1. Pathogenesis of vasculitis Eun Bong Lee Seoul National University College of Medicine WCU, November, 2014

2. Contents Vasculitis –Definition –Classification –Epidemiology –Pathophysiology –Treatment Pathogenesis of vasculitis –Immune complex mediated vascultis –ANCA-associated vasculitis –Granulomatous vasculitis

3. Vasculitis

4. Clinicopathologic process characterized by inflammation of and damage to blood vessels

5. Classification Large vessel vasculitis –Takayasu’s arteritis, Giant cell arteritis Medium vessel vasculitis –Polyarteritis nodosa, Kawasaki disease Small vessel vasculitis –Immune complex mediated Hypersensitivity vasculitis, cryoglobulnemic vasculits Connective tissue disorders, infection, paraneoplastic disease –ANCA-associated vasculitis Wegener’s granulomatosis Microscopic polyangiitis Churg-Strauss vasculitis

6. Epidemiology -Incidence U.S.AElsewhere Takayasu’s arteritis2/mil150/mil (Japan) Temporal cell arteritis 240/mil220-270/mil (EU) Polyarteritis nodosa7/mil7/mil (Spain) Kawasaki’s disease100/mil900/mil (Japan) Wegener’s granulomatosis4/mil8.5/mil (UK) Churg-Strauss disease4/mil1.1/mil (Spain)

7. Epidemiology - prevalent group Age (years)Sex (M:F) Takayasu’s arteritis15-251:9Asian Temporal cell arteritis>551:3Whites Polyarteritis nodosa40-502-3:1 Kawasaki’s disease1-51.5:1Asian HS* purpura4-71.5:1 Wegener’s granulomatosis-40-1:1Whites Churg-Strauss disease-44-1.3:1 Cutaneous vasculitisAny age1:1

8. Clinical manifestations Systemic symptoms Fever, weight loss* Skin Palpable purpura, nodule, ulcer, urticaria, livedo reticularis Cardiovascular system Infarction, CHF Nervous system Mononeuritis multiplex, CVA Gastrointestinal system Ischemia, infarction Renal system Glomerulonephritis, hypertension Musculoskeletal system Arthritis, myalgia *Leukocytosis, anemia of chronic disorder, elevation of ESR, CRP, hyper-  -globulinemia

9. Diagnosis Clinical features suggestive of vasculitis –Mononeuritis multiplex –Palpable purpura –Pulmonary renal involvement –Unexplained ischemic events Diagnostic tools –Angiogram –Biopsy

10. Pathogenesis of vasculitis

11. Pathology Leukocytoclasis –Henoch-Schoenliein purpura*, Hypersensitivity vasculitis Necrosis –Polyarteritis nodosa Granulomatous inflammation –Wegener’s granulomatosis, Churg- Strasuss syndrome, Takayasu’s arteritis, giant cell arteritis *IgA deposition

12. Pathophysiology Immune complex formation –Complement activation e.g. HS purpura, PAN (HBsAg), serum sickness essential mixed cryoglobulinemia (HCV) Anti-neutrophil cytoplasmic antibodies (ANCA) –C-ANCA, P-ANCA e.g. Wegener’s granulomatosis, Churg-Strauss vasculitis, microscopic polyangiitis T lymphocytes with granuloma formation –Delayed hypersensitivity e.g. Temporal arteritis, Takayasu’s arteritis, Kawasaki’s disease, Wegener’s granulomatosis, Churg-Strauss syndrome

13. 1) Immune complex-mediated vasculitis Polyarteritis nodosa (HBsAg-related) Henoch-Schoenlein purpura Cryoglobulinemic vasculitis

14. Polyarteritis nodosa Necrotizing inflammation of medium- and small-sized muscular arteries that spares the smallest blood vessels (arterioles, venules, and capillaries) Immune complex deposition with HBsAg (<5%) Clinical features –Livedo reticularis, renovascular hypertension, intestinal angina, mononeuritis multiplex Treatment –Glucocorticoid, immunosuppressants

15. Henoch-Schoelein purpura Small vessel vasculitis involving skin, joint, stomach/intestine, kidney Immune complex deposition, IgA Clinical features –Palpable purpura in lower extremities –Polyarthralgia –Colicky abdominal pain –Glomerulonephritis –Normal complement levels, elevated IgA Treatment –Glucocorticoids (arthralgia, abdominal pain)

16. Cryoglobulinemic vasculitis Systemic vasculitis associated with cryoglobulinemia Hepatitis C (5%) Clinical manifestations –Purpura, arthritis, peripheral neuropathy, glomerulonephritis (membranoproliferative GN) –RF, cryoglobulin, hypocomplementemia Treatment –Interferon-  and ribavirin for HCV infection –Glucocorticoids : transient response

17. Immune complex-mediated vasculitis Modfied from http://www.immunopaedia.org.za TNF ,IL1, IL17

18. Endothelial cell activation Upregulation of adhesion molecules –P-selection, E-selectin, VCAM-1, ICAM-1 etc Thrombotic tendency –Upregulation of tissue factor –Loss of thrombomodulin, heparan sulfate proteoglycan Angiogenesis –Vascular endothelial growth factor (VEGF), fibroblast growth facor-2(FGF2) Apoptosis of endothelial cells

