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COLLECTED REPORTS ON THE
Rheumatic Diseases2005SERIES 4 (REVISED)
Published by theArthritis Research Campaign (arc)
Editors:Ade O Adebajo FRCP(Glasgow)
D John Dickson MBChB FRCP(Glasgow) FRCP(London) MRCGP
These reports are produced under the direction of thearc
Education Sub-Committee.They were first published individually between 2000 and 2003and were subsequently reviewed for this volume.
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34
RHEUMATIC DISEASES
ASSOCIATED WITH
ANTINUCLEAR ANTIBODIES
First published September 2001; reviewed April 2005
A fully revised version of this paper is scheduled for publi-cation as Topical Reviews (Series 5) No 8, February 2006.
Peter J Maddison
Consultant Rheumatologist, North West Wales NHSTrust/Professor of Joint and Muscle Disorders, Schoolof Sport, Health and Exercise Sciences, University of
Wales, Bangor
Antinuclear antibodies (ANA) are aprominent feature of autoimmune
rheumatic diseases
Detection of ANA plays an important
part in diagnosis and, to some extent,
predicting prognosis (best use of
serology described below)
Immunouorescence using HEp-2
cells is a sensitive screening test for
ANA but has low positive predictive
value for diagnosing systemic lupus
erythematosus (SLE)
When considering the diagnosis of
lupus, it is not cost-effective to proceed
to specic assays if the ANA test is
negative unless the clinical picture
dictates
If the ANA test is positive it is importantto dene the ANA prole using specic
assays
ANA relevant to autoimmune rheumatic
diseases are usually present at the time
of clinical onset, tend to persist, and
may be helpful in predicting the pattern
of disease expression
INTRODUCTION
The presence of antinuclear antibodies (ANA) is a hall-
mark of autoimmune rheumatic diseases. Since first be-
ing detected by indirect immunofluorescence (IMF),1
ANA have been the subject of intensive study to under-
stand their origin and role in pathogenesis. Laboratory
methods to detect certain of these antibodies have pro-vided the clinician with valuable tools to assist in diag-
nosis and, to some extent, prognosis in patients with
autoimmune rheumatic diseases. Serology is of particu-
lar value in situations where clinical expression of a dis-
ease such as systemic lupus erythematosus (SLE) is in-
complete when the presence of a particular ANA profile
can be diagnostic. However, ANA can be found in a var-
iety of clinical settings and their occurrence does not
necessarily indicate the presence of disease at all. There-
fore it is imperative that ANA tests are planned and the
results are interpreted in the light of the clinical findings.
Conversely, to be of most use to the clinician the serology
laboratory should have the facility to detect a wide range
of relevant antibody specificities.
ANA are a diverse group of antibodies, often directed
to large cellular complexes containing protein and nu-
cleic acid components. The most frequently occurring
ANA react with components of deoxyribonucleic acid
(DNA)-protein or ribonucleic acid (RNA)-protein com-
plexes.2,3A large number of studies indicate that the pro-
duction of these autoantibodies, which are generally high-
titre, high-affinity immunoglobulin G (IgG) antibodies,
is T-cell dependent and driven by the host autoantigen.4
Screening tests for ANA generally employ techniques
such as IMF using cultured cell lines expressing a wide
range of autoantigen targets. As illustrated in Table 1,
in addition to autoimmune rheumatic diseases ANA are
found in organ-specific autoimmune diseases and in
other clinical settings such as infection and lymphopro-
liferative disorders. About 15% of healthy adults and 8%
of children have detectable ANA, usually in low titre.5
Thefrequency of ANA in normal people is higher in women
and increases with age so that at least 25% of women
over the age of 60 years are positive. The frequency is
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35
also higher in healthy first-degree relatives of patients
with autoimmune rheumatic diseases.6,7
An important observation is that ANA are directed to
very characteristic autoantigen targets in patients with
autoimmune rheumatic diseases. Furthermore, in the in-
dividual patient the ANA profile is often quite restricted.
It is now appreciated that certain autoantibody profiles
are associated with diagnostic categories of autoimmune
rheumatic diseases and sometimes with particular pat-
terns of clinical manifestations.8Therefore once ANA
have been detected with a screening test it is important
to determine their specificity. This is now part of the
standard operating procedures of serology laboratories
but the process is greatly facilitated by the clinician pro-
viding adequate clinical information when ANA testingis requested.
DETECTION OF ANTINUCLEAR
ANTIBODIES
IMF using whole cell preparations detects a wide range
of ANA specificities and is the technique used by most
serology laboratories as a primary screening test for ANA.
