UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE (UCTD) The clinical onset of Connective Tissue Diseases (CTDs) may undifferentiated. Signs and symptoms suggestive of a CTD, but not fulfilling the criteria for any defined CTDs. EVOLUTION OF THE WELL ESTABLISHED CTD Genetic factors Immunoserological +Enviromental abnormalities factors (hormones, drugs) Clinical symptoms + Serological abnormalities UCTD Established CTD SLE MCTD Sjögren sy PM/DM SSc RA FEATURES OF UCTD History: Systemic symptoms fatique fever weight loss Clinical symptoms Joints- Polyarthritis in the small joints Vascular- Raynaud’s phenomenon, color changes in the skin of the digits, history of arterial or venous thrombosis, or vasculitis Muscle- muscle weekness, muscle pain, or history of myositis Eyes- Dry eyes, conjunctivitis, or ocular inflammation Salivary glands- Dry mouth or salivary gland enlargement Pleuritis/ pericarditis FEATURES OF UCTD Clinical symptoms Skin- Malar rash, skin ulcers, purpura, alopecia, skin tightening urticaria, or pigmentation, erythema nodosum, discoid rash Nervous system- History of seizures, neuropathy, or altered mental status GIAnorexia, dysphagia, dyspepsia, Heart- Angina, dyspnoe, atypical chest pain Lung- Cough, wheezing, or pleuritic chest pain Fever Non-specific immunoserological abnormalities RF positivity High serum levels of IC-s Hypocomplementemia Elevated level of gamma globulin (Signs of inflammation, or other diseases) Lab Studies Routine screening: ESR urinanalysis chemistry panel (CK) Immunoserological abnormalities: Antibodies to nuclear os cytoplasmatic antigens Anti- ANA anti-ENA anti-DNA anti-Sm anti-RNP anti-SSA anti-SSB anti-centromer anti-Jo1 anti-cardiolipin Diagnosis of UCTD: 2 clinical symptoms + 1 presence of autoantibody Physical finding can be limited or may involve many organs Skin- teleangiectaia, purpura, digitals ulcers or scars, sclerodactyly, heliotrope eyelids, Eye- conjunctivitis, episcleral disease, uveitis, iritis, KCS Salivary glands- Xerostomia or salivary gland enlargement Reticuloendothelial- Lymohadenopathy or splenomegaly Lungs- Rales, pleural effusion, or pleural rub Heart- enlarged heart, murpur, pericardial rub, arrhytmia Vascular- acrocyanosis, absent pulses, arterial and/or venous thrombosis Muscles- Muscle tenderness, muscle atrophy, or proximal muscle weakness Joints- Joint tenderness, swelling, effusion, synovitis, or deformity GI- Hepatomegaly, esophageal dysmotiliy Nervous system- Cranial nerve palsy, peripheral motor neuropathy, sensory neuropathy, psychosis, or personal change Raynaud’s phenomenon Primary or Secondary Capillary microscope -vascular abnormalities may be the first sign of the CTD Polyarthritis: Diff dg. Bacterial infection Reactive arhritis (Bang, Widal, Yersinia, Clamydia) Inflammated arthrosis Hypergammaglobulinaemia (purpura, allergic reaction) -Lymphoma -CTD (connective tissue disease) Recurrent serositis Origin -virus or others? Immunological investigation Serositis (ANA positivity, a DNA) SLE Outcome of UCTD Well-established CTD (SLE, MCTD, Sj, SSc) 50% Remain undefined over time 30% Symptoms discontinued 20% Antibodies and clinical symptoms in UCTD a-nativ DNS a-hiszton a-Sm Kidney GN Skin Kidney- mucous ulcer a-U1RNP Raynaud, esophageal hypomotility MCTD a-SSA a-SSB Sicca coplex, skin skin Sjögren sy a-foszfolipid Recurrent thrombosis APL a-Mi2 Heliotrop rash PM/DM a-Jo1 Pulmonary fibrosis Anti- szintetáz szindróma-PM a-Scl70 a-centromer Skin, Raynaud skin Diffúz scleroderma Limitált scleroderma a-citrullinált peptid arthritis RA SLE Evolution of undifferentiated diseases to defined CTD Fever, serositis or photosensitivity + anti-DNA or anti-Sm homogeneous ANA SLE Polyarthritis, Raynaud + anti RNP granular ANA MCTD Raynaud, sclerodactyly + anti centromer anti-SCL-70 nucleolar ANA SSc KCS, Xerostomia + anti-SSA, anti-SSB Sjögren sy Polyarthritis + RF or anti CCP RA Evolution of undifferentiated diseases to defined CTD Recurrent thrombosis + anti-phospholipid ab APS anti-phospholipid sy recurrent abortion Myositis + elevated CK Myositis specific and associated AB PM/DM Myositis+ Raynaud + pulmonary fibrosis anti-Jo1 Anti-synthetase sy Outcome to CDS-s • • • • • Recurrent symptoms New symptoms Positive familiar anamnesis Positive immunological tests Good reactivity to CS treatment Therapy Only a small % of UCTD are treated NSAID 