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Clinical Utility of Rheumatologic Tests: A Guide to Interpretation

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Title: Clinical Utility of Rheumatologic Tests: A Guide to Interpretation


1
Clinical Utility of Rheumatologic Tests
A Guide to Interpretation
  • Sheetal Desai MD MSEd

2
Questions for you
  • 1. What is the most likely diagnosis of a patient
    with a positive ANA?
  • 2. What is the most common cause of an elevated
    ESR gt100?
  • 3. A preferred screening lab test has a high
    sensitivity or high specificity?
  • 4. Which of the following lab tests is most
    specific? ESR or CRP

3
Common Misperceptions
  • Positive result Disease
  • These tests are free, so order as many as you
    want
  • money grows on
  • trees

4
Rheumatology Lab Tests
  • Anti-CCP - 1998
  • ANCA - 1982
  • CRP - 1970s
  • anti-Smith - 1966
  • ANA - 1958
  • dsDNA - 1950s
  • RF - 1948

5
Rheumatology Lab Tests
  • Are relatively young
  • Have varied sensitivity and specificity
  • Little value as a screening test
  • Blind ordering can lead to diagnostic confusion

6
Clinical Scenario Case 1
  • 68 year old patient presents to the ER with
    fevers, chills and general malaise for one week.
  • PMH DM, HTN
  • Meds Metformin, Januvia, Norvasc, Lisinopril
  • NKDA
  • T 38.6 in ER, BP 110/60, HR 108
  • PE normal
  • Labs ESR 90, CRP 10mg/dl, WBC 10, Hg 12, Plt
    450,000, Cr 1.1, AST 30, ALT 28
  • Ddx?

7
Acute Phase Proteins
  • Proteins that show an increase gt25 with
    inflammation
  • Synthesized in the liver
  • Group 1- increases by 50 C3 and ceruloplasmin
  • Group 2- increases 2-4 fold fibrinogen,
    haptoglobin, alpha 1 antitrypsin, alpha 1
    chemotrypsin, alpha 1 glycoprotein
  • Group 3- increases by several hundred fold CRP,
    serum amyloid A

8
Erythrocyte Sedimentation Rate (ESR)
  • What exactly is it???
  • Indirect measure of acute phase protein
    fibrinogen
  • Measured by the Westergren method
  • Vertical column 200-300mm long
  • ESR the distance the RBC travel in one hour

9
What is a normal ESR???
  • At UCI 0-20 is normal
  • However ESR increases with age and is increased
    in women
  • For Men age/2
  • For Women (age 10)/2

10
Factors that Increase ESR
  • Inflammatory disease
  • Infections
  • Malignancy
  • Increase in globulin proteins
  • End Stage Renal Disease
  • Extensive Tissue Necrosis
  • Pregnancy
  • Age

11
Factors that Decrease ESR
  • Elevated plasma viscosity
  • Increased RBCs- Polycythemia
  • Abnormal RBC shape- Sickle Cell
  • Hepatic Necrosis
  • Hypofibrinoginemia
  • Congestive Heart Failure
  • Extreme Leukocytosis
  • Trichinosis

12
Etiology of ESR gt100
  • 1 Infection
  • 2 Malignancy
  • 3 Rheumatologic

13
How to Use ESR
  • Not very sensitive or specific
  • Use as diagnostic criterion only for Temporal
    Arteritis (TA) and PMR
  • Useful in monitoring PMR, TA, RA
  • Can be useful for monitoring disease course and
    treatment response
  • Extreme elevations in the ESR rarely occur
    without evidence of serious disease

14
C Reactive Protein (CRP)
  • What does the C stand for?
  • C-polysaccharide from the pneumococcus cell walls
  • Acute phase protein- Group 3
  • Exclusively produced by hepatocytes
  • Direct measure of inflammation

15
C Reactive Protein (CRP)
  • Normal Levels lt1
  • Moderate elevation 1-10
  • See in most of the rheumatic conditions- RA, SLE,
    Sjogrens
  • Marked elevation gt10
  • See in serious bacterial infections, severe RA,
    Vasculitis, PMR

16
C Reactive Protein (CRP)
  • Levels rise within hours of stimulus
  • Peaks within 2-3 days
  • Half life 8 hours
  • With effective treatment of the underlying cause,
    levels can normalize within 24-48 hours

17
CRP vs. ESR
  • Rises quickly
  • Falls quickly
  • Direct marker of inflammation
  • Narrow range of results
  • High sensitivity
  • High specificity
  • High reproducibility
  • NOT affected by factors (age, gender, anemia, RBC
    shape, plasma proteins)
  • Rises slowly
  • Falls slowly
  • Indirect marker of inflammation
  • Wide range of results
  • Mod sensitivity
  • Mod specificity
  • Mod reproducibility
  • Affected by many factors

