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الرحيم الرحمن الله بسم
Systemic Lupus Erythematosus&
Kawasaki disease
Systemic Lupus Erythematosus
Abbreviations: SLE or LupusAlternative Names: Disseminated lupus erythematosus; Discoid lupus
Definition
• SLE is a chronic multisystem inflammatory disease of autoimmune origin
• Mostly affects females of childbearing age • Female to male ratio 9:1
SLE
• A complex disorder of multifactorial origin resulting from interactions among genetic, hormonal and environmental factors
• The activation of helper T cells and B cells results in the formation of autoantibodies
Genetic & other factors1. Female hormones
-90% are female-unclear how sex hormone promotes SLE
2. Drug-induced lupus-best known : procainamide, hydralazine, quinidine
Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
Genetic & other factors3. Antecedent viral-like illness : EBV4. Ultraviolet radiation 5. Gene : 8 susceptibility loci
Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
GENETIC
Mary K Crow.Developments in the clinical understading of lupus.Arthritis Research & Therapy 2009;11:245
GENETIC
Mary K Crow.Developments in the clinical understading of lupus.Arthritis Research & Therapy 2009;11:245
Autoantibodies in lupusAutoantibodies in lupus
Autoantibodies in lupusAutoantibodies in lupus
Source of autoantigens in lupus
1. cellular debris (as result of apoptosis)-apoptotic bleb on surface of dying cell
Ag within cell expose on surface of blebs
Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
Source of autoantigens in lupus
Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
Source of autoantigens in lupus
2. Removal of apoptotic debris-C1q play role in phagocytosis-phagocytes in lupus pt. engulf less than phagocytes in healthy people
3. Deficiency of complement poor “waste disposal”
Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
Tissue damage by autoantibody
-Two main theories1. extracellular dsDNA bind to autoAb
enter bloodstream
complexes settle in renal glomerular basement membrane
Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
Tissue damage by autoantibody
2. Autoantibodies cross-react with cellular proteins
(Ag with similar epitopes or similar charge)
direct pathogenic effect on cells
Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
Cytokines in lupus1. IL-10
-high level in lupus pt. correlate with activity of disease-stimulate of polyclonal populations of B cells
2. Interferon(IFN-)3. TNF-
Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
Cytokines in lupus4. B-lymphocyte stimulator
-member of TNF-ligand superfamily-promote proliferation & survival of B cells -there is overexpression of stimulator in lupus pt.
Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
SLE
20 Harrison 19th edition
Aetiology/PathogenesisInate Susceptibility
•HLA type•Immunoregulatory genes•Hormonal levels•Complement levels
Environmental Stimuli•UV exposure•Microbial response•Medication
Autoimmune Proliferation•Hyperactive B-cell/T-cell activation•High ratio of CD4:CD8 T-cells•Defective immune complex clearance •Impaired tolerance
Autoantibody Production
•Apoptosis and self exposure•Self-recognition•Foreign-Ab cross reaction
SLE
• Genetic factors• Hormonal Influences• Environmental Triggers• Immune Dysregulation
• Most visceral lesions are mediated by immune complexes (Type III hypersensitivity)
• Autoantibodies against red cells, white cells and platelets mediate their effects via( Type II hypersensitivity )
Is this Lupus??!
fever, rash, arthritis, alopecia and renal involvement
Clinical Features____________SymptomsOccurrence
Achy joints (arthralgia)95%
Fever more than 38 degrees C90%
Arthritis90%
Prolonged or extreme fatigue81%
Skin rashes74%
Anaemia71%
Renal involvement50%
Pain in the chest on deep breathing (pleurisy)45%
Clinical Features____________SymptomsOccurrence
Butterfly-shaped rash across the cheeks and nose42%
Sun or light sensitivity (photosensitivity)30%
Hair loss27%
Abnormal blood-clotting problems20%
Raynaud’s phenomenon (fingers turning white and/or blue in the cold)
17%
Seizures15%
Mouth or nose ulcers12%
Butterfly Rash
Oral Ulcers
Raynaud’s Phenomenon
Diagnostic criteria (11)FeaturesCharacteristics
1-Malar rashFixed erythema, flat or raised, sparing the nasolabial folds
2-Discoid rashErythematous raised patches with adherent keratotic scarring and follicular plugging
3-PhotosensitivitySkin rash as a result of unusual reaction to sunlight
4-Oral ulcersOral or nasopharyngeal ulceration; may be painless
5-ArthritisNon-erosive, involving two or more peripheral joints
6-Serositisa. Pleuritis (convincing history of pleuritic pain, rub or pleural effusion) or
