Appropriate Serologic Testing to Evaluate Rheumatic Complaints

(1)

Appropriate Serologic Testing

to Evaluate Rheumatic

Complaints

Kathleen M Thomas DO Kathleen M Thomas DO Community Rheumatology Community Rheumatology Community Physician Network Community Physician Network

Noblesville, Indiana Noblesville, Indiana

April 26, 2012 April 26, 2012

(2)

Objectives

Describe lab tests most useful in the Describe lab tests most useful in the

evaluation of common rheumatic diseases evaluation of common rheumatic diseases

Recognize the serologic associations of Recognize the serologic associations of

rheumatic diseases rheumatic diseases

Apply sensitivity, specificity, likelihood Apply sensitivity, specificity, likelihood

ratio (LR) and positive predictive value to ratio (LR) and positive predictive value to

laboratory testing in clinical practice laboratory testing in clinical practice

(3)

Case study #1

28 28 yy--oo female with 6 months of female with 6 months of HAsHAs, , fatigue and

fatigue and arthralgiasarthralgias. She hurts all . She hurts all day, Advil, Tylenol provide no relief. day, Advil, Tylenol provide no relief.

Occasional oral ulcers around Occasional oral ulcers around

menses. Going through divorce and menses. Going through divorce and

worried about her kids worried about her kids

On exam muscle and joints, including On exam muscle and joints, including hands and feet, are tender, she is

hands and feet, are tender, she is weepy

(4)

Case study #1

What do you suspect?What do you suspect?

– – LupusLupus – – RARA – – FibromyalgiaFibromyalgia – – Depression/anxietyDepression/anxiety

What would you order?What would you order?

–

– ANA, RF, ESR, uric acidANA, RF, ESR, uric acid –

– Sleep studySleep study –

(5)

Objective 1

Describe lab tests most useful in the Describe lab tests most useful in the evaluation of common rheumatic

evaluation of common rheumatic diseases

(6)

Initial Approach When Faced with Diffuse

Rheumatic Disease Presentation

Is it arthritis (in the joints) or not Is it arthritis (in the joints) or not

(bursitis, fibromyalgia, etc) (bursitis, fibromyalgia, etc)

–

– Answer by H&PAnswer by H&P

Is it inflammatory or not?Is it inflammatory or not?

–

– Answer by H&PAnswer by H&P –

– Labs: ESR, CRP, CBCLabs: ESR, CRP, CBC

If arthritis, is it one of the common If arthritis, is it one of the common

inflammatory conditions? inflammatory conditions?

–

– Answer by H&PAnswer by H&P –

(7)

Diagnostic Laboratory Evaluation of

Possible Inflammatory Arthritis

Inflammatory markersInflammatory markers

–

– ESR and/or CRPESR and/or CRP

For diagnosis/prognosis: RF and CCPFor diagnosis/prognosis: RF and CCP

Consider ANA panelConsider ANA panel

–

– Patients may be Patients may be seronegativeseronegative early in early in disease, and even have normal

disease, and even have normal

ESR/CRP, but a +ANA may heighten ESR/CRP, but a +ANA may heighten suspicion

(8)

Rheumatoid Factor

(9)

Rheumatoid Factor

Present in 70Present in 70--80% of RA patients 80% of RA patients vsvs about 5% of normal population

about 5% of normal population

Also present in other rheumatic Also present in other rheumatic diseases and chronic disease

diseases and chronic disease

Prognostic value: Prognostic value: high levels high levels

associated with more severe joint

disease and extra

(10)

Rheumatoid Factor

Assists in diagnosisAssists in diagnosis

–

– In a patient with suggestive findings In a patient with suggestive findings (symmetric

(symmetric polyarthritispolyarthritis), presence increases ), presence increases the certainty of diagnosis, if other causes

the certainty of diagnosis, if other causes excluded

excluded

Assists in prognosisAssists in prognosis

–

– High titer increases the progression to erosive High titer increases the progression to erosive arthritis

arthritis

Assists in treatment decisionsAssists in treatment decisions

–

(11)

Clinical associations of RF

Rheumatoid arthritis (75Rheumatoid arthritis (75--80%)80%)