40 % low dose corticosteroids (8-12 mg/day) 30-50% antimalarial drugs 10-30 % Sometimes cytotoxic drugs (erythema nodosum, serositis) 3-4 % MIXED CONNECTIVE TISSUE DISEASE (MCTD) MIXED CONNECTIVE TISSUE DISEASE (MCTD) Well-established chronic inflammatory connective tissue disease. Female/ Male: 9:1 Characteristic signs Specific autoantibodies (anti-U1RNP) Genetic factors HLA-DR2/DR4 HLA-DR1- erosive arthritis HLA-DR3 pulmonary fibrosis CLASSIFICATION AND DIAGNOSTIC CRITERIA FOR MIXED CONNECTIVE TISSUE DISEASE Criteria 1. Serological Presence of the anti-U1RNP antibodies* 2. Clinical (at least three**) Edema of the hands Synovitis Myositis (laboratory or biopsy proven) Raynaud’s phenomenon (2 or 3 color phase) Acrosclerosis (with or without proximal scleroderma) *Anti-U1RNP was detected by ELISA and immunoblotting **The association of edema of the hands, Raynaud’s phenomenon and acrosclerosis requires of at least one of the other two criteria Alarcon-Segovia D. and Villarreal M. (1987) U1-RNP U1-RNP autoantitest kimutatás ranularis típus SA Hoffman et al. Clin Immunology 2008 PATHOGENESIS U1-70 kD peptides, modified self antigens and molecular mimicry Apoptotic and oxidative modification of U1-70 kD may play a role in autoimmunity Apoptotic modification- associated with skin disease Oxidative modification- Raynaud's phenomenon New findings about autoantibodies in MCTD Anti-hnNRNP-A2 subset specific for MCTD SYMPTOMS -May present as fever of unknown origin -Polyarthritis- 85 % 60 % frank arthritis, 50 % with erosion and deformation -Swollen hands and fingers -Proximal inflammatory myopathy – CK, Aldolase is muscle-specific and may also be checked biopsy or EMG Raynaud's phenomenon SYMPTOMS Esophageal hypomotility- x- ray, radionuclide method reflux, vomiting, esophageal hypomotility Pulmonary disease Interstitial lung disease (ILB)- 40 % Pulmonary hypertension 25-50% ILB - Diffuse alveolar inflammation and interstitial disease Fever, cough, dyspnoe, tachycardia decreased ventilation capacity Dg: Chest x ray- small opacity, bibasilar fibrosis High resolution CT Open lung biopsy Prokoagulant activity Thromboxán ? a-U1RNP, ANA, a-PL Proinflammatory cytokines VASCULAR REMODELLING PAI 1 Endothelial cell dysfunction Relaxing factors Endothelin NO Thromboxán Prosztaciklin VEGF Angiopoietin Vazoconstrictor factors Smooths cell activation ET-1 TGF-béta Media hypertrophia Cell proliferation Inflammation,fibrosis angiogenezis OTHER SYMPTOMS Myositis- usually focal and mild Renal involvements- 5-10 % Glomerulonephritis Cutaneous symptoms: vasculitis rashes teleangiectasia alopecia sclerodermatous skin- usually limited to fingers Serositis- rare Thrombosis – 25-30 % (MCTD+ APL) MCTD may associated with Sjögren sy and thyroiditis IMAGING STUDIES Chest radiograph Barium swallow to evaluate esophageal motility Echocardiography- PAH, myocardial and valvular function Pulmonary function tests Scintigraphy- alveolitis, pulmonary fibrosis MRI of the brain Renal function- urine, UH LABORATORY FINDINGS 1. 2. 3. 4. 5. 6. 7. 8. anti-U1RNP in patient’ sera ( anti-SSA, anti SSB) ANA positivity - granular pattern Marked hypergammaglobulinaemia Hypocomplementemia - 25% Circulating immune complexes in the active disease Leukopenia, thrombocytopenia Elevated level of CK Inflammation (lymphocytes, plasma cells) in various tissues TREATMENT - High dose CS (prednisone 1-2 mg/kg) - Pulmonary disease (ILB or PAH) or renal disease -Cytotoxic therapy (cyclophosphamide or azathioprine) Cyclophosphamid: 600 mg/m2/ month 3 month- 1 yr Therapy of the PAH • Pulsus steroid - 0,5-1 g/day 3 days, and 0.5-1 mg/kg/day 6-12 months Cyclophosphamid: 600 mg/m2/ month 3 month- 1 yr • Nitrit oxide or prostaglandins • Ca chanell blockers and oxygen may be effective • Aerosolized prostacyclin (Iloprost) is effective in early stage • ET-1 R blockers • Anticoagulant therapy (LMWH - warfarine) -Methotrexat myositis, arthritis – 15-25 mg/ week TREATMENT -Raynaud's diseaseVasodilatorsNitroglicerine Ca chanel blockers Alpha1-antagonists may also be effective Cyclosporine A- severe myositis, arthritis Dosage: 3 mg/tkg/day -NSAID- in the inactive stage -Antimalaric drugs -Pentoxyfilline -Mycophenolat mofetil-Biological therapy – anti-CD20, TNF-alpha blocker, or TNF- R blockers -Vascular prevention: statins, ACE inhibitors
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