autoimmune diseases mar 2003

7/27/2019 Autoimmune Diseases Mar 2003

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A REGULAR CASE-BASED SERIES ON PRACTICAL PATHOLOGY FOR GPs

The Royal College of Pathologists of AustralasiaThe Royal College of Pathologists of Australasia

MARCH 200

A JOINT INITIATIVE OF

AutoimmuneDiseasesAutoimmuneDiseases

CONTENTS• What tests to order

• How to interpret tests• Case studies

A REGULAR CASE-BASED SERIES ON PRACTICAL PATHOLOGY FOR GP

CSPCommon Sense Pathology



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4

Auto-antibody tests

Antinuclear antibody (ANA)

Antinuclear antibodies react with a vari-

ety of nucleoproteins (figure 1). The

serum under investigation is allowed to

react with the nuclei of a tissue substrate

on a microscope slide. If ANA are pres-

ent in the serum, they bind to the nucleo-

proteins and are revealed by a second

antibody, labelled with a fluorescent tag.

The specific antigens to which some

ANA bind have been determined and

include the extractable nuclear antigens

and DNA.

Antibodies to extractable nuclear anti-

gens (ENA)

ENA are specific nucleoprotein com-

plexes or cytoplasmic proteins that form

the targets for ANA. The presence of

antibodies to one or more of these auto-

antigens is characteristic of particular

autoimmune conditions and allows dif-

ferentiation between them.

Antibodies to double-stranded DNA

(dsDNA)

Anti-DNA antibodies bind to the double-

helical backbone of DNA molecules.

Their presence is characteristic of, and

highly specific for, SLE. The most specific

test to detect dsDNA is a radio-immuno-

assay in which the patient’s serum is

allowed to bind to DNA in solution.

Other tests that use DNA on a solid sur-

face — such as ELISAs — are also used.Positive tests using the latter methods are

less specific for SLE and can be found in

the sera of patients with autoimmune dis-

eases besides SLE.

Organ-specific autoimmune disease

Assays for auto-antibodies that are helpful

in the diagnosis of organ-specific autoim-

mune disorders often target hormone

receptors or other cell surfaces or cytoplas-

mic proteins specific to the organ (table 1).

Table 1: Spectrum of autoimmune diseases

DISEASES AVAILABLE DIAGNOSTIC TESTS

Systemic

SLE Antinuclear antibodies (ANA),

DNA, ENA

Systemic sclerosis ANA, ENA (Centromere, Scl-70)

Sjögrens syndrome ANA, ENA (SS-A, SS-B)

Mixed connective tissue disease ANA, ENA (nRNP)

Rheumatoid arthritis Rheumatoid factor, cyclic

citrullinated peptide

Phospholipid antibody syndrome Anticardiolipin antibody,

Beta-2-glycoprotein I antibody

Goodpasture’s disease Glomerular basement

membrane antibodies

Organ specific

Haemolytic anaemia Coombs’ test Autoimmune thyroid disease

(eg, Graves’ disease, Hashimoto’s) Thyroid-stimulating antibodies,

anti-thyroid peroxidase

Myasthenia gravis Acetylcholine receptor antibody

Adrenal insufficiency Adrenal antibodies

Gastrit is, pernicious anaemia Gastric parietal cel l antibodies

Chronic active hepatitis Smooth muscle antibodies

Primary biliary cirrhosis Mitochondrial antibodies

Figure 1a

Figure 1b

Figure 1c

Homogenous

as seen in

SLE.

Speckled as

seen in

Sjogren’s

syndrome.

Nucleolar

as seen in

scleroderma.

Typical patterns of positive ANA



Value of testing for auto-antibodiesAuto-antibodies may be used:

1. As a diagnostic tool to assist in the classification of

autoimmune disorders. Such classification may assist

in determining treatment selection and assessing

prognosis.

2. To monitor disease activity in selected conditions.

However, the use of auto-antibodies in diagnosis is

complicated because their detection is not always asso-

ciated with disease, and auto-antibodies present in

patients with autoimmune disease can also be found in

healthy people. For example, a positive ANA can be

found in up to 30% of the normal population, espe-

cially in elderly people and females, depending on the

dilution of the sample (figure 3). Thus, auto-antibody

tests should never be interpreted in isolation. Clinical

findings must be taken into account in analysing test

results.

Understanding the predictive value of auto-antibody

tests is important in the diagnostic evaluation of

patients with autoimmune disease, and depends on an

appreciation of the sensitivity and specificity of the

tests (figure 4 and table 2). A test’s sensitivity refers to

the proportion of people with a disease who have a

positive test result (ie, a highly sensitive test is positive

in a large proportion of patients with the disease —

many true-positive and few false-negative results). The

specificity of a test refers to the proportion of people

without the disease whose test is negative (ie, the test is

negative in the patients who do not have the disease —

many true-negative and few false-positive results). The

positive predictive value is a measure of the number of

people with a positive test who have

disease, compared with all people with

a positive test. The negative predictivevalue is defined as the number of peo-

ple without the disease, compared with

the total number of people with a neg-

ative test.

