1. Classification of and Approach to the Vasculitis 강동경희대학교병원 류마티스내과 송란

3. Definition of vasculitis The term vasculitis –several diseases involving inflammation of blood vessels with subsequent tissue destruction and/or organ failure. The spectrum of “vasculitis” –broad and spans many entities –individual names because of unique clinical, laboratory, or pathologic features. The systemic vasculitis –group of disorders –common inflammatory vascular disease as the primary or a substantive pathologic process

4. Consideration in the Classification of Systemic Vasculitis Size of predominant blood vessels affected Patient's demographic profile –Age, Gender, Ethnic, Background Pattern of organ involvement Pathologic Features –presence or absence of granulomatous inflammation –Immune complex deposition versus pauci-immune histopathology –Finding of characteristic autoantibodies ANCAs, anti-GBM antibodies, or rheumatoid factor in serum Certain infections known to cause specific forms of vasculitis

5. Classification of vasculitis Primary or Secondary By pathophysiology & pathogenesis –Pathogenic immune complex formation –Antineutrophilic cytoplasmic antibodies(ANCA) association –Pathogenic T lymphocyte response and granuloma formation By the size of blood vessel involved –Large (the aorta and its major branches) –Medium (muscular arteries and arterioles) –Small (capillaries and postcapillary venules)

6. Primary or Secondary Primary Vasculitis SyndromesSecondary Vasculitis Syndormes Wegener’s granulomatosis Churg-Strauss syndrome Polyarteritis nodosa Microscopic polyangiitis Giant cell arteritis Takayasu’s arteritis Henoch-Schönlein purpura Idiopathic cutaneous vasculitis Essential mixed cryoglobulinemia Behcet’s sydrome Isolated vasculitis of the CNS Cogan’s syndrome Kawasaki disease Drug-induced vasculitis Serum sickness Vasculitis associated with other primary disease Infection Malignancy Inflammatory bowel disease Rheumatic disease (CTD, RA …)

7. Selected Conditions Mimicking Primary Systemic Vasculitis Antiphospholipid syndrome Atheroembolic disease Atheromatous vascular disease Cocaine and amphetamine abuse Hypersensitivity reactions Infective endocarditis Multiple myeloma Paraneoplastic syndromes

8. History and Evolution of Vasculitis Classification Systems 1860’ Kussmaul & Maier “Periarteritis Nodosa” 1952’ Pearl Zeek 5 entities 1990’ ACR criteria 7 entities 1994’ CHCC definition (Chapel Hill Consesnsus Conference) 10 entities Giant cell arteritis Takayasu arteritis Polyarteritis nodosa ANCA-associated granulomatous vasculitis Churg-Strauss syndrome Henoch-Schonlein purpura Hypersensitivity vasculitis ACR criteria ( except Hypersensitivity vasculitis) + Kawasaki disease Microscopic polyangiitis Essential cryoglobulinemic vasculitis Cutaneous leukocytoclastic vasculitis ANCA Pathology

9. Concept of Definition, Classification System & Diagnostic Criteria

10. ACR criteria & CHCC definition ANCA-associated granulomatous vasculitis (Wegener granulomatosis) –ACR Criteria: need 2 of 4 criteria Nasal or oral inflammation Abnormal chest radiograph Urinary sediment Granulomatous inflammation on biopsy –CHCC Definition Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels (e.g., capillaries, venules, arterioles, and arteries) Necrotizing glomerulonephritis is common. a: ACR criteria b: CHCC definition QJM, 2005, 98: 97–111 prospective cohort of 99 patients from well-defined population in Norfolk, UK

11. Type of vessels Large Vessels Medium Vessels Small Vessels aorta major branches analogous veins main visceral arteries & veins their initial branches intraparenchymal arteries Arterioles capillaries venules & veins Arthritis Rheum 2013, 65: 1–11

12. Classification of vasculitis according to size KELLEY’s Textbook of Rheumatology, 9 th

13. Classification of primary systemic vasculitis according to size (Chapel Hill Consesnsus Condrence Nomenclature) Large Vessel Takayasu's arteritis Giant cell arteritis (temporal arteritis) Cogan's syndrome Behçet's disease Medium Vessel Polyarteritis nodosa Kawasaki disease Primary angiitis of the central nervous system Small Vessel Granulomatosis with polyan giitis (formerly Wegener's gr anulomatosis) Microscopic polyangiitis Churg-Strauss syndrome Renal-limited vasculitis Goodpasture's disease (anti–glomerular basement membrane disease) Cutaneous leukocytoclastic angiitis (“hypersensitivity va sculitis”) Henoch-Schönlein purpura Essential cryoglobulinemia

