Beruflich Dokumente
Kultur Dokumente
Marina Magrey
Abby Abelson
Published: August 2010
Contents
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.
The value of a test in diagnosing a certain condition depends on its pretest probability. A positive test result with high pretest
probability helps to make a diagnosis, but a negative test result with low pretest probability helps to rule out the diagnosis. However,
clinicians cannot rely heavily on blood tests in making the diagnosis of rheumatologic diseases, except for certain tests that are highly
specific for certain diseases. Improper application of these tests leads to misdiagnosis, inappropriate therapy, and unnecessary health
care expenses. This chapter discusses blood tests that are useful in evaluating various rheumatologic diseases.
Acutephase reactants
Acutephase reactants are proteins whose plasma concentration increases (positive acutephase proteins) or decreases (negative
acutephase proteins) by at least 25% during inflammatory states.1 Box 1 lists positive and negative acutephase reactants. The effect
of inflammatory molecules such as interleukin (IL)6, IL1, tumor necrosis factor α (TNFα), interferon gamma (IFNγ), and transforming
growth factor β (TGFβ) causes a change in hepatic protein synthesis collectively known as acutephase response. Erythrocyte
sedimentation rate (ESR) and Creactive protein (CRP) are the most widely measured acutephase reactants in clinical practice.
ESR is a measure of the height of erythrocytes that fall through plasma in a Westergen or a Wintrobe tube over a period of 1 hour.
ESR can be greatly influenced by the shape and number of red blood cells as well as other plasma constituents like fibrinogen,
globulins, and albumins. It can be spuriously high in the absence of inflammation, as in anemia, nephritic syndrome, and
hypergammaglobulinemia, and it can be spuriously normal in cryoglobulinemia and hemoglobinopathy. ESR increases steadily with
age, and the upper limit varies with sex; hence, ESR is difficult to interpret compared to CRP.
The concentration of CRP in serum is more sensitive than ESR to evaluate and monitor inflammation, and it is independent of factors
that affect ESR. It correlates better with disease activity, and the rise in CPR level is seen much earlier than that of other acutephase
reactants, usually 4 to 6 hours after tissue injury.
Box 1: Positive and Negative AcutePhase Reactants
Positive AcutePhase Reactants
Alpha1 antitrypsin
Ceruloplasmin
Complement components
Creactive protein
Ferritin
Fibrinogen
Haptoglobin
Serum amyloid A
Negative AcutePhase Reactants
Albumin
Transferrin
Transthyretin
Both ESR and CRP levels can be elevated in a wide variety of conditions including trauma, infection, infarction, neoplasms, and
inflammatory arthritis. Usually ESR and CRP levels correlate well, but in some patients levels may be discordant for reasons that are
unclear. They are very useful in monitoring disease activity in rheumatologic conditions such as rheumatoid arthritis, polymyalgia
rheumatica,2 and giant cell arteritis. Some studies have shown that the pretreatment ESR value is of some prognostic value in
polymyalgia rheumatica. Most patients with active lupus have normal or minimally elevated CRP levels, and markedly elevated
concentrations of CRP in SLE should raise a suspicion of bacterial infection. Other causes for elevated CRP in SLE patients include
serositis, synovitis, and vasculitis.
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Antinuclear antibodies
Antinuclear antibodies (ANAs) directed against a variety of nuclear antigens have been detected in the serum of patients with many
rheumatic and nonrheumatic diseases as well as in healthy persons. Various immunochemistry techniques are used to detect and
characterize these ANAs. These methods include immunofluorescence microscopy, hemagglutination, immunodiffusion, complement
fixation, and enzymelinked immunosorbent assay (ELISA).
Immunofluorescent microscopy performed on human epithelial2 (Hep2) cells is widely used for initial screening. It is a highly
sensitive test and is often abnormal in patients with ANAassociated diseases, but the specificity is low and the test has many false
positive results. It is reported as positive or negative and includes a titer. ANA testing performed using ELISA technology is very
sensitive and has a high incidence of falsepositive results (Figure 1).