These values are influenced by the

prevalence of the disease in the population. If the

prevalence of a disease in the population is low — as it

is for autoimmune diseases — then the positive predic-

tive value for that test will be low, even if the sensitivi-

ty and specificity of the tests to be used are excellent.

5

Table 2: Sensitivity, specificity and predictive value

Disease present Disease absentPositive test True positive False positive

Negative test False negative True negative

Sensitivity — true positive/true positive + false negative

Specificity — true negative/true negative + false positive

Positive predictive value — true positive/true positive + false positive

Negative predictive value — true negative/true negative + false negative

0

7

14

21

28

35

Percentage positive

1:40 1:80 1:160 1:320

Healthy

X Y

ANA titre

Number

of people

Autoimmune disease

Figure 3

Figure 4

As the titre increases, the test becomes more spe-

cific for disease. Setting the cut-off at the point

represented by the dotted line X would detect all

individuals with disease, but many healthy individ-

uals will also have positive tests. If the cut-off

point is set as the dotted line Y, all healthy individ-

uals will have a negative test, but diseased people

will also have negative tests.

ANA in a normal, healthy population

Titre



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8

Case 1A 28-year-old female presents with a

three-month history of mouth ulcers, ery-

thematous photosensitive rash and

arthralgias. Examination reveals synovi-

tis.

Question 1: Which test(s) would be use-

ful?

The clinical presentation is suggestive of

an autoimmune disease, particularly SLE. An ANA is a sensitive test for screening for connective tissue

diseases. Several patterns are distinguished which generally correlate with particular autoimmune dis-

orders (figure 1, page 4, and table 3, above). In this case, the ANA pattern was homogenous with a

titre of 1:2560.

Question 2: What is the titre’s signifi-

cance?

The titre for this kind of test is the high-

est dilution of serum at which the

immunofluorescent pattern indicating a

positive test result is still visible under

the microscope. The higher the titre, the

more likely a connective tissue disease

will be present (figure 4, page 5).

Question 3: What further tests should be performed?

In this case, SLE is suspected on the basis of the positive ANA. The ANA test is used for screening

because it has a sensitivity of greater than 99% for SLE diagnosis. However, because it is positive in

other autoimmune disorders, its specificity is only about 60%. Therefore, more specific tests should be

performed to help confirm this diagnosis. Tests for antibodies to dsDNA and ENAs may be helpful.

Antibodies to dsDNA are specific for SLE but are only found in 50-70% of patients, so this test is not

very sensitive. ENAs are ribonucleic acid complexes extracted from the nucleus of mammalian cells.

Some patients’ sera contain specific antibodies to these antigens. The presence of these antibodies

allows further classification of connective tissue diseases (table 4).

In view of the relatively low sensitivities of anti-dsDNA and ENA antibodies for autoimmune diseases,their absence does not invalidate a diagnosis of an autoimmune disease on clinical grounds. On the

other hand, detection of the antibodies confirms diagnosis and may assist with decisions about treat-

ment and prognosis.

Other investigations that should be performed to assess disease activity and organ involvement include

a full blood count, electrolytes and renal function tests, ESR, C-reactive protein, serum complement

levels, and urinalysis for protein, red cells and casts.

Question 4: Are auto-antibody tests useful for monitoring autoimmune disease?

There is no role for serial ANA measurements to monitor the activity of autoimmune disease because

the titre does not correlate with the disease’s activity or its response to treatment.

Table 3: Common ANA patterns and disease associations

Speckled Homogenous Nucleolar Centromere

SLE X X

MCTD* X X

Polymyositis X

Systemic

sclerosis

Limited X

Diffuse X

*MCTD — mixed connective tissue disease.

Table 4: Some common ENA and their associations

ENA Disease associations

SS-A(Ro) SLE, primary Sjögren’s syndrome

SS-B(La) SLE, primary Sjögren’s syndrome

SCL-70 Progressive systemic sclerosis

RNP MCTD

Sm SLE

Jo-1 Polymyositis



ENA testing at initial presentation is usually sufficient because, once developed, patients tend to

maintain the same auto-antibody profile over the course of their illness. None of the antibodies to

ENA is useful for evaluating disease changes or progression.

However, the levels of anti-DNA antibodies may be helpful in following serial progress of patients

and their response to treatment.

Case 2A 50-year-old male presents with a one-month history of right knee pain and recurrent low-grade

fever. In the past week he has experienced profound difficulty in walking due to pain. Examination

reveals a hot, swollen knee with a markedly limited range of movement. A recent test for ANA —

performed by another doctor — was positive, with a speckled pattern and titre of 1:640. The ESR

was 110 and he had normocytic, normochromic anaemia and mild leukocytosis.

