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Microscopic Polyangiitis

Microscopic Polyangiitis. Saori Kobayashi. Doll ’ s Festival : Mar 3. ANCA-associated vasculitis. Involve small~middle vasculature With or no immune deposits ( Pauci-immune ) Wegener ’ s granulomatosis(WG) Churg-Strauss syndrome microscopic polyangitiis(MPA)

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Microscopic Polyangiitis

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  1. Microscopic Polyangiitis Saori Kobayashi

  2. Doll’s Festival : Mar 3

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

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

  5. Treatment of MPA • induction phase→remission phase • Corticosteroids+IV/oral Cyclophosphamide • 90% of pts with MPA acquire remission within 12mo • NIH regimen: oral CYC 2mg/kg/day (for>1y after remisssion) +prednisolone (initial dose of 1mg/kg/day→taper) • 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…. monitor bone density, prophylaxis by Ca/ViD, biphosphonate, PPI/H2 blocker • CYC: bladder toxicity, bone marrow suppression, gonadal dysfunction → infection,infertility, cyctitis, ↑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 less infectious complications and leukopenia 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)

  8. Alternative medication in induction therapy • Methotrexate As effective as CYC, but higher rate of relapse Should not be administered to pts with serumCr>2.0mg/dl • 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 • 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) • MTX: higher relapse rate not indicated for pts with renal insufficiency • AZA: higher relapse rate?

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

  11. Mycophenolate mofetil • Effective in lupus nephritis • does not appear to be as effective in ANCA-associated vasculitis • should not be employed as an agent for the induction of remission • 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 　・upregulation of molecules involved in neutrophil adhesion to endotherium 　・release of oxygen radicals, toxic granules • Plasma levels of TNF-α are increased in pts with ANCA-associated GN • TNF-α is responsible for the increased production of proinflammatory cytokines

  13. Anti-TNF-α agent • Etanercept (Enbrel) fusion protein of p75 subunits of the TNF-αreceptor • Infliximab (Remicade) chimeric IgG1 mAb of TNF-α • Effective in RA, Crohn’s disease • 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 • Standard regimen+etanercept/placebo • No significant difference in remission rates, flares, disease activities • 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? • Infusion reaction • Infection • Carcinogenesis • Thromboembolic complications • Drug-induced lupus

  16. Rituximab • anti-CD20(anti-B cell) antibody • 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 • 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. • 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 • Their true efficacy remain to be seen and larger, randomized, controlled study is needed

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