Internal Medicine Journal 2004; 34: 338347
REVIEW
Update on the immunology, diagnosis and management of
systemic lupus erythematosus
G. E. M. REEVES
Department of Immunology and Infectious Diseases, John Hunter Hospital, Newcastle, New South Wales, Australia
Abstract
Lupus occurs with a prevalence of 29 in 10 000 people,
targeting female and indigenous populations in particu-
lar. Lupus and related systemic autoimmune syndromes
(scleroderma, Sjgrens syndrome, rheumatoid arthritis
and polymyositis) result from a similar set of genetically
and environmentally modulated immune disturbances,
and the diagnostic and management approach to these
conditions is broadly comparable. Evanescent , vague
symptoms, restrictive diagnostic criteria and low diagnostic
suspicion might have resulted in the under-diagnosis
of these problems in the past, imposing considerable
burdens on sufferers and the community. Serological
INTRODUCTION
Systemic lupus erythematosus (SLE)* occurs with a prev-
alence of 29 in 10 000 people,1,2 targeting female,
indigenous3 and possibly Asian populations in particular.
Lupus and related systemic autoimmune syndromes, such
as scleroderma, Sjgrens syndrome, rheumatoid arthritis
and polymyositis, represent a similar breakdown in
normal immune function, and the diagnostic and
management approach to these conditions is broadly
comparable. Short-lived, vague symptoms, restrictive
diagnostic criteria and low diagnostic suspicion can result
in the under-diagnosis of these problems.4 Current
medical literature features many comprehensive overviews
on lupus and related syndromes and the present article
focuses on major advances in the diagnosis and treatment
of these conditions.
AUTOIMMUNITY: UNDERSTANDING
THE BREAKDOWN OF TOLERANCE
Systemic lupus erythematosus and related syndromes
represent a breakdown in the bodys immune tolerance,
Correspondence to: Glenn E. M. Reeves, Immunology and Infectious Diseases
Department, John Hunter Hospital, Lookout Road, New Lambton Heights,
Newcastle, NSW 2305, Australia. Email:
Glenn.Reeves@hunter.health.nsw.gov.au
Received 29 May 2003; accepted 25 August 2003.
Funding: None
Conflicts of interest: None
*Please note that the (abbreviated) terms SLE and lupus have been used
interchangeably in this paper.
screening should be employed cautiously and wisely,
given the rapidly occurring changes in methodology,
which have lowered their specificity. Close liaison with
the immunology laboratories performing these tests is
therefore advisable. Clinicians should emphasize the
improving prognosis of lupus and related conditions as a
result of earlier disease detection, improved educational
support systems and refined medical therapies. (Intern
Med J 2004: 34: 338347)
Key words: systemic lupus erythematosus,
autoimmune, autoimmunity, antinuclear antibodies,
fibromyalgia.
where self-structures become the target of immune
attack, much as if they were microbes. To understand
these disorders, it is first important to comprehend the
basics of the immune response (Fig. 1). There are two
prime orchestrators of the immune system: antigen-
presenting cells (APC) and T cells. As their name
implies, APC must process antigen and present it in a
manner that the immune system can recognize; this
involves cleaving the antigen into smaller components
and presenting these small peptides in the cleft of a
histocompatibility molecule (major histocompatibility
complex (MHC) or human leucocyte antigen (HLA)
system). The capacity of APC to activate T cells, which
circulate and sample MHCpeptide complexes on APC
throughout the body, is dependent on a costimulation
signal provided by the APC. This costimulation is
believed to depend on certain APC-focused triggers, of
which the best characterized are the pattern motifs
possessed by microbes but not by self structures.
Examples of these motifs include bacterial DNA,
mannans and lipopolysaccharides.5 After T-cell activa-
tion has occurred, a range of further responses can be
facilitated by T-cell cooperation, including phagocyte
activation, cytolysis and B-cell help for antibody
production.
The fact that autoimmune disease remains a
syndromal diagnosis illustrates the current lack of under-
standing of the intricacies of autoimmune pathogenesis,
but one thing is clear: autoimmune diseases represent
multifactorial, multistep processes involving an interplay
of genetic inheritance and environmental factors that
impact on and disturb normal immune tolerance
(Fig. 2). Among these steps, some or all of the following
factors can be expected to play a role:
 Update on lupus 339

Figure 1 The immune response. MHC, major histocompatibility complex.

