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Systemic Lupus Erythematosus:pathogenesis, clinical

manifestationsand diagnosis

Naomi Sinaga

08-076


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Systemic Lupus erythematosus ( SLE ) isa syndrome of unknown aetiology mostcommonly affecting young women.Virtually any organ of the body may beinvolved .

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


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Pathogenesis Of SLE


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1. Genetic Factor

Many studies have described familial aggregation ofSLE. 5-13% of lupus have at least one first or seconddegree relative with lupus.

It was found a 24-58% concordance in monozygotictwins.

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 susceptibil i ty?

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.


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2. Environmental Factor

1. UV light, especially UVB, flares SLE in most patients. It isunclear whether exposure to UV light can initiate the lupus, butonset after a sunburn is not unusual. There is good evidencethat exposure of skin to UV light alters the location and

chemistry of DNA as well as the availability of Ro and RNPantigens.

2. Drug-induced lupus. Drugs ( hydralazine, procainamide, beta-

blokers, isoniazid, penicillamine) can induce lupus. Drug-induce lupus may resemble SLE both clinically andserologically. Usually the disease is mild, and renal andneurological complications are rare. Generally, lupus that iscaused 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, nonspecificactivation of T or B cells. There has been recent interest in

EB, CMV and other virus.


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3. Hormonal Factor

Female : Male = 9 : 1

The sex difference is most prominent during thefemale reproductive years.

In mice, castrating females and /or providingandrogens or antiestrogens protects fromdisease,whereas castrating males and providingestrogens 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 longerin women.

Neuroendocrine system. Hyperprolactinemia,

abnormalities in hypothalamic and/or pituitaryfunction.


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Clinical manifestations

of SLE


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Musculoskeletal system

The arthritis of lupus is usually found on both sidesof the body and does not cause deformity of the

joints. Swelling and tenderness must be present.

The most frequently involved joints are those ofthe hand, knees, and wrists.

People with lupus can suffer from a certain type of

low blood flow injury to a joint causing death ofthe bone in the joint.

The muscle involvement was reported in 30-50%

of lupus patients


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Nervous system

The brain , nerve problems and psychiatricsyndromes are common in lupus affecting up totwo-thirds of people.

Potential disorders include seizures, nerveparalysis, severe depression, and even psychosis.

Spinal cord involvement in lupus is rare andoccurs primarily when there is clot formation in acritical vessel that supplies blood to the spinal cord.


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Hematological abnormalities Red blood cells

a normochromic, normocytic anemia is frequentlyfound in SLE. They appears to be related to

chronic inflammation, drug-related haemorrhage.haemolytic anemia as detected by the Coombstest is the feature of SLE.

on rare occasion, a serum antibody may be

produced which impairs red cell production.


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Platelets

thrombocytopenia (


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White blood cell

leucopenia (


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Pulmonary manifestations

Pleurisy

it is the most common manifestation of pulmonary

involvement of SLE. The volume of pleuraleffusions 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.


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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.


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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


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Gastrointestinal and hepatic

manifestation

Esophagitis, dysphagia, nausea, vomiting: (drugrelated in most cases)

Chronic intestinal pseudo-obstruction, mesentericvasculitis, protein-losing enteropathy

Pancreatitis

Lupus hepatitis


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Secondary Antiphosphol ipid syndrome

Antiphospholipid syndrome (APS) is

characterized by recurrent arterial and /or

venous thrombosis, fetal loss andthrombocytopenia. High titer of

Antiphospholipid antibody can be found in APS

patients.


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Laboratory

investigation


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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 specificantoantibodies.


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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 skinbiopsy taken from an area with a visible

rash. With SLE such deposition can be

found in skin uninvolved by a rash, whereaswith DLE the immune complexes are found

only in involved skin.


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WHO classification of lupus nephritis

immunofluorence electron microscopy

Pattern mesangial peripheral mesangial subendothelial subepithelial

normal 0 0 0 0 0A mesangial deposit + 0 + 0 0B mesangial hypercellularity + 0 + 0 0 focal segmental GN ++ + ++ + +diffuse GN ++ ++ ++ ++ +membranous GN + ++ + + ++


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Semiquanti tative 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 atrophyIndicators 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


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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. TheAmerican 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


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Management and treatment


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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.


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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, cerebraland heart involvement.


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SLE disease activity index (SLEDAI)

Clinical feature scoreseizure , psychosis , organ brain syndrome 8

visual disturbance, cranial nerve disorder 8

lupus headache, cerebrovascular accidents, 8

vasculitis 8arthritis 4

myositis 4

urinary casts, hematuria, proteinure, pyuria 4

rash, alopecia, mucosal ulcers, 2

pleurisy, pericarditis 2low complement, increased DNA binding 2

fever 1

thrombocytopenia, leucopenia 1


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3. Clinical therapy

There are four main groups drugs useful in the

treatment of lupus: the non-steroid anti-

inflammatory drugs, anti-malarials, corticosteroidand 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


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Use of corticosteriod to treat various lupus manifestation

Clinical featureinitial dose of prenisolone

Arthritis (poorly responding to NSAIDs) 20-30mg/d, reducingpleuritis by about 5mg/wk if

Pericarditis symptoms abate

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

Thrombocytopenia reduce by 10mg/d if

blood tests improve

Nephritis 1mg/kg/d for about 1M

Neuropsychiatric controversal!

1-2mg/kg/d,

0.5-1g/d methylprednisolone


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