ANCA associated vasculitis in China Min Chen Renal Division, Peking University First Hospital, Beijing 100034, P. R. China 1
General introduction of AAV in China Disease spectrum and ANCA type Clinical and pathological study Treatment and outcomes Pathogenic studies Complement and neutrophils 2
General introduction of AAV in China Disease spectrum and ANCA type Clinical and pathological study Treatment and outcomes Pathogenic studies Complement and neutrophils 3
2012 Chapel Hill Consensus Conference Vasculitis Nomenclature Large Vessel Vasculitis Giant Cell Arteritis Takayasu Arteritis Medium Vessel Vasculitis Polyarteritis Nodosa Kawasaki Disease Small Vessel Vasculitis ANCA Associated Vasculitis Microscopic Polyangiitis Granulomatosis with Polyangiitis (Wegener s) Eosinophilic Granulomatosis with Polyangiitis (Churg Strauss) Immune Complex Vasculitis Anti GBM Disease IgA Vasculitis (Henoch Schönlein) Cryoglobulinemic Vasculitis Hypocomplementemic Urticarial Vasculitis (Anti C1q Vasculitis) Variable Vessel Vasculitis (Cogan s, Behcet s, etc.) Single Organ Vasculitis (cutaneous SVV, primary CNS vasculitis, etc.) Vasculitis Associated with Systemic Diseases (e.g. Rheumatoid, Lupus, Sarcoid, etc.) Vasculitis Associated with Probable Etiologies (e.g. HBV, HCV, drug, cancer, etc.) 4
ANCA vasculitis in China A common autoimmune disease in Western countries No epidemiological data available in China yet End of 1980s Began to diagnose a few patients End of 1990s Established methods for ANCA test The number of patients increased rapidly 2000s Start to establish our cohort More than 500 patients with long term regular follow up Nearly 300 patients with renal biopsy sample Biobank: blood, urine, renal biopsy, DNA In our center 5
Disease spectrum A striking preponderance of MPA: 60 80% of the patients % * * P<0.01, # P<0.001 with AAV In older patients, the proportion of MPA is even higher than youngers * # Chen M, et al. Postgrad Med J 2005; 81:723 7 Chen M, et al. Medicine (Baltimore) 2009; 87: 203 9 6
GPA: MPO ANCA (+) vs. PR3 ANCA(+) 100% 75% 61,8% 81,5% 55,8% 100% 75% 81.5% 61.8% 42.6% 70.6% 50% 27,8% 50% 25% 25% 0% eye ear 0% initial Scr male MPO -ANCA PR3-ANCA MPO-ANCA PR3-ANCA Compare with traditional PR3 ANCA(+) GPA, MPO ANCA(+) GPA was: female predominant less common on head and neck involvement More chronic lesion in renal histology? Chen M, et al. Kidney Int 2005 Chen M, et al. Nephrol Dial Transplant 2007 7
General introduction of AAV in China Disease spectrum and ANCA type Clinical and pathological study Treatment and outcomes Pathogenic studies Complement and neutrophils 8
Induction therapy Treatment Corticosteroids plus CTX /Rituximab Plasma exchange for severe ones Maintenance therapy AZA MMF Dose of immunosuppressant is less than Caucasians 9
Outcomes Mortality Relapse and treatment resistance Renal outcomes 10
Predictors of various outcomes in AAV A large cohort of 500+ pts., follow up more about 15 yr endpoint mortality predictors Age, Scr, infection relapse Pulmonary, Scr ESRD Normal G, T I lesion Lai QY, et al. J Rheumatol 2014 Chen M, et al. Medicine (Baltimore) 2008; 87: 203 9 Li ZY, et al. Arthritis Rheumatol 2014; 66: 1920 6 Li ZY, et al. Semin Arthritis Rheum 2013 11
Mortality Study from EUVAS: early mortality is a crucial issue Active vasculitis per se Complication from heavy burden of immunosuppressive therapy: esp. infection Ann Rheum Dis 2009
Mortality 398 patients, with a median follow up of 25.5 (range 1 196) months, with 83/135 death happening within the first year Lai QY, et al. J Rheumatol 2014 Chen M, et al. Medicine (Baltimore) 2008; 87: 203 9 13
Predictors of all cause mortality: older age (p<0.001), secondary infection (p<0.001) initial Scr (p<0.001) Leading cause of death Within 1 year: secondary infection (53/153, 39.3%) After 1 year: cardiovascular events (15/53, 28.8%) Predictors of secondary infection lymphocyte counts in the peripheral blood (p=0.004) basic pulmonary involvement of AAV (p<0.001) older age Lai QY, et al. J Rheumatol 2014 Chen M, et al. Medicine (Baltimore) 2008; 87: 203 9 14
Shi YY, et al. Medicine 2015 15
Cardiovascular outcomes 504 patients,median follow up 38 (1 228) months CV events:117, CV mortality: 41
Treatment resistance and relapse Relapse is an independent predictor of ESRD Study from North Carolina and France Predictors of relapse PR3-ANCA Upper respiratory tract and lung involvement Lung involvement Predictors of treatment resistance Older age Female African American MPO-ANCA Poor renal function Hogan SL, et al. Ann Intern Med. 2005;143:621-631. Pagnoux C, et al.. Arthritis Rheum. 2008;58:2908-2918.