Figure 2 Autoimmune pathogenesis paradigm. APC, antigen-presenting cell; MHC, major histocompatibility complex.

1 An at-risk genome6 that includes particular HLA parts of the genome, including polymorphisms for a
haplotypes, which are more likely to bind to and range of cytokines, receptors and apoptosis-regulators,
present self-peptides to T cells. Non-HLA-encoded are also important.

Internal Medicine Journal 2004; 34: 338347

340 Reeves

Table 1 1997 revision of 1982 American College of Rheumatology criteria for systemic lupus erythematosus

Malar rash Malar erythema, flat or raised

Discoid rash Erythematous raised patches with keratotic scaling and follicular plugging
Photosensitivity Rash as an unusual reaction to sunlight
Oral ulcers Oral/nasopharyngeal ulcers, usually painless, observed by physician
Arthritis Non-erosive arthritis involving 2 peripheral joints with tenderness, swelling or effusion
Serositis Pleuritis or pericarditis
Renal features Proteinuria or cellular casts
Neurological features Seizures or psychosis
Haematological features Haemolysis, leucopenia, lymphopenia or low platelets
Immunological features DNA, Smith antibody or antiphospholipid antibodies (based on positive cardiolipin, lupus
anticoagulant or false positive syphilis serology)
Antinuclear antibody-positive No drugs known to cause drug-induced lupus

LUPUS: A PROCESS NOT A CATEGORY

Figure 3 Photosensitive malar rash of systemic lupus
erythematosus.
2 Release of normally hidden (cryptic) antigens7 or a
new focus on such targets triggered by structurally
similar exogenous agents.
3 APC stimulation through infection of antigen-
presenting cells or stimulation of their receptors by
exogenous triggers (infective,8 inhaled or ingested9).
4 Downstream activation of T cells or B cells, prod-
ucing cell-mediated and antibody-mediated pathology,
respectively.
5 Modulation of these immune responses by other
components of the innate and acquired immune
response, such as complement, immune complexes,
cytokines and chemokines, as well as non-immune
factors, such as oestrogen,10 medications and ultraviolet
light.
The history of lupus diagnosis has moved from clinical
descriptions of malar rash (Fig. 3) through to the lupus
erythematosus cell test and finally to the measurement of
antinuclear antibodies (ANA),11 DNA antibodies and
antibodies to extractable nuclear antigens (ENA), with
the American College of Rheumatology (ACR) assem-
bling, then refining12 clinical and investigational criteria
for lupus and related conditions through the 1970s to
the 1990s. What was once designed as an epidemio-
logical and research standardization system should not
create a slavish devotion to categorization, as syndromal
diagnoses are clearly only steps toward a fuller under-
standing. Just as the description of a cough variant in
1979 widened the conception of asthma, new aspects of
lupus are being recognized that should broaden the
approach to SLE and its relatives. For example, the
modified ACR criteria for lupus require the presence of
four of 11 features (Table 1).12 Although this cut-off
level has been well-defined and has proven useful in
diagnosing lupus for many years, some patients fall
through the net (see the story of PL, Appendix I, Case
1) because they present with other recognized associa-
tions of systemic autoimmunity (e.g. urticaria) in the
absence of a full-house set of criteria. Excessive
rigidity in the application of diagnostic and therapeutic
tools to patients with suspected lupus-like conditions
can result in the withholding of potentially efficacious
therapy.4,13
LABELS: GOOD OR BAD?
The growing tendency towards the medicalization of
malaise is rightly questioned and the mere mention of
the word lupus can arouse dread and fear in patients.
This is despite the fact that most people with lupus now
experience much-improved life expectancies and quality
of life.14 Nevertheless, sufferers of systemic autoimmune
conditions are often females who have sought an expla-
nation for fleeting, relapsing and vague symptoms for
many years, without satisfaction. As we have seen with
PL (Appendix I, Case 1), standardized diagnostic
criteria are unhelpful in many settings,15 therapeutic dis-
cussions centred around a lupus-like autoimmune

Internal Medicine Journal 2004; 34: 338347

 Update on lupus 341

Figure 4 Antinuclear antibody (ANA) detection by indirect immunofluorescence provides ANA titre and pattern. Certain patterns
are associated with clinical syndromes, such as calcinosis, Raynauds, esophageal dysfunction, sclerodactyly and telangiectases
(CREST). CENP-A,B,C, centromere proteins A, B and C; dsDNA, double-stranded DNA; LE, lupus erythematosus; Pm-Scl,
polymyositis-scleroderma antibody; RNAP, anti-RNA polymerase; RNP, anti-uridine rich 1 ribonucleoprotein; Sjgrens, Sjgrens
syndrome; SLE, systemic lupus erythematosus; Sm, Smith antibody; SSA, Sjgrens syndrome antibody A; SSB, Sjgrens
syndrome antibody B.

