1. PRIMARY VASCULITIDES Amy Shultz, M.D.

2. VASCULITIS DEFINITION Presence of WBCs in vessel wall with reactive damage of mural structures Presence of WBCs in vessel wall with reactive damage of mural structures Leads to bleeding, tissue ischemia/necrosis Leads to bleeding, tissue ischemia/necrosis Primary—idiopathic Primary—idiopathic Secondary—to another underlying disease Secondary—to another underlying disease (SLE, RA, cryglobulinemia) (SLE, RA, cryglobulinemia)

3. HISTORY 1866: Kussmaul & Maier—described nodular inflammation of muscular arteries 1866: Kussmaul & Maier—described nodular inflammation of muscular arteries Termed periarteritis nodosa—later changed to polyarteritis nodosa (PAN) Termed periarteritis nodosa—later changed to polyarteritis nodosa (PAN)

4. PATHOGENESIS Remains largely unknown Remains largely unknown Hypothesis: ( Most likely multifactorial) Hypothesis: ( Most likely multifactorial) - Immune complex deposition/humoral responses - Immune complex deposition/humoral responses - Pathogenic T cell responses and granuloma formation - Autoantibodies - Cytokine activation - Infectious trigger—bacteria, mycobacteria, viruses - Drugs - Genetic predisposition

5. VASCULITIDES Fairly rare diseases Fairly rare diseases Presentation: highly variable making delays in diagnosis common Presentation: highly variable making delays in diagnosis common High morbidity and mortality High morbidity and mortality Therapeutic challenge often requiring prolonged & intensive immunosuppression. Therapeutic challenge often requiring prolonged & intensive immunosuppression.

6. CLASSIFICATION Individual diseases affect blood vessels of a particular size—clinical manifestations and wide range of disease severity. Individual diseases affect blood vessels of a particular size—clinical manifestations and wide range of disease severity. Large Vessel Vasculitis: Large Vessel Vasculitis: Takayasu arteritis Takayasu arteritis Giant cell arteritis Giant cell arteritis

7. CLASSIFICATION Medium vessel vasculitis: Medium vessel vasculitis: Polyarteritis nodosa Polyarteritis nodosa Kawasaki disease (children) Kawasaki disease (children) Small vessel vasculitis: Small vessel vasculitis: Churg-Strauss syndrome Churg-Strauss syndrome Wegener’s granulomatosis Wegener’s granulomatosis Microscopic polyangiitis Microscopic polyangiitis

8. TAKAYASU ARTERITIS (TA) Chronic granulomatous vasculitis that affects the aorta, its main branches, and pulmonary arteries Women affected in 80-90% of cases Age of onset: 10-40 years Worldwide distribution, but greatest prevalence in Asians. U.S. incidence rate: 2.6/million

9. TA (CLINICAL MANIFESTATIONS) Systemic symptoms:Early phase Systemic symptoms:Early phase Fatigue Fatigue Malaise Malaise Weight loss Weight loss Night sweats Night sweats Fever-low grade Fever-low grade Arthralgias~ 55% Arthralgias~ 55% Myalgias Myalgias

10. TA (CLINICAL MANIFESTATIONS) Vascular compromise: Late phase Vascular compromise: Late phase Aneurysm formation and rupture Aneurysm formation and rupture Vessel stenosis/occlusion--ischemia Vessel stenosis/occlusion--ischemia Catastrophic complications: Catastrophic complications: Aortic dissection/rupture Aortic dissection/rupture Aortic valve regurgitation Aortic valve regurgitation CVA CVA Hypertensive crisis Hypertensive crisis MI MI

11. ARTERY MANIFESTATION Subclavian Subclavian Common carotid Common carotid Renal Renal Aortic arch/root Aortic arch/root Vertebral Vertebral Pulmonary Pulmonary Coronary Coronary Arm claudication Visual changes, syncope, TIA, CVA, headaches HTN, renal failure AI, CHF Visual changes, dizziness Dyspnea, hemoptysis Chest pain, MI

12. TA (HISTOPATHOLOGY) Cell-mediated mechanisms: Cell-mediated mechanisms: Infiltrating cells mainly consist of killer cells and gamma delta T lymphocytes Infiltrating cells mainly consist of killer cells and gamma delta T lymphocytes All layers of large arteries affected: All layers of large arteries affected: Inflammation Inflammation Granuloma formation Granuloma formation Giant cells Giant cells

