Done by: Shatha Khtoum

Transcription

1 Done by: Shatha Khtoum

2 Overview Vasculitis -Vasculitis is a general term for vessel wall inflammation -Symptoms and signs depend on the tissue of which the vessels are affected. (slide 2) -There are usually also signs and symptoms of systemic inflammation, such as fever, myalgia, arthralgias, and malaise. -Small vessels are the most affected vessels (arterioles, capillaries, and venules). -There is considerable clinical and pathologic overlap among many of these disorders. -The two most common pathogenic mechanisms of vasculitis are immunemediated inflammation (non-infectious) and direct vascular invasion by infectious pathogens. - Physical and chemical injury may also cause vasculitis (Less common causes), including that due to radiation, mechanical trauma, and toxins, also can cause vasculitis. Noninfectious Vasculitis The main immunologic mechanisms underlying noninfectious vasculitis are: 1- Immune complex deposition 2- Antineutrophil cytoplasmic antibodies 3- Anti-endothelial cell antibodies; like Kawasaki disease. 4- Autoreactive T cells (slide 3) We will take about them one by one; 1- Immune complex deposition - This form of vasculitis is seen in immunologic disorders such as systemic lupus erythematosus (SLE) - They found that patients with SLE, the DNA/anti-DNA complexes (Ag-Ab complexes) are present in their vascular lesions (in their vessel wall). -Two important examples: 1- Drug hypersensitivity vasculitis; 1

3 -Penicillin for example Act as haptens by binding to host proteins (doesn t induce immune response alone but it binds to a self-normal carrier protein to become immunogenic). -Other agents are themselves foreign proteins (ex; streptokinase). -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, once the patient stops using these drugs, he/she will be cured. 2- Vasculitis due to immune response to certain infections; Antibody to microbial infections 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 antigen (HBsAg) and anti- HBsAg antibody. Antineutrophil cytoplasmic antibodies (ANCA): (slide 4) -Many patients with vasculitis have circulating antibodies that react with neutrophil cytoplasmic antigens, serum from those patients indicating the presence of (ANCAs). - ANCAs are directed against 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. - two are most important: 1- Antiproteinase-3 (PR3-ANCA), called c- ANCA. -PR3 is a neutrophil azurophilic granule constituent that resemble certain microbial peptides, possibly explaining the generation of C- ANCAs. -C-ANCAs are associated with Wegener granulomatosis. 2- Anti-myeloperoxidase (MPO-ANCA), called p-anca. 2

4 -MPO is a lysosomal granule constituent involved in oxygen free radical generation. -MPO-ANCAs are induced by several therapeutic agents, particularly propylthiouracil. -MPO-ANCAs are associated with microscopic polyangiitis and Churg-Strauss syndrome. Mechanisms of ANCA vasculitis: (slide 5+6) mechanism for ANCA vasculitis involves the following sequence: Drugs or cross-reactive microbial antigens induce ANCA formation; alternatively neutrophil surface expression or release of PR3 and MPO (in the setting of infections) will increased Subsequent infection, endotoxin exposure, or inflammatory stimulus elicits cytokines such as TNF upregulate the surface expression of PR3 and MPO on neutrophils and other cell types. ANCAs bind these cytokine-activated cells, causing further activation of neutrophils. ANCA-activated neutrophils cause endothelial cell injury by releasing granule contents and reactive oxygen species Drugs or cross-reactive microbial antigens Infection/endotoxin exposure/ inflammation ANCA formation Will bind Increased PR3 & MPO expression on neutrophil surface ANCAs activate neutrophils and neutrophils will attack the endothelium 3