Internal Medicine Journal 2004; 34: 338347

342 Reeves

Table 2 Extractable nuclear antigen tests

Sm (Smith) 95% specific for lupus, but only seen in 1530% of patients (predominantly seen in groups of Asian and
African-American people)
RNP Seen in a range of autoimmune conditions (rheumatoid arthritis, lupus, scleroderma, Sjgrens syndrome)
In lupus, it is associated with milder, non-renal disease
Isolated RNP elevation (without other extractable nuclear antigens) is associated with mixed connective tissue
disease (clinical constellation of Raynauds, swollen digits, arthropathy, serositis, myopathy and oesophageal
dysfunction)
SSA Associated with photosensitive lupus skin disease (subacute cutaneous lupus), neonatal lupus syndrome and
Sjgrens syndrome
SSB More specific for Sjgrens syndrome than SSA
Ribosomal-P 95% specific for lupus
Argument over its association with psychosis and renal disease
Scl-70 Highly specific for diffuse scleroderma, but only has a sensitivity of 30% for the disease
Associated with interstitial lung disease as well as severe skin and musculoskeletal involvement in scleroderma
Jo-1 Highly specific for polymyositis, but only has a sensitivity of 30%
Associated with development of interstitial lung disease
Jo-1, anti-histidyl t-RNA; RNP, anti-uridine rich 1 ribonucleoprotein, Scl-70, anti-DNA topoisomerase I; SSA, Sjgrens syndrome antibody A;
SSB, Sjgrens syndrome antibody B.

condition can open up new avenues for support and
therapy and these approaches are appropriate if offered
judiciously in the context of adequate ongoing support
and education. It must also be remembered that
systemic autoimmune syndromes often merge,16 com-
prising features of several different conditions, such as
the skin-thickening of scleroderma, the serositis of lupus,
the erosions of rheumatoid arthritis and the muscle
inflammation of polymyositis. The diagnostic labels
mixed connective tissue disease, overlap syndrome
and undifferentiated connective tissue disease testify to
the frequent presence of an incompletely defined disease
continuum. Because many of these patients display
evolving syndromes, the diagnosis and management of
patients with lupus variants should be confined to
clinics with specialized expertise in the treatment of
autoimmune conditions.
AUTOIMMUNITY IS NOT AUTOIMMUNE
DISEASE
ANA (see Fig. 4) are regarded as the hallmark of
systemic autoimmunity, but they also arise in the context
of a range of infective, ischaemic, inflammatory and
iatrogenic stimuli. The specificity of a positive ANA for
lupus is therefore poor (approximately 60%); recognized
associations include viral infections, anticonvulsant
therapy, myocardial infarction, having a first-degree
relative with autoimmunity, and ageing, to name but a
few. As outlined in Figure 2, the multistep process of
autoimmune disease may stop at the level of auto-
immunity; up to 10% of healthy patients carry positive
antibody results in their blood which seldom become
clinically relevant. Perhaps no more than 10% of asymp-
tomatic ANA-positive individuals ever develop overt
autoimmune disease.17 The widespread detection of
ANA has prompted some authorities to suggest that
ANA may serve an adaptive role, and there is some
evidence of a functional role for these antibodies in
controlling or limiting the sequelae of tissue damage.18
KW (Appendix I, Case 2) represents one example of the
importance of interpreting all test results in their clinical
context. This rule is particularly pertinent to the changes
being witnessed in serodiagnostic methodology.
SEROLOGICAL SCREENING:
CHANGING APPROACHES
Although clinical features are always paramount,
antibody results add greatly to diagnostic accuracy if
used properly. This is illustrated by the reliance of two
of the ARA lupus criteria on antibody-based test results.
The beauty of ANA testing is that a negative result
reduces the likelihood of a lupus-related condition
substantially. For example, in a 30-year-old woman with
early-morning stiffness in the hands, a pretest probability
of 35% for lupus can be reduced to approximately 6%
after a negative ANA result has been secured (see
Appendix II).19 Such statistically based approaches to
clinical decision-making have significant limitations, but
might serve partially to objectify what has previously
been labelled clinical acumen or judgement.
Sjgrens syndrome antibody A (SSA), anti-uridine
rich 1 ribonucleoprotein (RNP), Sjgrens syndrome
antibody B (SSB), anti-histidyl t-RNA synthetase (Jo-1),
anti-DNA topoisomerase I (Scl-70), anti-ribosomal ribo-
nucleoprotein (Ribo-P), Smith antibody (Sm) and a range
of less common but diagnostically useful antibodies are
grouped together as ENA because of their targets initial
extraction from calf thymus (Table 2). It was traditionally
believed that a negative ANA virtually excluded lupus-like
autoimmune disease. However, up to 5% of ANA-
negative patients display positive SSA results, a finding
associated with cutaneous and sometimes systemic lupus.
Furthermore, many autoantibodies target non-nuclear
(cytoplasmic) components of the cell, and patients with
such specificities are reported as ANA-negative. This is
despite the association of various cytoplasmic staining

