anca-associated vasculitis in china - hksn · 1 anca‐associated vasculitis in china renal...

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ANCA‐associated vasculitis in China

Renal Division, Peking University First Hospital,Beijing 100034, P. R. China

Min Chen

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• General introduction of AAV in China– Disease spectrum and ANCA type

• Clinical and pathological study– Treatment and outcomes

• Pathogenic studies – Complement and neutrophils

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Large Vessel VasculitisGiant Cell ArteritisTakayasu Arteritis

Medium Vessel VasculitisPolyarteritis NodosaKawasaki Disease

Small Vessel VasculitisANCA‐Associated Vasculitis

Microscopic PolyangiitisGranulomatosis with Polyangiitis (Wegener’s)Eosinophilic Granulomatosis with Polyangiitis (Churg‐Strauss)

Immune Complex VasculitisAnti‐GBM DiseaseIgA Vasculitis (Henoch‐Schönlein)Cryoglobulinemic VasculitisHypocomplementemic 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.)

2012 Chapel Hill Consensus Conference Vasculitis Nomenclature

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End of 1980s

End of 1990s

2000s

Began to diagnose a few patients

Established methods for ANCA testThe number of patients increased rapidly

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

ANCA vasculitis in China

A common autoimmune disease in Western countries

No epidemiological data available in China yet

In our center

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Disease spectrum

• A striking preponderance of

MPA: 60‐80% of the patients

with AAV

• In older patients, the

proportion of MPA is even

higher than youngers

%

*

*

#

* P<0.01, # P<0.001

Chen M, et al. Postgrad Med J 2005; 81:723‐7

Chen M, et al. Medicine (Baltimore) 2009; 87: 203‐9

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61,8%81,5%

27,8%

55,8%

0%

25%

50%

75%

100%

eye ear

MPO -ANCA PR3-ANCA

GPA: MPO‐ANCA (+) vs. PR3‐ANCA(+)

81.5%

61.8%

42.6%

70.6%

0%

25%

50%

75%

100%

initial Scr↑ male

MPO-ANCA PR3-ANCA

Chen M, et al. Kidney Int 2005

Chen M, et al. Nephrol Dial Transplant 2007

Compare with traditional PR3‐ANCA(+) GPA, MPO‐ANCA(+) GPA was：female predominantless common on head and neck involvementMore chronic lesion in renal histology ?

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Treatment• Induction therapy

– Corticosteroids plus CTX /Rituximab– Plasma exchange for severe ones

• Maintenance therapy– AZA– MMF– …

Dose of immunosuppressant is less than Caucasians

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Outcomes

• Mortality• Relapse and treatment resistance• Renal outcomes

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endpoint predictors

mortality

ESRD

relapse

Age, Scr, infection

Normal G, T‐I lesion

Pulmonary, Scr

Predictors of various outcomes in AAV

Lai QY, et al. J Rheumatol 2014


Li ZY, et al. Arthritis Rheumatol 2014; 66: 1920‐6

Li ZY, et al. Semin Arthritis Rheum 2013

A large cohort of 500+ pts. , follow‐up more about 15 yr

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

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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

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• 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


15Shi YY, et al. Medicine 2015

Cardiovascular outcomes• 504 patients，median follow up 38 (1‐228) months• CV events：117， CV mortality： 41

• 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

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• 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)

Treatment resistance and relapse

Li ZY, et al. Arthritis Rheumatol 2014; 66: 1920‐6

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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

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Prospective

• How to control active AAV

• How to avoid infection

• Cardiovascular disease

• Malignancy

• Quality of life/mental health

• Biomarkers to predict disease severity/outcomes

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• Pathogenic studies – Complement activation

PNAS 1990

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Complement did not play a key role

Ag‐Ab reaction complement activation

No hypocomplementemia Pauci‐immune

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.

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• Renal histology：

– Bb~ crescent,

– Bb~ TI lesion

• Urine

– Bb~ Scr

– Bb~ normal G

Gou SJ, et al. Clin J Am Soc Nephrol 2013

Bb in circulation ~ disease activity

Gou SJ, et al . Kidney Int 2013

Complement activation in circulation: AP

Chen SF, et al. Arthritis Res Ther 2015

Factor H：negative regulator of AP

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

Chen SF, et al. Clin Immunol 2017

The complement regulatory activity of FH was deficient in AAV

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AP in AAV• Overactivation• Dysregulation

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Huugen D, et al. Kidney Int 2007; 71: 646–54.Schreiber A, et al. J Am soc Nephrol 2009; 20: 289‐98Xiao H, et al. J Am soc Nephrol 2014; 25: 225‐31

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Pathogenic role of C5a

Kidney Int 2013Arthritis Rheumatol 2015

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Neutrophil extracellular traps，NETs

AP

neutrophils

Wang H, et al. Clin Exp Immunol 2015

PrimingTNF-α

ANCAPrimingC5a

BC3

PC3bC3

C3b(H2O)BbP C3a

C3bBp

C3bBbPC3 convertase

D

C5bC5

+C3b

(C3b)nBbPC5 convertase

Wang H, et al. Clin Exp Immunol 2015

• 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

(1) prednisone 60mg/day,

(2) CCX168 30 mg b.i.d.+ prednisone 20 mg

(3) CCX168 30 mg b.i.d.

+ CTX or RTX

C5aR/CD88 small molecule antagonist CCX168 in AAV: The CLEAR trial

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

anca-associated vasculitis in china - hksn · 1 anca‐associated vasculitis in china renal...

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