Other rheumatic diseaseOther rheumatic disease

–

– Sjogren’Sjogren’ss syndrome (~90%)syndrome (~90%) –

– SLE (15-SLE (15-20%)20%) –

– SarcoidosisSarcoidosis (~15%)(~15%) –

– Parvovirus arthropathyParvovirus arthropathy (~15%, transient)(~15%, transient) –

– Mixed cryoglobulinemiaMixed cryoglobulinemia (95%)(95%)

Chronic infectionsChronic infections

–

– Chronic Chronic HepHep CC –

– OsteomyelitisOsteomyelitis –

– Bacterial Bacterial endocarditisendocarditis

Monoclonal IgMMonoclonal IgM paraproteinsparaproteins

(12)

Frequency of +RF in Normal Population

by Age by Age 10 10--25%25% >70 yrs >70 yrs 5% 5% 60 60--70 yrs70 yrs 2 2--4%4% 20 20--60 yrs60 yrs Frequency of Frequency of +RF +RF AGE AGE

(13)

RF as

“

screening

”

RARA – – Prevalence of RA ~1.2% in USPrevalence of RA ~1.2% in US – – +RF 80%+RF 80% HCVHCV – – Prevalence ~1-Prevalence ~1-2% in US2% in US – – RF+ rate 40-RF+ rate 40-70%70%

Given positive RF in US population, risk of Given positive RF in US population, risk of

HCV about the same as RA HCV about the same as RA

Consider HCV arthritis in RF+ patient with Consider HCV arthritis in RF+ patient with

non

(14)

Cyclic

Citrullinated

Peptide

antibody

Also called Also called ACPAsACPAs

CitrullinationCitrullination is a postis a post--translational translational modification of

modification of argininearginine

Peptides after Peptides after citrullinationcitrullination have have

increased affinity for MHCII binding increased affinity for MHCII binding

groove of HLA DRB1 0401 allele groove of HLA DRB1 0401 allele

AntiAnti--CCP antibodies locally produced CCP antibodies locally produced by plasma cells in

(15)

Cyclic

Citrullinated

Peptide antibody

Similar sensitivity as RF, Similar sensitivity as RF, greatergreater

specificity

–

– Less common with Less common with SjogrensSjogrens or SLEor SLE –

– Not seen in HCV or other chronic Not seen in HCV or other chronic infections or PMR

infections or PMR

Often present Often present earlyearly, and predictive of , and predictive of severe, erosive disease

severe, erosive disease

(16)

RF and CCP

78% 78% 74% 74% RF RF 97% 97% 77% 77% Anti Anti-CCP-CCP Specificity Specificity Sensitivity Sensitivity

(17)

2010 Classification Criteria

More emphasis on clinical presentation, shift More emphasis on clinical presentation, shift

away from older criteria like nodules and away from older criteria like nodules and

radiographic damage radiographic damage

(18)

2010 ACR/EULAR

Classification Criteria for RA JOINT DISTRIBUTION (0

JOINT DISTRIBUTION (0--5)5)

1 large joint

1 large joint 00

2

2--10 large joints 10 large joints 11

1

1--3 small joints (large joints not counted)3 small joints (large joints not counted) 22

4

4--10 small joints (large joints not counted)10 small joints (large joints not counted) 33

>10 joints (at least one small joint)

>10 joints (at least one small joint) 55

SEROLOGY (0

SEROLOGY (0--3)3)

Negative RF

Negative RF ANDAND negative ACPAnegative ACPA 00

Low positive RF

Low positive RF ORORlow positive ACPAlow positive ACPA 22

High positive RF

High positive RF ORORhigh positive ACPAhigh positive ACPA 33

SYMPTOM DURATION (0 SYMPTOM DURATION (0--1)1) <6 weeks <6 weeks 00 ≥ ≥6 weeks6 weeks 11

ACUTE PHASE REACTANTS (0

ACUTE PHASE REACTANTS (0--1)1)

Normal CRP

Normal CRP ANDAND normal ESRnormal ESR 00

Abnormal CRP

Abnormal CRP ORORabnormal ESRabnormal ESR 11

≥6 = definite RA

What if the score is <6?