b. Pericarditis (rub, ECG evidence of effusion)
7-Renal disordera. Persistent proteinuria >0.5 g/day, or b. Cellular casts (red cell, granular or tubular)
8-Neurological disorder
Seizures or psychosis in the absence of offending drugs or metabolic derangement
FeaturesCharacteristics
9-Haematological disorder
a. Haemolytic anaemia orb. Leucopenia (<4000/mm3) orc. Lymphopenia (<1500/mm3) ord. Thrombocytopenia (<100 000/mm3) in the absence of
offending drugs
10-Immunology disorder
a. Anti-DNA antibodies in abnormal titre orb. Presence of antibody to Sm antigen or c. Positive antiphospholipid antibodies
11-Antinuclear antibody disorder
Abnormal titre of ANA by immunofluorescence
31
• 4 of 11 clinical and laboratory criteria must be met
• Antinuclear antibody titer is the primary laboratory test
• Antinuclear antibody titer of 1:40 and characteristic multi-organ system involvement can diagnose SLE without additional testing
• Patients with an antibody titer of 1:40 who fail to meet full clinical criteria should undergo additional testing:
including tests for antibody to double stranded DNA antigen and antibody to Sm nuclear antigen
AUTOANTIBODIES IN SLEAntibody %Clinical Utility
ANA98Best screening test
Anti dsDNA70Specific for SLE; Correlate with disease severity
Anti-Sm25Specific for SLE
Anti-RNP40MCTD
Anti-Ro(SS-A)30Predisposes to Subcutaneous Lupus, Neonatal Lupus with Congenital Heart Blocks.Decreased risk of Nephritis
Anti-La(SS-B) 10Decreased risk of Nepritis
34 Harrison 19th edition
Autoantibodies in SLE
Antibody %Clinical Utility
Anti Histone70Drug induced SLE
Antiphospholipid50Abortions, Thrombosis
Antierythrocyte60Hemolysis
Antiplatelet30Thrombocytopenia
Antineuronal60Active CNS lupus
Antiribosomal20Depression or Psychosis due to CNS lupus
35 Nelson 19th edition
ANA
• Present in 4-5% of healthy population and up to 14% of chronically ill patients.
• Its sensitivity is high for SLE (98%) but specificity is low
• Diseases associated : SLE, MCTD, Systemic sclerosis, Drug induced SLE, Inflammatory myopathies, RA, Sjogrens, Thyroid ds, AI hepatitis, PBC, Hep C
36 Nelson19th edition
ANA PATTERNS
37A. Homogenous B. Speckled C. Centromere D. Nucleolar pattern
ANA by immunofluorescence
International Society of Nephrology 2003 classification of lupus nephritis
Class IMinimal mesangialNormal light microscopy findings, abnormal electron microscopy findings
Class IIMesangial proliferative
Hypercellular on light microscopy
Class IIIFocal proliferative<50% of glomeruli involved
Class IVDiffuse proliferative>50% of glomeruli involved
Class VMembranousPredominantly nephrotic disease
Class VIAdvanced sclerosingChronic lesions and sclerosis
SLE
• Difficult to diagnose• No single diagnostic marker; • identified through a combination of clinical and
laboratory criteria• Early diagnosis is important as it reduces morbidity
and mortality (lupus nephritis)
Useful Investigations• General Investigations:
– TC, DC, Hb, PLT, ESR– Blood urea, Serum Creatinine– Urinalysis to check for protein, RBC and cellular casts– Spot urine test for Creatinine and protein concentration
(normal protein:creatinine ratio <0.2)– ANA
• Tests of SLE disease activity:– Anti-dsDNA, Complement determinations (C3, C4), CRP– Anti-nucleosome antibodies, anti-C1q antibodies
TREATMENT
• Goals of treatment: - prevent flares - treat flares when they occur - minimize organ damage and complications
• Treatment plans are based on patient age, sex and disease severity– Fever, skin, musculoskeletal and serositis - milder disease– CNS and renal involvement – Life-threatening SLE
41 Harrison 19th edition
TREATMENT - NON LIFE THREATENING SLE
• NSAIDS• Antimalarials – Hydroxychloroquine• Resistant cases – Low dose steroids (prednisolone 0.07 to 0.3mg/kg) - systemic immunosuppressants
• Dermatitis: Topical sunscreens, steroids, antimalarials or
Tacrolimus in resistent cases
42 Harrison 19th edition
TREATMENT - LIFE THREATENING SLE
• Glucocorticoids : - Prednisolone - 0.5-1mg/kg orally or - Methylprednisolone 1g/d for 3 days f/b oral therapy 4-6 wks - Maintenance dose 5-10 mg/day
• Cytotoxic therapy :- Induction therapy : Cyclophosphamide - 500-750 mg/mt2 monthly for 6 months Mycophenolate mofetil (MMF) 2-3 gm/day- Maintanence therapy : Azathioprine(2mg/kg/d) or MMF(1.5-3 gm/d)
43 Harrison 19th edition
TREATMENT
• Other drugs Chlorumbucil, Methotrexate, Leflunamide & Cyclosporine• Biological agents : used in resistant cases Rituximab (Anti CD20 Ab) Belimumab (Anti BLyS)
44
45 Harrison 19th edition
46 Harrison 19th edition
Kawasaki Disease
Mucocutaneous lymph node syndrome
What is Kawasaki Disease?
