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ANCA – Associated Vasculitis

ANCA – Associated Vasculitis. The Discovery of Anti-Neutrophil Cytoplasmic Antibodies (ANCA). First described in 1982 by Davies in 8 patients with necrotizing pauci-immune glomerulonephritis 1 Hall and colleagues identified ANCA in four patients with systemic vasculitis 2

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ANCA – Associated Vasculitis

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  1. ANCA – Associated Vasculitis

  2. The Discovery of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) • First described in 1982 by Davies in 8 patients with necrotizing pauci-immune glomerulonephritis1 • Hall and colleagues identified ANCA in four patients with systemic vasculitis2 • In 1985, Van der Woude suggested an association between ANCA and Wegener’s granulomatosis3 • ANCA subsequently reported in microscopic polyangiitis and in Churg Strauss syndrome4 1. Davies DJ, et al: Br Med J 285:606, 1982 2. Hall JB, et al: Aust NZ J Med 14:277, 1984 3. van der Woude FJ, et al: Lancet 1:425, 1985 4. Jennette CJ, Falk R: New Eng J Med 337:1512, 1997

  3. ANCA-Associated Vasculitis

  4. Shared Features of ANCA-Associated Vasculitides • Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), and Churg Strauss syndrome (CSS) • Can be considered together in view of a number of shared pathologic, clinical, and laboratory features • Preferentially involve small vessels (arterioles, capillaries, venules) • Similar glomerular lesions (crescents, focal necrosis, pauci-immune) • Propensity to present as lung-renal syndromes • Varying prevalence of ANCA positivity

  5. Detection of ANCA • ANCAs were originally described based on their immunofluorescence patterns • cytoplasmic (c-ANCA) and perinuclear (p-ANCA) • The antigens responsible for these patterns have also been identified • proteinase 3 (PR3) for c-ANCA • myeloperoxidase (MPO) for p-ANCA

  6. Immunofluorescence and Antigenic Specificity • In c-ANCA reactivity • PR3 is responsible for more than 90% of such reactions • Other antigens may occasionally contribute • bactericidal permeability-inducing protein (BPI) • rarely MPO • In p-ANCA reactivity • MPO is responsible for ~10% of such reactivity • Other antigens include • elastase, azurocidin, cathepsin G lysozyme, lactoferrin • antinuclear antibodies (ANA) can also have p-anca patterns

  7. ANCA Testing • International Consensus Statement for Testing and Reporting ANCA recommends • all sera are screened for ANCA by IIF • IIF-positivity is confirmed by direct ELISAs • Some laboratories test by direct ELISA alone • Others screen with direct ELISA and confirm positive sera by IIF • A few use capture (“sandwich”) ELISAs

  8. Problems in ANCA Testing • Diversity of antineutrophil cytoplasmic antibody target antigens • Assay standardization and performance • Application of antineutrophil cytoplasmic antibody testing in a clinical setting with a low pretest probability • The widespread assumption that antineutrophil cytoplasmic antibody titers alone may closely reflect disease activity and therefore may be used to guide therapy

  9. ANCA Frequencies in Vasculitis Hagen EC, et al: Kidney Int 53(3):743–753, 1998.

  10. ANCA in Other Diseases • Connective tissue diseases: • SLE, rheumatoid arthritis, myositis • Infections: • Endocarditis, HIV • Inflammatory bowel disease: • Ulcerative colitis > Crohn’s disease • Other autoimmune GI diseases • Sclerosing cholangitis, autoimmune hepatitis • Drug-induced ANCA: • Hydralazine, propylthiouracil, D-penicillamine and minocycline

  11. Schematic concept of proinflammatory effects of ANCA leading to vasculitis

  12. ANCA and Disease Activity • Pooled analysis studies by Davenport in Am J Nephrol 15(3):201–207, 1995 • 48% of rises followed by relapse • 51% of relapses preceded by rise • 100 patients followed serially for 2 years by Boomsma: Arthritis Rheum 43(9):2025–2033, 2000 • 92% of flares associated with rises in ANCA • Predictive value higher with ELISA than with IIF • Greatest utility when tests are negative

