ANCA-associated vasculitis

1. ANCA-associated vasculitis Liz Dehmer am report 11/18/08

2. 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.

3. 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

4. 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

5. 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

6. Clinical Manifestations

7. General symptoms Fever Malaise Anorexia Weight loss Myalgias Arthralgias

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

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

10. 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

11. 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

12. Nerves *peripheral: mononeuritis multiplex *central: vasculitis within the meninges 31yo ANCA vasculitis + headaches + positive ANCA titer, MRI shows enhancing leptomeningeal thickening of the cerebellum with extension into the falx. Meningeal biopsy c/w leptomeningeal involvement of Wegener�s. Mayo Clinic proceedings31yo ANCA vasculitis + headaches + positive ANCA titer, MRI shows enhancing leptomeningeal thickening of the cerebellum with extension into the falx. Meningeal biopsy c/w leptomeningeal involvement of Wegener�s. Mayo Clinic proceedings

13. 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

14. Diagnosis

15. 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

16. 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% �- 1/3 of patients with anti-GBM crescentic GN and � 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

17. Anti-neutrophil cytoplasmic autoantibodies

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

19. Treatment

20. Induction therapy Corticosteroids and cyclophosphamide Induces remission in 75% of patients at 3 mos and 90% at 6 mos 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. 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

21. 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

22. 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.

23. 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

24. 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

25. References J. Charles Jennette and Ronald J Falk. Renal and Systemic Vasculitis. Comprehensive Clinical Nephrology. Ed. John Feehally, Jurgen Floege, Richard J. Johnson. Philadelphia: Mosby, 2007. Klemmer PJ, Chalermskulrat W, Reif MS, Hogan SL, Henke DC, Falk RJ: Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small vessel vasculitis. Am J Kidney Dis 42: 1149-1153, 2003. de Lind van Wijngaarden RAF, Hauer HA, Wolterbeek R, Jayne DRW, Gaskin G, Rasmussen N, Noel L-H, Ferrario F, Waldherr R, Bruijn JA, Bajema IM, Hagen EC; for the European Vasculitis Study Group (EU-VAS): Chances of renal recovery for dialysis-dependent ANCA-associated glomerulonephritis. J Am Soc Nephrol 18: 2189-2197, 2007. Pusey CD, Rees AJ, Evans DJ, Peters DK, Lockwood CM: Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies. Kidney Int. 40: 757-763, 1991. Lionaki S and Falk RJ: Removing antibody and preserving glomeruli in ANCA small-vessel vasculitis. J Am Soc Nephrol 18: 1987-1989, 2007.