograph, creatinine and urinalysis are normal • What is the likelihood that he has Wegener’s granulomatosis?

  31. Positive Predictive Value of ANCA 1 2 3 4 100 1. Documented WG 2. Pulmonary-Renal Syndrome 3. Systemic Necrotizing Vasculitis 4. Rapidly Progressive GN 5. GN 6. Hospitalized Patient 5 Positive Predictive Value 50 This Patient 0 50 100 6 Disease Prevalence Jeanette: Amer J Kidney Dis 18:164, 1991

  32. 0.1 99 0.2 0.5 1000 95 1 90 500 2 200 80 100 70 50 5 60 20 50 10 10 40 5 30 20 2 1 20 30 0.5 40 0.2 10 50 0.1 60 5 0.05 70 0.02 80 0.01 2 0.005 0.002 90 1 95 0.5 0.001 0.2 99 0.1 Pre-test probability Post-test probability Likelihood ratio Wegener's is rare (~0.4/100,000). Without signs of progressive, necrotizing vasculitis, even a test with a high likelihood ratio is not helpful

  33. ANCA Characteristics • C-ANCA (Proteinase-3) • 90% specificity and 50-90% sensitivity for active Wegener's granulomatosis • P-ANCA • MPO - 60% of microscopic polyangiitis, Churg-Strauss • Cathepsins, lactoferrin, elastase • Should not take the place of tissue biopsy

  34. ANCAs and Rheumatic Autoimmune Diseases • P-ANCA (not directed against MPO) reported in: • RA, SLE, PM/DM, Sjögren's syndrome, Juvenile chronic arthritis , Reactive arthritis, Relapsing polychondritis* • C-ANCA • very rare in these diseases • ANCA is not associated with increased frequency of vasculitis in the autoimmune rheumatic diseases *Ann Intern Med 126:866-873, 1997

  35. ANCA and Inflammatory Bowel Disease • P-ANCA and some atypical patterns (not directed at MPO) • Ulcerative colitis - 40% to 80% • Crohn’s Disease - 10% to 40% • Does not facilitate the differential diagnosis of patients with inflammatory bowel disease • Correlation of titers with disease activity is not sufficiently reliable

  36. How are ANCAs detected? • Indirect immunofluorescence (IIF) • c-ANCA or p-ANCA pattern • Enzyme linked immunosorbent assay (ELISA) • specific antigens detected • PR3: (c-ANCA on IIF) • MPO: (p-ANCA on IIF) • ANCA testing is problematic because of lack of standardization between laboratories

  37. Summary • Connective tissue diseases have a low prevalence • Unselected “screening” of patients with “arthritis panels” will result in large numbers of false positives • Estimation of clinical pre-test probability and the knowledge of test characteristics are useful tools for rationally ordering and interpreting the results of diagnostic tests

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