1. Vasculitis

2. Vasculitis is a general term for vessel wall inflammation.
The clinical features of the various vasculitides are protean and largely depend on the vascular bed affected (e.g., CNS vs. heart vs. small bowel).
Besides the findings referable to the specific tissues involved, the clinical manifestations typically include constitutional signs and symptoms such as fever, myalgias, arthralgias, and malaise.

3. Vessels of any type in virtually any organ can be affected, but most vasculitides affect small vessels ranging in size from arterioles to capillaries to venules.
Some 20 primary forms of vasculitis are recognized, and classification schemes attempt (with variable success) to group them according to vessel diameter, role of immune complexes, presence of specific autoantibodies, granuloma formation, organ specificity, and even population demographics

4. Pathogenesis
The two common pathogenic mechanisms of vasculitis are immune-mediated inflammation and direct invasion of vascular walls by infectious pathogens.
Infections can also indirectly induce a noninfectious vasculitis, for example, by generating immune complexes or triggering a crossreactive immune response.
Physical and chemical injury, such as from irradiation,
mechanical trauma, and toxins, can also cause
vasculitis

5. In any given patient, it is critical to distinguish between infectious and immunologic mechanisms, because immunosuppressive therapy is appropriate for immune-mediated vasculitis but could very well be counter-productive for infectious vasculitides

7. Infectious Vasculitis
Arteritis can be caused by the direct invasion of infectious agents, usually bacteria (Pseudomonas being the classic example) or fungi, in particular Aspergillus and Mucor species. Vascular invasion can be part of a localized tissue infection (e.g., bacterial pneumonia or adjacent to abscesses), or—less commonly—can arise from hematogenous spread of microorganisms during septicemia or embolization from infective endocarditis. Vascular infections can weaken arterial walls and culminate in mycotic aneurysms, or can induce thrombosis and infarction.

8. Noninfectious Vasculitis
The major cause of noninfectious vasculitis is a local or systemic immune response. Immunologic injury in noninfectious vasculitis may be caused by: • Immune complex deposition • Antineutrophil cytoplasmic antibodies • Antiendothelial cell antibodies • Autoreactive T cells

9. Immune Complex-Associated Vasculitis
This form of vasculitis can be seen in systemic immunologic disorders such as systemic lupus erythematosus that are associated with autoantibody production and formation of immune complexes that deposit in vessels. This type of vasculitis presents a number of diagnostic challenges. Only rarely is the specific antigen responsible for immune complex formation identified. Also, in most cases it is not clear whether the pathogenic antigen-antibody complexes are deposited from the circulation or form in situ. In many suspected cases, even the antigen-antibody deposits are scarce. In such instances, the immune complexes may have been degraded by the time of biopsy; alternatively, other mechanisms may underlie such “pauci-immune” vasculitides.

10. Immune complex deposition is also implicated in the following vasculitides:
Drug hypersensitivity vasculitis: In some cases (e.g.,penicillin), drugs act as haptens by binding to serum proteins or vessel wall constituents; other agents are themselves foreign proteins (e.g., streptokinase).
Regardless, antibodies directed against the drug modified proteins or foreign molecules result in immune complex formation. The clinical manifestations can be mild and self-limiting, or severe and even fatal; skin lesions are most common. It is always important to consider drug hypersensitivity as a cause of vasculitis since discontinuation of the offending agent usually leads to resolution.
Vasculitis secondary to infections: Antibodies to microbial constituents can form immune complexes that circulate and deposit in vascular lesions. In up to 30% of patients with polyarteritis nodosa, the vasculitis is attributable to immune complexes composed of hepatitis B surface antigens (HBsAg) and anti-HBsAg antibody.

11. Antineutrophil Cytoplasmic Antibodies
ANCAs are a heterogeneous group of autoantibodies directed against constituents (mainly enzymes) of neutrophil primary granules, monocyte lysosomes, and endothelial cells.
ANCAs are very useful diagnostic markers; their titers generally mirror clinical severity, and a rise in titers after periods of quiescence is predictive of disease recurrence.
Although a number of ANCAs have been described, two are most important. These were previously grouped according to the intracellular distribution of the target antigens (cytoplasmic [c-ANCA] or perinuclear [p-ANCA]), but are now classified according to their antigen specificity:

12. Anti-proteinase-3 (PR3-ANCA, previously c-ANCA):
PR3 is a neutrophil azurophilic granule constituent that shares homology with numerous microbial peptides, raising the possibility that the generation of PR3- ANCAs is triggered by certain infections. PR3-ANCAs are associated with polyangiitis.
Anti-myeloperoxidase (MPO-ANCA, previously p-ANCA): MPO is a lysosomal granule constituent involved in oxygen free radical generation (Chapter 3). MPO ANCAs are induced by several therapeutic agents, particularly propylthiouracil. MPO-ANCAs are associated with microscopic polyangiitis and Churg-Strauss syndrome.
ANCAs can directly activate neutrophils, stimulating the release of reactive oxygen species and proteolytic enzymes; in vascular beds, such activation also leads to destructive interactions between inflammatory cells and endothelial cells.
While the antigenic targets of ANCA are primarily intracellular (and therefore not usually accessible to circulating antibodies), it is now clear that ANCA antigens (especially PR3) are either constitutively expressed at low levels on the plasma membrane or are translocated to the cell surface in activated and apoptotic leukocytes.

