Andre bindevevssykdommer
Abid Hussain Llohn
[email protected] Immunologisk og transfusjonsmedisinsk avdeling Akershus universitetssykehus HF 06.10.2011
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Andre bindevevssykdommer • • • •
Systemisk sklerose Polymyositt – dermatomyositt Sjögrens syndrom Blandet bindevevssykdom (MCTD)
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Systemic Sclerosis • Systemic disease • History ¤ Hippocrates ¤ Carlo Curzio (1752) ¤ Fantonetti (1836) • Prevalence: 7/100.000 • 3-5 times higher risk for women • Peak onset at age 30-50 years
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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 4 dysmotility, Sclerodactyli, Telangectasia)
Clinical (contd) • 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 5
Hypopigmentation. In black skin hypopigmentation and vitiligo can occur in scleroderma
1 The hands show an alteration in pigment and loss of shape on the terminal aspects of the fingers + flexion contractures of the fingers
Acrosclerosis and terminal digit resorption
2 Microstomia
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4
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5 Raynaud’s fenomen
Calcinosis
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Telangiectasia.
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Nail‐fold capillaroscopy: Tortuous, dilated capillary loops are seen at the base of the nail in 7 this patient.
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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) 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 8
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% 9
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 10
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 11
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 12
Autoantibodies in SSc Autoantibody
Method of testing
Clinical association
Prognosis
ACA (24-33%)
IIF, IB, ELISA
lcSSc, CREST Better than anti-Scl-70 Pulmonary hypertension No benifit in following levels over time
Anti-Scl-70 (20-43%)
ID, CIE, IB, ELISA
dcSSC, pulmonary fibrosis, cor pulmonale
Worse prognoosis Levels fluctuate with severity of disease
Anti-RNAP (15%)
IP, EIA
dcSSc, cor pulmonale, renal disease
Increased mortality
AFA (4%)
IP
dcSSc, pulmonary hypertension, renal disease
Younger patients with internal organ involvement
Anti-RNP (8%)
IIF,ELISA,HA IP/CIE/ID
lcSSc, cor pulmonale, sicca, myositis
Benign prognosis, response to steroids
CIE; counterimmunoelectrophoresis, HA; hemagglutination, IB; immunoblotting, ID; immunoduffusion, IP; immunoprecipitation, IIF; indirect immunofluorescence, ELISA; enzyme-linked immunosorbent assay
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Autoantibodies in SSc (cont) Autoantibody
Method of Clinical association testing
Prognosis
Anti-PM-Scl (3%) Anti-Th/TO (2-5%)
ID, IP
lcSSc PM/SSc overlap
Better response to steroids
IP
LCssC, ↓ joint involvment, ↑ Worse prognosis with puffy fingers, GIT reduced 10 years involvement, hypothyroidism survival
Anti-Ku
IB, IP, ELISA
Overlap syndrome with scleroderma features
Anti-Ro
ID, ELISA, IIF
Seen with 1/3-1/2 of SSc patients with sicca complex
Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93 14
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 15
Anti centromere antibody SSC versus: Normal controls Other CTDs Primary Raynaud
Non-SSc relatives
Sensitivity (%) 33 31 24 19
Specificity(%) 99.9 95-97 90 99
65 61 60 61
99.9 98 83 84
CREST versus: Normal controls
Other CTDs Primary Raynaud
SSc
Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93 Method: IIF
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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 17
Anti-Scl-70 antibody SSC versus:
Sensitivity (%) 43
Specificity (%) 100
Other CTDs
43
90
Primary Raynaud
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98
Non-SSc relatives
35.5
100
Normal controls
Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93 Method: ELISA 18
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 Autologous hematopoietic cell transplantation Blood. 2007 Aug 15;110(4):1388-96. 19
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
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Polymyositis – Dermatomyositis Clinical •
1- Dermatologic features Heliotrope rash / Guttron Papules Poikiloderma, calcinosis, mechanic’s hand
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2- Proximal muscle weakness Trunk, thighs, shoulders
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3- Muscle
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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
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Diagnostic Criteria:
PM: ≥ 4 findings fra 2-9; DM: ≥ 4 findings fra 2-9 +Skin changes
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Dermatomyositis. Poikilodermatous changes
Gottron’s papules.
Typical dermatomyositis shows the overlap features with early scleroderma, marked shininess and erythema on the knuckles.
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Clinical -2 • • • • •
Cardiac: CHF, arrhythmia Lung: Interstitial lung disease, pneumonia Gastrointestinal: Dysphagia Joints: Arthralgias, symmetric arthritis Antisynthetase syndrome 23
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 24
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?
