AN OVERVIEW OF ANCA-ASSOCIATED VASCULITIS

GRANULOMATOSIS WITH POLYANGIITIS (GPA), MICROSCOPIC POLYANGIITIS (MPA), and EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA) AN OVERVIEW OF ANCA-ASSOCIATED VASCULITIS

What is ANCA-associated Vasculitis? ANCA-ASSOCIATED VASCULITIDES ARE SYSTEMIC AUTOIMMUNE DISEASES THAT AFFECT SMALL- TO MEDIUM-SIZED BLOOD VESSELS 1 They show similar focal necrotizing lesions involving arterioles, venules, and capillaries 2 They are often associated with the serologic presence of antineutrophil cytoplasmic antibodies (ANCAs) against cytoplasmic proteins (proteinase 3 [PR3] and myeloperoxidase [MPO]) expressed on the surface of neutrophils 2 They form part of the ANCA-associated category of vasculitides, although not all patients with GPA, MPA, or EGPA have ANCAs 3 They often affect the kidneys and the upper and lower respiratory tract 2 There are 3 forms of ANCA-associated vasculitis. 4 Granulomatosis with polyangiitis (GPA) Formerly known as Wegener s granulomatosis Microscopic polyangiitis (MPA) Eosinophilic granulomatosis with polyangiitis (EGPA) Formerly known as Churg-Strauss syndrome All of these ANCA-associated vasculitides affect small- to medium-sized blood vessels and tend to be associated with the presence of autoantibodies to antigenic proteins normally present in the granules of neutrophils. 4 TYPES OF ANCA-ASSOCIATED VASCULITIS GPA Characterized by granulomatous inflammation of the upper and lower respiratory tract 5 Mainly associated with ANCAs against PR3 2 MPA Characterized by small-vessel vasculitis without granulomatous inflammation 5 Mainly associated with ANCAs against MPO 2 EGPA Characterized by granulomatous inflammation, asthma, and eosinophilia of the upper respiratory tract 5 Mainly associated with ANCAs against MPO 5 The significant and important potential outcome of ANCA-associated vasculitis is that it can result in damage to the vessel wall, leading to vessel occlusion, tissue ischemia, and localized necrosis. Those damaging effects all contribute to the clinical manifestations of GPA, MPA, and EGPA and may involve multiple organs of the body. 4,6,7 Visit ancaassociatedvasculitis.com/overview for much more, including: Interactive Classification of Systemic Vasculitides Overview of ANCA Glomerulonephritis Epidemiology of GPA, MPA, and EGPA Interactive Risk Factors Presentation REFERENCES: 1. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):187-192. 2. Pallan L, Savage CO, Harper L. ANCA-associated vasculitis: from bench research to novel treatments. Nat Rev Nephrol. 2009;5(5):278-286. 3. Falk RJ, Jennette JC. ANCA disease: where is this field heading? J Am Soc Nephrol. 2010;21(5):745-752. 4. Bosch X, Guilabert A, Espinosa G, Mirapeix E. Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review. JAMA. 2007;298(6):655-669. 5. Langford CA. Vasculitis. J Allergy Clin Immunol. 2010;125(2 suppl 2):S216-S225. 6. Gota CE. Vasculitis: Introduction. The Merck Manual Professional Edition. http://www. merckmanuals.com/professional/musculoskeletal_and_connective_tissue_disorders/vasculitis/overview_of_vasculitis.html?qt=red%20blood%20cell%20 casts&sc=&alt=sh. 2013. 7. Gómez-Puerta JA, Bosch X. Anti-neutrophil cytoplasmic antibody pathogenesis in small-vessel vasculitis: an update. Am J Pathol. 2009;175(5):1790-1798. 2

