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  1. Vasculitis Lia Trapaidze
  2. Vasculitis • DEFINITION AND PATHOGENESIS • A clinicopathologic process characterized by inflammation of and damage to blood vessels, compromise of vessel lumen, and resulting ischemia. • Clinical manifestations depend on size and location of affected vessel. • Most vasculitic syndromes appear to be mediated by immunemechanisms. • May be primary or sole manifestation of a disease or secondary to another disease process. • Unique vasculitic syndromes can differ greatly with regards to clinical features, disease severity, histology, and treatment.
  3. PRIMARY VASCULITIS SYNDROMES • Churg-Strauss Syndrome • Granulomatous vasculitis of multiple organ systems, particularly the lung; characterized by asthma, peripheral eosinophilia, eosinophilic tissue infiltration; glomerulonephritis can occur. • Polyarteritis Nodosa (PAN) • Medium-sized muscular arteries involved; frequently associated with arteriographic aneurysms; commonly affects renal arteries, liver, GI tract, peripheral nerves, skin, heart; can be associated with hepatitis B.
  4. PRIMARY VASCULITIS SYNDROMES • Microscopic Polyangiitis • Small-vessel vasculitis that can affect the glomerulus and lungs; mediumsized vessels also may be affected. • Giant Cell Arteritis • Inflammation of medium- and large-sized arteries; primarily involves temporal artery but systemic and large vessel involvement may occur; symptoms include headache, jaw/tongue claudication, scalp tenderness, fever, musculoskeletal symptoms (polymyalgia rheumatica); sudden blindness from involvement of optic vessels is a dreaded complication.
  5. PRIMARY VASCULITIS SYNDROMES • Takayasu’s Arteritis • Vasculitis of the large arteries with strong predilection for aortic arch and its branches; most common in young women; presents with inflammatory or ischemic symptoms in arms and neck, systemic inflammatory symptoms, aortic regurgitation. • Henoch-Schönlein Purpura • Characterized by involvement of skin, GI tract, kidneys; more common in children; may recur after initial remission.
  6. PRIMARY VASCULITIS SYNDROMES • Cryoglobulinemic Vasculitis • Majority of cases are associated with hepatitis C where an aberrant immune response leads to formation of cryoglobulin; characterized by cutaneous vasculitis, arthritis, peripheral neuropathy, and glomerulonephritis. • Idiopathic Cutaneous Vasculitis • Cutaneous vasculitis is defined broadly as inflammation of the blood vessels of the dermis; due to underlying disease in >70% of cases (see “Secondary Vasculitis Syndromes,” below) with 30% occurring idiopathically.
  7. PRIMARY VASCULITIS SYNDROMES • Miscellaneous Vasculitic Syndromes • Kawasaki disease (mucocutaneous lymph node syndrome) • Isolated vasculitis of the central nervous system • Behçet’s syndrome • Cogan’s syndrome • Polyangiitis overlap syndrome
  8. SECONDARY VASCULITIS SYNDROMES • Drug-induced vasculitis • Serum sickness • Vasculitis associated with infection, malignancy, rheumatic disease
  9. Vasculitis • EVALUATION • Thorough Hx and physical exam—special reference to ischemic manifestations and systemic inflammatory signs/symptoms. • Laboratories—important in assessing organ involvement: CBC with differential, ESR, renal function tests, UA. • Should also be obtained to rule out other diseases: ANA, rheumatoid factor, anti-GBM, hepatitis B/C serologies, HIV.