18
Clinical Scenario Case 1
  • 68 year old patient presents to the ER with
    fevers, chills and general malaise for one week.
  • PMH DM, HTN
  • Meds Metformin, Januvia, Norvasc, Lisinopril
  • NKDA
  • T 38.6 in ER, BP 110/60, HR 108
  • PE normal
  • Labs ESR 90, CRP 10mg/dl, WBC 10, Hg 12, Plt
    450,000, Cr 1.1, AST 30, ALT 28
  • Ddx? Ur Cx and Blood cx Gram neg rods

19
Clinical Scenario Case 2
  • 42 year old caucasian female, otherwise healthy,
    comes to clinic complaining of fatigue. She
    complains of fatigue, poor sleep habits and aches
    and pains over the past year. Her joints have
    been bothering her, especially her hands. There
    is a discomfort and stiffness that comes and
    goes, and usually involves one hand at a time.
    She states that at times her hands have been
    mildly swollen and have limited her function.

20
Clinical Scenario
  • Vitals T 99.2, BP 116/80, P 90 R 16 98RA
  • PE is unremarkable
  • HEENT WNL, no rash
  • CV RRR, no murmurs
  • Pulm CTA bilaterally
  • Abd benign, no organomegaly
  • Ext no edema, FROM of all joints, no appreciable
    joint swelling in wrist, MCP, PIP, DIP joints. No
    deformities. No rash

21
Clinical Scenario
  • Lab Tests
  • CBC WBC 6.3, Hg 12.7, Plt 266
  • Electrolytes Na 138, K 4.2, Cr 0.7
  • TSH 3.8 (normal 0.3-4.7)
  • RF negative
  • ANA positive, titer 180

22
ANA
  • What exactly are they?
  • Antibodies that bind to various antigens in the
    nucleus of a cell
  • How is it measured?
  • Indirect Immunofluorescence

23
Antinuclear antibodies
  • Indirect Immunofluorescence Assay
  • Take patient serum and add it cells
  • If there are antibodies they will bind
  • Add a fluorochrome tag
  • View under a fluorescent microscope
  • If it lights up in then positive 140
  • Dilute sample and repeat, 180, 1160, 1320,
    1640, 11280, etc

24
Antinuclear Antibodies
25
Antinuclear Antibodies
  • Staining Patterns
  • Observer dependent
  • Not sensitive
  • Not specific
  • Only LOOSELY associated with certain disease
    states

26
Antinuclear Antibodies
  • What does the staining pattern mean?
  • Homogenous SLE
  • Rim SLE
  • Speckled Sjogrens, MCTD
  • Diffuse nonspecific
  • Nucleolar Scleroderma
  • Anti-centromere CREST

27
Antinuclear Antibodies
28
Positive ANA
  • What disease states do you see it?

29
ANA associated Diseases
Rheumatic Conditions Rheumatic Conditions Auto- Immune Misc
Lupus Polymyositis Graves Aging
Drug-induced Lupus Dermato- myositis Primary Biliary Cirrhosis Primary Pulmonary Hypertension
Scleroderma RA Hashimoto Thyroiditis
Sjogrens Vasculitis Autoimmune Hepatitis
MCTD
30
ANA with age
  • For every year after age 50, percentage of ANA
    positivity increases 1/year
  • For example
  • Age 50 1
  • Age 55 5
  • Age 60 10

31
Rheumatic Causes of Positive ANA
  • 100 Drug Induced Lupus
  • 99 Lupus
  • 97 Scleroderma
  • 96 Sjogrens
  • 93 MCTD
  • 80 Myositis
  • 40 RA

32
ANA in Lupus
  • Sensitivity 93-99 in SLE
  • Sensitivity 95-100 in drug induced Lupus
  • Specificity is not great
  • Higher the titre, higher the specificity
  • 140- 30 normal population
  • 1160- seen in 5 of the population

33
Clinical Indications -ANA
  • ANA is NOT a good screening test given its low
    specificity
  • Presence of ANA does NOT mandate the presence of
    rheumatologic illness
  • A negative ANA is more useful and makes Lupus
    very unlikely
  • ANA titers correlate poorly with disease activity
    so serial measurements are not recommended
  • A positive ANA with anti-centromere pattern is
    very specific for limited scleroderma

34
Clinical Scenario Case 2
  • 42 year old caucasian female, otherwise healthy,
    comes to clinic complaining of fatigue. She
    complains of fatigue, poor sleep habits and aches
    and pains over the past year. Her joints have
    been bothering her, especially her hands. There
    is a discomfort and stiffness that comes and
    goes, and usually involves one hand at a time.
    She states that at times her hands have been
    mildly swollen and have limited her function.

