Systemic Lupus Erythematosus

• Systemic Lupus erythematosus ( SLE ) is a syndrome of unknown aetiology most commonly affecting young women. Virtually any organ of the body may be involved .
• Typically the course of the disease is a series of remissions and exacerbations.
• With good management, the ten years survival may be over 90%.

INTRODUCTION

Etiology and Pathogenesis of SLE

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
• It was found a 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.

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• What are the reasons of Genetic susceptibility?
• It seems likely that most of the genes predisposing to SLE are normal.
• An individual inherits an unlucky combination of normal genetic polymorphisms, each of which permit a little immune overreponse, or presentation of high quantities of target antigens in certain tissues. The combination of which is just enough to permit SLE to evolve after some environmental stimulus.
• C2, C4, C1q deficiencies, DR2, DR3, 1q41-42 region, Fc-r RIIA, IL10 and Bcl polymorphisms.

2. Environmental factors

1. UV light, especially UVB, flares SLE in most patients. It is unclear whether exposure to UV light can initiate the lupus, but onset after a sunburn is not unusual. There is good evidence that exposure of skin to UV light alters the location and chemistry of DNA as well as the availability of Ro and RNP antigens.
2. Drug-induced lupus. Drugs ( hydralazine, procainamide, beta-blokers, isoniazid, penicillamine) can induce lupus. Drug-induce lupus may resemble SLE both clinically and serologically. Usually the disease is mild, and renal and neurological complications are rare. Generally, lupus that is caused by a drug exposure goes away once the drug is stopped.

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3. Allergy. Does it induce lupus flare? No direct evidence.
4. Infection. There has been continuing interest in 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.

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3. Sex hormones

• Female : Male=9:1
• 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.

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• 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.

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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 T-cell.
• 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 observed and these may deposit in the kidney, skin, brain, lung, and other tissues. It causes inflammation and tissue damage by a number of mechanism, notably fixation and activation of the complement system.

Overview of the pathogenesis of SLE

Skin cell

T cell

T cell

B cell

APC

APC

Defective IC clearance

UV light

Infection

External Ag

Self Ag

Ab

IC

Target

Genetic susceptibility

Clinical manifestations of SLE

The clinical spectrum of SLE is very broad

It make SLE both fascinating but potentially difficult to diagnose and manage.

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.

• Raynaud’s phenomenon is commonly found in lupus. It lack specificity.

(a triphasic reaction of distal digits to cold or emotion, in which the skin colour changes from white to blue to red)

Dermatological involvement

• Up to 85% of SLE
• Butterfly rash
• Maculopapular eruption
• Discoid lupus
• Relapsing nodular non-suppurative panniculitis
• Vasculitic skin lesin
• Livedo reticularis
• Purpuric lesions
• Alopecia
• Oral ulcer

• Malar rash: This is a "butterfly-shaped" red rash over the cheeks below the eyes and across the bridge of the nose. It may be a flat or a raised rash.�The rashes are made worse by sun exposure.

• Maculopapular eruption

• Discoid lupus

These are red, raised patches with scaling of the overlying skin.

• Vasculitic skin lesin

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• Alopecia

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

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Musculoskeletal system

• The arthritis of lupus is usually found on both sides of the body and does not cause deformity of the joints. Swelling and tenderness must be present.
• The most frequently involved joints are those of the hand, knees, and wrists.
• People with lupus can suffer from a certain type of low blood flow injury to a joint causing death of the bone in the joint.
• The muscle involvement was reported in 30-50% of lupus patients

• Avacular necrosis of bone.

It may be caused by prednisone therapy

Kidney system

• Haematuria
• Proteinure (>0.5g protein/d or 3+ )
• Cast

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Nervous system

• The brain , nerve problems and psychiatric syndromes are common in lupus affecting up to two-thirds of people.
• Potential disorders include seizures, nerve paralysis, severe depression, and even psychosis.
• Spinal cord involvement in lupus is rare and occurs primarily when there is clot formation in a critical vessel that supplies blood to the spinal cord.

Hematological abnormalities

• Red blood cells

a normochromic, normocytic anemia is frequently found in SLE. They appears to be related to chronic inflammation, drug-related haemorrhage.

haemolytic anemia as detected by the Coombs’ test is the feature of SLE.

on rare occasion, a serum antibody may be produced which impairs red cell production.

• Platelets.

thrombocytopenia (<100*10⁹/L) appears to be mediated by anti-platelet antibodies or/and anti-phospholipid antibodies.

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• White blood cell

leucopenia (<4.0*10⁹/L), its cause is probably a combination of destruction of white cells by autoantibodies, decreased marrow production, increased or marginal splenic pooling, and complement activation.

it should also noted that the immunosuppressive drugs used in the treatment of SLE may cause a marked leucopenia.

