1. Systemic vasculitis
Dr.

2. Overview Introduction Classification Pathogenesis Clinical features
Differential diagnosis
Management
Conclusions

3. Introduction Systemic vasculitides are
Complex
Often serious group of disorders which,
While uncommon, require careful management in order to ensure optimal outcome
Primary systemic vasculitis has an incidence of
> 100 new cases per million
Clinical and Experimental Immunology 2010;160: 143–60

4. Introduction
End Stage Renal Disease (ESRD)

5. Introduction
Despite a significant reduction in mortality as a result of
Standard immunosuppression, most patients experience
Poor quality of life, characterized by
Relapse, persisting low grade disease activity and increasing burden of drug toxicity
Clinical and Experimental Immunology 2010;160: 143–60

6. Vasculitis classification– the first step

8. Primary Systemic Vasculitis classification

9. Classification of systemic vasculitis

10. Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis
Small vessel vasculitis
Wegener’s granulomatosis
Churg-Strauss syndrome
Microscopic polyangiitis
Henoch-Schonlein purpura
Essential cryoglobulinemic vasculitis
Cutaneous leukocytoclastic angiitis
Medium-sized vessel vasculitis
Polyarteritis nodosa
Kawasaki disease
Large-vessel vasculitis
Giant cell (temporal) arteritis
Takayasu arteritis
WG, C-S and MPA share an indistinguishable form of necrotizing small-vessel vasculitis that affects capillaries, venules, arterioles, and small arteries. These three are distinguished from similar forms of immune-complex small-vessel vasculitis s/a HSP + cryoglobulinemic vasculitis by absence or paucity of immune-complex deposits in vessel walls. The diagnosis of specific subtypes of pauci-immune small vessel vasculitidies can be made based on the accompanying syndrome. 10

11. Classification of systemic vasculitis
2 major groups based on clinical and histopathological features of vasculitis
1. Large vessel vasculitis: aorta and major branches
Giant cell arteritis / temporal arteritis
Takayasu arteritis
2. Medium-sized vasculitis: medium arteries
Polyarteritis nodosa (PAN)
Kawasaki disease

12. Classification of systemic vasculitis
2. medium-sized vasculitis: arterioles, capillaries and venules
Wegener’s granulomatosis (WG)
Churg-Strauss syndrome (CSS)
Microscopic polyangiitis (MPA)
3. small vessel vasculitis: venules, capillaries
Henoch Schonlein purpura (HSP)
Cryoglobulinaemic vasculitis

14. Epidemiology
Clinical and Experimental Immunology 2010;160: 143–60

15. Epidemiology Begin during the 5th, 6th, 7th decades of life
Male predominance
Caucasians have greater incidence than African Americans
Suspicion that Wegener’s more frequent in colder compared to warmer climates, and that microscopic polyangiitis has opposite trend 15

16. Pathogenesis of vasculitis
J Allergy Clin Immunol 2009;123:

17. Pathogenesis of vasculitis
Antibody mediated inflammation
Wegener’s granulomatosis (WG)
Churg-Strass syndrome (CSS)
Microscopic polyangiitis (MPA)

18. Pathogenesis of vasculitis
Immune complex-mediated inflammation
Henoch SchÖlein purpura (HSP)
Cryoglobulinaemic vasculitis
Polyarteritis nodosa (PAN)
Cell-mediated inflammation
Giant cell arteritis
Takayasu arteritis
Wegener’s granulomatosis (WG)
Churg-Strass syndrome (CSS)

19. Pathogenesis
All three associated with the presence in serum of autoantibodies against components of the cytoplasm of neutrophils: ANCA
ANCA activates neutrophils, which then adhere to endothelial cells and release mediators of inflammation and cell injury 19

20. Clinical features
J Allergy Clin Immunol 2009;123:

21. Definition – large vessel vasculitis
Clinical and Experimental Immunology 2010;160: 143–60

22. Definition – medium vessel vasculitis
Clinical and Experimental Immunology 2010;160: 143–60

23. Definition – small vessel vasculitis
Clinical and Experimental Immunology 2010;160: 143–60

24. Small vessel pauci-immune vasculitis
Wegener’s granulomatosis:
Necrotizing granulomatous inflammation, most often affecting respiratory tract
Churg-Strauss syndrome:
Occurs in association with asthma, eosinophilia, and necrotizing granulomatous inflammation
Microscopic polyangiitis:
Pauci-immune systemic vasculitis occurring in the absence of asthma and eosinophilia with no evidence of granulomatous inflammation
These three types share an indistinguishable pattern of glomerulonephritis which has necrosis and crescent formation and an absence or paucity of immunoglobulin deposition and is dubbed “pauci-immune crescentic GN”. This pattern can also occur in the absence of systemic vasculitis and is referred to in that case as renal vasculitis, renal=limited vasculitis or idiopathic rapidly progressive GN 24

