Andre bindevevssykdommer imm

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Information about Andre bindevevssykdommer imm

Published on January 4, 2008

Author: Sabatini


Andre bindevevssykdommer:  Andre bindevevssykdommer Abid Hussain Llohn Immunologisk og transfusjonsmedisinsk avd Akershus universitetssykehus Andre bindevevssykdommer:  Andre bindevevssykdommer Systemisk sklerose Polymyositt – dermatomyositt Sjögrens syndrom Blandet bindevevssykdom (MCTD) Systemic Sclerosis:  Systemic Sclerosis Systemic disease History ¤ Hippocrates ¤ Carlo Curzio (1752) ¤ Fantonetti (1836) Prevalence: 7/100.000 3-4 times higher risk for women Peak onset at age 30-50 years Systemic Sclerosis:  Systemic Sclerosis Clinical Vascular system Raynaud’s phenomenon 70% of patient initially present the symptoms 95% of all patients Skin Diffuse pruritis, induration, tightness, pigmentary changes Microstomia Telangiectasias Calcinosis CREST(Calcinosis, Raynaud’s phenomenon, Esophagus dysmotility, Sclerodactyli, Telangectasia) Clinical (2):  Clinical (2) Gastroesophageal reflux, Barrett metaplasia, anal sphincter incompetence Interstitial fibrosis, pulmonary hypertension Arthralgia, muscle weakness, acrosteolysis Facial pain and hand paresthesias due to sensory peripheral neuropathy Sicca syndrome in 5-7% of patients Renal crises Erectile dysfunction, dyspareunia Slide6:  6 1 2 3 4 Hypopigmentation. In black skin hypopigmentation and vitiligo can occur in scleroderma The hands show an alteration in pigment and loss of shape on the terminal aspects of the fingers +flexion contractures of the fingers Microstomia Acrosclerosis and terminal digit resorption Slide7:  5 6 7 8 Calcinosis Telangiectasia. Nail‐fold capillaroscopy: Tortuous, dilated capillary loops are seen at the base of the nail in this patient. Raynaud’s fenomen Systemic Sclerosis:  Systemic Sclerosis Classification Limited cutaneneous scleroderma (lcSSc) Raynaud’s phenomenon for years Skin changes limited to hands, face, feet, and forearms (acral distribution) Anti centromere antibodies (70%) CREST Pulmonary hypertension (10-15%) Diffuse cutaneous scleroderma (dcSSc) Raynaud’s phenomenon followed, within one year, by rapid skin changes (acral + truncal) Tendon friction rub Anti Scl-70 (30%), Anti-RNA polymerase III (12-15%) Renal crisis, interstitial fibrosis in lungs Scleroderma sine scleroderma Environmentally induced scleroderma Overlap syndrome Pre-scleroderma Major Immunologic features:  Major Immunologic features Antinuclear antibodies (ANA) Sensitivity: 85% Specificity: 54% Anti centromere antibodies (ACA) Sensitivity: 24-33% Specificity:90- 99,9% Anti topoisomerase 1 (Scl-70) antibodies Sensitivity: 20-43% Specificity: 90-100% Etiology/Pathogenesis:  Etiology/Pathogenesis Complex & yet incompletely understood Immune activation, vascular damage, and excessive synthesis of extracellular matrix with deposition of increased amounts of structurally normal collagen are all known to be important in the development of scleroderma Etiology/Pathogenesis:  Etiology/Pathogenesis Genetic Factors 20 times higher prevalence in Choctaw native-Americans in Oklahoma. HLA DQ7, DR2 strongly linked with anti-Scl-70. HLA-DQA1 *0501 allel in 42% of Caucasian men with dsSSc, 29% in healthy men. Infectious Agents CMV, Human Herpes virus 5 Noninfectious Environmental Petroleum-based products, Silica dust? Silicone implant? Dugs: Bleomycin, Pentazocine, Cocaine Microchimerism Etiology/Pathogenesis:  Etiology/Pathogenesis Role of autoantibodies Association with highly specific autoantibodies Presence at disease onset Correlation between aAB titers & SSc activity & severity SSc aAB share the feature of pathogenic immunoglobulins Autoantibodies in SSc:  Autoantibodies in SSc Anti centromere antibody (ACA):  Anti centromere antibody (ACA) Initially described in 1980 Six centromere proteins (CENP-A-F) All sera containing ACA react with CENP-B (80 kDa). Highly specific for SSc, strongly associated with CREST Anti centromere antibody:  Anti centromere antibody Anti-Scl-70 antibody:  Anti-Scl-70 antibody Scl-70 (70 kDa) was initially described in 1979 Subsequent analysis (1986) revealed topoisomerase 1 Interconverts different topological forms of DNA Located in the nucleoplasm, nucleolus & nucleolar organizing region (NOR) Variation in anti-Scl-70 levels (ELISA) with extent of disease involvement, even seronegative