Update on vasculitis

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

End Stage Renal Disease (ESRD)

Vasculitis classification– the first step

Primary Systemic Vasculitis classification

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. 6

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 7

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 8

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 9

Clinical Manifestations

General symptoms Fever Malaise Anorexia Weight loss Myalgias Arthralgias

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

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

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 14

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 15

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 16

Diagnosis

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 18

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 19

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% 20

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

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

Polyarteritis nodosa Takayasu’ s arteritis

Crescentic glomerulonephritis Classification by immune deposits

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

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

ANCA associated vasculitis

ANCA testing

ANCA induces neutrophil superoxide production

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

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

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

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

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

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

Causes of death

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

Treatment

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 41

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 42

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. 43

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 44

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 45

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

Treatment response in ‘generalised’ vasculitis Jayne, NEJM 2003

“CYCLOPS” IV cyclophosphamide regimen

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

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

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

Relapse risk Booth, Am J Kid Dis 2002

Azathioprine vs. prolonged oral cyclophosphamide

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

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

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

Steroid withdrawal and relapse (STAVE)

STAVE – Results

Drug toxicity Jayne, Kidney and Blood Pressure Res, 2003

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

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

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

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

197 new (49%) or relapsing WG/MPA Randomised, double-blind 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

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

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

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

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

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

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

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

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.

Treatment Thank You!