  13. Wegener’s Granulomatosis: History • WG is a granulomatous necrotizing vasculitis characterized by its predilection to affect the upper and lower respiratory tracts and the kidneys • First described in 1931 by Heinz Klinger, a German medical student • In 1936 and 1939, Dr. Friedrich Wegener provided detailed information about three patients with a similar illness • Remained relatively unknown in the American literature until the 1950s, when Godman and Churg published a detailed description of the disorder

  14. WG: Epidemiology • WG affects both sexes equally • Occurs in patients of all ages (mean age 41 years; range 9 to 78 years) • More commonly seen in Caucasian patients (97%) • Period prevalence of WG (1986-1990) was estimated to approximate 3 per 100,000 persons • It is likely that the prevalence of WG has been underestimated • Only since the early 90's has the existence of mild and more indolent forms of disease has been recognized

  15. WG: Clinical Features • Classic Triad: • Upper airway • Lower respiratory tract • Kidneys • Limited WG • Relatively mild and indolent without renal involvement

  16. WG: Upper Airway • Upper airway disease is the most common presenting feature • 70 percent of patients at onset • Develops in more than 90 percent of cases • Otologic manifestations • initial presentation in about 25 percent • 60 percent of cases during the course of disease • Serous otitis media is the most common ear problem encountered (25 to 44%) • Nasal disease • is a prominent presenting feature of WG in about one third of cases • eventually develops in 64 to 80%

  17. WG: Upper Airway • Sinusitis • Initial presentation in about one half to two thirds of patients with WG • 85 percent of cases during the entire course of disease • Laryngotracheal disease • asymptomatic • subtle hoarseness • stridor and life-threatening upper airway obstruction • The most characteristic lesion is that of subglottic stenosis (SGS), which occurs in up to 16 percent of patients • In pediatric and adolescent patients SGS is dramatically increased, reaching an alarming 48 percent prevalence

  18. WG: Pulmonary Manifestations • Pulmonary manifestations occur in • 45 percent of cases at presentation • 87 percent during the course of disease • Cough, hemoptysis, and pleuritis are the most common pulmonary symptoms • ~ 1/3 with radiographically demonstrable pulmonary lesions may not have lower airway symptoms • The most common radiologic findings include • pulmonary infiltrates (67%) • nodules (58%) • The pulmonary infiltrates in WG may be quite fleeting, appearing and resolving in some cases even before the institution of therapy

  19. WG: Pulmonary Manifestations • Persistent diffuse interstitial infiltrates are rare (less than 1%) and should suggest other diagnoses • Pulmonary nodules in WG are usually multiple, bilateral, and often cavitate (50%) • CT of the chest may reveal infiltrates and nodules that were undetected by conventional radiographs in 43 to 63 percent of cases • Less common pulmonary manifestations of WG include pleural effusions, diffuse pulmonary hemorrhage, and mediastinal or hilar lymph node enlargement or mass • Diffuse pulmonary hemorrhage has been reported in up to 8 percent of cases, and it carries a high fatality rate (50%)

  20. WG: Renal manifestations • Presence or absence of renal disease defines the subsets of generalized and limited WG • Frequency of renal involvement in WG is difficult to ascertain • Limited WG may go undiagnosed in patients with mild disease • By excluding such patients, published series may overestimate the frequency of renal disease in WG • Early renal disease may be clinically silent • Patients who appear to have limited WG at one time may later develop glomerulonephritis • Monitoring of renal status in all patients is important

  21. WG: Renal manifestations • Renal disease is estimated to occur in • 11 to 18% at presentation • 77 to 85% during the course of disease • Extrarenal manifestations often precede renal disease • Renal disease may progress to fulminant glomerulonephritis within days or weeks, resulting in end-stage renal failure • Untreated, mean survival time for this subset is about 5 months • Initial and recurrent renal damage may lead to chronic renal insufficiency in up to 42 percent of patients • dialysis (11%) • renal transplantation (5%)