Pathogenesis The Role of the Immune System in ANCA-ASSOCIATED VASCULITIS Cells Because ANCA-associated vasculitides are inflammatory disorders, immune cells and molecules are prominent in their disease pathogenesis. Following are some of the important cell types and molecules known or strongly suspected to be participants in the pathogenesis of ANCA-associated vasculitis. Neutrophils ANCAs have been shown to activate neutrophils to release internal granule contents. In addition, neutrophils may release cytokines and chemokines. Release of these compounds can contribute to local inflammation, increase endothelial cell expression of adhesion receptors, attract more neutrophils and other immune effector cells to an area, and contribute to tissue damage. 1 T Cells T cells are involved in ANCA-associated vasculitis pathogenesis. T cells infiltrate sites of inflammation in GPA 2 ANCAs are class-switched, high-affinity antibodies, implying T cells help in their production 1 T cell cytokines are increased in patients with active ANCA-associated vasculitis, and some of these cytokines affect other cells in the inflammatory process 1 B Cells B cells are involved in ANCA-associated vasculitis because, as terminally differentiated plasma cells, they produce ANCAs. In addition, B cells can regulate antigen-presenting cells and T-cell subsets through cytokine production. B cells can also serve as antigen-presenting cells. 3 Eosinophil Cells Severe eosinophilia ( 10%) is common in EGPA. 4 Contributors to eosinophilia include growth factors such as IL-13 and IL-5. 5 Elevated levels of IL-5 have been detected in the serum of EGPA patients 5 Increased IL-5 secretion stimulated by T cells may substantially contribute to eosinophilia 5 IL-5 is the most potent stimulator of eosinophil production 5 Molecules Antibodies Since their discovery decades ago, evidence has indicated a role for ANCAs in the pathogenic processes leading to development of vasculitides. ANCAs have been shown to activate neutrophils and cause them to release a number of effector molecules 1 Transfer of MPO-ANCA into normal and immunocompromised mice can induce necrotizing vasculitis 6 A case of maternal transfer of MPO-ANCA caused transient pulmonary hemorrhage and renal dysfunction in a neonate 7 Cytokines Stimulation of neutrophils by TNF-α or other inflammatory cytokines causes migration of ANCA antigens (PR3 and MPO) from granules to the cell surface and increased expression of adhesion molecules on neutrophil surfaces. Subsequently, neutrophils are activated by ANCAs and release granule enzymes and reactive oxygen species. 8 Complement Complement is also an important mediator of ANCA-associated vasculitis. Stimulation of neutrophils by ANCAs causes release of factors that activate the alternative complement pathway 9 Genetically engineered mice lacking the alternative complement pathway do not develop glomerulonephritis when infused with MPO-ANCA 9 3

Pathogenesis ANCAs The role of ANCAs in ANCA-associated vasculitis ANCAs activate cytokine-primed neutrophils and monocytes through both direct Fab 2 binding and Fc receptor engagement 10 Fc receptor binding causes neutrophils to adhere to the endothelium 10 Complement pathway activators are released, damaging the vascular walls 9 ANCA-activated neutrophils release proinflammatory cytokines, recruiting other inflammatory cells and exacerbating vascular damage 11 ANCAs play a pathogenic role in ANCA-associated vasculitis ANCAs promote degranulation of neutrophils and monocytes, facilitating endothelial damage 12 In animal models, the transfer of anti-mpo-igg resulted in development of necrotizing crescentic glomerulonephritis (NCGN) 12 In mice, immune responses induced by anti-pr3 antibodies produced NCGN 12 In support of the above evidence, in clinical observations ANCA titers correlate with response to treatment 10 4

Pathogenesis Frequency of MPO ANCA * and PR3 ANCA It should be noted that 14 : ANCAs are not detected in all patients with GPA, MPA, and EGPA ANCA status may change over time These figures are for patients with active, untreated disease. The frequency of ANCA positivity may be lower in treated patients or in those in remission * MPO ANCAs often cause a perinuclear immunofluorescence staining pattern (P-ANCA). 13 PR3 ANCAs often cause a cytoplasmic immunofluorescence staining pattern (C-ANCA). 13 Visit ancaassociatedvasculitis.com/pathogenesis for much more, including: Interactive Classification of Systemic Vasculitides REFERENCES: 1. Gómez-Puerta JA, Bosch X. Anti-neutrophil cytoplasmic antibody pathogenesis in small-vessel vasculitis: an update. Am J Pathol. 2009;175(5):1790-1798. 2. Rasmussen N, Petersen J. Cellular immune responses and pathogenesis in c-anca positive vasculitides. J Autoimmun. 1993;6(2):227-236. 3. Youinou P. B cell conducts the lymphocyte orchestra. J Autoimmun. 2007;28(2-3):143-151. 4. Baldini C, Talarico R, Della Rossa A, Bombardieri S. Clinical manifestations and treatment of Churg-Strauss syndrome. Rheum Dis Clin North Am. 2010;36(3):527-543. 5. Metzler C, Schnabel A, Gross WL, Hellmich B. A phase II study of interferon-alpha for the treatment of refractory Churg-Strauss syndrome. Clin Exp Rheumatol. 2008;26(3 suppl 49):S35-S40. 6. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002;110(7):955-963. 7. Schlieben DJ, Korbet SM, Kimura RE, Schwartz MM, Lewis EJ. Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs. Am J Kidney Dis. 2005;45(4):758-761. 8. Falk RJ, Jennette JC. ANCA disease: where is this field heading? J Am Soc Nephrol. 2010;21(5):745-752. 9. Xiao H, Schreiber A, Heeringa P, Falk RJ, Jennette JC. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol. 2007;170(1):52-64. 10. Jennette JC, Falk RJ, Gasim AH. Pathogenesis of antineutrophil cytoplasmic autoantibody vasculitis. Curr Opin Nephrol Hypertens. 2011;20(3):263-270. 11. Bosch X, Guilabert A, Espinosa G, Mirapeix E. Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review. JAMA. 2007;298(6):655-669. 12. Wilde B, van Paassen P, Witzke O, Tervaert JW. New pathophysiological insights and treatment of ANCA-associated vasculitis. Kidney Int. 2011;79(6):599-612. 13. Langford CA. Vasculitis. J Allergy Clin Immunol. 2010;125(2 suppl 2):S216-S225. 14. Stone JH. Clinical spectrum of antineutrophil cytoplasmic antibodies: Glassock RJ and Appel GB (eds). UpToDate. Waltham, MA; UpToDate: 2010. 5