Clinical Applications
ANA testing is very useful in establishing a diagnosis of systemic
lupus erythematosus (SLE). Nearly all patients with SLE have a
positive ANA test, with a sensitivity of 93% to 95% and a specificity of
57%.3 However, even healthy persons can have a positive ANA test
at lower titers. About 25% to 30% of healthy persons have a positive
test with a titer of 1 : 40, 10% to 15% at a titer of 1 : 80, and 5% at a
titer of 1 : 160 or greater. The frequency increases with age,
particularly in women. ANA titer of 1 : 40 is seen in 25% to 30% of
relatives of patients with rheumatologic disorders.3
A positive ANA in a patient with low pretest probability is often of
unclear significance. Due to the low prevalence of SLE (40
50/100,000), most people with positive ANA do not have lupus Figure 1: Click to Enlarge
(positive predictive value [PPV], 11%). However, a high ANA titer
(>1 : 640) should increase the suspicion for an autoimmune disorder, although not diagnostic of a disease, and patients with high
titers should be carefully followed for the development of connective tissue disorder. ANA titer is not routinely used for assessing the
disease activity in lupus, and serial ANA testing is therefore not useful.
In addition to lupus, ANA testing is helpful in diagnosing other rheumatic diseases such as systemic sclerosis and Sjögren's syndrome
(Table 1). The sensitivity of ANA in diagnosing systemic sclerosis is 85% and the specificity is 54%.3 Although ANA is not included in
the 2002 classification criteria for Sjögren's syndrome, it is found in 80% of patients with primary Sjögren's syndrome and at high titers
(>1 : 320) in nearly one half of the patients.4 Patients presenting with Raynaud's phenomenon should also have ANA testing because
a positive ANA test indicates an increased risk of developing an associated systemic rheumatic disease from 19% to 30%, whereas a
negative test indicates a risk of 7%.5 Additionally, ANA testing helps to stratify the risk of uveitis in patients with juvenile idiopathic
arthritis.
Table 1: Sensitivity and Specificity of Antinuclear Antibody in Various Connective Tissue Diseases
Disease Sensitivity (%) Specificity (%)
Systemic lupus erythematosus 9395 57
Scleroderma 85 54
Polymyositis, dermatomyositis 61 63
Rheumatoid arthritis 41 56
Sjögren's syndrome 48 52
Raynaud's phenomenon 64 41
Juvenile chronic arthritis 57 39
Juvenile chronic arthritis with uveitis 80 53
Antinuclear Antibodies in Other Diseases
ANA can also be positive in many autoimmune disease states not associated with connective tissue diseases, such as autoimmune
hepatitis, primary autoimmune cholangitis, primary biliary cirrhosis, and Crohn's disease. Other disorders associated with positive
ANA titer include such chronic infectious diseases as mononucleosis, subacute bacterial endocarditis, tuberculosis, and
lymphoproliferative diseases. Hence, ANA testing should be reserved for patients with high suspicion for systemic autoimmune
disease, such as young women with fatigue, joint pain, and rash, and should not be used as a screening test in patients complaining
of generalized fatigue and musculoskeletal pain, particularly elderly patients.
Types
There are different types of ANAs based on their target antigen, including singlestranded DNA (ssDNA) and doublestranded DNA
(dsDNA), nuclear histone and nonhistone nuclear proteins, and RNA protein complexes. The staining pattern seen on indirect
immunofluorescence (IIF) gives some indication of the specificity of the antibodies in the sample (Table 2 and see Figure 1).
Identification of the specificity for extractable nuclear antigens (ENA) is warranted because this can further differentiate between the
distinct types of autoimmune connective tissue diseases. Hence, a positive ANA test should be followed by an antiDNA antibodies
assay.
Table 2: Identifying Antinuclear Antibodies
Antigen Disease Association
Homogenous and Diffuse
DNAhistone complex (nucleosome) SLE (60%)
Druginduced lupus (95%)
Peripheral Rim
dsDNA SLE
Speckled
RNA polymerase types II and III Systemic sclerosis
RNP MCTD (100%)
Scl70 Systemic sclerosis (15%70%)
Sm SLE (25%30%)
SSA Sjögren's syndrome (8%70%)
SLE (35%40%)
SSB Sjögren's syndrome (14%60%)
SLE (15%)
Nucleolar
Nucleolar RNA, RNA polymerase 1 Systemic sclerosis
Pmscl Polymyositis
Centromere
CENP Limited scleroderma
MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosus.
