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1 Andre bindevevssykdommer Abid Hussain Llohn Immunologisk og transfusjonsmedisinsk avdeling Akershus universitetssykehus HF 06.10.2011.

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Presentation on theme: "1 Andre bindevevssykdommer Abid Hussain Llohn Immunologisk og transfusjonsmedisinsk avdeling Akershus universitetssykehus HF 06.10.2011."— Presentation transcript:

1 1 Andre bindevevssykdommer Abid Hussain Llohn Immunologisk og transfusjonsmedisinsk avdeling Akershus universitetssykehus HF

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

3 3 Systemic Sclerosis Systemic disease History ¤ Hippocrates ¤ Carlo Curzio (1752) ¤ Fantonetti (1836) Prevalence: 7/ times higher risk for women Peak onset at age years

4 4 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)

5 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 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 6

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

8 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 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: %

10 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 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 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 13 Autoantibodies in SSc AutoantibodyMethod of testing Clinical association Prognosis ACA (24-33%) IIF, IB, ELISAlcSSc, CREST Pulmonary hypertension Better than anti-Scl-70 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, EIAdcSSc, cor pulmonale, renal disease Increased mortality AFA (4%) IPdcSSc, 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

14 14 Autoantibodies in SSc (cont) AutoantibodyMethod of testing Clinical associationPrognosis Anti-PM-Scl (3%) ID, IPlcSSc PM/SSc overlap Better response to steroids Anti-Th/TO (2-5%) IPLCssC, ↓ joint involvment, ↑ puffy fingers, GIT involvement, hypothyroidism Worse prognosis with reduced 10 years survival Anti-Ku IB, IP, ELISAOverlap 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

15 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 16 Anti centromere antibody SSC versus:Sensitivity (%)Specificity(%) Normal controls Other CTDs Primary Raynaud 2490 Non-SSc relatives 1999 CREST versus: Normal controls Other CTDs 6198 Primary Raynaud 6083 SSc6184 Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93 Method: IIF

17 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 18 Anti-Scl-70 antibody SSC versus:Sensitivity (%) Specificity (%) Normal controls43100 Other CTDs4390 Primary Raynaud2898 Non-SSc relatives Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93 Method: ELISA

19 19 Treatment of SSc Skin Thickening: D-pencillamine, methtrexate, interferon gamma, cyclophosphamide Raynaud: Calcium blockers (Adalat), ACE inhibitors GIT symptoms : H 2 blockers, proton pump inhibitors Pulmonary fibrosis : cyclophosphamide Renal crisis : ACE inhibitors Myositis : steroids Arthralgias : NSAIDs Autologous hematopoietic cell transplantation Blood Aug 15;110(4):

20 20 Polymyositis – dermatomyositis Idiopathic inflammatory myopathy Incidence: 0,5-1/ /år 2 times higher risk for women Peak onset at age 50 (45-65) years 5-15 years in children

21 21 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

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

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

24 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 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 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 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 28 Anti-SRP Antigen: 7SL-RNA complex, 54-kD HLA DRw52 IIF pattern: cytoplasmic speckled Acute severe myositis No overlap with other CTDs

29 29 Myositis Specific antibodies AbAgClinical associationIIF pattern Jo-1 Histidyl-tRNA synthetase PM 30%; DM 13% Spec> 95% Lung fibrosis Cytoplasm: speckled 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 7SL- RNAcomplex PM 5%; spec 83% Acute onset; severe Cytoplasm: speckled Nucleolus Mi-2 Nuclear protein complex DM 15% - 35%; PM 5%-9% Nucleoplasm Fine speckled

30 30 Myositis-overlap Antibodies AutoantibodyClinical associationIIF pattern PM-SclPM 8% -12% Scleroderma 25% Nucleolus & nucleus Homogen SSA/RoPM/DM 5% - 10% Sjögren’s 90% Nucleoplasm Fine speckled U1-nRNPPM/DM 4% - 17% SLE & SSc 30% MCTD 95% Nucleoplasm Speckled U2-nRNPPM/DM 4% - 17% SLE & SSc 30% Nucleoplasm Speckled

31 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: Levine, TD. Rituximab in the treatment of Dermatomyositis. Arthritis Rheum 2005;52:

32 32 Sjögren’s Syndrome Systemic rheumatic disorder Mikulicz –1892 Sjögren – 1933 Prevalence. 1% (ca nordmenn) Female to male ratio: 9 to 1 Peak incidence: years, Children: rare

33 33 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

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

35 35 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

36 36 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%

37 37 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 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:

38 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: ** Venables PJ; et al. The response to Epstein-Barr virus infection in Sjogren's syndrome. J Autoimmun 1989;2: ** Triantafyllopoulou A, et al. Autoimmunity and coxsackievirus infection in primary Sjogren's syndrome. Ann N Y Acad Sci 2005;1050: ** Vernant, JC, et al. T-lymphocyte alveolitis, tropical spastic paresis, and Sjogren syndrome. Lancet 1988; 1:177.

39 39 Etiology/Pathogenesis Inflammatory reactivity Cell mediated immune response CD4 T cells (activated T H -1-type) predominates Cytokines (IL-1, IL-2, IL-6, TNF) B-cell abnormalities Hypergammaglobulinemia, elevated RF, anti- Ro/SSA & anti-La/SSB

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

41 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 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 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/ Peak incidence: years Female to male ratio: 10 to 1

44 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 45 Digital gangrene in MCTD 45

46 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 47 MCTD – Common clinical features Raynaud’s phenomenon96%74% Arthralgia/arthritis96%68% Esophageal hypomotility66%9% Pulmonary dysfunction66%rare Swollen hands66%45% Myositis51%2% Rash53%13% Leukopenia53%9% Sclerodactyly49%11% Pleuritis/pericarditis43%19% Pulmonary hypertension23%rare Cumulatively At presentation

48 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: Davies, JM. Introduction: Epitope mimicry as a component cause of autoimmune disease. Cell Mol Life Sci 2000; 57:523.

49 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 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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