Pulmonary manifestations

• Pleurisy

it is the most common manifestation of pulmonary involvement of SLE. The volume of pleural effusions usually is small to moderate and maybe unilateral or bilateral. Large pleural effusion are uncommon. It usually exudative in character.

Pleural effusions may also occur in SLE patients with nephrotic syndrome, infection, cardiac failure.

• Lung

1) acute lupus pneumonitis: fever, dyspnea, cough with scanty sputum, hemoptysis, tachypnea and pleuritic chest pain.

2) pulmonary hemorrhage

3) chronic diffuse interstitial lung disease.

the diagnosis should not be made until infectious processes such as viral pneumonia, tuberculosis, and other bacterial, fungal and pneumocystis carinii infection have been completely excluded.

Cardiovascular manifestations

• Pericarditis is the most common cardiac manifestation of SLE.
• Myocarditis (the clinical features of lupus myocarditis resembles that of viral myocarditis)
• Libman-Sacks endocarditis and valvular disease
• Hypertension, cardiac failure

• Pericarditis

• SLE can be associated with endocarditis. Shown here is Libman-Sacks endocarditis in which there are many flat, reddish-tan vegetations spreading over the mitral valve and chordae.

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Gastrointestinal and hepatic manifestation

• Esophagitis, dysphagia, nausea, vomiting: (drug related in most cases)
• Chronic intestinal pseudo-obstruction, mesenteric vasculitis, protein-losing enteropathy
• Pancreatitis
• Lupus hepatitis

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Eyes

• The eyes are rarely involved in lupus except for the retina. People with lupus often have to be screened by an ophthalmologist if they are taking the antimalarial drugs chloroquine or hydroxychloroquine

Secondary sjogren’s syndrome

• Dry eyes
• Dry mouth

exocrine glands were infiltrated with lymphocytes

Secondary Antiphospholipid syndrome

• Antiphospholipid syndrome (APS) is characterized by recurrent arterial and /or venous thrombosis, fetal loss and thrombocytopenia. High titer of Antiphospholipid antibody can be found in APS patients.

• 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.

Laboratory investigation

Autoantibodies in SLE

• Antibodies to cell nucleus component

ANA, anti-dsDNA, antibodies to extracellular nuclear antigen (ENA, anti-Sm, anti-RNP, anti-Jo1)

• Antibodies to cytoplasmic antigens

anti-SSA, anti-SSB

• Cell-specific autoantibodies

lymphocytotoxic antibodies, anti-neurone antibodies, anti-erythrocyte antibodies, anti-platelet antibodies

• Antibodies to serum components

antiphospholipid antibody

anticoagulants antiglobulin (rheumatoid factor)

Anti-nuclear antibodies

• The lupus erythematosus (LE) cell

it has been superseded by the ANA and anti-dsDNA techniques.

• ANA is a screening test

anti-Sm, anti-dsDNA antibodies are lupus specific antoantibodies.

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• This homogenous pattern of diffuse bright green staining of nuclei seen by immunofluorescence microscopy with a Hep2 cell substrate is called homogenous, and is the most common pattern with autoimmune diseases overall.

• This rim (peripheral ) pattern of linear bright green staining around the peripheral of nuclei seen by immunofluorescence microscopy with a Hep2 cell substrate .
• dsDNA

• Nucleolar pattern

• Speckled pattern

Scl70, SSA, SSB, Sm

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• These little Crithidia organisms have a small kinetoplast between the nucleus and the flagella which glows bright green under immunofluorescence microscopy, and is indicative of anti-native DNA antibody that is very specific for SLE.

• Immu-blotting method to detect anti-Sm, RNP, SSA, SSB, Jo1, Scl70 and ribosomal P.

Lupus band test

• Immunofluorescence of skin with antibody to IgG demonstrates a band-like deposition of immune complexes that is bright green at the dermal epidermal junction in this skin biopsy taken from an area with a visible rash. With SLE such deposition can be found in skin uninvolved by a rash, whereas with DLE the immune complexes are found only in involved skin.

Vasculitis

• Vasculitis in arteries throughout the body can account for signs and symptoms from a variety of organ involvements. Seen here is an artery with extensive vasculitis with chronic inflammatory cells.

• SLE is associated with a peculiar periarteriolar fibrosis in the spleen, as shown here.

Kidney biopsy

• WHO classification of lupus nephritis is based on light, immunofluorescence, and electron microscopic findings.