35
Clinical Scenario
  • Vitals T 99.2, BP 116/80, P 90 R 16 98RA
  • PE is unremarkable
  • HEENT WNL, no rash
  • CV RRR, no murmurs
  • Pulm CTA bilaterally
  • Abd benign, no organomegaly
  • Ext no edema, FROM of all joints, no appreciable
    joint swelling in wrist, MCP, PIP, DIP joints. No
    deformities. No rash

36
Clinical Scenario
  • Lab Tests
  • CBC WBC 6.3, Hg 12.7, Plt 266
  • Electrolytes Na 138, K 4.2, Cr 0.7
  • TSH 3.8 (normal 0.3-4.7)
  • RF negative
  • ANA positive, titer 180
  • Anti TPO ab positive

37
Further testing of ANA
  • This can be done to determine the exact nuclear
    target antigen
  • Some of these antibodies are specific for a
    particular disease
  • Include dsDNA, Smith, RO/SSA, La/SSB, U1RNP,
    Scl-70, centromere

38
Anti ds-DNA
  • Specificity for SLE 97
  • Present in about 60 of pt with SLE
  • Titers correlate with disease activity in SLE
  • Elevation correlates with Lupus nephritis
  • Seen in drug induced lupus

39
Anti- Smith
  • Very specific for SLE gt95
  • See in only 20-30 of patients
  • No evidence that it is useful to follow for
    disease activity in SLE
  • Important diagnostic marker for SLE

40
Anti-Ro or SSA
  • See in 70-97 of pt with Sjogrens
  • See in 40 of SLE - associated with a
    photosensitive skin rash, lymphopenia, and
    Interstitial lung disease
  • In pregnant patients, associated with neonatal
    lupus and congenital heart block

41
Anti-La or SSB
  • Usually see along with anti-Ro/SSA
  • Can see isolated activity in primary biliary
    cirrhosis and autoimmune hepatitis

42
Anti U1RNP
  • A defining features for MCTD
  • Very sensitive for MCTD, but not specific, so use
    to rule out disease
  • Also found in 30-40 of pt with SLE

43
Anti-histone Antibodies
  • Seen in drug-induced lupus
  • Sensitivity of 100
  • Not very specific, can see in 60-80 Lupus
  • Drugs commonly implicated
  • hydralazine
  • INH
  • procainamide, penacillamine
  • quinidine

44
Anti Scl-70
  • Also known as anti-topoisomerase 1
  • Very specific for diffuse scleroderma
  • Specificity is greater than 95
  • Sensitivity is low, range 22-40
  • Higher levels associated with greater disease
    activity
  • Presence correlates with a higher risk of
    Interstitial Lung Disease

45
Anti-centromere ab
  • Usually associated with scleroderma, specifically
    CREST
  • Also see it in SLE, Raynauds
  • Sensitivity for Scleroderma ranges from 30-60
  • Specificity for Scleroderma is high, greater than
    95

46
Clinical Scenario Case 3
  • 69 year old male at the VA, has known Hepatitis
    C. He comes into clinic complaining of
    generalized aches and pains in his joints. His
    left knee, right hand and right shoulder have
    been bothering him for a couple of months, and in
    the morning are stiff for 15 minutes. A
    Rheumatoid Factor is checked and this returns
    positive.

47
Rheumatoid Factor (RF)
  • What is it?
  • Autoantibody directed against the Fc portion of
    IgG, can be IgM or IgA

48
RF positivity
  • In what disease states do you see it?

49
RF positive disease states
Rheumatic Conditions Infections Pulmonary Disease Misc
RA SBE Silicosis Aging
SLE MCTD TB Leprosy Sarcoidosis Leukemia
Sjogrens Syndrome Syphilis IPF Colon Cancer
Systemic Sclerosis Viral infections Asbestosis Cirrhosis- Hep C/PBC
Cryoglobulinemia Parasitic Disease Sarcoidosis
50
Nonrheumatic RF Diseases
51
RF Positivity and Aging
  • Frequency of a positive RF increases with age
  • Age 20-60 2-4
  • Age 60-70 5
  • Agegt70 10-25

52
Rheumatoid Arthritis
53
Rheumatoid Factor in RA
  • Sensitivity for RA 80
  • Note that up to 40 of patients with RA may be
    seronegative early on
  • Specificity for RA 80-95
  • Higher the titer or value of RF, higher the
    specificity for RA

54
Clinical Indications for RF
  • Little value as a screening test for RA
  • A positive RF does NOT equate with RA
  • In those patients with RA, a RF usually predicts
    more aggressive erosive disease
  • Higher RF titers higher specificity higher
    positive predictive value for RA
  • Serial measurements are not indicated, and do not
    correspond with disease activity

55
Clinical Scenario
  • 69 year old male at the VA, has known Hepatitis
    C. Comes into clinic complaining of generalized
    aches and pains in his joints. His left knee,
    right hand and right shoulder have been bothering
    him for a couple of months, and in the morning is
    stiff for 15 minutes. A Rheumatoid Factor is
    checked and this returns positive.
  • Anti CCP is negative.

