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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 screening should be employed cautiously and wisely,


Lupus occurs with a prevalence of 29 in 10 000 people, given the rapidly occurring changes in methodology,
targeting female and indigenous populations in particu- which have lowered their specificity. Close liaison with
lar. Lupus and related systemic autoimmune syndromes the immunology laboratories performing these tests is
(scleroderma, Sjgrens syndrome, rheumatoid arthritis therefore advisable. Clinicians should emphasize the
and polymyositis) result from a similar set of genetically improving prognosis of lupus and related conditions as a
and environmentally modulated immune disturbances, result of earlier disease detection, improved educational
and the diagnostic and management approach to these support systems and refined medical therapies. (Intern
conditions is broadly comparable. Evanescent , vague Med J 2004: 34: 338347)
symptoms, restrictive diagnostic criteria and low diagnostic
suspicion might have resulted in the under-diagnosis Key words: systemic lupus erythematosus,
of these problems in the past, imposing considerable autoimmune, autoimmunity, antinuclear antibodies,
burdens on sufferers and the community. Serological fibromyalgia.

INTRODUCTION where self-structures become the target of immune


attack, much as if they were microbes. To understand
Systemic lupus erythematosus (SLE)* occurs with a prev- these disorders, it is first important to comprehend the
alence of 29 in 10 000 people,1,2 targeting female, basics of the immune response (Fig. 1). There are two
indigenous3 and possibly Asian populations in particular. prime orchestrators of the immune system: antigen-
Lupus and related systemic autoimmune syndromes, such presenting cells (APC) and T cells. As their name
as scleroderma, Sjgrens syndrome, rheumatoid arthritis implies, APC must process antigen and present it in a
and polymyositis, represent a similar breakdown in manner that the immune system can recognize; this
normal immune function, and the diagnostic and involves cleaving the antigen into smaller components
management approach to these conditions is broadly and presenting these small peptides in the cleft of a
comparable. Short-lived, vague symptoms, restrictive histocompatibility molecule (major histocompatibility
diagnostic criteria and low diagnostic suspicion can result complex (MHC) or human leucocyte antigen (HLA)
in the under-diagnosis of these problems.4 Current system). The capacity of APC to activate T cells, which
medical literature features many comprehensive overviews circulate and sample MHCpeptide complexes on APC
on lupus and related syndromes and the present article throughout the body, is dependent on a costimulation
focuses on major advances in the diagnosis and treatment signal provided by the APC. This costimulation is
of these conditions. believed to depend on certain APC-focused triggers, of
which the best characterized are the pattern motifs
AUTOIMMUNITY: UNDERSTANDING possessed by microbes but not by self structures.
Examples of these motifs include bacterial DNA,
THE BREAKDOWN OF TOLERANCE mannans and lipopolysaccharides.5 After T-cell activa-
Systemic lupus erythematosus and related syndromes tion has occurred, a range of further responses can be
represent a breakdown in the bodys immune tolerance, facilitated by T-cell cooperation, including phagocyte
activation, cytolysis and B-cell help for antibody
Correspondence to: Glenn E. M. Reeves, Immunology and Infectious Diseases
production.
Department, John Hunter Hospital, Lookout Road, New Lambton Heights, The fact that autoimmune disease remains a
Newcastle, NSW 2305, Australia. Email: syndromal diagnosis illustrates the current lack of under-
Glenn.Reeves@hunter.health.nsw.gov.au standing of the intricacies of autoimmune pathogenesis,
Received 29 May 2003; accepted 25 August 2003. but one thing is clear: autoimmune diseases represent
multifactorial, multistep processes involving an interplay
Funding: None
of genetic inheritance and environmental factors that
Conflicts of interest: None impact on and disturb normal immune tolerance
*Please note that the (abbreviated) terms SLE and lupus have been used (Fig. 2). Among these steps, some or all of the following
interchangeably in this paper. 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