Human cell lines particularly HEp-2 epithelial cells, de-
rived from a human laryngeal carcinoma are now used
in preference to cryostat sections of mammalian tissuessuch as mouse or rat liver or kidney. HEp-2 cells have the
advantage that, in addition to the easy visualisation of
individual cells and their organelles, as rapidly dividing
cells they present antigens only expressed during certain
stages of the cell cycle, which are either absent or occur
only in small quantities in the resting nuclei of tissue
sections. Also, ANA in autoimmune rheumatic diseases,
such as anti-Ro antibodies, are directed primarily to the
human antigen.9Interpretation of this assay still depends
on the skill of the technician, but with the advent of com-
mercially available cell-culture substrates, easily availablepositive standards,10and the requirement for labora-
tories to participate in quality assurance schemes, the
IMF technique is generally reliable and reproducible.
Both the ANA pattern and the titre will generally be re-
ported. The pattern of immunofluorescence will give
some hints to the principal ANA specificity in the serum
and may influence the subsequent approach to deter-
mine the antibody specificity.11Although a low-titre ANA
is not necessarily clinically insignificant, higher titres
(>1:160) are more likely to indicate the presence of anautoimmune rheumatic disease.12In some instances, the
IMF ANA test gives a false negative result. This may occur
if the antigen is located outside the nucleus (e.g. anti-
Jo-1 and anti-ribosomal P, both frequently categorised
under the umbrella term ANA) or if it is present in a
form not recognised by a particular autoantibody (e.g.
when anti-Ro is directed exclusively to determinants on
the native Ro molecule not expressed in cultured HEp-2
cells). In these situations the clinical picture will dictate
that specific assays need to be undertaken.
In order to reduce technician time and expertise by in-
troducing automation, a number of commercial enzyme-
linked assays for ANA screening are now available. These
employ various principles for preparing the substrate,
including whole cell extracts and specific mixtures of
purified or recombinant autoantigens. These assays vary
considerably in their sensitivity and specificity13and they
have not yet taken over from IMF, which is still the gold
standard.
Autoantibodies binding native, double-stranded DNA
(nDNA) and/or denatured, single-stranded DNA (ssDNA)
have a central place in the immunology of lupus. It is
techniques to detect anti-nDNA antibodies, which are
most specific for SLE,14that are routinely used in the di-
agnostic laboratory. Indirect immunofluorescence using
the haemoflagellate Crithidia luciliae15is a frequently
used technique for detecting anti-nDNA, combining
high sensitivity with high disease specificity,16but is only
semi-quantitative. This microorganism contains a giant
mitochondrion which consists of pure nDNA, and it is
the fluorescence of this which constitutes a positivetest. The Farr assay is a fluid phase radioimmunoassay
in which antibodies combined to 125I-labelled DNA are
precipitated by 50% saturated ammonium sulphate.17
TABLE 1.Antinuclear antibodies (ANA) in variousdiseases detected by indirect immunofluorescence.
1. Autoimmune rheumatic disease
Drug-induced lupus 100%
Systemic lupus erythematosus 98%
Systemic sclerosis 98%
Sjgrens syndrome 80%
Pauciarticular juvenile idiopathic arthritis 70%
Polymyositis/dermatomyositis 60%
Rheumatoid arthritis 50%
2. Organ-specific autoimmunity
Primary autoimmune cholangitis 100%
Autoimmune hepatititis 70%
Myaesthenia gravis 50%
Autoimmune thyroid disease 45%
3. Other conditions
Waldenstroms macroglobulinaemia 20%
Subacute bacterial endocarditis 20%
Infectious mononucleosis 15%
Leprosy 15%
4. Normal population
Children 8%
Adults 15%
Frequency of ANACondition
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36
Modifications of this include the use of filters or an anti-
human immunoglobulin serum. It is important that the
substrate is impeccably pure, double-stranded DNA. The
Farr assay detects high-affinity antibody and is at least as
specific as IMF using Crithidia, and titres correlate best
with disease activity. Increasingly, however, laboratories
are turning for convenience to enzyme-linked immuno-
assays (ELISA). The ELISA is more sensitive but generallyless specific than the Farr and IMF assays because it de-
tects low- as well as high-affinity antibody. Different com-
mercial ELISA assay systems are not always comparable18
and are influenced by important factors such as character-
istics of the DNA antigen, how the DNA is presented to
antibody in the serum, and the reaction conditions.
The presence of antibodies reacting with certain highly
conserved, nucleic acid-binding proteins (extractable nu-
clear antigens ENA) is a very characteristic feature of
autoimmune rheumatic diseases. The first observations
were made over 40 years ago when antibodies to what
are now called Ro and La were detected by immunodif-
fusion in the sera of patients with Sjgrens syndrome.19,20
Subsequent clinical interest in these systems results from
observations that certain profiles of these antibodies are
associated with particular patterns of disease.
