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Andre bindevevssykdommer

Andre bindevevssykdommer. Abid Hussain Llohn abll@ahus.no Immunologisk og transfusjonsmedisinsk avdeling Akershus universitetssykehus HF 06.10.2011. Andre bindevevssykdommer. Systemisk sklerose Polymyositt – dermatomyositt Sj ögrens syndrom Blandet bindevevssykdom (MCTD).

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Andre bindevevssykdommer

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  1. Andre bindevevssykdommer Abid HussainLlohn abll@ahus.no Immunologisk og transfusjonsmedisinsk avdeling Akershus universitetssykehus HF 06.10.2011

  2. Andre bindevevssykdommer • Systemisk sklerose • Polymyositt – dermatomyositt • Sjögrens syndrom • Blandet bindevevssykdom (MCTD)

  3. Systemic Sclerosis • Systemicdisease • 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

  4. Systemic Sclerosis • Clinical • Vascular system • Raynaud’s phenomenon 70% of patient initially presentthe symptoms 95% of all patients • Skin • Diffuse pruritis, induration, tightness, pigmentary changes • Microstomia • Telangiectasias • Calcinosis • CREST(Calcinosis, Raynaud’s phenomenon, Esophagus dysmotility, Sclerodactyli, Telangectasia)

  5. 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

  6. Hypopigmentation. In black skin hypopigmentation and vitiligo can occur in scleroderma Acrosclerosis and terminal digit resorption 2 1 The hands show an alteration in pigment and loss of shape on the terminal aspects of the fingers + flexion contractures of the fingers Microstomia 3 4 6 6

  7. Telangiectasia. Raynaud’s fenomen 5 6 Nail‐fold capillaroscopy: Tortuous, dilated capillary loops are seen at the base of the nail in this patient. Calcinosis 7 8 7

  8. 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

  9. 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%

  10. 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

  11. 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

  12. 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

  13. Autoantibodies in SSc CIE; counterimmunoelectrophoresis, HA; hemagglutination, IB; immunoblotting, ID; immunoduffusion, IP; immunoprecipitation, IIF; indirect immunofluorescence, ELISA; enzyme-linked immunosorbent assay

  14. Autoantibodies in SSc (cont) Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93

  15. 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

  16. Anti centromere antibody Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93 Method: IIF

  17. 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

  18. Anti-Scl-70 antibody Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93 Method: ELISA

  19. 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 transplantationBlood. 2007 Aug 15;110(4):1388-96.

  20. 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

  21. Polymyositis – DermatomyositisClinical • 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

  22. Dermatomyositis. Poikilodermatous changes Gottron’spapules. Typical dermatomyositis shows the overlap features with early scleroderma, marked shininess and erythema on the knuckles. 22

  23. Clinical -2 • Cardiac: CHF, arrhythmia • Lung: Interstitial lung disease, pneumonia • Gastrointestinal: Dysphagia • Joints: Arthralgias, symmetric arthritis • Antisynthetase syndrome

  24. 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

  25. 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?

  26. 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)

  27. 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

  28. Anti-SRP • Antigen: 7SL-RNA complex, 54-kD • HLA DRw52 • IIF pattern: cytoplasmic speckled • Acute severe myositis • No overlap with other CTDs

  29. Myositis Specific antibodies

  30. Myositis-overlap Antibodies

  31. Treatment • Corticosteroids • Methotrexate, Cyclophosphamide • IVIG • Rituximab • Ref. • 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. • Levine, TD. Rituximab in the treatment of Dermatomyositis. Arthritis Rheum 2005;52:601-607

  32. 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

  33. Sjögren’s SyndromeClinical 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

  34. Sjögren’s Syndrome • Primary Sjögren’s Syndrome Keratoconjunctivitis sicca • Secondary Sjögren’s Syndrome Keratoconjunctivitis sicca + Other rheumatic disease

  35. 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 Organ manifestations in pSS

  36. 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% Other clinical features in pSS

  37. Classification Criteria for SSAmerican-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 • 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.

  38. 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.

  39. 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

  40. Autoantibodies in SS • ANA 70-80% • RF 80-90% • Anti-RO/SSA 70% • Anti-La/SSB 50%

  41. 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%)

  42. Treatment of SS • Artificial tears • Dry skin: Hydrokortisone krem • Cholinergic agonists (pilocarpine) • NSAIDs • DMARDs: (disease modifying antirheumatic drugs) methotrexate, antimalarial drugs • Immunosuppressive agents: vasculitis, visceral involvement

  43. 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

  44. 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

  45. Digital gangrene in MCTD 45

  46. MCTD – Diagnostic Criteria • Common symptoms Raynaud’s phenomenon, swollen hands or fingers • Anti-U1-RNP (titer>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

  47. MCTD – Common clinical features Cumulatively At presentation

  48. 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.

  49. 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

  50. 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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