conversion with disease remission IIF pattern is homogeneous or fine nuclear speckled, condensed chromatin material during mitosis Anti-Scl-70 antibody:  Anti-Scl-70 antibody Method: ELISA Autoantibodies in SSc (2):  Autoantibodies in SSc (2) CIE, counterimmunoelectrophoresis; HA, hemagglutination; IB, immunoblotting ID, immunoduffusion; IP, immunoprecipitation; IIF, indirect immunofluorescence ELISA, enzyme-linked immunosorbent assay Treatment of SSc:  Treatment of SSc Skin Thickening: D-pencillamine, methtrexate, interferon gamma, cyclophosphamide Raynaud: Calcium blockers (Adalat), ACE inhibitors GIT symptoms: H2 blockers, proton pump inhibitors Pulmonary fibrosis: cyclophosphamide Renal crisis: ACE inhibitors Myositis: steroids Arthralgias: NSAIDs Polymyositis – dermatomyositis:  Polymyositis – dermatomyositis Idiopathic inflammatory myopathy Incidence: 0,5-1/100.000/år 2 times higher risk for women Peak onset at age 50 (45-65) years 5-15 years in children Polymyositis – Dermatomyositis Clinical:  Polymyositis – Dermatomyositis Clinical 1- Dermatologic features Heliotrope rash / Guttron Papules Poikiloderma, calcinosis, mechanic’s hand 2- Proximal muscle weakness Trunk, thighs, shoulders 3- Muscle pain on grasping or spontaneously 4- Non destructive arthritis or arthralgia 5- Increased serum CPK, Aldolase 6- EMG myogenic changes 7- Positive anti-Jo 1 antibody 8- Systemic inflammatory signs 9- Pathologic inflammatory signs Diagnostic Criteria: PM: ≥ 4 findings fra 2-9; DM: ≥ 4 findings fra 2-9 +Skin changes Slide22:  Dermatomyositis. Poikilodermatous changes Gottron’s papules. Typical dermatomyositis shows the overlap features with early scleroderma‐marked shininess and erythema on the knuckles. Clinical -2:  Clinical -2 Cardiac: CHF, arrhythmia Lung: Interstitial lung disease, pneumonia Gastrointestinal: Dysphagia Joints: Arthralgias, symmetric arthritis Antisynthetase syndrome Polymyositis – Dermatomyositis:  Polymyositis – Dermatomyositis Type 1: Idiopathic Polymyositis (33%) Type 2: Idiopathic Dermatomyositis (25%) Type 3: Neoplasia related Type4: Childhood Polymyositis – Dermatomyositis Type 5: Polymyositis – Dermatomyositis associated with others rheumatic diseases Type 6: Inclusion body myositis Etiology/Pathogenesis:  Etiology/Pathogenesis Genetic predisposition Association with DR3, DR5, DR7? Immunological abnormalities Perforin-dependent cytotoxicity of CD8 T cells in PM ↑ expression of HLA class I in muscle cells Humoral immunity play larger role in DM Perivascular deposition of CD4 & C5b-C9 complex Infectious agents: Viruses: Coxsackievirus, echovirus, HTLV-1, HIV Toxoplasma and Borrelia species Drugs: Hydroxyurea, Pencillamines, quinidine, phenylbutazone Silicon breast implants? Myositis Specific antibodies:  Myositis Specific antibodies Anti-tRNA-synthetase antibodies Anti-Jo-1 (anti-histidyl-) PL-7, PL-12, OJ, EJ Anti-SRP (Signal Recognition Particles) (classic PM) Anti-Mi-2 (classic DM) Anti-Jo-1:  Anti-Jo-1 Antigen: histidyl-tRNA-synthetase, 50-52kD Present in 20-40% of PM patients Specificity >95% IgG1 isotype IIF pattern: Cytoplasmic speckled HLA-DR3/-DRw52 Interstitial lung disease Drug induced PM (D-pencillamine) Rare in children & DM Anti-SRP:  Anti-SRP Antigen: 7SL-RNA complex, 54-kD HLA DRw52 IIF pattern: cytoplasmic speckled Acute severe myositis No overlap with other CTDs Myositis Specific antibodies:  Myositis Specific antibodies Myositis-overlap Antibodies:  Myositis-overlap Antibodies Treatment :  Treatment Corticosteroids Methotrexate, Cyclophosphamide IVIG Rituximab Sjögren’s Syndrome:  Sjögren’s Syndrome Systemic rheumatic disorder Mikulicz –1892 Sjögren – 1933 Prevalence. 1% (30-40000 nordmenn) Peak incidence: 40-50 years, Children: rare Female to male ratio: 9 to 1 Sjögren’s Syndrome Clinical:  Sjögren’s Syndrome Clinical Sicca syndrome Keratoconjunctivitis Dry eyes with, reduced tear production and sandy sensation under the lids; red eyes; photosensitivity Xerostomia ↓ saliva production → difficulties in chewing, swallowing, even speech; abnormality in taste & smell; dental caries Sjögren’s Syndrome:  Sjögren’s Syndrome Primary Sjögren’s Syndrome Keratoconjunctivitis sicca Secondary Sjögren’s Syndrome Keratoconjunctivitis sicca + Other rheumatic disease Organ manifestations in pSS:  Organ manifestations in pSS Dry mucous membranes Joint pain Fibromyalgi (20%) Interstitial nephritis Chronic