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Similar to Pulmonary vasculitis(wegner,s granulomatosis)
Pulmonary vasculitis(wegner,s granulomatosis)
- 1. PULMONARY VASCULITIS By Dr. RATANLAL MEENA Moderator Dr. MOHAMMED JAVED QURESHI
- 2. Introduction • Pulmonary vasculitisis usually manifestation of a systemic disorder leads to inflammations of different sizes vessels by variety of immunological mechanism. • Primary vasculitis are a heterogeneous group of syndromes of unknown etiology, which share a clinical response to immunosuppressive therapy. • Secondary vasculitis may represent significant management problems in the context of a well-defined underlying disorder like SLE ,RA etc.
- 3. When to thinkabout vasculitis? Feature alone or in combination to other are suggesting vasculitis • Constitutional illness (fever, fatigue, weight loss, myalgias , arthralgia) • Ulcerative upper airways lesions • Cavitary or nodular lesion • Microscopic heamaturia • Diffuse alveolar hemorrhage • Palpable purpura • Mononeuritis multiplex • Peripheral eosinophilia
- 5. Classification (CHCC Nomenculature2012) Primary vasculitis Small vessels vasculitis • ANCA(antineutrophilic cytoplasmic autoantibody) associated Granulomatosis with polyangitis (GPA) Microscopic polyangitis (MPA) Eosinophilic granulomatosis with polyangitis (EGPA) • Immune complex mediated Anti-GBM Disease IgA vasculitis Cryglobulinemic vasculitis Hypocomplementemic urticarial vasculitis
- 6. Classification (CHCC Nomenculature2012) Medium vessels vasculitis Polyarteritis nodosa Kawasaki disease Large vessels vasculitis Giant cell arteritis Takayasu arteritis Variable vessel vasculitis Behcet disease Secondary vasculitis Systemic lupus erythematus Rheumatoid artheritis Scleroderma Antiphospolipid antibody syndrome Inflamatory bowel disease Drug induced vasculitis
- 7. Etiopathogenesis Environmental association •Infectious agents: Staph. Aureus E- coli., Klebsiella • Silica • Drugs PTU, Allopurinol, Hydralazine, Minocycline, Levamisole Genotypic associations • HLA-DP • SERPIN A1 Gene-code for α1- antitrypsin • PRT3 Gene- code for PR3 • HLA-DQ
- 8. Etiopathogenesis Immune complexmediated • HSP • SLE &other collagen vascular disease • Polyarteritis nodosa • Essential mixed cryoglobulinaemia T-lymphocyte mediated –with Granuloma formation • Giant cell arteritis • Takayasu arteritis • GPA • EGPA ANCA mediated • GPA • MPA • EGPA
- 9.
- 10. ANCA associated vasculitis •ANCA associated vasculitis are characterised by more frequent lung invovement. • ANCAs are antibodies directed against the intracellular antigens (protienase-3,myloperoxidase)of neutrophils and monocytes. • Depends upon immunofluorescence pattern on ethanol fixed neutrophils that react with neutrophil granules • c-ANCA ( cytoplasmic pattern) • P-ANCA (perinuclear pattern)
- 11. P-ANCA • Antibodies tostrong cations • Target antigen is myeloperoxidase(MPO) • Positive in >50% patients with MPA &EGPA • Also positive in <10 % patients GPA C-ANCA • Antibodies to neutral proteins or weak cations • Target antigen is protienase-3(PR3) • Positive in > 80% patients with GPA • Rarely positive in MPA & EGPA
- 12. Pathophysiology Predisposing factor (microbs,genetics,environment,drugs) Productionsof pro-inflammatory cytokins Priming of neutrophil (exposure of cytoplasmic proteins to cell surface of PMN) Interctions with ANCA Activation of primed neutrophil Activated primed neutrophil attached to and transmigration through endothelium and accumulate within vessels wall These neutrophil degranulates and produce reactive oxygen radical Results in inflammation and apoptosis endothelial cells and tissue injury (fibrinoid necrosis)
- 13.