13. TA (PHYSICAL EXAMINATION) Asymmetric blood pressure measurements Asymmetric blood pressure measurements Diminished pulses/pulseless Diminished pulses/pulseless Bruits-subclavian, carotid, brachial, abd Bruits-subclavian, carotid, brachial, abd HTN- RAS or decreased elasticity of aorta HTN- RAS or decreased elasticity of aorta Decreased hair growth, cool extremities, muscle wasting, gangrenous digits Decreased hair growth, cool extremities, muscle wasting, gangrenous digits

14. TA (LAB ABNORMALITIES) Nonspecific: Nonspecific: Elevated ESR Elevated ESR Elevated CRP Elevated CRP Normochromic, normocytic anemia Normochromic, normocytic anemia Hypoalbuminemia Hypoalbuminemia Autoantibodies: Autoantibodies: Antiendothelial cell (recent studies value?) Antiendothelial cell (recent studies value?) ANA, ANCA, anti-DNA, APL: negative ANA, ANCA, anti-DNA, APL: negative

15. TA (IMAGING) Angiography usually necessary to confirm diagnosis and see extent of disease: Angiography usually necessary to confirm diagnosis and see extent of disease: Advantage: Provides clear outline of involved arteries & luminal patency Advantage: Provides clear outline of involved arteries & luminal patency Disadvantage: Does not show arterial thickening, invasive, & large dye load Disadvantage: Does not show arterial thickening, invasive, & large dye load Helical CT angiography and MRA Helical CT angiography and MRA Becoming more popular Becoming more popular Used to access continued disease activity Used to access continued disease activity Shows thickness and edema within wall Shows thickness and edema within wall

17. TA (CLASSIFICATION CRITERIA) Age of onset <40 Age of onset <40 Claudication of extremities Claudication of extremities Decreased pulsation in 1 or both brachials Decreased pulsation in 1 or both brachials >10mmHg SBP difference between arms >10mmHg SBP difference between arms Bruit over 1 or both subclavian or abd. Aorta Bruit over 1 or both subclavian or abd. Aorta Angiographic narrowing of aorta or branches Angiographic narrowing of aorta or branches Patients must meet at least 3 of the 6 criteria Patients must meet at least 3 of the 6 criteria

18. TA (TREATMENT) Corticosteroids: 60mg/day gradually tapered Corticosteroids: 60mg/day gradually tapered Cytotoxic drugs: Chronic active disease (50%) Cytotoxic drugs: Chronic active disease (50%) Methotrexate—17.5-25mg/week Methotrexate—17.5-25mg/week Azathioprine—2mg/kg/day Azathioprine—2mg/kg/day Anti-TNF agents: clinical trials ongoing Anti-TNF agents: clinical trials ongoing Revascularization: bypass grafts vs. PTCA Revascularization: bypass grafts vs. PTCA

19. GIANT CELL ARTERITIS (GCA) Granulomatous vasculitis affecting extra- cranial branches of arteries from the aortic arch Granulomatous vasculitis affecting extra- cranial branches of arteries from the aortic arch Most common systemic vasculitis: prevalence 200 per 100,000 Most common systemic vasculitis: prevalence 200 per 100,000 Occurs almost exclusively over 50 yrs of age Occurs almost exclusively over 50 yrs of age Female:male ratio 2:1 Female:male ratio 2:1

20. PATHOGENESIS Cell-mediated immune response against antigens in arterial wall. Cell-mediated immune response against antigens in arterial wall. Granulomatous inflammation Granulomatous inflammation T cells secreting IL-2 & interferon γ T cells secreting IL-2 & interferon γ Humoral response against antigens in the arterial wall. Humoral response against antigens in the arterial wall. Immunoglobulin and complement deposits. Immunoglobulin and complement deposits.

21. CLINICAL MANIFESTATIONS In most cases insidious onset of symptoms: In most cases insidious onset of symptoms: Fatigue Fatigue Fever Fever Weight loss Weight loss anorexia anorexia Headache most common symptom: lacinating localized to regions along arteries in the scalp. Headache most common symptom: lacinating localized to regions along arteries in the scalp.

