Use and Interpretation of Common Rheumatologic tests

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Use and Interpretation of Common Rheumatologic
tests
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Objectives

• What tests do you really need to order for
• A patient with possible rheumatic disease
• A patient with known rheumatic disease

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Case

• You see a 24 year old woman with arthralgia and
  fatigue
• Among other things your differential diagnosis
  includes rheumatoid arthritis and systemic lupus
  erythematosus

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How do I screen for RA and SLE?
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How do I screen for RA and SLE?

• Primarily by history and physical examination
• Increase your pretest probability by asking
  questions that support the diagnosis of
  inflammatory arthropathy or systemic rheumatic
  disease
• Look for clues on physical examination

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What blood tests do I order?
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What blood tests do I order?

• Routine blood tests may reveal helpful
  information
• Anemia, other cytopenias
• Urinary abnormalities
• Elevated creatinine
• Abnormal chest Xray
• Etc.

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Should I order ESR or CRP?
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Should I order ESR or CRP?

• Nonspecific tests
• Assess acute phase response in the blood

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Erythrocyte Sedimentation rate
200 mm
RBC repel one another due to electrostatic forces
(negatively charged). Therefore, they settle in
the tube at a certain rate
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Inflammatory state Increased ESR






Positively charged acute phase proteins
neutralize negative charges and allow RBC to
aggregate Now RBC fall at a faster rate, further
distance
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ESR

• Increased by
• Acute phase reactants
• Paraproteins
• Anemia (fewer cells, less repellent forces)
• ALSO
• Age, gender, pregnancy, diabetes, renal failure,
  malignancy,
• tissue damage (MI, CV)

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A good rule of thumb,

• For Men
• Upper limit of normal of ESR Age
• For Women
• Upper limit of normal of ESR Age 10

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Thus, test is of limited value in the elderly
population!
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ESR

• Elevated ESR remains an important diagnostic
  criterion for two rheumatic conditions
• PMR ? ESR gt40 mm/hr
• GCA ? ESR gt90mm/hr
• typical value

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ESR

• Limited utility for differentiating inflammatory
  joint disease from noninflammatory joint disease
• Not required for diagnosis of RA
• (good history and physical far more significant
  than ESR in establishing the diagnosis)

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CRP

• Direct measure of acute phase reactants
• Less sensitive to irrelevant factors
• Responds more quickly
• More expensive
• Dont always know how to interpret

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Key Concepts

• ESR,CRP
• Nonspecific indicators of inflammation
• Not useful as screening tests for rheumatic
  diseases
• Cannot differentiate one disease from another

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Should I order a Rheumatoid Factor?
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Rheumatoid Factor
IgM directed against Fc portion of IgG
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Rheumatoid Factor

• Sensitivity 80 in patients with RA

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Rheumatoid Factor
Sensitivity proportion of patients with positive
test who have the disease

• Sensitivity 80 in patients with RA

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Rheumatoid Factor

• Sensitivity 80 in patients with RA
• Specificity ranges from 80-90

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Rheumatoid Factor

• Sensitivity 80 in patients with RA
• Specificity ranges from 80-90

Specificity proportion of patients with negative
test who do not have the disease
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Rheumatoid Factor

• Sensitivity 80 in patients with RA
• Specificity ranges from 80-90
• Prevalence of RA is 0.5-3

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• So, lots of positive RF are
• false positive!

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Other conditions causing positive Rheumatoid
Factor

• Other systemic rheumatic diseases
• Cryoglobulinemia
• Infections- bacterial endocarditis
• Hepatitis, TB, Syphilis, parisitic disease, viral
• Pulmonary diseases
• Malignancy

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Rheumatoid Factor

• Thus, RF is not diagnostic for RA on its own

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Rheumatoid Factor

• Thus, RF is not diagnostic for RA on its own

Post Test probability Positive predictive
value The probability that the patient has the
disease given a positive test result
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• Thus, RF is not diagnostic for RA on its own
• Testing is most useful when there is a moderate
  level of suspicion for RA

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• Up to 20 of patients with RA are RF ve early in
  the disease
• Thus, clinical impression counts the most !

