Wegener s Granulomatosis

2. Wegener�s Granulomatosis Serena Ezzeddine Morning Report October 5, 2007

3. Vasculitis Large Vessel-Takayasu (aorta and branches), Giant Cell (cranial branches) Medium Vessel- Polyarteritis nodosa, Kawasaki (coronary arteries), isolated Central nervous system

4. Small Vessel Vasculitides Churg-Strauss- medium and small sized muscular arteries, often found with vascular and extravascular granulamatosis. Skin and lung Wegeners/MPA HSP- systemic, IgA immune complexes Cryoglobulinemic-precipitate in cold and dissolve on rewarming. Immunoglobulins and complement components. Hep C association Vasculitis secondary to connective tissue dz - ie Lupus, RA, Vasculitis secondary to viral infection -Hep B, C, also HIV, CMV,EBV, Parvo

5. ANCA Vasculitides Wegeners-90% ANCA +, most PR3 Microscopic polyangitis-70% ANCA +, most MPO Churg-Strauss-~50% ANCA, both PR3 and MPO, with slight predilection for MPO Renal Limited Vasculitis-majority ANCA +, 75-80% MPO, indistinguishable from WG.MPA on histo Drug induced-usually MPO, some offending agents are hydralazine, PTU, minocycline, methimazole

6. Definitions Wegener�s granulomatosis is a systemic vasculitis of the medium and small arteries, as well as venules, arterioles and occasionally large arteries. �Classic� Wegener�s primarily involves the upper and lower respiratory tracts and the kidneys �Limited� form have clinical findings isolated to the respiratory tract- can occur in � of cases, although 80% may go on to develop glomerulonephritis. Specifically, pts with limited disease are younger at disease onset, and more likely to be women.

7. Wegener�s continued. . . Renal involvement is manifested by acute renal failure with red cells, red cell and other casts , and proteinuria. Pts with microscopic polyangitis have a renal lesion that is essentially indistinguishable from that of pts with classic Wegener�s, the principle difference is the absence of granulomatosis inflammation,although some experts consider the presence of any significant upper respiratory tract involvement to be indicative of Wegener�s.

8. In addition to pulmonary and renal� Upper and lower airways, including subglottic region or trachea Joints (myalgias, arthralgias, arthritis) Eyes (conjuctivitis, corneal ulceration, episcleritis/scleritis, optic neuropathy, nasolacrimal duct obstruction�) Skin (hemorrhagic lesions, palpable purpura) Nervous system(cranial nerve abnormalities) GI tract/Heart, lower GU

9. Pathogenesis Production of ANCA (anti-neutrophil cytoplasmic antibodies) is one of the hallmarks of WG and related forms of vasculitis(Churg-strauss, MPA, pauciimmune glomerulonephritis, drug �induced). ANCA are directed against antigens present within the primary granules of neutrophils and monocytes, and thus produce tissue damage via interactions with primed neutrophils and endothelial calls. ~90% of pts with active generalized WG are ANCA positive, but some do not have ANCA, and those with limited forms of the dz, up to 40% may be ANCA negative, thus the absence of ANCA does not exclude the diagnosis of Wegener�s.

10. Pathogenesis Most common targeted antigens in WG : Proteinase 3 (PR3), observed in 70-80% of pts Myeloperoxidase (MPO)-target in approximately 10% Dual postivity is rare and , and generally indicated the presence of another condition such as SLE ~70% of pts with MPA are ANCA positive and most have MPO-ANCA, with only a minority having PR3

11. Presentation Most common presenting symptoms include persistent rhinorrhea, purulent/bloody nasal discharge, oral and/or nasal ulcers, polyarthraglias, myalgias, or sinus pain. Less common are hoarseness, stridor, earache, conductive and sensorineural hearing loss or otorrhea Frequent early complaints of lower tract include cough, dyspnea, hemoptysis, pleuritic pain Nonspecific complaints of fever, night sweats,anorexia, weight loss, and malaise Renal involvement � ACTIVE URINE SEDIMENT (microscopic hematuria w/or w/o red cell casts) and variable degrees of renal insufficiency

12. Diagnosis American College of Rheumatology �not intended to be used in routine clinical practice and established before ANCA. Presence of 2 or more yield 88% sensitivity and 92% specificity Nasal or oral inflammation Abnormal chest radiograph (nodules, alveolar opacities) Abnormal urine sediment Granulomatous inflammation on biopsy of an artery or perivascular area

13. Diagnosis Routine Labs-nonspecific- Leukocytosis, thrombocytosis (>400,000), marked ESR, and normocytic,normochromic anemia, mildly elevated RF ANCA- as previously described Tissue Biopsy- dx should be confirmed by tissue bx at site of active disease .Nasopharyngeal bx less invasive, but may not see full pathogenesis due to small amount of tissue- acute and chronic inflammation Renal bx-segmental necrotizing glomerulnephritis w or w/o cresents Skin-leukocytoclastic vasculitis with little or no complement and immunoglobulin Lung-granulomatous and vasculitis

14. Focal or diffuse necrotizing extracapillary glomerulonephritis is the histological hallmark of ANCA-associated Vasculitis

15. Massive necrosis is usually associated to diffuse circumferential extracapillary proliferation. From a clinical point of view, the patient is affected by rapidly progressive renal failure.

16. Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of Wegener granulomatosis Crescent formation

17. The biopsy specimen of a lung from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation

18. C-ANCA staining pattern of ethanol-fixed normal human neutrophil

19. Differential Dx of Vasculitis Fibromuscular dysplasia Cholesterol emboli Atrial myxoma with emboli Infective endocarditis Malignancies,ie lymphamatoid granulomatosis Bacteremia Rickettsial dz Amyloid SLE

20. Treatment Many physicians favor use of daily oral cyclophosphamide/corticosteroid combination therapy in the initial treatment of all pts dx with Wegener�s, and once remission is induced (which requires a minimum of 3-6 months for most pts), other less toxic immunosuppressives can be employed

21. Treatment Use of aggressive immunotherapy is justified b/c survival in untreated generalized Wegener�s is extremely poor, with up to 90% of pt�s dying with in 2 yrs from respiratory or renal failure, but mortality is markedly diminished with introduction of cyclophosphamide/corticosteroid therapy Response to therapy-partial or complete resolution of inflammatory manifestations, such as inactive urine sediment, although renal failure can persist.

22. Treatment IV Cyclophosphamide monthly- lowers the overall cumulative dose-role is incompletely defined, and both equal and decreased efficacy has been described in Wegener�s, which may be due to different pt populations in the studies, nonresponders had more severe disease, and those with incomplete response-switching to oral daily regimen may induce remission Methotrexate-mild dz, higher relapse rate, can�t use in Cr >2.0. Plasmapharesis-pts with renal dz needing dialysis, pulmonary hemorrhage, or also with anti-GBM

23. Treatment In one of largest nonrandomized prospective single center studies, outcomes of 158 pts with Wegener�s treated with varying regimens at NIH were reported. Standard low dose cyclophosphamide plus prednisone(133), cyclophos alone (8), glucocorticoids alone(10), or other cytotoxic agents plus steroids(6). Cyclophos administered for a mean of 2 yrs. Mean follow up 8 yrs-In cyclophos and steroids: Survival 80%, with deaths due to Wegners, side effects or both Significant clinical improvement was observed in more than 90% of pts, with 75% achieving complete remission Among the 98 pts followed for more than 5 yrs, more than half experienced remission of greater than 5 yrs

24. Treament So, based on studies, first line is daily oral cyclophosphamide/corticosteroid. Cyclophos at 1.5-2 mg/kg/day, steroid (1mg/kg/day). IV Cyclophosphamide can be used, not well studied, but associated with higher relapse and longer to remission Methotrexate-maybe used in mild disease, or in maintenance, but either way, higher relapse rate Azathioprine-maintence, esp in pts with renal insuffiency Steroids- no significant benefit in maintenance.

25. Treatment Duration of maintenance therapy- 12-18 months after stable remission. May need more long term maintenance esp if ANCA continues to be positive.

26. Prognosis Overall, the morbidity and mortality associated with Wegener�s granulomatosis and microscopic polyangiitis, results from the combined effects of irreversible organ dysfunction b/c of inflammatory injury occurring before and the early phase of effective therapy, consequences of immunsuppressive therapy, and natural hx of disease Morbidity-consequences of therapy (glucocorticoid toxicity, increased risk of malignancy ie bladder cancer, skin ca, sterility, organ failure); disease related damage (partial hearing loss and persistent proteinuria);increased risk of DVT/PE in ANCA

27. Prognosis Renal �ESRD eventually occurs in 20-25% of pts. Poor renal outcome associated with more severe renal dysfunction at presentation, lack of response to initial treatment,and enhanced amount of fibrotic changes on renal bx Mortality- Major causes of death are complications of underlying disease and therapy. 90% mortality rate in 2 yrs in untreated. Higher mortality in elderly, those with florid organ failure at presentation.

28. References cnserver0.nkf.med.ualberta.ca -images Emedicine-images www.ndt-educational.org �images Uptodate.com Harrisons Principles of Internal Medicine 15th ed Washington Manual