review for the generalist ana test
TRANSCRIPT
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Review for the generalist: The antinuclear antibody test in children - When to use it
and what to do with a positive titer
Peter N Malleson1,Murray J Mackinnon2,Michaela Sailer-Hoeck3and Charles H Spencer4*
Pediatric Rheumatology 2010,
Abstract
The antinuclear antibody test (ANA) is a much overused test in pediatrics. The ANA does have a role in serologic testing but it should be
a very limited one. It is often ordered as a screening test for rheumatic illnesses in a primary care setting. However, since it has low
specificity and sensitivity for most rheumatic and musculoskeletal illnesses in children, it should not be ordered as a screening test for
non-specific complaints such as musculoskeletal pain. It should only be used as a diagnostic test for children with probable Systemic
Lupus Erythematosus (SLE) or Mixed Connective Tissue Disease, (MCTD) and other possible overlap-like illnesses. Such children
should have developed definite signs and symptoms of a disease before the ANA is ordered. This review presents data supporting these
conclusions and a review of the ANA literature in adults and children.
By limiting ANA testing, primary care providers can avoid needless venipuncture pain, unnecessary referrals, extra medical expenses,
and most importantly, significant parental anxieties. It is best not to do the ANA test in most children but if it ordered and is positive in a
low titer (
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ANA in healthy populations
A number of studies have looked at the frequency of positive ANA tests in "healthy" individuals. A study by Arroyave et al. in 1988 [3]
screened sera from 241 "normal" children, testing for only IgG ANA, using both mouse kidney and human epithelial cells (HEp-2 cells).
The study found a maximum positivity rate of only 2.0% at the lowest dilutions. However, data from adult studies have found much
higher rates. In an adult study from 15 international laboratories using HEp-2 cells as substrate [4], ANA positive tests occurred in 31.7%
of a putatively normal population at a serum dilution of 1:40. Even at a dilution of 1:320, 3.3% of the sera were positive. Interestingly the
ANA frequency did not differ significantly across the age range of 20-60 years. The rate of ANA positivity among blood donors in
Holland was also quite high at 12.7%, with titers greater than 1:80 occurring in over 4% [5]. It is not clear why there is such a low
frequency of ANA positivity in children, compared to the much higher frequency found in most adult studies (of which only two of
many are referenced here). As ANA tests are usually performed on children or adults with musculoskeletal or rheumatologic symptoms
or signs, the frequency of ANA among clinic populations is more pertinent to our discussion than the situation in the normal population
ANA in cli nic populations-ANA ti ters
Chudwin et al. in 1983 [6] evaluated the clinical and laboratory findings in 138 children with a positive ANA test. The authors
interpreted the fact that two-thirds of the patients had a specific connective tissue disease as being indicative that the ANA test is useful.
Yet the fact that one third did not have a definitive inflammatory disease indicates that the ANA test has a very high false positivity rate.
We evaluated the results of all the ANA tests performed at British Columbia's Children's Hospital over a 5 year span [7]. We found that
the ANA test was positive at a titer of 1:20 or greater in 41% of all sera tested, and in 65% of all patients in whom a diagnosis could be
obtained from the ordering physician. The frequency was the same for those children with or without a diagnosis of a rheumatic disease.
At a screening serum dilution of 1:40 a positive test had a sensitivity of only 63% and a positive predictive value (the frequency that a
positive test is indicative of disease) of only 33% for any rheumatic disease.
For SLE, MCTD or overlap syndrome, the ANA had a very high sensitivity of 98%, but a very low positive predictive rate of only 10%.
Positive and negative predictive values are affected by the prevalence of the disease being tested. Therefore one might expect somewhat
better predictive values from a pediatric rheumatology clinic than from a wide population of ill children. We concluded from this study
that although a negative ANA test made the diagnosis of SLE or MCTD extremely unlikely, a positive test at even moderately high titers
of 1:160 has little or no diagnostic value [7].
ANA immunof luorescent staini ng
As our laboratory also provided information on the patterns of immunofluorescent staining, we have also been able to evaluate what
further use this information might provide (previously unpublished data). Of 1369 individual patients sera tested, 445 were ANA positive
in children with a known diagnosis. Of these children, 135 had a rheumatic disease (juvenile rheumatoid arthritis (JRA) (now known as
JIA-the terms are used interchangeably here), SLE, MCTD, or juvenile dermatomyositis (JDM) but 310 had no convincing evidence ofhaving a rheumatic disease.
