systrmic lupus erythematosus (sle)

8/18/2019 Systrmic Lupus Erythematosus (Sle)

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SYSTEMIC LUPUS

ERYTHEMATOSUS(SLE)


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Systemic lupus erythematosus (SLE) is an

autoimmune disease in which organs and cellsundergo damage initially mediated bytissue-

binding autoantibodies and immune

complexes.

In most patients, autoantibodies are present for a

few years before the first clinical symptom

appears; clinical manifestations are

heterogeneous. Ninety percent of patients at

diagnosis arewomen of childbearingyears;

people of all genders, ages, and ethnic groups aresusceptible. Prevalence of SLE in the United

States is10 to 400 per 100,000depending on

race and gender; highest prevalence is in black

women and lowest is in white men.


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PATHOGENESIS AND ETIOLOGY

Interactions between susceptibility genes and environmental

factors result inabnormal immune responses, which vary

among different patients.

Those responses may include

(1) activation of innate immunity (dendritic cells,

monocyte/macrophages) by CpG DNA, DNA in immune

complexes, viral RNA, and RNA in RNA/protein self-antigens; (2)lowered activation thresholds and abnormal activation pathways

in adaptive immunity cells (T and B lymphocytes); (3) ineffective

regulatory CD4+ and CD8+ T cells; and

(4) reduced clearance of immune complexes and of apoptotic cells.

Self-antigens (nucleosomal DNA/protein; RNA/protein in Sm, Ro,and La; phospholipids) are available for recognition by the

immune system in surface blebs of apoptotic cells;thus antigens,

autoantibodies, and immune complexes persist for

prolonged periods of time, allowing inflammation and

disease to develop.


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Immune cell activation is accompanied by increased secretion of

proinflammatory type 1 and 2 interferons (IFNs),tumor necrosis

factor(TNF-), interleukin (IL)-17and B cell–maturation/survival

cytokines B lymphocyte stimulator (BLyS/BAFF), andIL-10.

Upregulation of genes induced by interferons is a genetic "signature" in

peripheral blood cells of SLE in approximately 50% of patients.

Decreased production of other cytokines also contributes to SLE:Lupus

T and natural killer(NK)cells fail to produce enoughIL-2 and

transforming growth factor(TGF-)to induce and sustain regulatory

CD4+ and CD8+ T cells.The result of these abnormalities is sustained production of

autoantibodies and immune complexes; pathogenic subsets bind target

tissues, with activation of complement, leading to release of cytokines,

chemokines, vasoactive peptides, oxidants, and destructive enzymes.

This is accompanied by influx into target tissues of T cells,monocyte/macrophages, and dendritic cells, as well as activation of

resident macrophages and dendritic cells.

In the setting of chronic inflammation, accumulation of growth

factors and products of chronic oxidation contribute to

irreversible tissue damage, including fibrosis/sclerosis, inglomeruli, arteries, brain, lungs, and other tissues.


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SLE is amultigenic disease.

Rare single-gene defects confer high hazard ratios (HR)

for SLE (5–25), including homozygous deficiencies of

early components of complement (C1q,r,s; C2; C4) and amutation in TREX1 on the X chromosome.

In most genetically susceptible individuals, normal

alleles of multiple genes each contribute a small amount

to abnormal immune/inflammation/tissue damageresponses; if enough predisposing variations are present,

disease results.

Thirty to forty predisposing genes have been identified in

recent genome-wide association studies in thousands ofNorthern European white patients and controls. They

confer HR for SLE of 1.5–3. Such relatively weak gene

polymorphisms that increase risk for SLE can be

classified by their potential role in pathogenesis


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Female sex is permissive for SLE with evidence for

hormone effects, genes on the X chromosome, and

epigenetic differences between genders playing a role.

Females of many mammalian species make higher

antibody responses than males.Women exposed to

estrogen-containing oral contraceptives or

hormone replacement have an increased risk of

developing SLE(1.2–2-fold).

Estradiol binds to receptors on T and B lymphocytes,

increasing activation and survival of those cells, thus

favoring prolonged immune responses. Genes on the X

chromosome that influence SLE, such as TREX-1, mayplay a role in gender predisposition—possibly because

some genes on the second X in females are not silent.

People with XXY karyotype (Klinefelter's syndrome)

have a significantly increased risk for SLE.


