SMALL TO MEDIUM VASCULITIS: RENAL ASPECT RATANA CHAWANASUNTORAPOJ UPDATE IN INTERNAL MEDICINE 2018
OUTLINE Renal involvement in vasculitis Curr Rheumatol Rep 2013
Renal involvement in ANCA vasculitis GN***: Nephritis, RPGN, vasculitis, interstitial nephritis Pyelonephritis, hydronephrosis: vasculitis, ureteral stenosis Renal medullary angiitis, Papillary necrosis Perirenal hematoma: a. aneurysm rupture Lymphoreticular malignancy with neoplastic infiltration of renal parenchyma
Class Focal Inclusion Criteria Normal glomeruli > 50%, good renal outcome Crescentic Cellular crescent > 50% Sclerotic Mixed Global sclerosis > 50%, poor renal outcome < 50% of normal glomeruli, global sclerosis
ARTERIAL BRANCH
FIBRINOID NECROSIS INTIMAL THICKENING
TUBULOINTERSTITIAL INVOLVEMENT
38 cases - 30 Dx ANCA 19 ANCA ab + - 11 non ANCA: 20%-IgA - 8 unknown ANCA: 50% pauci-immunegn
5/23 (22%) renal papillary necrosis
ANCA
ANCA ASSOCIATED VASCULITIS (AAV): SYSTEMIC, RENAL LIMITED VASCULITIS (RSV) ANCA associated systemic vasculitis (AAV) Renal limited vasculitis (RLV) or ANCA glomerulonephritis AAV Patient survival without Rx : 80% Patient survival with Rx - 1 year: 85% ESRD : 28% of surviving patients RLV - 5 year: 75% (ANCA-GN) ESRD : 14-37% Walton EW. BMJ 1958; 2: 265 Booth AD, et al. AJKD 2003; 41: 776
GRANULOMATOSIS WITH POLYANGIITIS (GPA) GPA, first described in 1930s by Friedrich Wegener (WG) Necrotizing granulomatous vasculitis of respiratory tract, GN, small to medium vessel vasculitis ANCA, first described in 1982 C-ANCA, anti-pr3
MICROSCOPIC POLYANGIITIS (MPA) Dr. A. Kussmaul Rudolf Robert Maier PAN, first described in 1852 by Rokitansky. PAN, completely described in 1860s by Kussmaul and Maier. MPA, first named in 1950s by Wainwright and Davson. P-ANCA K. Rokitansky
EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA) EGPA, first described in 1951 by Churg and Strauss
CLASSIFICATION OF ANCA-ASSOCIATED VASCULITIS ACR 1990 (American College of Rheumatology) CHCC 1994 (Chapel Hill Consensus Conference) EMA 2007 (European Medicines Agency) CHCC 2012: Definition (nomenclature) DCVAS (The Diagnostic and Classification Criteria for Vasculitis)
CHCC 2012 NOMENCLATURE OF VASCULITIDES Large vessel vasculitis (LVV) - Takayasu arteritis - Giant cell arteritis Medium vessel vasculitis(mvv) - Polyarteritis nodosa - Kawasaki disease Small vessel vasculitis (SVV) 1) ANCA associated vasculitis -GPA (WG) -MPA - EGPA (CSS) 2) Immune complex SVV - anti-gbm - Cryoglobulinemic vasculitis - Henoch Schonlein purpura - anti-c1q vasculitis Variable vessel vasculitis (VVV) - Bechet s disease - Cogan s syndrome Single-organ vasculitis - Cutaneous LCV - Cutaneous arteritis - Primary CNS vasculitis - Others Vasculitis assoc w systemic dis - Lupus vasculitis - Rheumatoid vasculitis - Sarcoid vasculitis Vasculitis assoc w prob etiology - HCV assoc cryoglob. vasc. - HBV assoc vasculitis - Syphilis associated aortitis - Drug induced vasculitis - Cancer associated vasculitis
SF Elgueta et al. Ann Rheum Dis 2017;76:1257
Nat Rev Rheumatol 2017
Organ MPA GPA EGPA RSV Kidney 90-99.2 80-89.7 45 100 Lung 50-59.5 81.2-90 70 0 ENT 35-36.7 75.2-90 50 0 Neurologic 30 50 70 0 Gastrointestinal 50 50 50 0 Skin 40 40 60 0 Musculoskeletal 60 60 50 0 MPO 58.7 25.6 60 81 PR3 41.3 74.4 10 19
Curr Opin Rheumatol 2015
PROGNOSTIC MARKERS Poor renal outcome Initial low GFR Non response, relapse Elderly > 65 years Sclerotic lesion Treatment resistant Female (Black) Severe renal disease Poor patient outcome Irreversible organ dysfunction *lung hemorrhage Elderly > 65 years Untreated with CYC Prolonged immunosuppress. Treatment related infection Anual Int Med 2005 *J Rheumatol 2014 Arthritis Rhem 2014
PROGNOSTIC MARKERS Risk of relapse Persistence PR3-ANCA History of upper respiratory tract disease History of lower respiratory tract disease* Any of three increase risk 1.7x, all three increase 3.7x Anual Int Med 2005 *J Rheumatol 2014 Lung involvement, lower initial creatinine (439 Chinese) Arthritis Rhem 2014