13. A plausible mechanism for ANCA vasculitis is the following:
- Drugs or cross-reactive microbial antigens induce ANCA formation; alternatively, leukocyte surface expression or release of PR3 and MPO (in the setting of infections) incites ANCA development in a susceptible host.
- Subsequent infection, endotoxin exposure, or inflammatory stimulus elicits cytokines such as TNF that upregulate the surface expression of PR3 and MPO on neutrophils and other cell types.
- ANCAs react with these cytokine-activated cells, causing either direct injury (e.g., to endothelial cells) or further activation (e.g., of neutrophils).
- ANCA-activated neutrophils cause tissue injury by releasing granule contents and reactive oxygen species.
Since ANCA autoantibodies are directed against cellular constituents and do not form circulating immune complexes, the vascular lesions do not typically contain demonstrable antibody and complement. Thus, ANCA-associated vasculitides are often described as “pauci-immune.”

14. Antiendothelial Cell Antibodies
Antibodies to endothelial cells, perhaps induced by defects in immune regulation, may predispose to certain vasculitides, for example, Kawasaki disease

16. Giant Cell (Temporal) Arteritis
Giant cell (temporal) arteritis is the most common form of vasculitis among older individuals in the United States and Europe
It is a chronic inflammatory disorder of large to small-sized arteries that principally affects arteries in the head—especially the temporal arteries—but also the vertebral and ophthalmic arteries.
Ophthalmic arterial involvement can lead abruptly to permanent blindness; consequently, giant cell arteritis is a medical emergency requiring prompt recognition and treatment.
Lesions also occur in other arteries, including the aorta (giant cell aortitis)

17. Pathogenesis:
Most evidence suggests that giant cell arteritis
stems from a T-cell–mediated immune response
against one of handful of vessel wall antigens that drives subsequent proinflammatory cytokine production (particularly TNF). A cellular immune etiology is supported by the characteristic granulomatous response, a correlation with certain MHC class II haplotypes, and a prompt therapeutic response to steroids.

18. MORPHOLOGY:
- Involved arterial segments develop intimal thickening that reduces the luminal diameter.
Classic lesions exhibit medial granulomatous inflammation centered on the internal elastic lamina that produce elastic lamina fragmentation
An infiltrate of T cells (CD4+ > CD8+) and macrophages.
Inflammatory lesions are only focally distributed along the vessel (segmental)

19. Clinical Features:
- Giant cell arteritis is rare before age 50.
Symptoms may be only vague and constitutional—fever, fatigue, weight loss—or there may be facial pain or headache, most intense along the course of the superficial temporal artery, which can be painful to palpation. Ocular symptoms (associated with involvement of the ophthalmic artery) appear abruptly in about 50% of patients; these range from diplopia to complete vision loss.
Diagnosis depends on biopsy and histologic confirmation. However, because giant cell arteritis can be extremely focal within an artery, adequate biopsy requires at least a 1-cm segment; even then, a negative biopsy result does not exclude the diagnosis.
Corticosteroids or anti-TNF therapies are typically effective.

21. Takayasu Arteritis
This is a granulomatous vasculitis of medium and larger arteries characterized principally by ocular disturbances and marked weakening of the pulses in the upper extremities (hence the name pulseless disease).
manifests with transmural fibrous thickening of the aorta— particularly the aortic arch and great vessels—with severe luminal narrowing of the major branch vessels
shares many attributes with giant cell aortitis, including clinical features and histology. Indeed, the distinction is typically made based on the age of the patient; younger than 50

22. Polyarteritis Nodosa
Polyarteritis nodosa (PAN) is a systemic vasculitis of small- or medium-sized muscular arteries, typically involving renal and visceral vessels but sparing the pulmonary circulation.
about 30% of patients with PAN have chronic hepatitis B and deposits containing HBsAg-HBsAb complexes in affected vessels, indicating an immune complex–mediated etiology in that subset.
The cause remains unknown in the remaining cases; there may be etiologic and clinical distinctions between classic idiopathic PAN, the cutaneous forms of PAN, and the PAN associated with chronic hepatitis.

