ANCA associated vasculitides 이상헌

ANCA (Anti-Neutrophilic Cytoplasmic Antibody) Introduction ANCA (Anti-Neutrophilic Cytoplasmic Antibody) In 1982, 1st described in patients with pauci-immune GN 1985, ANCA had been linked to Wegener's granulomatosis (WG) 2 types of ANCA assays Indirect immunofluorescence assay : more sensitive ELISA : more specific 2 Relevant target antigen Proteinase 3 (PR3) & Myeloperoxidase (MPO) Azurophilic granules of neutrophil, Peroxidase(+) lysosomes of monocyte PR3-ANCA (PR3 specific), MPO-ANCA (MPO specific)

IF patterns in vasculitis Introduction IF patterns in vasculitis  C-ANCA pattern diffuse throughout the cytoplasm, against PR3 P-ANCA pattern usually directed against MPO (and only occasionally PR3)

Granulomatosis with polyangiitis (Wegener’s) Disease Association  Granulomatosis with polyangiitis (Wegener’s) Microscopic polyangiitis (MPA)  Renal-limited vasculitis Eosinophilic granulomatosis with polyangiitis (CSS) Anti-GBM antibody disease Drug-induced ANCA-associated vasculitis 

Sensitivity : 88% Specificity : 92% Not discirminate GPA & MPA > 2 more + ANCA(+) Sensitivity : 88% Specificity : 92% Not discirminate GPA & MPA ACR criteria In 1990, American College of Rheumatology   Nasal or oral inflammation (painful or painless oral ulcers/purulent or bloody nasal discharge) Abnormal chest x-ray (nodules, fixed infiltrates, cavities) Abnormal urinary sediment (microscopic hematuria with or without red cell casts) Granulomatous inflammation on biopsy of an artery or perivascular area  

European Medicines Agency (EMA) algorithm GPA European Medicines Agency (EMA) algorithm Upper airways : Bloody nasal discharge & Crust for >1 month Chronic sinusitis, otitis media or mastitis for >3 month Retro-orbital mass on inflammation Subglottic stenosis, saddle nose deformity Lower airways : x-ray evidence fixed pulmonary Infiltration, nodule or cavitation for more >1 month , or bronchial stenosis GN : Hematuria with RBC cast or > 10 dysmorphic RBC 2+ hematuria or 2+ proteinuria on dipstick ANCA (+) : surrogate markers for GPA  

Lab finding GPA ANCA test should be performed 82 ~ 94% of patients with either GPA & MPA : ANCA(+) GPA : PR3-ANCA (C-ANCA) MPA : MPO-ANCA (P-ANCA) Renal limited vasculitis : MPO-ANCA(75~80%) 20%  alternative ANCA 10%  ANCA(-)

NIH study Manifestation Renal disease of GPA Evident GN : only 18% of patients at presentation within 2 years, GN developed in 77~85% Manifestation Asymptomatic hematuria AKI with hematuria & cellular cast Proteinuria : usually subnephroic, > 3g  later in the course of dz RPGN is common

Histologic finding Renal disease of GPA Severity of renal biopsy ≒ severity of clinical presentation May have granulomatous change (not in MPA) Arteritis Pauci-immune GN : few or no immune deposit in glomeruli 94% ANCA(+)

Renal limited vasculitis Present with renal limited Pauci-immune necrotizing GN MPO-ANCA (75 ~ 80 %) Part of the GPA/MPA spectrum Histopathologic findings are indistinguishable Eventually exhibit extrarenal manifestations More glomerulosclerosis  detect later d/t absence of extrarenal symptom

Other clinical manifestation of GPA ENT disease Either GPA & MPA (more common in GPA, 90% VS 35%) Bony & cartilage destruction  Saddle nose Pulmonary disease Hoarsness, cough, dyspnea, stridor, wheezing, hemoptysis  Tracheal or subglottic stenosis Pulmonary consolidation, effusion Pulmonary HTN or fibrosis  

Pulmonary manifestation

Granulomatous inflammation in MPA (-) GPA : PR3-ANCA, MPA : MPO-ANCA GPA VS MPA GPA VS MPA Granulomatous inflammation in MPA (-) GPA : PR3-ANCA, MPA : MPO-ANCA Significantly low rate of upper air way involvement in MPA Lower rate of relapse in MPA (After remission)  

Immunosuppressive Tx.

Who should be treated ? Immunosuppressive Tx. Even patients with advanced renal disease (HD patients) may receive benefit from aggressive Tx. 155 patients with GPA, MPA, renal limited, 87% of patients on HD All patients treated with cyclophosphamide & glucocorticoid  After 4month 51% did not require HD, 35% HD, 14% died (Clin J Am Soc Nephrol 9: 905–913, 2014) 240 patients eGFR < 30  remission 72% 188 patients eGFR < 20  remission 68% 96 patients eGFR < 10  remission 57% (Ann Intern Med. 2005;143(9):621)  

Immunosuppressive Tx. Conclusion Primary endpoint : remission of disease without use of prednisolone at 6 month 197 patients, 1 : 1 ratio, Rituximab (375mg/m2, weekly for 4 times), Oral cyclophosphamide (2mg/kg/day), M-PDL pulse (1000mg) 3 days + PDL (1mg/kg/day) CR rate  Rituximab group 63 patients (64%) , Cyclophosphamide 52 patients (53%) (P < 0.001), Relapsing  Rituximab 67%, Cyclophophamide 42% (P=0.01) Adverse event : no significant difference  

Immunosuppressive Tx.