  22. Early Segmental Fibrinoid Necrosis and Infiltration by Neutrophils in an ANCA Positive Patient with WG

  23. WG: Ocular Manifestations • Reported to occur in 28 to 58 percent of patients with WG and may be part of the initial presentation in 8 to 16 percent of cases • Any compartment of the eye may be affected • Keratitis, conjunctivitis, scleritis, episcleritis, nasolacrimal duct obstruction, uveitis, retroorbital pseudotumor with proptosis, retinal vessel occlusion, and optic neuritis have all been described • Most ocular findings are nonspecific • proptosis is a diagnostically helpful finding • poor prognostic sign for vision

  24. WG: Cutaneous Manifestations • Reported in 40 to 50 percent of patients with WG and may be part of the initial presentation in 13 to 25 percent of cases • The cutaneous manifestations of WG have included • ulcers, palpable purpura, subcutaneous nodules, papules, and vesicles • Cutaneous lesions tend to parallel disease activity in other organs • The presence of active skin lesions is a reliable clinical marker for active systemic disease

  25. WG: Joint Disease • Arthritis is observed in up to 28 percent of patients • several patterns can be observed, including monoarticular disease, migratory oligoarthritis, and symmetric or asymmetric polyarthritis of small and large joints. • Symmetric polyarthritis of small and large joints may be mistaken for RA • A positive test for rheumatoid factor (RF) may be observed in as many as 50 to 60 percent of cases • In contrast to RA, the symmetric polyarthritis of WG is generally nonerosive and nondeforming

  26. WG: Neurologic • Rarely a presenting feature of WG, may develop during the course of disease in 22-50% • Multiple neurologic complications may occur in up to 11 percent of patients • Peripheral neuropathy is the most common single neurologic manifestation (10 to 16%) • Mononeuritis multiplex (12 to 15%) • Distal and symmetric polyneuropathy (2%) • Cranial neuropathy occurs in 6 to 9% • Cerebrovascular events (4%) • cerebral or brain stem infarction, subdural hematoma, and subarachnoid hemorrhage • Diffuse meningeal and periventricular white matter disease has been reported

  27. WG: Other Manifestations • Gastrointestinal: • Abdominal pain, diarrhea, and bleeding are the most frequently reported symptoms • Relate to the presence of ulcerations in the bowel • Perforation may occur • Genitourinary • Case-reports of bladder wall, prostate involvement • Hemorrhagic cystitis – complication of cyclophosphamide • Cardiac • Pericarditis • Myocarditis • Arteritis

  28. WG: Diagnosis • Non-specific abnormalities • Leucocytosis, thrombocytosis, high ESR, anemia • Organ specific • Urinalysis, sediment, creatinine • The sensitivity of PR3-ANCA is about 90 percent in active WG and 40 percent when disease is in remission • The specificity of PR3-ANCA in the diagnosis of WG exceeds 95 percent • In general, the presence of high-titer ANCA by IFA combined with confirmatory antigen-specific assay for either PR3 or MPO in the setting of a high index of suspicion for vasculitis (i.e., high pretest probability) is sufficient for diagnosis, even in the absence of tissue confirmation

  29. Positive Predictive Value of ANCA 1 2 100 3 4 1. Documented WG 2. Pulmonary-Renal Syndrome 3. Systemic Necrotizing Vasculitis 4. Rapidly Progressive GN 5. GN 6. Hospitalized Patient 5 50 Positive Predictive Value 0 50 100 6 Disease Prevalence Jennette. Amer J Kidney Dis 18:164, 1991