Homogeneous, mitotic staining patterns were seen much more commonly in children with a rheumatic disease than those without (p =
0.001). Interestingly, a nucleolar pattern of staining was seen more commonly in children without a rheumatic disease (p = 0.03). This
lack of an association of the nucleolar pattern in children with scleroderma specifically, and rheumatic disease in general has been
commented on previously [8,9].
In our lab, no combination of ANA titer, or staining pattern was specific for any particular rheumatic disease. The test combinations with
the best positive predictive values for a rheumatic disease were: a) a titer 1:640 with mitotic positive staining or b) a titer 1:640 with a
homogenous and mitotic staining pattern. These tests had positive predictive values of 77% and 72% respectively. Yet these results were
only slightly higher than the positive predictive value of 69% obtained with a titer of 1:640 alone, ignoring the pattern of staining.
Although the addition of patterns somewhat increases the specificity and positive predictive value of the ANA test for a rheumatic
disease, it does so at the expense of both the sensitivity and negative predictive value of the test using titers alone.
The pattern of staining also does not appear to be helpful in distinguishing between rheumatic diseases. For example, although high titer
homogenous, mitotic positive staining was the most common combination seen in children with SLE, it was actually found in only
27.3% of ANA positive lupus patients. This combination was also found in 12.5% of ANA positive JRA and 5.4% of ANA positive JDM
patients. This lack of specificity of the ANA immunofluorescent pattern has been recognized previously, both for adults and
children [8,10,11]. A study by Parker et al. [11] evaluated the usefulness of combining ANA titer and pattern. Although they felt that
knowledge of both titer and pattern was helpful, they did not calculate specific test characteristics, and in fact no combination was
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restricted to any single rheumatic disease. Our assessment of these data is that the addition of information about patterns of
immunofluorescence does not appear to significantly improve the utility of the ANA test.
Practical Concerns about ANA Testing
Referr als for positi ve ANA ti ters
As part of a study exploring what precipitated a referral to a pediatric rheumatologist, McGhee et al. [12] found that children referred, at
least in part, because of a positive ANA test were no more likely to have a chronic inflammatory disease than children with a negative
test.
In another study from a pediatric rheumatology clinic, only 55% of all of the children with a positive ANA test had an inflammatory
rheumatic disease. Positive antibodies to double-stranded DNA or to extractable nuclear antigens (Sm, RNP) indicating SLE or MCTD
were strongly correlated with an ANA titer 1:640. The authors recommended therefore , that these more specific tests be performed only
if the child had a positive ANA test at high titer[13].
McGhee and colleagues reviewed the ANA titer clinical utility in 2004 [14]. One hundred and ten children were evaluated who had been
referred for a positive ANA. Of the 110, 10 subsequently were found to have SLE, 18 had JRA, 1 had MCTD, and 1 had Raynaud's
phenomenon. Neither a positive ANA neither titer nor the degree of positivity of the ANA helped pick out the children with SLE from
the children without a chronic inflammatory disease. Tellingly, it wasn't the elevated ANA titer that distinguished the children with JRA
from those with other musculoskeletal problems, but the history (e.g., morning stiffness) and the physical exam (e.g., presence of rash,
swollen joints).
All these studies demonstrate that a positive ANA test is found frequently in a pediatric hospital population, and even in high titer has
only a poor ability to determine whether a child has an inflammatory rheumatic disease.
Development of rheumatic diseases in ANA posit ive individuals
It could be argued that the finding of a positive ANA test indicates that the child has an occult disease that will become manifest later. Is
there any evidence to support or refute this?
There is some evidence that ANA may sometimes precede the development of SLE by several years. Using Finland's Social Security
Institution's population registry, Aho et al. [15] were able to trace 16 serum samples from apparently healthy subjects who later
developed SLE or MCTD. Ten of the 16 (62.5%) samples were positive for ANA. Eight of the 11 (72.7%) were positive when the
interval from sampling to onset of first symptoms was 2 years and 2 of 5 cases (40%) were positive when the interval was > 3 years.
Based on an incidence rate of lupus of 5/100,000/year, the authors calculated that lupus would develop in less than one percent of the
ANA positive individuals. Cabral et al. [16] followed the course of 24 children who were considered clinically not to have an
inflammatory disease despite being ANA positive and found that no patient developed an overt inflammatory disease during a follow-up
period of 61 months (range 13 to 138 months).