AntiDNA Antibodies
Antibodies to dsDNA are often measured in SLE and are commonly referred to as antiDNA antibodies. They are very useful in the
diagnosis of SLE and assessment of disease activity, and they are associated with lupus nephritis.
The most commonly used techniques for measuring antidsDNA antibodies are ELISA and immunofluorescence (e.g., using Crithidia
luciliae as substrate). Radioimmunoassay (e.g., the Farr assay) is still available but its use has declined. The hemoflagellate Crithidia
luciliae contains in its kinetoplast pure dsDNA, not complexed to proteins. Serially diluted serum samples are added to the slide
carrying Crithidia cells. Binding of antibodies is visualized by fluorescinated antiimmunoglobulin (Ig) G antibodies. This method can
be used to confirm the presence of antidsDNA antibodies when the ELISA results are discrepant.
The sensitivity of antidsDNA antibody for diagnosis of SLE is 57.3% and the specificity is 97.4%.6 These antibodies are present at
some time in the course of the disease as the levels fluctuate and may be absent at times. AntiDNA antibodies have been reported in
patients with a variety of other rheumatologic and nonrheumatologic diseases including rheumatoid arthritis, Sjögren's syndrome,
scleroderma, druginduced lupus, Raynaud's phenomenon, mixed connective tissue disease, discoid lupus, myositis, chronic active
hepatitis, uveitis, Graves’ disease, and anticardiolipin antibody syndrome and in women with silicone breast implants. Not all patients
with SLE have positive antidsDNA antibodies; therefore, a negative test does not exclude the diagnosis of SLE. The prevalence of
patients with a positive antiDNA assay despite a negative ANA has been reported to be 0% to 0.8%. Therefore, unless there is a
reasonable suspicion that the ANA is falsely negative, antiDNA antibody testing is not generally indicated in ANAnegative patients.
AntiSmith and Antiribonucleoprotein Antibodies
Antibodies directed against small nuclear riboprotein include antiSmith (antiSm) antibody and antiribonuclear protein (antiRNP)
antibodies. They bind to related but distinct antibodies.
AntiSm antibodies are very useful for confirming the diagnosis of SLE. A positive test result strongly supports the diagnosis, although
a negative test result cannot exclude it. The sensitivity of antiSM antibody for diagnosis of lupus ranges from 24% to 30%, and
specificity ranges from 96% to 98%.7
AntiRNP antibodies bind to protein containing U1RNA. They coexist with antiSm antibodies in many patients with SLE. They have a
very low sensitivity and moderate specificity for diagnosing SLE, but they are very useful in diagnosing mixed connective tissue
disease. The sensitivity of antiRNP antibodies for diagnosing mixed connective tissue disease is 71% to 100% and the specificity is
84% to 100%.
Sjögren's Syndrome Antibodies
The Sjögren's syndrome A antigen (antiSSA/Ro) consists of 52 and 60kDa proteins (called Ro52 and Ro60) complexed with Y1Y5
RNAs. AntiSSA/Ro and antiSSB/La antibodies are detected by counterimmunoelectrophoresis, ELISA, and Western blot. ELISA and
Western blot are the most sensitive assays but are less specific.
AntiSSA antibodies are seen in 50% to 60% of patients with primary Sjögren's syndrome and rarely in healthy persons.8 These
antibodies are also detected in other autoimmune diseases including rheumatoid arthritis, SLE, and polymyositis. About 10% to 15%
of patients with secondary Sjögren's syndrome and 35% to 40% of patients with SLE have antiSSA antibodies. Moreover, their
presence is associated with development of extraglandular features including vasculitis, lymphadenopathy, nephritis, and leukopenia
in patients with Sjögren's syndrome4 and with features including photosensitivity, subacute cutaneous lupus, cutaneous vasculitis,
neonatal lupus, and congenital heart block.