Patient might fulfill the criteria…

_{Prospectively}_{over time}

(cumulatively)

_{Retrospectively}_{if data on all}

four domains have been

(19)

Acute Phase Proteins

Proteins whose plasma Proteins whose plasma

concentrations change by at least concentrations change by at least

25% during inflammatory states 25% during inflammatory states

Those that increase are called Those that increase are called

positive phase reactants, e.g. CRP, positive phase reactants, e.g. CRP,

haptoglobin

haptoglobin, , ferritinferritin

Negative reactants decrease with Negative reactants decrease with inflammation, e.g. albumin,

inflammation, e.g. albumin, transferrin

(20)

Acute Phase Reactants

Lack specificity, but can be useful in Lack specificity, but can be useful in reflecting the presence and intensity reflecting the presence and intensity

of inflammatory process of inflammatory process

(21)

Case # 2

76 76 yoyo female awoke with stiffness in her female awoke with stiffness in her

neck and shoulders, trouble climbing out neck and shoulders, trouble climbing out

of bed; persisted for weeks of bed; persisted for weeks

Fatigue, anorexia, pain awakens her at Fatigue, anorexia, pain awakens her at

night, feels weak, no swollen joints or night, feels weak, no swollen joints or

vision changes vision changes

One exam, normal temporal arteries, no One exam, normal temporal arteries, no

scalp tenderness. She moves slowly, scalp tenderness. She moves slowly,

temp 100.1, give

temp 100.1, give--way weakness of way weakness of proximal muscles due to pain

proximal muscles due to pain

(22)

ESR

A measure of the distance in A measure of the distance in millimeters that

millimeters that RBCsRBCs fall in a tube fall in a tube over an hour

over an hour

An An indirectindirect measurement of measurement of alterations in acute

alterations in acute-phase reactants-phase reactants

Results can be affected by anemiaResults can be affected by anemia

Changes slowly with change in Changes slowly with change in condition

condition

(23)

ESR

Markedly elevated (>100mm/hr)Markedly elevated (>100mm/hr)

–

– InfectionInfection –

– MalignancyMalignancy –

– VasculitisVasculitis (CTD-(CTD-related, GCA)related, GCA)

Markedly lowMarkedly low

–

– AfibrinogenemiaAfibrinogenemia –

– AgammaglobulinemiaAgammaglobulinemia –

– Extreme polycythemiaExtreme polycythemia ((Hct>65%)Hct>65%) –

(24)

ESR

It has been suggested that patients It has been suggested that patients with PMR presenting with lower ESR with PMR presenting with lower ESR may require lower doses of steroids may require lower doses of steroids

and shorter duration of treatment and shorter duration of treatment

Patients with GCA and lower ESR at Patients with GCA and lower ESR at higher risk for visual complications higher risk for visual complications

(25)

CRP

AcuteAcute--phase reactant produced in phase reactant produced in response to IL

response to IL--6 and other cytokines6 and other cytokines

Elevation occurs within 4 hours of Elevation occurs within 4 hours of injury and peaks in 24

injury and peaks in 24--72 hours72 hours

Able to activate the classic Able to activate the classic complement cascade

(26)

ESR

vs

CRP

CRPCRP

–

– Better correlates with RA and seronegativeBetter correlates with RA and seronegative spondyloarthritis

spondyloarthritis disease activitydisease activity

ESRESR

–

– Better correlates with SLE activityBetter correlates with SLE activity

Discrepancies found with some frequencyDiscrepancies found with some frequency

–

– Probably due to differences in production of Probably due to differences in production of specific cytokines or their modulators in

specific cytokines or their modulators in different diseases

(27)

ESR and CRP

Measurement of any acute phase reactant Measurement of any acute phase reactant

must take into account how the results must take into account how the results

will affect management will affect management

–

– H&P generally more reliable reflection of H&P generally more reliable reflection of disease activity

disease activity

Knowing which acute phase reactant Knowing which acute phase reactant

historically correlates with the patient historically correlates with the patient’s ’s

disease helps chose which to follow over disease helps chose which to follow over

time time

(28)

Case # 3

57 y o with acute 57 y o with acute

onset of toe and onset of toe and

ankle pain ankle pain HTN, DM IIHTN, DM II No traumaNo trauma

Low grade feverLow grade fever

What do you What do you

order? order?