26. Clinical Manifestations

27. General symptoms Fever Malaise Anorexia Weight loss Myalgias
Arthralgias

28. Renal involvement *less frequent in Churg-Strauss
*hematuria, proteinuria and renal failure
*renal failure usually has characteristics of rapidly progressive glomerulonephriti s 28

29. Skin
*Purpura most common in lower extremities, occurs as recurrent crops.
*Nodular lesions occur more frequently in Churg-Strauss and Wegener’s 29

30. Upper and lower respiratory tract
*pulmonary hemorrhage
*nodular or cavitary lesions in Wegener’s and Churg-Strauss
*subglottic stenosis, sinusitis, rhinitis, otitis media, ocular inflammation most common in Wegener’s
Pulm hemorrhage caused by hemorrhagic capillaritis
CXR and CT from Wegener’s showing bilateral nodules and masses primarily at bases 30

31. Cardiac *identified in 50% of pts with Churg-Strauss
*<20% in Wegener’s and microscopic polyangiitis
*transient heart block, ventricular hypokinesis, infarction, myocarditis, endocarditis, pericarditis
17yo Wegener’s aortic valve insufficiency found to have two perforations in the aortic valve leaflets 31

32. Gastrointestinal
*typically abdominal pain, blood in the stool, mesenteric ischemia and rarely perforation
*can also mimic pancreatitis and hepatitis
Small bowel loops are edematous, inflamed, and hemorrhagic 32

33. Diagnosis

34. Update on vasculitis: J Allergy Clin Immunol 2009

35. Update on vasculitis: J Allergy Clin Immunol 2009

38. Differential Dx of Vasculitis
Fibromuscular dysplasia
Cholesterol emboli
Atrial myxoma with emboli
Infective endocarditis
Malignancies,ie lymphamatoid granulomatosis
Bacteremia
Rickettsial dz
Amyloid
SLE

39. Differential Diagnosis: Pulmonary-Renal Syndrome
Goodpasture’s disease
SLE
Henoch-Schoenlein purpura
Behcet’s syndrome
Essential mixed cryoglobulinemia
Rheumatoid vasculitis
Drugs: penicillamine, hydralazine, propylthiouracil
Acute renal failure with hypervolemia
Severe cardiac failure
Severe bacterial pna with renal failure
Hantavirus infection
Opportunistic infections
ARDS w/ renal failure in multi-organ failure
Paraquat poisoning
Renal vein/IVC thrombosis w/ PE 39

40. Differential of Pulmonary Renal Syndrome
Goodpasture’s Disease
Systemic Vasculitis
Wegener’s Granulomatosis
Microscopic Polyangiitis
Churg-Strauss Syndrome
Cryoglobulinemia
Henoch-Schonlein Purpura
Connective Tissue Disease
Polymyositis/Dermatomyositis
Progressive Systemic Sclerosis
SLE
Primary Glomerular Disease
IgA Nephropathy
Post-Infectious GN
Membranoproliferative GN

41. Anti-neutrophil cytoplasmic autoantibodies
Serologic testing for ANCA is useful diagnostic test, but should be interpreted in the context of other patient characteristics
Testing should include both indirect immunoflourescence microscopy (IFA) and enzyme immunoassay (EIA)
Sensitivity for pauci-immune small vessel vasculitis and GN is 80-90%
¼- 1/3 of patients with anti-GBM crescentic GN and ¼ of patients with idiopathic immune-complex crescentic GN are ANCA positive
Pts with concurrent ANCA and anti-GBM antibodies have worse prognosis than those with ANCA alone 41

42. Anti-neutrophil cytoplasmic autoantibodies
Proteinase 3
(PR3/c-Anca)
Myeloperoxidase
(MPO/p-ANCA)
Negative
Wegener’s granulomatosis
70%
25% 5%
Microscopic polyangiitis
40%
50%
10%
Churg-Strauss syndrome
60%
30%
Pauci-immune glomerulonephritis
20% 42

44. Pathologic diagnosis Biopsy of involved site Skin Muscle Nerve Gut
Kidney 44

45. Size of vessel involvement
Glomerular vasculitis
Focal necrosis, crescents
Rapidly progressive glomerulonephritis
Extra-glomerular vasculitis
Arteritis of small/medium/large renal arteries

