Case-Based Approach to Vasculitis

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

Miyakis S, et al. J Thromb Haemast 4(2): 2006; 295-306. Spectrum of Anti-phospholipid Syndrome

1. Primary aPL syndrome Incidence of thrombosis • 6 times of aPL(-) SLE 2. Secondary aPL syndrome • 11 times of non-SLE

Autoimmune: IgG (IgG2, IgG4) SLE, RA, MCTD, myopathies, etc.

Infection: IgM (IgG1, IgG3) Mump, malaria, leprosy, syphilis,

infectious mononucleosis, AIDS, herpes, parvovirus, prostatic infection

Malignancy: Lymphoma, solid tumors

Hematologic diseases: ITP, AIHA, myelofibrosis, sickle cell anemia

Drugs: Procainamide, phenothiazine, ethosuximide, hydralazine,

chlorothiazide, OC, quinine, fluphenazine, haloperidol, pencillin, procaine,

streptomycin, sulfonamide

3. Normal healthy person: 8% increase in age. Extra-criteria for APS Obstetric: Pregnancy loss, placental infarct, eclampsia Peripheral venous system: Deep venous thrombosis CNS: CVA, sinus thrombosis, migraine, TV myelitis, chorea GB syndrome, dementia Hematologic: Thrombocytopenia, hemolytic anemia (+) Coomb Pulmonary: PE, PAH GI: Budd-Chiari syndrome, portal vein thrombosis Skin: Livedo reticularis, purpura, infarcts/ulceration Cardiac: Libman-Sacks valvulopathy, IHD Ocular: Amaurosis, retinal vein thrombosis Renal : Thrombotic microangiopathy, renal vein thrombosis Adrenal gld: Infarction / hge Musculoskeletal: AVN Cryoglobulinemia

Type I Mixed cryoglobulinemia (25%) Type II (25%) Type III (50%) Associated Lymphoproliferative HCV infection HCV infection diseases disorders (LPD) CNTD (SLE, SjS, RA) CNTD (SLE, SjS, RA) Essential, LPD, Essential Other infections Other infections

4 ºC 37 ºC Conc > 5 mg/ml Conc < 1 mg/ml Conc < 1 mg/ml

Monoclonal Ig Monoclonal IgM (RF) Polyclonal IgM Cryoprecipitate (IgM > IgG, IgA, LC) Polyclonal IgG Polyclonal IgG Cryoglobulinemia

Symptoms and signs Type I Type II Type III

• Purpura + +++ +++ • Gangrene/acrocyanosis +++ + to ++ ± • Arthralgia > arthritis + ++ +++ • Renal + ++ + • Neurologic + ++ ++ • Liver ± ++ +++ 47 year-old woman, Housewife, NakornRachasima Systemic Lupus Erythematosus (SLE) AIHA Low complement Cutaneous vasculitis ± serositis Positive ANA Glomerulonephritis (NS) Positive anti-nucleosome Secondary anti-phospholipid syndrome (APS) Abortion criteria Positive anti-β2GP1 Livedo racemosa

Mixed cryoglobulinemia Positive RF Positive cryoglobulins Low complement levels Cirrhosis of liver Chronic liver disease Positive anti-HBc Portal hypertension (ascites) antibodies Active SLE, liver cirrhosis (HBV infection) secondary APL syndrome and mixed cryoglobulinemia

Management Active SLE GN with NS Prednisolone (5 mg/tab) 1 mg/kg/day (4 tab x 3 pc) AIHA Induction therapy: Vasculitis Monthly bolus IV cyclophosphamide 0.75 g/m2 BSA Daily hydroxychloroquine 200 mg OD (or AD) Liver cirrhosis Aspirin (80 mg) 1 tab x 1 pc HBV infection Lamivudine (150 mg) 1 x OD Calcium, vitamin D, and folic acid supplementation Closed monitor of liver function (viral reactivation) Patient education and regular follow-up Thank You