SYSTEMIC LUPUS ERYTHEMATOSUS

BY ASMAA HEGAZY INTERNAL MEDICINE RHEUMATOLOGY & IMMUNOLOGY

OUTLINE
Definition Epidemiology Pathophysiology Classification and diagnosis Clinical Features Lupus related syndromes Treatment Prognosis

DEFINITION
Inflammatory autoimmune disorder affecting multiple organ systems characterized by the production of autoantibodies directed against cell nuclei

EPIDEMIOLOGY
Prevalence influenced by age, gender, race, and genetics
Prevalence: 1:2000 Peak incidence 14-45 years Black > White (1:250 vs. 1:1000) Female predominance 10:1 HLA DR3 association, Family History

Severity is equal in male and female

Etiology
Genetic (HLA DR3 association)
Abnormal immune response Environmental

UV
Viruses Hormones (Estrogen)

1. Genetic factor
Many studies have described familial aggregation of SLE. 5-13% of lupus have at least one first or second degree relative with lupus 24-58% concordance in monozygotic twins. 2-5% concordance in dizygotic twins or siblings The risk of a child developing lupus born from a mother (or father) with lupus is calculated to be 3-4% at worst.

2. Environmental factors
UV light, especially UVB, flares SLE in most patients. There is good evidence that exposure of skin to UV light alters the location and chemistry of DNA

3. Allergy. Does it induce lupus flare? No direct evidence. 4. Infection. the possibility that infectious agents might initiate or flare SLE. Mechanism might include molecular mimicry between external Ag and a self-Ag, epitope spreading, nonspecific activation of T or B cells. There has been recent interest in EB, CMV and other virus.

3. Sex hormones
Female : Male=10:1 The sex difference is most prominent during the female reproductive years. In mice, castrating females and /or providing androgens or antiestrogens protects from disease,whereas castrating males and providing estrogens accelerates and worsens SLE.

The metabolish of sex hormone is abnormal in some lupus patients. Men and women with lupus metabolized testosterone more rapidly than normal, and estrogenic metabolites of estradial persist longer in women.

Neuroendocrine system.
Hyperprolactinemia, abnormalities in hypothalamic and/or pituitary function.

4. Abnormal immune system

Sustained presence of autoantigens: increased apoptosis , impaired clearance of apoptosis Hyperactivity in B and T lymphocyte. Increased expression of surface molecules participating in cell activation in both B- and Tcell. Overproduction of IL-6 and IL-10 Defective regulatory mechanism.

Autoantibodies to DNA, RNA, and a host of other cell nucleus antigens. Circulating immune complexes are frequently deposit in the kidney, skin, brain, lung, and other tissues. It causes inflammation and tissue damage

Overview of the pathogenesis of SLE

UV light Infectio n

Self Ag

Skin cell

External Ag

APC Genetic susceptibility T cell T cell

IC

APC

B cell

Ab

Target

Defective IC clearance

CLINICAL FEATURES

General symptoms
The most common symptoms listed as initial complaints are fatigue, fever, and weight loss. Fever: fever secondary to active disease was recorded from 50% to 86%. No fever curve or pattern is characteristic. It can be difficult, but very important to distinguish the fever of SLE from that caused by complicating infections.

Fatigue is common in patients with SLE, especially during periods of disease activity. It is also often the only symptom that remains after treatment of acute flares. Low grade fever, anemia, or any source of inflammation can result in fatigue.

CLINICAL FEATURES: Mucocutaneous

Malar Rash (butterfly erythema) Discoid rash Photosensitive rash Subacute cutaneous LE Livedo reticularis Alopecia Raynauds

Vasculitic ulceration Oral ulceration Nasal septal perforation Nailfold capillary changes

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

Alopecia

Subacute Cutaneous Lupus

Follicular Plugging

Livedo Reticularis

ACR

ORAL ULCERS

Oral or nasopharyngeal ulceration Usually painless, observed by a physician

 Oral ulcer: Painless sores in the nose or mouth need to be observed and documented by a doctor.