14. Typical Clinical Manifestations of Large, Medium, and Small Vessel Involvement by Vasculitis Large vessel Limb claudication Asymmetric blood pressures Absence of pulses Bruits Aortic dilation Renovascular hypertension Medium vessel Cutaneous nodules Ulcers Livedo reticularis Digital gangrene Mononeuritis multiplex Microaneurysms Renovascular hypertension Small vessel Purpura Vesiculobullous lesions Urticaria Glomerulonephritis Alveolar hemorrhage Cutaneous extravascular necrotizing Splinter hemorrhages Uveitis/episcleritis/scleritis

15. Classification of vasculitis by pathogenesis Pathogenic Immune Complex Formation and/or Deposition Henoch-Schonlein purpura Vasculitis associated with collagen vascular disease Serum sickness and cutaneous vasculitis syndrome Hepatitis C-associated essential mixed cryoglobulinemia Hepatitis B-associated polyarteritis nodosa Production of ANCA Wegener’s granulomatosis Churg-Strauss syndrome Microscopic polyangiitis Pathogenic T lymphocyte responses and granuloma formation Giant cell arteritis Takayasu’s arteritis Wegener’s granulomatosis Churg-Strauss syndrome

16. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitis Arthritis Rheum 2013, 65: 1–11 28 participants from 12 countries nephrology, otolaryngology, pathology, pulmonology, rheumatology, pediatrics

17. Definitions for vasculitis adopted by the CHCC2012

18. Rename Wegener’s granulomatosis Friedrich Wegener : German pathologist called by the name Wegener’s granulomatosis since the 1950s Wegener joined the Nazi Party in 1932 The American College of Chest physicians(ACCP) awarded Wegener a “master clinician” prize in 1989. After his Nazi past was discovered in 2000, the ACCP rescinded the prize Campaign was begun to rename Wegener’s granulomatosis to ANCA-associated granulomatous vasculitis In 2011, several journals proposed the name 'granulomatosis with polyangiitis‘.

19. Where was that ??

20. Components of a vasculitis diagnosis Compatible clinical phenotype Supported by specific serology (ex. ANCA) or radiology (ex. Angiography) Confirmation by tissue biopsy Exclusion of mimics and secondray causes Observation over time to improve certainty of diagosis

21. Suspected Vasculitis FUO with constitutional symptoms Unexplained multisystem organ disease Unexplained inflammatory arthritis Unexplained myositis Suspicious rash Unexplained peripheral neuropathy Unexplained and organ ischemia Glomerulonephritis Vasculitis?

22. Clinical Features of Major Systemic Vasculitis Am Fam Physician, Vol. 83, No. 5

23. Initial investigations for vasculitis Full blood count, ESR, Clotting screen Hematology Urea, electrolytes, creatinine (estimated GFR) Liver function tests C-reactive protein Immunoglobulins and protein electrophoresis Biochemistry ANCA, ANA, ENA, Rheumatoid factor, Complement (C3 and C4), Anti-cardiolipin antibodies, Cryoglobulins Immunology Hepatitis B and hepatitis C serology Consider HIV testing Urine microscopy and culture analysis Microbiology Chest X-ray Radiology

24. Further investigations and opinions for organ specific features Specialist review and biopsy CT (or MR) scan Ear nose and throat Specialist review Consider orbital CT (or MR) Eye Specialist review CT scan Consider bronchoscopy and biopsy Chest Specialist review Echocardiograph Consider cardiac MR, angiography Heart Specialist review Renal ultrasound Kidney biopsy Kidney Specialist review Peripheral nerve, consider nerve conduction studies Central nervous system, brain MR, CSF examination, consider angiography Nervous system

25. Definitive diagnosis of systemic vasculitis Systemic Vasculitis Histologic evidence of vasculitis Positive serology for ANCA Specific indirect evidence of vasculitis

26. LARGE VESSEL VASCULITIS

27. ACR Classification Criteria for Giant Cell Arteritis CriteriaDefinition Age at disease onset ≥ 50 yr Development of symptoms or findings beginning at age 50 or older New headache New onset or new type of localized pain in the head Temporal artery abnormality Temporal artery tenderness to palpation or decreased pulsation, unrelated to arteriosclerosis of cervical arteries Elevated ESR ESR ≥50 mm/hr by the Westergren method Abnormal artery biopsy Biopsy specimen with artery showing vasculitis characterized by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells

28. ACR Classification Criteria for Takayasu's Arteritis Onset before age 40 yr Limb claudication Decreased brachial artery pulse Unequal arm blood pressure (>10 mm Hg) Subclavian or aortic bruit Angiographic evidence of narrowing or occlusion of aorta or its primary branches, or large limb arteritis ** The presence of three or more of the six criteria is sensitive (91%) and specific (98%) for the diagnosis of Takayasu's arteritis.

