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Vasculitis ANCA positivo
2015
Dr. Cristhian Mauricio Bueno Lara
Especialista en medicina interna – Universidad Autónoma de Bucaramanga
Fellow en Nefrología – Universidad del Valle
Conceptos
Comprenhensive Clinical Nephrology 4th Edition
11Para el
nefrólogo
1 2 3 4
5 6 7 8 9 10 11
91 caso por cada
1000 a 10000
habitantes/año
1
3 4 7 865 9
2
3Vasculitis ANCA
positivo 1 32
Conceptos
Síndrome riñón - Pulmón
Glomerulonefritis
rápidamente progresiva
Glomerulonefritis
pauciinmune
Vasculitis ANCA positivo
Glomerulonefritis rápidamente progresiva – Hemorragia
alveolar difusa
Disfunción renal en días/semanas
Proteinuria – Hematuria – Semilunas celulares
Presión arterial normal
Escasos depósitos de inmunoglobulinas o complemento en
glomérulo vasos renales
Poliangeítis granulomatosa
Poliangeítis microscópica
Poliangeítis granulomatosa eosinofílica
Stephen C West, Nishkantha Arulkumaran, Philip W Ind, Charles D Pusey. Pulmonary-renal syndrome: a life
threatening but treatable condition. Postgrad Med J 2013
Clasificación
American College of Rheumatology 1990
Clasificación
Chapel Hill Consensus Conference 1994
Clasificación
The European Medicines Agency 2008
Clasificación
Eoin F. McKinney & Lisa C. Willcocks & Verena Broecker. The immunopathology of ANCA-associated vasculitis. Semin
Immunopathol (2014) 36:461–478
99 Pacientes
ANCA positivo
Friedrich Wegener
• Nacimiento: 4 abril 1907, Noreste
de Alemania.
• Médico y asistente en patología
• Granulomatosis rinógena singular
• Retiro de la medicina en 1970 en
medio del reconocimiento.
• Muerte: 1990 a los 83 años.
• Título: Master Clinician of the
American College of Chest
Physician
Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener’s granulomatosis). Journal of
Autoimmunity 48-49 (2014) 94e98
• 50 a 100 autopsias en judíos al mes
• Año 2007: Destitución de titulo de
Master por ACCP
Jacob Churg – Lotte Strauss
• 1951: 13 necropsias
en pacientes con
asma y vasculitis
sistémica.
• Chumbley y Lanham
han cambiado los
criterios.
Diagnosis and classication of eosinophilic granulomatosis with polyangiitis (formerly named Churge Strauss syndrome)
Journal of Autoimmunity 48-49 (2014) 99e103
Clasificación
Chapel Hill Consensus Conference 2012
Clasificación
Chapel Hill Consensus Conference 2012
Vasculitis de pequeño vaso
2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Vol. 65, No. 1, January
2013, pp 1–11
Clasificación
Chapel Hill Consensus Conference 2012
Vasculitis ANCA positivo
2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Vol. 65, No. 1, January
2013, pp 1–11
Vasculitis necrotizante
Sin o muy poco depósitos inmunes
Afectación de pequeño vaso
Asociado a ANCA Mieloperoxidasa o Proteinasa 3
Poliangeítis microscópica
Glomerulonefritis necrotizante
Capilaritis pulmonar es frecuente
No inflamación granulomatosa
Poliangeítis granulomatosa
Inflamación granulomatosa necrotizante
Compromiso respiratorio alto o bajo
Glomerulonefritis necrotizante
Poliangeítis granulomatosa
eosinofílica
Inflamación granulomatosa necrotizante y rica en eosinófilos
Asociada a asma con eosinofilia
Afectación del tracto respiratorio
Epidemiología
Classification, epidemiology and clinical subgrouping
of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant (2015) 30: i14–i22
Por millón de habitantes
Epidemiología local
2015
85%
Hispanos
48%
Caucásicos
Fisiopatología
Diagnosis and classication of eosinophilic granulomatosis with polyangiitis (formerly named Churge Strauss syndrome)
Journal of Autoimmunity 48-49 (2014) 99e103
Fisiopatología
Comprenhensive Clinical Nephrology 4th Edition
Manifestaciones Clínicas
Comparison of disease activity measures for anti-neutrophil
cytoplasmic autoantibody (ANCA)-associated vasculitis
PA Merkel1, DD Cuthbertson2, B Hellmich3, GS Hoffman4, DRW Jayne5, CGM Kallenberg6,
JP Krischer2, R Luqmani7, AD Mahr8, EL Matteson9, U Specks9, and JH Stone10 for the
Vasculitis Clinical Research Consortium
1Boston University School of Medicine, Boston, Massachussets, USA 2University of South
Florida, Tampa, Florida, USA 3Kreiskrankenhaus Plochingen, Plochingen, Germany 4Cleveland
Clinic, Cleveland, Ohio, USA 5Addenbrookes Hospital, Cambridge, UK 6University Medical Center
Groningen, University of Groningen, Groningen, The Netherlands 7University of Oxford, Oxford,
UK 8Hospital Cochin, Paris, France 9Mayo Clinic, Rochester, Minnesota, USA 10Massachusetts
General Hospital, Boston, Massachussets, USA
Abstract
Aim—Currently, several different instruments are used to measure disease activity and extent in
clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading
to division among investigative groups and difficulty comparing study results. An exercise
comparing six different vasculitis instruments was performed.
