1. CASE Review

2. Current Problems Underlying Graves’ disease Administration of propylthiouracil Pancytopenia Hemoptysis Serology : ANA (+) Anti- Ro, Anti- La antibody (+) Anti-dsDNA antibody (-) Anti-smith antibody (-) ANCA (+)

3. Diffuse Alveolar Hemorrhage Triad - diffuse alveolar infiltration - hemoptysis - drop in hematocrit or hemoglobin Injury to pulmonary circulation rather than bronchial circulation - arteriole, venule, alveolar septal wall damage - disruption of alveolar – capillary basement mambrane Three category according to histologic patterns - pulmonary capillaritis - bland pulmonary hemorrhage - diffuse alveolar damage

4. §Three category according to histologic patterns 1. Pulmonary capillaritis - neutrophilic infiltration into alveolar septa (lung interstitium) - necrosis and loss of integrity of capillary structure - pouring of red blood cell into alveolar space

5. 2. Bland pulmonary hemorrhage - hemorrhage into alveolar space without inflammation of alveolar structure §Three category according to histologic patterns

6. 3. Diffuse alveolar damage - diffuse edema of alveolar septa and lining of the alveolar space by hyaline membrane ; characterized by ARDS §Three category according to histologic patterns

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8. Clinical presentation - abrupt onset and short duration(< 7days) - initial symptoms : fever, cough, dyspnea - hemoptysis : absent in 33% of all DAH from any cause  falling in Hb, new alveolar infiltration, hemorrhagic BAL favor Dx

9. √ Clue to specific underlying etiology 1. History - exposure to possible offending drug : penicillamine, nitrofurantoin, amiodarone, propylthiouracil - condition associated with development of ARDS : BMT, Cytotoxic drugs - systemic vasculitis, collagen vascular disease, mitral valve disease 2. Abnormal laboratory finding - ANCA : pANCA - Wegener granulomatosis, cANCA - microscopic polyangitis, CSS, isolated pulmonary capillaritis - Anti-GBM antibody : Goodpature syndrome - Serologic finding suggestive of SLE : hypocomplementemia, ANA, anti-dsDNA antibody, anti-Sm etc. - Antiphospholipid antibody : APS - Antistreptococcal antibody, positive blood culture : PSGN, Bacterial endocarditis - Cocaine abuse

10. 3. Biopsy - Diagnostic clues can be found (usually kidney or lung) -Linear IgG deposition along the capillary basement membranes : Goodpasture's syndrome, isolated to the lungs (5 to 10 %) - Marked granular immune complex deposition : SLE, primarily IgA, Henoch-Schönlein purpura or IgA nephropathy - few, if any, deposits by immunofluorescence or electron microscopy : Wegener's granulomatosis, microscopic polyangiitis, or isolated pulmonary capillaritis

11. The patient with DAH and without systemic finding - Goodpature syndrome confined to lung - isolated pulmonary capillaritis with p-ANCA - isolated pulmonary capillaritis without autoantibody - idiopathic pulmonary hemosiderosis : established by lung biopsy demonstrating bland pulmonary hemorrhage without immune complexes

12. Clinical Differentiation of Common Diffuse Alveolar Hemorrhage Syndromes Murray & Nadel's Textbook of Respiratory Medicine, 4th ed

13. WG The four clinical criteria (2/4)—sensitivity 88%, specificity 92% -Nasal or oral inflammation (painful or painless oral ulcers or purulent or bloody nasal discharge) -Abnormal chest radiograph showing nodules, fixed infiltrates, or cavities -Abnormal urinary sediment (microscopic hematuria with or without red cell casts) -Granulomatous inflammation on biopsy of an artery or perivascular area c-ANCA/anti-PR3(proteinase-3) ELISA : 85~90% sensitivity 95% specificity

15. Propylthiouracil Adverse reaction of PTU - haematologic : agranulocytosis, thrombocytopenia, pancytopenia, aplastic anemia - association of ANCA- positive vasculitis : DAH, dermatologic leukoclastic vasculitis, focal segmental glomerulonephritis - hepatotoxicity PTU and Lupus - one of the most frequent drug causing drug-induced lupus

18. Possibility of SLE Clinical manifestation of specific organ involvement - Arthritis - Mucocutaneous - Raynaud phenomenon - Renal - Gastrointestinal : nausea, sometimes with vomiting and diarrhea - Pulmonary : pleuritis with or without effusion, pneumonitis, ILD, diffuse alveolar hemorrhage - Cardiovascular - Neurologic - Ophthalmologic - Haematologic : leukopenia, thrombocytopenia mild anemia most commonly due to chronic disease occasionally hemolytic anemia

19. Autoantibodies of SLE

20. Diagnostic Criteria for Diagnosis of SLE Many criteria – Classical SLE 4 or more criteria - Definite SLE 3 criteria – Probable SLE 2 criteria – Possible SLE

22. Semin Arthritis Rheum 36:4-9

23. Possible Clinical Scenario 1.Graves’s disase + PTU-induced ANCA-associated vasculitis 2.Graves’ disease + SLE - associated pancytopenia and lung manifestation 3. Graves’ disease + Isolated pulmonary capillaritis + PTU-induced pancytopenia 4. Graves’ disease + PTU - induced lupus + lupus - associated pancytopenia and lung menifestation 5.Graves’ disase + WG 6.Graves’ disase + WG + PTU-induced ANCA-associated vasculitis