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PATHOLOGY


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In SLE, biopsies of affected skin show deposition of

Ig at the dermal-epidermal junction (DEJ), injury to

basal keratinocytes, and inflammation dominated by

T lymphocytes in the DEJ and around blood vesselsand dermal appendages. Clinically unaffected skin

may also show Ig deposition at the DEJ.

In renal biopsies, the pattern and severity of injury

are important in diagnosis and in selecting the besttherapy.

Many clinical studies of lupus nephritis have used

the World Health Organization (WHO) classification

of lupus nephritis. However, theInternational

Society of Nephrology (ISN)and theRenalPathology Society (RPS)have published a newer,

similar classification(Table 319-2) that is replacing

WHO standards.


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An advantage of the ISN/RPS classification is the

addition of "a" for active and "c" for chronic changes,

giving the physician information regarding the

potential reversibility of disease. All the classification systems focus on glomerular

disease, although the presence of tubular interstitial

and vascular disease is important to clinical outcomes.

In general, class III and IV disease, as well as class Vaccompanied by III or IV disease, should be treated

with aggressive immunosuppression if possible,

because there is a high risk for end-stage renal disease

(ESRD) if patients are untreated or undertreated.Treatment for lupus nephritis is not recommended in

patients with class I or II disease or with extensive

irreversible changes. In children, a diagnosis of SLE

can be established on the basis of renal histology

without meeting additional diagnostic criteria


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DIAGNOSIS


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The diagnosis of SLE is based on characteristic clinical

features and autoantibodies.

Current criteria for classification are listed in Table 319-3, and

an algorithm for diagnosis and initial therapy is shown inFig.319-2.

The criteria are intended for confirming the diagnosis of SLE in

patients included in studies; the author uses them in individual

patients for estimating the probability that a disease is SLE. Any combination of 4 of 11 criteria, well documented at any

time during an individual's history, makes it likely that the

patient has SLE. (Specificity and sensitivity are 95% and 75%,

respectively.)

In many patients, criteria accrue over time. Antinuclearantibodies(ANA)are positive in >98% of patients during the

course of disease; repeated negative tests suggest that the

diagnosis is not SLE, unless other autoantibodies are present

(Fig. 319-2).


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> 4 SLE


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INTERPRETATIONOFCLINICAL


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INTERPRETATION OF CLINICAL

MANIFESTATIONS

When a diagnosis of SLE is made, it is important

to establish the severity and potentialreversibility of the illness and to estimate the

possible consequences of various therapeutic

interventions.

In the following sections, descriptions of somedisease manifestations begin with relatively mild

problems and progress to those more life-

threatening.


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OVERVIEW AND SYSTEMIC

MANIFESTATIONS

At its onset, SLE may involve one or several organ systems; over

time, additional manifestations may occur

Most of the autoantibodies characteristic of each person are

present at the time clinical manifestations appear (Tables 319-1

and 319-3).

Severity of SLE varies from mild and intermittent to severe andfulminant.

Most patients experience exacerbations interspersed with

periods of relative quiescence; permanent complete remissions

(absence of symptoms with no treatment) are rare.Systemic symptoms, particularlyfatigue and

myalgias/arthralgias,are present most of the time. Severe

systemic illness requiring glucocorticoid therapy can occur with

fever, prostration, weight loss, and anemia with or without other

organ-targeted manifestations.


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MANIFESTATIONS

Most people with SLE have intermittent polyarthritis, varying

from mild to disabling, characterized by soft tissue swelling and

tenderness in joints, most commonly in hands, wrists, and knees.

Joint deformities (hands and feet) develop in only 10% of patients.

Erosions on joint x-rays are rare; their presence suggests a non-

lupus inflammatory arthropathy such as rheumatoid arthritis ;

some experts think that erosions can occur in SLE.If pain persists in a single joint, such as knee, shoulder, or hip, a

diagnosis of ischemic necrosis of bone should be considered,

particularly if there are no other manifestations of active SLE.

The prevalence of ischemic necrosis of bone is increased in SLE,

especially in patients treated with systemic glucocorticoids.Myositis with clinical muscle weakness, elevated creatine kinase

levels, positive MRI scan, and muscle necrosis and inflammation

on biopsy can occur, although most patients have myalgias without

frank myositis


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CUTANEOUS MANIFESTATIONS

Lupus dermatitis can be classified as discoid lupus

erythematosus (DLE), systemic rash, subacutecutaneous lupus

erythematosus (SCLE), or "other."Discoid lesions are roughly circular with slightly raised, scaly

hyperpigmented erythematous rims and depigmented, atrophic

centers in which all dermal appendages are permanently

destroyed.