Some studies have evaluated the outcome in patients with fibromyalgia. Fibromyalgia is a musculoskeletal pain condition not thought to
be an autoimmune disease. Interestingly, some fibromyalgia patients are also ANA positive, but there has been no evidence that the
occurrence of a positive ANA influences patient outcome. Al-Allaf et al. [17] found the ANA positivity rate (titers not given, a positive
result was simply defined as "plus") in their adult patients with fibromyalgia was 8.8%. This rate was almost identical to the 8.9% ANA
positivity rate in their control patients with osteoarthritis. The 12 individuals who had fibromyalgia and were ANA positive were
matched for age and sex with 12 ANA negative patients. Over a 2-4 year follow-up period one patient in the ANA positive group
fulfilled criteria for SLE, and one in the ANA negative group fulfilled criteria for Sjgren's syndrome. The authors concluded that the
ANA test (at least in low titer) was not a good predictor of future connective tissue disease.
In a separate study of 59 pediatric patients with fibromyalgia, 17 (28.8%) were ANA positive (mean titer 1:160). Fifty patients were
followed for a mean of 18.3 months and during that time no patient developed a connective tissue disease [18]. We would conclude from
these findings that only rarely is the presence of ANA the harbinger of occult SLE or another connective tissue disease.
ANA and other diseases
It should also be remembered that ANA are associated not only with the classical autoimmune diseases, but also with infection [19],
malignancy [20,21] and drugs (Table1)[22]. To illustrate this point, a study of Jones et al in 2006 analyzed 71 children who presented to
a rheumatologist and who eventually were diagnosed with acute lymphocytic leukemia. Of the 71 children, 47 were tested for the ANA
titer performed upon referral. Of the 47 ALL children, 8 (17%) had an elevated ANA titer[21]. Not only is the ANA test often positive
in non-rheumatic diseases, it is often negative in many rheumatic diseases (Table 2).
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Table 1.Diseases or syndromes that are frequently associated with an positive ANA test
Table 2.ANA positivity in rheumatic diseases in children
Environmental toxins may also predispose to ANA production. Although hopefully not relevant in pediatrics, there is evidence of an
increased frequency of ANA in individuals with silicone breast implants [23], and at least two studies have suggested that rural
populations have a higher frequency of ANA positivity than urban populations, perhaps due to toxin exposure [24,25]. Therefore the
finding of a positive ANA test should not blind the physician to the possibility of a non-autoimmune diagnosis.
A situation where a positive ANA test may be of some value is in children diagnosed with idiopathic thrombocytopenic purpura (ITP). In
a study of 87 children with ITP, it was found that 36% of those with a positive ANA (titer 1:40) developed further "autoimmu ne
symptoms". Five children developed SLE, compared to none of those who were ANA negative (p < 0.001). [26]
ANA positi vity as a risk factor for uveiti s in children with JI A
There is little doubt that in children with JIA the ANA test is more frequently positive in those with uveitis than in children without
uveitis. The American Academy of Pediatrics recommends performing the ANA test as part of the screen for uveitis [27]. However,
although there is a statistically significant difference between children with and without uveitis, we would argue that this difference itself
is of little clinical significance.
In a recent study from Finland [28], for example, uveitis was found in 104 of 426 new cases of juvenile idiopathic arthritis. Antinuclear
antibodies were found in 66% of those with uveitis compared to 37% of those without uveitis, a statistically significant difference.
However if the presence or absence of a positive ANA test was used in determining the frequency of ophthalmologic examinations, it is
possible that some of the 46/104 children with uveitis and negative ANA's might well have had a delayed diagnosis due to the partial
reliance on the ANA positivity to determine the frequency of eye checkups. So there is risk for ANA negative children as well. This
should not detract from the utility of a positive ANA in selecting out a population of children with arthritis who are at a higher risk for
uveitis.
What should be done?
So what should be done with a positive ANA test? Our answer would be exemplified by the answer a local inhabitant gave when asked
directions from place A to B by a foreign tourist: "I wouldn't be leaving from here!" In other words, it would be best if the ANA test had
not been done in the first place! We would suggest that a positive ANA test can safely be ignored unless there are other suggestive
clinical signs, and simple laboratory tests (such as a raised ESR or cytopenias) that point towards a diagnosis of lupus or similar
connective tissue disease, particularly if the ANA titer is less than 1:640. Given the high false positive rate of ANA tests, a positive test
cannot be used as confirmatory evidence that the child with a swollen joint has JIA, rather than some other serious condition such as
septic arthritis, leukemia, or hemophilia. Similarly, symptoms such as fatigue and aches and pains in a child should not be ascribed to
SLE simply because of a positive ANA test. It is much more likely that such a child has an idiopathic pain syndrome such as
fibromyalgia or hypermobility. A negative ANA test is more useful than a positive one, as it does, for all practical purposes, exclude the
diagnosis of SLE in a child.