Methods—A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in
the literature of Wegener granulomatosis or microscopic polyangiitis using 6 disease assessment
NIH Public Access
Author Manuscript
Ann Rheum Dis. Author manuscript; available in PMC 2011 July 19.
Published in final edited form as:
Ann Rheum Dis. 2009 January ; 68(1): 103–106. doi:10.1136/ard.2008.097758.
Comparison of disease activity measures for anti-neutrophil
cytoplasmic autoantibody (ANCA)-associated vasculitis
PA Merkel1, DD Cuthbertson2, B Hellmich3, GS Hoffman4, DRW Jayne5, CGM Kallenberg6,
JP Krischer2, R Luqmani7, AD Mahr8, EL Matteson9, U Specks9, and JH Stone10 for the
Vasculitis Clinical Research Consortium
1Boston University School of Medicine, Boston, Massachussets, USA 2University of South
Florida, Tampa, Florida, USA 3Kreiskrankenhaus Plochingen, Plochingen, Germany 4Cleveland
Clinic, Cleveland, Ohio, USA 5Addenbrookes Hospital, Cambridge, UK 6University Medical Center
Groningen, University of Groningen, Groningen, The Netherlands 7University of Oxford, Oxford,
UK 8Hospital Cochin, Paris, France 9Mayo Clinic, Rochester, Minnesota, USA 10Massachusetts
General Hospital, Boston, Massachussets, USA
Abstract
Aim—Currently, several different instruments are used to measure disease activity and extent in
clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading
to division among investigative groups and difficulty comparing study results. An exercise
comparing six different vasculitis instruments was performed.
Methods—A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in
NIH Public Access
Author Manuscript
Ann Rheum Dis. Author manuscript; available in PMC 2011 July 19.
Published in final edited form as:
Ann Rheum Dis. 2009 January ; 68(1): 103–106. doi:10.1136/ard.2008.097758.
2009
Poliangeítis microscópica
82% compromiso glomerular
Piel, Articulaciones y pulmonar
Poliangeítis granulomatosa
80% compromiso glomerular
90% compromiso pulmonar (Alto o bajo)
Poliangeítis granulomatosa
eosinofílica
50% frecuente compromiso glomerular
100% Asma
72% Sistema nervioso periférico
Manifestaciones Clínicas
Comprenhensive Clinical Nephrology 4th Edition
Diagnóstico
Estudio inicial
Exámenes iniciales
Hemograma tipo IV
Creatinina
Nitrógeno ureico en sangre
Uroanálisis
Anticuerpos antinucleares
Función hepática
Clínica ANCAs
Comprenhensive Clinical Nephrology 4th Edition
Diagnóstico
ANCA dirigido a auto-antígenos
Clinical features and diagnosis of small-vessel vasculitis. doi:10.3949/ccjm.79.s3.01
Mejor prueba para la evaluación de los ANCA
Valor pronóstico de los ANCA
Implicación clínica del tipo de ANCA
toemphasizethat t
usedintheselabora
whereIFTwithor w
A variety of dif
tionof ANCAshav
includingthird-ge
based multiplex a
for analysingANC
summarizesthem
methodologyand
testinginvasculitis
applyingthesetech
Automated ana
Despitetheemerge
IFTremainstherec
ingin vasculitis. H
dependsonanum
conjugatesandfixa
cells,storagecond
andwashing.7
Furt
consuming,requir
performance compared with conventional assays and can be used for PR3-ANCA
and MPO-ANCAdetection
The new methods for ANCAdetection and evaluation in ANCA-associated
vasculitis should be urgentlyevaluated in multicentre studies, in anticipation
of updating of standardization processes and a revision of existing strategies
a b
Figure 1 | ANCAIIFpattern differentiation byautomated signal intensityanalysis.
