News on an old problemNephrology view
Dr. Oğuz Söylemezoğlu
Gazi University Pediatric NephrologyAnkara,Turkey
Challenging issues about vasculitis
Vasculitis
Inflammation and damage to vessel wall
Independent of size or vessel type
Localized vs. systemic disease
Diverse symptoms and overlap
Difficult classification
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 ??
Eular/Pres Ozen, Dillon et alDedeoglu,Sundel . Rheum Dis P Clin N Am2007
2006
Turkish survey of paediatric vasculitis (Vasculitis study group. Clin Rheum 2007)
Overview : ANCA Associated VasculitisWhat 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
The stages of the management of the disease
Very few studies in childhood
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
IV pulse vs daily oral Cyclophosphamide ??
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
Strategies to reduce relapses ??How to treat resistant disese ??
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
Rituximab
Part mouse , part human
Originallyused for lymphcancer ,RA
Knocks outB cells
Usually given 2 injections,2w apart
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)
Chan AT,Autoimmunity Rev. 2006
Hypothetical events in the pathogenesis of ANCA small vessel vasculitis
Jennette JC,Falk RJ. Curr Op Rheum 2008
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
BEHCET’S DISEASE
Behcet’s DiseaseVasculitis with triad
oral, genital ulcers,
uveitis or iritis
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
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
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