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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
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 ??
2007 Dedeoglu,Sundel . Rheum Dis P Clin N Am
2006
Eular/Pres Ozen, Dillon et al
Turkish survey of paediatric vasculitis
(Vasculitis study group. Clin Rheum 2007)

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

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 ??
Strategies to reduce relapses ??
How to treat resistant disese ??

Leflunomide


Infliximab and etanercept (TNF blockade)




WGET (70% remission , high rate relaps )
Infliximab induced 88% remission
IVIG
Antithymocyte Globulin


Remission maintenance in WG
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
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
Part mouse , part human
Knocks
out
B cells
Rituximab
Usually given 2 injections,
2w apart
Originally
used
for lymph
cancer ,
RA
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


ANCA –negative vasculitis and vasculitis affecting
different sizes of vessels


The role of respiratory epithelium in the induction
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 Disease
Vasculitis 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