SLE pathphysiology and treatment targets

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Systemic Lupus Erythematosus

• Tafazzul H Mahmud
• Department of Rheumatology and Immunology

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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.

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Etiology and Pathogenesis of SLE
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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.

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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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• 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.

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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.

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• 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.

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B Cell
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Activation of B cells
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B cells communicate with other inflammatory cells
with cytokines
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T Cell
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T cells once activated can directly kill their
target
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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.

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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.
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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
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Clinical manifestations of SLE
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The clinical spectrum of SLE is very broad It
make SLE both fascinating but potentially
difficult to diagnose and manage.
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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.

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• 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.

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• 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)

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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

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• 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.

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• Maculopapular eruption

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

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• Vasculitic skin lesin

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• Alopecia

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• 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

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

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Kidney system

• Haematuria
• Proteinure (gt0.5g 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.

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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.

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

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• 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.

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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.

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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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• Pericarditis

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• 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

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Secondary sjogrens syndrome

• Dry eyes
• Dry mouth
• exocrine glands were infiltrated with lymphocytes

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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.

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• 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.

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Laboratory investigation
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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)

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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
  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.

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

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• Nucleolar pattern

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• 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.

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

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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 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.

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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.

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

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Kidney biopsy

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

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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. 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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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
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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, 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
  
  

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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,
  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 lt10mg/d can be used

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Other therapy

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

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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.

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Thanks