Download Making the Rheumatological Diagnosis

William M. Wason, MD, PhD
Confusion Abounds
9/24/2010
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 g
– 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
Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.
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%)
Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.
William M. Wason, MD, PhD
9/24/2010
Rheumatoid factor in rheumatic disease
Rheumatoid arthritis
Systemic lupus erythematosus
Sjögren's syndrome
Systemic sclerosis
Dermatomyositis/polymyositis
Vasculitis
Cryoglobulinemia
Juvenile rheumatoid arthritis
Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.
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
Anti‐CCP Antibody (CCP)
Anti‐cyclic citrullinated protein
Parasitic diseases
Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.
Rheumatoid factor in nonrheumatic diseases, cont’d
Anti‐CCP
Lymphoproliferative disease
Interstitial lung disease
Chronic liver disease
Sarcoidosis
• Positive test has 94% certainty patient has RA
• Negative does not R/O RA
Post-vaccination
Malignancies
• Strongly positive test associated with more severe disease
• Test may become positive a few years before disease becomes apparent
Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.
William M. Wason, MD, PhD
9/24/2010
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
Principle of indirect immunofluorescence (diagram)
• Rheumatoid Factor has lots of “False +” and lots of “False –” tests
• CCP has very few has very few “False
False ++”
• ESR and CRP are useful in determining severity of disease activity
Copyright © 1972‐2004 American College of Rheumatology Slide Collection. All rights reserved.
Systemic lupus erythematosus: malar rash, face
Antinuclear antibodies (photomicrographs)
Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.
Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.
William M. Wason, MD, PhD
9/24/2010
Immunofluorescent Testing
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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
M hl
Much less likely to interpretation bias
lik l t i t
t ti bi
Misses many minor ANAs found on immunofluorescent testing
• Most literature based on older immunofluorescent method
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Anti‐Nuclear Antibodies (ANA)
• ELISA solid phase immunoassay
– Usually limited to 8‐10 antigens
– Usually >100 are considered positive
Usually >100 are considered positive
Principles of enzyme‐linked immunosorbent assay (diagram)
Common ANA sub‐types ‐ ELISA
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SS – DNA
DS – DNA
Anti‐Smith
Anti‐Histone
Anti‐RNP
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SSA (Ro)
SSB (La)
Scl‐70
Anti‐Centromere
JO‐1 Antibody
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 B d i if
t
iti
ill t
positive sub‐type antigen
– Cost depends on Negative/Positive result
• ?Best Test
Copyright © 1972‐2004 American College of Rheumatology Slide Collection. All rights reserved.
– Screen with ELISA
– Confirm with IF at >1:40 titer
– Sub‐type with ELISA
William M. Wason, MD, PhD
9/24/2010
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
Summary
Hepatitis C
• Negative ANA, generally excludes
• Patients with Hep C infections have false positive tests for virtually all rheumatology l b
labs
– SLE
– Drug induced SLE
– MCTD
• Positive ANA, has only a 20% probability of being associated with significant CVD
associated with significant CVD
• Low titer ANA rarely associated with significant CVD
– CCP antibody appears to be the only exception
• Positive CCP antibody, generally confirms RA
• Patients need to be cautioned these tests are not fool‐
proof and must be interpreted with the clinical circumstances