- 14. Granulomatosis with polyangitis •Also known as wegener’s granulomatosis • The Chapel Hill Consensus Conference defined GPA as “necrotizing granulomatous inflammation usually involving the respiratory tract, and necrotizing vasculitis affecting predominantly small- to medium-sized vessels • It is characterized clinically by triad; o Upper airway disease(nasal,oral,sinus inflammation) o Lower respiratory tract disease o Kidneys(glumerulonephritis)
- 15. Granulomatosis with polyangitis Limited GPA (non severe) • Pathology is predominantly a necrotizing granulomatous inflammation, and the vasculitis seen on biopsy is of lesser clinical significance • No immediate threat either to the patient’s life or that the affected organ is at risk for irreversible damage. Severe GPA • Threatens to the patient’s life • Vital organ with the risk of irreversible damage
- 16. Clinical feature NOSE • Nasal congestion •Epistaxis • Nasal septum perforation • Saddle nose ORAL • Gingival hyperplasia • Oro- pharyngeal ulceration Upper airways involvement (in 90-95% patients) • Chronic serous ottitis THROAT • Subglottic stenosis • approx 20% of patient EAR
- 17. Clinical feature Upper airwaysinvolvement
- 18. Clinical feature Parenchymalinvolvement (in 54-85% patients) • Cough • Dyspnea • Chest pain Diffuse alveolar heamorrhage(in 5-15% patients) • Progressive dyspnea • Hemoptysis • Anaemia Hemoptysis may be absent in about 1/3 patients With DAH patient deteriorate rapidly and experience respiratory failure which has mortality rate up to 50% lower respiratory tract
- 19. Glomerulonephritis (in51-80% patients) • Is most concerning disease manifestation of GPA as it can progress to complete renal failure in the absence of symptoms • Usually detected by abnormal lab. Results such as o Microscopic heamaturia (>5 RBC/HPF) o Red cell cast o Protienuria o Declining renal functions Clinical feature Renal invovement
- 20. Clinical feature EYE • In35-52% patients • Conjunctivitis • Scleritis • Keratitis • Uveitis • Retroorbital pseudotumor CNS • In 20-50% patients • Mononeuritis multiplex • Pachy- meningitis Other system involvement • In 8-16% patients • Pericarditis • Valvulitis • Regional wall motion abnormality frequent Echo finding SKINCARDIAC • In 33-46% patients • Palpable purpura
- 21. Criteria of theAmerican College of Rheumatology (ACR1990) (presence of at least 2 out of the 4 of following) Criterior • Nasal or oral inflamation • Abnormal chest radiograph • Urinary sediment • Granulomatous inflammation on biopsy Definition • Development of oral ulcer or nasal discharge • Nodules fixed infiltrates or cavities • Microhematuria(> 5 RBCs/HPF or red cell cast) • Granulomatous inflammation within the wall of artery or in the perivascular or extravascular area
- 22. Radiology Pulmonary • Nodule/mass Cavitating /non-cavitating, single /multiple • Alveolar opacities Ground glass opacities Consolidation • Airways Subglotic stenosis • Pleural effusion • Mediastinal lymphadenopathy Extrapulmonary • Paranasal sinuses • Ophthalmic
- 25. Granulomatosis with polyangitis Pulmonary capillaritis • Usually causes fibrinoid necrosis of alveolar and vessels wall • Leukocytoclasis; presence of pyknotic cells and nuclear fragments from neutrophils undergoing apoptosis Lung nodule • Small necrotising microabcesses appears to be earliest lesion. • Typical geographical and basophilic appearance of necrosis after enlarge and coalsce to each other. • Necrotic centre is surrounded by palisading histiocytes and scattred giant cell • Mixed cellular infiltrates containing lymphocytes, plasma cell ,eosinophil Histopathology
- 26. Granulomatosis with polyangitis Gross pathology • Lung specimen showing cavitating grey white lesion Histopathology Alveolar capillaritis • showing alveolar hemorrhage Lung nodule • Showing geographical basophilic necrosis with palisading histiocytes
- 27.
- 28. Granulomatosis with polyangitis •C-ANCA pattern on indirect immunofluorescence • Staining in the cytoplasm while the multi-lobulated nuclei (clear zone ) are nonreactive • Positive in >80% of patients • P-ANCA pattern on indirect immunofluorescence • Perinuclear staining of the multi-lobulated nucleus with poorly defined cell border • Positive in <10% of patients ANCA testing
- 29. Microscopic polyangitis • Itis non-granulomatus necrotising small vessels ANCA associated vasculitis • More common in male,average age 50 years • Incidence ; 10 to 12 per million • Most patients (40% to 80%)have P-ANCA variety, reacting with MPO. • C-ANCA reacting with PR3 is seen less frequently • Several cases of MPA in association with severe obstructive airway disease or bronchiectasis have also been described.