  30. Diagnostic Yield of Biopsy in WG • Inflammatory lesions in WG • Necrosis • Granulomatous changes • Vasculitis • Diagnostic yield of a biopsy • Nasal, paranasal sinus biopsies • Small amount of tissue available in may make it difficult to identify all of the pathologic features • Complete diagnostic triad is only seen in 3 to 16% • Lung • Transbronchial biopsies are rarely diagnostic (less than 7%) • Open lung biopsies reveal various combinations of vasculitis, granulomas, and necrosis in 90% • Kidney • Focal and segmental GN • True vasculitis of medium-sized renal arteries is only occasionally noted (3 to 15%), and granulomatous changes are equally rare (3%) • The results of kidney biopsies usually not diagnostic of WG

  31. Wegener’s granulomatosis: lung (photomicrographs)

  32. WG: Principles of Treatment • General: • Rapid diagnosis, assessment of extent of disease activity • Untreated – high mortality • Pharmacotherapy • Induction of remission • Prevention of relapse • Management of drug-toxicity

  33. WG: Induction of Remission • Glucocorticoids (GC) • Pulse therapy for life threatening disease • 1g Solu-Medrol daily for 3 days • High dose steroid treatment 1mg/Kg daily • Taper after 1 month • For classic WG (with renal involvement) • Begin concurrent daily oral cyclophosphamide (CTX) 2mg/Kg/day • Pulse cyclophosphamide has been studied but not currently recommended • Consider methotrexate for less severe or limited disease

  34. WG: NIH experienceHoffman GS, et al: Ann Intern Med 116(6):488–498, 1992. • 158 patients with WG followed at the NIH for up to 24 years (mean follow-up period of 8 years) • 84% received "standard" therapy with daily CTX and GC • Marked improvement in 91% • Complete remission in 75% • Disease relapse was seen in 50% • permanent morbidity from disease occurring in 86% • chronic renal insufficiency (42%) • hearing loss (35%) • nasal deformities (28%) • tracheal stenosis (13%) • visual loss (8%) • Permanent morbidity as a result of treatment with GC and CTX occurred in 42% • 46% experienced serious infectious episodes

  35. Summary of Cyclophosphamide • Cyclophosphamide induces remission, but • Relapses are common, and • Cyclophosphamide causes toxicity

  36. WG: Efforts to find less toxic alternatives to cyclophosphamide • NIH open label study (Sneller MC, et al Arthritis Rheum 38(5):608–613, 1995) • open-label study of weekly low-dose MTX plus GC in 42 patients with biopsy-proven WG • Patients with life-threatening disease excluded • serum creatinine above 2.5 mg/dl or acute pulmonary hemorrhage • 50 percent had active glomerulonephritis • remission in 71% after a median of 4.2 months • relapses occurred in 36% after a median of 29 months • Toxicity: PCP in 4 with 2 deaths

  37. WG: Efforts to find less toxic alternatives to cyclophosphamide • EUVAS trial of MTX vs CYC (de Groot, et al Arthritis Rheum; 52:2461–9, 2005) in ANCA associated vasculitis • 94% had WG • Patients with life-threatening disease excluded • serum creatinine above 2.5 mg/dl or acute pulmonary hemorrhage • 30% had active glomerulonephritis • At 6 months, the remission rate with MTX (89.8%) was not inferior to CYC (93.5%) • Relapse rates at 18 months were 69.5% in the MTX group and 46.5% in the CYC group

  38. Summary of Methotrexate as an alternative to Cyclophosphamide for induction • MTX, given at a dosage of 20–25 mg per week in combination with glucocorticoids, has emerged as the standard remission induction regimen for WG in patients whose disease is classified as “limited,” “early systemic,” or “non–life or organ threatening.” • However relapse remains a problem

  39. WG: Maintaining remission • Options • Continue cyclophosphamide for 12 months after remission is achieved • Switch to methotrexate or azathioprine as soon as remission is achieved (usually 3-6 months) • Methotrexate to maintain remission • De Groot, et al. Arthritis Rheum 1996; 39:2052 • Langford, et al. Arthritis Rheum 1999; 42:2666 • Azathioprine to maintain remission • Jayne et al.. N Engl J Med 2003; 349:36

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