RCPT 2018 Case-based Approach to Vasculitis A middle-aged woman with skin lesions and ascites 47 year-old woman, Housewife, NakornRachasima CC: Enlarged abdomen and dyspnea 5 months 5 months PTA: Low-grade fever Pitting edema at both legs Skin lesions (both thighs, legs) Diffusely enlarged abdomen Foamy urine Progressive dyspnea No underlying disease Married with 2 healthy offsprings No Raynaud’s, no alopecia Two abortions (10th wk, 3rd mo) No photosensitivity (blood transfusion, postpartum) No oral / genital ulcers Heavy alcohol drinking No arthralgia or inflamed joints No drug addiction or IVDU 47 year-old woman, Housewife, NakornRachasima T 38.2 C, PR 95, RR 20, BP 160/100 Normal S1, S2 Moderate anemia, jaundice 1+ No lung crepitation or wheezing Anasarca, pretibial pitting edema 4+ No hepatosplenomegaly Palmar erythema Ascites 4+ Palpable purpura Livedo racemosa Cutaneous Vasculitis Palpable purpura Post-capillary venules LCV, any type of vasculitis of medium- (medium-sized vessels) and small-sized vasculitis in dermis Less commonly capillaries and arterioles LVR Small arterioles PAN, cryoglob, SLE, RA, D/M, APS (perpendicular branches in (Sneddon’s syndrome), lymphoma, dermis) TB, syphilis, drug, PRV, IVDU Nodules Medium-sized vessels PAN, TK, GPA, RA, SLE, infection, drug, Behcet’s disease, sarcoidosis, malignancy, ulcerative colitis Ulcers Arterioles to small arteries PAN, EGPA, GPA Gangrene Medium sized vessels to Hypersensitivity vasculitis, PAN, EGPA, capillaries GPA, cryoglobulinemic vasculitis Livedo reticularis Neonatal cutis marmorata Idiopathic (cutis marmorata): asymptomatic Cutis marmorata telangiectatica congenita Physiologic cutis marmorata: common benign course, young women during winter Secondary (livedo racemosa): Symptomatic Autoimmune disease: PAN, SLE, DM, RA, APL syndrome Livedoid vasculopathy – Ulcer around ankle and forefoot Sneddon syndrome – Livedoid vasculopathy + stroke + anti-phospholipid Abs. Hematologic malignancies: Lymphoma, leukemia Cryoglobulinemic vasculitis Inflammation: Pancreatitis Infection: TB, syphilis, leprosy (Lucio’s), Lyme disease Drugs: Amantadine, quinine, quinidine Obstruction of capillaries: Cryoglobulinemia, APL syndrome, hypercalcemia, CKD, PRV, thrombocytosis, DIC, cholesterol emboli, atrial myxoma, IVDU 47 year-old woman, Housewife, NakornRachasima CBC: Hct 30%, WBC 13,500, N 96%, L 3%, E 1%, Platelet 174,000 AIHA Lc count 405, spherocyte 1+, polychromasia 2+, dCoombs’ test 2+ Lymphopenia UA: Prot 3+, dysmorphic RBC 50-100, WBC 10-20, CGC 1-2/hpf GN UPCI 4.8 NS Cr 1.1, Alb 2.31, Glob 1.86, TB 2.1, DB 1.4, AST 10, ALT 16, AP 133 HBsAg, anti-HBs, HBeAg, Anti-HBe : negative; Anti-HBc (IgG): positive HBV HBV DNA viral load: negative infection Anti-HCV: negative, Anti-HIV: negative, VDRL: negative CXR: Moderate bilateral pleural effusion, no pulmonary infiltration Echocardiogram: Mild pericardial effusion, LVH, EF 61% Cirrhosis US/CT abdomen: Ascites 4+, enlarged Lt lobe/caudate, no thrombosis, no stone Ascitic fluid analysis: Protein 1 g/dl , WBC 95, N 10%, L 90%, SAAG 1.2 Culture: no growth, Gene expert: negative for TB Serum-Ascites Albumin Gradient (SAAG) and Ascites protein Source of