5 -ANCA associated vasculitides are often described as pauciimmune because Ab- Ag complexes & complements are not typically detected in vascular lesions. -Other types of ANCAs can be seen in patients with nonvasculitic inflammatory disorders (ex; inflammatory bowel disease, sclerosing cholangitis, and rheumatoid arthritis). 1)Giant Cell (Temporal) Arteritis; (slide 7) -The most common type of the vasculitis, is an acute and chronic, often granulomatous inflammation of large to small size arteries. -Temporal arteritis affects mainly the arteries in the head especially the temporal arteries and the vertebral and ophthalmic arteries, as well as the aorta (giant cell aortitis). -Because ophthalmic artery involvement can lead to sudden and permanent blindness. So, affected persons must be diagnosed and treated promptly. -The mechanism: - T-cell-mediated immune response to an unknown, possibly vessel wall antigen. - Pro-inflammatory cytokines (especially TNF) and anti-endothelial cell antibodies also contribute. So, we can treat it by anti-tnf. -The presence of granulomas and the patient s response to anti-inflammatory drugs and corticosteroids, conclude that it s a T-cell-mediated immune response to an antigen. This antigen could be the intercellular adhesion molecule 1 (on endothelial cells), this molecule mediates cellular interaction between cells of the immune system and endothelial cells. So, when we have problem in the immunity this protein will be considered as a foreign protein and we will have an immune-mediated response. -Temporal arteritis is rare before the age of 50. (F:M = 2:1). 4

6 Signs and symptoms: - fever, fatigue, weight loss, malaise -Intense facial pain or headache if the superficial temporal artery is involved. (which is painful to palpation). -Ocular symptoms (associated with involvement of the ophthalmic artery) appear in about 50% of patients; these range from diplopia to complete vision loss. - The diagnosis depends on biopsy and histological confirmation. However, because involvement in temporal arteritis is patchy a negative biopsy result does not exclude the diagnosis. -High ESR. Giant Cell (Temporal) Arteritis, biopsy (slide 8) -The pathologic changes are patchy along the length of affected vessels. -Involved arterial segments exhibit nodular intimal thickening (and occasional thromboses) that reduce the lumen diameter and cause distal ischemia. - Granulomatous inflammation (75% of cases) within the inner media centered on the internal elastic membrane; there is an infiltrate of lymphocytes and macrophages, with multinucleate giant cells, and fragmentation of the internal elastic lamina. - Healing is marked by medial and adventitial fibrosis and intimal thickening. - Lesions at different stages of development are seen in the same artery. 2) Takayasu arteritis: (slide 9+10) -Takayasu arteritis is not only in Japan, it has a global distribution. -It s a granulomatous vasculitis of medium sized and larger arteries. -Characterized principally by ocular disturbances and marked weakening of the pulses in the upper extremities and carotid artery (pulseless disease). - This disorder manifests with transmural scarring and thickening of the aorta, particularly the aortic arch and great vessels with severe luminal narrowing of the major branch vessels. -Aortic lesions may resemble the clinical and histologic features of giant cell aortitis. 5

7 - Occasionally, aortic root involvement causes dilation and aortic valve insufficiency. - Pulmonary arteries are involved in 50% of patients, and pulmonary artery involvement can cause pulmonary hypertension. - Renal and coronary arteries also can be affected, and involvement of the renal arteries causes systemic hypertension in roughly half of the patients. - Distal aorta disease can manifest as leg claudication. - Initial signs and symptoms usually are nonspecific, including fatigue, weight loss, and fever. With progression, vascular signs and symptoms appear as we said before. -Rarely happens after 50* 3)Polyarteritis nodosa (PAN) (slides 11+12) -a systemic vasculitis of small or medium-sized muscular arteries that typically involves the renal and visceral vessels, but spares the pulmonary circulation. - There is no association with ANCAs, but a third of the patients have chronic hepatitis B infection, which leads to the formation of immune complexes containing hepatitis B antigens that deposit in affected vessels. - Involvement: Classic PAN is a segmental transmural necrotizing inflammation of small to medium-sized arteries, often with superimposed thrombosis. - Lesions usually involve only part of the vessel circumference. -The branched points are preferred. -Kidney, heart, liver, and gastrointestinal tract vessels are affected in descending order of frequency. -Impaired perfusion may lead to ulcerations, infarcts, ischemic atrophy, or hemorrhages in the distribution of affected vessels. - Initially, there is transmural mixed inflammatory infiltrate composed of neutrophils and mononuclear cells, frequently accompanied by fibrinoid necrosis and luminal thrombosis. - Older lesions show fibrous thickening of the vessel wall extending into the adventitia. - Different stages of activity (from early to late) coexist in different vessels or even within the same vessel. - PAN is mainly found in young adults but can occur in all age groups. 6