AntiSSB antibodies are present in 40% to 50% of patients with primary Sjögren's syndrome and in 15% of patients with SLE but
rarely in other connective tissue diseases. These antibodies are sometimes seen in patients with autoimmune hepatitis.
Antibodies to both SSA and SSB antibodies should be checked in patients with sicca symptoms. Patients with primary Sjögren's
syndrome and positive SSA and SSB antibodies represent a subset of patients who have more active disease and who need very
close followup to watch for the development of extraglandular features.4
Antiribosomal P Protein Antibodies
Some studies have shown antiribosomal P protein antibodies to be highly specific for lupus and associated with neuropsychiatric
lupus. They are detected in 10% to 20% of patients with SLE. However, the diagnosis of neuropsychiatric lupus is still based on
clinical grounds.
Antihistone Antibodies
Antihistone antibodies are present in more than 95% patients with druginduced lupus and up to 80% of patients with idiopathic lupus.
However, the mere presence of antihistone antibodies does not indicate druginduced lupus. Up to 80% of patients taking
procainamide for 1 to 2 years develop positive ANAs, but most do not develop druginduced lupus.
Anticentromere, AntiScl70, and AntiU3Ribonuclearprotein Antibodies
Anticentromere antibodies are associated with limited cutaneous systemic sclerosis, previously called CREST (calcinosis, Raynaud's
phenomenon, esophageal dysmotility,sclerodactyly, telangectasia] syndrome).They are rarely found in patients with other connective
tissue diseases or in healthy persons, making them highly specific for diagnosing systemic sclerosis. The sensitivity of anticentromere
antibodies for the diagnosis of limitied cutaneous systemic sclerosis is 31%, and specificity is 97%.9 They are very useful in
distinguishing patients with limited systemic sclerosis from patients with diffuse systemic sclerosis or with primary Raynaud's
phenomenon. Anticentromes antibodies are predictive of limited cutaneous involvement or decreased likelihood of investital being
displayed in systemic sclerosis.
AntiScl70 antibody is also very useful in diagnosing systemic sclerosis. This antibody is seen in 20.2 % of patients with systemic
sclerosis and is highly specific (100%) for diffuse disease.9 Anti Scl70 and anticentromere antibodies rarely coexist in the same
person. The presence of antiScl70 antibodies is useful in predicting a greater likelihood for the development of diffuse cutaneous
involvement and radiographic pulmonary fibrosis with an abnormal pulmonary function test.
The antinucleolar antibodies (such as RNApolymerase I, II, and III; antiPM Scl; and antiTh/To) are infrequently present in patients
with systemic sclerosis, which limits their predictive value in the diagnosis. However, they are highly specific for the diagnosis of
systemic sclerosis.
Miscellaneous Antinuclear Antibodies
Polymyositis and dermatomyositis are associated with autoantibodies against a group of aminoacyl tRNA synthetases. These include
Jo1,PL7,PL12,EJ, and OJ. The antiJo1 antibodies are present in 20% to 25% of adult myositis patients and are highly specific for
myositis associated with a constellation of symptoms including skin involvement, lung disease, Raynaud's phenomenon, inflammatory
arthritis, and fever. AntiMi2 antibodies are more specific for dermatomyositis and are associated with a favorable longterm
prognosis.
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Rheumatoid factor
Rheumatoid factor (RF) autoantibodies are directed against the Fc portion of IgG. The most commonly measured RF is IgM. The other
RFs include IgG, IgE, and IgA. Box 2 shows RF positivity in different diseases.
