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



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



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



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



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



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



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”



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



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



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



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



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)



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



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



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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Lecture3 4 ConnectiveTissueDiseases Basic Ancuta