ANCA – Associated VasculitisANCA – Associated Vasculitis
The Discovery of Anti-Neutrophil The Discovery of Anti-Neutrophil Cytoplasmic Antibodies (ANCA)Cytoplasmic Antibodies (ANCA)
First described in 1982 by Davies in 8 patients with First described in 1982 by Davies in 8 patients with necrotizing pauci-immune glomerulonephritisnecrotizing pauci-immune glomerulonephritis11
Hall and colleagues identified ANCA in four patients with Hall and colleagues identified ANCA in four patients with systemic vasculitissystemic vasculitis22
In 1985, Van der Woude suggested an association In 1985, Van der Woude suggested an association between ANCA and Wegener’s granulomatosisbetween ANCA and Wegener’s granulomatosis33
ANCA subsequently reported in microscopic polyangiitis ANCA subsequently reported in microscopic polyangiitis and in Churg Strauss syndromeand in Churg Strauss syndrome44
1. Davies DJ, et al: Br Med J 285:606, 19821. Davies DJ, et al: Br Med J 285:606, 1982
2. Hall JB, et al: Aust NZ J Med 14:277, 1984 2. Hall JB, et al: Aust NZ J Med 14:277, 1984
3. van der Woude FJ, et al: Lancet 1:425, 19853. van der Woude FJ, et al: Lancet 1:425, 1985
4. Jennette CJ, Falk R: New Eng J Med 337:1512, 1997 4. Jennette CJ, Falk R: New Eng J Med 337:1512, 1997
ANCA-Associated Vasculitis
Shared Features of ANCA-Associated Shared Features of ANCA-Associated VasculitidesVasculitides
Wegener's granulomatosis (WG), microscopic Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), and Churg Strauss syndrome (CSS)polyangiitis (MPA), and Churg Strauss syndrome (CSS)
Can be considered together in view of a number of Can be considered together in view of a number of shared pathologic, clinical, and laboratory featuresshared pathologic, clinical, and laboratory features
Preferentially involve Preferentially involve small vesselssmall vessels (arterioles, capillaries, (arterioles, capillaries, venules)venules)
Similar glomerular lesionsSimilar glomerular lesions (crescents, focal necrosis, pauci- (crescents, focal necrosis, pauci-immune)immune)
Propensity to present as Propensity to present as lung-renal syndromeslung-renal syndromes Varying prevalence of ANCA positivityVarying prevalence of ANCA positivity
Detection of ANCADetection of ANCA
ANCAs were originally described based on their ANCAs were originally described based on their immunofluorescence patternsimmunofluorescence patterns
cytoplasmic (c-ANCA) and perinuclear (p-ANCA)cytoplasmic (c-ANCA) and perinuclear (p-ANCA)
The antigens responsible for these patterns have also The antigens responsible for these patterns have also been identifiedbeen identified
proteinase 3 (PR3) for c-ANCA proteinase 3 (PR3) for c-ANCA myeloperoxidase (MPO) for p-ANCAmyeloperoxidase (MPO) for p-ANCA
Immunofluorescence and Antigenic Immunofluorescence and Antigenic SpecificitySpecificity
In c-ANCA reactivityIn c-ANCA reactivity PR3 is responsible for more than 90% of such reactionsPR3 is responsible for more than 90% of such reactions Other antigens may occasionally contributeOther antigens may occasionally contribute
• bactericidal permeability-inducing protein (BPI)bactericidal permeability-inducing protein (BPI)
• rarely MPOrarely MPO
In p-ANCA reactivityIn p-ANCA reactivity MPO is responsible for ~10% of such reactivityMPO is responsible for ~10% of such reactivity Other antigens includeOther antigens include
• elastase, azurocidin, cathepsin G lysozyme, lactoferrinelastase, azurocidin, cathepsin G lysozyme, lactoferrin
• antinuclear antibodies (ANA) can also have p-anca patternsantinuclear antibodies (ANA) can also have p-anca patterns
ANCA TestingANCA Testing
International Consensus Statement for Testing and International Consensus Statement for Testing and Reporting ANCA recommendsReporting ANCA recommends
all sera are screened for ANCA by IIF all sera are screened for ANCA by IIF IIF-positivity is confirmed by direct ELISAsIIF-positivity is confirmed by direct ELISAs
Some laboratories test by direct ELISA aloneSome laboratories test by direct ELISA alone Others screen with direct ELISA and confirm positive Others screen with direct ELISA and confirm positive
sera by IIFsera by IIF A few use capture (“sandwich”) ELISAsA few use capture (“sandwich”) ELISAs
Problems in ANCA TestingProblems in ANCA Testing
Diversity of antineutrophil cytoplasmic antibody target Diversity of antineutrophil cytoplasmic antibody target antigensantigens
Assay standardization and performanceAssay standardization and performance Application of antineutrophil cytoplasmic antibody testing Application of antineutrophil cytoplasmic antibody testing
in a clinical setting with a low pretest probabilityin a clinical setting with a low pretest probability The widespread assumption that antineutrophil The widespread assumption that antineutrophil
cytoplasmic antibody titers alone may closely reflect cytoplasmic antibody titers alone may closely reflect disease activity and therefore may be used to guide disease activity and therefore may be used to guide therapy therapy
ANCA Frequencies in VasculitisANCA Frequencies in Vasculitis
0
10
20
30
40
50
60
70
80
90
100
WG MPA iRPGN CSS
P-ANCA
C-ANCA
Hagen EC, et al: Kidney Int 53(3):743–753, 1998.Hagen EC, et al: Kidney Int 53(3):743–753, 1998.
