Small- Vessel Vasculitides

1. Small- Vessel Vasculitides

2. Learning Objectives Review the 4 types of hypersensitivity reactions Understand the ANCA test Differentiate then consolidate the different ANCA diseases and Pulmonary-Renal syndromes Do some questions

3. Vasculitis: A clinicopathologic process characterized by inflammation of and damage to blood vessels, often resulting in complete or partial occlusion of the involved vessels, with resulting ischemic damage to the supplied organ/tissue.

4. Vasculitis may be a primary or secondary manifestation of a disease process May affect a single, or multiple organs

5. Etiology Several have been proposed, however, there is no uniform consensus For now, let�s focus on immune complex deposition � a process similar to serum sickness

6. Etiology Ag-Ab complexes deposit in blood vessel walls whose integrity have already been compromised by vasogenic amines (histamine, leukotrienes, bradykinin) released from activated platelets and mast cells Complement components (primarily the classical pathway) are activated and recruit PMN�s

7. Etiology Exactly why only certain immune complexes cause vasculitis and why only certain blood vessels are affected remains in large part a mystery

8. Hypersensitivity Reactions Type I � immediate HS �classic� allergy Prior sensitization IgE mediated Massive degranulation Early and late responses Type 2 � cytotoxic HS IgG binds to target tissue C� activation Direct cytotoxic action AIHA ITP Goodpasture�s Myasthenia Gravis

9. Hypersensitivity Reactions Type 3 � IC HS �serum sickness� Ab form complex with circulating Ag Deposition results in C� activation Leukocytoclastic vasculitis is hallmark manifestation Arthus reaction Type 4 � cell-mediated HS Delayed-type HS Previously sensitized T-cells are required Mantoux test Contact dermatitis Allograft rejection

10. ANCA Anti-Neutrophil Cytoplasmic Antibodies Ab directed against proteins in the cytoplasmic granules of PMN�s and monocytes Wegener�s Granulomatosis Microscopic Polyangiitis Churg-Strauss Crescentic/necrotizing GN

11. c-ANCA Serum from patients bind to cytoplasmic granules and show a granular appearance on immunofluorescence Proteinase-3 (PR-3) is the major antigen Serine protease Present in azurophilic granules Most labs reflexively send a confirmatory test for PR-3 when this pattern is seen, or have eliminated the immunofluorescence aspect entirely

12. p-ANCA Localized, peri-nuclear staining pattern on PMN�s Myeloperoxidase (MPO) is the major target Ag Elastase Cathepsin G Lactoferrin Lysozyme Permeability-increasing protein Only MPO has been convincingly associated with vasculitis, the others may be seen in other ANCA+ diseases (IBD, drugs, endocarditis)

13. Proposed Mechanism of Disease PR-3 and MPO are mobilized to surface of PMN�s and monocytes when activated by TNF-a or IL-1 Now can react with circulating ANCA PMN�s degranulate and induce inflammation locally How the ANCA are generated in the first place is less clear

14. Wegener�s Systemic disease Granulomatous vasculitis of upper and lower respiratory tract with associated GN, variable degrees of disseminated vasculitis Involves small arteries and veins Prevalence: 3 per 100,000 Extremely rare in blacks Equal M:F ratio Mean age of onset is 40

15. Wegener�s Multiple b/l nodular cavitary infiltrates Lung biopsy: classic granulomatous necrotizing vasculitis Nasal ulcers, sinus disease, septal perforation, saddle-bridge deformity, tracheal stenosis Nasal biopsy: usually reveals the same, not as sensitive FSGS ? RPGN Kidney biopsy: rarely shows granulomas or immune complex deposition (focal, segmental, necrotizing pauci-immune GN)

16. Wegener�s Peripheral WBC tests indicate an unbalanced TH1 cytokine pattern 90% are PR-3 positive (c-ANCA) during active disease A few pt�s will be MPO positive rather than PR-3 BUT� You must establish tissue diagnosis!! Aim for lungs. Must differentiate from other rare diseases such as angiocentric immunoproliferative diseases and lymphomatoid granulomatosis

17. Wegener�s Rx Previously, uniformly fatal in matter of weeks to months Cyclophosphamide (2mg/kg/day) Maintain WBC >3000 & PMN >1500 6-12 months!! Glucocorticoids 1mg/kg/day, taper at 1 month and off at 6 months Remission rate: 75% 90% have marked improvement Plasmapheresis in refractory/progressive cases

18. Microscopic Polyangiitis Disease entity characterized by a necrotizing vasculitis with few or no immune complexes, affecting small vessels (arterioles, capillaries, venules) First coined in ???

19. Microscopic Polyangiitis Disease entity characterized by a necrotizing vasculitis with few or no immune complexes, affecting small vessels (arterioles, capillaries, venules) First coined in 1992, by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides Incidence is uncertain due to previous lumping together with PAN. Etiology unknown.

20. Microscopic Polyangiitis Pauci-immune GN is very common (79%) renal biopsy is identical to that in Wegener�s Pulmonary infiltrates and hemorrhage may occur as a result of capillaritis, but biopsies lack granulomas Upper airway disease and pulm nodules/cavities absent Immunohistochemical staining lacks IC deposition, suggesting that IC complex formation is not part of the pathogenesis

21. Microscopic Polyangiitis 75% of patients are c-ANCA+ Treatment is identical to Wegener�s, and distinguishing between the two is somewhat academic 5-yr survival is 74%

22. Churg-Strauss Syndrome Incidence: ~1 per 1,000,000 Occurs at any age, but mean is 48yrs Clinical Tetrad Asthma Eosinophilia (blood and peripheral) Extravascular granuloma Vasculitis affecting mutiple organs Involves small and medium-sized arteries, capillaries, and veins

23. Churg-Strauss Syndrome Granulomatous inflammation with eosinophilic infiltration of involved organs Lung Kidney Skin Heart Presents as systemic syndrome (fever, malaise, anorexia, weight loss) with severe asthma attacks (may be precipitated by initiation of leukotriene inhibitors)

24. Churg-Strauss Syndrome p-ANCA sensitivity: 48% Treatment Glucocorticoids titrated to control asthma Add cyclophosphamide as second line as in Wegener�s

25. Goodpasture�s Syndrome A specific subset of anti-GBM disease in which pulmonary hemorrhage occurs Target: noncollagenous domain of a3 chain of Type IV collagen Typically seen in young males (5-40y/o) Type II HS reaction - inflammation and tissue destruction mediated by direct Ab binding and secondary activation of classical C� pathway or direct activation of cytotoxic T-cells or phagocytes

26. Goodpasture�s Syndrome Kidney RPGN and crescentic GN are most common Pulmonary hemorrhage (50-60% of all pt�s), quite rare in patients >50y/o NOT associated with ANCA positivity

27. Goodpasture�s Syndrome Gold standard diagnostic test? Renal biopsy with immunohistochemical staining Circulating anti-GBM antibodies (IgG) is 90-95% sensitive Levels directly correlate with severity, organ survival, and relapse Treatment Plasmapheresis daily until titers undetectable (1-2 weeks!) Prednisone 1mg/kg/day Cyclophosphamide or azathioprine