Internal Medicine Journal 2004; 34: 338347


#
Figure 5 Screening for systemic lupus-related conditions. (*) If screening immunological laboratory uses enzyme-linked
immunosorbent assay (ELISA) for extractable nuclear antigens (ENA), consider requesting further specific ENA, especially
ribosomal-P; (#) specificity of DNA for lupus drops from >95% radioimmunoassay (RIA) to approximately 60% (ELISA).
ANA, antinuclear antibodies.
antibodies with disease states. For example, ribosomal-P
antibodies, seen in up to 15% of adults with lupus and
even more frequently in juvenile lupus patients,20 are
frequently associated with cytoplasmic staining in the
absence of nuclear fluorescence, and hence may be
reported as ANA-negative;21 the reporting laboratorys
discretion to add comments on additional staining
patterns is often not exercised. The detection of anti-
bodies to ribosomal-P can carry the same diagnostic
significance as DNA or Sm antibodies, as all three of these
antibodies have approximately 95% specificity for lupus if
immunoprecipitation methods are used.
Great caution should be used in test interpretation,
however. For example, the reported high specificity
(approximately 95%) of Sm, double-stranded DNA
(dsDNA) and Ribosomal-P antibodies22 for lupus dates
from the days when these tests were performed with
precipitation-based methods, and, with the growing
economic and time-related attractions of new enzyme-
linked immunosorbent assay (ELISA) kits, specificity
suffers, often greatly, albeit in the presence of enhanced
sensitivity. For example, DNA antibody measurement
by the traditional Farr radioimmunoassay method,
although only approximately 30% sensitive, displays
high specificity for lupus (up to 99%); in contrast,
ELISA tests are more sensitive (7595%), but less
specific, with up to 40% of results being falsely positive.
Therefore, a positive antibody to dsDNA can no longer
be regarded as virtually clinching a lupus diagnosis,
Update on lupus 343
#
even though such over-reliance on test results in a
clinical vacuum would always be ill-advised.
For this reason, a modified screening paradigm is
suggested (Fig. 5), where ENA assessment is added to
ANA as part of the initial screen, rather than being
reserved only for ANA-positive samples. Depending on
the laboratory used, however, only six of the broad range
of ENA specificities will be included (ELISA ENA
screens currently generally incorporate testing for Sm,
RNP, SSA, SSB, Jo-1 and Scl-70). Thus, further specific
testing, such as a request for ribosomal-P, may be indi-
cated in selected circumstances; these occasions are
likely to be uncommon, but the possibility of false
negatives should be considered.
In summary, the entire diagnostic performance of avail-
able antibody assays is currently undergoing method-
related upheaval and clinicians should be aware that this
is a labile and active area that remains incompletely
defined. Ongoing standardization problems with auto-
immune assays, especially those for dsDNA and phos-
pholipid antibodies,23 highlight the importance of basing
diagnoses on clinical features rather than test results.
Table 3 illustrates some of the changes in diagnostic
performance of the commonly used serologies.22,24
DONT ALWAYS BLAME THE LUPUS!
Once lupus or a related condition has been diagnosed,
one must resist the temptation to attribute all ill-health
Internal Medicine Journal 2004; 34: 338347
344 Reeves