ANCA in Other DiseasesANCA in Other Diseases
Connective tissue diseases:Connective tissue diseases: SLE, rheumatoid arthritis, myositisSLE, rheumatoid arthritis, myositis
Infections:Infections: Endocarditis, HIVEndocarditis, HIV
Inflammatory bowel disease:Inflammatory bowel disease: Ulcerative colitis > Crohn’s diseaseUlcerative colitis > Crohn’s disease
Other autoimmune GI diseasesOther autoimmune GI diseases Sclerosing cholangitis, autoimmune hepatitisSclerosing cholangitis, autoimmune hepatitis
Drug-induced ANCA:Drug-induced ANCA: Hydralazine, propylthiouracil, D-penicillamine and minocyclineHydralazine, propylthiouracil, D-penicillamine and minocycline
Schematic concept of proinflammatory Schematic concept of proinflammatory effects of ANCA leading to vasculitiseffects of ANCA leading to vasculitis
ANCA and Disease ActivityANCA and Disease Activity
Pooled analysis studies by Davenport in Am J Nephrol Pooled analysis studies by Davenport in Am J Nephrol 15(3):201–207, 1995 15(3):201–207, 1995
48% of rises followed by relapse48% of rises followed by relapse 51% of relapses preceded by rise51% of relapses preceded by rise
100 patients followed serially for 2 years by Boomsma: 100 patients followed serially for 2 years by Boomsma: Arthritis Rheum 43(9):2025–2033, 2000Arthritis Rheum 43(9):2025–2033, 2000
92% of flares associated with rises in ANCA92% of flares associated with rises in ANCA
Predictive value higher with ELISA than with IIFPredictive value higher with ELISA than with IIF Greatest utility when tests are negative Greatest utility when tests are negative
Wegener’s Granulomatosis: HistoryWegener’s Granulomatosis: History
WG is a granulomatous necrotizing vasculitis WG is a granulomatous necrotizing vasculitis characterized by its predilection to affect the upper and characterized by its predilection to affect the upper and lower respiratory tracts and the kidneyslower respiratory tracts and the kidneys
First described in 1931 by Heinz Klinger, a German First described in 1931 by Heinz Klinger, a German medical studentmedical student
In 1936 and 1939, Dr. Friedrich Wegener provided In 1936 and 1939, Dr. Friedrich Wegener provided detailed information about three patients with a similar detailed information about three patients with a similar illnessillness
Remained relatively unknown in the American literature Remained relatively unknown in the American literature until the 1950s, when Godman and Churg published a until the 1950s, when Godman and Churg published a detailed description of the disorderdetailed description of the disorder
WG: EpidemiologyWG: Epidemiology
WG affects both sexes equallyWG affects both sexes equally Occurs in patients of all ages (mean age 41 years; range Occurs in patients of all ages (mean age 41 years; range
9 to 78 years)9 to 78 years) More commonly seen in Caucasian patients (97%)More commonly seen in Caucasian patients (97%) Period prevalence of WG (1986-1990) was estimated to Period prevalence of WG (1986-1990) was estimated to
approximate 3 per 100,000 personsapproximate 3 per 100,000 persons It is likely that the prevalence of WG has been It is likely that the prevalence of WG has been
underestimatedunderestimated Only since the early 90's has the existence of mild and Only since the early 90's has the existence of mild and
more indolent forms of disease has been recognizedmore indolent forms of disease has been recognized
WG: Clinical FeaturesWG: Clinical Features
Classic Triad:Classic Triad: Upper airwayUpper airway Lower respiratory tractLower respiratory tract KidneysKidneys
Limited WGLimited WG Relatively mild and Relatively mild and
indolent without renal indolent without renal involvementinvolvement
WG: Upper AirwayWG: Upper Airway
Upper airway disease is the most common presenting Upper airway disease is the most common presenting featurefeature
70 percent of patients at onset 70 percent of patients at onset Develops in more than 90 percent of casesDevelops in more than 90 percent of cases
Otologic manifestations Otologic manifestations initial presentation in about 25 percent initial presentation in about 25 percent 60 percent of cases during the course of disease60 percent of cases during the course of disease Serous otitis media is the most common ear problem Serous otitis media is the most common ear problem
encountered (25 to 44%)encountered (25 to 44%) Nasal diseaseNasal disease
is a prominent presenting feature of WG in about one third of is a prominent presenting feature of WG in about one third of casescases
eventually develops in 64 to 80%eventually develops in 64 to 80%
WG: Upper AirwayWG: Upper Airway
SinusitisSinusitis Initial presentation in about one half to two thirds of patients with Initial presentation in about one half to two thirds of patients with