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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) 26
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 27
Anti-SRP • • • • •
Antigen: 7SL-RNA complex, 54-kD HLA DRw52 IIF pattern: cytoplasmic speckled Acute severe myositis No overlap with other CTDs
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Myositis Specific antibodies Ab
Ag
Clinical association
IIF pattern
Jo-1
Histidyl-tRNA synthetase
PM 30%; DM 13% Spec> 95% Cytoplasm: speckled Lung fibrosis
PL-7
Threonyl-tRNA synthetase PM/DM 3%-5%, lung fibrosis
Cytoplasm: speckled
PL-12
Alanyl-tRNA-synthetase
PM/DM 3%, lung fibrosis
Cytoplasm: speckled
EJ
Glycyl-tRNA synthetase
PM 3%; DM 80%, Lung fibrosis
Cytoplasm: speckled
OJ
Isoleucyl-tRNA synthetase PM/DM 3%, lung fibrosis
SRP
54 kD protein in 7SLRNAcomplex
PM 5%; spec 83% Acute onset; severe
Cytoplasm: speckled Nucleolus
Mi-2
Nuclear protein complex
DM 15% - 35%; PM 5%-9%
Nucleoplasm Fine speckled
?
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Myositis-overlap Antibodies Autoantibody
Clinical association
IIF pattern
PM-Scl
PM 8% -12% Scleroderma 25% PM/DM 5% - 10% Sjögren’s 90% PM/DM 4% - 17% SLE & SSc 30% MCTD 95% PM/DM 4% - 17% SLE & SSc 30%
Nucleolus & nucleus Homogen
SSA/Ro U1-nRNP
U2-nRNP
Nucleoplasm Fine speckled Nucleoplasm Speckled Nucleoplasm Speckled
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Treatment • • • •
Corticosteroids Methotrexate, Cyclophosphamide IVIG Rituximab
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Ref.
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Dalakas MC, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993-2000.
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Levine, TD. Rituximab in the treatment of Dermatomyositis. Arthritis Rheum 2005;52:601-607 31
Sjögren’s Syndrome • • • • • •
Systemic rheumatic disorder Mikulicz –1892 Sjögren – 1933 Prevalence. 1% (ca 40000 nordmenn) Female to male ratio: 9 to 1 Peak incidence: 40-50 years, Children: rare 32
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 33
Sjögren’s Syndrome • Primary Sjögren’s Syndrome Keratoconjunctivitis sicca
• Secondary Sjögren’s Syndrome Keratoconjunctivitis sicca
+ Other rheumatic disease 34
Organ manifestations in pSS • • • • •
Dry mucous membranes Joint pain Fibromyalgia (20%) Interstitial nephritis Chronic atrophic gastritis • Primary biliary cirrhosis • Peripheral neuropathy
• Mild interstitial disease • Myalgia, muscle
• • • •
weakness Autoimmune thyroiditis Pregnants + SSA/SSB risk for CHB Lymphomas ↑ risk CNS disorders 35
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% 36
Classification Criteria for SS American-European revised Rules for Classification of SS
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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)
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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
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Ref. Vitali, C, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 61:664-558. 37
Etiology/Pathogenesis • Genetics: HLA-DR3, HLA-B8, DQ-2 *
• Sex hormones
• Virus infection ** Epstein Barr virus Retrovirus: HIV, HTLV-I Coxsackievirus * Price EJ, et al. The etiopathogenesis of Sjogren's syndrome. Semin Arthritis Rheum 1995; 25:117-33. ** Venables PJ; et al. The response to Epstein-Barr virus infection in Sjogren's syndrome. J Autoimmun 1989;2:439-48. ** Triantafyllopoulou A, et al. Autoimmunity and coxsackievirus infection in primary Sjogren's syndrome. Ann N Y Acad Sci 2005;1050:389-96. ** Vernant, JC, et al. T-lymphocyte alveolitis, tropical spastic paresis, and Sjogren syndrome. Lancet 1988; 1:177.
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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, antiRo/SSA & anti-La/SSB 39
Autoantibodies in SS • ANA 70-80%
• RF 80-90% • Anti-RO/SSA 70% • Anti-La/SSB 50% 40
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 (1600) • 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 Ref. Doria, A et al. J Rheumatol 1992;19:259
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MCTD – Common clinical features Cumulatively At presentation Raynaud’s phenomenon Arthralgia/arthritis Esophageal hypomotility Pulmonary dysfunction Swollen hands Myositis Rash Leukopenia Sclerodactyly Pleuritis/pericarditis Pulmonary hypertension
96% 96% 66% 66% 66% 51% 53% 53% 49% 43% 23%
74% 68% 9% rare 45% 2% 13% 9% 11% 19% rare
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Etiology/Pathogenesis • Immune response against apoptically modified self-antigens
• Molecular mimicry • B lymphocyte hyperactivity Ref. Greidinger EL, et al. A major B cell epitope present on the apoptotic but not the intact form of the
U1-
70-kDa ribonucleoprotein autoantigen. J Immunol 2004; 172: 709-16. Davies, JM. Introduction: Epitope mimicry as a component cause of autoimmune disease. Cell Mol Life Sci 2000; 57:523. 48
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
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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 50