IIFimages, taken automatically byAKLIDES®, can discriminate a | P-ANCA-specific
and b | C-ANCA-specific staining of neutrophils byuse of mathematical algorithms
for pattern differentiation. Chromatin is stained byDAPI (blue) and specific ANCA
Diagnóstico
ANCA dirigido a auto-antígenos
Clinical features and diagnosis of small-vessel vasculitis. doi:10.3949/ccjm.79.s3.01
Mejor prueba para la evaluación de los ANCA
Inmunofluorescencia
Pruebas antígeno-
específicas
Diagnóstico
ANCA dirigido a auto-antígenos
Current and emerging techniques for ANCA detection in vasculitis Nat. Rev. Rheumatol. 10, 494–501 (2014)
rapidANCA testing.35
In thisassay,IFT iscombinedwitha
dot-blot test for PR3-ANCA and MPO-ANCA. However,
theresultsobtained areonly qualitativeand should be
confirmed and quantified by other ANCA assays.
patientswith suspected vasculitisneedstobeevaluated in
prospectivestudies.
Clinical usefulness of ANCA testing
Table 1 | Comparison of methods for testing for PR3-ANCA and MPO-ANCA in ANCA-associated vasculitis
Patient population
(n) vs comparison
group (n)
Method Sensitivity
(%)
Specificity
(%)
PPV
(%)
NPV
(%)
AUC/ ROC Comments
GPA (86) vs
non-vasculitic
disease (450)28
IFT
Direct PR3-ANCA ELISA
Capture ELISA
Anchor ELISA
92
60
72
96
99
99
99.3
98.5
Nd Nd 0.96 (0.94–0.98)
0.80 (0.76–0.83)
0.86 (0.82–0.89)
0.96 (0.94–0.98)
Histological
diagnosis
Retrospective
study
GPA (232) vs
in ammatory
diseases (661)29
IFT
Anchor ELISA
77.9
80.4
90.9
97.4
73
88
93
93
Nd Histological
diagnosis
Prospective
study
GPA (59* ) vs
in ammatory and
infectious diseases
(585)30
Hn–hr PR3-ANCA ELISA
Capture ELISA
Direct (hn) PR3-ANCA
94
66
64
99
(prede ned)
Nd Nd Nd Histological
diagnosis
Retrospective
study
GPA (34) vs SLE
(65)31
Direct PR3-ANCA
Anchor ELISA
97.1 98.4 Nd Nd 0.999
(0.947–1.00)
Clinical
diagnosis
Retrospective
study
GPA (40) vs RA
or SLE (20)32
IFT
Direct PR3-ANCA (n= 5 kits)
Capture ELISA (n=2 kits)
Anchor ELISA (n= 4 kits)
62.5
45–55
60–62.5
60–62.5
95–100 Nd Nd Nd Histological
diagnosis
Retrospective
study
MPA (40) vs RA
or SLE (20)32
IFT
Direct MPO-ANCA ELISA
(n= 8 kits)
Capture ELISA (n=2 kits)
Anchor ELISA (n= 1 kit)
82.5
62.5–85
80
75
95–100 Nd Nd Nd Histological
diagnosis
Retrospective
study
GPA (55) vs
suspected
vasculitis (175)33
IFT
Direct PR3-ANCA ELISA
(n= 2 kits)
Capture ELISA (n=2 kits)
Anchor ELISA (n= 3 kits)
Other assays (n=2)
69.1
61.8–72.7
70.9–72.7
61.8–72.7
72.7–74.5
100
95.4–96.4
95.9–99.5
98.5–99.0
95.9–97.9
Nd Nd Nd
0.856–0.879
0.862–0.878
0.833–0.881
0.878–0.902
Clinical
diagnosis
Retrospective
study
* 47 of 59 patients in the GPA group had a cytoplasmic ANCA pattern on IFT. Abbreviations: ANCA, antineutrophil cytoplasmic antibody; AUC, area under the
curve; GPA, granulomatosis with polyangiitis; hn, human native; hr, human recombinant; IFT, indirect immunofluorescence technique; MPA, microscopic
polyangiitis; MPO, myeloperoxidase; Nd, not determined; NPV, negative predictive value; PPV, positive predictive value; PR3, proteinase 3; RA, rheumatoid
arthritis; ROC, receiver operating characteristics; SLE, systemic lupus erythematosus.