WG WG 85 percent of cases during the entire course of disease85 percent of cases during the entire course of disease
Laryngotracheal disease Laryngotracheal disease asymptomatic asymptomatic subtle hoarsenesssubtle hoarseness stridor and life-threatening upper airway obstructionstridor and life-threatening upper airway obstruction The most characteristic lesion is that of subglottic stenosis The most characteristic lesion is that of subglottic stenosis
(SGS), which occurs in up to 16 percent of patients(SGS), which occurs in up to 16 percent of patients
In pediatric and adolescent patients SGS is dramatically In pediatric and adolescent patients SGS is dramatically increased, reaching an alarming 48 percent prevalenceincreased, reaching an alarming 48 percent prevalence
WG: Pulmonary ManifestationsWG: Pulmonary Manifestations
Pulmonary manifestations occur in Pulmonary manifestations occur in 45 percent of cases at presentation45 percent of cases at presentation 87 percent during the course of disease87 percent during the course of disease
Cough, hemoptysis, and pleuritis are the most common pulmonary Cough, hemoptysis, and pleuritis are the most common pulmonary symptomssymptoms
~ 1/3 with radiographically demonstrable pulmonary lesions may not ~ 1/3 with radiographically demonstrable pulmonary lesions may not have lower airway symptomshave lower airway symptoms
The most common radiologic findings include The most common radiologic findings include pulmonary infiltrates (67%) pulmonary infiltrates (67%) nodules (58%)nodules (58%)
The pulmonary infiltrates in WG may be quite fleeting, appearing The pulmonary infiltrates in WG may be quite fleeting, appearing and resolving in some cases even before the institution of therapyand resolving in some cases even before the institution of therapy
WG: Pulmonary ManifestationsWG: Pulmonary Manifestations
Persistent diffuse interstitial infiltrates are rare (less than 1%) and Persistent diffuse interstitial infiltrates are rare (less than 1%) and should suggest other diagnosesshould suggest other diagnoses
Pulmonary nodules in WG are usually multiple, bilateral, and often Pulmonary nodules in WG are usually multiple, bilateral, and often cavitate (50%)cavitate (50%)
CT of the chest may reveal infiltrates and nodules that were CT of the chest may reveal infiltrates and nodules that were undetected by conventional radiographs in 43 to 63 percent of undetected by conventional radiographs in 43 to 63 percent of casescases
Less common pulmonary manifestations of WG include pleural Less common pulmonary manifestations of WG include pleural effusions, diffuse pulmonary hemorrhage, and mediastinal or hilar effusions, diffuse pulmonary hemorrhage, and mediastinal or hilar lymph node enlargement or masslymph node enlargement or mass
Diffuse pulmonary hemorrhage has been reported in up to 8 percent Diffuse pulmonary hemorrhage has been reported in up to 8 percent of cases, and it carries a high fatality rate (50%)of cases, and it carries a high fatality rate (50%)
WG: Renal manifestationsWG: Renal manifestations
Presence or absence of renal disease defines the Presence or absence of renal disease defines the subsets of generalized and limited WGsubsets of generalized and limited WG
Frequency of renal involvement in WG is difficult to Frequency of renal involvement in WG is difficult to ascertainascertain
Limited WG may go undiagnosed in patients with mild diseaseLimited WG may go undiagnosed in patients with mild disease By excluding such patients, published series may overestimate By excluding such patients, published series may overestimate
the frequency of renal disease in WGthe frequency of renal disease in WG
Early renal disease may be clinically silent Early renal disease may be clinically silent Patients who appear to have limited WG at one time may Patients who appear to have limited WG at one time may
later develop glomerulonephritislater develop glomerulonephritis Monitoring of renal status in all patients is importantMonitoring of renal status in all patients is important
WG: Renal manifestationsWG: Renal manifestations
Renal disease is estimated to occur inRenal disease is estimated to occur in 11 to 18% at presentation 11 to 18% at presentation 77 to 85% during the course of disease77 to 85% during the course of disease
Extrarenal manifestations often precede renal diseaseExtrarenal manifestations often precede renal disease Renal disease may progress to fulminant Renal disease may progress to fulminant
glomerulonephritis within days or weeks, resulting in glomerulonephritis within days or weeks, resulting in end-stage renal failureend-stage renal failure
Untreated, mean survival time for this subset is about 5 monthsUntreated, mean survival time for this subset is about 5 months Initial and recurrent renal damage may lead to chronic Initial and recurrent renal damage may lead to chronic