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In patients with established RA

• RF correlates with severe articular disease and
  extra-articular manifestations
• May have prognostic value
• Once test is positive, no value in re-testing
• does not change with disease activity

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Anti-CCP

• Antibody directed against citrullinated
  peptide residues present within inflammatory
  sites
• Sensitivity equivalent to RF
• Greater specificity than IgM RF
• May be detected in healthy people years before
  onset of RA

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Key Concepts

• Rheumatoid Factor
• Rheumatoid factor is not diagnostic for
  rheumatoid arthritis
• The tests utility is greatest when there is a
  moderate pre-test probability of disease

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Should I order an ANA?
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Antinuclear Antibodies

• A group of antibodies that bind to various
  nuclear (and some cytoplasmic) antigens

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Anti-Nuclear Antibody IFA
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Anti-Nuclear Antibody ELISA
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• Sensitivity 95 in patients with SLE
• Almost all patients with SLE have positive ANA
• The ANA test is not specific for SLE

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• ANA 140 Seen in almost 32 of normals
• ANA 180 Seen in almost 13
• ANA 1160 Seen in almost 5
• ANA 1320 Seen in almost 3
• There is no set titer that can distinguish
  between those with and without SLE
• Most people with positive ANA dont have disease

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Non-rheumatic conditions causing positive ANA

• Normal individuals females gt males, increasing
  age, relatives of patients with rheumatic
  disease, pregnancy
• Hepatic diseases eg. chronic active hepatitis
• Pulmonary diseases eg. idiopathic pulmonary
  fibrosis
• Chronic infections
• Malignancies lymphoma, leukemia, melanoma, solid
  tumors (ovary, breast, lung, kidney)
• Hematologic disorders idiopathic
  thrombocytopenic purpura, autoimmune hemolytic
  anemia
• Drug- induced
• Miscellaneous autoimmune thyroiditis, type 1
  diabetes mellitus,

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For higher titres, patterns of ANA may be given

• Homogeneous -Rim
• Speckled
• Nucleolar

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For higher titres, patterns of ANA may be given

• Homogeneous -Rim
• Speckled
• Nucleolar

Staining patterns are not specific and not
reliable for diagnosing different diseases
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So, when should I order an ANA?

• When your pre-test probability for lupus is
  moderate
• Not recommended as a random screening test
• Not useful to diagnose other conditions but may
  support a clinical diagnosis

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Once ANA is positive

• ANA has no utility for disease monitoring
• There is no need to repeat it

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Once ANA is positive

• Specific autoantibody tests possess diagnostic
  significance in the right clinical setting

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• Anti-dsDNA
• Specific for SLE (60-70)
• Single stranded DNA nonspecific
• Farr assay preferable to ELISA
• May fluctuate with disease activity
• Anti-Sm
• Highly specific for SLE (but not sensitive)

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• Anti-centromere antibody (ACA)
• Associated with scleroderma (CREST)
• Anti-topoisomerase I (Scl-70)
• Associated with diffuse scleroderma

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• Anti-Ro (SS-A) and La (SS-B)
• Associated with Sjogrens
• Can be seen in SLE
• May be associated with neonatal heart block in
  babies of mothers with this antibody

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• Anti-U1 snRNP
• Nonspecific
• Part of criteria for mixed connective tissue
  disease (MCTD)
• May be seen in other systemic rheumatic diseases

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• Anti-Jo-1 (anti-histidyl-tRNA synthestase)
• Specific for myositis associated with
  interstitial lung disease, Raynauds

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Key Concepts

• ANA
• Not recommended as a screening test
• Greatest utility for diagnosis of lupus with
  moderate pre-test probability
• Virtually rules out SLE when negative

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What other tests might be helpful?
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Serum complements

• Not an antibody test, but useful for monitoring
  disease activity in SLE
• Low C3, C4
• Reflect consumption of complement
• Usually caused by presence of immune complexes in
  SLE
• Seen in some forms of vasculitis

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ANCA

• Group of autoantibodies directed against enzymes
  found within granules, lysozymes
• Seen on immunofluorescence as
• Perinuclear staining - P-ANCA or
• Cytoplasmic staining -C-ANCA

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• The major target antigens are
• proteinase 3 (PR3) for cANCA
• myeloperoxidase (MPO) for pANCA

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• ANCA most strongly associated with necrotizing
  vasculitis
• C-ANCA (PR3)? Wegeners granulomatosis
• P-ANCA (MPO)? Microscopic polyangiitis
  Churg-Strauss vasculitis

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Key Concepts

• ANCA
• ANCA alone is not diagnostic for vasculitis
• Positive predictive value of testing best with
  combination of IF plus ELISA for PR3 and MPO
• If not PR3 or MPO positive, consider diagnosis
  other than vasculitis

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HLA-B27

• Sensitivity 95 for patients with ankylosing
  spondylitis
• Present in 5-8 general population
• Incidence of disease is 0.5-1.0
• HLA B27 of no value in diagnosing usual patient
  with back pain

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HLA-B27

• May be of help in patient with inflammatory
  sounding back pain but no sacroiliitis visible on
  plain Xray
• Not required to confirm a clinical and radiologic
  diagnosis of ankylosing spondylitis

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Key Concepts

• Use clinical picture to guide ordering
• Tests dont make the diagnosis!
• Watch out for false positives
• Pretest probability matters
• Routine tests may have more important
  information than serology
• Avoid using rheumatology panel to screen for
  rheumatic disease