1 / 77

Systemic Vasculitides by Dr P.Harischandra

Systemic Vasculitides by Dr P.Harischandra. Definition. Vasculitis is a clinico pathologic process characterized by inflammation of and damage to blood vessels

ehren
Download Presentation

Systemic Vasculitides by Dr P.Harischandra

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Systemic Vasculitidesby DrP.Harischandra

  2. Definition • Vasculitis is a clinico pathologic process characterized by inflammation of and damage to blood vessels • The vessel lumen is usually compromised, and this is associated with ischemia of the tissues supplied by the involved vessel • Hetergenous group due to any size vessel involved. • Can be primary disease or manifestation • Single organ(skin) or multi organ

  3. Common Vasculitic Condition

  4. Pathology and pathogenesis • Mostly immune mediated syndromes-antigenic stimuli • Still unkown why only certain individuals affected • Likely multifactorial in expression of vasculitis syndrome • Genetic predisposition, environmental exposure, regulatory mechanisms to certain antigens

  5. Potential mechanism of vessel damage

  6. Pathogenic immune complex formation • Immune deposit in vessel walls –widely accepted –but not established • Pts with active vasculitis don’t show immune complexes • Actual antigen still unidentified • Hep B- Antigen seen in PAN , Cryglobulinemicvasculitis – Hep C Association • Serum sickness type of complex mediated vasculitis –Ant-AnbCmplx in antigen excess-deposit on vessel walls-> increases permeability –histamines, bradykinin, leukotrienes- IgE triggered mechanisms

  7. Antineutrophil Cytoplasmic Antibodies(ANCA) • ANCA are antibodies directed against certain proteins in the cytoplasmic granules of neutrophils and monocytes • Present in a high % -active granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis, & lower % with Churg-Strauss syndrome (ANCA assoc Vasculitis) • 2 major types- cANCA , pANCA • cANCA-serum antibodies bind to neutrophils- Wegener’s 90% • pANCA –perinuclear staining of indicator neutrophils –Churg-Strauss, PSC, PAN, Microscopic Polyangitis, FCGN,RA

  8. Pathogenic T Lymphocyte Response & Granuloma Formation • Delayed hypersensitvity , Cell mediated injury –seen in granulomatous vasculitis • Vascular Endothelium can secrete HLA II class molecules – activation by cytokines – Interferon-γ • Endothelial cell-secrete IL-I-> T cells –immune response • Endothelial-leukocyte adhesion molecule 1 (ELAM-1), vascular adhesion molecule 1 (VCAM-1 ) enhances adhesion of leukocytes to endothelial cells in blood vessels

  9. Approach to the Patient: General Principles of Diagnosis • Diagnosis of vasculitis is often considered in any patient with an unexplained systemic illness • Certain clinical abnormalities that when present alone or in combination should suggest a diagnosis of vasculitis • Palpable purpura, pulmonary infiltrates and microscopic haematuria, chronic inflammatory sinusitis, mononeuritis multiplex, unexplained ischemic events, and glomerulonephritis with evidence of multisystem disease • Note:- Exclude other diseases –that mimic features, infectious diseases

  10. 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 Neoplasms Atrial myxoma     Lymphoma Carcinomatosis Drug toxicity     Cocaine     Amphetamines     Ergot alkaloids Methysergide     Arsenic Sarcoidosis Atheroembolic disease Antiglomerular basement membrane disease (Goodpasture's syndrome) Amyloidosis Migraine

  11. Approach

  12. General Principles of Treatment • Vasculitis established – Offending antigen to be removed • Treat infection, neoplasm, connective tissue disorder • Treat according to underlying category • Risk versus benefit to be weighed due to toxic side effects • Glucocorticoids , cytotoxic therapy – immediately in irreversible organ damage, high morality • W/H high toxic therapy in reversibility possible

  13. Cytotoxic agents have not proved to be beneficial in idiopathic cutaneous vasculitis • Glucocorticoids should be initiated in those systemic vasculitides that cannot be specifically categorized • Remission is achieved, one should continually attempt to taper glucocorticoids and discontinue when possible • Morbidity and mortality can occur as a result of treatment and strategies to monitor for and prevent toxicity represent an essential part of patient care

  14. Glucocorticoids are an important part of treatment for most vasculitides • Monitoring and prevention of glucocorticoid-induced bone loss is important in all patients • Cyclophosphamide -once in the morning - fluid throughout the day -maintain -dilute urine -reduce -bladder injury-monitoring for bladder cancer – Years • Monitoring of the complete blood count every 1–2 weeks for as long as the patient receives cyclophosphamide • Maintaining the white blood count (WBC) at >3000/L and the neutrophil count >1500/L is essential to reduce the risk of life-threatening infections.