renal insufficiency in up to 42 percent of patientsrenal insufficiency in up to 42 percent of patients dialysis (11%)dialysis (11%) renal transplantation (5%)renal transplantation (5%)
Early Segmental Fibrinoid Necrosis and Infiltration by Early Segmental Fibrinoid Necrosis and Infiltration by Neutrophils in an ANCA Positive Patient with WG Neutrophils in an ANCA Positive Patient with WG
WG: Ocular ManifestationsWG: Ocular Manifestations
Reported to occur in 28 to 58 percent of patients with Reported to occur in 28 to 58 percent of patients with WG and may be part of the initial presentation in 8 to 16 WG and may be part of the initial presentation in 8 to 16 percent of casespercent of cases
Any compartment of the eye may be affectedAny compartment of the eye may be affected Keratitis, conjunctivitis, scleritis, episcleritis, nasolacrimal duct Keratitis, conjunctivitis, scleritis, episcleritis, nasolacrimal duct
obstruction, uveitis, retroorbital pseudotumor with proptosis, obstruction, uveitis, retroorbital pseudotumor with proptosis, retinal vessel occlusion, and optic neuritis have all been retinal vessel occlusion, and optic neuritis have all been describeddescribed
Most ocular findings are nonspecificMost ocular findings are nonspecific proptosis is a diagnostically helpful finding proptosis is a diagnostically helpful finding poor prognostic sign for visionpoor prognostic sign for vision
WG: Cutaneous ManifestationsWG: Cutaneous Manifestations
Reported in 40 to 50 percent of patients with WG and Reported in 40 to 50 percent of patients with WG and may be part of the initial presentation in 13 to 25 percent may be part of the initial presentation in 13 to 25 percent of casesof cases
The cutaneous manifestations of WG have includedThe cutaneous manifestations of WG have included ulcers, palpable purpura, subcutaneous nodules, papules, and ulcers, palpable purpura, subcutaneous nodules, papules, and
vesiclesvesicles
Cutaneous lesions tend to parallel disease activity in Cutaneous lesions tend to parallel disease activity in other organsother organs
The presence of active skin lesions is a reliable clinical The presence of active skin lesions is a reliable clinical marker for active systemic diseasemarker for active systemic disease
WG: Joint DiseaseWG: Joint Disease
Arthritis is observed in up to 28 percent of patientsArthritis is observed in up to 28 percent of patients several patterns can be observed, including monoarticular several patterns can be observed, including monoarticular
disease, migratory oligoarthritis, and symmetric or asymmetric disease, migratory oligoarthritis, and symmetric or asymmetric polyarthritis of small and large joints. polyarthritis of small and large joints.
Symmetric polyarthritis of small and large joints may be Symmetric polyarthritis of small and large joints may be mistaken for RAmistaken for RA
A positive test for rheumatoid factor (RF) may be A positive test for rheumatoid factor (RF) may be observed in as many as 50 to 60 percent of casesobserved in as many as 50 to 60 percent of cases
In contrast to RA, the symmetric polyarthritis of WG is In contrast to RA, the symmetric polyarthritis of WG is generally nonerosive and nondeforminggenerally nonerosive and nondeforming
WG: NeurologicWG: Neurologic
Rarely a presenting feature of WG, may develop during the course Rarely a presenting feature of WG, may develop during the course of disease in 22-50%of disease in 22-50%
Multiple neurologic complications may occur in up to 11 percent of Multiple neurologic complications may occur in up to 11 percent of patientspatients
Peripheral neuropathy is the most common single neurologic Peripheral neuropathy is the most common single neurologic manifestation (10 to 16%)manifestation (10 to 16%)
Mononeuritis multiplex (12 to 15%)Mononeuritis multiplex (12 to 15%) Distal and symmetric polyneuropathy (2%)Distal and symmetric polyneuropathy (2%)
Cranial neuropathy occurs in 6 to 9%Cranial neuropathy occurs in 6 to 9% Cerebrovascular events (4%)Cerebrovascular events (4%)
cerebral or brain stem infarction, subdural hematoma, and subarachnoid cerebral or brain stem infarction, subdural hematoma, and subarachnoid hemorrhagehemorrhage
Diffuse meningeal and periventricular white matter disease has Diffuse meningeal and periventricular white matter disease has been reportedbeen reported
WG: Other ManifestationsWG: Other Manifestations
Gastrointestinal:Gastrointestinal: Abdominal pain, diarrhea, and bleeding are the most frequently Abdominal pain, diarrhea, and bleeding are the most frequently
reported symptomsreported symptoms Relate to the presence of ulcerations in the bowelRelate to the presence of ulcerations in the bowel Perforation may occurPerforation may occur