Lesions can be disfiguring, particularly on the face and scalp.

Treatment consists primarily of topical or locally injected

glucocorticoids and systemic antimalarials.

Only 5% of people with DLE have SLE (although one-half have

positive ANA); however, among individuals with SLE, as many as20% have DLE.

The most common SLE rash is a photosensitive, slightly raised

erythema, occasionally scaly, on the face (particularly the cheeks

and nose—the "butterfly" rash), ears, chin, V region of the neck

and chest, upper back, and extensor surfaces of the arms.


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RENAL MANIFESTATIONS

Nephritis is usually the most serious manifestation of SLE,

particularly since nephritis and infection are the leading causes

of mortality in the first decade of disease.

Since nephritis is asymptomatic in most lupus patients,

urinalysis should be ordered in any person suspected of having

SLE.

The classification of lupus nephritis is primarily histologic.

Renal biopsy is useful in planning current and near-futuretherapies.

Patients with dangerous proliferative forms of glomerular

damage (ISN III and IV) usually have microscopic hematuria and

proteinuria (>500 mg per 24 h); approximately one-half develop

nephrotic syndrome, and most develop hypertension.If diffuse proliferative glomerulonephritis (DPGN) is untreated,

virtually all patients develop ESRD within 2 years of diagnosis.

Therefore, aggressive immunosuppression is indicated (usually

systemic glucocorticoids plus a cytotoxic drug), unless 90% of

glomeruli have irreversible damage


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Mesangial proliferative lupus nephritis with moderate

mesangial hypercellularity.

From International Society of Nephrology/Renal Pathology

Society 2003 class II (×200, hematoxylin-eosin).


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NERVOUS SYSTEM MANIFESTATIONS

There are many central nervous system (CNS) and

peripheral nervous system manifestations of SLE; in some

patients these are the major cause of morbidity and

mortality.

It is useful to approach this diagnostically by asking first

whether the symptoms result from SLE or another condition

(such as infection in immunosuppressed individuals).If symptoms are related to SLE, it should be determined

whether they are caused by a diffuse process (requiring

immunosuppression) or vascular occlusive disease (requiring

anticoagulation).

The most common manifestation of diffuse CNS lupus is

cognitive dysfunction, including difficulties with memory and

reasoning.

Headaches are also common


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This axial, T2-weighted

brain magnetic resonance

image (MRI)

demonstrates an area of

ischemia in the right

periventricular white

matter of a 41-year-old

woman with long-

standing systemic lupus

erythematosus (SLE).

She presented withheadache and subtle

cognitive impairments

but no motor deficits.


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VASCULAR OCCLUSIONS

The prevalence of transient ischemic attacks, strokes, and myocardial

infarctions is increased in patients with SLE.

These vascular events are increased in, but not exclusive to, SLE patients

withantibodies to phospholipids (aPL).

Antiphospholipid antibodies are associated with hypercoagulability and

acute thrombotic events, whereas chronic disease is associated with

accelerated atherosclerosis.

Ischemia in the brain can be caused by focal occlusion (either

noninflammatory or associated with vasculitis) or by embolization from

carotid artery plaque or from fibrinous vegetations of Libman-Sacks

endocarditis. Appropriate tests for aPL and for sources of emboli should be ordered in

such patients to estimate the need for, intensity of, and duration of anti-

inflammatory and/or anticoagulant therapies.

In SLE, myocardial infarctions are primarily manifestations of accelerated

atherosclerosis


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PULMONARY MANIFESTATIONS

The most common pulmonary manifestation of SLE is

pleuritis with or without pleural effusion.This manifestation, when mild, may respond to treatment

with nonsteroidal anti-inflammatory drugs (NSAIDs); when

more severe, patients require a brief course of glucocorticoid

therapy.

Pulmonary infiltrates also occur as a manifestation of active

SLE and are difficult to distinguish from infection on

imaging studies.

Life-threatening pulmonary manifestations include

interstitial inflammation leading to fibrosis, shrinking lung

syndrome, and intra-alveolar hemorrhage; all of these

probably require early aggressive immunosuppressive

therapy as well as supportive care.