Idiopathic multisystem disease characterized by vasculitis of small & medium blood
vessels, including coronary arteries
*Burns, J. Adv. Pediatr. 48:157. 2001.
Kawasaki Disease (KD)
• A self-limited vasculitis of unknown etiology that predominantly affects children younger than 5 years.
• It is now the most common cause of acquired heart disease in children
• Coronary artery aneurysms develop in 15% to 25% of untreated children & can lead to– ischemic heart disease or– sudden death
Background• 1967 - Tomisaku Kawasaki reports a series of 50
patients and establishes the clinical criteria for diagnosis (in Japanese)
• 1974 - first English language report of Kawasaki syndrome by Kawasaki
• 1976 - first series of American patients reported by Melish, Hawaii
• 1977 - landing and Larson establish that Kawasaki disease and infantile polyarteritis nodosa are pathologically indistinguishable
• 1988 - American academy of pediatrics endorses high does IVIG plus ASA as recommended therapy for Kawasaki disease
Dr Tomisaku Kawasaki
Epidemiology
• More prevalent in Japan and in children of Japanese ancestry (annual incidence of 112 cases per 100 000 children <5 years old)
• 80% of cases in children < 4 yrs• Males:females = 2:1• Annual incidence of 4-15/100,000 children
under 5 years of age
Aetiology and Pathogenesis
• Aetiology of KD remains unknown, (although clinical and epidemiological features strongly suggest an infectious
cause)
• Most children are under age 5– Most common in Asian boys
• 10 day “window” to diagnosis– Heart problem occurrences increase after 10 days
• Estimated 80% fully recover– 1 % will die from Kawasaki disease
56
Pathology
• Generalized systemic vasculitis involving blood vessels throughout the body
• Aneurysms may occur in coronary artery, celiac, mesenteric, femoral, iliac, renal, axillary, and brachial arteries)
• Active inflammation is replaced over several weeks to months by progressive fibrosis, with scar formation
May 1, 2023
Clinical Features
1. Prolonged fever – FUO/PUO2. Bilateral non exudative conjunctivitis3. Erythema of the lips and oral mucosa4. Changes in the extremities – oedema, peeling5. Rash – non-vesicular6. Cervical lymphadenopathy – unilateral
Trager, J. D. N Engl J Med 333(21): 1391. 1995.
Kawasaki diseaseAcute febril phase Subacute phase Convalescent phase
1- 2 wk 2 – 4 wk 6 – 8 wk 1- 2 wk
Phases of Disease
• Acute (1-2 weeks from onset)– Febrile, irritable, toxic appearing– Oral changes, rash, edema/erythema of feet
• Subacute (2-4 weeks from onset)– Desquamation, may have persistent arthritis or
arthralgias– Gradual improvement even without treatment
• Convalescent (Months to years later)
Phase 1 – Phase 1 – LastsLasts 2 Weeks2 Weeks• 39° temperature for
5 days
• Red eyes
• Sore throat
• Swollen lymph nodes
64
65
Skin&m.m.Skin&m.m. ReactionsReactions
66
SkinSkin ReactionsReactions• Red rash on body
67
• Palms of hands swell
• Soles of feet swell
• Red - purple in color
Phase 2 – Phase 2 – LastsLasts 2 Weeks2 Weeks• Skin peels from
hands and feet
• Swollen painful
joints
• VomitingDiarrheaAbdominal pain
68
Differential Diagnosis
• Infectious– Measles & Group A beta-hemolytic strep – Bacterial: severe staph infections w/toxin release– Viral: adenovirus, enterovirus, EBV, roseola
• Immunological/Allergic– JIA (systemic onset)– Hypersensitivity reactions
Other clinical features of KD• Irritability
– Aseptic meningitis (~25% ) (CSF - ↑ lymph's, N glucose/protein)
– Arthritis - probably less common since IVIG treatment– Hydrops of the gallbladder (RUQ pain, seen on USS)– Sterile pyuria, urethritis and diarrhoea– Pulmonary infiltrates or pneumonitis
• Inflammation at site of BCG scar– Cross-reactivity of T cells in KD patients with BCG
Kawasaki Disease: Diagnostic CriteriaCriterionDescription
FeverDuration of 5 days or more plus 4 of the following:
1ConjunctivitisBilateral, bulbar, non-suppurative
2LymphadenopathyCervical, >1.5 cm
3RashPolymorphous, no vesicles or crusts
4Changes of lips or oral mucosa
Red cracked lips; "strawberry" tongue; or diffuse erythema of oropharynx
5Changes of extremities
Initial stage: erythema and oedema of palms and solesConvalescent stage: peeling of skin from fingertips
KD may be diagnosed with fewer than 4 of these features if coronary artery aneurysms are detected.