Patient presentation Systemic features Because ANCA-associated vasculitis can affect almost any organ of the body, symptoms can be quite varied, and multiple symptoms often present simultaneously. The combination of systemic symptoms with specific organ system symptoms may generate the first suspicion of vasculitis. 1,2 Patients typically present with flu-like symptoms of several weeks or months duration, such as 3 : Fever Myalgias Arthralgias Headache Malaise Anorexia Weight loss General symptoms and patient history may include 1,4 : Chronic sinusitis Concurrent pulmonary (dyspnea, cough, hemoptysis, obstructive symptoms) and renal (hematuria, proteinuria) manifestations Peripheral nerve symptoms (numbness, tingling, weakness) Musculoskeletal symptoms (arthralgia, myalgia, arthritis) Skin manifestations (rash, purpura, nodules) Some patients may initially present with focal vasculitic diseases, such as 3 : Rash (cutaneous vasculitis) Bloody-purulent rhinitis Scleritis Arthritis Physical examination may reveal 1,5 : Crackles or wheezing on lung examination Saddle-nose deformity and nasoseptal perforation Palpable purpura, nodules of the skin, or digital ischemia/necrosis Peripheral nervous system signs (paresis, hypoesthesia) Cardiovascular rhythm abnormalities or signs of heart failure In these patients, careful examination of other organ systems may show other disease manifestations. 3 Visit ancaassociatedvasculitis.com/patient-presentation for much more, including: Interactive Manifestations of ANCA-associated Vasculitis Vasculitis Damage and Activity Indices, including downloadable evaluation forms Types of Diagnosis, with reference images REFERENCES: 1. Gaffo AL. Diagnostic approach to ANCA-associated vasculitides. Rheum Dis Clin North Am. Aug 2010;36(3):491-506. 2. Hunder GG. Classification of and approach to the vasculitides in adults. In: Stone JH (ed). UpToDate. Waltham, MA; UpToDate; 2010. 3. Berden A, Göçeroglu A, Jayne D, et al. Diagnosis and management of ANCA associated vasculitis. BMJ. 2012;344:e26. 4. Lionaki S, Jennette JC, Falk RJ. Anti-neutrophil cytoplasmic (ANCA) and anti-glomerular basement membrane (GBM) autoantibodies in necrotizing and crescentic glomerulonephritis. Semin Immunopathol. Nov 2007;29(4):459-474. 5. King TE and Stone JH. Clinical manifestations and diagnosis of Wegener s granulomatosis and microscopic polyangiitis. In: Glassock RJ and Appel GB (eds). UpToDate. Waltham, MA; UpToDate: 2010. 6

Disease management ANCA-associated Vasculitis Management Survival rates for patients with ANCA-associated vasculitis can vary with subtype. Five-year survival for patients with ANCA-associated vasculitis receiving immunosuppressant and corticosteroid treatment is as follows 1 : GPA is estimated to be 74% to 91% MPA appears to be somewhat worse, ranging from 45% to 76% EGPA ranges from 60% to 97% Five-year survival rates for patients with ANCA-associated vasculitis subtypes with treatment by immunosuppressant plus corticosteroids ANCA-ASSOCIATED VASCULITIS Treatment Goals 2 Control disease activity to prevent further damage to organs Reduce relapse Prevent recurrence of vasculitis Manage treatment toxicity Other considerations Other considerations in the management of these diseases: Managing treatment toxicity is an important part of patient care 3 The optimum length of maintenance therapy has not yet been determined 2 Regular visits to a specialist are required to check disease activity and treatment side effects and to manage consequences of tissue damage, such as renal failure 2 Relapse can occur after many years in remission, so follow-up should be indefinite 2 REFERENCES: 1. Mukhtyar C, Flossmann O, Hellmich B, et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis. 2008;67(7):1004-1010. 2. Berden A, Göçeroglu A, Jayne D, et al. Diagnosis and management of ANCA associated vasculitis. BMJ. 2012;344:e26. 3. Nataraja A, Mukhtyar C, Hellmich B, Langford C, Luqmani R. Outpatient assessment of systemic vasculitis. Best Pract Res Clin Rheumatol. 2007;21(4):713-732. 2014 Genentech, Inc., South San Francisco, CA RRA/092714/0021 7