ascites Hepatic sinusoids Peritoneum SAAG > 1.1 SAAG < 1.1 Capillarized sinusoid Normal “leaky” sinusoid Peritoneal lymph Ascites protein < 2.5 Ascites protein > 2.5 Ascites protein > 2.5 Sinusoidal Post sinusoidal hypertension hypertension Peritoneal pathology Cirrhosis Cirrhosis Malignancy Late Budd-Chiari Early Budd-Chiari Tuberculosis Veno-occlusive disease 47 year-old woman, Housewife, NakornRachasima ANA: 1: 320 (homogeneous + speckled), anti-dsDNA: negative Anti-U1RNP, anti-Sm, anti-Ro52, anti-SS-A, anti-La: negative Anti-nucleosome: positive, ANCA: negative Coagulogram: normal, anti-cardiolipin antibodies: negative Anti-β2GP1 antibodies (IgG): 26.6 GPL 4 ºC 37 ºC C3 0.5 (0.9-2.1), C4 0.06 (0.1-0.4) RF: 76.1 (0-14), ACPA: negative Cryoglobulins: positive IEP: ↓ Alb 47.8% (55.8-66.1) Skin biopsy: Leucocytoclastic vasculitis α1 9.8% (2.9-4.9) Bone marrow study: Hypercellularity, α2 12.9% (7.1-11.8) myeloid hyperplasia, progressive kappa 72.6% (3.3-19.4) maturation, no malignant cells, Fe (+) 47 year-old woman, Housewife, NakornRachasima Problem lists What is the most likely diagnosis? 1. Palpable purpura (LCV) 2. Livedo racemosa (small arteriolitis) A. SLE 3. Glomerulonephritis (nephrotic range) B. Primary 4. AIHA anti-phospholipid 5. ? Polyserositis syndrome 6. HBV infection C. Cryoglobulinemic 7. Liver cirrhosis with ascites vasculitis 8. Low complement D. ANCA-associated 9. Positive ANA (anti-nucleosome) 10.Positive RF vasculitis 11.Positive anti-β2GP1 (abortion criteria) E. HBV-associated 12.Positive cryoglobulins vasculitis 47 year-old woman, Housewife, NakornRachasima Problem lists What is the most likely diagnosis? 1. Palpable purpura (LCV) 2. Livedo racemosa (small arteriolitis) A. SLE 3. Glomerulonephritis (nephrotic range) B. Primary 4. AIHA anti-phospholipid 5. ? Polyserositis syndrome 6. HBV infection C. Cryoglobulinemic 7. Liver cirrhosis with ascites vasculitis 8. Low complement D. ANCA-associated 9. Positive ANA (anti-nucleosome) 10.Positive RF vasculitis 11.Positive anti-β2GP1 (abortion criteria) E. HBV-associated 12.Positive cryoglobulins vasculitis SLE criteria used in the SLICC classification system 2012 Clinical criteria Met 4 classification Immunologic criteria 1. Acute OR subacute cut. LE criteria; 1. ANA above reference range 2. Chronic cutaneous LE including at least 2. Anti-dsDNA (or 2-fold ELISA) 3. Oral OR nasal ulcers one clinical 4. Non-scarring alopecia criterion 3. Anti-Sm positivity + 5. Synovitis (≥ 2) OR tenderness one 4. Anti-phospholipid antibodies immunologic (≥ 2) + MS ≥ 30 min. criterion LAC, false (+) VDRL, aCL ab, 6. Serositis OR 7. Renal (500 mg/d OR RBC cast) anti–β2GPI 8. Neurologic involvement Biopsy-proven 5. Low complement lupus nephritis 9. Hemolytic anemia + (C3, C4, CH50) 10. Leukopenia (4,000) ANAs OR 6. Direct Coombs’ test OR Lymphopenia (1,000) anti-dsDNA 11. Thrombocytopenia (100,000) antibodies (no hemolytic anemia) Shoulder area Dermo-epidermal junction Continuous granular staining Common: IgM OR IgM + IgG & C3 Poor prognosis: IgG + C3 Volar surface of upper 1/3 of forearms Immunofluorescent findings in Lupus nephritis (Class II up) Granular deposits (lumpy-bumpy pattern) IgG & C3 : Main components C1q : in class IV (anti-C1q antibodies) LN class IV (DPGN) IgG, IgA, IgM, C1q & C3 deposition (Full house immunofluorescent staining) + fibrin Nucleosome and anti-nucleosome (anti-NCS) abs. Anti-nucleosome antibodies dsDNA (B-form) wrapped twice around octameric core (2 of H2A, H2B, H3, H4) Anti-histone Anti-DNA antibodies antibodies Anti-nucleosome (anti-NCS) antibodies: Complementary biomarkers for diagnosis and disease activity of SLE Apoptotic cells Type II immune- mediated tissue injury dsDNA NCS exposure Type III immune- mediated tissue injury Anti-nucleosome GBMM Rekvig OP. Nat Rev Rheum 2015; 11, 530–540. Anti-dsDNA Anti-histone CLIFT (Crithidiae luciliae IF test) Inactive SLE Sensitivity 13-47% X-reaction Specificity 99-100% with kidney autoantigen Sensitivity 44-79% Sensitivity 50-100% Specificity 71-97% Specificity 97-100% Immune complex in kidney SLE Inactive SLE Other diseases (early, low activity) Drug-induced LE Active SLE Tissue damage Lemerle et al., Lupus Open Access 2017, 2:2. Anti-nucleosome (anti-NCS) antibodies in patients with SLE SLE vs Healthy controls Diagnosis for lupus nephritis Diagnosis in SLE vs Healthy controls Dx. SLE vs other autoimmune disease Correlation of autoantibodies and SLE activity (SLEDAI) Anti-nucleosome antibodies: Stronger diagnostic value than anti-dsDNA antibodies among SLE (esp; LN) > other systemic autoimmune diseases > healthy population Weaker association with SLE activity than anti-dsDNA antibodies Saigal R, et al. J Association Physicians India 2013; 61. Anti-NCS and anti-C1q: New non-invasive markers of SLE Anti- nucleosome Cut-off (U/ml) Anti-dsDNA, anti-NCS and anti-C1q: Association with SLE and lupus nephritis (LN) activity Potential usefulness in predicting LN and assessing disease activity Zivkovic V, et al. Srp Arh Celok Lek. 2014; 142(7-8):431-6. Autoantibodies Freq Specificity Disease association Anti-dsDNA 40-90% High LN, skin disease Anti-nucleosome (anti-NCS) 60-90% High LN, skin dis, drug-induced LE Anti-C1q 40-100% High LN Anti-SSA /Ro 30-40% Low LN, skin disease, cong. HB Anti-SSB /La 12-20% Low CHB Anti-Sm 5-30% High LN Anti-NMDAR (N-methyl-D- 30-50% Low NP-SLE aspartate receptor) Anti-phospholipid 20-30% High Thrombosis, habitual abortion Anti-NCS and anti-C1q antibodies: Play role in pathogenesis of SLE, associated with anti-dsDNA abs. May aid in SLE diagnosis in (~ 45%) patients with (-) anti-dsDNA abs. Marks SD, et al. Pediatr Nephrol 2011; 2078-4. Lemerle et al., Lupus Open Access 2017, 2:2. International Consensus Statement on an Update of the Classification Criteria for Definite APL Syndrome. 2006 (Revised Sydney Criteria) Clinical criteria 1. Vascular thrombosis 2. Pregnancy morbidities th Laboratory criteria ≥ 1 unexplained deaths of normal fetuses at ≥ 10 wk ≥ 1 premature births of neonates at ≥ 34th wk (eclampsia) 1. Lupus anticoagulant ≥ 3 unexplained consecutive spont. abortions < 10th wk 2. aCL-Ab (IgG or IgM) in medium or high titer (ELISA) (> 40 GPL (MPL) or > 99th percentile) 3. Anti-ß2 GP1 Ab. (IgG or IgM) in high titer (ELISA) (> 99th percentile) ≥ 2 occasions, ≥ 12 weeks apart Met criteria : ≥ 1 clinical criteria + 1 laboratory criteria