1. ANCA – Associated Vasculitis

3. 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

4. ANCA-Associated Vasculitis

5. 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

6. 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

9. 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

10. 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

11. 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

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

13. ANCA in Other Diseases Connective tissue diseases: Infections:
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

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

16. 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

17. 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

18. 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 ( ) 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

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

20. 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%

21. Wegener’s granulomatosis: face
This patient with Wegener’s granulomatosis developed a saddle nose deformity with destruction of the dorsal nasal cartilage. Other nasal complications in Wegener’s granulomatosis include perforated nasal septum, mucosal ulceration, epistaxis, and boggy nasal turbinates with purulent nasal discharge. #

22. WG: Upper Airway Sinusitis Laryngotracheal disease
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

25. 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

26. 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%)

28. Wegener’s granulomatosis: lungs (radiograph)
These chest radiographs show large cavitary lesions with air-fluid levels from a patient with Wegener’s granulomatosis. #

29. 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

30. 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%)

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

32. 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

34. 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

36. 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

37. 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

38. 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

39. WG: Diagnosis Non-specific abnormalities Organ specific
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

40. Positive Predictive Value of ANCA1
100 2 3 4
1. Documented WG
2. Pulmonary-Renal Syndrome
3. Systemic Necrotizing Vasculitis
4. Rapidly Progressive GN
5. GN
6. Hospitalized Patient 5
Positive Predictive Value 50 50
100 6
Disease Prevalence
Jennette. Amer J Kidney Dis 18:164, 1991

41. 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

42. Wegener’s granulomatosis: lung (photomicrographs)
Left, The pulmonary parenchyma has been entirely obliterated by a granulomatous inflammatory reaction bordering large necrotic areas. The necrotic areas stain darkly because they contain many fragmented pyknotic nuclei. The inflammatory cells in the lighter staining (viable) areas include several multinucleated giant cells. A large blood vessel forms the center of one necrotic focus. (hematoxylin-eosin; low power)
Right, A high-power view of an inflamed blood vessel reveals that most of the wall is necrotic and bordered by palisaded histiocytes. The surrounding tissue is intensely infiltrated by lymphocytes, histiocytes, and a few multinucleated giant cells resembling Langhans' cells. With this stain it is impossible to determine whether the vessel is an artery or a vein. (hematoxylin-eosin; high power) #

43. 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

44. 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

45. WG: NIH experience Hoffman 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

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

47. 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

48. 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

49. 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

50. 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

51. WG: New agents Etanercept Rituximab
WGET trial (N Engl J Med 2005;352:351-61)
Failed to show that etanercept was effective in maintaining remission (no difference when compared with control groups)
6 solid tumors versus none in controls
Rituximab
11 refractory patients all responded with remission and decrease in ANCA titers (8/11 became ANCA negative)
Arthritis Rheum Jan;52(1):262-8

52. Microscopic Polyangiitis (MPA)
MPA was first recognized as a distinct entity by Davson and colleagues in 1948
described as a subgroup of polyarteritis nodosa, distinguished by the presence of segmental necrotizing glomerulonephritis.
The Chapel Hill International Consensus Criteria defined MPA as
a necrotizing vasculitis (with few or no deposits) affecting small vessels (i.e., capillaries, venules, or arterioles)
It was noted that MPA is frequently associated with necrotizing glomerulonephritis and pulmonary capillaritis

53. MPA: Clinical Features
Percentage
Constitutional symptoms
76-79
Fever
50-72
Renal Disease
100
Arthralgia
28-65
Purpura
40-44
Pulmonary Disease 50
Neurologic Disease 28
ENT 32

54. MPA: Renal Disease 100 % occurrence reflects ascertainment bias
The renal lesion of MPA is that of necrotizing glomerulonephritis
It is indistinguishable from the renal lesion of WG

55. MPA: Pulmonary Disease
Lung involvement is common in MPA and is present in more than half of reported cases in most series
Diffuse alveolar hemorrhage (DAH) is the most serious form of lung involvement and has been reported in 12 to 29 percent of patients in several series
The clinical manifestations range from mild dyspnea and anemia without any hemoptysis to massive hemorrhage and bleeding with profound hypoxia with acute onset in most patients
The radiographic features of DAH are nonspecific, demonstrating patchy or diffuse alveolar infiltration
The characteristic histopathology of MPA is that of pulmonary capillaritis

56. MPA: Diagnosis Problems in diagnosis Variable clinical presentation
Histologic findings not specific
Imperfect association with p-ANCA (anti-MPO)
c-ANCA (anti-PR3) can be positive in MPA
Differentiation from WG may at times be difficult
granulomas are not always found in WG
Prominent involvement of the upper respiratory tract or the presence of PR3-ANCA should seriously raise the possibility of WG

57. Churg Strauss Syndrome (CSS)
The syndrome defined by Churg and Strauss in 1951 has undergone several redefinitions but is still characterized by three histopathologic features:
necrotizing vasculitis
infiltration by eosinophils
extravascular granulomas
The 1994, Chapel Hill classification defined the disease as
an eosinophil-rich and granulomatous inflammation involving the respiratory tract
necrotizing vasculitis involving the medium-sized vessels
associated with asthma and eosinophilia

58. Churg-Strauss syndrome: bowel (photomicrograph)
The biopsy of the bowel wall in a patient with with Churg-Strauss syndrome shows a blood vessel with subendothelial fibrin accumulation and non-necrotizing transmural inflammation with lymphocytes and polymorphonuclear leukocytes. Eosinophils and scattered multinucleated giant cells are also present. (hematoxylin-eosin; medium power) #

59. CSS: Clinical Features
CSS is characterized by three distinct phases
Prodrome, dominated by allergic features, is common in patients ultimately diagnosed with CSS
Allergic rhinitis and asthma may often precede diagnosis of vasculitis by 3 to 7 years
Systemic vasculitis

60. CSS: Organ Involvement
Pulmonary Disease
Pulmonary infiltrates
Pleural effusions (often eosinophilic)
Pulmonary hemorrhage
Nervous System Involvement
Peripheral neurologic involvement often dominates the clinical picture and has been reported in the majority of patients
Renal Disease
Kidney involvement is less common in CSS than MPA or WG
Skin involvement
has often led to confusion, for the term Churg-Strauss granuloma may be seen in other disorders
Palpable purpura has been observed in nearly 50 percent of CSS patients

61. Diagnostic Approach to Small Vessel Vasculitis
Vasculitis suspected (lung-renal syndrome, purpura, neuropathy)
ANCA associated
Not ANCA associated
Granulomatous
IgA deposit
Yes No
Yes No
Asthma/eosinophilia
MPA
HSP
Cryoglobulins
Yes No
Yes No
CSS WG
Cryoglobulinemia
Other

62. Summary
ANCA-associated vasculitides are still rare but life-threatening disorders
ANCA testing is yet to fully standardized
ANCA-associated vasculitides may present with lung-renal syndromes often with neurologic, ocular or cutaneous manifestations
MPA and WG may be hard to separate when the clinical presentation is incomplete
CSS appears to be a more distinctive disorder
The treatment approach is similar and largely successful
Relapse and long-term morbidity are still serious issues