VASCULITIS

1. VASCULITIS PROF. DR. FERDA ÖZKAN

2. VASCULITIS This is a heterogenous group of disorders characterized byinflammation & damageof blood vessels followed bythrombosis & ischemic manifestationsin the tissues supplied by the blood vessels.

3. Classification • the size and type of blood vessel involved • vascular beds and organs affected • associated clinical features • etiology • pathogenic mechanisms • hypersensitivity – drugs, serum sickness • infections • immune-mediated injury.

4. Classification of vasculitis based on Pathogenesis • Direct infection • Immunologic • Unknown

5. 1-Direct infection • Bacterial- Neissera • Rickettsial-Rocky mountain spotted fever • Spirochetal-Syphilis • Fungal-aspergillosis, mucormycosis • Viral-herpes zoster-varicella

6. Infectious arteritis • Rickettsial disease, syphilis, septic emboli, walls of abscesses. • A mycotic aneurysm is a spot at a branch-point of an artery where a septic embolus (usually) has lodged and set up an infection, weakening the wall.

7. 2-Immunologic • Immune complex-mediated • Antineutrophil cytoplasmic antibody (ANCA)-mediated • Direct antibody mediated • Cell-mediated • Inflammatory bowel disease • Paraneoplastic vasculitis

8. 3-Unknown • Giant cell (temporal) arteritis • Takayasu arteritis • Polyarteritis nodosa

9. Immunologic-Immune complex-mediated • Infection induced-hepatitis B,C • Henoch-Schönlein purpura • SLE and RA • Drug induced • Cryoglobulinemia • Serum sickness

10. Immunologic-ANCA-mediated • Wegener granulomatosis • Microscopic polyangiitis (microscopic polyarteritis) • Churg-Strauss syndrome

11. Immunologic-Direct antibody mediated • Goodpasture syndrome (anti-GBM antibodies) • Kawasaki disease (anti-endothelial antibodies)

12. Immunologic -Cell mediated Organ allograft rejection

13. Pathogenesis of Noninfectious Vasculitis • Immune complex deposition • ANCA’s • Anti-endothelial cell antibodies • Autoreactive T cells

14. Immune mediated vasculitis Vasculitis related to deposition of immune complexes • Consequence of immune complex formation and localization • Ability of the immune complex to activate complement • Release of local vasoactive factors which can increase vascular permeability

15. Immune complex deposition • The vascular lesions resemble those found in experimental immune complex-mediated conditions, such as the local Arthus phenomenon and serum sickness . • Immune reactants and complement can be detected in the serum or vessels of patients with vasculitis (e.g., DNA-anti-DNA complexes are present in the vascular lesions of systemic lupus erythematosus-associated vasculitis and IgG, IgM, and complement in cryoglobulinemic vasculitis).

16. Hypersensitivity to drugs causes approximately 10% of vasculitic skin lesions, largely through vascular deposits of immune complexes. Some, such as penicillin, conjugate serum proteins; others, like streptokinase , are themselves foreign proteins. • The manifestations vary and range from small-vessel hypersensitivity and leukocytoclastic vasculitis to polyarteritis nodosa, Wegener granulomatosis, and Churg-Strauss syndrome and from mild and self-limiting to severe and even fatal.

17. In vasculitis associated with viral infections, immune complexes can be found in the serum and in the vascular lesions of some patients, particularly in cases of polyarteritis nodosa (for example, HBsAg-anti-HbsAg in hepatitis-induced vasculitis).

18. ANCA’S • ANCAs are a heterogeneous group of autoantibodies directed against enzymes mainly found within the azurophil or primary granules in neutrophils, in the lysosomes of monocytes, and in ECs.

19. The description of these autoantibodies is based on the immunofluorescent patterns of staining of ethanol-fixed neutrophils. • Two main patterns are recognized: • one shows cytoplasmic localization of the staining (c-ANCA), and the most common target antigen is proteinase-3 (PR3), a neutrophil granule constituent. • The second shows perinuclear staining (p-ANCA) and is usually specific for myeloperoxidase (MPO).

20. Antineutrophil cytoplasmic antibody (ANCA) • ANCA has been found in patients with: Wegener’s granulomatosis, microscopic polyangitis; polyarteritis nodosa; Churg-Strauss syndrome. • c-ANCA: classical, diffuse cytoplasmic ANCA; stains the entire cytoplasm of alcohol fixed white cells in a granular pattern; • associated with Wegener’s (found in 95%) • p-ANCA: anti-neutrophil antibodies to myelooperoxidase; stain the peri-nuclear region • associated with microscopic polyangitis, Churg-Strauss syndrome, and crescentic glomerulonephritis.