22. GCA (CLINICAL MANIFESTATIONS) Headache Headache Weight loss/anorexia Weight loss/anorexia Jaw claudication Jaw claudication Fever Fever Malaise/fatigue Malaise/fatigue PMR PMR Transient visual symptom Transient visual symptom Synovitis Synovitis Fixed visual symptom Fixed visual symptom 68% 50% 45% 42% 40% 39% 16% 15% 14%

23. GCA (PE AND LAB) Physical exam: Nodularity, tenderness, absent pulsations, bruits of involved arteries Physical exam: Nodularity, tenderness, absent pulsations, bruits of involved arteries Fundoscopic examination in patients with visual loss: pale, swollen disc with blurred margins Fundoscopic examination in patients with visual loss: pale, swollen disc with blurred margins Lab: Markedly elevated ESR Lab: Markedly elevated ESR

27. GCA (DIAGNOSIS) Clinical Suspicion: Elderly patient with headache, visual symptoms, and high ESR Clinical Suspicion: Elderly patient with headache, visual symptoms, and high ESR Diagnosis confirmed by temporal artery biopsy: Diagnosis confirmed by temporal artery biopsy: Shows panmural mononuclear cell infiltration with granulomas and giant cells Shows panmural mononuclear cell infiltration with granulomas and giant cells Treatment should be instituted promptly while biopsy is arranged Treatment should be instituted promptly while biopsy is arranged

28. GCA (TREATMENT) Prednisone 40 to 60mg/day: initial dose Prednisone 40 to 60mg/day: initial dose In patients with acute visual loss: Solu- medrol 1g/day x 3 days In patients with acute visual loss: Solu- medrol 1g/day x 3 days Steroids can be tapered after clinical remission achieved: ESR and CRP normalized Steroids can be tapered after clinical remission achieved: ESR and CRP normalized Most patients off steroids by 2 years. Relapse rate 26-90% (highly variable). Most patients off steroids by 2 years. Relapse rate 26-90% (highly variable). Methotrexate studied in 2 RCT: conflicting results in ability to decrease relapse & steroid usage Methotrexate studied in 2 RCT: conflicting results in ability to decrease relapse & steroid usage

29. GCA ( Follow-up) Thoracic aortic aneurysms: Late manifestation Thoracic aortic aneurysms: Late manifestation GCA patients 17 times more likely than age and sex matched people to develop these GCA patients 17 times more likely than age and sex matched people to develop these Yearly chest x-rays are recommended for up to 10 years to identify patients with aneurysms prior to rupture. Yearly chest x-rays are recommended for up to 10 years to identify patients with aneurysms prior to rupture.

30. POLYARTERITIS NODOSA (PAN) Systemic panmural necrotizing vasculitis typically affecting small and medium-sized arteries—fibrinoid necrosis Systemic panmural necrotizing vasculitis typically affecting small and medium-sized arteries—fibrinoid necrosis Most cases are idiopathic Most cases are idiopathic 7 to 22% of cases associated with hepatitis B infection : must be r/o in all patients 7 to 22% of cases associated with hepatitis B infection : must be r/o in all patients Smaller percentage found in hairy cell leukemia, hepatitis C, and HIV Smaller percentage found in hairy cell leukemia, hepatitis C, and HIV Classical PAN: ANCA negative Classical PAN: ANCA negative

31. PAN EPIDEMIOLOGY Incidence: 0.7/100,000 Incidence: 0.7/100,000 Male:female ~ 2:1 Male:female ~ 2:1 Seen in all ages--peak 40-60 years of age Seen in all ages--peak 40-60 years of age May range in severity from mild limited to 1 organ system to fulminate multisystem involvement. May range in severity from mild limited to 1 organ system to fulminate multisystem involvement.

32. PAN (CLINICAL MANIFESTATIONS) Systemic symptoms: fatigue, weakness, fever, arthalgias, myalgias (60-70%) Systemic symptoms: fatigue, weakness, fever, arthalgias, myalgias (60-70%) PNS: Mononeuritis multiplex— motor & sensory deficits (50-70%) PNS: Mononeuritis multiplex— motor & sensory deficits (50-70%) Skin: livedo reticularis, digital necrosis, skin ulcers, bullous eruptions, nodules, palpable purpura (45-60%) Skin: livedo reticularis, digital necrosis, skin ulcers, bullous eruptions, nodules, palpable purpura (45-60%) Renal: Extra-glomerular vasculopathy mostly some GN—renal insufficiency, hypertension, and renal infarction (40-70%) Renal: Extra-glomerular vasculopathy mostly some GN—renal insufficiency, hypertension, and renal infarction (40-70%)

35. PAN (CLINICAL MANIFESTATIONS) GI: (30-50%) Mesenteric arteritis  ischemia  GI: (30-50%) Mesenteric arteritis  ischemia  Stomach Stomach Intestines Intestines Liver Liver Gallbladder Gallbladder Orchitis: rare seen more with HBV Orchitis: rare seen more with HBV Lab: non-specific (95%) Lab: non-specific (95%) ↑ESR Normochromic/normocytic anemia ↑ESR Normochromic/normocytic anemia Thrombocytosis↓albumin Thrombocytosis↓albumin