- 30. Microscopic polyangitis RENAL • M/Cup to 80% involvement • Glomerulone phritis Hematuria Red cast proteinuria Muskulo- skeletal • 30 to 60% involvement • Myalgias • arthralgias Clinical feature • Parenchymal disease (in 20% patients) Cough Chest pain Dyspnea • Alveolar – hemorrhage (in 10-50% patients) hemoptysis anaemia SKIN • Up to 62% invovement • Palpable purpura PULMONARY
- 31. Microscopic polyangitis • Constitutionalsymptoms such as fever, malaise, and weight loss. • Gastrointestinal involvement occurs in about one-third of patients • MPA and GPA seem to be a part of a clinical spectrum,however Absence of granuloma formation Sparing of the upper repiratory tract are feature of MPA • In contrast to EGPA there is no H/O ASTHMA and no eosinophilia Clinical feature
- 32. Eosinophilic granulomatosis withpolyangitis • Also known as CHURG-STRAUSS SYNDROME • Annual incidence; 1-3/million • Male>female • It is ANCA associated small vessels vasculitis Where pANCA are predominant type and cANCA positivity is rarely seen • Other association are in patient using leukotriene receptor antagonists due to unmasking of vasculitic symptoms in asthma, by allowing dose reductions or discontinuation of oral glucocorticoid therapy • Late age of onset(mean age of 32) asthma allow us to distin- guish EGPA asthma from typical asthma in general population.
- 33. Eosinophilic granulomatosis withpolyangitis 1. Churg and strauss(1951) • H/O asthma • Tissue eosinophilia • Extravascular granuloma formation • Systemic vasculitis • Fibrinoid necrosis of connective tissue 2. Lanhaman & colleagues(1984) • Asthma • Peripheral blood eosinophilia(1.5x 109) • Systemic vasculitis involving 2 or more extrapulmonary organ Clinical criteria
- 34. Eosinophilic granulomatosis withpolyangitis 3. American college of rheumatology criteria (1990) (4 out of 6 in following below) • Asthma • Eosinophilia(>10%) • Neuropathy • Transient pulmonary infiltrates • Paranasal sinus abnormality • Extravascular eosinophil infiltration 4. Chapel Hill Consensus updated (2012)definition “eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory, and necrotizing vasculitis predominantly affecting small- to medium-sized vessels, and associated with asthma and eosinophilia.” Clinical criteria
- 35. Eosinophilic granulomatosis withpolyangitis Prodromal Late -onset allergic disease • Evidence of asthma Cough , Wheeze Dyspnea • Allergic rhinitis • Nasal polyposis Vasculitic • Vasculitis of small or medium size vessels • Vascular or extravascular granuloma • Constitutional symptoms Clinical phases • Marked peripheral eosinophilia • Eosinophilic tissue infiltration of LUNG ,GI tracts or SKIN Eosinophilic
- 36. Eosinophilic granulomatosis withpolyangitis Pulmonary • Parenchymal involvement occurs in 30 -40% of patients • Alveolar hemorrhage is exceedingly rare Renal involvement less prominent (<25%) than GPA& MPA Peripheral nerve invovement(70-80%) • In form of mononeuritis multiplex result from capillaritis and direct toxicity from eosinophil granules Skin, heart and abdominal viscera may also be involved Prognosis of EGPA is better than that of GPA and MPA, as the overall mortality is lower ,Most deaths are secondary to cardiac involvement.