46. Polyarteritis nodosa
Takayasu’ s arteritis

48. Crescentic glomerulonephritis Classification by immune deposits

49. Rapidly Progressive glomerulonephritis (RPGN)
Definition and disease associations
The kidney in ANCA vasculitis
Pathogenesis
Treatment and outcomes

51. Renal vasculitis (glomerulonephritis): presentation
Rapidly progressive glomerulonephritis
rising creatinine + crescents on biopsy (oliguria)
Urine
haematuria, red cell casts + proteinuria
Imaging
kidneys normal size

52. ANCA associated vasculitis

53. ANCA testing

54. ANCA induces neutrophil superoxide production

55. MPO-ANCA in Rag-/- mice
Xiao et al, JCI, 2002

56. Epidemiology - ANCA associated vasculitis
EUVAS; Lane 2004, Arthritis Rheum

57. Ultra violet light and incidence of vasculitis
Gatenby, Arthritis Rheum 2009

58. Rapidly Progressive glomerulonephritis (RPGN)
Definition and disease associations
The kidney in ANCA vasculitis
Pathogenesis
Treatment and outcomes

59. EUVAS disease categorization of ANCA-associated vasculitis
Therapeutics and Clinical Risk Management 2010:6 253–264

60. Long-term follow up of ANCA vasculitis
Flossmann, ASN 2007

61. Causes of death

62. ANCA-associated vasculitis: severity subgrouping
Rasmussen et al., Glin Exp Immunol, 1995

63. Treatment

64. Induction therapy Corticosteroids and cyclophosphamide
Induces remission in
75% of patients at 3 mos and
90% at 6 mos
Steroids: typically methylpred 7 mg/kg/day x3 days, then oral pred 1 mg/kg/day tapering to alternate day regimen and off by 3-4 months.
Cyclophosphamide: 2 mg/kg/day oral, or IV at 0.5g/m^2 per month adjusted to 1g/m^2 based on leukocyte count after 2 weeks, target nadir of 3000 cells/mm^3 64

65. Maintenance therapy
Intensity should be reduced as much as possible to reduce toxic side effects
Can stop induction therapy after 6-12 months if patient is in full remission and at low risk for relapse
IV cyclophosphamide regimens afford 1/3-1/2 the total dose of cyclophosphamide given in oral regimens
Can replace cyclophosphamide with azathioprine 2 mg/kg/day after 3-6 months
Other therapies being studied include anti-TNFα (infliximab, etanercept), anti-CD20 (rituximab), mycophenolate mofetil 65

66. Relapse therapy
One fourth to one half of patients will experience a relapse within several years
Diagnosis based on solid clinical and pathologic evidence of recurrent disease, not an increase in ANCA titers alone
Most often, a treatment similar to induction regimen is used though less intensive or less toxic therapy may be adequate. 66

67. Renal transplantation
Frequency of recurrence about 20%
Graft loss caused by recurrence < 5%
Positive ANCA titer at time of transplant does not increase risk of recurrent disease in transplant
Recurrent ANCA GN in transplant responds to therapy similarly to recurrent disease in native kidneys 67

68. Prognosis
With adequate immunosuppressive therapy, 5-year renal and patient survival is 65-75%
Older age, higher serum creatinine at presentation, pulmonary hemorrhage, and dialysis-dependent renal failure correlate with overall poor outcome
Patients with MPO-ANCA have slightly better renal outcome
Patients with PR3-ANCA have more extrarenal organ manifestations, higher chance for relapse and higher mortality
Regardless of ANCA type, best clinical predictor of renal outcome is GFR at time of diagnosis. Best pathologic predictor of response to treatment is extent of active necrosis and cellular crescents in biopsy specimens 68

69. Remission induction: cyclophosphamide + steroids 3 vs 12 months
Jayne, NEJM 2003

70. Treatment response in ‘generalised’ vasculitis
Jayne, NEJM 2003

72. “CYCLOPS” IV cyclophosphamide regimen

73. Severe renal disease: additional therapy
IV methyl predsnisolone ( mg)
? Plasma exchange
Role of plasma exchange is controversial
Klemmer et al: Retrospective review of all pts presenting to UNC with DAH and small-vessel vasculitis. All treated w/ apheresis and IV cyclophosphamide and/or IV methylprednisolone. DAH resolved in 20/20 pts (100%) with average 6.4 treatments
Pusey et al: Dialysis dependent patients (N=19) were more likely to have recovered renal function if tx with plasma exchange as well as drugs (10/11) compared to drugs alone (3/8). No difference in outcome in patients not on dialysis
de Lind van Wijngaarden et al: 69 dialysis-dependent patients with ANCA-associated glomerulonephritis received standard immunosuppressive therapy plus either IV methylpred or plasma exchange. Plasma exchange was superior to methylprednisolone for coming off dialysis

