Immunotherapy for antineutrophil cytoplasmic antibody–associated vasculitis: challenging the therapeutic status quo?
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usually manifests as a diffuse pulmonary hemorrhage,
ReviewANCA are now believed to play a major role in the de-velopment of necrotising vasculitis in these disorders.However, thus far, there are no data showing that ANCA
Corresponding author: Bosch, X. (firstname.lastname@example.org).* These authors contributed equally to this work.paving the way to new biologicals that are now awaitingtesting.
Anti-neutrophil cytoplasmic antibodyassociatedvasculitis: Wegeners granulomatosis, Churg-Strausssyndrome and microscopic polyangiitisAnti-neutrophil cytoplasmic antibodies (ANCA) are IgGantibodies directed against antigenic constituents of neu-trophils contained in the azurophilic granules andmonocytelysosomes. After indirect immunofluorescence of ethanol-fixed neutrophils, two characteristic immunostainingpatterns can be observed: cytoplasmic (C-ANCA) and peri-nuclear (P-ANCA) (Figures 1a and 1b, respectively). Mostcases of C- and P-ANCA are directed against proteinase 3(PR3) and myeloperoxidase (MPO), respectively.
Systemic vasculitides are uncommon life-threateningdisorders where vascular inflammation of an autoimmunenature causes occlusion and ischemia of affected tissues.Among these diseases, vasculitis with serum positivity forANCA [ANCA-associated vasculitis (AAV)] is a well-established subgroup of disorder that affects small- (e.g.
which commonly leads the patient to respiratory insuffi-ciency. In contrast to MPA, patients with WG and CSSexhibit granulomatous destructive inflammation of therespiratory tract, which in the case of CSS is rich ineosinophils. Early in the course of the disease, CSSpatients present asthma and peripheral blood eosinophi-lia and, subsequently, the lung and the heart may beinfiltrated by eosinophils, producing eosinophilic pneumo-nia and rapid-onset heart failure, respectively.  In CSS,vasculitic damage, which appears late in the disease, isusually less severe than in MPA and WG. Other organsthat can be affected in AAV include peripheral nerves,skeletal muscle, skin and joints. 
Between 80% and 90% of WG and MPA patients haveANCA, mainly directed against PR3 in the case of WG andagainst MPO in the case of MPA . The few WG patientswho are ANCA negative mostly have a granulomatousdisease limited to the respiratory tract, although ANCAoften appear later . ANCA are detected in 40% of CSSpatients, with a predominance of MPO-ANCA . Inaddition to their unquestionable value as disease markers,advances in the knowledge of AAV pathogenesis are
prompted interest in biological agents. Continuous features of WG and MPA. In MPA, lung involvementImmunotherapy forcytoplasmic antibovasculitis: challengistatus quo?Xavier Bosch1*, Antonio Guilabert2*, Ger1Department of Internal Medicine, Hospital Clnic, Institut dInvof Barcelona, Barcelona, Spain2Department of Dermatology, Hospital Clnic, Institut dInvestigBarcelona, Barcelona, Spain3Department of Autoimmune Diseases, Hospital Clnic, InstitutUniversity of Barcelona, Barcelona, Spain4Department of Nephrology, Hospital Clnic, Institut dInvestigaBarcelona, Barcelona, Spain
Anti-neutrophil cytoplasmic antibodies (ANCA) are IgGantibodies directed against antigenic constituents ofneutrophils contained in the azurophilic granules andmonocyte lysosomes. Systemic vasculitis with ANCA[ANCA-associated vasculitides (AAV)] is a subgroup oflife-threatening inflammatory disorders affecting small-to medium-sized vessels; immunosuppressants and glu-cocorticoids represent the current therapeutic mainstay.Although these agents have improved patients survival,25% present with severe adverse events, and standardtherapy does not sustain remission. Therefore, an unmetneed for safer and more effective therapies has280 1471-4906/$ see front matter 2008 Elantineutrophilyassociatedg the therapeutic
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capillaries) to medium-sized vessels (e.g. renal arteries).Wegeners granulomatosis (WG), microscopic polyangiitis(MPA) and Churg-Strauss syndrome (CSS) are the threeforms of AAV . The incidence of AAV in the developedworld ranges from 2.4 cases permillion (CSS) to 3.6 (MPA)to 8.5 (WG) . AAV are more frequent among whites(90% of cases), and the mean age of presentation is 55years . The clinical manifestations of AAV are diverseand sometimes overlapping. Necrotizing and crescenticglomerulonephritis (NCGN) a severe form of renal vas-cular disorder that produces rapidly progressive renalinsufficiency and pulmonary capillaritis are commonsevier Ltd. All rights reserved. doi:10.1016/j.it.2008.03.001 Available online 24 April 2008
Revieware the driving force of granuloma formation in WG andCSS.