ANCA NEGATIVE GLOMERULONEPHRITIS ANCA -ve vasculitis 10% AAV, ANCA -ve GN 10-30% pauci-immune GN
RENAL SURVIVAL IN ANCA (-) GN Min Chen et al. Nat Rev Nephrol 2009
DOUBLE POSITIVE ANCA & ANTI-GBM McAdoo SP. KI 2017
DOUBLE POSITIVE ANCA & ANTI-GBM McAdoo SP. KI 2017
TREATMENT
DISEASE STAGES IN AAV Stage EUVAS/EULAR def. Systemic outside ENT or lung Threatened vital organ Cr. (mg/dl) Localized Respiratory No No < 1.4 Early systemic Any disease without life-threatening organ Yes No < 1.4 Generalized Renal or organ threatening dis Yes Yes < 5.7 Severe Renal or vital organ Yes Organ failure > 5.7 Refractory Progressive dis unresponsive to standard Rx Yes Yes Any
CLINICAL ISSUES FOR THERAPY Remission induction/initial treatment Aim: Rapidly induce remission Remission maintenance/maintenance therapy Aim: Prevent relapse with less exposure to toxic drug
KDIGO 2012: GUIDELINE IN PAUCI-IMMUNE GN Derive from patients with ANCA vasculitis + GN 10% : ANCA neg MPA or WG or pauci-immune GN
KDIGO 2012 Initial Rx 1. Recommend: steroid + cyclophosphamide (1A) 2. Steroid + rituximab (1B) = alternative initial Rx in non severe case or can not use CYC Special patients 1. Plasmapheresis for patients requiring dialysis or rapidly increasing Cr (1C) 2. Plasmapheresis in lung hemorrhage (2C) 3. Plasmapheresis in ANCA + anti-gbm (2D) 4. Discontinue CYC after 3 months in dialysis-dependent and no extrarenal involvement (2C)
RECOMMENDED RX REGIMENS FOR ANCA-GN Agents Route Initial dose CYC i.v. 0.75 g/m 2 q 3-4 wk or keep nadir WBC > 3,000/mm 3 CYC p.o. 1.5-2 mg/kg/d keep WBC > 3,000/mm 3 Steroid i.v. Pulse methylprednisolone 500 mg i.v. x 3 days Steroid p.o. Prednisolone 1 mg/kg/d x 4 wk (< 60 mg) taper down 3-4 mo Rituximab i.v. 375 mg/m 2 weekly x 4 Plasmapheresis 60 ml/kg volume replace Vasculitis: 7 Rx over 14 days diffufuse lung hemorrhage daily till bleeding stop then alternate day, total 7-10 Rx Vasculitis+antiGBM: daily x 14 or undetectable anti-gbm abs
RECOMMENDED REGIMENS FOR INDUCTION Disease stage Regimen Dose Trial Localized Methotrexate + steroid 15 mg/wk, 20-25 mg/wk + folic acid + steroid NA Early systemic Methotrexate + steroid 15 mg/wk, 20-25 mg/wk + folic acid + steroid NORAM Generalized CYC IVCY 15 mg/kg q 2 wk, then q 3 wk x 6-9 doses Or oral CYC 2 mg/kg/d 3-6 mo Generalized Severe Rituximab + steroid Plasmapheresis + Standard Rx CYCLOPS 375 mg/m 2 q 1 wk x 4 doses RAVE RITUXVAS Plasma exchange 60 ml/kg X 7 rounds (or more) MEPEX Refractory Rituximab 375 mg/m 2 or 1 g iv q 4-6 mo Holle et al. Refractory IVIg 2 g/kg Jayne et al. Refractory MMF 2 g/day Joy et al.
KDIGO 2012 Maintenance therapy 1. Maintenance in remission cases (1B) 2. > 18 months in complete remission (1C) 3. No maintenance Rx in dialysis-dependent and no extrarenal manifestations (1C) Drugs 1. Azathioprine (AZA) 1-2 mg/kg/d (1B) 2. MMF 2 g/d in patients who can not use AZA (2C) 3. Trimethoprim-sulfamethoxazole as adjunt to maintenance Rx in up respiratory tract disease (2B) 4. MTX in contraindicated to AZA/MMF w GFR > 60 ml/min/1.73 m 2 (1C) 5. Not using etanercept as adjunctive Rx (1A)
RECOMMENDED REGIMENS FOR MAINTENANCE Disease stage Regimen Dose Trial Localized Co-trimazole 960 mg bid NA Early systemic Methotrexate 20-25 mg/wk + low dose prednisolone Generalized Azathioprine 2 mg/kg/d x 12 mo, 1.5 mg/kg/d x 6 mo + low dose pred Generalized Methotrexate 20-25 mg/wk + low dose prednisolone NORAM WEGENT LEM CYCAZAREM WEGENT Generalized Leflunomide 20 mg/d + low dose pred LEM Generalized Rituximab 375 mg/m 2 or 1 g iv q 4-6 mo Ongoing
??????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????
RCT for Induction of Remission in AAV Nat Rev Nephrol 2014
RCT for Maintenance of Remission in AAV Nat Rev Nephrol 2014
ANCA TESTING