Systemic Lupus Erythematosis

Systemic Lupus Erythematosus (SLE)

Etiology – Unknown

involves production of autoantibodies – from overactive helper T cells and inactivated suppressor T cells, less IL-1 and 2
average patient has three autoantibodies, but it is unclear how it is related to disease (cause or effect?)

can be anti-DNA, anti-histone, anti-nuclear, anti-cytoplasmic, anti-cell membrane components

genetic component – only 0.1% in population, but 70% chance of developing if identical twin, 5% if 1^st degree relative

certain HLA haplotypes predispose to development of disease
also disproportionately affects women of color (4x as often as Caucasian)

hormonal predisposition – predominantly affects women of childbearing age (15-50); men affected only 1/9 as often

exogenous agents – perhaps drug or viral infection (analogous to AIDS), although not yet identified

Clinical Presentation – quite varied; can affect entire body (skin, heart, lung, blood, brain, kidney, reproduction)

can be fatal or relatively minor (causing fatigue/arthralgia)
55% present with arthritis, 20% with skin involvement, 5% with nephritis, 5% with fever
many other possibilities – e.g., isolated lymphadenopathy

Prognosis – much better in recent years – less than 50% 5-year survival in 1953

corticosteroids: increase 5-year survival from 50% of 70%
antihypertensives: increase 5-year survival to >90% today (95% if kidney is not affected)

Diagnostic Criteria for SLE – 98% chance of SLE if 4 of 11 are present

(1) Malar rash – flat or raised erythema on cheek sparing the nasal labial folds – present in 70% of SLE patients

(2) Discoid rash – raised patches, adherent kerototic scaling, follicular plugging (focal alopecia), scarring (older lesions)

present in 30% of SLE patients
as long as no scarring has occurred, treatment can resolve rashes
rash on inner ear occurs only with SLE

(3) Photosensitivity – skin rash from sunlight; also severe fatigue when in sunlight

probably due to deposition of immune complexes in dermal-epidermal junction

(4) Painless mucosal ulceration – usually oral, nasopharyngeal, or vaginal – not always painless – 15% of SLE patients

(5) Inflammatory arthritis of two or more peripheral joints–not erosive as in rheumatoid; sporadic (can resolve in a day)

90% of SLE patients have joint pain – most common symptom
often PIP or MP joint; no ulnar deviation or deformation

(6) Serositis – inflammation of serosal surfaces (pleuritis, pericarditis, etc.) – 60% of SLE patients

(7) Kidney disorders – 98% of patients have involvement by EM, 50% symptomatic

prior to dialysis and transplantation, renal failure was the #1 cause of death due to SLE
light microscopy is usually normal, but deposition of immune complexes visible in almost all SLE patients
mesangial/interstitial/tubular SLE nephritis, mild focal/diffuse proliferative/membanous glomeronephritis

(8) Neurological disorders – seizures or psychosis, but can be any neurological symptom – 15% of patient

CNS: seisures, hemiparisis, cranial nerve lesions, brain stem/cord lesions, aseptic meningitis, transverse myelitis
PNS: peripheral neuropathies, myasthenia gravis-like symptoms, mononeuritis multiplex
psychiatric: organic and inorganic disorders of mental function – resolvable if SLE treated

(9) Hemotological disorders – all three blood cell lineages (RBC, WBC, platelets)

also telangiectasia (sometimes just one dot)

infarction – particularly mesenteric (bowel ischemia is 2^nd most common cause of death for SLE patients)

Reynaud’s phenomenon – fingers white Þ blue (venous congestion) Þ red (hyperemia) – 20% of SLE patients

many patients end up with avascular necrosis leading to dead bone (steroids also cause this)

(10) Immunological disorders – PMN phagocytosis – test no longer routinely performed

most SLE patients die from therapeutic immunosuppression

(11) Antinuclear antibody (ANA) test – only 0.3% of SLE patients are ANA negative

positive ANA is more common in general population than SLE (5%)

Tests for SLE – no test is diagnostic, but can indicate prognosis

(1) Acute phase proteins – test for inflammatory substances released from liver – repeat test to determine prognosis

erythrocyte sedimentation rate (ESR) – cheap, easy, known for thousands of years

not specific (many things cause elevated ESR), but can indicate prognosis

test for C-reactive protein (CRP) – protein of unknown function made in response to physiological stress

better than ESR because no gender/age variation, not affected by anemia, single protein so more accurate

(2) Rheumatoid factor – anti-IgG present in rheumatoid as well as SLE – positive result indicates worse disease

75% of SLE patients have RF, but only 15% of patients with RF have SLE – not diagnostic; performed only once

(3) Anti-nuclear factor (ANF or ANA) – ability to make this antibody is the hallmark of SLE – performed once

indirect immunofluorescence test is cheap and fast – nuclei can stain homogenously, speckled, nucleolus only, etc.
only 1 in 400 patients with ANA have SLE, but nearly every patient with SLE has ANA – neg. result excludes SLE

(4) Other autoantibodies – especially anti-nuclear antibodies (against dsDNA, ssDNA, histones, nucleolus, etc.)

anti-dsDNA – only SLE patients make antibodies to dsDNA! – reason for this is not known

even animals will never make anti-DNA antibodies
test involves Crithidia lucilliae, a boll fly bacterium with large dsDNA-rich mitochondria (kineoplast; propels flagellum)
levels of anti-dsDNA change over time, and are closely associated with disease severity/prognosis

this is the most useful test for SLE

histones – usually associated with homogenous pattern ANF – variety of specificities; many drugs can cause this

"sicca" group of anti-ENA – anti-SS-A or anti-SS-B, often seen in sjorgens sydrome – have little diagnostic specificty

however – anti-Ro (anti-SS-A) attacks fetal heart conduction system, and can cause miscarriage
can be used to identify small group of patients with "ANA negative SLE"

anti-centromere antibodies – detection for rapidly dividing cells – also characteristic of CREST (a type of scleroderma)

anti-neutrophil cytoplasmic antibodies (ANCA) – detected by immunofluorescence or enzyme immunoassay

several antigenic specificities (C-ANCA, P-ANCA) – level and specificity might correlate with disease severity
very specific for severe or nectrotizing vasculitis (especially Wegener’s syndrome)

Many other autoantibody tests are available; most are expensive and not very helpful.

(5) Complement system – nine proteins involved in many inflammatory disorders that are "burned up" during SLE

levels of serum complement proteins inversely correlate with disease severity – successful treatment increases levels

(6) Circulating immune complexes – presence of antigen-antibody complexes correlate with heart, joint, kidney disease

however, many conditions involve immune complexes, so measurement is of little clinical value

Anti-phospholipid Syndrome – can be present with or without SLE

Etiology – antibodies to phospholipids, similar to SLE – predominantly affects young or middle-aged women

Clinical Presentation – venous/arterial thromboses (can lead to infarction) or thrombocytopenia

recurrent spontaneous miscarriage – some patients only have this problem – resolvable with anticoagulants
livedo reticularis – lacy skin rash on legs caused by venous congestion – many other things cause this
CNS effects – causes UBO (unidentified bright objects) on MRI that looks like multiple sclerosis – lead to misdiagnosis

Tests – no definitive diagnostic test

"lupus anticoagulant" – a misnomer, since the protein is neither isolated to lupus nor an anticoagulant

prolonged PTT or PT even when serum added; not deficient clotting factor – antibody interferes with in vitro tests

anti-cardiolipin antibody – detected by ELISA
characterized by false positive syphilis serology – positive VDRL but negative FTA-ABS