  15. Major Toxic Side Effects of Drugs Commonly Used in the Treatment of Systemic Vasculitis

  16. Methotrexate and azathioprine are also associated with bone marrow suppression • Prior to initiation of azathioprine, thiopurine methyltransferase (TPMT), an enzyme involved in the metabolism of azathioprine, should be assayed • Pneumocystis jiroveci and certain fungi can be seen even in the face of WBCs that are within normal limits---receiving daily glucocorticoids in combination with a cytotoxic drug should receive (TMP-SMX) or another prophylactic therapy

  17. Granulomatosis with Polyangitis (Wegener’s) • Granulomatosis with polyangiitis (Wegener's) is a distinct clinicopathologic entity characterized by granulomatous vasculitis of the upper and lower respiratory tracts together with glomerulonephritis • Variable degrees of disseminated vasculitis involving both small arteries and veins may occur

  18. Incidence , Prevalence • Uncommon disease with an estimated prevalence of 3 per 100,000 • Extremely rare in blacks compared with whites; the male-to-female ratio is 1:1 • Seen at any age; 15% of patients are <19 years of age, but only rarely does the disease occur before adolescence • Mean age of onset is 40

  19. Pathology and Pathogenesis • hallmarks-are necrotizing vasculitis of small arteries and veins together with granuloma formation, which may be either intravascular or extravascular • Lung involvement typically appears as multiple, bilateral, nodular cavitary infiltrates -necrotizing granulomatous vasculitis • Upper Airway-inflammation, necrosis, and granuloma formation, with or without vasculitis

  20. This area of geographic necrosis has a serpiginous border of histiocytes and giant cells surrounding a central necrotic zone. Vasculitis is also present with neutrophils and lymphocytes infiltrating the wall of a small arteriole (upper right

  21. Computed tomography scan of a patient with granulomatosis with polyangiitis (Wegener's). The patient developed multiple, bilateral, and cavitary infiltrates.

  22. Pathology • Earliest form, renal involvement is characterized by a focal and segmental glomerulitis that may evolve into a rapidly progressive crescentic glomerulonephritis • Granuloma formation is only rarely seen on renal biopsy-contrast to other forms of glomerulonephritis, evidence of immune complex deposition is not found • classic triad of disease of the upper and lower respiratory tracts and kidney • virtually any organ can be involved with vasculitis, granuloma, or both.

  23. Although the involvement of upper airways and lungs with granulomatous vasculitis suggests an aberrant cell-mediated immune response to an exogenous or even endogenous antigen • A high percentage of patients with granulomatosis with polyangiitis (Wegener's) develop ANCA, and these autoantibodies may play a role in the pathogenesis of this disease

  24. Clinical and Lab Manifestations • Upper airways occurs in 95% of patients • Severe upper respiratory tract findings such as paranasal sinus pain and drainage and purulent or bloody nasal discharge, -nasal mucosal ulceration • Nasal septal perforation ->leading to saddle nose deformity. • Serous otitis media ,Subglottic tracheal stenosis -result in severe airway obstruction.

  25. Pulmonary Sx-cough, hemoptysis, dyspnea, and chest discomfort- 85-90% • Fibrous scarring, may lead to obstruction with atelectasis • Mild conjunctivitis to dacryocystitis, episcleritis, scleritis, granulomatous sclerouveitis, ciliary vessel vasculitis, and retroorbital mass lesions leading to proptosis 52% • Skin-papules, vesicles, palpable purpura, ulcers, or subcutaneous nodules; biopsy reveals vasculitis, granuloma

  26. Cardiac -8% - pericarditis, coronary vasculitis, or, rarely, cardiomyopathy • CNS-23%-cranial neuritis, mononeuritis multiplex, or, rarely, cerebral vasculitis and/or granuloma • Renal-generally dominates the clinical picture -accounts directly or indirectly for most of the mortality rate in this disease • Some cases as a mild glomerulitis with proteinuria, hematuria, and red blood cell casts • clinically - RF impairment occurs-rapidly progressive renal failure usually ensues unless appropriate treatment is instituted.