An unmet need for treatment of AAVCurrently, immunosuppressants (e.g., cyclophosphamideor methotrexate) in combination with glucocorticoids arethe mainstay of AAV treatment . Although dramaticallyimproving patient survival, they are far from perfect, with25% of patients having treatment-related severe adverseevents (e.g. infections and malignancy) . Furthermore,these drugs do not sustain remission efficaciously (there isa 50% relapse rate ), meaning that AAV become chronic,relapsing disorders, with accumulative, irreversible organdamage occurring because of repetitive episodes of diseaseactivity leading to intensification of toxic immunosuppres-sants. Approximately 10% of AAV patients  are refrac-tory for the standard immunosuppressant combinationand are at high risk of death . Therefore,more efficaciousand safer alternative treatments are needed to improve theglobal outcome of AAV patients. This, together withgreater insight into AAV pathogenesis, has prompted in-terest in biological agents. A more pathogenesis-orientedtherapeutic approach could overcome the deficiencies ofcurrent therapies by ablating key immune pathways withless toxicity . We will discuss the role of the biologicaltreatments most used in AAV, paying special attention totheir pathogenesis and the immunological rationale ofbiological agents.
Figure 1. (a) Characteristic cytoplasmic anti-neutrophil cytoplasmic antibodies (C-
ANCA) and (b) perinuclear (P-ANCA) patterns of ANCA binding. Indirect
immunofluorescence of ethanol-fixed neutrophils. Original magnification, 1000(a) and 2500 (b).Pathogenesis of ANCA-associated vasculitisGranuloma formation in WGWG usually starts as a granulomatous disease of therespiratory tract, and in most patients, progresses tosystemic disease with PR3-ANCAassociated vasculitis. This suggests that WG may start with an aberrantcell-mediated immune response to an exogenous orendogenous antigen in the respiratory tract, which resultsin granuloma formation, with humoral autoimmunity toPR3 occurring at a later stage . However, granulomatain WG and their relationship with systemic vasculitis ispoorly understood. No ANCA animal model has yet repro-duced the typical granulomata of WG [14,15].
Multiple cell types are present in WG granulomas in-cluding PR3+ cell clusters (neutrophils and monocytes)surrounded by antigen-presenting cells and abundantTh1-type CD4+CD28- effector memory T cells (TEMs).Maturing B and plasma cells are also present, suggestingneoformation of lymphoid like tissue (Figures 2a and 2c).
In WG, there is an alteration of T-cell differentiation,with T cells lacking the co-stimulatory molecule CD28being detected early in localized disease with furtherexpansion as WG generalizes . These cells displayfeatures of TEMs with several potent effector functions. Being a major source of Th1-type cytokines [princi-pally tumor necrosis factor a (TNF-a) and interferon g(IFN-g)], CD4+CD28-T cells are thought to be the drivingforce of granuloma formation [19,20]. These cells expressb2-integrin and the Th1-type CC-chemokine receptor 5(CCR5)  and also have cytotoxic potential . None-theless, the cause of CD4+CD28 T-cell proliferationremains unclear and might be an antigen (possiblyPR3)-driven process and/or the result of T regulatory celldysfunction in genetically susceptible individuals. In fact,Abdulahad et al.  have recently observed that patientswith WG in remission have an expanded number of regu-latory T cells with a defective suppressive function, whichmay be an important factor accounting not only for thedevelopment of WG but also for its relapsing nature.
It has recently been postulated that WG granulomamight not be simply a haphazard, deleterious aggregationof immune cells but could also represent a lymphoid struc-ture ultimately responsible for PR3-ANCA production. Forinstance Voswinkel et al.  found B lymphocyterichfollicle-like aggregates within the granulomatous lesions ofendonasal specimens ofWG patients in the vicinity of PR3+
cells and plasma cells (Figure 2a, c). Analysis of the immu-noglobulin gene repertoire showed autoreactive B cellswith potential affinity for PR3. Chronic secretion ofTNF-a and IFN-g in the granuloma might provide a favor-able proinflammatory environment for the neogenesis ofgerminal centre-like structures, where T and B cellscooperate to break tolerance and maintain antibody pro-duction against PR3. An interesting theory of PR3-directedautoimmunity has recently been proposed. This involvescPR3, the complementary peptide of PR3 encoded by theantisense strand of the PR3 gene . If the immunesystem is exposed to cPR3, antibodies against it can
Trends in Immunology Vol.29 No.6appear, which in turn generate anti-idiotype antibodiesthat cross-react with PR3. Accordingly, PR3-encoding gene