(29)

Mono/

pauciarthritis

The Eye of the NeedleThe Eye of the Needle

–

– Rule out Rule out infection,trauma,hemarthrosisinfection,trauma,hemarthrosis –

– Confirm crystalsConfirm crystals

MSU –MSU – goutgout

CPPD –CPPD – pseudogoutpseudogout

Apatite –Apatite – pseudogout, crystals not pseudogout, crystals not birefringentbirefringent, not , not

seen on polarizing microscope seen on polarizing microscope

LabsLabs

–

– Uric acidUric acid –

– Inflammatory markersInflammatory markers –

(30)

Serum uric acid

Males postMales post--puberty mean puberty mean urateurate 5.25.2

–

– ULN ~ 7mg/dlULN ~ 7mg/dl –

– Men with Men with sUAsUA>9.0, 22% develop gout >9.0, 22% develop gout after 5 years

after 5 years

PrePre--menopausal women mean 4.0menopausal women mean 4.0

–

– Estrogens have a Estrogens have a uricosuricuricosuric effecteffect

PostPost--menopausal mean 4.7menopausal mean 4.7

–

(31)

Uric acid

Do not treat asymptomatic Do not treat asymptomatic hyperuricemiahyperuricemia

–

– 43 million have hyperuricemia43 million have hyperuricemia, 8 million with gout, 8 million with gout

During gout flare, During gout flare, urateurate can be high, normal or can be high, normal or

low low

–

– Best time to check baseline is 2 weeks after flare has Best time to check baseline is 2 weeks after flare has resolved

resolved

90% gout patients are 90% gout patients are underexcretorsunderexcretors

–

– 24 hour urine for 24 hour urine for urateurate and Cr excretion on regular and Cr excretion on regular purine

purine dietdiet –

– UrateUrate >800mg, overproducer; <800mg is >800mg, overproducer; <800mg is underexcretorunderexcretor –

(32)

What if crystal exam is negative?

Repeat synovial fluid analysis Repeat synovial fluid analysis improves sensitivity

improves sensitivity

EULAR does allow for presumptive EULAR does allow for presumptive diagnosis

(33)

Case # 4

52 y o female 52 y o female complains of complains of fatigue, trouble fatigue, trouble climbing stairs, climbing stairs,

getting dressed but getting dressed but

no pain no pain

Rash noted on Rash noted on

exam, strength 4/5 exam, strength 4/5

proximal muscles proximal muscles

(34)

Idiopathic Inflammatory

Myopathies

Polymyositis/Dermatomyositis

Nonspecific abnormalitiesNonspecific abnormalities

–

– CK, aldolaseCK, aldolase, AST, ALT, ESR, LDH, AST, ALT, ESR, LDH –

– Elevations of CK can be due to macro-Elevations of CK can be due to macro-CKCK

MyositisMyositis--associated and associated and myositismyositis--specific specific

autoantibodies autoantibodies

Mimics/Mimics/DDxDDx

–

– TSH, serum and urine myoglobinTSH, serum and urine myoglobin, , VitVit D, drug D, drug screen, HIV

screen, HIV –

– In In myositismyositis vsvs rhabdomyolysis, CK rarely rhabdomyolysis, CK rarely above 50 x ULN

(35)

Myositis

-

associated abs

ANA (50ANA (50--80%)80%)

AntiAnti--RNP RNP abab (MCTD/OCTD)(MCTD/OCTD)

AntiAnti--PMPM--SclScl abab (PM(PM--scleroderma)scleroderma)

(36)

Myositis

-

specific abs

Classic Classic DM DM 5 5--10%10% Anti Anti--Mi-Mi-22 Severe Severe Resistant Resistant PM PM <5% <5% Anti Anti--SRPSRP Antisynthetase Antisynthetase Syndrome Syndrome 20 20--50%50% Antisynthetase Antisynthetase e.g. anti

e.g. anti--JoJo--11

Clinical Clinical Association Association Prevalence Prevalence DM/PM DM/PM Autoantibody Autoantibody

(37)

Objective #2

Recognize the serologic associations Recognize the serologic associations of rheumatic diseases

(38)

Case # 5

34 34 y-y-oo presents presents

with rash after with rash after

cruise to Caribbean cruise to Caribbean

AcheyAchey joints, low joints, low

grade fevers, grade fevers,

fatigue, weight loss fatigue, weight loss

What do you What do you

order? order?

