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News on an old problem Nephrology view Dr. Oğuz Söylemezoğlu Gazi University Pediatric Nephrology

Challenging issues about vasculitis. News on an old problem Nephrology view Dr. Oğuz Söylemezoğlu Gazi University Pediatric Nephrology Ankara,Turkey. Vasculitis. Inflammation and damage to vessel wall Independent of size or vessel type Localized vs. systemic disease

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News on an old problem Nephrology view Dr. Oğuz Söylemezoğlu Gazi University Pediatric Nephrology

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  1. Challenging issues about vasculitis News on an old problem Nephrology view Dr. Oğuz Söylemezoğlu Gazi University Pediatric Nephrology Ankara,Turkey

  2. Vasculitis Inflammation and damage to vessel wall Independent of size or vessel type Localized vs. systemic disease Diverse symptoms and overlap Difficult classification

  3. Pathophysiology of Vasculitis • Pathogenic immune complex formation and/or deposition • Pathogenic T-lymphocyte responses and granuloma formation • Non-endothelial structures of the vessel wall are involved in controlling the inflammatory process, eg acting as antigen presenting cells and contributing pro-inflammatory mediators. • Pathogenetic role of ANCA ??

  4. 2006 Eular/Pres Ozen, Dillon et al Dedeoglu,Sundel . Rheum Dis P Clin N Am 2007

  5. Turkish survey of paediatric vasculitis (Vasculitis study group. Clin Rheum 2007)

  6. Overview : ANCA Associated Vasculitis • What are the challenges • Non toxic effective treatments • Earlier diagnosis at 1st presentation and relapse • Animal models • A move towards designer biologic therapies • Targeting B cells • Targeting T cells

  7. The stages of the management of the disease

  8. Very few studies in childhood

  9. Wegener’s Granulomatosis • General • necrotizing granulomas of upper airway, lower airway, kidney • bilateral pneumonitis 95% • chonic sinusitis 90% • mucosal ulceration of nasopharynx 75% • renal disease 50-80% • hallmark pathologic lesion • necrotizing granulomatous vasculitis

  10. IV pulse vs daily oral Cyclophosphamide ??

  11. Strategies to reduce relapses ?? How to treat resistant disese ?? • Leflunomide • Remission maintenance in WG • Infliximab and etanercept (TNF blockade) • WGET (70% remission , high rate relaps ) • Infliximab induced 88% remission • IVIG • Antithymocyte Globulin • SOLUTION study in refractory WG • Deoxyspergualin • Blocks the Transcriptional activation of  L chain expression B Cell • Blocks the development of cytotoxic T cells • Trials underway

  12. Blocking B lyS • Campath 1(Alemtuzumab) anti-CD 52 • Belimumab (Lymphostat-B) • In phase lll clinical trials in SLE • Atacicept:TACI Bloker(Phase ll) • BR3-Fc: BAFF Bloker

  13. Part mouse , part human Originally used for lymph cancer , RA Knocks out B cells Rituximab Usually given 2 injections, 2w apart

  14. Abatacept (Orencia) • Only targets T cells that are activated to cause damage and makes them ‘anergic’ • Potential to be highly selective therapy • Currently undergoing phase lll therapy • ABAVAS (BMS)

  15. Chan AT,Autoimmunity Rev. 2006

  16. Hypothetical events in the pathogenesis of ANCA small vessel vasculitis Jennette JC,Falk RJ. Curr Op Rheum 2008

  17. Microscopic polyangiitis: the future • Differences between MPA and WG • The role of respiratory epithelium in the induction • ANCA –negative vasculitis and vasculitis affecting different sizes of vessels • Molecular approches to classification will address • Therapeutics will have reduced steroids • Newer targets :Improve the speed and quality of remission • intracellular regulators of cytokines • Complement components • Antioxidants (N –acetyl cysteine

  18. BEHCET’S DISEASE

  19. Behcet’s Disease • Vasculitis with triad • oral, genital ulcers, • uveitis or iritis

  20. Renal Involvement in BD ? • The frequency of renal problems vary between 0% to 55%. • Amyloidosis • glomerulonephritis • renal vascular disease, • interstitial nephritis Akpolat .T et al Semin Arthritis Rheum. 2008

  21. What are the news in BD? • TNF--1031 C allele was associated with disease susceptibility Akman A,et al Br J Dermatol 2006 • T helper type 1 immune reaction in active disease Yanagihori et alJ Invest Dermatol,2006 • IL-12 B heterozygocity is associated with BD • E-NOS gene polymorphism (Glu 298Asp) associated with BD Oksel et al. Clin Exp Rheumatol 2006 • IL-18 levels were high in BD and correlated with activity Musabak et al, Rheumatol Int 2006 • Anti-SBP(Sleneium Binding protein) positive with uveitis Okunuki et al Exp Eye Res 2007 Therapy • Anti-TNF agents • Topical G-CSF for ulcers • Granulocytopheresis for refractory uveoretinitis

  22. Conclusions • Childhood forms of vasculitis are in similar spectrum to adult disease • Long term treatment is similar • Emphasis on KD,HSP less WG and MPA • Large controlled trials of infliximab and rituximab are required • Therapy still depends on conventional drugs • Effects of disease and treatment on growth and development need to be addressed in children

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