atrophic gastritis Primary biliary cirrhosis Peripheral neuropathy Mild interstitial disease Myalgia, muscle weakness Autoimmune thyroiditis Gravide SSA/SSB+ risiko for CHB Lymphomas ↑risiko CNS disorders Other clinical features in pSS :  Other clinical features in pSS Fatigue 88% Dry skin 88% Arthralgia (hands) 85% Dryness in URT 83% Hoarseness 68% Dysphagia 68% Dry cough 54% Diarrhea 54% Vaginitis 53% Dyspareunia 36% ↓sense of smell 37% Synovitis (hands) 32% Raynaud 29% Purpura (legs) 15% Bergen Classification Criteria for SS American-European revised Rules for Classification of SS:  Classification Criteria for SS American-European revised Rules for Classification of SS I- Ocular symptoms of inadequate tear production II- Oral symptoms of decreased saliva production III- Ocular signs of corneal damage due to inadequate tearing IV- Salivary gland histopathology demonstrating foci of lymphocytes V- Tests indicating impaired salivary gland function VI- Presence of autoantibodies (anti-Ro/SSA, anti-La/SSB, or both) Primary SS: I- The presence of any 4 of 6, as long as either IV or VI is positive II- The presence of any 3 of the 4 objective items III-VI Secondary SS: The presence of item I or II plus 2 from III-IV plus another well defined CTD Exclusion Criteria: Past head and neck radiation treatment; hepatitis C infection; AIDS, pre-existing lymphoma; GvHD, Use of anticholinergic drugs (since a time shorter than 4-fold the half life of drug) Etiology/Pathogenesis:  Etiology/Pathogenesis Genetics: HLA-DR3, HLA-B8, DQ-2 Sex hormones Virus infection Epstein Barr virus Retrovirus: HIV, HTLV-I Coxsackievirus Etiology/Pathogenesis :  Etiology/Pathogenesis Inflammatory reactivity Cell mediated immune response CD4 T cells (activated TH-1-type) predominates Cytokines (IL-1, IL-2, IL-6, TNF) B-cell abnormalities Hypergammaglobulinemia, elevated RF, anti-Ro/SSA & anti-La/SSB Autoantibodies in SS:  Autoantibodies in SS ANA 70-80% RF 80-90% Anti-RO/SSA 70% Anti-La/SSB 50% Anti-La/SSB:  Anti-La/SSB 48 kD antigen: termination factor for RNA polymerase IIF: Fine speckled Clinical: Sjögren’s syndrome (40-50%) SLE (15%) RA (5%) Systemic sclerosis (1%) MCTD (<5%) Treatment of SS:  Treatment of SS Artificial tears Cholinergic agonists (pilocarpine) NSAIDs DMARDs: (disease modifying antirheumatic drugs) methotrexate Dry skin: Hydrokortisone krem Immunosuppressive agents: vasculitis, visceral involvement Mixed Connective Tissue Disease (MCTD):  Mixed Connective Tissue Disease (MCTD) Generalized CT disorder characterized by presence of anti-RNP with some clinical features of SLE, SSc, & PM Incidence. 1/100000 Peak incidence: 15-25 years Female to male ratio: 10 to 1 MCTD – Clinical manifestations:  MCTD – Clinical manifestations Raynaud’s Phenomenon & swollen hands or puffy fingers Absence of severe renal and CNS disease More severe arthritis & insidious onset of pulmonary hypertension Anti-U1 RNP autoantibodies Slide45:  Digital gangrene in MCTD MCTD – Diagnostic Criteria:  MCTD – Diagnostic Criteria Common symptoms Raynaud’s phenomenon, swollen hands or fingers Anti-U1-RNP (titer>160) Mixed clinical features SLE-like findings Polyarthritis, lymphadenopathy, pericarditis or pleuritis, leukopenia or thrombocytopenia, facial erythema Scleroderma –like findings Sclerodactyly, pulmonary fibrosis, hypomotility of esophagus Polymyositis-like findings Muscle weakness, ↑serum muscle enzymes, myogenic pattern on EMG Diagnosis: Positive anti-U1-RNP + one common symptom + one or more findings in two or three diseases MCTD – Common clinical features:  MCTD – Common clinical features Cumulatively At presentation Etiology/Pathogenesis:  Etiology/Pathogenesis Immune response against apoptically modified self-antigens Molecular mimicry B lymphocyte hyperactivity Autoantibodies in MCTD:  Autoantibodies in MCTD ANA Sensitivity: > 95% with low specificity Anti-U1-RNP Sensitivity: > 90% IIF pattern: Coarse speckled Others: RF, Antiphosphlipid antibodies Absence of anti-Sm, anti-dsDNA, anti-Scl-70, anticentrmere Treatment/Prognosis:  Treatment/Prognosis Steroids, NSAIDs, COX-2 inhibitors, Proton pump inhibitors, antimalarial agents, Prostaglandins, cytotoxic agents, Calcium channel blocking agents Occasionally evolve into SSc, SLE & other CTD Pulmonary hypertension is the most frequent disease-associated cause of death

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