(39)

ANA

ANA panelANA panel

ANA 95ANA 95--100% sensitive in SLE, but 100% sensitive in SLE, but far less specific

far less specific

AutoantibodiesAutoantibodies are hallmark of SLE: are hallmark of SLE: some diagnostic criteria, some useful some diagnostic criteria, some useful

for prognosis/markers of disease for prognosis/markers of disease

activity activity

(40)

ANA

Presence of a high titer (>1:640) Presence of a high titer (>1:640)

increases suspicion of an autoimmune increases suspicion of an autoimmune

disease, but is not diagnostic disease, but is not diagnostic

Titers can fluctuateTiters can fluctuate

–

– This is not reflective of disease activity, and it This is not reflective of disease activity, and it is not indicated to follow serially

is not indicated to follow serially

–

– Titers that disappear are less clinically Titers that disappear are less clinically significant

significant

Low titers common in general population Low titers common in general population

and in first

and in first--degree relatives of patients degree relatives of patients with ANA

(41)

Sensitivity of ANA in Rheumatic

Diseases

SLE (95SLE (95--100%)100%) Scleroderma (60Scleroderma (60--80%)80%) MCTD (100%)MCTD (100%) RA (50%)RA (50%) SjogrenSjogren’’ss (40(40--70%)70%)

Discoid lupus (15%)Discoid lupus (15%)

(42)

Non

-

rheumatic diseases

associated with +ANA

HashimotoHashimoto’’s s thyroiditisthyroiditis (46% (46% sensitivity)

sensitivity)

GravesGraves’’ disease (50%)disease (50%)

Autoimmune hepatitis (100%)Autoimmune hepatitis (100%)

Primary autoimmune Primary autoimmune cholangitischolangitis (100%)

(100%)

Primary pulmonary hypertension Primary pulmonary hypertension (40%)

(43)

SLE and Autoantibody Subsets

ENA 1

SmithSmith

–

– A diagnostic criteria and highly specificA diagnostic criteria and highly specific –

– Sensitivity 20Sensitivity 20--30%30%

RNPRNP

–

(44)

Autoantibody Subsets

ENA 2

Ro/SSARo/SSA –

– Part of diagnostic criteria for SjogrenPart of diagnostic criteria for Sjogren’’ss

High titer associated with extraglandularHigh titer associated with extraglandular featuresfeatures

–

– ANA-ANA-negative SLEnegative SLE –

– Neonatal lupus and CHBNeonatal lupus and CHB

Mother antiMother anti--Ro+, risk of fetus with CHB 2Ro+, risk of fetus with CHB 2--5%5%

–

– SubacuteSubacute cutaneouscutaneous lupus, cutaneouslupus, cutaneous vasculitis, ILD and vasculitis, ILD and photosensitive dermatitis (normal population)

photosensitive dermatitis (normal population)

La/SSBLa/SSB

–

– Part of diagnostic criteria for SjogrenPart of diagnostic criteria for Sjogren’’ss –

– 15% of SLE patients but rare in other systemic 15% of SLE patients but rare in other systemic rheumatic diseases

rheumatic diseases –

(45)

SLE and Autoantibody Subsets

dsDNAdsDNA

–

– A diagnostic criteriaA diagnostic criteria –

– Highly specific ~95%Highly specific ~95%

Sensitivity ~80%Sensitivity ~80%

–

– Marker of disease activity (renal) Marker of disease activity (renal) especially with low complement; especially with low complement; elevations often precede flares elevations often precede flares

(46)

Autoantibodies

in Systemic

Lupus

Department of Department of Defense Serum Defense Serum Repository; Repository; evaluated 130 evaluated 130 controls prior to controls prior to SLE diagnosis SLE diagnosis 115/130 115/130 (88%)present (88%)present before diagnosis before diagnosis (up to 9.4 years, (up to 9.4 years, mean 3.3) mean 3.3) ANA 78%ANA 78% dsDNAdsDNA 55%55% Progression of Progression of development: development: –

– ANA, Ro/La, APL absANA, Ro/La, APL abs –

– Later dsDNALater dsDNA then then Sm

Sm/RNP/RNP

Arbuckle, et al. (2003). Development of autoantibodies before the clinical onset of systemic lupus erythematousus. NEJM, 34 1526-1533.

