Testing for RA. The Ideal Lab Test. William M. Wason, MD, PhD 9/24/2010. Confusion Abounds

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1 Confusion Abounds Rheumatoid arthritis: ulnar deviation and muscle artrophy, hands Poor sensitivity and specificity Hepatitis C causes lots of false + tests Changing technology in how tests are done Historic data based on immunofluorescent testing 125 different antigens ANA Current testing based largely on ELISA test tube technology 10 antigens No absolute standardization between labs Values can vary from week to week even in the same lab with the same patient Serologic Testing should Ideally be used to Confirm a Diagnosis, not Shotgun a Problematic Patient Testing for RA Diagnosis of RA still remains a clinical diagnosis Symmetrical inflammatory arthritis affecting large and small joints lasting 6 weeks or longer Lab tests that are helpful Rheumatoid Factor Anti CCP antibody ESR, CRP The Ideal Lab Test Rheumatoid factors (diagram) True positive: Sick people correctly diagnosed as sick (sensitivity 100%) True negative: Healthy people correctly identified as healthy (specificity 100%)

2 Rheumatoid factor in rheumatic disease Rheumatoid arthritis Systemic lupus erythematosus Sjögren's syndrome Systemic sclerosis Dermatomyositis/polymyositis Vasculitis Cryoglobulinemia Juvenile rheumatoid arthritis Rheumatoid factor in nonrheumatic diseases Normal individuals (< 5%) Elderly Bacterial infections Endocarditis Leprosy Syphilis Lyme disease Periodontal disease Viral infections Hepatitis C (also A & B) Parvovirus Rubella CMV HIV EBV Parasitic diseases Anti CCP Antibody (CCP) Anti cyclic citrullinated protein Rheumatoid factor in nonrheumatic diseases, cont d Lymphoproliferative disease Interstitial lung disease Chronic liver disease Sarcoidosis Post-vaccination Malignancies Anti CCP Positive test has 94% certainty patient has RA Negative does not R/O RA Strongly positive test associated with more severe disease Test may become positive a few years before disease becomes apparent

3 Anti Nuclear Antibodies (ANA) Immunofluorescent test on HEP 2 cells 125 different antigens detected Positive titers reported: 1:40 to 1:1280 Lab Testing for RA Rheumatoid Factor has lots of False + and lots of False tests Principle of indirect immunofluorescence (diagram) CCP has very few False + ESR and CRP are useful in determining severity of disease activity Copyright American College of Rheumatology Slide Collection. All rights reserved. Systemic lupus erythematosus: malar rash, face Antinuclear antibodies (photomicrographs)

4 Immunofluorescent Testing Homogenous Diffuse Peripheral Rim Speckled Nucleolar Anti centromere, etc. Subject to operator interpretation Labor intensive Most literature based on this methodology ELISA Most commonly used today Highly reproducible Automated Much hless likely l to interpretation t ti bias Misses many minor ANAs found on immunofluorescent testing Most literature based on older immunofluorescent method Anti Nuclear Antibodies (ANA) Common ANA sub types ELISA ELISA solid phase immunoassay Usually limited to 8 10 antigens Usually >100 are considered positive SS DNA DS DNA Anti Smith Anti Histone Anti RNP SSA (Ro) SSB (La) Scl 70 Anti Centromere JO 1 Antibody Principles of enzyme linked immunosorbent assay (diagram) Copyright American College of Rheumatology Slide Collection. All rights reserved. ANA with Reflex testing (ELISA) Screening test to mixture of all antigens Negative no further testing Positive Will do specific testing to all antigens By design, if you get a positive screen, you will get a positive sub type antigen Cost depends on Negative/Positive result?best Test Screen with ELISA Confirm with IF at >1:40 titer Sub type with ELISA

5 Other Labs CBC Chem Profile Urine Analysis Spot Urine Protein/Creatinine Ratio Uric Acid (gout) CPK (inflammatory muscle disease) ESR >50 Hepatitis C False + tests, Cryoglobulinemia, Arthritis, Vasculitis Hepatitis B Reactivation with immunosuppression, PAN CXR Interstitial Lung Disease, Occult Malignancy, Sarcoidosis, Rheumatoid Nodules, Baseline for Drug Tx. Random Protein/Creatinine Ratio Technique: Random urine collection Calculate Urine Protein mg to Urine Creatinine mg Ratio Interpretation of Urine Protein to Urine Creatinine Ratio Adults and children over age 2 years Normal ratio <0.2 grams protein per gram Creatinine Correlates with 0.2 g protein/day Nephrotic Ratio >3.5 (correlates with 3.5 g protein) References Ruggenenti (1998) BMJ 316:504 (2002) Am J Kidney Dis 39:S1 Hepatitis C Patients with Hep C infections have false positive tests for virtually all rheumatology lb labs CCP antibody appears to be the only exception Summary Negative ANA, generally excludes SLE Drug induced SLE MCTD Positive ANA, has only a 20% probability of being associatedwithsignificant significant CVD Low titer ANA rarely associated with significant CVD Positive CCP antibody, generally confirms RA Patients need to be cautioned these tests are not foolproof and must be interpreted with the clinical circumstances