Box 2: Rheumatoid Factor Positivity in Different Diseases
Rheumatic Conditions (Sensitivity)
Cryoglobulinemia (40%100%)
Polymyositis and dermatomyositis (5%10%)
Rheumatoid arthritis (50%90%)
Sjögren's syndrome (75%95%)
Systemic lupus erythematosus (15%35%)
Systemic sclerosis (20%30%)
Nonrheumatic Conditions
Bacterial endocarditis
Infections
Hepatitis
Leprosy
Parasites
Syphilis
Tuberculosis
Malignancy
Pulmonary disease
Interstitial pulmonary fibrosis
Sarcodosis
Silicosis
Primary biliary cirrhosis
RF is detected in a wide variety of rheumatic and nonrheumatic conditions, as shown inBox 2. It is commonly used in diagnosing
rheumatoid arthritis. The sensitivity of RF for diagnosing rheumatoid arthritis is around 50% to 80%, and specificity is 85% to 90%, as
reported by some studies where patients with advanced disease were tested. RF may be negative in the early stages of rheumatoid
arthritis, and positivity increases over time.
RF alone cannot be used for diagnosis of rheumatoid arthritis. Around 15% to 20% of patients with rheumatoid arthritis never have RF
positivity, and 2% to 10% of healthy persons are RF positive. Hence, positive RF alone does not confirm rheumatoid arthritis and
negative RF does not exclude it.10 RF testing must be ordered more selectively, and the best time to obtain the test may be when the
suspicion of rheumatoid arthritis is low and a negative test would provide significant reassurance.10 There is a correlation between
higher RF concentrations and moresevere disease and poor prognosis, but the use of RF in monitoring disease activity is unclear.
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Anti–cyclic citrullinated peptide antibodies
Anti–cyclic citrullinated peptide (antiCCP) antibodies are directed against citrulline residues formed in posttranslational modification
of arginine. They are often elevated in patients with rheumatoid arthritis. They have a reported sensitivity of 30% to 60% and a
specificity of 95% to 98% among patients meeting the criteria for rheumatoid arthritis.
Two of the most important clinical uses of this test are its high specificity for the disease and the presence of antiCCP antibodies in
earlyphase rheumatoid arthritis. Some studies have shown that antiCCP antibodies can appear in the circulation several years
before the onset of rheumatoid arthritis. The presence of antiCCP antibodies in early disease is highly predictive for morerapid
radiographic progression of disease, meaning patients with antiCCP antibodies have significantly more joint damage than patients
without this antibody.11 Hence, antiCCP antibody should be checked in patients in whom rheumatoid arthritis is suspected on clinical
grounds.
Patients with chronic hepatitis C virus infection sometimes have high titers of RF and a variety of rheumatic symptoms, but antiCCP
antibody is rarely found in these patients.12 Presence of antiCCP antibody in such cases supports the diagnosis of concomitant
rheumatoid arthritis, although a negative test does not exclude it.
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Antineutrophil cytoplasmic antibodies
Antineutrophil cytoplasmic antibodies (ANCAs) are useful adjuncts to the clinical diagnosis of certain specific diseases, such as
Wegener's granulomatosis and microscopic polyangiitis. These antibodies are directed against several neutrophilic cytoplasmic
components. The two main techniques for detecting ANCAs are IIF and ELISA.
IIF assay does not identify the specific antigen responsible for the immunofluorescence. ELISA is more specific and helps to identify
the specific target antigen. The two relevant target antigens are proteinase 3 (PR3) and myeloperoxidase (MPO). Both PR3 and MPO
are located in the azurophilic granules of neutrophils and peroxidasepositive lysosomes of monocytes. Antibodies with target
specificities for PR3 and MPO are called PR3ANCA and MPOANCA. IIF without identification of MPO and PR3 antigen is incomplete
and of no value.
Pattern
When serum from patients with vasculitis is incubated with ethanolfixed human neutrophils, two major immunofluorescence patterns
are observed: the cANCA pattern and the pANCA pattern (Figure 2). The accuracy of the results is based on the experience of the
laboratory personnel interpreting ANCA immunofluorescence results.13
The cANCA pattern indicates diffuse staining throughout the cytoplasm, and in most cases the antibodies responsible for this pattern
are directed against PR3. However, autoantibodies against other defined and undefined cytoplasmic agents, including
bactericidal/permeabilityincreasing protein (BPI) and, rarely, MPO, can cause cytoplasmic fluorescence.
The pANCA pattern indicates staining around the nucleus, and the antibody responsible for this
pattern is usually against MPO. However, autoantibodies against elastase, cathepsin G, lactoferrin,
lysozyme, and azurocidin have also been identified as causing the pANCA pattern.