29. Differential Diagnosis of Takayasu’s arteritis Other disease that can affect the aorta Disease TypeSpecific Entities Rheumatic Giant cell arteritis, Cogan's syndrome, relapsing polychrondritis, ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, Buerger's disease, Behçet's disease Infectious Syphilis, tuberculosis Other Atherosclerosis, ergotism, radiation-induced damage, retroperitoneal fibrosis, inflammatory bowel disease, sarcoidosis, neurofibromatosis, congenital coarctation, Marfan's syndrome, Ehlers-Danlos syndrome, IgG4-related systemic disease

30. Comparison of Giant cell arteritis & Takayasu’s arteritis FeatureGiant Cell ArteritisTakayasu's Arteritis Female-male ratio 2 : 12 : 18 : 18 : 1 Age range (yr)≥50<40 Average age of onset (yr)7225 Visual loss10%-30%Rare Involvement of aorta or its major branches 25%100% HistopathologyGranulomatous arteritis Pulmonary artery involvementNoOccasionally Renal hypertensionRareCommon ClaudicationUncommonCommon Ethnic groups with highest ] incidence ScandinaviansAsians Corticosteroid responsiveYes Bruits presentMinorityMajority Surgical intervention neededRareCommon

31. POLYARTERITIS NODOSA & MICROSCOPIC POLYANGIITIS

32. 1990 ACR Criteria for Polyarteritis Nodosa Weight loss > 4 kg Livedo reticularis Testicular pain or tenderness Myalgias, weakness, or polyneuropathy Mononeuropathy or polyneuropathy Diastolic BP > 90 mm Hg Increased BUN or creatinine Hepatitis B virus Arteriographic abnormality Biopsy of small or medium-sized artery ** least 3 of these 10 criteria 1994 CHCC Definition Polyarteritis nodosa Microscopic polyangiitis Necrotizing inflammation of medium- sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules Necrotizing vasculitis with few or no immune deposits affecting small vessels (capillaries, venules, arterioles). Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing glomerulo- nephritis is very common. Pulmonary capillaritis often occurs

33. ANCA ASSOCIATED VASCULITIS

34. ANCA (Antineutrophil cytoplasmic antibody) Directed against antigens that reside within the primary granules of neutrophils and monocytes ANCAs directed against proteinase-3 (PR3): Cytoplasmic-ANCA –serine protease found within the primary granules of neutrophils and monocytes ANCAs directed against myeloperoxidase(MPO): Perinuclear-ANCA c-ANCA p-ANCA

35. ANCA-associated vasculitis pathogenic model JAMA, August 8, 2007—Vol 298, No. 6

36. Significance of c-ANCA Directed Against PR-3 Disease Frequency (%) Wegener’s granulomatosis90 Microscopic polyangiitis50 Polyarteritis nodosa5 – 10 Churg-Strauss syndrome10 Hypersensitivity vasculitisRare Henoch-Schonlein purpuraRare IgA nephropathyRare Postinfectious glomerulonephritisRare SLERare Kawasaki disease+ Controls± Rheumatology 5th edition

37. Significance of p-ANCA Directed Against MPO DiseaseFrequency (%) Microscopic polyangiitis50 – 70 Idiopathic necrotizing glomerulonephritis50 – 85 Churg-Strauss syndrome70 - 85 Goodpasture’s syndrome10 - 30 Wegener’s granulomatois5 - 10 Polyarteritis nodosa+ Polyangiitis overlap+ SLE+ Kawasaki disease+ Rheumatology 5th edition

38. Clinical manifestations of ANCA associated vasculitis BMJ 2012;344:e26

39. Systemic Symptoms Fever, Weight loss Skin Palpable purpura, nodule, ulcer, urticaria, Cardiovascular system Infarction CHF Renal system Glomerulo- nephritis, hypertension Nervous system Peripheral neuropathy, CVA Gastro- intestinal system Ischemia, infarction Musculo- skeletal system Arthritis, myalgia