  10. Vasculitis • EVALUATION • Antineutrophil cytoplasmic autoantibodies (ANCA)—associated with granulomatosis with polyangiitis (Wegener’s), microscopic polyangiitis, and some pts with Churg-Strauss syndrome; presence of ANCA is adjunctive and should not be used in place of biopsy as a means of diagnosis or to guide treatment decisions. • Radiographs—CXR should be performed even in the absence of symptoms. • Diagnosis—can usually be made only by arteriogram or biopsy of affected organ(s). • DIFFERENTIAL DIAGNOSIS • Guided by organ manifestations. In many instances includes infections and neoplasms, which must be ruled out prior to beginning immunosuppressive therapy. Consideration must also be given for diseases that can mimic vasculitis
  11. CONDITIONS THAT CAN MIMIC VASCULITIS • Infectious diseases • Bacterial endocarditis • Disseminated gonococcal infection • Pulmonary histoplasmosis • Coccidioidomycosis • Syphilis • Lyme disease • Rocky Mountain spotted fever • Whipple’s disease • Coagulopathies/thrombotic microangiopathies • Antiphospholipid antibody syndrome • Thrombotic thrombocytopenic purpura
  12. CONDITIONS THAT CAN MIMIC VASCULITIS • Neoplasms • Atrial myxoma • Lymphoma • Carcinomatosis • Drug toxicity • Cocaine • Amphetamines • Ergot alkaloids • Methysergide • Arsenic • Sarcoidosis • Atheroembolic disease • Anti–glomerular basement membrane antibody disease (Goodpasture’s syndrome) • Amyloidosis • Migraine
  13. Vasculitis • TREATMENT • Therapy is based on the specific vasculitic syndrome and the severity of its manifestations. • Immunosuppressive therapy should be avoided in disease that rarely results in irreversible organ system dysfunction or that usually does not respond to such agents (e.g., isolated cutaneous vasculitis). • Antiviral agents play an important role in treating vasculitis occurring with hepatitis B or C.
  14. Vasculitis • TREATMENT • Glucocorticoids alone may control giant cell arteritis and Takayasu’s arteritis. • Therapy that combines glucocorticoids with another immunosuppressive agent is particularly important in syndromes with life- threatening organ system involvement, especially active glomerulonephritis.
  15. Vasculitis • TREATMENT • Frequently used agents: • Prednisone • Cyclophosphamide • Rituximab • Methotrexate • Azathioprine • Mycophenolate mofetil • Plasmapheresis may have an adjunctive role in rapidly progressive glomerulonephritis.
  16. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) • Granulomatosis with polyangiitis is characterized by necrotizing granulomatous inflammation, small- and medium-sized vessel vasculitis, and focal necrotizing glomerulonephritis, often with crescent formation. • Typically, the upper and lower respiratory tract and the kidneys are affected, but any organ may be. • Symptoms vary depending on the organs and systems affected. Patients may present with upper and lower respiratory tract symptoms (eg, recurrent nasal discharge or epistaxis, cough), followed by hypertension and edema, or with symptoms reflecting multiorgan involvement. • Diagnosis usually requires biopsy. • Treatment is with corticosteroids plus an immunosuppressant. Remission is usually possible, although relapses are common.
  17. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) • Granulomatosis with polyangiitis (GPA) occurs in about 1/25,000 people; it is most common among whites but can occur in all ethnic groups and at any age. Mean age at onset is 40. • The cause of GPA is unknown, although immunologic mechanisms play a role. Most patients with active generalized disease have antineutrophil cytoplasmic antibodies (ANCA).
  18. Pathophysiology • Characteristically, granulomas form with histiocytic epithelioid cells and often with giant cells. Plasma cells, lymphocytes, neutrophils, and eosinophils are present. • Inflammation affects tissues as well as vessels; vasculitis may be a small or large component of the disease. • Micronecrosis, usually with neutrophils (microabscesses), occurs early. Micronecrosis progresses to macronecrosis. • A central area of necrosis (called geographic necrosis) is rimmed by lymphocytes, plasma cells, macrophages, and giant cells. A zone of fibroblastic proliferation with palisading histiocytes may surround the area.
  19. Pathophysiology • Nonspecific chronic inflammation and tissue necrosis occur in the nose. • The lungs are most likely to display the full spectrum of histopathologic abnormalities, but diagnostic features are not typically identified on the small tissue samples obtained by transbronchial biopsy. • In the kidneys, the most common finding is a pauci- immune crescentic focal glomerulonephritis with necrosis and thrombosis of individual loops or larger segments of the glomerulus. Vasculitic lesions and disseminated granulomas occur only occasionally.