REVIEWS
Diagnóstico
ANCA dirigido a auto-antígenos
Valor pronóstico de los ANCA
Comparison of disease activity measures for anti-neutrophil
cytoplasmic autoantibody (ANCA)-associated vasculitis
PA Merkel1, DD Cuthbertson2, B Hellmich3, GS Hoffman4, DRW Jayne5, CGM Kallenberg6,
JP Krischer2, R Luqmani7, AD Mahr8, EL Matteson9, U Specks9, and JH Stone10 for the
Vasculitis Clinical Research Consortium
1Boston University School of Medicine, Boston, Massachussets, USA 2University of South
Florida, Tampa, Florida, USA 3Kreiskrankenhaus Plochingen, Plochingen, Germany 4Cleveland
Clinic, Cleveland, Ohio, USA 5Addenbrookes Hospital, Cambridge, UK 6University Medical Center
Groningen, University of Groningen, Groningen, The Netherlands 7University of Oxford, Oxford,
UK 8Hospital Cochin, Paris, France 9Mayo Clinic, Rochester, Minnesota, USA 10Massachusetts
General Hospital, Boston, Massachussets, USA
Abstract
NIH Public Access
Author Manuscript
Ann Rheum Dis. Author manuscript; available in PMC 2011 July 19.
Published in final edited form as:
AnnRheumDis. 2009 January ; 68(1): 103–106. doi:10.1136/ard.2008.097758.
Comparison of disease activity measures for anti-neutrophil
cytoplasmic autoantibody (ANCA)-associated vasculitis
PA Merkel1, DD Cuthbertson2, B Hellmich3, GS Hoffman4, DRW Jayne5, CGM Kallenberg6,
JP Krischer2, R Luqmani7, AD Mahr8, EL Matteson9, U Specks9, and JH Stone10 for the
Vasculitis Clinical Research Consortium
1Boston University School of Medicine, Boston, Massachussets, USA 2University of South
Florida, Tampa, Florida, USA 3Kreiskrankenhaus Plochingen, Plochingen, Germany 4Cleveland
Clinic, Cleveland, Ohio, USA 5Addenbrookes Hospital, Cambridge, UK 6University Medical Center
Groningen, University of Groningen, Groningen, The Netherlands 7University of Oxford, Oxford,
UK 8Hospital Cochin, Paris, France 9Mayo Clinic, Rochester, Minnesota, USA 10Massachusetts
General Hospital, Boston, Massachussets, USA
NIH Public Access
Author Manuscript
Ann Rheum Dis. Author manuscript; available in PMC 2011 July 19.
Published in final edited form as:
Ann Rheum Dis. 2009 January ; 68(1): 103–106. doi:10.1136/ard.2008.097758.
NIH-PAAuthorManuscriptNIH-P
2009
NO
Diagnóstico
ANCA dirigido a auto-antígenos
Implicación clínica del tipo de ANCA
1995
Diagnóstico
Imágenes
Pathogenesis of ANCA-Associated Vasculitis: New Possibilities for Intervention. Am J Kidney Dis. 62(6):1176-1187
Nódulos pulmonares múltiples
Cavitaciones
Patrón en vidrio esmerilado
Diagnóstico
Histopatología
Focal
Creciente
Mixto
Esclerótica
2010
Diagnóstico
Histopatología
Histopathological classification of pauci-immune glomerulonephritis and its impact on outcome. Rheumatol Int
(2014) 34:1721–1727
Diagnóstico
Clinical features and diagnosis of small-vessel vasculitis. doi:10.3949/ccjm.79.s3.01
Diagnóstico
2008
Tratamiento
Ciclofosfamida
2009
Tratamiento
Treatment of ANCA-Associated Vasculitis: New Therapies and a Look at Old Entities. Advances in Chronic Kidney
Disease, Vol 21, No 2 (March), 2014: pp 182-193
1. Ciclofosfamida 15 mg/Kg/dosis cada 2 semanas por 3
dosis.
2. Continuar con Ciclofosfamida 15 mg/Kg/dosis cada 3
semanas hasta la remisión de la enfermedad
3. Continuar hasta 3 meses posterior a remisión de la
enfermedad con medicación oral o endovenosa
(Mantenimiento)
Ciclofosfamida
Tratamiento
Rituximab
2015
Tratamiento
Plasmaféresis
2013
Tratamiento
Inmunoglobulina
2009
Tratamiento
Inmunoglobulina
Intravenousimmunoglobulin asadjuvant therapy for
Wegener’sgranulomatosis(Review)
Fortin PM, Tejani AM, Bassett K, Musini VM
Figure 1. QUORUM (qualityof reportingmeta-analyses) flowchart of studyselection
Included studies
For detailsof theincluded study seeCharacteristicsof included
studies.