40. Suggestive features of AAV Glomerulonephritis especially rapidly progressive Pulmonary hemorrhage or pulmonary-renal syndrome Cutaneous rash with fever, weight loss, myalgia, arthralgia or arthritis At least one lung nodule Epistaxis or erosive nasal mucosa changes Long-standing sinusitis or otitis Subglottic, tracheal stenosis Mononeuritis multiplex or other peripheral neuropathy Retro-orbital mass ANCA test

41. ACR criteria for Granulomatosis with polyangiitis (GPA) (= Wegener's granulomatosis ) Abnormal urinary sediment (red cell casts or greater than five red blood cells per high-power field) Abnormal findings on chest radiograph (nodules, cavities, or fixed infiltrates) Oral ulcers or nasal discharge Granulomatous inflammation on biopsy ** The presence of two or more of these four criteria was associated with a sensitivity of 88.2% and a specificity of 92%.

42. Asthma Eosinophilia greater than 10% on differential blood cell count Mononeuropathy (including multiplex) or polyneuropathy Nonfixed pulmonary infiltrates on chest radiograph Paranasal sinus abnormality Biopsy containing a blood vessel with extravascular eosinophis ** The presence of four or more of these six criteria gave a sensitivity of 85% and a specificity of 99.7%. ACR criteria for CSS ( = allergic granulomatosis with polyangiitis, AGPA)

43. Classification Criteria & Definition For CSS Lanham (requires 2 of 3)ACR(requires 4 of 6)CHCC Asthma Eosinophilia (>10% WBC count or >1.5 × 10 9 ) Systemic vasculitis affecting at least two extrapulmonary sites Asthma Eosinophilia Neuropathy (mono or polyneuropathy) Pulmonary infiltrates Paranasal sinus abnormality Extravascular eosinophils Eosinophil-rich and granulomatous inflammation involving the respiratory tract, necrotizing vasculitis affecting small to medium-sized vessels, and associated with asthma and eosinophilia

44. Comparison of ANCA-associated Vasculitis WGMPACSS ANCA positive (%)80-90%75%50% Typical resultsC-ANCA/proteinase 3P-ANCA/MPO Upper respiratory tract Nasal septal perforation “Saddle-nose” deformity Subglottic stenosis Usually absent or mild Nasal polyps Allergic rhinitis Lung Nodules, infiltrates, or cavitary lesions Alveolar hemorrhageAsthma infiltrates Kidney NCGN, occasional granulomatous features NCGN Distinguishing features Destructive upper airway disease, granulomatous inflammation No granulomatous inflammation Asthma, allergy, eosinophilia, granulomatous infiltrates—with abundant eosinophils

45. Algorithm for the classification of vasculitis Cases with a clinical diagnosis of ANCA associated vasculitis or PAN Fulfils ACR or Lanham criteria for CSS? Fulfils ACR criteria for WG Histology compatible with CHCC WQ Histology compatible with CHCC MPA +WG surrogate markers No Histology, WG surrogate markers present AND+ve PR3-ANCA or PRO-ANCA Histology compatible with small vessel Vasculitis. No WG surrogate markers No Histology. No WG surrogate markers. Surrogate markers for renal vasculitis AND + ve PR3-ANCA or MPO-ANCA *includes renal limited vasculitis Histology compatible with CHCC cPAN or Angiogenic Features typical of cPAN Unclassified CSS YES No WG No MPA YES No cPAN YES No Ann Rheum Dis 2007, 66:222–7

46. Surrogate markers for vasculitis Surrogate markers for WG (granulomatous disease) –Lower airways X-ray evidence of fixed pulmonary infiltrates, nodules or cavitations present for >1 month. Bronchial stenosis –Upper airways bloody nasal discharge and crusting for >1 month, or nasal ulceration chronic sinusitis, otitis media or mastoiditis for >3 months retro-orbital mass or inflammation (pseudotumour) subglottic stenosis saddle-nose deformity/destructive sinonasal disease Surrogate markers for renal vasculitis (glomerulonephritis) –haematuria associated with red cell casts or >10% dysmorphic erythrocytes –or 2+ haematuria AND 2+ proteinuria on urinalysis

48. Conclusions Vasculitis are a heterogeneous group of diseases linked by common clinical, laboratory, and pathophysiologic features The 1990 American College of Rheumatology (ACR) Classification Criteria and the Chapel Hill Consensus Conference (CHCC) Nomenclature of Systemic Vasculitis are widely utilized for clinical research in vasculitis. Suspicion of vascluitis is an important first step to begin a process of investigation to make diagnosis When the diagnosis remains uncertain, observation over time, repeat investigation and a therapeutic trial may improve the probability of the diagnosis or identify an alternative disease

49. You can do it !!