(47)

(48)

Anti

-

Centromere

antibody (ACA)

Highly specific for scleroderma ~98%Highly specific for scleroderma ~98%

Found almost exclusively in limited Found almost exclusively in limited systemic sclerosis (CREST) (57%) systemic sclerosis (CREST) (57%)

–

– CCalcinosisalcinosis –

– RRaynaudsaynauds –

– EEsophageal dysmotilitysophageal dysmotility –

– SSclerodatylyclerodatyly –

(49)

Anti

-

SCL

-

70 antibodies

(topoisomerase

-

1)

Highly specific for scleroderma ~95%Highly specific for scleroderma ~95%

Tightly affiliated with diffuse Tightly affiliated with diffuse systemic sclerosis

systemic sclerosis

–

(50)

Anti

-

histone

antibodies

Present in 95% of DIL (drugPresent in 95% of DIL (drug--induced induced lupus) patients

lupus) patients

ProcainamideProcainamide, , HydralazineHydralazine, , IsoniazidIsoniazid

(51)

Positive ANA

High probability of autoimmune rheumatic disease Identify specific antigen Search for evidence of other disease or organ involvement

Ancillary tests e.g. Complement,

(52)

Positive ANA

Low probability of autoimmune rheumatic disease Low titer or transient titer: Reassure patient High titer or persistent titer: Search for alternative dx High titer or persistent titer: Follow patient

(53)

ANA

A hallmark of rheumatic diseaseA hallmark of rheumatic disease

For diagnosis of SLE, sensitivity of For diagnosis of SLE, sensitivity of ~95% and specificity of 57%

~95% and specificity of 57%

Primary utility diagnostically is the Primary utility diagnostically is the

NPV for SLE if ANA is negative

May support the diagnosis of other May support the diagnosis of other rheumatic disease but does not rule rheumatic disease but does not rule

in or out other specific diseases in or out other specific diseases

(54)

Case # 6

60 60 yoyo male hospitalized with male hospitalized with pneumonia,dehydration

pneumonia,dehydration/nausea from /nausea from oral antibiotics oral antibiotics Cr 1.1 Cr 1.1 HbHb 12 12 pltplt 120 WBC 12 120 WBC 12 cANCA cANCA 1:1601:160

Does this patient have Does this patient have Granulomatosis

Granulomatosis with with PolyangiiitisPolyangiiitis (

(55)

Anti

-

Neutrophil

Cytoplasmic

Antibody (ANCA)

Two patterns:Two patterns:

–

– c-c-ANCA = diffuse granular staining throughout ANCA = diffuse granular staining throughout cytoplasm

cytoplasm

Antigen recognized is usually a PMN granule Antigen recognized is usually a PMN granule

constituent proteinase

constituent proteinase--3 (Pr3 (Pr--3)3)

Found primarily in GranulomatosisFound primarily in Granulomatosis with with PolyangiitisPolyangiitis

(

(WegenersWegeners))

–

– p-p-ANCA = ANCA = perinuclearperinuclear staining of cytoplasmstaining of cytoplasm

Many antigens (elastaseMany antigens (elastase, , lysozymelysozyme, , lactoferrinlactoferrin) but ) but

most common and important is PMN granule

constitutent

constitutent myeloperoxidasemyeloperoxidase (MPO)(MPO)

Non-Non-MPO MPO pANCAspANCAs seen with non-seen with non-rheumatic diseases rheumatic diseases

(IBD, HIV, drug

(IBD, HIV, drug--induced ANCA e.g.); recognized as induced ANCA e.g.); recognized as atypical

(56)

