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