GenitourinaryGenitourinary Case-reports of bladder wall, prostate involvementCase-reports of bladder wall, prostate involvement Hemorrhagic cystitis – complication of cyclophosphamideHemorrhagic cystitis – complication of cyclophosphamide
CardiacCardiac PericarditisPericarditis MyocarditisMyocarditis ArteritisArteritis
WG: DiagnosisWG: Diagnosis
Non-specific abnormalitiesNon-specific abnormalities Leucocytosis, thrombocytosis, high ESR, anemiaLeucocytosis, thrombocytosis, high ESR, anemia
Organ specificOrgan specific Urinalysis, sediment, creatinineUrinalysis, sediment, creatinine
The sensitivity of PR3-ANCA is about 90 percent in active WG and The sensitivity of PR3-ANCA is about 90 percent in active WG and 40 percent when disease is in remission40 percent when disease is in remission
The specificity of PR3-ANCA in the diagnosis of WG exceeds 95 The specificity of PR3-ANCA in the diagnosis of WG exceeds 95 percentpercent
In general, the presence of high-titer ANCA by IFA combined with In general, the presence of high-titer ANCA by IFA combined with confirmatory antigen-specific assay for either PR3 or MPO in the confirmatory antigen-specific assay for either PR3 or MPO in the setting of a high index of suspicion for vasculitis (i.e., high pretest setting of a high index of suspicion for vasculitis (i.e., high pretest probability) is sufficient for diagnosis, even in the absence of tissue probability) is sufficient for diagnosis, even in the absence of tissue confirmationconfirmation
Positive Predictive Value of ANCAPositive Predictive Value of ANCA
66
55
44 33 22 11
Posi
tive P
red
icti
ve V
alu
ePosi
tive P
red
icti
ve V
alu
e100100
00
5050
5050 100100Disease PrevalenceDisease Prevalence
1. Documented WG1. Documented WG2. Pulmonary-Renal Syndrome2. Pulmonary-Renal Syndrome3. Systemic Necrotizing Vasculitis3. Systemic Necrotizing Vasculitis4. Rapidly Progressive GN4. Rapidly Progressive GN5. GN5. GN6. Hospitalized Patient6. Hospitalized Patient
Jennette. Amer J Kidney Dis 18:164, 1991Jennette. Amer J Kidney Dis 18:164, 1991
Diagnostic Yield of Biopsy in WGDiagnostic Yield of Biopsy in WG Inflammatory lesions in WG Inflammatory lesions in WG
NecrosisNecrosis Granulomatous changesGranulomatous changes VasculitisVasculitis
Diagnostic yield of a biopsyDiagnostic yield of a biopsy Nasal, paranasal sinus biopsiesNasal, paranasal sinus biopsies
• Small amount of tissue available in may make it difficult to identify all of the Small amount of tissue available in may make it difficult to identify all of the pathologic featurespathologic features
• Complete diagnostic triad is only seen in 3 to 16%Complete diagnostic triad is only seen in 3 to 16% LungLung
• Transbronchial biopsies are rarely diagnostic (less than 7%)Transbronchial biopsies are rarely diagnostic (less than 7%)• Open lung biopsies reveal various combinations of vasculitis, granulomas, Open lung biopsies reveal various combinations of vasculitis, granulomas,
and necrosis in 90%and necrosis in 90% Kidney Kidney
• Focal and segmental GNFocal and segmental GN• True vasculitis of medium-sized renal arteries is only occasionally noted (3 True vasculitis of medium-sized renal arteries is only occasionally noted (3
to 15%), and granulomatous changes are equally rare (3%)to 15%), and granulomatous changes are equally rare (3%)• The results of kidney biopsies usually not diagnostic of WGThe results of kidney biopsies usually not diagnostic of WG
Wegener’s granulomatosis: Wegener’s granulomatosis: lung (photomicrographs)lung (photomicrographs)
WG: Principles of TreatmentWG: Principles of Treatment
General:General: Rapid diagnosis, assessment of extent of disease activityRapid diagnosis, assessment of extent of disease activity Untreated – high mortalityUntreated – high mortality
PharmacotherapyPharmacotherapy Induction of remissionInduction of remission Prevention of relapsePrevention of relapse Management of drug-toxicityManagement of drug-toxicity
WG: Induction of RemissionWG: Induction of Remission
Glucocorticoids (GC)Glucocorticoids (GC) Pulse therapy for life threatening diseasePulse therapy for life threatening disease
• 1g Solu-Medrol daily for 3 days1g Solu-Medrol daily for 3 days High dose steroid treatment 1mg/Kg dailyHigh dose steroid treatment 1mg/Kg daily Taper after 1 monthTaper after 1 month
For classic WG (with renal involvement)For classic WG (with renal involvement) Begin concurrent daily oral cyclophosphamide (CTX) Begin concurrent daily oral cyclophosphamide (CTX)
2mg/Kg/day2mg/Kg/day Pulse cyclophosphamide has been studied but not currently Pulse cyclophosphamide has been studied but not currently
recommendedrecommended Consider methotrexate for less severe or limited diseaseConsider methotrexate for less severe or limited disease
WG: NIH experienceWG: NIH experienceHoffman GS, et al: Ann Intern Med 116(6):488–498, 1992. Hoffman GS, et al: Ann Intern Med 116(6):488–498, 1992.