  20. Histologic pattern • May not correlate with the clinical presentation • Various histological types of glomerulonephritis
  21. Crescentic GN
  22. Symptoms and Signs • Onset of granulomatosis with polyangiitis may be insidious or acute; the full spectrum of the disease may take years to evolve. • Some patients present initially with upper and lower respiratory tract symptoms; at some point later, the kidneys are affected. • In other patients, onset of systemic manifestations is relatively acute; several organs and systems, such as the upper respiratory tract, peripheral nervous system (causing multiple mononeuropathy [mononeuritis multiplex]), kidneys (causing glomerulonephritis), and lower respiratory tract (causing hemorrhage, • lung nodules, cavities, or a combination), are simultaneously affected.
  23. Symptoms and Signs • Upper respiratory tract: • Sinus pain, serosanguineous or purulent discharge, and epistaxis may occur. • The mucosa appears granular (like cobblestones) and is friable; ulcers, thick dark crusts, and septal perforation are common. • Nasal chondritis can occur with swelling, pain, and collapse of the nasal bridge (saddle nose). • Patients may report recurrent sinusitis that has responded inadequately to multiple antibiotic regimens and has required one or more sinus operations before diagnosis. • Secondary infections (eg, due to Staphylococcus aureus) may develop. Subglottic stenosis may develop, causing symptoms such as pain in the larynx, hoarseness, dyspnea, wheezing, and stridor.
  24. Symptoms and Signs • Ears: • Otitis, sensorineural hearing loss, vertigo, and chondritis may occur. The middle ear, inner ear, and mastoids are often affected. • Eyes: • Eyes may appear red and swollen. Nasolacrimal duct inflammation and obstruction, conjunctivitis, scleritis, uveitis, or retinal vasculitis may also occur. Inflammatory infiltrates in the retro-orbital space (orbital pseudotumor) can cause proptosis, compression of the optic nerve, and blindness. Extension into the extraocular muscles leads to diplopia. If serious eye symptoms develop, evaluation and treatment are required immediately to prevent permanent vision loss.
  25. Symptoms and Signs • Lower respiratory tract: • Respiratory manifestations are common. Inflammation of the major bronchi and branches can cause localized wheezing, postobstructive pneumonia, and atelectasis. Single or multiple pulmonary nodules, with or without cavitation, and parenchymal infiltrates, sometimes cause symptoms, such as chest pain, shortness of breath, and productive cough. Dyspnea with bilateral infiltrates, with or without hemoptysis, may indicate alveolar hemorrhage and must be evaluated immediately. • Heart: Coronary artery disease may occur but rarely. • Musculoskeletal system: Patients frequently present with myalgias, arthralgias, or nonerosive inflammatory arthritis.
  26. Symptoms and Signs • Skin: Palpable purpura, tender subcutaneous nodules, papules, livedo reticularis, or ulcers may develop. • Nervous system: Vasculitis may cause ischemic peripheral neuropathy, brain lesions, or extension of lesions from contiguous sites. Lesions that originate in the sinuses or middle ear may extend directly to the retropharyngeal area and base of the skull, leading to cranial neuropathy, proptosis, diabetes insipidus, or meningitis. • Kidneys: Symptoms and signs of glomerulonephritis develop. Urinary sediment is frequently abnormal, and serum creatinine may increase rapidly. Edema and hypertension may result. Rapidly progressive glomerulonephritis, which is life threatening, can develop. • Venous system: Deep venous thrombosis can affect the lower extremities mostly when granulomatosis with polyangiitis is active. • Other organs: Occasionally, an inflammatory mass occurs in the breasts, kidneys, prostate, or other organs.
  27. Granulomatosis with Polyangiitis (GPA)
  28. Diagnosis • Routine laboratory tests, including urinalysis • Tests for antineutrophil cytoplasmic antibodies • Biopsy for definitive diagnosis • Granulomatosis with polyangiitis should be suspected in patients with chronic, unexplained respiratory symptoms and signs (including otitis media in adults), particularly if manifestations in other organ systems, especially the kidneys, also suggest the disorder. Routine laboratory tests are done, but ANCA testing and biopsy yield the most specific findings.
  29. Diagnosis • Routine laboratory tests include: • ESR, • C-reactive protein, • CBC with differential, • Serum albumin and total protein, • Serum creatinine, • Urinalysis, • 24-hour urine protein, • Chest x-ray. • Chest CT without contrast is nearly always necessary because the chest x- ray may miss nodules, masses, and/or cavitary lesions caused by granulomatosis with polyangiitis. • In most patients with active disease, ESR and C-reactive protein are elevated, and serum albumin and total protein are decreased; anemia, thrombocytosis, and mild-to-moderate eosinophilia are detected. • Dysmorphic RBCs and RBC casts, detected during urinalysis, indicate glomerular involvement. Proteinuria may be detected. Serum creatinine may be increased.