36. PAN (DIAGNOSIS) Visceral/renal angiography: microaneurysms, ectasia, stenoses in medium- sized vessels Visceral/renal angiography: microaneurysms, ectasia, stenoses in medium- sized vessels Biopsy: peripheral nerve or skin—focal segmental necrotizing vasculitis with mixed cell infiltrate and no granulomata affecting medium- sized arteries. Biopsy: peripheral nerve or skin—focal segmental necrotizing vasculitis with mixed cell infiltrate and no granulomata affecting medium- sized arteries.

40. PAN (PROGNOSIS) Untreated: 13% 5 year survival rate Untreated: 13% 5 year survival rate Main causes of death: renal failure, mesenteric, cardiac, cerebral infarction Main causes of death: renal failure, mesenteric, cardiac, cerebral infarction Five-factor score: French vasculitis group Five-factor score: French vasculitis group Proteinuria >1g/day Proteinuria >1g/day GI bleeding, perforation, infarct, pancreatitis GI bleeding, perforation, infarct, pancreatitis Renal insufficiency Renal insufficiency Cardiomyopathy Cardiomyopathy CNS involvement CNS involvement

41. PAN (TREATMENT) Prednisone 1mg/kg/day Cyclophosphamide 2mg/kg + steroids Azathioprine 2mg/kg + steroids Optimal duration of therapy is unknown. Relapse rate~40% If Hep B present, must treat.

42. ANCA-ASSOCIATED VASCULITIS Antineutrophilic cytoplasmic antibodies: Antineutrophilic cytoplasmic antibodies: C-ANCA (cytoplamic pattern) antigen— proteinase-3 C-ANCA (cytoplamic pattern) antigen— proteinase-3 P-ANCA (perinuclear pattern) antigen— myeloperoxidase P-ANCA (perinuclear pattern) antigen— myeloperoxidase Binding of C-ANCA & P-ANCA to their antigen targets in neutrophils →degranulation, respiratory burst, NO production, chemotaxis→contributes to vascular damage.

44. CHURG-STRAUSS SYNDROME Allergic granulomatosis & angiitis characterized by: Allergic granulomatosis & angiitis characterized by: Allergic rhinitis Allergic rhinitis Asthma Asthma Peripheral blood eosinophilia Peripheral blood eosinophilia Systemic vasculitis Systemic vasculitis Slight male predominance Slight male predominance Mean age at diagnosis: 40 years Mean age at diagnosis: 40 years

45. CHURG-STRAUSS (CLINICAL FEATURES) Prodromal phase: 2 nd to 3 rd decades of life —atopic disease, allergic rhinitis, asthma Prodromal phase: 2 nd to 3 rd decades of life —atopic disease, allergic rhinitis, asthma Eosinophilic phase: Peripheral blood eosinophilia and infiltration of multiple organs especially lungs and GI tract Eosinophilic phase: Peripheral blood eosinophilia and infiltration of multiple organs especially lungs and GI tract Vasculitic phase: 3 rd to 4 th decades of life—systemic vasculitis Vasculitic phase: 3 rd to 4 th decades of life—systemic vasculitis

46. CHURG-STRAUSS (CLINICAL FEATURES) Asthma—98-100% Asthma—98-100% Mononeuritis multiplex—50-80% Mononeuritis multiplex—50-80% Skin: palpable purpura, rash, tender subcutaneous nodules (50-80%) Skin: palpable purpura, rash, tender subcutaneous nodules (50-80%) Sinusitis —20-70% Sinusitis —20-70% CV—pericarditis, CHF, MI (35-50%) CV—pericarditis, CHF, MI (35-50%) GI—eosinophilic gastritis: pain, bleeding, colitis (30-60%) GI—eosinophilic gastritis: pain, bleeding, colitis (30-60%)

47. CHURG-STRAUSS (CLINICAL FEATURES) Renal—focal segmental GN (10-50%) less common than in WG or MPA Renal—focal segmental GN (10-50%) less common than in WG or MPA Pulmonary infiltrates-40-75% Pulmonary infiltrates-40-75% Transient patchy infiltrates Transient patchy infiltrates Pulmonary hemorrhage Pulmonary hemorrhage Bilateral, nodular disease without cavitation Bilateral, nodular disease without cavitation Pleural effusions: exudative & rich in eosinophils Pleural effusions: exudative & rich in eosinophils