- 37. Eosinophilic granulomatosis withpolyangitis Skin rashes Subcutaneus nodule
- 38. Radiology • Transient alveolartype of infiltrates are most common • Predominantly peripheral distribution • Nodular lesions occasionaly • Sinusitis
- 39. Eosinophilic granulomatosis withpolyangitis • Necrotising vasculitis • Eosinophilic tissue infiltration • Extravascular granuloma Histology
- 40. System GPA MPAEGPA Pulmonary •70–95%; •Tracheobronchial 10–50% •fixed nodules, cavitation •10–30%, •most of the pts will have alveolar hemorrhage •Asthma is universal; Renal RPGN in 50–80% of patients RPGN -universal RPGN in 10–25% Upper Airway 90–95% of pts; Ulcerating and destructive lesions Almost none Sinusitis - 20–70% of pts but lacks destructive nature
- 41. System GPA MPAEGPA Constitutional Common Very common and often precedes RPGN Common Ocular Common,35–52% <5% Uncommon Cardiac 5–16%. 10–15% 30–50% and a major cause of mortality Gastrointestinal Uncommon Common,up to 35% 30-60% Neurologic 20 – 30% Mononeuritis multiplex 40–60% Mononeuritis multiplex > 70%
- 42. System GPA MPAEGPA Chest Imaging Abnormal-80%. alveolar, interstitial or mixed infiltrates, or nodular / cavitary lesions Pulmonary infiltrates occur in 10–30% Transient infiltrates - 40-75% Peripheral distribution ANCA c-ANCA positive in 90% and p-ANCA in 10% positive-50–75% p-ANCA positive in 45–70% most of these being p-ANCA Biopsy Necrotizing palisading (coagulative) granulomas dominates necrotising vasculitis with No granuloma formation biopsy containing a blood vessel with extravascular eosinophils.
- 43. Treatment • Principle oftherapy 1. Remission induction 2. Remmision maintenance 3. Monitoring • Disease activity assesment • Drug toxicity/adverse events • Superimposed infection • Disease recurrence after achieving drug free remmision • Disease complication(e.g. tracheal stenosis)
- 44. Remmision induction therapy LocalisedGPA • Trimethoprim/sulfamethoxazole (T/S) 160/800 mg BD • It related to antimicrobial effects on S. aureus, the organism most frequently cultured from the nostrils of patients with GPA • continued long-term observation required, as some will later develop more severe disease manifestations Limited GPA or MPA • oral prednisolone at doses of 0.5 to 1 mg/kg per day • in combination with methotraxate with a target dose of 20 to 25 mg once a week. • To minimize toxicity and the risk of Pneumocystis pneumonia folic acid, 1 mg/d and standard PCP prophylaxis should be added.
- 45. Severe GPA orMPA • Oral prednisone in combination with oral cyclophosphamide at a dose of 2 mg/kg /day for 3 to 6 months OR • IV pulse therapy with cyclophosphamide three pulses of 15 mg/kg given 2 weeks apart • followed by 15 mg/kg pulses given every 3 weeks for 6 months . OR • Rituximab (375 mg/m2 of body surface ) once weekly 4 doses.
- 46. Rapidly progressive fulminantdisease, • Such as those presenting with alveolar hemorrhage or rapidly deteriorating renal function, • IV methylprednisolone, 1000 mg per day for 3 to 5 days • If this therapy does not generate the desired effects, plasma exchange should be implemented Severe disease relapse, • Rituximab was found to be superior to cyclophosphamide Refractory GPA • 10% of patients do not respond adequately to therapy with cyclophosphamide and fail to achieve remission • rituximab has now become standard of care for refractory GPA.
- 47. Remmision maitenance therapy •For at least 12 months beyond achievement of remission, and longer in patients who have suffered relapses • limited or “nonsevere” disease should be maintained on methotrexate • Patients treated with cyclophosphamide for remission induction should be switched to either methotrexate or azathioprine(1-2mg/kg/day) • Azathioprine is preferred in patients with any degree of renal insufficiency
- 48. Treatment of EGPA •EGPAusually responds to prednisolone alone. •Induction of remission with oral prednisolone (40-60 mg/day). •After the first month prednisone is gradually tapered down. •Other immunosuppressive drugs in steroid resistant cases , • azathioprine, • methotrexate, or •cyclophosphamide. •High doses of i.v. methylprednisolone with severe or refractory •The course of therapy can last for 1 to 2 years •steroid therapy has increased the 5-yr survival more than 50%.
- 49. EUVAS Grading ofANCA associated vasculitis (Disease Severity and first line management) Class - Consti.Symp.- Renal Fns - Vital Organ DysFn- Therapy Limited No Creat≤1.4 mg/dl No Steroids/ MTX/AZT Early gen. Yes Creat≤1.4 mg/dl No Steroids+Cyclo/MTX Active gen. Yes Creat ≤ 5.7 mg/dl Yes Cyclo + steroids Severe Yes Creat≥5.7 mg/dl Yes Cyclo+steroids+ Plasmapheresis Refractory Yes Any Yes Newer agents
- 50. Supportive Therapy • Pneumocystispneumonia still carries a mortality of up to 35%. So, T/S (180/600) is recommended for all non sulpha allergic patients • To minimize toxicity of immunosuppressive regimen it should be supplemented by folic acid, 1 mg/d • Patients undergoing intense immunosuppression during the remission induction phase so prophylactic antifungal therapy. • Patient treated with glucocorticoids for AAV should receive osteoporosis prophylaxis with calcium and vitamin-D supplementation.
