Lecture3 4 ConnectiveTissueDiseases Basic Ancuta
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Transcript of Lecture3 4 ConnectiveTissueDiseases Basic Ancuta
CONNECTIVE TISSUE DISORDERS (CTD)
Codrina Ancuta, MD, PhD, lecturer
Rheumatology-Rehabilitation
§ Systemic Lupus Erythematosus (SLE)§ Systemic sclerosis (SSc)§ Polymyositis/ Dermatomyositis (PM/DM)§Mixed Connective Tissue Disease (MCTD)
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Overview
§Definition§Pathogenesis§Presentation §§Presentation § Investigations§Management
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SYSTEMIC LUPUS ERYTHEMATOSUS: DEFINITION
§ Multi-system inflammatory CTD, in which inflammation,auto-antibodies production, immune complex depositionresult in organ damage
Subsets:§ SLE; § SLE; § Chronic cutaneous lupus; § Subacute cutaneous lupus;§ Drug-induced lupus;§ Neonatal lupus;§ Overlap syndromes
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SLE PATHOGENESIS
Genetic predisposition (HLA, non-HLA)
Trigger factors (UV,
Immune abnormalitiesPolyclonal B activation
Pathologic antibody productionTrigger factors (UV,
infections, drugs)
Hormonal status(estrogens)
Pathologic antibody production
Impaired immune complexes clearance & tissue deposition
Complement activation
Distrubed apoptosis
Organ damage
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SLE PRESENTATION§ Skin (lupus specific & non-specific; “butterfly”;
photosensitivity; oral ulcerations)§ Musculo-skeletal (non-erosive arthritis RA-like)§ Cardio-vascular (pericarditis, myocarditis, Liebmann
Sachs endocarditis, early accelerated atherosclerosis)§ Renal (nephritis - 6 WHO classes)§ Renal (nephritis - 6 WHO classes)§ Respiratory (pleuritis, pleuresy, pneumonitis,
alveolitis, embolism, etc)§ Neurologic (neuro-lupus; peripheral neuropathy)
ACR 1997 Diagnostic Criteria Negative prognostic factors
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SLE INVESTIGATIONS§ Inflammatory syndrome (ESR; CRP level)
§ Hematologic assessment (cytopenia)
§ Immune abnormalities (total ANA, anti-dsDNA, -Sm, -Ro, -La, -phospholipids, total complement and fractions, etc)
§ Renal assessment (including Addis & proteinuria; kidney§ Renal assessment (including Addis & proteinuria; kidneybiopsy)
§ Pulmonary, cardio-vascular, neurologic, muscularassessment s
§ Osteodensitometry (chronic glucocorticoid administration!)
Disease activity versus organ damage (SLEDAI, BILAG scores)Therapeutic response
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SLE MANAGEMENT
§ Chronic corticosteroids (iv, oral): high dosesaccording to different visceral involvement
§ Immunosuppressives (Methotrexate,§ Immunosuppressives (Methotrexate,Azathioprine, Cyclophosphamide, CyclosporineA, mycofenolat mofetil) and immuno-modulators (antimalarials)
§ Biological therapy: inhibitors Blys, anti-CD20agents
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SYSTEMIC SCLEROSIS: DEFINITION
Multi-systemic chronic inflammatory CTDcharacterized by:
§Vascular abnormalities (structural & functional)
§ Skin and internal organs excessive fibrosis§ Skin and internal organs excessive fibrosis
§ Immune system activation
§ Classification: diffuse cutaneous SSc, limitedcutaneous SSc (CREST); “scleroderma sinescleroderma”
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SSc PATHOGENESIS SSc PATHOGENESIS
Genetic predisposition Environmental factors
Immune system endothelial cell Immune system activation
endothelial cell activation /damage
Fibroblast activation
End-stage pathology Obliterative vasculitis
Fibrosis
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SSc PRESENTATION§ Vascular involvement – Raynaud phenomenon; pitting scars
§ Skin involvement – sclerodactyly, SSc facies, RODNAN score