158 patients with WG followed at the NIH for up to 24 158 patients with WG followed at the NIH for up to 24 years (mean follow-up period of 8 years)years (mean follow-up period of 8 years)
84% received "standard" therapy with daily CTX and GC84% received "standard" therapy with daily CTX and GC Marked improvement in 91%Marked improvement in 91% Complete remission in 75%Complete remission in 75% Disease relapse was seen in 50% Disease relapse was seen in 50%
• permanent morbidity from disease occurring in 86%permanent morbidity from disease occurring in 86% chronic renal insufficiency (42%)chronic renal insufficiency (42%) hearing loss (35%)hearing loss (35%) nasal deformities (28%)nasal deformities (28%) tracheal stenosis (13%)tracheal stenosis (13%) visual loss (8%)visual loss (8%)
Permanent morbidity as a result of treatment with GC and CTX Permanent morbidity as a result of treatment with GC and CTX occurred in 42%occurred in 42%
46% experienced serious infectious episodes46% experienced serious infectious episodes
Summary of CyclophosphamideSummary of Cyclophosphamide
Cyclophosphamide induces remission, Cyclophosphamide induces remission, butbut Relapses are common, Relapses are common, andand Cyclophosphamide causes toxicityCyclophosphamide causes toxicity
WG: Efforts to find less toxic alternatives to WG: Efforts to find less toxic alternatives to cyclophosphamidecyclophosphamide
NIH open label study (Sneller MC, et al Arthritis Rheum NIH open label study (Sneller MC, et al Arthritis Rheum 38(5):608–613, 1995)38(5):608–613, 1995)
open-label study of weekly low-dose MTX plus GC in 42 patients open-label study of weekly low-dose MTX plus GC in 42 patients with biopsy-proven WGwith biopsy-proven WG
Patients with life-threatening disease excludedPatients with life-threatening disease excluded• serum creatinine above 2.5 mg/dl or acute pulmonary hemorrhageserum creatinine above 2.5 mg/dl or acute pulmonary hemorrhage
50 percent had active glomerulonephritis50 percent had active glomerulonephritis remission in 71% after a median of 4.2 monthsremission in 71% after a median of 4.2 months relapses occurred in 36% after a median of 29 monthsrelapses occurred in 36% after a median of 29 months Toxicity: PCP in 4 with 2 deathsToxicity: PCP in 4 with 2 deaths
WG: Efforts to find less toxic alternatives to WG: Efforts to find less toxic alternatives to cyclophosphamidecyclophosphamide
EUVAS trial of MTX vs CYC (de Groot, et al Arthritis EUVAS trial of MTX vs CYC (de Groot, et al Arthritis Rheum; 52:2461–9, 2005) in ANCA associated vasculitisRheum; 52:2461–9, 2005) in ANCA associated vasculitis
94% had WG94% had WG Patients with life-threatening disease excludedPatients with life-threatening disease excluded
• serum creatinine above 2.5 mg/dl or acute pulmonary hemorrhageserum creatinine above 2.5 mg/dl or acute pulmonary hemorrhage 30% had active glomerulonephritis30% had active glomerulonephritis At 6 months, the remission rate with MTX (89.8%) was not At 6 months, the remission rate with MTX (89.8%) was not
inferior to CYC (93.5%)inferior to CYC (93.5%) Relapse rates at 18 months were 69.5% in the MTX group and Relapse rates at 18 months were 69.5% in the MTX group and
46.5% in the CYC group46.5% in the CYC group
Summary of Methotrexate as an alternative Summary of Methotrexate as an alternative to Cyclophosphamide for inductionto Cyclophosphamide for induction
MTX, given at a dosage of 20–25 mg per week in MTX, given at a dosage of 20–25 mg per week in combination with glucocorticoids, has emerged as the combination with glucocorticoids, has emerged as the standard remission induction regimen for WG in patients standard remission induction regimen for WG in patients whose disease is classified as “limited,” “early systemic,” whose disease is classified as “limited,” “early systemic,” or “non–life or organ threatening.”or “non–life or organ threatening.”