23. MORPHOLOGY:
Classic polyarteritis nodosa is characterized by segmental transmural necrotizing inflammation of small- to medium sized arteries.
Vessels of the kidneys, heart, liver, and gastrointestinal tract are involved in descending order of frequency. The inflammatory process weakens the arterial wall and can lead to aneurysms or even rupture. Impaired perfusion with ulcerations, infarcts, ischemic atrophy, or hemorrhages may be the first sign of disease.
During the acute phase, there is mixed infiltrate of neutrophils, eosinophils, and mononuclear cells, frequently accompanied by fibrinoid necrosis . Later, the acute inflammatory infiltrate is replaced by fibrous (occasionally nodular) thickening of the vessel wall that can extend into the adventitia.
Characteristically, all stages of activity (from early to late) may coexist in different vessels or even within the same vessel, suggesting ongoing and recurrent insults.

25. Clinical Features.:
- Although typically a disease of young adults, PAN can also occur in pediatric and geriatric populations.
Clinical manifestations result from ischemia and infarction of affected tissues and organs.
The course is frequently remitting and episodic, with long symptom-free intervals.
A “classic” presentation can involve some combination of rapidly accelerating hypertension due to renal artery involvement; abdominal pain and bloody stools caused by vascular gastrointestinal lesions; diffuse myalgias; and peripheral neuritis, predominantly affecting motor nerves. Renal involvement is often prominent and a major cause of mortality.
Untreated, PAN is typically fatal; however, immunosuppression can yield remissions or cures in 90% of cases.

26. Kawasaki Disease
Kawasaki disease is an acute febrile, usually self-limited illness of infancy and childhood (80% of patients are 4 years old or younger);
it is associated with an arteritis affecting large to medium-sized, and even small vessels.
Its clinical significance stems primarily from a predilection for coronary artery involvement that can cause aneurysms that rupture or thrombose, resulting in acute myocardial infarctions.
Originally described in Japan, the disease has a worldwide distribution and is the leading cause of acquired heart disease in children.

27. The pathogenesis of Kawasaki disease is unknown
The pathogenesis of Kawasaki disease is unknown. A variety of infectious agents (mostly viral) have been implicated in triggering the disease in genetically susceptible individuals. The vascular damage is primarily mediated by activated T cells and monocytes/macrophages.

28. MORPHOLOGY:
The vasculitis resembles that seen in polyarteritis nodosa, although the fibrinoid
necrosis is usually less prominent than in PAN.

29. Clinical Features:
Kawasaki disease typically presents with conjunctival and oral erythema and blistering, edema of the hands and feet, erythema of the palms and soles, a desquamative rash, and cervical lymph node enlargement (hence its other name, mucocutaneous lymph node syndrome).
Approximately 20% of untreated patients develop cardiovascular sequelae, ranging from asymptomatic coronary arteritis, to coronary artery ectasia, to giant coronary artery aneurysms (7 to 8 mm) leading to rupture or thrombosis, myocardial infarction, and sudden death.
If the disease is recognized early in its course, treatment with intravenous immunoglobulin and aspirin sharply reduce the risk of symptomatic coronary artery disease.

30. Microscopic Polyangiitis
Microscopic polyangiitis is a necrotizing vasculitis that generally affects capillaries, as well as small arterioles and venules.
It is also called hypersensitivity vasculitis or leukocytoclastic vasculitis.
Necrotizing glomerulonephritis (90% of patients) and pulmonary capillaritis are particularly common.
Can be a feature of a number of immune disorders, such as Henoch-Schönlein purpura, essential mixed cryoglobulinemia, and vasculitis associated with connective tissue disorders.

31. Pathogenesis: In some cases, antibody responses to antigens such as drugs (e.g., penicillin), microorganisms (e.g., streptococci), heterologous proteins, or tumor proteins have been implicated. These can either lead to immune complex deposition or trigger secondary immune responses (e.g., the development of ANCAs) that are pathogenic. Indeed, most cases are associated with MPO-ANCA.
Recruitment and activation of neutrophils within affected vascular beds is likely responsible for the disease manifestations.

32. MORPHOLOGY:
These lesions morphologically resemble PAN but typically spare medium-sized and larger arteries; consequently, infarcts are uncommon.
In some areas (typically postcapillary venules), only infiltrating neutrophils, many undergoing apoptosis, are seen, giving rise to the term leukocytoclastic vasculitis (Fig A). little or no immunoglobulin are found in most lesions (so-called “pauci-immune injury”).

34. Clinical Features:
Depending on the vascular bed involved,
major clinical features include hemoptysis, hematuria and proteinuria, bowel pain or bleeding, muscle pain or weakness, and palpable cutaneous purpura.
Except in those in whom widespread renal or brain involvement develop, immunosuppression induces remission and markedly improves long-term survival

35. Churg-Strauss Syndrome
Churg-Strauss syndrome is a small-vessel necrotizing vasculitis classically associated with asthma, allergic rhinitis, lung infiltrates, peripheral hypereosinophilia, and extravascular necrotizing granulomata.
Also called allergic granulomatosis and angiitis, it is a relatively rare disease.
Vascular lesions can be histologically similar to polyarteritis nodosa or microscopic polyangiitis, but are also characteristically accompanied by granulomas and eosinophils.
ANCAs (mostly MPO-ANCAs) are present in less than half the cases, when present, the ANCAs are likely involved in the pathogenesis of the vascular lesions.