21. ANCA staining c-ANCAp-ANCA

22. One plausible hypothesis for a causative role of ANCAs in vasculitis is summarized briefly as follows: • (1) An underlying disorder (e.g., an infection) elicits pro-inflammatory cytokines such as TNF, and granulocyte-macrophage colony-stimulating factor, and microbial products such as endotoxin, which together cause neutrophils and other inflammatory cells to express PR3 and MPO on their surfaces. • (2) These stimulate the formation of ANCAs. • (3) ANCAs react with circulating cytokine-primed neutrophils and cause them to degranulate • (4) PMNs activated by ANCA cause endothelial cell toxicity and other direct tissue injury.

23. ANCAs directed against neutrophil constituents other than PR3 and MPO are also found in some patients with a wide range of inflammatory but nonvasculitic disorders such as inflammatory bowel disease, autoimmune liver disease, primary sclerosing cholangitis, and rheumatoid arthritis, and in some patients with malignancies and infections

24. Anti-endothelial Cell Antibodies Antibodies to ECs, perhaps induced by defects in immune regulation, may predispose to certain vasculitides, such as those associated with SLE and Kawasaki disease.

25. Diagrammatic representation of the sites of the vasculature involved by the major forms of vasculitis. The widths of the trapezoids indicate the frequencies of involvement of various portions. LCA, leukocytoclastic angiitis. Small-vessel vasculitis

26. Vasculitis • Immune mediated vaculitides • Wegener’s Granulomatosis • Bürger’s Disease (thromboangitis obliterans) • Takayasu Arteritis • Kawasaki’s disease • Infectious arteritis • Raynaud’s disease

27. Pathology:Small vesselsHypersensitivity vasculitis • Examples include serum sickness, drug-induced vasculitis- many of the lesions show immune complexes in lesions. • Skin is most commonly affected, but a wide range of organs can be. • Pathology:(in skin) • fibrinoid necrosis – vessels break down; brisk inflammatory reaction with PMN infiltrate • leukocytoclastic vasculitis - karyorrhexis (nuclear fragmentation) of WBCs in vasculitic lesion • palpable purpura – extravasation of RBCs from necrotic vessel + inflammation.

28. Causes Connective tissue diseases - SLE, RA Infections - Hepatitis B Drugs (all 'P's) - Penicillins, Phenothiazines, Phenylbutazones, Propylthiouracil Hematologic disease - Cryoglobulinemia, Paraproteinemia - e.g. multiple myeloma Idiopathic Antigens microorganisms, drugs, tumor, autoantigens.

29. Pathology:Small vesselsHenoch-Schönlein Purpura • form of hypersensitivity vasculitis in kids, young adults • clinical: • purpura on buttocks, arms, legs • necrotizing vasculitis involving small dermal vessels • arthritis • abdominal pain – often with bloody diarrhea/other evidence of intestinal bleeding, due to mucosal/submucosal vasculitis • kidney involvement in 1/3 – proteinuria, nephrotic syndrome, gross/microscopic hematuria. • Pathology: • glomerulonephritis is often focal, mesangial proliferative in type; often self-limiting • IgA is predominant Ab in glomerular and skin lesions.

30. Pathology:Small vesselsMixed Cryoglobulinemia syndrome • Clinical: • widespread small vessel vasculitis, often associated with severe glomerulonephritis • purpura • arthralgia or arthritis • cryoglobulins • reversibly precipitatie in the cold • consist of IgM rheumatoid factors • most seen in patients with HCV

31. Pathology: • vessels show deposits containing cryoglobulins and complement • leukocytoclastic vasculitis.

32. Leukocytoclastic vasculitis

33. Pathology: Small to Medium-sized vesselsWegener’s Granulomatosis • can occur from teens to old age; peak at age 40, slight male proponderance. 82% die in a year without treatment. • serious systemic disorder characterized by: • acute necrotizing granulomas in upper and/or lower respiratory tract • focal necrotizing or granulomatous vasculitis, affecting small to medium sized vessels in lungs mostly • also skin, joints, nerves, ears • glomerulonephritis, often crescenteric proliferative  renal failure

34. symptoms: • upper respiratory tract (sinusitis, epistaxis, nasal obstruction, otitis media, deafness), • lower respiratory tract (productive cough, hemoptysis, dyspnea), • renal failure.