74. ‘Severe renal’ - MEPEX n=151
Jayne, JASN 2007

75. Plasma exchange – renal survival (creatinine> 500)
Jayne, JASN 2007

76. Relapse risk
Booth, Am J Kid Dis 2002

77. Azathioprine vs. prolonged oral cyclophosphamide

78. ANCA and relapse 128, PR3-ANCA + Oral CYC 2 years or
CYC followed by AZA
ANCA status at switch
Slot, Arthritis Rheum 2005

79. Mycophenolate mofetil vs
Mycophenolate mofetil vs. azathioprine IMPROVE trial: Cumulative Incidence of Relapse
Hiemstra,14th International ANCA workshop 2009

80. Prednisolone dosing Induction Remission maintenance 60mg/day
Reduce in steps to 10mg/day by 12 weeks
Remission maintenance
5-10mg/day
Continue to 12 months
Attempt withdrawal

81. Steroid withdrawal and relapse (STAVE)

82. STAVE – Results

83. Drug toxicity
Jayne, Kidney and Blood Pressure Res, 2003

84. Conclusions on standard therapies
Early diagnosis improves outcomes
Induction
Cyclophosphamide and high dose prednisolone (3-6 months)
IV cyclophosphamide effective
Maintenance
AZA≅MTX: LEF, MMF alternatives
Lower dose prednisolone
Assess relapse risk
Adverse events
Avoid leukopaenia, especially in elderly

85. Newer therapies, Biologic or non-Biologic?
IVIg
Anti-TNF
Rituximab
ATG
Alemtuzumab
Abatacept
Mycophenolic acid
Mycophenolate mofetil
Enteric coated MPA
Leflunomide
Deoxyspergualin

86. Rituximab for refractory vasculitis n = 63
Jones, Arthritis Rheum 2009

87. Randomised trial of rituximab vs
Randomised trial of rituximab vs. cyclophosphamide for renal vasculitis (RITUXVAS)
Jones, ASN 2008

89. Randomised trial of rituximab versus cyclophosphamide in ANCA vasculitis RAVE
197 new (49%) or relapsing WG/MPA
Creatinine < 4.0mg/dl, no lung haemorrhage
Randomised, double-blind
Rituximab 375mg/m2/wk x4 vs. oral CYC
Both with IV/oral prednisone, stop at 6 months
Primary end-point
Remission and steroid withdrawal at 6 months
Non-inferiority design
Stone J et al, ACR 2009

90. RAVE results Primary end-point 6 months 62% RTX, 55% CYC (p=0.2)
Safety
Similar AE rates
Absolute number AEs less with RTX (p=0.03)
18 month data end 2010
Stone J et al, ACR 2009

91. Suggested schema for the management of ANCA-associated vasculitis
Therapeutics and Clinical Risk Management 2010:6 253–264

92. Conclusions
Current approaches to treatment in induction and maintenance of AAV are well established
(Table in earlier slide)
The EULAR guidelines for the management of small and medium vessel vasculitis have recently been published and
The role of newer agents such as MMF is being defined by clinical trials
EULAR: European League against Rheumatism,
AAV : (ANCA)-associated vasculitides

93. Conclusions (continued)
The success and safety profile of rituximab in refractory disease has led to trials in maintenance and induction therapy which may see it recommended as standard practice, although
High cost may limit its use

94. Conclusions (continued)
The wide range of newer biologic agents now available brings huge possibilities for immunotherapy in relapsing or refractory disease
However, the rarity of AAV is a hindrance to developing an evidence base for practice
Therefore, international cooperation and collaborative trials remain essential if patients are to receive appropriate, effective therapy

95. Conclusions (continued)
Renal vasculitis
Any size of renal vessel
Necrotizing glomerulonephritis (ANCA) most common
Pathogenesis
Role of ANCA
Neutrophil mediated endothelial toxicity

96. Conclusions (continued)
Treatment and outcomes
Dominated by severity at diagnosis - early diagnosis
Relapse only minor issue – long-term monitoring
Need for newer therapies

97. Thank You!