1. Microscopic Polyangiitis Saori Kobayashi

2. Doll ’ s Festival : Mar 3

3. ANCA-associated vasculitis Involve small~middle vasculature Involve small~middle vasculature With or no immune deposits (Pauci-immune) With or no immune deposits (Pauci-immune) Wegener ’ s granulomatosis(WG) Wegener ’ s granulomatosis(WG) Churg-Strauss syndrome Churg-Strauss syndrome microscopic polyangitiis(MPA) microscopic polyangitiis(MPA) renal limited form of MPA/idiopathic crescentic glomerulonephritis renal limited form of MPA/idiopathic crescentic glomerulonephritis

4. MPA: clinical features Most common cause of acute renal-pulmonary syndrome Most common cause of acute renal-pulmonary syndrome Necrotizing glomerulonephritis(90%) Necrotizing glomerulonephritis(90%) →crescent formation, red blood casts Pulmonary capillaritis(50%) Pulmonary capillaritis(50%) →Alveolar hemorrhage, hemoptysis Systemic symptoms: fever, weight loss Systemic symptoms: fever, weight loss (-) granulomatous inflammation (-) granulomatous inflammation (+)p-ANCA (+)p-ANCA

5. Treatment of MPA induction phase→remission phase induction phase→remission phase Corticosteroids+IV/oral Cyclophosphamide Corticosteroids+IV/oral Cyclophosphamide 90% of pts with MPA acquire remission within 12mo 90% of pts with MPA acquire remission within 12mo NIH regimen: NIH regimen: oral CYC 2mg/kg/day (for>1y after remisssion) +prednisolone (initial dose of 1mg/kg/day→taper) EuVas regimen EuVas regimen oral CYC (up to 12mo)+steroid →substitute CYC with AZA after induction of remittion

6. Monitoring/reducing side-effects Steroids: osteoporosis, gastritis, cataracts, DM …. Steroids: osteoporosis, gastritis, cataracts, DM …. monitor bone density, prophylaxis by Ca/ViD, biphosphonate, PPI/H2 blocker monitor bone density, prophylaxis by Ca/ViD, biphosphonate, PPI/H2 blocker CYC: bladder toxicity, bone marrow suppression, gonadal dysfunction CYC: bladder toxicity, bone marrow suppression, gonadal dysfunction → infection, infertility, cyctitis, ↑risk of bladder/hematological malignancies ↑risk of bladder/hematological malignancies monitor blood count, urinalysis, TMP/SMZ for PCP

7. CYC: IV vs oral IV route is as effective as oral route at inducing remission with IV route is as effective as oral route at inducing remission with less infectious complications and leukopenia less infectious complications and leukopenia higher risk of relapse higher risk of relapse Pulsed IV (monthly 0.5 to 1.0 g/m² BSA until a stable remission is induced ) reduce cumulative dose and toxicity (study for efficacy is under trial) Pulsed IV (monthly 0.5 to 1.0 g/m² BSA until a stable remission is induced ) reduce cumulative dose and toxicity (study for efficacy is under trial)

8. Alternative medication in induction therapy Methotrexate Methotrexate As effective as CYC, but higher rate of relapse Should not be administered to pts with serum Cr>2.0mg/dl Plasma exchange( to remove ANCA) Plasma exchange( to remove ANCA) Effective to pts with severe pulmonary hemorrhage, severe renal disease/hemodialysis

9. Maintenance Therapy 12-18 mo after remission is induced 12-18 mo after remission is induced Longer maintenance therapy should be done to those who have relapse Longer maintenance therapy should be done to those who have relapse CYC should be switched to either MTX or AZA as soon as a stable remission is attained (generally within 3-6 mo) CYC should be switched to either MTX or AZA as soon as a stable remission is attained (generally within 3-6 mo) MTX: higher relapse rate MTX: higher relapse rate not indicated for pts with renal insufficiency not indicated for pts with renal insufficiency AZA: higher relapse rate? AZA: higher relapse rate?