36. Behçet Disease
Behçet disease is a small- to medium-vessel neutrophilic vasculitis that classically presents as a clinical triad of recurrent oral aphthous ulcers, genital ulcers, and uveitis.
There is an association with certain HLA haplotypes (HLA-B51, in particular) and a cross-reactive immune response to certain microorganisms is implicated.

37. Granulomatosis with Polyangiitis
Previously called Wegener granulomatosis
It is a necrotizing vasculitis characterized by a triad of:
1- Necrotizing granulomas of the upper respiratory tract (ear, nose, sinuses, throat) or the lower respiratory tract (lung) or both.
2- Necrotizing or granulomatous vasculitis affecting small to medium-sized vessels (e.g., capillaries, venules, arterioles, and arteries), most prominent in the lungs and upper airways but involving other sites as well.
3- Focal necrotizing, often crescentic, glomerulonephritis.
“Limited” forms of this disease may be restricted to the respiratory tract. Conversely, a widespread form of the disease can affect eyes, skin, and other organs, notably the heart; clinically, this resembles PAN except that there is also respiratory involvement.

38. Pathogenesis:
Granulomatosis with polyangiitis likely represents a form of T-cell–mediated hypersensitivity response to normally “innocuous” inhaled microbial or other environmental agents; such a pathogenesis is supported by the presence of granulomas and a dramatic response to immunosuppressive therapy.
PR3-ANCAs are also present in up to 95% of cases; they are a useful marker of disease activity and may participate in disease pathogenesis. Most patients in remission have a negative test or falling titers

39. MORPHOLOGY:
Upper respiratory tract lesions range from inflammatory sinusitis with mucosal granulomas to ulcerative lesions of the nose, palate, or pharynx, rimmed by granulomas with geographic patterns of central necrosis and accompanying vasculitis.
The necrotizing granulomas are surrounded by a zone of proliferating fibroblasts associated with giant cells and leukocytic infiltrate, reminiscent of mycobacterial or fungal infections.
Multiple granulomas can coalesce to produce radiographically visible nodules that can also cavitate; late stage disease may be marked by extensive necrotizing granulomatous involvement of the parenchyma , and alveolar hemorrhage may be prominent.
A spectrum of renal lesions can be seen . In early stages, glomeruli exhibit only focal necrosis(focal and segmental necrotizing glomerulonephritis). More advanced glomerular lesions are characterized by crescentic glomerulonephritis.

40. Clinical Features:
Males are affected more often than females, at an average age of about 40 years.
Classic features include persistent pneumonitis with bilateral nodular and cavitary infiltrates (95%), chronic sinusitis (90%), mucosal ulcerations of the nasopharynx (75%), and evidence of renal disease (80%).
Other features include rashes, myalgias, articular involvement, neural inflammation, and fever.
Left untreated, the disease is usually rapidly fatal, with 80% mortality within 1 year.
Treatment with steroids, cyclophosphamide, and more recently TNF antagonists have turned this formerly fatal condition into a chronic relapsing and remitting disease.

41. Thromboangiitis Obliterans (Buerger Disease)
Thromboangiitis obliterans (Buerger disease) is characterized by segmental, thrombosing, acute and chronic inflammation of medium-sized and small arteries,principally the tibial and radial arteries, with occasional secondary extension into the veins and nerves of the extremities.
It is a distinctive disease that often leads to vascular insufficiency, typically of the extremities.
It occurs almost exclusively in heavy cigarette smokers, usually before age 35.

42. Pathogenesis:
The strong relationship with cigarette smoking may stem from either a direct idiosyncratic endothelial cell toxicity caused by some component of tobacco, or an immune response to components of tobacco smoke that modify host vascular wall proteins.
There is an increased prevalence in certain ethnic groups (Israeli, Indian subcontinent, Japanese) and an association with particular HLA haplotypes.

44. Clinical Features:
Early manifestations include cold induced Raynaud phenomenon , leg pain induced by exercise that is relieved on rest (intermittent claudication), instep foot pain induced by exercise (instep claudication), and a superficial nodular phlebitis (venous inflammation).
severe pain—even at rest—undoubtedly due to the neural involvement.
Chronic extremity ulcerations develop, progressing over time to frank gangrene.
Smoking abstinence in the early stages of the disease can often ameliorate further attacks; however, once established, the vascular lesions typically do not respond to smoking abstinence.