Systemic lupus erythematosis & Kawasaki disease

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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

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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

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• 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

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Autoantibodies in SLE

Antibody %Clinical Utility

Anti Histone70Drug induced SLE

Antiphospholipid50Abortions, Thrombosis

Antierythrocyte60Hemolysis

Antiplatelet30Thrombocytopenia

Antineuronal60Active CNS lupus

Antiribosomal20Depression or Psychosis due to CNS lupus

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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

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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

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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

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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)

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TREATMENT

• Other drugs Chlorumbucil, Methotrexate, Leflunamide & Cyclosporine• Biological agents : used in resistant cases Rituximab (Anti CD20 Ab) Belimumab (Anti BLyS)

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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

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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

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Skin&m.m.Skin&m.m. ReactionsReactions

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SkinSkin ReactionsReactions• Red rash on body

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• 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

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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