10. Alternative of maintenance therapy Mycophenolate mofetil Mycophenolate mofetil Anti-TNF alpha agent (etanercept and infliximab) Anti-TNF alpha agent (etanercept and infliximab) Rituximab Rituximab Anti-T-cell agent Anti-T-cell agent IVIG IVIG Plasmapheresis Plasmapheresis

11. Mycophenolate mofetil Effective in lupus nephritis Effective in lupus nephritis does not appear to be as effective in ANCA- associated vasculitis does not appear to be as effective in ANCA- associated vasculitis should not be employed as an agent for the induction of remission should not be employed as an agent for the induction of remission Limited data suggest this agent may have a role in remission maintenance. Limited data suggest this agent may have a role in remission maintenance.

12. TNF-α in ANCA-associated vasculitis ANCA-induced neutrophil activation is enhanced by TNF-α ANCA-induced neutrophil activation is enhanced by TNF-α ・ upregulation of molecules involved in neutrophil adhesion to endotherium ・ upregulation of molecules involved in neutrophil adhesion to endotherium ・ release of oxygen radicals, toxic granules ・ release of oxygen radicals, toxic granules Plasma levels of TNF-α are increased in pts with ANCA-associated GN Plasma levels of TNF-α are increased in pts with ANCA-associated GN TNF-α is responsible for the increased production of proinflammatory cytokines TNF-α is responsible for the increased production of proinflammatory cytokines

13. Anti-TNF-α agent Anti-TNF-α agent Etanercept (Enbrel) Etanercept (Enbrel) fusion protein of p75 subunits of the TNF-αreceptor Infliximab (Remicade) Infliximab (Remicade) chimeric IgG1 mAb of TNF-α Effective in RA, Crohn ’ s disease Effective in RA, Crohn ’ s disease It may be hypothesized that anti-TNF-α agent is effective for ANCA-associated vasculitis It may be hypothesized that anti-TNF-α agent is effective for ANCA-associated vasculitis

14. Human studies on TNF-α inhibition Double-blind controlled trial among 181pts with WG Double-blind controlled trial among 181pts with WG Standard regimen+etanercept/placebo Standard regimen+etanercept/placebo No significant difference in remission rates, flares, disease activities No significant difference in remission rates, flares, disease activities Higher incidence of cancer in etanercept group Higher incidence of cancer in etanercept group →as for etanercept, this should not be used

15. Limitations to anti-TNF-α Is anti-TNF-α really safe? Is anti-TNF-α really safe? Infusion reaction Infusion reaction Infection Infection Carcinogenesis Carcinogenesis Thromboembolic complications Thromboembolic complications Drug-induced lupus Drug-induced lupus

16. Rituximab anti-CD20(anti-B cell) antibody anti-CD20(anti-B cell) antibody Used for lymphoma, several autoimmune diseases Used for lymphoma, several autoimmune diseases Studies suggest that Rituximab is effective both for induction and maintenance with rare adverse events for pts who had not conventional therapy Studies suggest that Rituximab is effective both for induction and maintenance with rare adverse events for pts who had not conventional therapy The response was associated with elimination of circulating B lymphocytes, and a decrease in ANCA titers. The response was associated with elimination of circulating B lymphocytes, and a decrease in ANCA titers.

17. Conculusion For MPA and other ANCA-associated vasculitis, steroid combined with CYC is the standard. For MPA and other ANCA-associated vasculitis, steroid combined with CYC is the standard. CYC has problematic toxicity and some pts don ’ t respond the regimen or have relapse CYC has problematic toxicity and some pts don ’ t respond the regimen or have relapse There are several alternative therapy but they are not as effective as had been expected There are several alternative therapy but they are not as effective as had been expected Their true efficacy remain to be seen and larger, randomized, controlled study is needed Their true efficacy remain to be seen and larger, randomized, controlled study is needed