Table 3 Changing performance of diagnostic serologies in lupus-related conditions

Test Sensitivity (%) Specificity (%)

Traditional method New method (ELISA) Traditional method New method (ELISA)

Sm 840 3445 98100 88100

SSA 29 61 99 8093
SSB 14 2735 99 8897
RNP 835 3964 8399 8497
Jo-1 2530 8090 95 6090
Scl-70 2040 6095 95 8090
Ribosomal-P 510 1015 95 8090
DNA 3040 7595 9599 6080
ENA offered on ENA ELISA. Traditional method referred to is immunoprecipitation in gel (conterimmunoelectrophoresis; for extractable
nuclear antigen (ENA) analysis) or by radioimmunoassay (commonly used for DNA until recently) figures quoted represent pooled results from
a range of studies using different antigen sources and purification methods; Sm prevalence in lupus is race-dependent, seen more commonly in
groups of African-American and Asian people. ELISA, enzyme-linked immunosorbent assay; Jo-1, anti-histidyl t-RNA synthetase; RNP, anti-
uridine rich 1 ribonucleoprotein; Scl-70, anti-DNA topoisomerase I; Sm, Smith antibody; SSA, Sjgrens syndrome antibody A; SSB, Sjgrens
syndrome antibody B.

experienced thereafter to the autoimmune disease. For
example, the prevalence of fibromyalgia (22%),25
depression (37%),26 vasculopathy (15%),27 phospholipid
antibody syndrome (2061%)28 and osteoarthritis is elevated
in people with lupus, and the inappropriate escalation
of steroids or other immunosuppressive therapies for
symptoms related to these problems is potentially detri-
mental. By far the commonest cause of cognitive and
mood disturbance in the setting of chronic autoimmune
disease is secondary depression arising from ill-health,
prognostic uncertainty and medications such as corticos-
teroids.29 Cerebral lupus vasculitis is a rare entity usually
only seen in the setting of generalized active disease.
Contrary to earlier beliefs, organ-specific and systemic
autoimmune syndromes frequently coexist. Clinicians
caring for the person with lupus should therefore
maintain vigilance for associated conditions, such as
coeliac disease, autoimmune thyroiditis, autoimmune
urticaria and pernicious anaemia.
FIBROMYALGIA
A noteworthy example of the hazards of blaming all
aches and pains in the lupus patient on lupus is fibro-
myalgia. This condition, another syndromal diagnosis
featuring widespread body pains in the presence of 11/18
tender points, is seen in up to 22% of patients with
lupus,30 as well as a range of other chronic conditions. It
has been pointed out that fibromyalgia shares a number
of demographic, clinical and psychosocial features with
other ill-defined clinical syndromes, such as chronic
fatigue syndrome and irritable bowel syndrome, with
the choice of label partly dictated by the dominant
complaint and the area of specialty of the practitioner
making the diagnosis.30 The relative contribution of
physiological (pain perception and neurotransmitter)
and biopsychosocial factors to these conditions remains
the subject of speculation, but it appears increasingly
clear that the stress of living with prolonged illness,
particularly in the absence of appropriate information
and follow up, adds an extra dimension to lupus-related
suffering which is independent of the underlying activity
of the autoimmune syndrome.
CENTRAL ASPECTS OF TREATMENT
The provision of support and education in the context of
a trusting therapeutic partnership is associated with
improved health outcomes and reduced health-care
costs.31 A multidisciplinary approach combining educa-
tion and support with standard medical care is the
optimal treatment for chronic autoimmune conditions.32,33
Autoimmune-disease support groups with the participa-
tion of dedicated specialists can facilitate this process.34
Adequate education is particularly important given the
widely variable quality of alternative information sources
(e.g. the Internet, television and old textbooks). Improve-
ments in prognosis should be particularly emphasized
given the general shift of lupus and related conditions
toward a milder spectrum of disease as enhanced diag-
nostic tools detect ever more subtle disease variants.
Both quality and quantity of life are enhanced by current
treatments (Table 4), with anti-inflammatory drugs
improving pain, and hydroxychloroquine offering relief
for lupus-related fatigue, rash and arthralgias with little
potential toxicity.35 The 5-year survival for lupus patients
has risen from 76% (in the 1970s)36 to 9397% (in
2000),37 thus moving the burden of mortality away from
active lupus toward atherosclerotic disease as the prime
cause of death.38 Close attention should therefore be
paid to correcting vascular risk factors, such as exer-
cise, obesity, cholesterol levels, hypertension, cigarette
smoking and corticosteroid usage.39 Only patients with
severe disease affecting internal organs or symptomatic
disease refractory to milder options should be exposed to
the potential toxicity of long-term corticosteroids and
immunosuppressants. Nevertheless, where disease control
requires more than 6 weeks of prednisone at a dose of
more than 10 mg/day, agents such as methotrexate offer
anti-inflammatory and steroid-sparing effects that are