  30. Diagnosis • Serologic testing to detect antineutrophil cytoplasmic antibodies (ANCA) is followed by enzyme-linked immunosorbent assay (ELISA) to check for specific antibodies. • Most patients with active disease have cytoplasmic ANCA (c-ANCA), with antibodies against proteinase-3 (PR3); these findings plus characteristic clinical findings suggest GPA.
  31. Diagnosis • Some patients with other disorders (eg, bacterial endocarditis, cocaine abuse, systemic lupus erythematosus, amebiasis, tuberculosis) test positive for ANCA. • Because tests for rare diseases are likely to be falsely positive when ordered for the general population and the positive predictive value of a positive ANCA test is around 50%, • ANCA testing should be reserved for patients in whom the pretest probability for GPA or another ANCA-associated vasculitis is at least moderately high (eg, patients with alveolar hemorrhage, glomerulonephritis, or multiple mononeuropathy plus other features of microscopic polyangiitis or GPA).
  32. Diagnosis • A positive ANCA test does not rule out mycobacterial and fungal infections; thus, patients with positive ANCA results and cavitary lung lesions still require bronchoscopy and adequate cultures and other tests for tuberculosis and fungal infections. • ANCA testing (titre) should not be used to guide subsequent treatment. • During apparent remission, ANCA may increase or ANCA test results may change from negative to positive. • In some of these patients, symptoms do not recur; in others, symptoms recur or worsen soon after the test is done or during the next few weeks, months, or sometimes years.
  33. Diagnosis • Biopsy should be done if possible to confirm the diagnosis of GPA. • Clinically abnormal sites may be biopsied first. • Biopsy of affected lung tissue is most likely to reveal characteristic findings; open thoracotomy provides the best access. • Biopsies of lung or sinus tissue are cultured to exclude infection. • Renal biopsy that shows pauci-immune necrotizing focal crescentic or noncrescentic glomerulonephritis strongly supports the diagnosis. • Biopsy results of various tissues may also provide histologic information that can help guide treatment (eg, renal fibrosis). • Differential diagnosis includes other vasculitic disorders that affect small- and medium-sized vessels. • Infections, especially those due to slow-growing fungi or acid-fast organisms, should be ruled out by staining and culture of the sampled tissues. •
  34. Treatment • To induce remission in life- or organ-threatening GPA, high- dose corticosteroids plus either cyclophosphamide or rituximab • To induce remission in less severe GPA, corticosteroids and either methotrexate or rituximab • To maintain remission, rituximab alone or another drug such as methotrexate, azathioprine, or mycophenolate mofetil (rituximab plus another of these drugs, sometimes with a low dose of a corticosteroid, if patients have multiple relapses or GPA is difficult to control) • Kidney transplantation if necessary. • Treatment of granulomatosis with polyangiitis depends on the severity of disease. A multidisciplinary approach is required for multiorgan disease, often including a rheumatologist, otorhinolaryngologist, pulmonologist, and nephrologist.
  35. Treatment • Patients who have severe life-threatening or organ- threatening manifestations (eg, alveolar hemorrhage, rapidly progressive glomerulonephritis, multiple mononeuropathy with motor involvement) require immediate hospital admission for treatment to induce remission. These patients require high-dose corticosteroids and cyclophosphamide or rituximab. • Efficacies of rituximab and cyclophosphamide appear to be similar for inducing and maintaining remission. • Although the evidence supporting use of plasma exchange is weaker than that for the other interventions, plasma exchange can be added to the standard treatment regimen in patients with severe acute renal insufficiency (particularly if the anti–glomerular basement membrane antibody test is not known to be negative, so that rapidly progressive glomerulonephritis has not been excluded) or alveolar hemorrhage.