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CARDIAC MANIFESTATIONS

Pericarditisis the most frequent cardiac manifestation; it

usually responds to anti-inflammatory therapy and infrequently

leads to tamponade.

More serious cardiac manifestations are myocarditis and fibrinous

endocarditis of Libman-Sacks.

The endocardial involvement can lead to valvular insufficiencies,

most commonly of the mitral or aortic valves, or to embolic events.It has not been proven that glucocorticoid or other

immunosuppressive therapies lead to improvement of lupus

myocarditis or endocarditis, but it is usual practice to administer a

trial of high-dose steroids along with appropriate supportive

therapy for heart failure, arrhythmia, or embolic events. Asdiscussed above, patients with SLE are at increased risk for

myocardial infarction, usually due to accelerated atherosclerosis,

which probably results from immune attack, chronic

inflammation, and/or chronic oxidative damage to arteries.


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HEMATOLOGIC MANIFESTATIONS

The most frequent hematologic manifestation of SLE is

anemia, usually normochromic normocytic, reflecting

chronic illness.

Hemolysis can be rapid in onset and severe, requiring high-

dose glucocorticoid therapy, which is effective in most

patients.

Leukopenia is also common and almost always consists oflymphopenia, not granulocytopenia; this rarely predisposes

to infections and by itself usually does not require therapy.

Thrombocytopenia may be a recurring problem. If platelet

counts are >40,000/L and abnormal bleeding is absent,therapy may not be required. High-dose glucocorticoid

therapy (e.g., 1 mg/kg per day of prednisone or equivalent)

is usually effective for the first few episodes of severe

thrombocytopenia

GASTROINTESTINAL


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GASTROINTESTINAL

MANIFESTATIONS

Nausea, sometimes with vomiting and diarrhea, can be

manifestations of an SLE flare, as can diffuse abdominalpain probably caused by autoimmune peritonitis and/or

intestinal vasculitis.

Increases in serum aspartate aminotransferase (AST)

and alanine aminotransferase (ALT) are common whenSLE is active.

These manifestations usually improve promptly during

systemic glucocorticoid therapy.

Vasculitis involving the intestine may be life-threatening;perforations, ischemia, bleeding, and sepsis are frequent

complications. Aggressive immunosuppressive therapy

with high-dose glucocorticoids is recommended for short-

term control; evidence of recurrence is an indication for

additional therapies


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OCULAR MANIFESTATIONS

Sicca syndrome (Sjögren's syndrome); and nonspecific

conjunctivitis are common in SLE and rarely threatenvision.

In contrast, retinal vasculitis and optic neuritis are

serious manifestations: blindness can develop over

days to weeks. Aggressive immunosuppression is recommended,

although there are no controlled trials to prove

effectiveness. Complications of glucocorticoid therapy

include cataracts (common) and glaucoma


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LABORATORY TESTS


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(1) to establish or rule out the diagnosis;

(2) to follow the course of disease, particularly to

suggest that a flare is occurring or organ damage

is developing; and

(3) to identify adverse effects of therapies.

TESTSFORAUTOANTIBODIES


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TESTS FOR AUTOANTIBODIES

Diagnostically, the most important autoantibodies to detect

are ANA as the test is positive in >95% of patients, usually at

the onset of symptoms. A few patients develop ANA within 1year of symptom onset; repeated testing may thus be useful.

ANA-negative lupus exists but is rare in adults and is usually

associated with other autoantibodies (anti-Ro or anti-DNA).

High-titer IgG antibodies to double-stranded DNA(dsDNA)

(but not to single-stranded DNA) are specific for SLE.There is no international standardized test for ANA;

variability between different service laboratories is high.

Enzyme-linked immunosorbent assays (ELISA) and

immunofluorescent reactions of sera with the dsDNA in the

flagellateCrithidia luciliae have 60% sensitivity for SLE;

identification of high-avidity anti-dsDNA in the Farr assay is

not as sensitive but may correlate better with risk for

nephritis


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Titers of anti-dsDNA vary over time. In some patients, increases

in quantities of anti-dsDNA herald a flare, particularly of

nephritis or vasculitis, especially when associated with declining

levels of C3 or C4 complement.

Antibodies to Smare also specific for SLE and assist in

diagnosis; anti-Sm antibodies do not usually correlate with

disease activity or clinical manifestations.

aPL are not specific for SLE, but their presence fulfills one

classification criterion, and they identify patients at increasedrisk for venous or arterial clotting, thrombocytopenia, and fetal

loss.