  27. Lab • Elevated ESR • Mild Anemia & leukocytosis • Mild hypergammaglobulinemia-IgA • RA factor-mild • Thrombocytosis • 90% cANCA-active disease, 60%-inactive disease, 20%-negative • Increased Thrombotic events-wary of DVT, PE routine anticoagulation not recommended

  28. Diagnosis • Demonstrate-necrotizing granulomatous vasculitis on tissue biopsy-pulmonary • Biopsy of upper airway tissue usually reveals granulomatous inflammation with necrosis • Renal biopsy -pauci-immune glomerulonephritis. • DDs-atypical presentation-antiglomerular basement membrane disease (Goodpasture's syndrome), relapsing polychondritis, tumors of the upper airway or lung, and infections-histoplasmosis , mucocutaneousleishmaniasis , rhinoscleroma, noninfectious granulomatous diseases

  29. Cocaine-induced tissue injury can be another important mimic of granulomatosis with polyangiitis • Granulomatosis with polyangiitis (Wegener's) must also be differentiated from lymphomatoid granulomatosis

  30. Treatment • Previously fatal-within few months • Glucocorticoids alone led to some symptomatic improvement, with little effect on the ultimate course of the disease • Cyclophosphamide – changed outcome /improvement ->90% of patients, complete remission -75% / 5-year survival-80%. • 50–70% of remissions –Relapse- to be ruled by infection, toxicity, chronic sequelae • ANCA titers misleading not to assess disease • Reinduction of remission after relapse is almost always achieved; however, a high percentage of patients ultimately have some degree of damage-renal insufficiency, hearing loss, tracheal stenosis, saddle nose deformity, and chronically impaired sinus function • Remission-Renal transplant

  31. Treatment… • Cyclophosphamide-side effects- two regimens –Induction, Maintenance • Severe disease, daily cyclophosphamide combined with glucocorticoids • Initiation-prednisone, 1 mg/kg per day for the first month, gradual tapering on an alternate-day or daily schedule with discontinuation after 6–9 months • Cyclophosphamide is given in doses of 2 mg/kg per day orally- dosage change renal impairment

  32. IV cyclophosphamide -2 mg/kg daily given for 3 months followed by 1.5 mg/kg daily • blood count monitoring every 1–2 weeks • Duration of induction exposure to 3–6 months. • Life-threatening disease, such as rapidly progressive glomerulonephritis or pulmonary hemorrhage requiring mechanical ventilation, a regimen of daily cyclophosphamide and glucocorticoids • Adjunctive plasmapheresis -creatinine of greater than 5.8 mg/dL

  33. Remission Maintenance after Cyclophosphamide • After 3–6 months of induction –stop cyclophosphamide • Methotrexate -orally or SC-start-at a dose-0.3 mg/kg 1/week, <15 mg/week • well tolerated -1–2 weeks -increase by 2.5 mg weekly -dose 20–25 mg/week Maintain • Azathioprine, 2 mg/kg/day • choice of agent is often based on toxicity profile-CKD, CLD • Relapse-mycophenolate mofetil, 1000 mg BID/day, may sustain remission • optimal duration of maintenance therapy is uncertain-minimum of 2 years -tapering over a 6–12 months stop

  34. Other drugs • For Patients with Cyclophos – toxicity – Methotrex with glucorticoids –alternative therapy with maintenance regimen • Rituximab –debatable • Etanercept- should not be used • TMX-SMZ – not to be used alone –only benefits upper airways • Organ specific-isolated sinus, joints skin- monitor, subglottic obstruction –do not respond to cytotoxic treatment- monitor

  35. Microscopic Polyangitis • microscopic polyarteritis was introduced into the literature by Davson in 1948- later named microscopic polyangitis – due to GN in patients with PAN • GN is common , pulmonary capillaritis also occurs • Absence of granulomatous inflammation – differentiates –from Wegener’s

  36. Incidence , Pathology • Age of onset-mean57 , males>females • Predilection for capillaries,venules,small,medium arteries • Immune response absent in disease • Renal lesion similar to wegener’s • Associated with ANCA

  37. Clinical and Lab Manifestations • Similar clinical features-Wegeners-small vessels, microscopic polyangitis • Gradualonset, fever, weight loss, musculoskeletalpain • GN in 79%- leads to Renal failure • Hemoptysis –first Sx, 12% of alveolar hemmorhage • Mononeuritis multiplex, GI and cutaneous vasculitis, Airway lesions not typical –if present suggest wegener’s • Elevated ESR, Anemia, leukocytosis, thrombocytosis, • ANCA75% +ve, Antimyeloperoxidase Predominant.

  38. Diagnosis-Rx • Histology evidence-vasculitis or pauci immune GN with multi system disease • ANCA associated –no sensitivity or specificity • 5 yr survival 74% , mortality from alveolar hemorrhage , GI, cardiac or renal disease. • Same Rx as Wegener’s • Life threatening- Prednisone, daily cyclophosphamide • Relapse 34%

  39. Churg -Strauss syndrome • Also referred to as allergic angiitis and granulomatosis • characterized by asthma, peripheral and tissue eosinophilia, extravascular granuloma formation, and vasculitis of multiple organ systems. • uncommon disease with an estimated annual incidence of 1–3 per million • occur at any age with the possible exception of infants-mean age of onset is 48 , female-to-male ratio of 1.2:1.