  36. Treatment • Rituximab seems to be particularly helpful in patients with recurrent disease. In one study that included patients with GPA and other ANCA-associated vasculitides, major relapses occurred in only 5% of patients treated with rituximab but occurred in 29% of patients treated with azathioprine. • Whether rituximab should be given alone or in combination with another drug and the dose and frequency of rituximab are not entirely clear. However, in one retrospective study, relapse rates were lower when rituximab was combined with methotrexate, azathioprine, or mycophenolate mofetil than when rituximab was used alone. • The optimal dosage of rituximab for maintenance therapy has not been established. A corticosteroid, given at a low dose, is often used to help maintain remission.
  37. Treatment • For less severe disease, corticosteroids and methotrexate are used to induce remission. • Rituximab may be used instead of methotrexate. • For upper respiratory tract manifestations, rituximab appears to maintain remission better than cyclophosphamide, methotrexate, or azathioprine. • Corticosteroids are tapered to as low a dose as possible or discontinued. • Irrigation of sinuses with saline, with or without mupirocin 2% nasal ointment, helps minimize crusting and secondary staphylococcal infections.
  38. Treatment • Treatment of subglottic stenosis is difficult. Systemic immunosuppressants may not be effective. Intralesional injection of long-acting corticosteroids, with gentle progressive dilation, markedly improves outcome and limits the need for tracheostomy. • Patients should be taught about the disorder so that relapses can be detected early. Patients should learn how to test their urine for blood and protein and be instructed to notify their physician of any sign of hematuria. • Kidney transplantation has been successful; the risk of relapse after transplantation is reduced compared with maintenance dialysis treatment (possibly due in part to use of immunosuppressants to prevent rejection).
  39. Goodpasture's Syndrome; Anti-GBM Antibody Disease • Goodpasture syndrome, a subtype of pulmonary-renal syndrome, is an autoimmune syndrome of alveolar hemorrhage and glomerulonephritis caused by circulating anti- glomerular basement membrane (anti-GBM) antibodies. • Goodpasture syndrome most often develops in genetically susceptible people who smoke cigarettes, but hydrocarbon exposure and viral respiratory infections are additional possible triggers. • Symptoms are dyspnea, cough, fatigue, hemoptysis, and hematuria. • Goodpasture syndrome is suspected in patients with hemoptysis or hematuria and is confirmed by the presence of anti-GBM antibodies in the blood or in a renal biopsy specimen. • Prognosis is good when treatment is begun before onset of respiratory or renal failure. Treatment includes plasma exchange, corticosteroids, and immunosuppressants, such as cyclophosphamide.
  40. Pathophysiology • Goodpasture syndrome is the combination of glomerulonephritis with alveolar hemorrhage and anti-GBM antibodies. Goodpasture syndrome most often manifests as diffuse alveolar hemorrhage and glomerulonephritis together but can occasionally cause glomerulonephritis (10 to 20%) or pulmonary disease (10%) alone. • Men are affected more often than women. • Anti-GBM antibodies are directed against the noncollagenous (NC-1) domain of the alpha3 chain of type IV collagen, which occurs in highest concentration in the basement membranes of renal and pulmonary capillaries.
  41. Pathophysiology • Environmental exposures—cigarette smoking, viral URI, and hydrocarbon solvent inhalation most commonly and pneumonia less commonly—expose alveolar capillary antigens to circulating antibody in genetically susceptible people, most notably those with HLA-DRw15, -DR4, and -DRB1 alleles. • Circulating anti-GBM antibodies bind to basement membranes, fix complement, and trigger a cell-mediated inflammatory response, causing glomerulonephritis, pulmonary capillaritis, or both.
  42. Symptoms and Signs • Hemoptysis is the most prominent symptom; however, hemoptysis may not occur in patients with alveolar hemorrhage, and patients may present with only chest x-ray infiltrates or with infiltrates and respiratory distress, respiratory failure, or both. • Other common symptoms include: • Dyspnea • Cough • Fatigue • Fever • Weight loss • Hematuria
  43. Symptoms and Signs • Up to 40% of patients have gross hematuria, although pulmonary hemorrhage may precede renal manifestations by weeks to years. • Signs vary over time and range from clear lungs on auscultation to crackles and rhonchi. • Some patients have peripheral edema due to renal failure and pallor due to anemia.
