1. ANCA associated vasculitides
이상헌

2. 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)

3. 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)

4. 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 

5. 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

6. 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

7. 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(-)

8. 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

9. 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(+)

10. 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

11. 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

12. Pulmonary manifestation

13. 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)

14. Immunosuppressive Tx.

15. 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)

16. 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

17. Immunosuppressive Tx.

18. Immunosuppressive Tx.

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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.

25. Case Past hx : DM(-), HTN(-), 폐가 좋지 않아 서울대 F/U 했었다50pack/yr smoking
Lab
CBC / K, BUN/Cr (19.6/4.12) GFR(13.5) OT/PT(65/53)
Electro ( ) 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

26. 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

27. Case (Chest PA & PNS water’s view)

28. Case (Abdomen USG)

29. Case (외부 Chest CT)

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

31. 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

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

33. Kidney biopsy

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