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Transcript of RHEUMATIC DISEASE LABORATORY TESTING. BASICS OF LAB TEST ORDERING Pitfalls: Misdiagnosis Permanent...
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RHEUMATIC DISEASE LABORATORY TESTING
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BASICS OF LAB TEST ORDERING
Pitfalls: Misdiagnosis Permanent labeling
of patient Needless additional
testing Inappropriate therapy
and/or referral Expense Overlooking the
correct diagnosis NEEDLESS ANXIETY
FOR PATIENT!!!
Intent: Establish a
diagnosis Determine prognosis Monitor disease
activity Indicate organ
involvement Monitor stage of
disease Indicate disease
mechanisms Guide treatment Monitor toxicity
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BASICS OF LAB TEST ORDERING
“We checked an ANA, ESR, & RF to look for connective tissue disease…..”
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TWO BY TWO TABLE
DIS (+)
DIS(-)
TEST (+)
A (TP)
B (FP)
PPV =A/A+B
TEST(-)
C (FN)
D (TN)
NPV =D/C+D
SENS =TP/TP+FN
SPEC = TN/FP+TN
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DISEASE PREVALENCE & PREDICTIVE VALUES
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SNOUT
A test with highSeNsitivity is excellentFor ruling OUT a dx…
“SNOUT”
Sensitivity is true posover true pos plusfalse negatives
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SPIN
A test with a highSPecificity is great forRuling IN a dx
“SPIN”
Specificity is true negative over true negative plus false positive
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TYPES OF LABS1. High sensitivity labs - SNOUT:
good for “screening” or “ruling out” ESR (inflammation) ANA (lupus – but NOT “CTD”)
2. High specificity labs - SPIN: good for “diagnosing” or “ruling in”
ds-DNA (lupus) Scl-70 (PSS) Jo-1 (ILD in polymyositis) C-ANCA (WG)
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TYPES OF LABS3. Disease activity labs:
How is treatment working ? CPK complement levels (lupus) ds-DNA (lupus) ESR, CRP (RA, GCA, PMR)
4. Prognosis labs: Should I be aggressive early with meds?
RF (RA) ds-DNA antibody (SLE) Citrulline antibody (RA)
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“THE NET” – looking for organ damage and mimickers UA with micro
glomerulonephritis CBC
anemia chronic disease Lipids
accelerated atherogenesis w/ inflammation Hep B & Hep C
extrahepatic disease features. TSH CPK Chem Panel and LFT’s ? Vitamin D (fibromyalgia)
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ESR
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ESR The king of non-specific lab tests
but very sensitive Infection / malignancy/CTD all raise
the ESR Westergren method used at
NMCSD (up to 120 mm/hr) Useful for “ruling out” systemic
inflammatory disease
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ESR Non-inflammatory factors that raise ESR
Aging Female Sex Obesity Pregnancy Anemia
Markedly Low ESR (0 mm/hr) Afribinogenemia/dysfibrinogenemia Agammaglobulinemia Extreme polycythemia (HCT > 65) Increased plasma viscosity
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ESR Adjunctive Testing
Good history and physical Repeat test 1-3 mo? Prior ESRs? CRP SPEP, Quantitative Immune Globulins Age Appropriate Malignancy Screen
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CRP (“Can’t refuse prednisone”) Produced as an acute-phase reactant by the liver in response
to IL-6 and other cytokines Seen in sera of patients with pneumococcal pneumonia in
1930 (protein could precipitate C-polysaccharide of pneumococcus)
Can recognize phosphocholine, other phospholipids Can activate complement (classic) Can bind to and modulate the behavior of phagocytic cells in
both pro and anti-inflammatory ways Quicker rise and fall than ESR Sensitive but not diagnostic of any particular condition “CRP rises with infection and ESR rises with CTD’s….” (not
always true!!!) Normal less than 1.0 mg/dl > 8-10 mg/dl, think bacterial infection, systemic vasculitis, or
widely metastatic cancer
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CRP
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OTHER ACUTE PHASE REACTANTS Polyclonal Immunglobulins (SPEP) Alkaline phosphatase Transaminases Fibrinogen Haptoglobin Serum amyloid A Platelet count Ferritin Alpha-1 antitrypsin Decreased albumin (“negative” APR)
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COMPLEMENT A system of interacting serum proteins that
function sequentially as initiators, regulators, and effectors of cell lysis and inflammation
Provide innate defense against microbes and a “complement” to humoral immunity
Biologic cascade in which, by limited proteolysis, one component activates the next, causing rapid and robust amplification of the system
Critical to normal processing of immune complexes
Causes host tissue damage in antibody-mediated autoimmune syndromes
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COMPLEMENT Measurement useful if:
concern for inherited deficiency states which can pre-dispose to infectious and rheumatic syndromes
immune-complex mediated disease