  44. Diagnosis • Serum anti-GBM antibody tests • Sometimes renal biopsy • Patients are tested for serum anti-GBM antibodies by indirect immunofluorescence testing or, when available, direct enzyme-linked immunosorbent assay (ELISA) with recombinant or human NC-1 alpha3. • Presence of these antibodies confirms the diagnosis. • Antineutrophil cytoplasmic antibodies (ANCA) testing is positive (in a peripheral pattern) in only 25% of patients with Goodpasture syndrome.
  45. Diagnosis • If anti-GBM antibodies are absent and patients have evidence of glomerulonephritis (hematuria, proteinuria, red cell casts detected with urinalysis, renal insufficiency, or a combination of these findings), renal biopsy is indicated to confirm the diagnosis. • A rapidly progressive focal segmental necrotizing glomerulonephritis with crescent formation is found in biopsy specimens in patients with Goodpasture syndrome and all other causes of pulmonary-renal syndrome. • Immunofluorescence staining of renal or lung tissue classically shows linear IgG deposition along the glomerular or alveolar capillaries. IgG deposition also occurs in the kidneys of patients with diabetes or with fibrillary glomerulonephritis (a rare disorder causing the pulmonary- renal syndrome), but GBM binding of antibodies in these disorders is nonspecific and does not occur in linear patterns.
  46. Treatment • Plasma exchange • Corticosteroids and cyclophosphamide • Immediate survival in patients with pulmonary hemorrhage and respiratory failure is linked to airway control; endotracheal intubation and mechanical ventilation are recommended for patients with borderline ABGs and impending respiratory failure. • Patients with significant renal impairment may require dialysis or kidney transplantation.
  47. Treatment • Treatment is daily or every-other-day plasma exchange for 2 to 3 wk using 4-L exchanges to remove anti-GBM antibodies, combined with a corticosteroid (usually methylprednisolone 1 g IV over 20 min once/day or every other day for 3 doses followed by prednisone (1 mg/kg po once/day for 3 wk, then titrated down to 20 mg po once/day for 6 to 12 mo) and cyclophosphamide (2 mg/kg po or IV once/day for 6 to 12 mo) to prevent formation of new antibodies. • Therapy can be tapered when pulmonary and renal function stop improving. • Rituximab could be used in some patients who have severe adverse effects due to cyclophosphamide or refuse cyclophosphamide as treatment, but it has not been studied in patients with Goodpasture syndrome.
  48. Idiopathic pulmonary hemosiderosis • Idiopathic pulmonary hemosiderosis is a rare disease that causes recurrent diffuse alveolar hemorrhage with no detectable underlying disorder; it occurs mainly in children < 10 years. In patients with idiopathic pulmonary hemosiderosis, repeated alveolar bleeding can eventually result in pulmonary hemosiderosis and fibrosis. • The disease is thought to be due to a defect in the alveolar capillary endothelium, possibly due to autoimmune injury. Many affected patients have celiac disease.
  49. Idiopathic pulmonary hemosiderosis • Symptoms and Signs • Symptoms and signs of idiopathic pulmonary hemosiderosis in children include recurrent episodes of dyspnea and cough, particularly nonproductive cough initially. Hemoptysis occurs later. • Children with idiopathic pulmonary hemosiderosis may present with only failure to thrive and iron deficiency anemia. • The most common symptoms in adults are exertional dyspnea and fatigue due to pulmonary hemorrhage and iron deficiency anemia.
  50. Idiopathic pulmonary hemosiderosis • Diagnosis • Bronchoalveolar lavage • Diagnosis of idiopathic pulmonary hemosiderosis involves demonstration of a combination of characteristic clinical findings, iron deficiency anemia, and hemosiderin-laden macrophages in bronchoalveolar lavage (BAL) fluid or lung biopsy specimens plus no evidence of small-vessel vasculitis (pulmonary capillaritis) or another explanatory diagnosis; it is confirmed by lung biopsy if other findings are inconclusive.
  51. Idiopathic pulmonary hemosiderosis • Treatment • Corticosteroids • Corticosteroids may reduce the morbidity and mortality of acute episodes of alveolar bleeding and may control the disease progression of pulmonary fibrosis. • Some patients may require additional immunosuppressive drugs. • Patients with celiac disease should be on a gluten-free diet.