Traditionally these antibodies have been detected by im-
munodiffusion using buffered saline extracts of mam-
malian tissue, such as rabbit or calf thymus extract and
human spleen extract. A range of prototype sera, avail-
able from the Centers for Disease Control and Prevention
(CDC), Atlanta, are used to detect a precipitin system.
Increasingly, more sensitive methods of antibody detec-
tion are being used, such as immunoblotting, protein
or RNA immunoprecipitation, and ELISA. The techniques
of immunoblotting and immunoprecipitation are de-
scribed elsewhere.21They tend to be too labour inten-
sive for the routine laboratory but are the principal ways
of identifying many of the myositis- and scleroderma-
associated antibodies. ELISAs using purified antigens have
been developed and provide a sensitive, quantitative wayof detecting these antibodies. Initially, immunoaffinity-
purified antigens were used, but recombinant antigens
are increasingly used as the substrate. Commercial ELISAs
vary in their performance22but generally show high sen-
sitivity but a corresponding lack of disease specificity
compared to immunodiffusion.
CLINICAL ASSOCIATIONS WITH
ANTINUCLEAR ANTIBODY PROFILES
Systemic lupus erythematosusThe use of HEp-2 cells enhances the sensitivity of the
ANA test in SLE so that ANA can be detected in 95%
of active, untreated patients. The main difference from
using rodent substrates is the increased detection of
patients with an immune response predominantly to
Ro. The identification of this patient subset can be fur-
ther enhanced by using HEp-2 cells transfected with
human 60 kD Ro antigen gene.23Thus in the situation
where the clinician wishes to exclude the possibility of
SLE, IMF is sufficient as a screening test for ANA, and it
is not cost-effective automatically to test for anti-DNAor other antibody specificities.24However, a very small
number of SLE patients are ANA-negative even using
HEp-2 cells, and proceeding with other techniques to
look for SLE-associated antibodies is indicated if the
clinical picture dictates. Conversely, since the positive
predictive value in an ANA test for SLE is low as low
as 11% in some studies25 once the ANA test is positive
it is then important to look for antibodies reacting with
DNA or nucleic acid-binding proteins.
Approximately 70% of untreated patients with active SLE
have anti-nDNA detected by IMF or the Farr technique.
In some patients, but not in all, a steady increase in anti-
DNA levels followed by a sharp drop in titre precedes a
clinical exacerbation.26Consequently there is value in
monitoring serial serum anti-DNA levels. In studies where
the relative proportion of high- and low-avidity anti-DNA
antibodies was measured, clinical exacerbation was often
heralded by an increase in high-avidity antibodies.26
In SLE, antibodies react most frequently with four groups
of RNA-binding proteins, namely Sm, U1RNP, Ro, and La.27
The antigens have been well characterised at a molecular
level.28,29High titres of these antibodies, for example as
detected by immunodiffusion, are found frequently and
almost exclusively in the context of autoimmune rheu-
matic diseases. Anti-Sm has the greatest specificity for SLE
but there is a marked ethnic variation in the presence of
these antibodies, being more commonly found in Afro-
Caribbeans than in northern European Caucasians.30These
antibodies identify distinctive serological subsets within
the spectrum of SLE. Antibodies to Sm frequently occur
in association with anti-U1RNP and antibodies to La are
virtually always accompanied by anti-Ro. It is apparent
that these serological subsets are associated with certain
patterns of disease expression (Table 2) in which they may
have a pathogenetic role. These antibodies are usually
present from the beginning of the clinical presentation and
are detectable throughout the course of the disease. Using
an ELISA, fluctuations in antibody titre can be detected,
but there is an inconsistent relationship between titres
measured in longitudinal studies and disease activity.31A
variety of other antibody specificities, for example anti-
PCNA (cyclin),32
SL (Ki),33
and ribosomal P protein,34
canbe detected in SLE. They occur in a small proportion of
sera and although clinical associations have been reported,
such as anti-ribosomal P proteins and CNS lupus, these
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associations require confirmation in larger, prospectivestudies and the role of these antibodies in routine SLE
serology is not yet defined.
Sjgrens syndrome
With sensitive techniques, antibodies to Ro and La can be
detected in virtually all patients.35They are a marker for
Sjgrens syndrome developing in SLE, systemic sclerosis
and primary biliary cirrhosis. Several studies, including
that of Pease et al,36have shown that antibodies to Ro
and La identify patients at greatest risk of developing
extraglandular complications such as vasculitis.
Systemic sclerosis
Antinuclear and/or antinucleolar antibodies are an
almost universal feature of patients with systemic scler-
osis (SSc). Several of these antibodies are highly specific
for the disease, are rarely found in other clinical settings,
and occur as an early feature so that their identification
has an important role in early diagnosis.37Certain of these
antibodies can be detected in the routine serology lab-
oratory by observing a typical pattern of IMF (in the caseof anticentromere antibodies) or using immunodiffusion
or a specific ELISA (in the case of anti-topoisomerase-1).