Sensitivity of c

-

ANCA for

Granulomatosis

with

Polyangiitis

35% 35% 65% 65% Limited WG Limited WG 65% 65% 95% 95% Classic, multi Classic, multi- -system WG system WG Inactive Inactive (treated) (treated) Disease Disease Active Active Disease Disease

(57)

Case # 6

No history renal No history renal dzdz, sinusitis, , sinusitis, hemoptysis

hemoptysis

No prior med use, only No prior med use, only LevaquinLevaquin

CXR RLL infiltrate, sinus films CXR RLL infiltrate, sinus films negative

negative

Patient is unlikely to have Patient is unlikely to have Granulomatosis

Granulomatosis with with PolyangiitisPolyangiitis because of

(58)

ANCAs

The predictive value depends upon The predictive value depends upon clinical presentation

clinical presentation

Negative ANCA does not exclude the Negative ANCA does not exclude the diagnosis of AAV

(59)

Objective 3

Apply sensitivity, specificity, Apply sensitivity, specificity, likelihood ratio and positive likelihood ratio and positive

predictive value to laboratory testing predictive value to laboratory testing

in clinical practice in clinical practice

(60)

Sensitivity and Specificity

Sensitivity = True Sensitivity = True

Positives/Total with Positives/Total with Disease Disease TP/(TP+FN)TP/(TP+FN)

Specificity = True Specificity = True

Negatives/Total Negatives/Total without Disease without Disease TN/(TN+FP)TN/(TN+FP) True True Neg. Neg. (TN) (TN) False False Positive Positive (FP) (FP) Subject Subject W/o W/o Dx Dx False False Neg. Neg. (FN) (FN) True True Positive Positive (TP) (TP) Subject Subject With With Dx Dx Negative Negative Test Test Result Result Positive Positive Test Test Result Result

(61)

Prevalence of SLE in USA

2008 reported to be 100 per 100,000 2008 reported to be 100 per 100,000 adult women

adult women

Prevalence of 0.1%Prevalence of 0.1%

SLE in men 1/10SLE in men 1/10thth

(62)

Does +ANA = SLE? NO

1,000,0 1,000,0 00 00 999,000 999,000 1000 1000 ~949,000 ~949,000 50 50 ANA ANA - -~50,000 ~50,000 950 950 ANA + ANA + SLE SLE No No SLE SLE Yes Yes

If ANA 95% sensitive and 95% specific

+ANA post-test probability = 950/50,000 = 1/50 =2%

(63)

What if ANA only 80% Specific?

1,000,0 1,000,0 00 00 999,000 999,000 1000 1000 799,250 799,250 ~799,200 ~799,200 50 50 ANA ANA - -200,750 200,750 ~199,800 ~199,800 950 950 ANA + ANA + Totals Totals SLE SLE No No SLE SLE Yes Yes

+ANA post-test probability = 950/200,750 = 0.5%

ANA 95% sensitive and 80% specific

(64)

Likelihood Ratio

Positive LRPositive LR

–

– True positive rate/True positive rate/ false positive rate false positive rate –

– TP/FPTP/FP

Negative LRNegative LR

–

– False neg. rate/False neg. rate/ true neg. rate true neg. rate –

(65)

Likelihood Ratio

Positive LRPositive LR

–

– Higher is betterHigher is better –

– LR+>5 considered good testLR+>5 considered good test

Negative LRNegative LR

–

– Lower is betterLower is better –

– LR-LR-<0.2 considered good test<0.2 considered good test

LR+ or LRLR+ or LR-- close to 1.0: test not close to 1.0: test not

predictive predictive

LR multiplied by preLR multiplied by pre--test odds = posttest odds = post-

-test odds

(66)

LR with Low Pre

-

test Probability

ANA 1:40 threshold, 95% sensitivity and ANA 1:40 threshold, 95% sensitivity and

specificity for given lab specificity for given lab

–

– LR+ = 95%/5% = 19LR+ = 95%/5% = 19 –

– LRLR-- =5%/95% = 0.053=5%/95% = 0.053

Patient with estimated prePatient with estimated pre--test probability test probability

of SLE of 1% (0.01) of SLE of 1% (0.01)