  40. Pathology and Pathogenesis • Necrotizing vasculitis - involves small and medium-sized muscular arteries, capillaries, veins, and venules • Feature -is granulomatous reactions that may be present in the tissues or even within the walls of the vessels themselves-infiltration of the tissues with eosinophils • Can occur in any organ in the body; lung involvement is predominant, with skin, cardiovascular system, kidney, peripheral nervous system, and gastrointestinal tract • Strong association with asthma and its clinicopathologic manifestations, including eosinophilia, granuloma, and vasculitis, point to aberrant immunologic phenomena

  41. Clinical and Laboratory Manifestations • Exhibit nonspecific manifestations such as fever, malaise, anorexia, and weight loss-multisystem disease • pulmonary findings -severe asthmatic attacks and the presence of pulmonary infiltrates • Mononeuritis multiplex -2nd most common -manifestation and occurs in up to 72% • Allergic rhinitis & sinusitis -61%-early disease • heart disease occurs in 14% of patients and is an important cause of mortality • Skin lesions occur in 51% of patients and include purpura in addition to cutaneous and subcutaneous nodules. • Renal disease in Churg-Strauss syndrome is less common-<Wegener’s

  42. Striking eosinophilia >1000cells-80% • Elevated ESR, Fibrinogen Alpha globulins elevated • ANCA Positive-pANCA • Diagnosis-biopsy-Churg-Strauss syndrome, a patient should have evidence of asthma, peripheral blood eosinophilia, and clinical features consistent with vasculitis.

  43. Rx-Churg-Strauss Syndrome • Churg-Strauss syndrome is poor, with a reported 5-year survival of 25% • Myocardial involvement is the most frequent cause of death and is responsible for 39% • Glucocorticoids alone appear to be effective in many patients • Dosage tapering is often limited by asthma, patients require low-dose prednisone for persistent asthma many years after clinical recovery from vasculitis • glucocorticoid failure or in patients who present with fulminant multisystem disease, the treatment of choice is a combined regimen of daily cyclophosphamide and prednisone

  44. PolyarteritisNodosa • PAN, also referred to as classic PAN-1866 by Kussmaul and Maier • Multisystem, necrotizing vasculitis of small and medium-sized muscular arteries in which involvement of the renal and visceral arteries is characteristic • PAN does not involve pulmonary arteries, although bronchial vessels may be involved; granulomas, significant eosinophilia, and an allergic diathesis are not observed. • PAN, as currently defined, is felt to be a very uncommon disease

  45. Pathology and pathogenesis • Vascular lesion in PAN is a necrotizing inflammation of small and medium-sized muscular arteries • The lesions are segmental and tend to involve bifurcations and branchings of arteries • involvement of venules is not seen in PAN and, if present, suggests microscopic polyangiitis • acute stages -polymorphonuclear neutrophils infiltrate all layers of the vessel ,perivascular areas • Mononuclear cells infiltrate the area as the lesions progress to the subacute and chronic stages • Fibrinoid necrosis of the vessels ensues with compromise of the lumen, thrombosis, infarction of the tissues ->lesions heal, there is collagen deposition, which may lead to further occlusion of the vessel lumen->Aneurysmal dilations up to 1 cm in size along the involved arteries are characteristic of PAN

  46. Multiple organ systems are involved, --degree and location of vessel involvement and the resulting ischemic changes • kidney in classic PAN -arteritis without glomerulonephritis • Significant hypertension, typical pathologic features of glomerulosclerosis • PAN-like vasculitis in patients with hepatitis B-isolation of circulating immune complexes composed of hepatitis B antigen -suggest the role of immunologic phenomena

  47. Clinical and Laboratory Manifestations • Nonspecific signs and symptoms are the hallmarks of PAN • Fever, weight loss, and malaise are present in over one-half of cases • vague symptoms such as weakness, malaise, headache, abdominal pain, and myalgias • Specific complaints related to the vascular involvement within a particular organ system may also dominate • renal involvement most commonly manifests as hypertension, renal insufficiency, or hemorrhage due to microaneurysms

  48. Clinical Manifestations Related to Organ System Involvement in Classic PolyarteritisNodosa

  49. There are no diagnostic serologic tests for PAN • >75% of patients, the leukocyte count is elevated with a predominance of neutrophils • anemia of chronic disease may be seen • elevated ESR is almost always present • Hypergammaglobulinemia may be present • all patients should be screened for hepatitis B • ANCA negative usually

More Related