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SLE pathphysiology and treatment targets

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Title: SLE pathphysiology and treatment targets


1
Systemic Lupus Erythematosus
  • Tafazzul H Mahmud
  • Department of Rheumatology and Immunology

2
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.

3
Etiology and Pathogenesis of SLE
4
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.

5
  • 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.

6
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.

7
  • Allergy. Does it induce lupus flare? No direct
    evidence.
  • 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.

8
3. Sex hormones
  • Female Male91
  • 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.

9
  • The metabolism 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.

10
B Cell
11
Activation of B cells
12
B cells communicate with other inflammatory cells
with cytokines
13
T Cell
14
T cells once activated can directly kill their
target
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17
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.

18
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.
19
Overview of the pathogenesis of SLE

Infection
UV light
External Ag
Self Ag
Skin cell
APC
Genetic susceptibility
T cell
T cell
IC
APC
B cell
Target
Ab
Defective IC clearance
20
Clinical manifestations of SLE
21
The clinical spectrum of SLE is very broad It
make SLE both fascinating but potentially
difficult to diagnose and manage.
22
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.

23
  • 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.

24
  • Raynauds 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)

25
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

26
  • 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.

27
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28
  • Maculopapular eruption

29
  • Discoid lupus
  • These are red, raised patches with scaling of
    the overlying skin.

30
  • Vasculitic skin lesin

31
  • Alopecia

32
  • Oral ulcer Painless sores in the nose or mouth
    need to be observed and documented by a doctor.

33
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

34
  • Avacular necrosis of bone.
  • It may be caused by prednisone therapy

35
Kidney system
  • Haematuria
  • Proteinure (gt0.5g protein/d or 3 )
  • Cast

36
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.

37
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.

38
  • Platelets.
  • thrombocytopenia (lt100109/L) appears to be
    mediated by anti-platelet antibodies or/and
    anti-phospholipid antibodies.

39
  • White blood cell
  • leucopenia (lt4.0109/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.

40
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.

41
  • 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.

42
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43
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

44
  • Pericarditis

45
  • 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.

46
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

47
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

48
Secondary sjogrens syndrome
  • Dry eyes
  • Dry mouth
  • exocrine glands were infiltrated with lymphocytes

49
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.

50
  • 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.

51
Laboratory investigation
52
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)

53
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.

54
  • 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.

55
  • This rim (peripheral ) pattern of linear bright
    green staining around the peripheral of nuclei
    seen by immunofluorescence microscopy with a Hep2
    cell substrate .
  • dsDNA

56
  • Nucleolar pattern

57
  • Speckled pattern
  • Scl70, SSA, SSB, Sm

58
  • 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.

59
  • Immune-blotting method to detect anti-Sm, RNP,
    SSA, SSB, Jo1, Scl70 and ribosomal P.

60
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.

61
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.

62
  • SLE is associated with a peculiar periarteriolar
    fibrosis in the spleen, as shown here.

63
Kidney biopsy
  • WHO classification of lupus nephritis is based on
    light, immunofluorescence, and electron
    microscopic findings.

64
Diagnosis
65
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

66
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. ArthritisTenderness, swelling,
effusion in 2 or more peripheral joints 6.
Serositis A) pleuritis or B) pericarditis 7.
Renal disorder A) proteinuriagt0.5g/24hour or 3
or B) cellular casts 8. Neurological disorder
A) seizures or B) psychiatric disorder (having
excluded other causes, e.g. drugs) 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 antibody binding or C)
anti-Sm antibody or D) false positive serological
test for syphilis. 11. Positive antinuclear
antibody
67
Management and treatment
68
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.

69
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.

70
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


71
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.

72
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 lt10mg/d can be used

73
Other therapy
  • Plasma exchange
  • Intravenous Immunoglobulin
  • Stem cell transplantation
  • Immune therapy ( anti-IL10, anti-CD20, and immune
    tolerance therapy)

74
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.

75
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