Review for the Generalist ANA Test

7/28/2019 Review for the Generalist ANA Test

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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.

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.com/pubmed/10406347http://www.ped-rheum.com/pubmed/7738944http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=8019798http://www.ped-rheum.com/pubmed/8019798http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=16651289http://www.ped-rheum.com/pubmed/16651289http://dx.doi.org/10.1002/1097-0142(19900601)65:11%3C2554::AID-CNCR2820651126%3E3.0.CO;2-Whttp://www.ped-rheum.com/pubmed/2337872http://dx.doi.org/10.1111/j.1440-1754.1991.tb00343.xhttp://www.ped-rheum.com/pubmed/2043388http://www.ped-rheum.com/pubmed/10895386http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=12447630http://www.ped-rheum.com/pubmed/12447630


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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

Review for the Generalist ANA Test

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