3 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
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 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 6 1 2 34 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 56 78 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 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 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 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 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 SSC versus:Sensitivity (%)Specificity(%) Normal controls 3399.9 Other CTDs 3195-97 Primary Raynaud 2490 Non-SSc relatives 1999 CREST versus: Normal controls 6599.9 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 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 SSC versus:Sensitivity (%) Specificity (%) Normal controls43100 Other CTDs4390 Primary Raynaud2898 Non-SSc relatives35.5100 Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93 Method: ELISA
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?
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 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
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 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; 61:664-558.
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.
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 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 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