49. CHURG-STRAUSS (LAB ABNORMALITIES) Peripheral eosinophilia >10% Peripheral eosinophilia >10% Elevated IgE levels Elevated IgE levels P-ANCA/anti-MPO—70% P-ANCA/anti-MPO—70% Elevated ESR Elevated ESR Normochromic/normocytic anemia Normochromic/normocytic anemia BAL—high percentage of eosinophils BAL—high percentage of eosinophils

50. CHURG-STRAUSS (DIAGNOSIS) Confirmed by surgical lung biopsy or biopsy of other affected tissues: Confirmed by surgical lung biopsy or biopsy of other affected tissues: Eosinophilic infiltrates Eosinophilic infiltrates Extensive areas of fibrinoid necrosis Extensive areas of fibrinoid necrosis Giant cell vasculitis of small arteries and veins Giant cell vasculitis of small arteries and veins Necrotizing granulomas Necrotizing granulomas

51. CHURG-STRAUSS (TREATMENT) Corticosteroids 1mg/kg/day until disease resolution. Corticosteroids 1mg/kg/day until disease resolution. Normalization of eosinophil count and ESR Normalization of eosinophil count and ESR Severe, fulminant disease— cyclophosphamide, azathioprine Severe, fulminant disease— cyclophosphamide, azathioprine Prior to use of steroids: uniformly fatal Prior to use of steroids: uniformly fatal 5 year survival—70% 5 year survival—70%

52. WEGENER’S GRANULOMATOSIS(WG) Necrotizing, granulomatous vasculitis affecting small & medium-sized vessels Necrotizing, granulomatous vasculitis affecting small & medium-sized vessels Predilection for upper & lower respiratory tracts & kidneys Predilection for upper & lower respiratory tracts & kidneys Occurs at any age peak 4 th to 5 th decades Occurs at any age peak 4 th to 5 th decades Men and women affected equally Men and women affected equally May be indolent or rapidly progressive May be indolent or rapidly progressive Upper airway disease most common presenting feature Upper airway disease most common presenting feature

53. WG (CLINICAL MANIFESTATIONS) Pulmonary: cough, pleuritis, hemoptysis, dyspnea (70-95%) Pulmonary: cough, pleuritis, hemoptysis, dyspnea (70-95%) Upper airway: nasal ulcers, epistaxis, sinusitis, otitis, hearing inpairment, destructive lesions/deformitities from cartilaginous ischemia (70-95%) Upper airway: nasal ulcers, epistaxis, sinusitis, otitis, hearing inpairment, destructive lesions/deformitities from cartilaginous ischemia (70-95%) Renal: FS crescentic GN with no immune complexes, ARF (50-85%) Renal: FS crescentic GN with no immune complexes, ARF (50-85%)

54. WG (CLINICAL MANIFESTATIONS) Tracheobronchial: subglottic stenosis, bronchial stenosis, hemorrhage (10-55%) Tracheobronchial: subglottic stenosis, bronchial stenosis, hemorrhage (10-55%) Skin: purpura, ulcers, vesicles (45-60%) Skin: purpura, ulcers, vesicles (45-60%) MS: arthalgias, myalgias, arthritis (30-70%) MS: arthalgias, myalgias, arthritis (30-70%) Ocular: conjunctivitis, uveitis, corneal ulcers, retinal vasculitis, proptosis (25-55%) Ocular: conjunctivitis, uveitis, corneal ulcers, retinal vasculitis, proptosis (25-55%)

57. WG ( RADIOGRAPHIC FINDINGS) Abnormal chest x-ray: 85-100% Abnormal chest x-ray: 85-100% Nodules Nodules Bilateral patchy infiltrates Bilateral patchy infiltrates Localized consolidations Localized consolidations Cavitary disease: culture to r/o fungal/mycobacteria Cavitary disease: culture to r/o fungal/mycobacteria Bilateral disease more common than unilateral Bilateral disease more common than unilateral CT of sinuses should be done to evaluate extent of disease CT of sinuses should be done to evaluate extent of disease

60. WG (LAB ABNORMALITIES) c-ANCA/anti-PR3: 85-90% active disease: usually parallels disease course c-ANCA/anti-PR3: 85-90% active disease: usually parallels disease course ESR: 90-95mm/h ESR: 90-95mm/h Elevated CRP Elevated CRP RF positive: 50-60% RF positive: 50-60% Microscopic hematuria, rbc casts, proteinuria Microscopic hematuria, rbc casts, proteinuria