Question: What is the most likely diagnosis?

The clinical presentation suggests an inflammatory joint disease. Because a single joint is involved,

an infective arthritis must be excluded by aspirating the joint. Examination of the joint fluid will

also help to exclude other causes of

monoarthritis, such as gout or other

crystal-induced arthritis. Despite the

positive test for ANA, an autoimmune

disease is unlikely. ANA may be pres-

ent in inflammatory conditions other

than autoimmune disorders, including

infections and other causes of inflammation (table 5). In these cases, the ANA is usually transient

and resolves after the underlying inflammatory process has been treated.

Case 3A 50-year-old female presents with a two-year history

of Raynaud’s phenomenon. She also complains of indi-

gestion and nocturnal cough and has noticed skin

changes. Examination shows mild skin thickening over

her fingers. An ANA test is positive at a titre of

1:2560, with the pattern as demonstrated in figure 5.

Question 1: What is the most likely diagnosis?

The clinical history is consistent with a diagnosis of systemic sclerosis. The auto-antibody detecteddisplays an anti-centromere pattern that supports the diagnosis of CREST syndrome, also called

limited variant systemic sclerosis.

This is one of the few situations where the ANA is diagnostic. The importance of the distinction

between systemic sclerosis — characterised by Scl-70 antibodies — and CREST is that the latter has

a more favourable prognosis. A centromere pattern can also be present in primary biliary cirrhosis

and in generalised systemic sclerosis.

Case 4A 70-year-old woman presents with a six-month history of weight gain, hair loss and cold intoler-

ance. Examination reveals a goitre.

9

Table 5: Other non-autoimmune diseases associated

with positive ANA

Disease % ANA positive

Chronic infections 10-50

Drug-associated SLE syndromes 50

Rheumatoid arthritis 40-80

Neoplastic diseases 10-30

Figure 5



10

Question 1: Apart from thyroid function tests, what auto-antibody tests may be useful?Anti-thyroid peroxidase antibodies — formerly anti-thyroid microsomal antibodies — are useful to

establish an underlying autoimmune basis for thyroid disease. They are not useful for subclassification

of thyroid disease because, although they are found in 80–99% of people with hypothyroid autoim-

mune thyroiditis, they may also be found in up to 80% of cases of hyperthyroidism secondary to

Graves’ disease. Anti-thyroglobulin antibodies are less useful than anti-thyroid peroxidase antibodies

because the latter may be the sole antibody present in up to 65% of cases.

In addition to these thyroid auto-antibodies, measurement of antibodies against gastric parietal cells is

indicated. Detection of these antibodies is more commonly found in people with autoimmune thyroid

disorders and is often associated with vitamin B12 deficiency, secondary to autoimmune gastritis.

Question 2: What is the significance of the detection of anti-thyroid peroxidase antibodies in the

absence of overt hypothyroidism?Subclinical hypothyroidism — raised TSH, normal T4 — may be present in up to 5–10% of women,

whereas biochemical hypothyroidism is present in only 1%. The detection of antithyroid peroxidase

antibodies is associated with the development of hypothyroidism, although this progression is slow

and may take up to 20 years to occur.3 This progression is generally more rapid the higher the anti-

body titre and the higher the initial TSH. In these circumstances, patients should be screened yearly

for thyroid function.

Case 5A 60-year-old man presents with dizziness. On examination, he is found to have pigmentation of his

buccal mucosa and postural hypotension.

Question 1: What auto-antibody tests may help in establishing the diagnosis?The clinical presentation raises the possibility of Addison’s disease. Anti-adrenal antibodies are detect-

ed by indirect immunofluorescence using human or mammalian adrenal gland. These are present in

50-90% of patients with Addison’s disease. However, these antibodies may also be detected in up to

5% of healthy people, although long-term follow-up suggests the majority of such patients will

develop adrenal insufficiency in time. This is true for several organ-specific autoimmune disorders —

such as diabetes — in which autoimmune reactivity precedes the overt clinical manifestations of the

condition. This is because the symptoms of disease appear only when most of the endocrine organ has

been destroyed by the autoimmune process.

Question 2: What other autoimmune diseases may be present?

There is considerable overlap between the presence of auto-antibodies to the adrenal and antibodies to

other steroid-producing organs, such as the ovary. Therefore, patients with anti-adrenal antibodies are

at increased risk of developing gonadal failure.

References and reading list available on request.

Practice pointsnNot all auto-antibodies are associated with autoimmune disease

nThe detection of auto-antibodies does not on its own support a diagnosis of autoimmune disease

nTesting for auto-antibodies should be done selectively and only when the suspicion of disease is high

nDiagnosis of systemic connective tissue disease is best accomplished by using a sequential testing approach —

screening with the most sensitive test first and, if positive, confirm with more specific tests

nOrgan-specific autoimmune diseases often occur in clusters



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