Treatment resistance and relapse Our center: 439 AAV patients Treatment resistance: 47/439 (10.7%) higher Scr (OR 1.087, 95%CI 1.001 1.180, P=0.047) ESR level (OR 1.009, 95%CI 1.001 1.018, P=0.025) Relapse: 128/392 in 48 (range 3 171) months lung involvement (HR 1.768, 95%CI 1.088 2.872, P=0.021) lower Scr (HR 0.925, 95%CI 0.872 0.981, P=0.009) Li ZY, et al. Arthritis Rheumatol 2014; 66: 1920 6 19
Predictors for renal restoration in severe ANCA GN 89 ANCA GN patients on dialysis at presentation At the 6th month of treatment, 28.1% dialysis independent, 50.6% ESRD, 21.3% died, including 9/19 died from infection Predictor of renal restoration Proportion of normal G Extent of tubular atrophy and intersititial fibrosis Leading cause of death: infection Li ZY, et al. Semin Arthritis Rheum 2013 20
Prospective How to control active AAV How to avoid infection Cardiovascular disease Malignancy Quality of life/mental health Biomarkers to predict disease severity/outcomes 21
General introduction of AAV in China Disease spectrum and ANCA type Clinical and pathological study Treatment and outcomes Pathogenic studies Complement activation 22
PNAS 1990
Pauci immune No hypocomplementemia Complement did not play a key role Ag Ab reaction complement activation C3c deposition, more severe disease Complement activation C3c: 37/112 (33.0%), severe renal lesion Heavy proteinuria Poor renal function More crescent Severe TI injury Chen M et al. Nephrol Dial Transplant 2009;48(4):355 8. 24
Renal histology: Bb~ crescent, Bb~ TI lesion Urine Bb~ Scr Bb~ normal G Gou SJ, et al. Clin J Am Soc Nephrol 2013 25
Complement activation in circulation: AP Bb in circulation ~ disease activity Gou SJ, et al. Kidney Int 2013
Factor H:negative regulator of AP Chen SF, et al. Arthritis Res Ther 2015
MPO released from ANCA activated neutrophil binds mcrp Such binding may block the binding of mcrp FH, thus inhibit the regulatory effect of FH on AP Xu PC, et al. Innate Immunity 2014
The complement regulatory activity of FH was deficient in AAV AP in AAV Overactivation Dysregulation Chen SF, et al. Clin Immunol 2017 29
Huugen D, et al. Kidney Int 2007; 71: 646 54. Schreiber A, et al. J Am soc Nephrol 2009; 20: 289 98 Xiao H, et al. J Am soc Nephrol 2014; 25: 225 31 30
Pathogenic role of C5a Arthritis Rheumatol 2015 Kidney Int 2013 31
Neutrophil extracellular traps,nets AP neutrophils Wang H, et al. Clin Exp Immunol 2015 32
Priming TNF-α C5a Priming ANCA C5 C5b (C3b)nBbP C5 convertase C3 C3bBbP C3 convertase C3b(H 2 O)BbP +C3b C3b C3a C3bB p D C3 B P Wang H, et al. Clin Exp Immunol 2015
C5aR/CD88 small molecule antagonist CCX168 in AAV: The CLEAR trial (1) prednisone 60mg/day, (2) CCX168 30 mg b.i.d.+ prednisone 20 mg + CTX or RTX (3) CCX168 30 mg b.i.d. CCX168 successfully replaced glucocorticoid treatment, with a more rapid onset of action based on BVAS, UACR, HRQOL, a lower incidence of steroid-related adverse effects. Jayne D et al. J Am Soc Nephrol 2017
Two players: ANCA, neutrophils
Three players: ANCA, neutrophils, complement
Take home message AAV is a group of common autoimmune disease in China, MPO AAV is the most common type Pred + CTX is the mainstay of treatment, secondary infection the main cause of death nowadays. Complement activation is a crucial aspect in the pathogenesis and treatment target
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