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COMPLEMENT
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COMPLEMENT
CLASSICAL:
Ag-Ab complexes such as SLE
ALTERNATIVE:
EndotoxinIgADrugs
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COMPLEMENT
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COMPLEMENT REGULATION C1 inhibitor – [prevents C1s from activating
C4 and C2] deficiency -> hereditary angioneurotic edema
and chronic C4 activation/consumption with resulting low C4
C3 and C4 nephritic factors Autoantibodies against alternative and classical
pathway C3 convertases, respectively Stabilizes antibody, increasing half-life causing
excessive C3 cleavage Secondary deficiency of C3
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ROUTINE COMPLEMENT LEVEL TESTING
CH 50 reflects a functionally intact classic pathway;
good screen for deficiency state (C1-9) C3
useful screen for BOTH classic and alternative pathways
C4 depressed with activation of classic pathway or
in patients with angioneurotic edema C5-9
terminal attack complex
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DIMINISHED COMPLEMENT LEVELS
partial or complete inherited deficiency C1q inhibitor deficiency -> hereditary
angioedema and low C4 C2 or C4 deficiency -> SLE C3 deficiency -> recurrent infections (bacterial) C5a inhibitor deficiency -> FMF C5-9 deficiency -> recurrent neisserial
infxn
immune complex consumption (SLE / post-strep GN, cryoglobulinemia, SBE,
membranoproliferative GN, Sjogren’s, other vasculitides)
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RHEUMATOID FACTOR
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RHEUMATOID FACTOR Hemagglutinating
activity noted in 1940, associated with RA in 1949
Heterogeneous family of IgM abys directed against IgG
RF response transiently associated with many infectious diseases (TB, SBE, syphillis, HCV)
RF response more permanent with chronic diseases
1-4% of healthy whites, 10-25% age > 70 , 30% some NA Indians
80% of RA pts (+) 80-90% of SS (+) 70% of chronic HCV (+) Both Types II and III
cryoglobulins worse prognosis and
more aggressive RA Not specific for RA No correlation with RA
disease activity
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RHEUMATOID FACTOR
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RHEUMATOID FACTOR
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Elevated RF (ChRONIC immune stimulation) Ch- chronic disease (esp hepatic
and pulmonary) R- rheumatoid arthritis O- other connective tissue disease N- neoplasms (lymphoproliferative
diseases, esp after XRT, chemo) I – Infections C - cyroglobulins
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ANTI-CITRULLINE AB ELISA available against CCP (cyclic
citrullinated peptide) – one of the anti-filaggrin antibodies
Very specific, not very sensitive (SPIN) Utility may be in defining early and
aggressive RA, prior to development of RF Useful in RF (+) positive conditions that
mimic RA Sjogren’s Hep C cryoglobulinemia
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ANA ANA’s are directed against a variety of
nuclear antigens in serum of patients with/without rheumatic disease as well as in normal persons
The ANA IS NOT a useful screen for rheumatic disease (nor is the RF) not sensitive enough (SNOUT) not specific enough (SPIN)
The ANA IS a useful screen for SLE is very sensitive-95% (SNOUT) Offers less in area of specificity (SPIN)
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ANA many false positives
5% of healthy controls pos at 1:160 dilution 10-15% of healthy controls pos at 1:80 dilution 30% of healthy controls pos at 1:40 dilution positive with SBE / age / liver disease / thyroid dz
should be done on HEp2 cell line pattern is important and helps w/ dx titer doesn’t correlate with disease activity a negative ANA “rules out” SLE most of the
time
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ANA TESTINGPre-testAssessment
ANA Your Action
Low likelihood
< 1:80> 1:160
IgnoreObserve; look elsewhere
Moderatelikelihood
< 1:80> 1:160
Observe; look elsewhereDisease specific antibodies
Highlikelihood
negativepositive
Fill out consult to RheumDisease specific antibodies
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ANA PATTERNS
NUCLEOLAR NUCLEOLAR
RIM RIM
SPECKLEDSPECKLED
HOMOGENEOUSHOMOGENEOUS
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ANA PATTERNS
NUCLEOLAR Against RNA Nonspecific Associated with
PSS PM-DM SLE vasculitis
RIM or PERIPHERAL Against DNA Specific for SLE Should trigger
check for ds-DNA SLE More active
disease Nephritis
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ANA PATTERNS
CENTROMERE Associated with
CREST Calcinosis Raynaud’s Esophageal
Dysmotility Sclerodactyly Telangeictases
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ANA PATTERNS
HOMOGENEOUS Against DNA &
histone Nonspecific Associated with
SLE Drug induced lupus RA Vasculitis PM-DM
SPECKLED Against the various
ENA’s “More” specific-
SPIN Associated with
SLE Sjogren’s PSS PM-DM RA
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SPECIFIC ANA’s