35. Inflammation (vasculitis) of a small artery along with adjacent granulomatous inflammation, in which epithelioid cells and giant cells

36. Clinical Findings • Respiratory System – upper respiratory tract infections, saddle nose deformity, pneumonitis, pleural effusion • Renal - hematuria, hypertension, renal failure • Ocular - conjunctivitis, uveitis • Skin - urticaria, palpable purpura, livedo reticularis.

37. Diagnosis: c-ANCA found in majority but not specific • Pathology:lung lesions are most diagnostic • lesions usually multiple, well circumscribed, variable size • coagulative necrosis surrounded by granulation tissue; ghost outlines of vessels in necrotic zone, multinucleate giant cells may be present • extrapulmonary lesions – same combo of granulomatous inflammation and vasculitis in upper respiratory tract, skin. • Elsewhere vasculitis predominates.

38. The lung of a patient with fatal Wegener granulomatosis, demonstrating large nodular lesions

39. Pathology:Medium-sized vesselsBuerger’s Disease (thromboangitis obliterans) • predominates in young adult male (20-45) tobacco smokers; female smokers as well. Sligtly more common in Asians, Ashkenazi Jews. • clinical: • ischemia, usually of lower limbs, progressing to gangrene • absence of atherosclerotic stigmata or risk factors • associated with migratory thrombophlebitis

40. The lumen is occluded by a thrombus containing two abscesses

41. Pathology:Medium-sized vesselsPolyarteritis Nodosa • 40-50s, M:F 2:1. May be life threatenting; 5 year survival <15%, 80% with therapy • fever, myalgia, weight loss, foot drop, weakness, abdominal pain, hypertension from renal arteriole involvement • mononeuritis complex - asymmetric peripheral neuropathy with sudden or subacute onset due to nerve infarction; many modalities lost in one nerve • local ischemia, inflammation of affected organs • kidney, GI tract, joints/muscles, heart, nervous system, skin, lungs may be affected.

42. Pathogenesis (no single mechanism, some cases are idiopathic) : • Immune Complex deposition: Hepatitis B Ag, tumor Ag, certain drugs

43. Pathology • All stages of activity may coexist in different vessels, even in one vessel. • Early: focal, fibrinoid necrosis of artery/arteriole wall; transmural inflammation – PMN, eosinophilic poly infiltrate • Intermediate:mural/occlusive thrombi • Late:aneurysms if segmental involvement • with healing, wall infiltrated by fibroblasts -> fibrous thickening of wall -> nodular appearance.

44. Pathology:Large vesselsGiant cell arteritis and temporal arteritis • Mean age of onset 70 years; • Commonly associated with clinical syndrome polymyalgia rheumatica: • pain, stiffness in shoulder & pelvic girdles in absence of evidence of weakness or atrophy •  ESR • response to low-moderate steroid doses.

45. Temporal (giant cell) arteritis

46. Granulomatous inflammatory process can affect any elastic and muscular artery: • most often seen in superficial temporal artery, other cranial arteries • chief clinical risk is blindness • clinical presentation: headache, scalp tenderness, claudication of the jaw(tired jaw on chewing), transient visual disturbances, musculoskeletal symptoms (polymyalgia rheumatica) , fever, malaise, weight loss, anemia.

47. Extracranial disease in 10-15%: • intermittent claudication is common • arterial bruits, blood pressure abnormalities. • Treatment: responds well to steroids. • Complications • coronary artery involvement  myocardial ischemia • aortic valve incompetence • aortic dissection • aortic aneurysm, may rupture.

48. Pathology • Inflammation confined to media; mixed cell infiltrate – lymphocytes, macrophages • Giant cells may be present at junction of intima and media (eating internal elastic lamina) • Intimal proliferation.

49. Elastic tissue stain demonstrating focal destruction of internal elastic membrane (arrow) and intimal thickening (IT) characteristic of long-standing or healed arteritis

50. Pathology:Large vesselsTakayasu Arteritis or Aortitis • Common in Far east; women 15-45 affected • Chronic inflammatory disease involving both systemic and pulmonary circulations • Aorta & major branches most commonly affected – coronaries • Clinical: stenosis is characteristic • Pathology: artery wall inflammation  fibromuscular intimal proliferation, mural thrombi • granulomatous panarteritis • vessel converted into rigid tube, associated with stenosis.