What is needed is a cost-effectiveness study to evaluate whether the ANA test should be replaced by testing initially for anti-dsDNA and
anti-ENA (anti-Sm, RNP, SSA and SSB) antibodies. Until that study is done, we would recommend that non-rheumatologists only do an
ANA test if there is a fairly high probability (perhaps a 10+% chance) that a child's symptoms could be due to SLE or MCTD. If the test
is positive at a titer of > 1:160 then it would be appropriate to order antibodies to dsDNA and ENA, with lower titers being ignored as
well as complement levels.
We would strongly recommend that the ANA test is not ordered indiscriminately as part of "a rheumatologic work-up". This is not a new
message. Other pediatric rheumatologists have pointed out in the literature that the ANA is a poor screening test and is being used
inappropriately[7,9,12,14,16,29,30]. It is our hope that a continued demonstration of these facts will gradually decrease its inappropriate
use. The cost of inappropriate referrals, extra venipuncture, unnecessary expense, and increased parental and child anxiety is a
considerable problem that pediatric rheumatologists see every day.
Conclusion
The question why the ANA test is so frequently positive in populations without an autoimmune disease remains a fascinating one. It
suggests that the breaking of immunological tolerance is really quite common, but that this tolerance breakdown only rarely leads to
disease. It is possible that antinuclear antibodies have some useful function that is not yet fully understood.
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However, the ANA test has such a high false-positivity rate that a positive test is of little, if any, clinical utility as a screening test and
should not be ordered routinely to screen children with musculoskeletal complaints. Its use should be limited to the diagnosis of SLE,
MCTD, and similar systemic illnesses. If the test is performed, low titer ANA results (< 1:640) in most cases should be ignored unless
the child is systemically ill and shows signs of SLE or a similar systemic disease.
Abbreviations
ANA: antinuclear antibody titer; SLE or lupus: systemic lupus erythematosus; HEp-2 cells: human epithelial cells used as ANA
substrate; ENA: extranuclear antigens; MCTD: mixed connective tissue disease; JRA: juvenile rheumatoid arthritis; [(JIA): also known
as juvenile idiopathic arthritis]; JDM: juvenile dermatomyositis; dsDNA: double stranded DNA antibodies; Sm: Smith antigen (one of
the extractable nuclear antigens); RNP: ribonuclear protein antigen; (another of the extractable nuclear antigens): SSA: Sjgren's
syndrome A antigen; (Ro): (one more of the extractable nuclear antigens); SSB: Sjgren's syndrome B antigen; (La): (another of the
extractable nuclear antigens); ITP: idiopathic thrombocytopenic purpura; (JRA): juvenile rheumatoid arthritis; (JIA): and juvenile
idiopathic arthritis are the old and new classification terms for chronic arthritis diseases in children. JRA is used preferentially here as the
data collection began before the term JIA was more universally accepted.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
PM conceived the project, acquired the data, and reviewed the results; MM did the statistical analyses. PM, MSH, and CHS were
responsible for the interpretation of the data and literature as well as preparation of the manuscript. The final manuscript was approved
by the authors.
Acknowledgements
We would like to acknowledge the help of Louis Wadsworth MBBS, FRCPC, Director, Hematopathology Program British Columbia's
Children's Hospital who provided generous help with acquiring the ANA data presented here.
References
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30.Jarvis J: Commentary-ordering lab tests for suspected rheumatic disease.Pediatric Rheumatology Online Journal2008, 6:19-
23.PubMed Abstract|BioMed Central Full Text |PubMed Central Full Text
Extractable nuclear antigens
Extractable Nuclear Antigens are over 100 different soluble cytoplasmic and nuclear antigens.
Autoantibodies to these antigens are associated with particular connective tissue disorders.
The six main antigens used in immunological laboratories for detection are Ro, La, Sm, RNP, Scl-70 and
Jo1,[1] which are screened for by Ouchterlony double immuno diffusion techniques and confirmed by
immunoblotting.
On anti-nuclear antibody tests, these antigens have a speckled pattern.