SLE - VASCULOPATHY
Small vessel vasculitis

Raynauds phenomenon
Antiphospholipid antibody syndrome

CLINICAL FEATURES: Musculoskeletal

Arthritis is NONEROSIVE, transient, symmetrical, affecting small joints, seldom deforming, less severe than RA Most common presenting feature of SLE

Jaccouds Arthopathy: Nonerosive, Reducible Deformities

CLINICAL FEATURES: Musculoskeletal

Synovitis-90% patients, often the earliest sign Osteoporosis From SLE itself and therapy (usually steroids) Osteonecrosis (avascular necrosis) Can occur with & without history of steroid therapy

CLINICAL FEATURES: Ocular

Conjunctivitis Photophobia Monocular blindness-transient or permanent Blurred vision Cotton-Wool spots on retina-degeneration nerves fibers due to occlusion retinal blood vessels

CLINICAL FEATURES: PLEUROPULMONAR

Pleuritis/Pleural effusion Infiltrates/ Discoid Atelectasis Acute lupus pneumonitis Pulmonary hemorrhage Shrinking lung - diaphragm dysfunction Restrictive lung disease

CLINICAL FEATURES: Cardiac

Pericarditis in majority of patients Libman Sacks endocarditis

Cardiac failure
Cardiac Arrythmias-common Valvular heart disease

Coronary Artery Disease

Lupus - Endocarditis

Noninfective thrombotic endocarditis involving mitral valve in SLE. Note nodular vegetations along line of closure and extending onto chordae tendineae.

CLINICAL FEATURES: HEMATOLOGIC DISORDER

A) B) C) Hemolytic anemia - with reticulocytosis OR Leukopenia - less than 4,000/mm3 total on 2 or more occasions OR Lymphopenia - less than 1,500/mm3 on 2 or more occasions OR Thrombocytopenia - less than 100,000/mm3 in the absence of offending drugs

D)

CLINICAL FEATURES: Neurologic

Behavior/Personality changes, depression Cognitive dysfunction Psychosis Seizures Stroke Chorea Pseudotumor cerebri Transverse myelitis Peripheral neuropathy Total of 19 manifestations described May be difficult to distinguish from steroid psychosis or primary psychiatric disease

CLINICAL FEATURES: Renal (Lupus Nephritis)

Develops in up to 50% of patients 10% SLE patients go to dialysis or transplant Hallmark clinical finding is proteinuria

Nephritis remains the most frequent cause of disease-related death.

Why should we worry about kidney problems

50% of all lupus patients will have kidney involvement during their life

of these, 50 % will have serious kidney disease

Patients may not be aware that kidney problems exist

How does lupus damage the kidneys?

Autoantibodies are formed against antigens in the glomerulus basement membrane

Circulating immune complexes bind to the basement membrane of the glomeruli (the sieve)
These result in inflammation of the glomeruli (glomerulonephritis)

CLINICAL FEATURES: Renal (Lupus Nephritis)

Usually asymptomatic Gross hematuria Nephrotic syndrome Acute renal failure Hypertension End stage renal failure

What happens if lupus kidney disease is suspected?

Many things will occur:
Blood and urine evaluation Consultations with Rheumatologist, Nephrologist Ultrasound of the kidneys Kidney biopsy

shows a picture of how much inflammation is present and where it is occurring

Do I really need a biopsy?

Most likely - YES
depends upon the treating physician

Kidney biopsies are important to

dictate how to treat
predict how long to treat predict the chance for kidney function recovery

WHO CLASSIFICATION OF LUPUS NEPHRITIS

Class I Class II

Normal Mesangial

IIA IIB Class III

Class IV Class V

Class VI

Minimal alteration Mesangial glomerulitis Focal and segmental proliferative glomerulonephritis Diffuse proliferative glomerulonephritis Membranous glomerulonephritis Glomerular sclerosis

All lupus patients should:

See their health care provider routinely Have both blood and urine examined regularly Monitor blood pressure Report any symptoms of lupus to their health care provider

CLINICAL FEATURES: Gastrointestinal & Hepatic

Uncommon SLE manifestations Severe abdominal pain syndromes in SLE often indicate mesenteric vasculitis, resembling medium vessel vasculitis (PAN) Diverticulitis may be masked by steroids Hepatic abnormalities more often due to therapy than to SLE itself

Laboratory Findings

Laboratory Findings
Complete blood count
Anemia Leukopenia Lymphopenia Thrombocytopenia

Urine Analysis
Hematuria Proteinuria Granular casts

Immunological findings
ANA - 95-100%-sensitive but not specific for SLE Anti -ds DNA-specific(60%)-specific for SLE, but positive to other non lupus conditions 4 RNA associated antibodies
Anti-Sm (Smith) Anti Ro/SSA-antibody Anti La/SSB-antibody Anti-RNP
Biologic false + RPR Lupus anticoagulant-antibodies tocoagulation factors. risk factor for venous and arterial thrombosis and miscarriage. Prolonged aPTT Anti-cardiolipin