Atypical ANCA patterns are sometimes observed on immunofluorescence in patients with immune
mediated conditions other than systemic vasculitis, such as inflammatory bowel disease,
autoimmune liver disease, malignancies, and other rheumatic diseases. Such patterns are often
confused with the pANCA pattern.
Interpretation Figure 2: Click to Enlarge
Clinicians interpreting ANCA results should bear in mind that the results can vary from laboratory to
laboratory, and hence serial determinations should be performed by the same laboratory.13 The predictive value of ANCA testing
depends heavily on the clinical presentation of the patient in whom the test is performed. ANCA assays should be ordered only when
the pretest probability for Wegener's granulomatosis and microscopic polyangiitis is very high.
Clinical Utility
Wegener's granulomatosis is almost always associated with ANCA positivity. Between 70% and 90% of patients with Wegener's
granulomatosis are ANCA positive, with the cANCA pattern and antibodies directed against PR3. About 5% to 20% of patients with
Wegener's granulomatosis have the pANCA pattern, with antibodies directed against MPO. The sensitivity of cANCA and PR3
ANCA is related to the extent, severity, and activity of disease at the time of testing. Patients with mild Wegener's granulomatosis may
be ANCA negative. Diagnosis of Wegener's granulomatosis is based on the clinical picture; PR3ANCA just assists in diagnosis.
Between 40% and 80% of patients with microscopic polyangiitis are ANCA positive. These patients usually have the pANCA pattern
with MPO specificity.
ANCAs, both with PR3 and MPO specificity, have been detected in ChurgStrauss syndrome, but MPO specificity is more common.
Antiglomerular basement membrane (antiGBM) antibody disease may be associated with ANCAs. The clinical significance of anti
GBM antibodies and ANCA is uncertain.
DrugInduced Vasculitis
Certain drugs are reported to induce ANCA reactivity with varying symptoms. Minocyclineassociated arthritis, fever, and livedo
reticularis can be ANCA positive, with antiMPO antibodies. Propylthiouracilinduced vasculitis is also ANCA positive, with specificity
to several different target antigens including PR3, MPO, and elastase. Hydralazineassociated vasculitis may be ANCA positive, with
antiMPO antibodies.
Monitoring
A rise in ANCA titers may be associated with relapses, but not always. Elevated ANCA titer should not be used as a sole parameter for
preemptive therapy.14 Therapy should only be based on clinical or pathologic evidence of relapse. The role of sequential ANCA titers
after the diagnosis is established is unclear. One study showed a weak association between disease activity and ANCA levels.
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Complement
The complement system consists of plasma and membrane proteins that provide innate defense against microbial pathogens.
Complement activation is usually assessed by determining the levels of individual complement components such as C3 and C4 and
by quantifying the CH50 (total hemolytic complement) activity. Complement levels are measured by either functional or antigenic
assays. CH50 is a useful tool for assessing all nine components of the classic pathway (C1, C2, C3, C4, C5, C6, C7, C8, and C9).
CH50 is undetectable when there is complete deficiency of any individual complement component. Classic pathway activation is
indicated by low levels of C3 and C4. Alternate pathway activation is indicated by low levels of C3 but normal C4.
Complement measurement is an important diagnostic tool in many connective tissue disorders. Hypocomplementemia is present in
disorders associated with excessive levels of immune complexes such as SLE and cryoglobulinemia. There is a significant
association between low complement levels and lupus nephropathy.15 The utility of low complement levels as predictors of lupus
flares is controversial; some studies have found a clear association with lupus activity and others show no correlation. A high
frequency of positive ANA and antidsDNA in patients with primary antiphospholipid antibody syndrome with hypocomplementemia
probably suggests that these patients might develop a lupuslike illness.
Low complement levels are also seen in inherited complement deficiency. Inherited complement deficiencies of C1, C2, and C4
predispose to SLE. Complete deficiency of C3 is rare and manifests in childhood as severe recurrent infections with pyogenic
organisms. Complete deficiency of C4 is rare because four genes encode the C4 protein. Partial deficiency due to the presence of
one, two, or three null alleles can produce persistently low levels of C4 and predispose to SLE. Deficiency of C1 esterase inhibitor
leads to unregulated C1 esterase and to depression of C4 levels.