Terminology
ENAs originally referred to proteins found in a saline extract of cell nuclei[citation needed]. Its
components have since been more clearly identified and in fact include many cytoplasmic molecules.
The misnomer however has stuck. These proteins are intimately associated with various RNA molecules
and are thus called ribonucleoproteins, but the nomenclature used for them is often a source of
confusion, Sm, Ro and La were named after the first 2 letters of the surnames of the patients in whom
they were first found. Two proteins associated with Sjogren's Syndrome were independently described
as antigens A and B, but are now known to be identical to Ro and La respectively. i.e. SS-A = Ro and SS-B
= La.
ENA 4
ENA 4 is a grouping of antibodies often used to screen for mixed connective tissue disease (MCTD),
Sjgren's syndrome and systemic lupus erythematosus and commonly is composed of four tests:[3]
anti-Sm (for SLE) anti-RNP (for MCTD) anti-La (for Sjgren's) anti-Ro (for Sjgren's)
Systemic Lupus Erythematosus
Description
http://www.ped-rheum.com/pubmed/19014701http://www.ped-rheum.com/pubmed/19014701http://www.ped-rheum.com/pubmed/19014701http://dx.doi.org/10.1186/1546-0096-6-19http://dx.doi.org/10.1186/1546-0096-6-19http://dx.doi.org/10.1186/1546-0096-6-19http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19014701http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19014701http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19014701http://www.ped-rheum.com/sfx_links?ui=1546-0096-8-27&bibl=B30http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19014701http://dx.doi.org/10.1186/1546-0096-6-19http://www.ped-rheum.com/pubmed/19014701 -
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Systemic lupus erythematosus (SLE) is a chronic multisystemic disease of autoimmune origin
SLE characteristically affects skin and joints, although any system can be involved
SLE commonly affects women aged 20-45 years but may affect all age groups and both sexes
American College of Rheumatology criteria for diagnosis of SLE suggest that four or more of the
following must be present for the diagnosis to be made: malar rash, discoid rash, photosensitivity, oral
ulcers, arthritis, serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic
disorder, antinuclear antibody (ANA)
Treatment options are vast and dictated by the severity of disease; options include the use of
nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, hydroxychloroquine, and more
aggressive medications, such as cyclophosphamide and mycophenolate mofetil
Synonyms
SLE
Lupus
Immediate action
Cardiac, pulmonary, hematologic, renal, and neurologic symptoms and/or sepsis may be life- and/or
organ-threatening. They must therefore be evaluated immediately.
Urgent action
Urgent outpatient referral is appropriate if the diagnosis of SLE is suspected based on positive tests.
Key points
SLE is a chronic autoimmune multisystem disease with a fluctuating course
It most commonly affects the skin and joints, and is most common in women aged 20-45 years, but does
occur in all adult age groups of both sexes and can involve any body system
The diagnosis is made on clinical grounds and on the presence of antibodies to nuclear antigens and to
double-stranded DNA
The most common presentation is with a butterfly rash on the face, low-grade fever, and nondeforming
arthritis
In mild cases, symptoms can be controlled by rest, NSAIDs, and avoidance of sunlight
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NSAIDs are useful for arthralgia and hydroxychloroquine for the rashes
More severe cases with multisystem involvement need treatment with systemic corticosteroids and/or
other immunosuppressive agents
Background
Cardinal features
Cardinal features are difficult to define, as patterns of presentation are individual to the patient.
Systemic lupus erythematosus (SLE) is characterized by flares and remissions, and virtually any body
system can be involved. There is a wide variation in severity of the disease.
Cardinal features are best summed up from the criteria produced by the American College of
Rheumatology:
Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus
erythematosus. Arthritis Rheum 1982;25:1271-7. The criteria were updated in 1997: Hochberg MC.