61. WG (DIAGNOSIS) Confirmed by tissue biopsy at site of active disease Confirmed by tissue biopsy at site of active disease Small & medium vessel vasculitis Small & medium vessel vasculitis Necrotizing granulomata Necrotizing granulomata Inflammatory infiltrate Inflammatory infiltrate Special stains & cultures should be done to exclude infectious processes that produce granulomas Special stains & cultures should be done to exclude infectious processes that produce granulomas

62. WG (TREATMENT) Aggressive immunotherapy justified: untreated 90% of patients die in 2 years Aggressive immunotherapy justified: untreated 90% of patients die in 2 years Cyclophosphamide 2mg/kg/day + prednisone 1mg/kg/day Cyclophosphamide 2mg/kg/day + prednisone 1mg/kg/day Nonrandomized prospective studies with mean f/u 8 years: Nonrandomized prospective studies with mean f/u 8 years: Survival: 80% Survival: 80% Clinical improvement: 90% Clinical improvement: 90% Remission: 75% median time 12 months Remission: 75% median time 12 months

63. WG (TREATMENT) Once remission is induced, substitute less toxic agents for cyclophosphamide Once remission is induced, substitute less toxic agents for cyclophosphamide Toxicities: amenorrhea, infertility, cystitis, bladder ca, myelodysplasia, & lymphoma Toxicities: amenorrhea, infertility, cystitis, bladder ca, myelodysplasia, & lymphoma Maintenance agents: Maintenance agents: Methotrexate 20 to 25mg/week if Cr <2.0 Methotrexate 20 to 25mg/week if Cr <2.0 Azathioprine 2mg/kg/day Azathioprine 2mg/kg/day Reduce steroids Reduce steroids

64. MICROSCOPIC POLYANGIITIS Systemic, necrotizing vasculitis affecting venules, arterioles, & capillaries. No granulomas Systemic, necrotizing vasculitis affecting venules, arterioles, & capillaries. No granulomas Prodromal phase: weight loss, fatigue, fevers, arthalgias, myalgias, or hemoptysis Prodromal phase: weight loss, fatigue, fevers, arthalgias, myalgias, or hemoptysis 100% of patients get RPGN 100% of patients get RPGN p-ANCA/anti-MPO: 75% p-ANCA/anti-MPO: 75% Treatment: similar to Wegner’s Treatment: similar to Wegner’s

65. REFERENCES Frankel, SK. Vasculitis: Wegner’s Granulomatosis, Churg-Strauss Syndrome, Microscopic Polyangiitis, Polyarteritis Nodosa, and Takayasu arteritis. Critical Care Clinics. Oct. 2002. Vol. 18. Frankel, SK. Vasculitis: Wegner’s Granulomatosis, Churg-Strauss Syndrome, Microscopic Polyangiitis, Polyarteritis Nodosa, and Takayasu arteritis. Critical Care Clinics. Oct. 2002. Vol. 18. Langford, CA. Vasculitis. Journal of Allergy and Clinical Immunology. Feb. 2003 Vol. 111. Langford, CA. Vasculitis. Journal of Allergy and Clinical Immunology. Feb. 2003 Vol. 111. Rasmussen, JD. A Randomized Trial of Maintenance Therapy for Vasculitis Associated with Antineutrophil Cytoplasmic Autoantibodies. N Engl J MED 2003; 349-36. Rasmussen, JD. A Randomized Trial of Maintenance Therapy for Vasculitis Associated with Antineutrophil Cytoplasmic Autoantibodies. N Engl J MED 2003; 349-36.

66. REFERENCES Conn, DL. Polyarteritis. In: Rheumatology, Klipper, JH, Dieppe, PA, Mosby, St. Louis, 1994. Conn, DL. Polyarteritis. In: Rheumatology, Klipper, JH, Dieppe, PA, Mosby, St. Louis, 1994. D’Cruz, DP. Difficult Asthma or Churg-Strauss Syndrome? BMJ 1999; 318:475. D’Cruz, DP. Difficult Asthma or Churg-Strauss Syndrome? BMJ 1999; 318:475. Langford, CA. Chronic Immunosuppressive Therapy for Systemic Vasculitis. Curr Opin Rheumatol 1997; 9:41. Langford, CA. Chronic Immunosuppressive Therapy for Systemic Vasculitis. Curr Opin Rheumatol 1997; 9:41.