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Systemic Lupus Erythematosus: pathogenesis, clinical manifestations and diagnosis

Naomi Sinaga 08-076

INTRODUCTION 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%.

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.

What are the reasons of Genetic susceptibility?

1. It seems likely that most of the genes predisposing to SLE are normal.

2. 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.
3. C2, C4, C1q deficiencies, DR2, DR3, 1q41-42 region, Fc-r RIIA, IL10 and Bcl polymorphisms.

2. Environmental Factor
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. Drug-induced lupus. Drugs ( hydralazine, procainamide, betablokers, isoniazid, penicillamine) can induce lupus. Druginduce 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.


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.

3. Hormonal Factor
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.

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.

Clinical manifestations of SLE

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

Dermatological Involvement
The butterfly rash is erythematous, often blotchy, and found mainly over the malar bones and across the bridge of the nose. Lesions such as maculopapular and discoid lesions, splinter haemorrhages, dilated capillaries at the nail base, bullous lesions, angioneurotic oedema, livedo reticularis and buccal, genital and nasal ulceration have also been described.

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.

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.

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

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

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.

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, antierythrocyte 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 antidsDNA techniques. ANA is a screening test anti-Sm, anti-dsDNA antibodies are lupus specific antoantibodies.

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.

WHO classification of lupus nephritis

mesangial peripheral mesangial

electron microscopy
subendothelial subepithelial

normal A mesangial deposit B mesangial hypercellularity focal segmental GN diffuse GN membranous GN

0 + + ++ ++ +

0 0 0 + ++ ++

0 + + ++ ++ +

0 0 0 + ++ +

0 0 0 + + ++

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.


Criteria for diagnosing lupus

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:

Criteria of the ARA for the classification of SLE

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

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 testblood 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.

SLE disease activity index (SLEDAI)

Clinical feature score

seizure , psychosis , organ brain syndrome visual disturbance, cranial nerve disorder lupus headache, cerebrovascular accidents, vasculitis arthritis myositis urinary casts, hematuria, proteinure, pyuria rash, alopecia, mucosal ulcers, pleurisy, pericarditis low complement, increased DNA binding fever thrombocytopenia, leucopenia

8 8 8 8 4 4 4 2 2 2 1 1

3. Clinical therapy
There are four main groups drugs useful in the treatment of lupus: the non-steroid antiinflammatory 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.

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 Arthritis (poorly responding to NSAIDs) pleuritis Pericarditis Haemolytic anemia Thrombocytopenia dose of prenisolone 20-30mg/d, reducing by about 5mg/wk if symptoms abate 1mg/kg/d for about 1M reduce by 10mg/d if blood tests improve 1mg/kg/d for about 1M controversal! 1-2mg/kg/d, 0.5-1g/d methylprednisolone

Nephritis Neuropsychiatric

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