Updating the American College of Rheumatology revised criteria for the classification of systemic lupus
erythematosus [letter]. Arthritis Rheum 1997;40:1725
These criteria were designed for standardizing the inclusion of patients in clinical trials; however, they
are useful as general clinical guidelines in the initial assessment of patients with suspected SLE:
Malar rash: fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial
folds
Discoid rash: erythematous, raised patches with adherent keratotic scaling and follicular plugging;
atrophic scarring may occur in older lesions
Photosensitivity: skin rash as a result of unusual reaction to sunlight, by patient history or physician
observation
Oral ulcers: oral or nasopharyngeal ulceration, usually painless, observed by physician
Arthritis: nonerosive arthritis involving two or more peripheral joints, characterized by tenderness,
swelling, or effusion
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Serositis: (a) pleuritis - convincing history of pleuritic pain or pleural rub heard by a physician or
evidence of pleural effusion, or (b) pericarditis - documented by electrocardiogram or pericardial rub or
evidence of pericardial effusion
Renal disorders: (a) persistent proteinuria greater than 0.5g/day or greater than 3+ (dipstick) if
quantitation not performed, or (b) cellular casts - may be red cell, hemoglobin, granular, tubular, ormixed
Neurologic disorder: (a) seizures in the absence of offending drugs or known metabolic derangements,
e.g. uremia, ketoacidosis, or electrolyte imbalance, or (b) psychosis in the absence of offending drugs or
known metabolic derangements, e.g. uremia, ketoacidosis, or electrolyte imbalance, (c) symptoms of
stroke, (d) migrainous type headaches, (e) peripheral neuropathy, (f) transverse myelitis, (g) depression,
(h) cognitive dysfunction
Hematologic disorder: (a) hemolytic anemia with reticulocytosis, or (b) leukopenia
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Other features: including lymphadenopathy, splenomegaly, venous and arterial thrombosis
Causes
Common causes
The cause is unknown. Research involves:
The role of viruses
Hormonal factors (the female predominance and peak incidence in women of childbearing age is
circumstantial evidence for hormonal factors in the pathogenesis of SLE)
Genetic abnormalities (they may create a tendency for autoimmune responses, which are then triggered
by additional factors, such as viruses or sunlight)
Environmental factors (virus, sunlight)
Immune complex formation - many of the clinical manifestations are due to the effects of circulating
immune complexes on various tissues or to the direct effects of antibodies to cell-surface components
Abnormal apoptosis
Serious causes
SLE may be potentially life-threatening. Death most frequently occurs from nephritis or infection.
Contributory or predisposing factors
Research suggests that many factors contribute to the immune dysfunction shown in lupus. These
factors include:
Genetic factors: evidence for genetic predisposition is shown by a concordance rate in monozygotic
twins of around 30-50%
Hormonal factors: evidence for hormonal influence can be deduced from the recognized fluctuations
with flares in the postovulatory phase of the menstrual cycle. Pregnancy often exacerbates the disease
(especially in those with nephritis or hypertension)
Environmental factors (e.g. ultraviolet light and sunlight): evidence for photosensitivity comes from the
fact that sunlight can precipitate SLE flares, particularly skin disease
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Infectious agents are thought to possibly induce autoimmune responses by molecular mimicry or other
as yet unknown mechanisms
Drug-induced lupus syndrome: a syndrome with an SLE-like picture may be produced by several drugs,
including procainamide, hydralazine, isoniazid, chlorpromazine, methyldopa, and TNF blocking agents.
Most patients improve on withdrawal of the offending drug
Epidemiology
Incidence and prevalence
The incidence and prevalence of SLE varies across the world by race and ethnicity as well as geography.
Incidence
Varies from 1.8-7.6/100,000 per year in the US
In northern Europe it has been reported to be 4/100,000
Prevalence
Worldwide ranges from 2.9-400/100,000
Variable reporting results in a range from 14.6-50.8/100,000, with an average of 20/100,000 in the US
Demographics
Age
Childbearing years (20-45 years) see the highest frequency (80% of cases)
Can occur in all age groups, although uncommon before 8 years of age
Under age 15 years, the reported incidence is 0.5/100,000 in the US
Gender
Reported female:male ratios vary from 3:1 to 9:1 in adults, and are as low as 2:1 in prepubertal children.
Race
More common in African-Americans than Caucasians: US prevalence rates of up to 250/100,000 have
been measured in Native Americans, Hispanics, Asians, and African-American patients
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Certain communities have a higher prevalence rate - the Western Cape of South Africa has a high rate
amongst those of mixed ancestry, but it is rare amongst the rural African population of South Africa
Genetics
No proven genetic transmission: genetic makeup may predispose to SLE
Definite family relationships have been noted and some genetic profiles described
The 1982 American College of Rheumatology (ACR) criteria summarized features necessary to diagnose
SLE.[88, 5] These criteria were last updated in 1997.[5, 6] The presence of 4 of the 11 criteria yields a
sensitivity of 85% and a specificity of 95% for SLE (see Table 1). Keep in mind that individual features are
variably sensitive and specific. Patients with SLE may present with any combination of clinical features
and serologic evidence of lupus.