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
Figure 3 Photosensitive malar rash of systemic lupus absence of a full-house set of criteria. Excessive
erythematosus. 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
2 Release of normally hidden (cryptic) antigens7 or a
new focus on such targets triggered by structurally
similar exogenous agents.
LABELS: GOOD OR BAD?
3 APC stimulation through infection of antigen- The growing tendency towards the medicalization of
presenting cells or stimulation of their receptors by malaise is rightly questioned and the mere mention of
exogenous triggers (infective,8 inhaled or ingested9). the word lupus can arouse dread and fear in patients.
4 Downstream activation of T cells or B cells, prod- This is despite the fact that most people with lupus now
ucing cell-mediated and antibody-mediated pathology, experience much-improved life expectancies and quality
respectively. of life.14 Nevertheless, sufferers of systemic autoimmune
5 Modulation of these immune responses by other conditions are often females who have sought an expla-
components of the innate and acquired immune nation for fleeting, relapsing and vague symptoms for
response, such as complement, immune complexes, many years, without satisfaction. As we have seen with
cytokines and chemokines, as well as non-immune PL (Appendix I, Case 1), standardized diagnostic
factors, such as oestrogen,10 medications and ultraviolet criteria are unhelpful in many settings,15 therapeutic dis-
light. 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 controlling or limiting the sequelae of tissue damage.18
therapy and these approaches are appropriate if offered KW (Appendix I, Case 2) represents one example of the
judiciously in the context of adequate ongoing support importance of interpreting all test results in their clinical
and education. It must also be remembered that context. This rule is particularly pertinent to the changes
systemic autoimmune syndromes often merge,16 com- being witnessed in serodiagnostic methodology.
prising features of several different conditions, such as
the skin-thickening of scleroderma, the serositis of lupus, SEROLOGICAL SCREENING:
the erosions of rheumatoid arthritis and the muscle CHANGING APPROACHES
inflammation of polymyositis. The diagnostic labels
mixed connective tissue disease, overlap syndrome Although clinical features are always paramount,
and undifferentiated connective tissue disease testify to antibody results add greatly to diagnostic accuracy if
the frequent presence of an incompletely defined disease used properly. This is illustrated by the reliance of two
continuum. Because many of these patients display of the ARA lupus criteria on antibody-based test results.
evolving syndromes, the diagnosis and management of The beauty of ANA testing is that a negative result
patients with lupus variants should be confined to reduces the likelihood of a lupus-related condition
clinics with specialized expertise in the treatment of substantially. For example, in a 30-year-old woman with
autoimmune conditions. early-morning stiffness in the hands, a pretest probability
of 35% for lupus can be reduced to approximately 6%
AUTOIMMUNITY IS NOT AUTOIMMUNE after a negative ANA result has been secured (see
Appendix II).19 Such statistically based approaches to
DISEASE clinical decision-making have significant limitations, but
ANA (see Fig. 4) are regarded as the hallmark of might serve partially to objectify what has previously
systemic autoimmunity, but they also arise in the context been labelled clinical acumen or judgement.
of a range of infective, ischaemic, inflammatory and Sjgrens syndrome antibody A (SSA), anti-uridine
iatrogenic stimuli. The specificity of a positive ANA for rich 1 ribonucleoprotein (RNP), Sjgrens syndrome
lupus is therefore poor (approximately 60%); recognized antibody B (SSB), anti-histidyl t-RNA synthetase (Jo-1),
associations include viral infections, anticonvulsant anti-DNA topoisomerase I (Scl-70), anti-ribosomal ribo-
therapy, myocardial infarction, having a first-degree nucleoprotein (Ribo-P), Smith antibody (Sm) and a range
relative with autoimmunity, and ageing, to name but a of less common but diagnostically useful antibodies are
few. As outlined in Figure 2, the multistep process of grouped together as ENA because of their targets initial
autoimmune disease may stop at the level of auto- extraction from calf thymus (Table 2). It was traditionally
immunity; up to 10% of healthy patients carry positive believed that a negative ANA virtually excluded lupus-like
antibody results in their blood which seldom become autoimmune disease. However, up to 5% of ANA-
clinically relevant. Perhaps no more than 10% of asymp- negative patients display positive SSA results, a finding
tomatic ANA-positive individuals ever develop overt associated with cutaneous and sometimes systemic lupus.
autoimmune disease.17 The widespread detection of Furthermore, many autoantibodies target non-nuclear
ANA has prompted some authorities to suggest that (cytoplasmic) components of the cell, and patients with
ANA may serve an adaptive role, and there is some such specificities are reported as ANA-negative. This is
evidence of a functional role for these antibodies in despite the association of various cytoplasmic staining

Internal Medicine Journal 2004; 34: 338347


Update on lupus 343

#
#

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

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

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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, The chronic systemic autoimmune disorders, of which
other modalities, including azathioprine41 and lefluno- lupus is the best-known, represent a complex interplay
mide42 could be necessary. Mycophenolate mofetil between genetically and environmentally modulated
appears particularly promising for its utility in managing immune disturbances. Serological screening should be
proliferative lupus nephritis,43 offering equal efficacy to employed cautiously and wisely, given the rapidly occur-
i.v. cyclophosphamide in remission induction. Other ring changes in methodology, which have lowered their
more experimental approaches for severe disease include specificity. Close liaison with the immunology laborato-
myeloablation with bone-marrow transplantation,44 and ries performing these tests is therefore advisable. Clinicians
biological therapies such as anti-CD20 (rituximab),45 should emphasize the improving prognosis of lupus and
CD40-ligand blockade and anti-interleukin-10. Tumour related conditions in terms of generally milder disease
necrosis factor blockade might precipitate ANA-positivity and improved therapies.
and even lupus-like syndromes, so this treatment is
not generally recommended. Web-assisted education,
support and feedback may provide a valuable adjunct ACKNOWLEDGEMENTS
to traditional face-to-face approaches,46 but computer
availability and literacy levels should be considered. It is Rachel Rossiter (Newcastle Scleroderma/Lupus Resource Centre),
important to treat the patient as well as the condition. Dr Michael Boyle (Director of Immunology and Infectious Diseases,
John Hunter Hospital) and Professor Robert Clancy (Director, Hunter
Several studies demonstrate that poor patient adher- Immunology Unit) provided valuable advice during the preparation of
ence is related to a failure of physicians to attend to this article.
patients ideas, expectations, feelings and values.47 The
increasing use of herbal remedies roughly parallels this
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Update on lupus 347

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

Internal Medicine Journal 2004; 34: 338347


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