Kawasaki disease - AHA diagnostic criteriaFever of 5 days duration + four of five criteria
Oropharyngeal changes
(90%+ of cases)
1.
Changes in peripheralextremities
(90% +of cases)
2.
Cervical lymphadenopathy
~(75% of cases)
5.
Polymorphous rash
(95% +of cases)
4.
Bilateral non-purulent conjunctival injection
(90% +of cases)
3.
Atypical or Incomplete Kawasaki Disease
• Present with < 4 of 5 diagnostic criteria• Compatible laboratory findings• Still develop coronary artery aneurysms• No other explanation for the illness• More common in children < 1 year of age
Kawasaki Disease: Labs
• Early– Leukocytosis– Left shift– Mild anemia– Thrombocytopenia/
Thrombocytosis– Elevated ESR– Elevated CRP– Hypoalbuminemia– Elevated transaminases– Sterile pyuria
• Late– Thrombocytosis– Elevated CRP
Cardiovascular Manifestations of Acute Kawasaki Disease
• ECG changes– Arrhythmias– Prolonged PR and/or QT intervals– Low voltage– ST-T–wave changes.
• CXR–cardiomegaly
Coronary Arterial Changes
• Vary in severity from asymptomatic coronary artery ectasia to giant aneurysms
• May lead to myocardial infarction, sudden death, or ischemic heart disease
Coronary Aneurysms
• Patients most likely to develop aneurysms– Younger than 6 months, older than 8 years– Males– Fevers persist for greater than 14 days– Persistently elevated ESR– Thrombocytosis– Pts who manifest s/s of cardiac involvement
Newburger, J. W. et al. Circulation 2004;110:2747-2771
Coronary angiogram demonstrating giant aneurysm of the LAD with obstruction and giant aneurysm of the RCA with area of severe narrowing in
6-year-old boy
Recommended guideline for the management of Kawasaki disease
• Establish diagnosis (1) Complete Kawasaki disease (any age) (2) Incomplete Kawasaki (<1 year)
• Treatment–IVIG 2 g/kg as a single infusion over 12 hours–Aspirin 80–100 mg/kg/day in 4 divided doses until afebrile x 48 hrs &/or decrease in acute phase reactants–Decrease to low dose (3-5 mg/kg/day) for 6-8 weeks or until platelet levels normalize–Echocardiography and ECG
Disease defervescence:Repeat echocardiography at 2 and 6 weeks
No CAACAA <8 mm, no stenoses
CAA > 8 mm and/or stenoses
Stop aspirin at 6 weeks
Continue aspirinLifelong aspirin 3–5 mg/kg/day
Lifelong follow up at least every 2 years
Repeat echocardiography and ECG at 6 monthly intervals
Consider warfarin
Discontinue aspirin if resolves
Consider coronary aneurysm angiography and exercise stress testing
Consider exercise stress test if multiple aneurysms
Repeat echocardiography and ECG at 6 monthly intervals
Specific advice on minimizing atheroma risk factors
Specific advice on minimizing atheroma risk factors
Lifelong follow upLifelong follow up
No disease defervescence within 48 hours, or disease recrudescence within 2 weeks: Seek expert advice to consider:
• Second dose of IVIG at 2 gm/kg/day• Pulsed methylprednisolone at 600 mg/m2 twice daily for 3 days or prednisolone 2 mg/kg/day once daily, weaning over 6 weeks
May 1, 2023
Evaluation of suspected incomplete Kawasaki disease
Supplemental laboratory criteria:
1. albumin 3.0 g/dL
2. anaemia for age
3. elevation of ALT
4. platelets after 7 day 450 000/mm3
5. WBC 15 000/mm3
6. urine - 10 WBC/HPF
Diagnosis is the Key
• Kawasaki disease should be considered in the DD of every child with prolonged fever accompanied by rash and non-purulent conjunctivitis
• the age of the child :(those under 6 months with persistent fever for seven days and evidence of inflammation must have an echocardiogram even in the absence of positive clinical criteria)
Nelson19th edition
Thank you
Dr Tai Al AkawyAlexandria University Children’s
Hospital
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