ds-DNA Nearly 100%
specific for SLE Correlates well
with disease activity
Probably pathogenic
Moderate Sensitivity
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SPECIFIC ANA’sSmith (Sm)
RNA/protein complex involved in processing messenger RNA
More severe disease Speckled ANA Higher prevalence in AA & Asians Moderate sensitivity (30%) Highly specific for SLE
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SPECIFIC ANA’s
RNP (U1 RNP) Ribonucleoprotein Speckled ANA Diagnostic of
MCTD if: High titer No other ENA’s Features of SLE,
PM, RA, and PSS RF (+)
HISTONE High sensitivity
and low specificity Drug induced
lupus gives anti-histone alone
SLE gives anti-histone along with ds-DNA
Also seen in RA
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SPECIFIC ANA’sRo/SS-A
Protein-RNA complex found in both nucleus and cytoplasm
Sjogren’s and lupus The rare ANA-neg
lupus Subacute cutaneous
lupus (a very photosensitive lupus)
Neonatal SLE and congenital heart block
La/SS-B Protein-RNA complex
found in both nucleus and cytoplasm
Sjogren’s and lupus The rare ANA-neg
lupus May protect against
renal disease Usually also have
antibodies to Ro/SS-A
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Ro/SS-A & La/SS-B
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SPECIFIC ANA’sSCL-70
Anti-topoisomerase I
Found in 20% of patients with PSS
VERY specific NOT sensitive Lung disease Associated with
nucleolar ANA pattern
Jo-1 Anti-histidyl tRNA
synthetase A cytoplasmic
protein Found in 30% of
PM/DM patients – often with lung involvement/ILD
Highly specific
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CRYOGLOBULINS
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CRYOGLOBULINSA group of serum Ig’s with conformationalchange in the cold:
Precipitate or gel on cold exposure
Phenomenon reversible with rewarming
Found in variety of clinical situations
Other labs: RF, low complement, QIG, ESR
TYPE I Single monoclonal Ig
or light chain TYPE II (essential)
“mixed” – a monoclonal directed against polyclonal IgG (rheumatoid factor activity)
TYPE III “polyclonal” – no
monoclonal Ig also RF activity
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CRYOGLOBULINS Type I (myeloproliferative disorders)
Myeloma, lymphoma, Waldenstrom’s Type II
Infections (majority HCV and some HBV), CTD (Sjogren’s, lupus),
Type III CTD, Infection lymphoproliferative disorder
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CRYOGLOBULINS “Essential mixed cryoglobulinemia” is
now recognized as driven by chronic Hep C in most cases.
Clinical features: Acrocyanosis / digital necrosis (type I) Palpable purpura (type II and III) Livedo reticularis Raynaud’s Arthritis / GN / peripheral neuropathies
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HLA B-27 Class I MHC cell surface marker found in 6-8% of NA whites, 3-4% of NA
AA’s, 18-50% of Haida Indians 90-100% of AS pts/lesser frequency in other
spondyloarthropathies NOT a “screening” test for the SNSA’s
IBD-associated arthritis – 50% Ankylosing spondylitis (AS) – 90% Reactive / Reiter’s – 80% Psoriatic arthritis – 50% w/ spine; 15% peripheral
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HLA B-27
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ANTIPHOSPHOLIPID AB’s lupus anticoagulant
1. prolonged PTT or PT or final common pathway (DRVVT)
2. Failure to correct by mixing patient plasma w/ nml plasma
3. Correction with addition of excess phospholipid or platelets
4. Ruling out other coagulopathies anticardiolipin antibodies
via ELISA antibodies against beta-2 glycoprotein
Via ELISA
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NEJM 7 Mar 2002
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ANCAC-ANCA and P-ANCA
Originally defined by indirect IF staining of neutrophils C-ANCA
Cytoplasmic IF pattern
P-ANCA Perinuclear IF pattern
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ANCA (“C3PO”)C-ANCA Ab against PR3
(proteinase-3) (found in neuts/monos)
Wegener’s granulomatosis
C-ANCA usually found in widespread WG
C-ANCA seen less frequently with limited WG
Correlates with dz activity in 60% of cases
P-ANCA Ab against MPO
(myeloperoxidase), elastase, lactoferrin, others
Churg-Strauss MPAN Crescentic GN (pauci-
immune GN) Drug-induced (PTU,
minocycline, hydralizine) IBD SLE / RA/HIV No correlation with
disease activity
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ARTHROCENTESIS NORMAL/NONINFLAMMATORY (0-2,000 WBC)
Transparent / < 25% POLYS osteoarthritis / AVN / sympathetic effusion
INFLAMMATORY (2,000-60,000 WBC) Translucent / > 50% POLYS RA / SLE / crystal / spondyloarthropathies
PURULENT (80,000-100,000 WBC) Infection / predominantly POLYS
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SUMMARY
No lab test is as good as your history and physical exam
No lab test “screens” for CTD’s Disease pattern recognition is far
more helpful than any serology or test Know the SENS and SPEC of lab tests
for different diseases Say “NO” to laboratory panels
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QUESTIONS!!!