1. VASCULITIS
PROF. DR. FERDA ÖZKAN

2. VASCULITIS
This is a heterogenous group of disorders characterized by inflammation & damage of blood vessels followed by thrombosis & ischemic manifestations in 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-ANCA p-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 vessels Hypersensitivity 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 Antigens 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 vessels Henoch-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 vessels Mixed 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 vessels Wegener’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 vessels Buerger’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 vessels Polyarteritis 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 vessels Giant 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 vessels Takayasu Arteritis or Aortitis
Common in Far east; women 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.

51. The right carotid artery taken at autopsy of the patient demonstrating marked intimal thickening with minimal residual lumen

52. Aortitis is literally inflammation of the aorta, and it is representative of a cluster of large-vessel diseases that have various or unknown etiologies.
While inflammation can occur in response to any injury, including trauma, the most common known causes are infections or connective tissue disorders.
Infections can trigger a noninfectious vasculitis by generating immune complexes or by cross-reactivity.
The etiology is important because immunosuppressive therapy, the main treatment for vasculitis, could aggravate an active infectious process.

53. Inflammation of the aorta can cause aortic dilation, resulting in aortic insufficiency.
Also, it can cause fibrous thickening and ostial stenosis of major branches, resulting in reduced or absent pulses, low blood pressure in the arms, possibly with central hypertension due to renal artery stenosis.
Depending on what other vessels are involved, ocular disturbances, neurological deficits, claudication, and other manifestations of vascular impairment may accompany this disorder.

54. The disease has 3 phases:
Phase I is (prepulseless inflammatory period)
Phase II (vascular inflammation)
Phase III (fibrosis stage)

55. Pathologic changes involved in Takayasu arteritis are the same as for giant cell arteritis.
Involved vessel walls develop irregular thickening and intimal wrinkling.
Early in the disease, mononuclear infiltration with perivascular cuffing is seen.
That extends to the media, followed by granulomatous changes and patches of necrosis and scarring (fibrosis) of all layers, especially the intima.
Late stages have lymphocytic infiltration.

56. When the abdominal aorta and its branches, eg, the renal arteries, are involved, central hypertension may develop.
Accurate blood pressure measurement may be difficult because of arterial lesions affecting supply to the extremities.
Takayasu arteritis primarily involves the aorta, its main branches, and, in 50% of cases, the pulmonary artery.
The initial vascular lesions frequently occur in or at the origin of the left subclavian artery, which can cause weakened radial pulse and easy fatigability in the left arm.
As the disease progresses, the left common carotid, vertebral, brachiocephalic, right-middle or proximal subclavian, right carotid, and vertebral arteries, as well as the aorta, also are affected, as well as retinal vessels.

57. Destruction of the arterial media by mononuclear inflammation with giant cells

58. Complications:
Aortic insufficiency,
angina pectoris,
myocardial infarction,
stroke,
limb ischemia,
renal artery hypertension,
all consequences of vascular diseases.

59. Cogan's disease
Cogan's disease is another rare disease usually affecting young adults.
It features abrupt onset of
nerve deafness,
interstitial keratitis, and/or
a systemic vasculitis often with
aortic aneurysm formation.
It's apparently caused by an autoantibody against inner ear and endothelium

60. Kawasaki's disease
A febrile disease which resembles adult polyarteritis nodosa histologically but occurs in babies.
Need to see five of these six signs:
fever (will last more than five days)
non-purulent conjunctivitis in both eyes
rash
red cracked lips and/or strawberry tongue and/or red oral mucosa
red palms and soles (later they desquamate)
a big (1.5 cm or more) lymph node in the neck.

61. Most patients are of Japanese of Korean ancestry, regardless of where they live, but no HLA links are found.
The most serious concern is coronary vasculitis, which causes myocardial infarcts. Healing can produce coronary aneurysms,
The cause remains obscure.

62. Raynaud's disease & phenomenon
Spasm and occlusion of the arteries supplying the fingers, which turn white, then red, then blue.
Triggered by cold weather, it's most often idiopathic; known causes range from vasculitis syndromes to operating jack-hammers.
Scleroderma patients and some others have this process greatly exacerbated by hyperplastic arteriolar sclerosis in the digital arteries.

63. Large and medium-sized arteries Small muscular arteries
Type of vasculitis
Aorta and its branches
Large and medium-sized arteries
Medium-sized muscular arteries
Small muscular arteries
Venules, arterioles
Takayasus arteritis
+++ +
Giant cell arteritis
Polyarteritis
Wegeners granulomatosis ++
Kawasaki disease
Vasculitis associated with connective tissue disease
Leukocytoclastic vasculitis: Henoch-Schönlein purpura, hypersensitivity vasculitis, others

64. Thank you for you
attention