- 51.
- 52. Giant cell arteritis •A generalized inflammatory disorder involve large and medium sized arteries. • M/C in white population, elderly patients • Annual incidence ; 13 per million • Respiratory symptoms have been reported up to 25% of patients Cough Horseness Throat pain • Symptoms are usually resolve with prednislone therapy
- 53. Takayasu arteritis • Alarge vessels vasculitis predominantly affecting aorta and branches. • Annual incidence ;1-2 per million , young patients • Pulmonary complication in half of patients result from unique arteriopathy • Progressive defects in the outer media of the arteries and ingrowth of granulation tissue–like capillaries associated with thickened intima and sub-endothelial smooth muscle proliferation • Which lead to pulmonary artery stenosis and occlusion as well as pulmonary hypertension in up to one-half of all patients.
- 54. Behcet disease • Itis immune complex mediated chronically relapsing systemic inflammatory disorder. • Characterised by aphthous oral ulcers (>2 time/year) • and at least two or more of the following; aphthous genital ulcers, uveitis, cutaneous nodules, meningoencephalitis. • Respiratory manifestation; Cough, hemoptysis ,chest pain ,dyspnea • Pulmonary artery aneurysm; on CT or MR angiography Due to massive hemoptysis there is destruction of elastic lamina of pulmonary artery
- 55. AntiGBM disease • Alsoknown as “Good pasture syndrome” • Caused by autoantibodies directed against the NC1-domain of the α3 chain of basement membrane collagen type IV. • This epitope is only accessible for autoantibodies in the basement membranes of kidneys and lungs. • Diffuse alveolar hemorrhage is common in Inhalational injury(smoking,hydrocarbon exposure) • A definitive diagnosis depends on the documentation of linear anti-GBM deposits in the kidney or lung • Early implementation of immunosuppressive therapy in conjunction with plasma exchange is the key to a favorable outcome.
- 56. AntiGBM disease 1.Diffuse alveolarhemorrhage 2. Glomerulonephritis
- 57. Antiphospholipid syndrome • Definedby arterial and venous thromboses, or recurrent miscarriages occurring in patients with antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant, or both) • Capillaritis of APS appears to be immune complex mediated • Tissue necrosis from microthrombosis as well as pulmonary capillaritis has been implicated as the cause of alveolar hemorrhage
- 58. Drug induced vasculitis Small- to medium-sized vessels are usually affected Propyl-thiouracil, D-penicillamine, hydralazine, sulfasalazine, minocycline, allopurinol, and others can induce ANCA-associated vasculitis All-trans-retinoic acid (ATR) used in acute promyelocytic leukemia can cause a fever, leukocytosis, fluid retention, hemorrhage, thrombosis, and organ failure Chronic nasal cocaine abusers develop severe midline destructive lesions. • In early stage, such a lesion is clinically and histopathologically difficult to differentiate from limited Wegener granulomatosis. • The presence of ANCA reacting with human neutrophil elastase (HNE) appears to be an immunological marker separating patients with cocaine-induced midline destructive lesions from those with Wegener granulomatosis. • The clinical picture of patients exposed to levamisole can mimic systemic vasculitis
- 59. Systemic lupus erythematous •The development of pulmonary capillaritis in SLE is thought to be immune complex mediated • The onset of diffuse alveolar hemorrhage in patients with SLE is usually abrupt, and it is seldom the first sign of SLE majority of Patients • The rapid development of pulmonary infiltrates is associated with fever • Hemoptysis may be absent in up to one-half of the patients • Lung biopsy of a patient with lupus erythematosus and alveolar hemorrhage showing so-called lumpy, bumpy deposition of immune complexes as demonstrated by direct immunofluorescence • Treatment consists of glucocorticoids and cyclophosphamide. • The use of plasma exchange has been suggested,but its benefit remains unproved.