19. Leukocyte adhesion Muller, Lab invest, 2002

20. 2) ANCA-associated vasculitis Granulomatosis with polyangiitis (GPA) –Wegener’s granulomatosis Microscopic polyangiitis (MPA) Eosinophilic granulomatosis with polyangiitis (EGPA) –Churg Strauss syndrome

21. Granulomatosis with polyangiitis Granulomatous vasculitis –Upper respiratory tract –Lower respiratory tract –Glomerulonephritis Clinical features –Sinusitis (pain, nasal discharge, saddle nose) –Chest pain, hemoptysis –Rapidly progressive glomerulonephritis –Systemic symptoms Fever, weight loss, cold sweating Treatment –Glucocorticoid, cyclophosphamide

22. Microscopic polyangiitis Pauciimmune necrotizing small vessel vasculitis without granuloma Clinical features –Pulmonary renal syndrome –Renal involvement (90%) –Alveolar hemorrhage (50%) –Less common involvement of eye, nose and throat Treatment –Prednisolone, cyclophosphamide

23. Eosinophilic granulomatosis with polyangiitis Eosinophil-rich and granulomatous, necrotizing vasculitis Clinical features –Asthma, pulmonary infiltrates –Allergic rhinitis, sinusitis –Mononeuritis multiplex –Peripheral eosinophilia Treatment –Glucocorticoids, immunosuppressants

24. ANCA* Cytoplasmic-ANCA –Proteinase-3 Perinuclear-ANCA –Myeloperoxidase, –Elastase, cathepsin G, lactoferrin, lysozyme, bactericidal/permeability increasing protein Neutrophil *Anti-neutrophil cytoplasmic antibody

25. ANCA in vasculitis Disease entitySensitivity of PR3-ANCA (%)MPO-ANCA (%) Granulomatosis with polyangiitis6624 Microscopic polyangiitis2658 Eosinophilic granulomatosis with polyangiitis 3064 Idiopathic crescentic glomerulonephritis <540

26. ANCA as a pathogenic factor In vitro –Killing of endothelial cells by ANCA-activated neutrophil –ANCA induce IL1 , TNF , IL6, IL8, MCP1 and Leukotriene B4 Animal –Mouse model of ANCA disease by injection of anti-MPO IgG Human –Development of pulmonary hemorrhage and glomerulonephritis in a neonate after birth from a mother with MPO-ANCA –Therapeutic effect of plasma exchange Falk RJ, Proc Natl Acad Sci, 1990;87:4115 Xiao H, J Clin Invest, 2002;110:955 Bansal PJ, Ann Allergy Asthma Immunol, 2004;93

27. Glomerular lesions in Rag2-/- mice 6 days after receiving anti-MPO IgG Segmental fibrinoid necrosis Crescent formation Fibrin stainingIgG staining Xiao H, J Clin Invest, 2002;110:955

28. Bosch X, JAMA, 2007 Blood vessel Endothelial cells Fc  receptor Neutrophil TNF  ANCA PR3, MPO TNF receptor Adhesion molecules Fc  receptor Reactive oxygen species Transmigratin g neutrophil Cytokines Pathogenesis of ANCA associated vasculitis

29. ANCA development Etiology –Genetic predisposition Polymorphisms of proteinase III, Fc-gamma receptor, adhesion molecules –Environmental factors Silica, farming, solvent, allergy in general, asbestos, persticides Mechanism –Autoantigen complementarity theory –Dysfunction of neutrophil apoptosis

30. Autoantigen complementarity theory Induced by complementary peptide or its mimic S aureus, E hitolytica Pendergraft, Nat Med, 2004

31. 3) Granulomatous vasculitis Giant cell arteritis (temporal arteritis) Takayasu’s arteritis

32. A chronic vasculitis of unknown etiology, primarily affecting the aorta and its primary branches, in Asian young women Clinical features –Systemic features Fatigue, weight loss, low-grade fever –Vascular features Claudication of arm and leg, syncope, ulceration, skin lesion Treatment –Glucocorticoid immunosuppressant

33. Giant cell arteritis A chronic vasculitis of large and medium sized vessels, predominantly involving the cranial branches of the arteries that originate from aortic arch Usually affecting female Caucasians

34. Ocular involvement Posterior cilliary artery occlusion Central retinal artery occlusion Anterior ischemic optic neuropathy

35. Pathology Temporal artery biopsy Unilateral biopsy, length 1.5-3.0cm size Chronic granulamatous inflammation with lymphocytes, macrophages and multinucleate giant cells Internal elastic membrane Adventitia Media Intima

36. Activation of dendritic cells Immature dendritic cells Mature dendritic cells CD83, CD86 CCL19, IL18 CCR7 : arrest Weyand CM, NEJM, 2003 Antigens: Autoantigen vs virus (parvovirus, varicella- zoster virus, Chlamydia)

37. Activation of T cells and macrophages

38. Response to injury

39. Take-home message Immune complex formation –Henoch-Schoenlein purpura, cryoglobulinemic vasculitis, polyarteritis nodosa Antineutrophil cytoplasmic antibodies (ANCA) –Wegener’s granulomatosis, Churg-Strauss vasculitis, microscopic polyangiitis T lymphocytes with granuloma formation Temporal arteritis, Takayasu’s arteritis

41. Polymyalgia rheumatica Polymyagia rheumatica Giant cell arteritis Older age at onset Similar sex ratio Increased acute phase reactants Rapid response to glucocorticoids 16-21% among polymyalgia rheumatica 40-60% among Giant cell arteritis Salvarani, Lancet, 2008