However relapse remains a problemHowever relapse remains a problem
WG: Maintaining remissionWG: Maintaining remission
OptionsOptions Continue cyclophosphamide for 12 months after remission is Continue cyclophosphamide for 12 months after remission is
achievedachieved Switch to methotrexate or azathioprine as soon as remission is Switch to methotrexate or azathioprine as soon as remission is
achieved (usually 3-6 months)achieved (usually 3-6 months)
Methotrexate to maintain remissionMethotrexate to maintain remission De Groot, et al.De Groot, et al. Arthritis Rheum 1996; 39:2052 Arthritis Rheum 1996; 39:2052 Langford, et al. Arthritis Rheum 1999; 42:2666Langford, et al. Arthritis Rheum 1999; 42:2666
Azathioprine to maintain remissionAzathioprine to maintain remission Jayne et al.. N Engl J Med 2003; 349:36Jayne et al.. N Engl J Med 2003; 349:36
WG: New agentsWG: New agents
EtanerceptEtanercept WGET trial (N Engl J Med 2005;352:351-61)WGET trial (N Engl J Med 2005;352:351-61)
• Failed to show that etanercept was effective in maintaining Failed to show that etanercept was effective in maintaining remission (no difference when compared with control groups)remission (no difference when compared with control groups)
• 6 solid tumors versus none in controls6 solid tumors versus none in controls
RituximabRituximab 11 refractory patients all responded with remission and decrease 11 refractory patients all responded with remission and decrease
in ANCA titers (8/11 became ANCA negative)in ANCA titers (8/11 became ANCA negative)• Arthritis Rheum. 2005 Jan;52(1):262-8Arthritis Rheum. 2005 Jan;52(1):262-8
Microscopic Polyangiitis (MPA)Microscopic Polyangiitis (MPA)
MPA was first recognized as a distinct entity by Davson MPA was first recognized as a distinct entity by Davson and colleagues in 1948and colleagues in 1948
described as a subgroup of polyarteritis nodosa, distinguished described as a subgroup of polyarteritis nodosa, distinguished by the presence of segmental necrotizing glomerulonephritis.by the presence of segmental necrotizing glomerulonephritis.
The Chapel Hill International Consensus Criteria defined The Chapel Hill International Consensus Criteria defined MPA as MPA as
a necrotizing vasculitis (with few or no deposits) affecting small a necrotizing vasculitis (with few or no deposits) affecting small vessels (i.e., capillaries, venules, or arterioles)vessels (i.e., capillaries, venules, or arterioles)
It was noted that MPA is frequently associated with necrotizing It was noted that MPA is frequently associated with necrotizing glomerulonephritis and pulmonary capillaritisglomerulonephritis and pulmonary capillaritis
MPA: Clinical FeaturesMPA: Clinical Features
Clinical FeatureClinical Feature PercentagePercentage
Constitutional symptoms Constitutional symptoms 76-7976-79
FeverFever 50-7250-72
Renal DiseaseRenal Disease 100100
ArthralgiaArthralgia 28-6528-65
PurpuraPurpura 40-4440-44
Pulmonary DiseasePulmonary Disease 5050
Neurologic DiseaseNeurologic Disease 2828
ENTENT 3232
MPA: Renal DiseaseMPA: Renal Disease
100 % occurrence reflects ascertainment bias100 % occurrence reflects ascertainment bias The renal lesion of MPA is that of necrotizing The renal lesion of MPA is that of necrotizing
glomerulonephritisglomerulonephritis It is indistinguishable from the renal lesion of WGIt is indistinguishable from the renal lesion of WG
MPA: Pulmonary DiseaseMPA: Pulmonary Disease
Lung involvement is common in MPA and is present in more than Lung involvement is common in MPA and is present in more than half of reported cases in most serieshalf of reported cases in most series
Diffuse alveolar hemorrhage (DAH) is the most serious form of lung Diffuse alveolar hemorrhage (DAH) is the most serious form of lung involvement and has been reported in 12 to 29 percent of patients in involvement and has been reported in 12 to 29 percent of patients in several seriesseveral series
The clinical manifestations range from mild dyspnea and anemia The clinical manifestations range from mild dyspnea and anemia without any hemoptysis to massive hemorrhage and bleeding with without any hemoptysis to massive hemorrhage and bleeding with profound hypoxia with acute onset in most patientsprofound hypoxia with acute onset in most patients
The radiographic features of DAH are nonspecific, demonstrating The radiographic features of DAH are nonspecific, demonstrating patchy or diffuse alveolar infiltrationpatchy or diffuse alveolar infiltration
The characteristic histopathology of MPA is that of pulmonary The characteristic histopathology of MPA is that of pulmonary capillaritis capillaritis
MPA: DiagnosisMPA: Diagnosis