However, many of these systems require techniques such
as immunoprecipitation for their detection and it is rec-ommended to have sera from SSc patients analysed by
a specialised reference laboratory when possible. An im-
portant observation is that there is virtually no overlap
between subsets of patients identified by a particular anti-
body profile and these subsets tend to be associated with
certain patterns of clinical expression. Thus anticentro-
mere antibodies38and antibodies to the nucleolar con-
stituent ThRNP are almost exclusively found in patients
with limited cutaneous systemic sclerosis39and identify
patients at risk of micro- and macrovascular disease. By
contrast, antibodies to topoisomerase-1, RNA polym-
erases I, II and III and to U3RNP identify clinical subsets
of SSc with severe disease involving extensive sclero-
derma and visceral organ involvement.40
Dermatomyositis and polymyositis
Multiple antibody systems are also found in polymyositis
or dermatomyositis. These include a number of myositis-
specific antibodies.41Each specificity occurs in a small
proportion of patients and is associated with a charac-
teristic pattern of clinical expression (Table 2). Antibodiesto Jo-1 (histidyl-tRNA synthetase) is the most common
specificity, occurring in approximately 20% of adult
patients with polymyositis. These patients frequently
TABLE 2.Antinuclear antibody (ANA) specificities in diagnosis and disease expression.
Disease
Systemic lupuserythematosus
Sjgrenssyndrome
Systemicsclerosis
Dermato/polymyositis
Antibody
Anti-nDNA
Anti-Sm
Anti-U1RNP
Anti-Ro
Anti-La
Anti-rRNP
Anti-Ro
Anti-La
Anticentromere
Anti-ThRNP
Anti-topoisomerase-1
Anti-RNA-polymerases
Anti-U3RNP
Anti-PM-Scl
Anti-Ku
Anti-Jo-1
(antibodies to othertRNA synthetases)
Anti-SRP
Anti-Mi2
Frequency
70%
1025%*
30%
40%
15%
15%
6090%**
3585%**
30%
4%
25%
20%
5%
5%
2%
30%
(3%)
4%
10%
Clinical association
Lupus nephritis
Vasculitis; CNS lupus
Raynauds phenomenon, swollen fingers, arthritis,myositis, MCTD
Photosensitive rash, SCLE, neonatal lupus, CHB,Sjgrenssyndrome
As for anti-Ro
CNS lupus
Extraglandular disease, vasculitis, lymphoma
As for anti-Ro
Limited cutaneous disease, micro/macrovascular disease,telangiectasia
Limited cutaneous disease
Diffuse cutaneous disease, interstitial lung disease
Diffuse cutaneous disease, renal disease
Diffuse cutaneous disease, pulmonary hypertension
Scleroderma/polymyositis overlap
Scleroderma/polymyositis overlap
Antisynthetase syndrome
(Antisynthetase syndrome)
Severe myositis
Dermatomyositis
* higher frequency in blacks and Asians ** using sensitive ELISA assays
CHB congenital heart block; CNS central nervous system; MCTD mixed connective tissue disease; SCLE subacute cutaneous lupuserythematosus
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develop additional clinical features such as interstitial
lung disease, polyarthritis, Raynauds phenomenon and
mechanics fingers (the antisynthetase syndrome). Anti-
Jo-1 antibodies can be detected in the routine serology
laboratory by ELISA but other myositis-specific antibodies
require the input of a specialised reference laboratory.
ROLE OF ANTINUCLEAR ANTIBODIESIN DISEASE
The current view is that while most ANA are the result
rather than the cause of disease, certain ANA speci-
ficities may be directly involved in pathogenesis of tis-
sue injury. For example, there is evidence that subsets
of anti-DNA antibodies cause lupus nephritis. This in-
cludes observations that high titres of anti-DNA predict
exacerbations of nephritis,26the elution of anti-DNA
antibodies from affected kidneys,42and, more recently,
the demonstration that some, but not all, monoclonalanti-DNA antibodies, of both mouse and human ori-
gin, can cause renal pathology when infused into non-
autoimmune mice.43There is similar evidence44,45suggest-
ing that antibodies to Ro can also be pathogenic. The
striking association between anti-Ro and anti-La and neo-
natal lupus and congenital heartblock is particularly per-
suasive for a role of these antibodies in pathogenesis.46
To what extent tissue injury results from direct binding of
antibodies to autoantigens expressed in the target organ
or from the presence of immune complexes is still not
known. Additional mechanisms for antibody-mediated
injury may also be operating. There is some evidence,
for example, that certain autoantibodies such as anti-
DNA, anti-ribosomal P and anti-U1RNP can penetrate
living cells and influence the process of apoptosis,47,48
thereby inducing tissue damage or dysregulation of im-
mune functions.
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