Internal Medicine Journal 2004; 34: 338347

 Update on lupus 345

Table 4 Pharmacological therapies for lupus and related conditions

Class Examples Uses

Generic name Trade names

Non-steroidal anti-inflammatory Ibuprofen Brufen, Nurofen Relief of inflammatory pains in muscles, joints,
drugs serosae etc.
Naproxen Naprosyn
Indomethacin Indocid
Celecoxib Celebrex COX-2 inhibitors (? less GI toxicity)
Rofecoxib Vioxx
Antimalarials Hydroxychloroquine Plaquenil Autoimmune-related fatigue, arthropathy and
rash; limited evidence of efficacy for sicca,
thrombophilia and pain
Corticosteroids Prednisone Serositis, cytopenias, major organ involvement;
low-dose transient use for refractory
musculocutaneous features
Potent immunomodulators Azathioprine Imuran All potent immunomodulators have the
Methotrexate Methoblastin following uses:
Cyclosporine Neoral severe organ involvement or cytopenia,
Cyclophosphamide Cycloblastin steroid-sparing role where disease relapses
Leflunomide Arava with attempted steroid weaning, and
Mycophenolate Cellcept introduced relatively early in moderatesevere
Myfortic rheumatoid arthritis to limit joint damage
COX-2, cyclooxygenase-2 selective inhibitors; GI, gastrointestinal. The following are the manufacturer details for the listed trade names:
Arava (Aventis Pharma, Sydney, Australia); Brufen (Abbott Australasia, Sydney, Australia); Celebrex (Pharmacia Australia, Sydney, Australia);
Cellcept (Roche Products, Sydney, Australia); Cycloblastin (Pharmacia Australia, Sydney, Australia); Imuran (GlaxoSmithKline Australia,
Melbourne, Australia); Indocid (Merck Sharp & Dohme, Sydney, Australia); Methoblastin (Pharmacia Australia, Sydney, Australia); Myfortic
(Novartis Pharmaceuticals Australia, Sydney, Australia); Naprosyn (Roche Products, Sydney, Australia); Neoral (Novartis Pharmaceuticals
Australia, Sydney, Australia); Nurofen (Boots Healthcare Australia, Sydney, Australia); Plaquenil (Sanofi-Synthelabo Australia, Sydney, Australia);
Vioxx (Merck Sharp & Dohme, Sydney, Australia).