Immunosuppressive Tx.

Cyclophosphamide regimen Use 0.5g/m2 every 2 weeks for 3 to 6 months (6~12 times) WBC > 3500, ANC > 1000  2 weeks later, increase dose 0.75g/m2 Use MESNA Methyl-prednisolone pulse (500~1000mg) 3 days Followed by oral PDL (1mg/kg/day, max 80mg)  initial dose 2~4 weeks  tappering to 20mg/day for 2 months. Total duration : 6 months, after 6 month  higher infection rate PCP prophylaxis : Septrin 1T daily  

Initially 1g Rituximab  14 days later 1g Rituximab Rituximab regimen 375mg/m2 per week for 4 weeks Initially 1g Rituximab  14 days later 1g Rituximab Methyl-prednisolone pulse (500~1000mg) 3 days Followed by oral PDL (1mg/kg/day, max 80mg)  initial dose 2~4 weeks  tappering to 20mg/day for 2 months. Total duration : 6 months, after 6 month  higher infection rate PCP prophylaxis : Septrin 1T daily  

1996, University of North Carolina Definition of CR Complete remission In 1992, NIH   Systemic inflammatory disease (-) : fever, serositis Pul. infiltrates (-), stable scarring Inactive urine sediment or improvement in renal function 1996, University of North Carolina Stabilization of or reduction in the serum creatinine Resolution of extrarenal manifestations Persistent proteinuria  Not considered a persistent dz activity Renal remission < 5 RBC/HPF

Monitor at monthly for 3 ~ 6 month after remission Monitoring of disease BVAS/GPA score ANCA titer Monitor at monthly for 3 ~ 6 month after remission Titer stable  monitor every 3 to 4 months Do not recommend treatment for relapse based solely upon ANCA titer  Rise in ANCA titer is not consistently predictive of disease flare  

Risk factor for relapse Seropositivity for PR3-ANCA Involvement of lung & upper respiratory tract Persistence of elevated ANCA titer, particular PR3-ANCA Rising ANCA titer S. aureus nasal carriage : not fully understood, but may involve the staphylococcal toxic shock syndrome toxin-1 Past Hx of relapsing disease  

1869396 조 O O M/72 Case C.C : For AVF OP Brief Hx Past Hx : 2014/3/4 Cr 2.0, Hb 10.0 으로 원자력 병원 신장내과 내원. 2014/5/ 7까지 OPD F/U 이후 F/U Loss. 2014/11/ 29, 전신쇠약, 부종으로 원자력 병원 신장내과 입원 2014/12/08일까지 보존적 치료. 투석 치료 시작해야 한다는 소견 듣고 을지병원으로 전원. 을지병원에서 화,목,토 투석하고 입원 중 HAP로 치료 시행함.

Case Past hx : DM(-), HTN(-), 폐가 좋지 않아 서울대 F/U 했었다50pack/yr smoking Lab CBC 7700-10.2/31.4-127K, BUN/Cr (19.6/4.12) GFR(13.5) OT/PT(65/53) Electro (136-2.7-97-23) CRP (5.7) RUA : Prt 3+, Blood 4+, RBC (numerous), WBC (10-29) ACR 2381mg/g, TCR 4053mg/g 을지병원 Lab Anti-SM Ab(+), Jo-1 Ab(-), Histone Ab(-), Anti-ds DNA(-) PR3-ANCA(-), MPO-ANCA(+) > 600, C3 52↓, C4 15, Anti-GBM Ab(-) ANA(+, 1:640 thin homogenous) Serum electrophoresis : polyclonal gammopathy

Case Serology lab Serum Immunofixation : polyclonal gammopathy Ig G (2004 ↑), Ig G4 (2060), C3 (90), C4 (22), ASO (10) ANCA(+) : MPO-ANCA (+, > 8.0), PR3-ANCA (-) Anti-ds DNA (-), ANA (-), Anti-GBM Ab (-), CH50 (46.6) Serum Immunofixation : polyclonal gammopathy Free kappa & lambda light chain : 224/206

Case (Chest PA & PNS water’s view)

Case (Abdomen USG)

Case (외부 Chest CT)

R/O Malignant lymphoma Case (외부 PET) R/O Malignant lymphoma

Impression Hospital course Case ESRD on HD d/t renal limited vasculitis (ANCA+) Emphysema R/O Malignant lymphoma Hospital course Kidney biopsy : 2015/1/22 Excional biopsy (Rt. Axilla) : Axillar USG  Too small to biopsy

Case (Chest CT F/U. 15/1/30)

Kidney biopsy

Treatment Case Methyl-prednisolone pulse 500mg IV 3 days Oral PDL 40mg Change 15/2/3 Oral Cyclophosphamide 50mg qd start