There are two widely accepted tests that measure different

antibodies (anticardiolipin and the lupus anticoagulant): (1)

ELISA for anticardiolipin (internationally standardized with goodreproducibility) and (2) a sensitive phospholipid-based activated

prothrombin time such as the dilute Russell venom viper test.

Some centers also recommend measurement of antibodies to2

glycoprotein 1, a serum protein cofactor that is the target of most

antibodies to cardiolipin and some lupus anticoagulants.


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TREATMENT:SYSTEMIC LUPUS

ERYTHEMATOSUS


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There is no cure for SLE, and complete sustained

remissions are rare. Therefore, the physician should

plan to induce improvement of acute flares and then

maintain improvements with strategies that suppress

symptoms to an acceptable level and prevent organdamage.

Usually patients will endure some adverse effects of

medications.

Therapeutic choices depend on (1) whether disease

manifestations are life-threatening or likely to cause

organ damage, justifying aggressive therapies; (2) whether

manifestations are potentially reversible; and (3) the best

approaches to preventing complications of disease and its

treatments


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CONSERVATIVE THERAPIES FOR

MANAGEMENT OF NON-LIFE-THREATENING

DISEASE

Among patients with fatigue, pain, and autoantibodies of SLE,

but without major organ involvement, management can be

directed to suppression of symptoms.

Analgesics and antimalarialsare mainstays.

NSAIDs are useful analgesics/anti-inflammatories, particularlyfor arthritis/arthralgias.

However, two major issues currently indicate caution in using

NSAIDs. First, SLE patients compared with the general

population are at increased risk for NSAID-induced aseptic

meningitis, elevated serum transaminases, hypertension, andrenal dysfunction. Second, all NSAIDs, particularly those that

inhibit cyclooxygenase-2 specifically, may increase risk for

myocardial infarction.

Acetaminophen to control pain may be a good strategy,

but NSAIDs are more effective in some patients

A ti l il(hd hl i hl i d


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Antimalarials (hydroxychloroquine, chloroquine, and

quinacrine) often reduce dermatitis, arthritis, and

fatigue.

A randomized, placebo-controlled, prospective trial hasshown that withdrawal of hydroxychloroquine results in

increased numbers of disease flares. Hydroxychloroquine

reduces accrual of tissue damage over time.

Because of potential retinal toxicity, patients receivingantimalarials should undergo ophthalmologic

examinations annually.

A placebo-controlled prospective trial suggests that

administration of dehydroepiandrosterone may reduce

disease activity.

If quality of life is inadequate in spite of these

conservative measures, treatment with low doses

of systemic glucocorticoids may be necessary.


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MEDICATIONS FOR THE

MANAGEMENTOFSLE


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PATIENT OUTCOMES,PROGNOSIS, AND

SURVIVAL


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Survival in patients with SLE in the United States,

Canada, Europe, and China is approximately 95% at 5

years, 90% at 10 years, and 78% at 20 years.

In the United States, African Americans and Hispanic Americans with a mestizo heritage have a worse

prognosis than whites, whereas Africans in Africa and

Hispanic Americans with a Puerto Rican origin do not.

The relative importance of gene mixtures and

environmental differences accounting for ethnicdifferences is not known.

Poor prognosis (50% mortality in 10 years) in most

series is associated with (at the time of diagnosis) high

serum creatinine levels [>124 mol/L (>1.4 mg/dL)],

hypertension, nephrotic syndrome (24-h urine proteinexcretion >2.6 g), anemia [hemoglobin


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Data regarding outcomes in SLE patients with renal

transplants show mixed results: some series have a twofold

increase in graft rejection compared to patients with other

causes of ESRD, whereas others show no differences. Overallpatient survival is comparable (85% at 2 years).

Lupus nephritis occurs in approximately 10% of

transplanted kidneys.

Disability in patients with SLE is common due primarily tochronic fatigue, arthritis, and pain, as well as renal disease.

As many as 25% of patients may experience remissions,

sometimes for a few years, but these are rarely permanent.

Theleading causes of death in the first decade ofdisease are systemic disease activity, renal failure,

and infections; subsequently, thromboembolic events

become increasingly frequent causes of mortality.

systrmic lupus erythematosus (sle)

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