Problems in diagnosisProblems in diagnosis Variable clinical presentationVariable clinical presentation Histologic findings not specificHistologic findings not specific Imperfect association with p-ANCA (anti-MPO)Imperfect association with p-ANCA (anti-MPO) c-ANCA (anti-PR3) can be positive in MPAc-ANCA (anti-PR3) can be positive in MPA Differentiation from WG may at times be difficultDifferentiation from WG may at times be difficult
• granulomas are not always found in WGgranulomas are not always found in WG
• Prominent involvement of the upper respiratory tract or the presence Prominent involvement of the upper respiratory tract or the presence of PR3-ANCA should seriously raise the possibility of WGof PR3-ANCA should seriously raise the possibility of WG
Churg Strauss Syndrome (CSS)Churg Strauss Syndrome (CSS)
The syndrome defined by Churg and Strauss in 1951 has The syndrome defined by Churg and Strauss in 1951 has undergone several redefinitions but is still characterized by undergone several redefinitions but is still characterized by three histopathologic features: three histopathologic features:
necrotizing vasculitisnecrotizing vasculitis infiltration by eosinophilsinfiltration by eosinophils extravascular granulomasextravascular granulomas
The 1994, Chapel Hill classification defined the disease as The 1994, Chapel Hill classification defined the disease as an eosinophil-rich and granulomatous inflammation involving the an eosinophil-rich and granulomatous inflammation involving the
respiratory tract respiratory tract necrotizing vasculitis involving the medium-sized vesselsnecrotizing vasculitis involving the medium-sized vessels associated with asthma and eosinophiliaassociated with asthma and eosinophilia
Churg-Strauss syndrome: Churg-Strauss syndrome: bowel (photomicrograph)bowel (photomicrograph)
CSS: Clinical FeaturesCSS: Clinical Features
CSS is characterized by three distinct phasesCSS is characterized by three distinct phases Prodrome, dominated by allergic features, is common in patients Prodrome, dominated by allergic features, is common in patients
ultimately diagnosed with CSSultimately diagnosed with CSS Allergic rhinitis and asthma may often precede diagnosis of Allergic rhinitis and asthma may often precede diagnosis of
vasculitis by 3 to 7 years vasculitis by 3 to 7 years Systemic vasculitisSystemic vasculitis
CSS: Organ InvolvementCSS: Organ Involvement
Pulmonary DiseasePulmonary Disease Pulmonary infiltratesPulmonary infiltrates Pleural effusions (often eosinophilic)Pleural effusions (often eosinophilic) Pulmonary hemorrhage Pulmonary hemorrhage
Nervous System InvolvementNervous System Involvement Peripheral neurologic involvement often dominates the clinical picture Peripheral neurologic involvement often dominates the clinical picture
and has been reported in the majority of patientsand has been reported in the majority of patients Renal DiseaseRenal Disease
Kidney involvement is less common in CSS than MPA or WGKidney involvement is less common in CSS than MPA or WG Skin involvement Skin involvement
has often led to confusion, for the term has often led to confusion, for the term Churg-Strauss granulomaChurg-Strauss granuloma may may be seen in other disordersbe seen in other disorders
Palpable purpura has been observed in nearly 50 percent of CSS Palpable purpura has been observed in nearly 50 percent of CSS patientspatients
Diagnostic Approach to Small Vessel VasculitisDiagnostic Approach to Small Vessel Vasculitis
Vasculitis suspected (lung-renal Vasculitis suspected (lung-renal syndrome, purpura, neuropathy)syndrome, purpura, neuropathy)
ANCA associatedANCA associated Not ANCA associatedNot ANCA associated
GranulomatousGranulomatous
YesYes NoNo
WGWG
YesYes NoNo
Asthma/eosinophiliaAsthma/eosinophilia
CSSCSS
IgA depositIgA deposit
YesYes NoNo
MPAMPA HSPHSP CryoglobulinsCryoglobulins
YesYes NoNo
CryoglobulinemiaCryoglobulinemia OtherOther
SummarySummary
ANCA-associated vasculitides are still rare but life-ANCA-associated vasculitides are still rare but life-threatening disordersthreatening disorders
ANCA testing is yet to fully standardizedANCA testing is yet to fully standardized ANCA-associated vasculitides may present with lung-ANCA-associated vasculitides may present with lung-
renal syndromes often with neurologic, ocular or renal syndromes often with neurologic, ocular or cutaneous manifestationscutaneous manifestations
MPA and WG may be hard to separate when the clinical MPA and WG may be hard to separate when the clinical presentation is incompletepresentation is incomplete
CSS appears to be a more distinctive disorderCSS appears to be a more distinctive disorder The treatment approach is similar and largely successfulThe treatment approach is similar and largely successful Relapse and long-term morbidity are still serious issuesRelapse and long-term morbidity are still serious issues