8 - The clinical course may range from acute to chronic but typically is episodic, with long symptom-free intervals. - A classic presentation can involve rapidly accelerating hypertension due to renal artery involvement. - When abdominal artery involved; abdominal pain and bloody stools caused by vascular gastrointestinal lesions. - When peripheral nerves involved; diffuse muscular aches and pains; and peripheral neuritis, predominantly affecting motor nerves. - Renal involvement often is prominent and constitutes a major cause of death in these patients. -Untreated, PAN typically is fatal. -However, immunosuppression can yield remission or cure in 90% of the cases. 4)Kawasaki disease (slides 13+14) - Originally described in Japan, the disease is now recognized in elsewhere. -It is an acute, febrile, usually self-limited illness of infancy and childhood (80% of the patients are younger than 4 years of age) associated with an arteritis of mainly large to medium-sized vessels. - The most important: involvement of coronary arteries. -Coronary arteritis can cause aneurysms that rupture or thrombose, resulting in myocardial infarction and sudden death. Pathogenesis: - In genetically susceptible persons, a variety of infectious agents (mostly viral) have been set to trigger the disease. - The vasculitis may result from a delayed-type hypersensitivity response directed against cross-reactive or newly uncovered vascular antigen(s). Subsequent cytokine production by T-cells and polyclonal B cell activation result in autoantibodies to endothelial cells and smooth muscle cells that precipitate the vasculitis. -The vasculitis resembles that seen in polyarteritis nodosa. -There is a dense transmural inflammatory infiltrate, although the fibrinoid necrosis usually is less prominent than in polyarteritis nodosa. -The acute vasculitis resolves spontaneously or in response to treatment, but aneurysm formation due to wall damage can be a problem. 7

9 - As with other vasculitis, healed lesions also can cause intimal thickening and narrowing. -Pathologic changes outside the cardiovascular system are rarely significant. Kawasaki disease typically manifests with conjunctival and oral erythema and blistering, edema of the hands and feet, erythema of the palms and soles, a desquamative rash, swollen tongue (strawberry tongue) 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 large coronary artery aneurysms with rupture or thrombosis, myocardial infarction, and sudden death. - Therapy with intravenous immunoglobulin and aspirin is good. 5)Microscopic polyangiitis (slides ) - It s a necrotizing vasculitis that generally affects capillaries, as well as small arterioles and venules. - It also is called hypersensitivity vasculitis or leukocytoclastic vasculitis. - Unlike in polyarteritis nodosa, all lesions of microscopic polyangiitis tend to be of the same age in any given patient. - The skin (purpura), mucous membranes, lungs*, brain, heart, gastrointestinal tract, kidneys, CNS and muscle all can be involved. -Necrotizing glomerulonephritis (seen in 90% of patients). -Pulmonary capillaritis are particularly common. - Depending on the vascular bed involved, major features include hemoptysis, hematuria, proteinuria, abdominal pain or bleeding, muscle pain or weakness, and palpable cutaneous purpura. -Can be seen in some immune disorders, such as Henoch-Schönlein purpura. -Can be induced by antibody responses to antigens such as drugs (penicillin), microorganisms, heterologous proteins, or tumor proteins (antigens). - Most cases are associated with MPO-ANCA. - Microscopic polyangiitis is characterized by: Segmental fibrinoid necrosis of the media with focal transmural necrotizing lesions; like PAN. Granulomatous inflammation is absent. 8