The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the ACR SLE
classification criteria in 2012.[7] According to the revision, a patient is classified as having SLE if the
patient has biopsy-proven lupus nephritis with ANA or anti-dsDNA antibodies or if the patient satisfies 4
of the diagnostic criteria (see below), including at least 1 clinical and 1 immunologic criterion.[7]
Also in 2012, the ACR published Guidelines for the Screening, Diagnosis, Treatment and Monit oring of
Lupus Nephritis in Adults, as well as an evidence report for lupus nephritis.[91]
ACR mnemonic of SLE diagnostic criteria
The following are the ACR diagnostic criteria in SLE, presented in the "SOAP BRAIN MD" mnemonic:
Serositis - Pleurisy, pericarditis on examination or diagnostic electrocardiogram (ECG) or imaging
Oral ulcers - Oral or nasopharyngeal, usually painless; palate is most specific
Arthritis - Nonerosive, 2 or more peripheral joints with tenderness or swelling
Photosensitivity - Unusual skin reaction to light exposure
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Blood disorders - Leukopenia (< 4 103 cells/L on >1 occasion), lymphopenia (< 1500 cells/L on >1
occasion), thrombocytopenia (< 100 103 cells/L in the absence of offending medications), hemolytic
anemia
Renal involvement Based on presence of proteinuria (>0.5 g/day or 3+ positive on dipstick testing) or
cellular casts (including red blood cells [RBCs], hemoglobin, granular, tubular, or mixed)[91] or based on
the opinion of a rheumatologist or nephrologist[91]
Antinuclear antibodies (ANAs) - Higher titers generally more specific (>1:160); must be in the absence of
medications associated with drug-induced lupus
Immunologic phenomena - dsDNA; anti-Smith (Sm) antibodies; antiphospholipid antibodies
(anticardiolipin immunoglobulin G [IgG] or immunoglobulin M [IgM] or lupus anticoagulant); biologic
false-positive serologic test results for syphilis, lupus erythematosus (LE) cells (omitted in 1997 revised
criteria)
Neurologic disorder - Seizures or psychosis in the absence of other causes
Malar rash - Fixed erythema over the cheeks and nasal bridge, flat or raised
Discoid rash - Erythematous raised-rimmed lesions with keratotic scaling and follicular plugging, often
scarring
In patients with high clinical suspicion and/or high ANA titers, additional testing is indicated. This
commonly includes evaluation of antibodies to dsDNA, complement, and ANA subtypes such as Sm, SSA,
SSB, and ribonucleoprotein (RNP) (often called the ENA panel), as well as screening anticardiolipin
antibodies, lupus anticoagulant, and +/- beta-2 glycoprotein antibodies.
Diagnostic Studies
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Standard laboratory studies that are diagnostically useful when systemic lupus erythematosus (SLE) is
suspected should include the following:
Complete blood count (CBC) with differential
Serum creatinine
Urinalysis with microscopy
The CBC count may help screen for leukopenia, lymphopenia, anemia, and thrombocytopenia. Urinalysis
and creatinine studies may be useful to screen for kidney disease.
Other laboratory tests that may be used in the diagnosis of SLE are as follows:
Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
Complement levels
Liver function tests
Creatine kinase assay
Spot protein/spot creatinine ratio
Levels of inflammatory markers, including the ESR and CRP, may be elevated in any inflammatory
condition, including SLE. However, the level of ESR elevation may show a discrepancy relative to a
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normal CRP level in SLE flares; if both markers are markedly elevated, suspect the presence of an
infectious process. CRP levels change more acutely, and the ESR lags behind disease changes.
Measurement of complement may be useful, because C3 and C4 levels are often depressed in patients
with active SLE as a result of consumption by immune complexinduced inflammation. In addition, some
patients have congenital complement deficiency that predisposes them to SLE.
Liver test results may be mildly elevated in acute SLE or in response to therapies such as azathioprine or
nonsteroidal anti-inflammatory drugs (NSAIDS). Creatine kinase levels may be elevated in myositis or
overlap syndromes.