potentially highly valuable.40 For the minority of individ- SUMMARY

uals with severe organ-threatening or refractory lupus,
other modalities, including azathioprine41 and lefluno-
mide42 could be necessary. Mycophenolate mofetil
appears particularly promising for its utility in managing
proliferative lupus nephritis,43 offering equal efficacy to
i.v. cyclophosphamide in remission induction. Other
more experimental approaches for severe disease include
myeloablation with bone-marrow transplantation,44 and
biological therapies such as anti-CD20 (rituximab),45
CD40-ligand blockade and anti-interleukin-10. Tumour
necrosis factor blockade might precipitate ANA-positivity
and even lupus-like syndromes, so this treatment is
not generally recommended. Web-assisted education,
support and feedback may provide a valuable adjunct
to traditional face-to-face approaches,46 but computer
availability and literacy levels should be considered. It is
important to treat the patient as well as the condition.
Several studies demonstrate that poor patient adher-
ence is related to a failure of physicians to attend to
patients ideas, expectations, feelings and values.47 The
increasing use of herbal remedies roughly parallels this
rising patient disenchantment with traditional medical
approaches and, although specific treatments (e.g.
hypericum in depression48) may be helpful, the potential
for toxicity, particularly in patients with lupus, should be
remembered; for example, the literature carries (anec-
dotal) reports of lupus flares with alfalfa.49
The chronic systemic autoimmune disorders, of which
lupus is the best-known, represent a complex interplay
between genetically and environmentally modulated
immune disturbances. Serological screening should be
employed cautiously and wisely, given the rapidly occur-
ring changes in methodology, which have lowered their
specificity. Close liaison with the immunology laborato-
ries performing these tests is therefore advisable. Clinicians
should emphasize the improving prognosis of lupus and
related conditions in terms of generally milder disease
and improved therapies.
ACKNOWLEDGEMENTS
Rachel Rossiter (Newcastle Scleroderma/Lupus Resource Centre),
Dr Michael Boyle (Director of Immunology and Infectious Diseases,
John Hunter Hospital) and Professor Robert Clancy (Director, Hunter
Immunology Unit) provided valuable advice during the preparation of
this article.
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APPENDIX I
Clinical cases Case 2: KW 55-year-old woman
Case 1: PL 48-year-old woman Previously healthy apart from hypertension.
Presented to local medical officer with aching hands
Three- to four-year history of urticaria/angioedema and fatigue.
every 2 months. ANA performed and found to be positive (1:640
Background: homogeneous).
Allergic rhinoconjunctivitis/asthma Further review:
Hypertension No history of other lupus features
Urticaria system review: no anti-inflammatory drug Hand aches worse with activity (knitting), better with
use, thyroid disease or food allergy rest.
Complained of inflammatory hand arthralgias Examination:
Behaviour of urticarial lesions consistent with vasculitis Heberdens nodes
Investigations: No synovitis/inflammatory arthropathy
Skin biopsy: vasculitic urticaria ENA, DNA, C-reactive protein, erythrocyte sedimen-
Antinuclear antibody (ANA) 1:1280 homogeneous tation rate all normal.
pattern X-ray: changes consistent with osteoarthritis.
DNA, extractable nuclear antigens (ENA) negative Diagnosis: Osteoarthritis with irrelevant ANA.
Provisional diagnosis: lupus-like condition. Improved with naproxen therapy.
Benefited from hydroxychloroquine.
Reduced urticaria frequency and improved joint pains
and energy levels.

APPENDIX II
Quantifying clinical judgement
SLE No SLE Totals

Positive ANA True positives False positives

95 399 960 400 055
Negative ANA False negatives True negatives
5 599 940 599 945
100 999 900 1 000 000
Assume a prevalence of lupus and related conditions of 0.01% and assume that antinuclear antibody (ANA) displays 95% sensitivity and 60%
specificity. Positive likelihood ratio = 2.375 (defined as the odds that a positive finding would occur in a patient with, as opposed to a patient
without, the target disorder; equal to sensitivity divided by (1 specificity) = 0.95/0.40 = 2.375). Negative likelihood ratio = 0.083 (defined as
the odds that a negative finding would occur in a patient with, as opposed to a patient without, the target disorder; equal to (1 sensitivity)/
specificity = 0.05/0.60 = 0.083). SLE, systemic lupus erythematosus.

Assuming a 35-year-old woman with stiff and aching
hands is judged to have a pretest likelihood of auto-
immune disease of 35%, this equates to an odds of
0.54:1.00. Odds are calculated by the following formula,
where P represents the probability of disease being
present, as judged by the clinician based on personal and
historical medical experience:
Odds = P/(1 P) = 0.35/0.65 = 0.54:1.00.
Post-test odds after a negative antinuclear antibody
(ANA) result now become (0.540 0.083) to 1.000, or
0.045:1.000, which equates with a disease probability of
0.04 (4%). Recall that 0.083 represents the negative like-
lihood ratio associated with a negative ANA reading. To
convert back from odds to a probability, the following
formula is used, with o representing the calculated odds:
Probability = o/(1 + o) = 0.045/1.045 = 0.040 = 4%.
In other words, the likelihood of lupus is lowered
significantly by a negative result, but a small possibility
remains if the initial clinical suspicion for disease is
moderately high.

Internal Medicine Journal 2004; 34: 338347

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