§ Musculo-skeletal involvement – non-erosive RA pattern;myositis; acroosteolysis; calcinosis
§ Digestive involvement – specific esophageal involvement
§§ Pulmonary involvement: diffuse fibrosis; pulmonaryhypertension
§ Cardiac involvement
§ Renal involvement – “scleroderma renal crisis”
ACR diagnostic criteriaLeRoy & Medsger criteria
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SSc INVESTIGATIONS
IMMUNOLOGY
§ Anti-Scl70 antibodies
§ Anti-centromere antibodies
§ Digestive tract assessment(endoscopy, manometry,barium)
§ Chest X-ray, (high§ Anti-U3RNP antibodies
§ Anti-RNA polymerase III
antibodies
Characteristic clinical pattern
with different antibodies
§ Chest X-ray, (highresolution) CT, spirometry
§ Capillaroscopy
§ Cardiac ultrasound, rightheart catheterism
§ Skin biopsy
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SSc MANAGEMENT§ Immunosuppressants & anti-fibrotics: methotrexate,
azathioprine, cyclosporine A, cyclophosphamide
§ Corticosteroids – limited indications (early edematousSSc, pulmonar involvement)
§ Vasodilators: calcium channel blockers, i.v. prostaglandins§ Vasodilators: calcium channel blockers, i.v. prostaglandins(Iloprost, Epoprostenol); 5-phosfodiesterase inhibitors(Sildenafil); endothelin receptor inhibitors (Bosentan,Sixtasentan)
§ Other symptomatic therapy
Aiming to improveVascular & immune abnormalities
Excessive fibrosisPDF created with pdfFactory trial version www.pdffactory.com
POLY/DERMATOMIOSYTIS: DEFINITION chronic inflammatory immune-mediated muscular disordercharacterized by:§ non-suppurative chronic inflammatory infiltrate affecting
skeletal muscle
§ proximal myalgias & muscle weakness
ClassificationClassification§ Idiopathic inflammatory myopathies (PM, DM, juvenile DM,
myositis associated with other CTD)§ Myositis associatis with malignancies§ Inclusion body myositis§ other: eozinophylic myositis, ossifiant myositis, localized myositis,
giant cells myositis§ Infectious myopathies§ Drug-induced and toxic myopathies
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PM/DM PATHOGENESIS§ Genetic susceptibility
§ Environmental factors§ Infections – retroviruses§Drugs: corticosteroids, antimalarials, etc§Drugs: corticosteroids, antimalarials, etc
§ Immune factors§Cells ( TCD4+, CD8+, Mo/Mf)§Cytokines (TNF, IL1, IL6, etc)
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PM/DM PRESENTATION§ Muscle findings: Myalgias & muscle weakness
§ Skin findings: heliotrope rash, shawl sign and V sign,Mechanic's hands, Gottron's sign
§ Articular: RA non-erosive pattern§ Visceral: digestive, pulmonary (diffuse interstitial
lung disease & anti-synthetase syndrome), cardiac;lung disease & anti-synthetase syndrome), cardiac;§ General
1975 Bohan & Peter CriteriaMalignancy in up to 20% DM
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PM/DM INVESTIGATIONSSerum muscle enzymes§ Creatine kinase, lactate
dehydrogenase, aldolase,aspartate aminotransferase(AST) and alanineaminotransferase (ALT)
Electromyography (EMG)
Auto-antibodiesMyositis-specific auto-antibodiesAnti-synthetase : Jo1, PL7, PL12,
OJ, EJ, etcElectromyography (EMG)§ Increased insertional activity
and spontaneous fibrillations§ Abnormal myopathic low
amplitude, short–durationpolyphasic motor potentials§ complex repetitive dischargesMuscle biopsy Inflammator infiltrate + fiber
necrosis, regeneration, atrophy
OJ, EJ, etc§ Anti-Mi2, anti-SRP § Myositis profile!
myositis associated autoantibodies§ ANA, RF, anti-PM-scl
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PM/DM MANAGEMENT
1. Corticosteroids (CS)2. Immunosuppressives including methotrexate,
azathioprine, cyclophosphamide (for CS non-responders or side effects)
clinical (muscle force), enzymatic & EMG improvement
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