10 These lesions resemble those of polyarteritis nodosa but spare medium-sized and larger arteries, so that macroscopic infarcts are uncommon. - Most lesions are pauci-immune. -Treated by immunosuppression & removal of offending agents. destroyed and fragmented WBCs 6)Wegener granulomatosis; (slides 18+19) -it is a necrotizing vasculitis characterized by a specific triad of findings: Granulomas of the lung and/or the upper respiratory tract (ear, nose, sinuses, throat) Vasculitis of small to medium-sized vessels (capillaries, venules, arterioles, and arteries), most prominently in the lungs and upper respiratory tract Glomerulonephritis - More in middle aged males. - Limited forms of disease can be restricted to the respiratory tract. - Widespread form of the disease can affect eyes, skin, and other organs, notably the heart; clinically, this resembles polyarteritis nodosa with the additional feature of respiratory involvement. -PR3-ANCAs are present in almost 95% of cases and probably drive the subsequent tissue injury; they also are useful markers of disease activity. - There is multifocal necrotizing granulomatous vasculitis with a surrounding fibroblastic proliferation. - Multiple granulomata can coalesce to produce radiographically visible nodules with central cavitation. 9

11 - Most patients with Wegener granulomatosis now survive, but remain at high risk for relapses that can ultimately lead to renal failure. - If untreated, the mortality rate at 1 year is 80%. Classic presentations: bilateral pneumonitis with nodules and cavitary lesions (95%), chronic sinusitis (90%), mucosal ulcerations of the nasopharynx (75%), and renal disease (80%) 7)Churg-Strauss syndrome (slides 20+21) -Also called allergic granulomatosis and angiitis, it s a small vessel necrotizing vasculitis classically associated with asthma, allergic rhinitis, lung infiltrates, peripheral eosinophilia, extravascular necrotizing granulomas, and a striking infiltration of vessels and perivascular tissues by eosinophils. -It is a rare disorder. -Cutaneous involvement (with palpable purpura), gastrointestinal bleeding, and renal disease are the major associations. -Cytotoxicity produced by the myocardial eosinophilic infiltrates often leads to cardiomyopathy; cardiac involvement is seen in 60% of patients and is a major cause of morbidity and death. -MPO-ANCAs are present in a minority of cases, suggesting that the disorder is pathogenically heterogeneous. - The vascular lesions differ from those of polyarteritis nodosa or microscopic polyangiitis by the presence of granulomas and eosinophils. 10

12 8)Thromboangiitis Obliterans (Buerger Disease) (slides ) It is a distinctive disease which leads to vascular insufficiency and it is characterized by segmental, thrombosing, acute and chronic inflammation of medium and small arteries -Most common arteries involved are: tibial and radial arteries and adjacent veins and nerves. -Usually lower arteries are involved more. - Symptoms of presentation usually will be ischemia (pain, cyanosis, infarction in the limbs ). It has similar symptoms to diabetes, it may lead to gangrene. -It is more in males and cigarette smokers before age 35 (that's why it's common), Females can be affected if they are smokers. - In early stages: mixed inflammatory infiltrates are accompanied by luminal thrombosis. small microabscesses. occasionally rimmed by granulomatous inflammation. - Inflammation often extends into contiguous veins and nerves (a feature that is rare in other forms of vasculitis) -With time, thrombi can organize and recanalize, and eventually the artery and adjacent structures become fibrous tissue. Clinical Features of Buerger Disease -Early manifestations include: -cold-induced Raynaud phenomenon. -instep foot pain induced by exercise (instep claudication). -superficial nodular phlebitis (venous inflammation). The vascular insufficiency of Buerger disease tends to be accompanied by severe pain from the neural involvement. -Chronic extremity ulcerations can develop, progressing over time to gangrene. -Smoking abstinence in the early stages of the disease often can improve further attacks. However, the vascular lesions do not respond to smoking abstinence. kill them with success and bury them with a smile 11