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Antiphospholipid antibodies
Antiphospholipid antibodies include antibodies directed against phospholipidassociated proteins such as cardiolipin, β2
glycoprotein 1, and prothrombin. These antibodies are usually measured in patients with SLE, recurrent thrombosis, and recurrent
fetal loss, raising the possibility of antiphospholipid antibody syndrome. The antiphospholipid syndrome is characterized by venous
thrombolism, arterial thrombosis, or pregnancy morbidity (individually or in combination), together with antiphospholipid antibodies
and lupus anticoagulant.
The anticardiolipin antibodies are measured by ELISA and usually include three serotypes: IgG, IgM, and IgA. International criteria for
negative, low, medium, and high levels have been set, and standards are available for laboratory calibrations. These antibodies
should be present in medium to high concentrations on at least two occasions about 12 weeks apart to establish a diagnosis of
antiphospholipid antibody syndrome, along with some clinical criteria. A number of studies have shown that acute medical illness and
infections can lead to a transient increase of the antibodies.
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Summary
ESR and CRP are markers of inflammation and are elevated in inflammation. ESR can be elevated without inflammation in
hypergammaglobulinemia or anemia.
CRP is a more sensitive marker of inflammation and is independent of factors affecting ESR.
Many patients with active lupus do not have elevated CRP levels; elevated CRP can suggest bacterial infection.
ANA testing is very useful in establishing a diagnosis of SLE. Nearly all patients with lupus have a positive ANA (sensitivity is
93%95%, but specificity is 57%). However, most patients with positive ANA do not have lupus, because the prevalence of
lupus is low in the general population.
ANA titer is not used for assessing the disease activity in lupus. Thus, serial ANA testing is of unknown value.
AntiDNA antibody testing is very useful in the diagnosis of SLE and is also a useful biomarker of SLE disease activity.
AntiScl 70 antibody is very useful in diagnosing systemic sclerosis and anticentromere antibody in diagnosing limited
scleroderma. AntiScl 70 and anticentromere antibodies rarely coexist in the same patient.
SSA and SSB antibodies should be checked in patients with sicca symptoms. Patients with primary Sjögren's syndrome with
SSA or SSB antibodies represent the most clinically and immunologically active subset. These patients need very close follow
up for development of extraglandular features.
The sensitivity of rheumatoid factor for rheumatoid arthritis is around 50% to 80% and specificity is 85% to 90%. It may be
negative in the early stages of rheumatoid arthritis, and positivity increases over time.
Between 70% and 90% of patients with Wegener's granulomatosis test positive for ANCAs in the cANCA pattern, with
antibodies directed against PR3. A negative ANCA assay does not exclude Wegener's granulomatosis.
Between 40% and 80% of patients with microscopic polyangiitis are ANCA positive and usually have the pANCA pattern with
MPO specificity.
The role of sequential ANCA titers after the diagnosis is established is unclear. A recent study showed a weak association
between disease activity and ANCA levels.
Inherited deficiencies of complements C1, C2, and C4 predispose to SLE.
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Suggested Readings
Blumenthal DE. Tired, aching, ANApositive: Does your patient have lupus or fibromyalgia?. Cleve Clin J Med. 2002, 69: (2):
143146, 151152.
Nishimura K, Sugiyama D, Kogata Y, et al: Metaanalysis: Diagnostic accuracy of anticyclic citrullinated peptide antibody and
rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007, 146: (11): 816817.
Sibley J. Laboratory tests. Rheum Dis Clin North Am. 1995, 21: 407428.
Slater CA, Davis RB, Shmerling RH. Antinuclear antibody testing. A study of clinical utility. Arch Intern Med. 1996, 156: (13):
14211425.
Tedeschi A, Baratè C, Minola E, Morra E. Cryoglobulinemia. Blood Rev. 2007, 21: (4): 183200.
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