56
Anti- CCP
  • What are they?
  • Antibodies to cyclic citrullinated peptide
  • Antibodies that target citrullinated proteins
  • Citrulline a modified arginine amino acid
  • May be one of the major autoantigens driving the
    local immune response

57
Anti- CCP
  • Sensitivity 50-75
  • Specificity greater than 90-95
  • Found in low frequency in other rheumatic
    diseases
  • May be detected in patients with early RA
  • May predate the clinical development of RA by
    several years
  • Predictor of more erosive disease

58
Anti- CCP- Indications for Clinical Use
  • A disease-specific autoantibody that is very
    useful for the diagnosis of RA
  • Just as sensitive, and even more specific than RF
  • May predict eventual development of RA when found
    in undifferentiated arthritis
  • A marker of erosive disease

59
ANCAs
  • What are they???
  • Anti-neutrophil cytoplasmic antibodies
  • How are they measured?
  • Two step procedure

60
ANCAs
  • Step 1- Indirect Immunofluorescence Assay
  • Take patient serum and add it cells
  • If there are antibodies they will bind
  • Add a fluorochrome tag
  • View under a fluorescent microscope
  • If it lights up in the cytoplasm, then it is
    Cytoplasmic-ANCA (cANCA) positive
  • If is lights up around the nucleus, then it is
    Perinuclear-ANCA (pANCA) positive
  • Sensitive but not specific

61
Cytoplasmic-ANCA
62
Perinuclear-ANCA
63
ANCAs
  • Step 2- Enzyme Immunoassay
  • Helps determine the specific antigen that the
    antibody is binding to
  • Two most common are Proteinase 3 (PR3) and
    Myeloperoxidase (MPO)
  • Not observer dependent
  • High specificity
  • High positive predictive value

64
Cytoplasmic-ANCA
  • More specific for vasculitis
  • c-ANCA is associated with proteinase 3 (PR3)
  • Sensitivity reaches 90 in active generalized
    Wegeners
  • Thus absence of ANCA does not rule out Wegeners

65
p-ANCA Disease States
  • Microscopic Polyangiitis
  • Churg Strauss Syndrome
  • Pauciimmune Glomerulonephritis
  • Goodpasteurs
  • Drug-Induced Vasculitis
  • Ulcerative Colitis
  • Crohns Colitis
  • Primary Sclerosing Cholangitis
  • Endocarditis
  • Malaria

66
Perinuclear-ANCA
  • Less specific for vasculitis
  • It is associated with Myeloperoxidase (MPO)
  • Helpful in differentiating polyarteritis nodosa
    from microscopic polyangiitis

67
Clinical Indications for ANCA testing
  • Do not use it as a screening test
  • Using the pr3 and MPO increases the positive
    predictive value
  • Controversy regarding following ANCAs to monitor
    disease activity

68
HLA-B27
  • Human Leukocyte Antigen B-27
  • 95 sensitivity for Ankylosing Spondylitis
  • 80 sensitivity for Reactive Arthritis
  • Low specificity
  • Background prevalence of 6-10 in caucasian
    populations

69
Rheumatologic Testing
  • These labs are NOT useful as screening test
  • A positive test may or may not be associated with
    the disease
  • Selective ordering in patient with a high pretest
    probability
  • Ordering Rheum Panel is not recommended

70
From Cleveland Clinic
  • The diagnosis of rheumatologic diseases is based
    on clinical information, blood and imaging tests,
    and in some cases on histology. Blood tests are
    useful in confirming clinically suspected
    diagnosis and monitoring the disease activity.
    The tests should be used as adjuncts to a
    comprehensive history and physical examination.

71
What labs would you order?
  • 1. A patient with known lupus admitted for flare
    of lupus nephritis

72
What labs would you order?
  • 2. A patient with inflammatory arthritis
    involving PIPs, MCPs, wrists, knees admitted for
    a flare

73
Differential Diagnosis?
  • 3. 58 year old patient with fevers and an ESR 99
    and CRP of 10mg/dl
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