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Challenging issues about vasculitis
News on an old problem Nephrology view Dr. Oğuz Söylemezoğlu Gazi University Pediatric Nephrology Ankara,Turkey
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Vasculitis Inflammation and damage to vessel wall
Independent of size or vessel type Localized vs. systemic disease Diverse symptoms and overlap Difficult classification
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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 ??
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2006 Eular/Pres Ozen, Dillon et al 2007 Dedeoglu,Sundel . Rheum Dis P Clin N Am
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Turkish survey of paediatric vasculitis (Vasculitis study group
Turkish survey of paediatric vasculitis (Vasculitis study group. Clin Rheum 2007)
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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
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The stages of the management of the disease
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Very few studies in childhood
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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
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IV pulse vs daily oral Cyclophosphamide ??
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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
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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
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Part mouse , part human Originally used for lymph cancer , RA Knocks out B cells Rituximab Usually given 2 injections, 2w apart
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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)
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Chan AT,Autoimmunity Rev. 2006
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Hypothetical events in the pathogenesis of ANCA small vessel vasculitis
Jennette JC,Falk RJ. Curr Op Rheum 2008
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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
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BEHCET’S DISEASE
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Behcet’s Disease Vasculitis with triad oral, genital ulcers, uveitis or iritis
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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
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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
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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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