WHO classification of lupus nephritis

immunofluorence electron microscopy

Pattern mesangial peripheral mesangial subendothelial subepithelial

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Ⅰnormal 0 0 0 0 0

ⅡA mesangial deposit + 0 + 0 0

ⅡB mesangial hypercellularity + 0 + 0 0

Ⅲ focal segmental GN ++ + ++ + +

Ⅳ diffuse GN ++ ++ ++ ++ +

Ⅴ membranous GN + ++ + + ++

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Semiquantitative assessment of activity and chronicity

• Active indicators

cellular proliferation, necrosis, karyorrhexis, cellular crescents, wire loops, hyaline thrombi, leukocytic infiltration, interstitial infiltration.

• Chronicity indicators

glomerular sclerosis, fibrous crescents, interstitial fibrosis, tubular atrophy

Indicators are scored on a scale of 0 to 3,with necrosis, karyorrhexis, and cellular crescents weighted two times. The maximum of activity is 24, and the maximum of chronicity is 12.

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Diagnosis

Criteria for diagnosing lupus

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• The diagnosis of lupus is a clinical one made by observing symptoms. Lab tests provide only a part of the picture. The American College of Rheumatology has designated 11 criteria for diagnosis. To receive the diagnosis of lupus, a person must have 4 or more of these criteria:

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1. Malar rash: Fixed erythema over malar areas, sparing nasolabial folds

2. Discoid rash: Erythematous raised patches with keratotic scaling and follicular plugging

3. Photosensitivity: Skin rash after exposure to sunlight, history or physical exam

4. Oral ulcers: Oral or nasopharyngeal, painless, by physical exam

5. Arthritis:Tenderness, swelling, effusion in 2 or more peripheral joints

6. Serositis: A) pleuritis or B) pericarditis

7. Renal disorder A) proteinuria>0.5g/24hour or 3+ or B) cellular casts

8. Neurological disorder: A) seizures or B) psychiatric disorder (having excluded other causes, e.g. drigs)

9. Haematological disorder: A) haemolytic anaemia or B) leucopenia or C) thrombocytopenia

10. Immunologic disorder: A) positive LE cells or B) raised anti-native DNA antibdy binding or C) anti-Sm antibody or D) false positive serological test for syphilis.

11. Positive antinuclear antibody:

Criteria of the ARA for the classification of SLE

Management and treatment

1. Monitoring the lupus patients

• It cannot be emphasized too strongly that lupus is a disease requiring regular and careful follow-up.
• Important initial advice should be given about avoiding UV light, infections, extreme stress or fatigue
• Laboratory test—blood test, ESR, C3,IC, liver function tests and anti-dsDNA.

2. Grading clinical activity

• The highly variable nature of the syndrome
• Evaluation of lupus activity is the base or beginning of therapy.
• Non-life-threatening features such as arthralgia, skin rash, RP, alopecia
• Severe complication such as renal, cerebral and heart involvement.

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SLE disease activity index (SLEDAI)

Clinical feature score

seizure , psychosis , organ brain syndrome 8

visual disturbance, cranial nerve disorder 8

lupus headache, cerebrovascular accidents, 8

vasculitis 8

arthritis 4

myositis 4

urinary casts, hematuria, proteinure, pyuria 4

rash, alopecia, mucosal ulcers, 2

pleurisy, pericarditis 2

low complement, increased DNA binding 2

fever 1

thrombocytopenia, leucopenia 1

3. Clinical therapy

• There are four main groups drugs useful in the treatment of lupus: the non-steroid anti-inflammatory drugs, anti-malarials, corticosteroid and cytotoxic drugs.
• How to treat lupus is a kind of art. Which and the dosage of drugs will be used to treat the patient depend on lupus activity.

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Mildly active lupus

• It can be managed with combination of NSAID and / or anti-malarials.
• Prednisolone remain the drugs of first choice to control lupus activity.

Low dosage <=10mg/d can be used

Use of corticosteriod to treat various lupus manifestation

Clinical featureinitial dose of prenisolone

Arthritis (poorly responding to NSAIDs) 20-30mg/d, reducing

pleuritis by about 5mg/wk if

Pericarditis symptoms abate

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Haemolytic anemia 1mg/kg/d for about 1M

Thrombocytopenia reduce by 10mg/d if

blood tests improve

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Nephritis 1mg/kg/d for about 1M

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Neuropsychiatric controversal!

1-2mg/kg/d,

0.5-1g/d methylprednisolone

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Other therapy

• Plasma exchange
• Intravenous Immunoglobulin
• Stem cell transplantation
• Immune therapy ( anti-IL10, anti-CD20, and immune tolerance therapy)

SLE and pregnancy

• SLE has been stable for more than 1 year.
• Prednisone is no more than 10mg/d, and cytotoxic drug has been stopped for more than 6 moth.

SLE patients can plan to have a baby.

Thanks