Antiphospholipid antibody

Depressed serum complement Anti histones antibodies

CLASSIFICATION
THE 1982 REVISED CRITERIA FOR CLASSIFICATION OF SLE

1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis 6. Serositis 7. Renal disease. > 0.5 g/d proteinuria 3+ dipstick proteinuria Cellular casts 8. Neurologic disease. Seizures Psychosis (without other cause)

9. Hematologic disorders. Hemolytic anemia Leukopenia (< 4000/uL) Lymphopenia (< 1500/uL) Thrombocytopenia (< 100,000/uL) 10. Immunologic abnormalities. Positive LE cell Anti-ds- DNA Anti- Sm Any antiphospholipid 11. Positive ANA ( 95-100% )

CLASSIFICATION CRITERIA
Must have 4 of 11 for Classification
Sensitivity 96% Specificity 96%

Not all Lupus is SLE

Discoid Lupus Overlap syndrome Drug induced lupus Subacute Cutaneous Lupus

DIFFERENTIAL DIAGNOSIS
Rheumatic: RA, Sjogrens syndrome, systemic sclerosis, dermatomyositis
Nonrheumatic: HIV, endocarditis, viral infections, hematologic malignancies, vasculitis, ITP, other causes of nephritis Overlap Syndrome (UCTD, MCTD)

LUPUS RELATED SYNDROMES

LUPUS RELATED SYNDROMES

Drug Induced Lupus
Classically associated with hydralazine, isoniazid, procainamide Male:Female ratio is equal Nephritis and CNS abnormalities rare Normal complement and no anti-DNA antibodies Symptoms usually resolve with stopping drug

SLE and pregnancy

SLE has been stable for more than 1 year. Prednisone is no more than 10mg/d,

cytotoxic drug has been stopped for more than 6 month.

SLE patients can plan to have a baby.

LUPUS RELATED SYNDROMES

Antiphospholipid Syndrome (APS)
Hypercoagulability with recurrent thrombosis of either venous or arterial circulation Thrombocytopenia-common Pregnancy complication-miscarriage in first trimester Lifelong anticoagulation warfarin is currently recommended for patients with serious complications due to common recurrence of thrombosis Antiphospholipid Antibodies Primary when present without other SLE feature. Secondary when usual SLE features present

 Deep venous thrombosis (blood clot). Notice the contrast between the involved left leg and the normal right leg. Redness, swelling, and warmth combined with discomfort in the involved leg are cardinal manifestations of a deep venous thrombosis.

LUPUS RELATED SYNDROMES

Raynauds Syndrome: -Not part of the diagnostic criteria for SLE - Does NOT warrant ANA if no other clinical evidence to suggest autoimmune disease

Secondary sjogrens syndrome

Dry eyes Dry mouth

exocrine glands were infiltrated with lymphocytes

Treatment

THERAPEUTIC MODALITIES
STEROIDS ANTI-MALARIAL DRUGS CYCLOPHOSPHAMIDE AZATHIOPRINE

CYCLOSPORIN
Plasmapheresis IV Ig

Biological therapy

SLE treatment I.
Mild cases (mild skin or joint involvement): NSAID, local treatment, hydroxy-chloroquin Cases of intermediate severity (serositis, cytopenia, marked skin or joint involvement): corticosteroid (12-64 mg methylprednisolon), azathioprin, methotrexat

SLE treatment II.

Severe, life-threatening organ involvements (carditis, nephritis, systemic vasculitis, cerebral manifestations): high-dose intravenous corticosteroid + iv. cyclophosphamide + in some cases: plasmapheresis or iv. immunoglobulin, or, instead of cyclophosphamide: mycophenolate mofetil Some cases of nephritis (especially membranous), myositis, thrombocytopenia: cyclosporine

TREATMENT
Antiphospholipid Syndrome
Anticoagulation with warfarin (teratogenic) subcutaneous heparin and aspirin is usual approach in pregnancy

Lupus and Pregnancy

No longer contraindicated No changes in therapy other than avoiding fetal toxic drugs Complications related to renal failure, antiphospholipid antibodies, SSA/SSB

PROGNOSIS

PROGNOSIS
Unpredictable course 10 year survival rates exceed 85% With good managemen Most SLE patients die from infection, probably related to therapy which suppresses immune system Typically the course of the disease is a series of remissions and exacerbations.