If ANA negative at 1:40, then post-If ANA negative at 1:40, then post-test test

odds ~ 0.01x0.05 = 0.0005 (1:2000) odds ~ 0.01x0.05 = 0.0005 (1:2000)

If ANA positive at 1:40, then postIf ANA positive at 1:40, then post--test test

odds ~ 0.01x19 = 0.19 (1:5) odds still odds ~ 0.01x19 = 0.19 (1:5) odds still

strongly against having SLE strongly against having SLE

(67)

LR with High Pre

-

test Probability

ANA 1:40 threshold, 95% sensitivity and ANA 1:40 threshold, 95% sensitivity and

specificity for given lab specificity for given lab

–

– LR+ = 95%/5% = 19LR+ = 95%/5% = 19 –

– LRLR-- =5%/95% = 0.053=5%/95% = 0.053

Patient with estimated prePatient with estimated pre--test probability test probability

of SLE 50% (odds 1:1 or 1.0) of SLE 50% (odds 1:1 or 1.0)

If ANA is negative at 1:40, then postIf ANA is negative at 1:40, then post-test -test

odds ~ 1.0 x 0.5 =1:19 odds ~ 1.0 x 0.5 =1:19

If ANA is positive at 1:40, then post-If ANA is positive at 1:40, then post-test test

odds ~ 1 x 19 =

odds ~ 1 x 19 = 1919 = 19:1 odds, strongly = 19:1 odds, strongly in favor of SLE

(68)

Positive Predictive Value

How many of test positive patients How many of test positive patients truly have the disease

truly have the disease

–

– TP/TP+FPTP/TP+FP

Dependent on the prevalence of the Dependent on the prevalence of the disease in the population being

disease in the population being examined (pretest probability of examined (pretest probability of

disease) disease)

(69)

Positive Predictive Value

PPV= (sensitivity)(prevalence)

(70)

Case # 6

The PPV of cThe PPV of c--ANCA is low because:ANCA is low because:

–

– cANCAcANCA specificity is only 25%specificity is only 25% –

– cANCAcANCA sensitivity is only 40%sensitivity is only 40% –

– Low prevalanceLow prevalance of diseaseof disease –

(71)

Case # 6

Does he have Does he have GranulomatosisGranulomatosis with with Polyangiitis Polyangiitis?? NONO WHY?WHY? –

– Low prevalence of diseaseLow prevalence of disease –

(72)

Conclusions

Lab tests can be supportive of the Lab tests can be supportive of the diagnosis and useful to monitor

diagnosis and useful to monitor disease activity,

disease activity, but are rarely but are rarely diagnostic

diagnostic

Lab test must be interpreted in the Lab test must be interpreted in the context of clinical presentation, and context of clinical presentation, and

understanding of sensitivity, understanding of sensitivity,

specificity, prevalence of disease specificity, prevalence of disease

(73)

Case # 1

28 28 yy--oo female, tired, female, tired, HAsHAs, hurts , hurts allover

allover

ANA 1:160ANA 1:160

What does she have?What does she have?

(74)

References

ACR online Advanced Rheumatology ACR online Advanced Rheumatology Course

Course

Practical RheumatologyPractical Rheumatology. 3. 3rdrd edition, edition, 2004, pp 57

2004, pp 57--72.72.

Rheumatology SecretsRheumatology Secrets. 2. 2ndnd edition, edition,

Sterling G West MD, editor. 2002, pp Sterling G West MD, editor. 2002, pp

52

(75)

Clinical Pearls

Upper limit of ESR for men age/2 but for Upper limit of ESR for men age/2 but for

women (age + 10)/2 women (age + 10)/2

High RF and CCP+ is highly specific for RA High RF and CCP+ is highly specific for RA

and portends a worse prognosis and portends a worse prognosis

High RF and negative CCP: think High RF and negative CCP: think HepCHepC

The negative predictive value of an ANA is The negative predictive value of an ANA is

high, but the PPV is low high, but the PPV is low

Gout does not occur in premenopausal Gout does not occur in premenopausal

women women

DonDon’’t order a lab test unless it will change t order a lab test unless it will change

your management plan your management plan