The spot protein/spot creatinine ratio may be used to quantify proteinuria. The 2012 ACR guidelines for
lupus nephritis indicate that a spot protein/spot creatinine ratio greater than 0.5 g/day can substitute
for the 24-hour protein measurement and that an active urinary sediment (defined as >5 red blood cells
[RBCs] per high-power field [hpf]; >5 white blood cells [WBCs]/hpf in the absence of infection; or cellular
casts limited to RBC or WBC casts) can substitute for cellular casts.[91]
Autoantibody tests
Table 3, below, summarizes the autoantibody tests that are used in the diagnosis of SLE.[92]
Table 3. Autoantibody Tests for SLE (Open Table in a new window)
Test Description
ANA Screening test; sensitivity 95%; not diagnostic without clinical features
Anti-dsDNA High specificity; sensitivity only 70%; level is variable based on disease activity
Anti-Sm Most specific antibody for SLE; only 30-40% sensitivity
Anti-SSA (Ro) or
Anti-SSB (La)
Present in 15% of patients with SLE and other connective-tissue diseases such as
Sjgren syndrome; associated with neonatal lupus
Anti-ribosomal P Uncommon antibodies that may correlate with risk for CNS disease, includingincreased hazards of psychosis in a large inception cohort, although the exact
role in clinical diagnosis is debated[93]
Anti-RNP Included with anti-Sm, SSA, and SSB in the ENA profile; may indicate mixed
connective-tissue disease with overlap SLE, scleroderma, and myositis
Anticardiolipin IgG/IgM variants measured with ELISA are among the antiphospholipid
antibodies used to screen for antiphospholipid antibody syndrome and pertinent
in SLE diagnosis
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Lupus anticoagulant Multiple tests (eg, direct Russell viper venom test) to screen for inhibitors in the
clotting cascade in antiphospholipid antibody syndrome
Direct Coombs test Coombs testpositive anemia to denote antibodies on RBCs
Anti-histone Drug-induced lupus ANA antibodies are often of this type (eg, with procainamide
or hydralazine; p-ANCApositive in minocycline-induced drug-induced lupus)
ANA = antinuclear antibody; CNS = central nervous system; ds-DNA = double-stranded DNA; ELISA =enzyme-linked immunoassay; ENA = extractable nuclear antigen; Ig = immunoglobulin; p-ANCA =
perinuclear antineutrophil cytoplasmic antibody; RBCs = red blood cells; RNP = ribonucleic protein; SLE =
systemic lupus erythematosus; Sm = Smith; SSA = Sjgren syndrome A; SSB = Sjgren syndrome B.
Symptoms & Signs
Symptoms vary from person to person, and may come and go. The condition may affect one organ or
body system first. Others may become involved later.
Almost all people with SLE have joint pain and swelling. Some develop arthritis. Frequently affected
joints are the fingers, hands, wrists, and knees.
Other common symptoms include:
Chest pain when taking a deep breath Fatigue Fever with no other cause General discomfort, uneasiness, or ill feeling (malaise) Hair loss
Mouth sores Sensitivity to sunlight Skin rash -- a "butterfly" rash over the cheeks and bridge of the nose affects about half of people
with SLE. The rash gets worse in sunlight. The rash may also be widespread.
Swollen lymph nodesOther symptoms depend on what part of the body is affected:
Brain and nervous system: Headaches Mild cognitive impairment Numbness, tingling, or pain in the arms or legs Personality change Psychosis Risk of stroke Seizures Vision problems
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Digestive tract: abdominal pain, nausea, and vomiting Heart: abnormal heart rhythms (arrhythmias) Kidney: blood in the urine Lung: coughing up blood and difficulty breathing Skin: patchy skin color, fingers that change color when cold (Raynaud's phenomenon)
Diagnosis & Tests
The diagnosis of SLE is based upon the presence of at least four out of eleven typical characteristics of
the disease. The doctor will listen to your chest with a stethoscope. A sound called a heart friction rub or
pleural friction rub may be heard. A neurological exam will also be performed.
Tests used to diagnose SLE may include:
Antibody tests, including: Antinuclear antibody (ANA) panel Anti-double strand (ds) DNA Anti-phospholipid antibodies Anti-smith antibodies CBC to show low white blood cells, hemoglobin, or platelets Chest x-ray showing pleuritis or pericarditis Kidney biopsy Urinalysis to show blood, casts, or protein in the urine
This disease may also alter the results of the following tests:
Anti-SSA or -SSB antibodies Anti-thyroglobulin antibody Anti-thyroid microsomal antibody Complement components (C3 and C4) Coombs' test - direct Cryoglobulins ESR Rheumatoid factor RPR - a test for syphilis Serum globulin electrophoresis Serum protein electrophoresis