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