Update on vasculitis

1. Update on vasculitis

2. Overview Vasculitis Classification, involvement of kidney The kidney in ANCA vasculitis Pathogenesis Treatment and outcomes Newer therapies Conclusions

3. End Stage Renal Disease (ESRD)

4. Vasculitis classification– the first step

5. Primary Systemic Vasculitis classification

6. 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. 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.

7. 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 GNThese 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

8. 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

9. 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

10. Clinical Manifestations

11. General symptoms Fever Malaise Anorexia Weight loss Myalgias Arthralgias

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

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

14. 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 basesPulm hemorrhage caused by hemorrhagic capillaritis CXR and CT from Wegener’s showing bilateral nodules and masses primarily at bases

15. 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 leaflets17yo Wegener’s aortic valve insufficiency found to have two perforations in the aortic valve leaflets

16. 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 hemorrhagicSmall bowel loops are edematous, inflamed, and hemorrhagic

17. Diagnosis

18. 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

19. 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

20. Anti-neutrophil cytoplasmic autoantibodies

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

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

25. Crescentic glomerulonephritisClassification by immune deposits

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

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

29. ANCA associated vasculitis

30. ANCA testing

31. ANCA induces neutrophil superoxide production

32. MPO-ANCA in Rag-/- mice

33. Epidemiology - ANCA associated vasculitis

34. Ultra violet light and incidence of vasculitis

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

36. EUVAS disease categorization of ANCA-associated vasculitis

37. Long-term follow up of ANCA vasculitis

38. Causes of death

39. ANCA-associated vasculitis:severity subgrouping

40. Treatment

41. 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 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

42. 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-TNFa (infliximab, etanercept), anti-CD20 (rituximab), mycophenolate mofetil

43. 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.

44. 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

45. 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

46. Remission induction:cyclophosphamide + steroids 3 vs 12 months

47. Treatment response in ‘generalised’ vasculitis

49. “CYCLOPS” IV cyclophosphamide regimen

50. Severe renal disease: additional therapy IV methyl predsnisolone (1000-3000 mg) ? Plasma exchange Role of plasma exchange is controversial Klemmer et al: Retrospective review of all pts presenting to UNC 1995-2001 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

51. ‘Severe renal’ - MEPEX n=151

52. Plasma exchange – renal survival (creatinine> 500)

53. Relapse risk

54. Azathioprine vs. prolonged oral cyclophosphamide

55. ANCA and relapse 128, PR3-ANCA + Oral CYC 2 years or CYC followed by AZA ANCA status at switch

56. Mycophenolate mofetil vs. azathioprineIMPROVE trial: Cumulative Incidence of Relapse

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

58. Steroid withdrawal and relapse (STAVE)

59. STAVE – Results

60. Drug toxicity

61. 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

62. Newer therapies, Biologic or non-Biologic? IVIg Anti-TNF Rituximab ATG Alemtuzumab Abatacept

63. Rituximab for refractory vasculitis n = 63

64. Randomised trial of rituximab vs. cyclophosphamide for renal vasculitis (RITUXVAS)

66. Randomised trial of rituximab versuscyclophosphamide 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

67. 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

68. Suggested schema for the management of ANCA-associated vasculitis

69. 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

70. 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

71. 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

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

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

74. Further reading EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on ANCA-associated vasculitis. Ann Rheum Dis. 2007;66:605-617. BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology (Oxford) 2007;46:1615-1616. EULAR Recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2008;68:310-317. EULAR Recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2008;68:318-323.

75. Treatment