Thisstudywasaprospective,randomized,double-blind,placebo-
controlled multicenter trial. Thirty four patientswererandomly
assignedtoreceiveIVIg(total dose=2g/kg,n=17)or placebo(n
patientseither relapsing on steroidsalone(or steroidsin combi-
nation with immunosuppressant therapy) or thosethat did not
achievefull remission on steroidsin combination with immuno-
suppressant therapyfollowinginitial presentation.
Patients were excluded from participating in the trial if they
had any of the following characteristics: IVIg therapy during
the previous three months, history of anaphylaxis to properly
matchedbloodproducts,selectiveIgAdeficiency,rapidlyprogres-
Main results
WeincludedoneRCT with34participantswhowererandomlyassignedtoreceiveIVIgor placebooncedailyinaddition toazathioprine
and prednisolone for remission maintenance. Therewere no significant differencesbetween adjuvant IVIg and adjuvant placebo in
mortality, seriousadverseevents, timetorelapse, open-label rescuetherapy, and infection rates. Thefall in diseaseactivity score, derived
from patient-reported symptoms, was slightly greater in the IVIg group than in the placebo group at one month (MD 2.30; 95%
Confidenceinterval (CI) 1.12 to 3.48, P<0.01) and threemonths(MD 1.80; 95% CI 0.35 to 3.25, P=0.01). Therewasasignificant
increasein total adverseeventsin theIVIggroup (relativerisk (RR) 3.50; 95% CI 1.44 to 8.48, P< 0.01).
Authors’ conclusions
Thereisinsufficient evidencefromoneRCT that IVIgadjuvant therapyprovidesatherapeuticadvantagecomparedwiththecombination
of steroids and immunosuppressants for patients with WG. Given the high cost of IVIg (one dose at 2 g/kg for a 70 kg patient =
$8,400), it should belimited to treat WG in thecontext of awell conducted RCT powered to detect patient-relevant outcomes.
P L A I N L A N G U A G E S U M M A R Y
Intravenousimmunoglobulin in addition to standard treatmentsfor Wegener’sgranulomatosis
Wegener’sgranulomatosis isararedisorder that causesinflammation of theblood vessels. Thisinflammation restrictsblood flow to
2013
Tratamiento
Treatment of ANCA-Associated Vasculitis: New Therapies and a Look at Old Entities. Advances in Chronic Kidney
Disease, Vol 21, No 2 (March), 2014: pp 182-193
Futuro
2015

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Vasculitis anca positivo 2015

  • 1. Vasculitis ANCA positivo 2015 Dr. Cristhian Mauricio Bueno Lara Especialista en medicina interna – Universidad Autónoma de Bucaramanga Fellow en Nefrología – Universidad del Valle
  • 2. Conceptos Comprenhensive Clinical Nephrology 4th Edition 11Para el nefrólogo 1 2 3 4 5 6 7 8 9 10 11 91 caso por cada 1000 a 10000 habitantes/año 1 3 4 7 865 9 2 3Vasculitis ANCA positivo 1 32
  • 3. Conceptos Síndrome riñón - Pulmón Glomerulonefritis rápidamente progresiva Glomerulonefritis pauciinmune Vasculitis ANCA positivo Glomerulonefritis rápidamente progresiva – Hemorragia alveolar difusa Disfunción renal en días/semanas Proteinuria – Hematuria – Semilunas celulares Presión arterial normal Escasos depósitos de inmunoglobulinas o complemento en glomérulo vasos renales Poliangeítis granulomatosa Poliangeítis microscópica Poliangeítis granulomatosa eosinofílica Stephen C West, Nishkantha Arulkumaran, Philip W Ind, Charles D Pusey. Pulmonary-renal syndrome: a life threatening but treatable condition. Postgrad Med J 2013
  • 7. Clasificación Eoin F. McKinney & Lisa C. Willcocks & Verena Broecker. The immunopathology of ANCA-associated vasculitis. Semin Immunopathol (2014) 36:461–478 99 Pacientes ANCA positivo
  • 8. Friedrich Wegener • Nacimiento: 4 abril 1907, Noreste de Alemania. • Médico y asistente en patología • Granulomatosis rinógena singular • Retiro de la medicina en 1970 en medio del reconocimiento. • Muerte: 1990 a los 83 años. • Título: Master Clinician of the American College of Chest Physician Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener’s granulomatosis). Journal of Autoimmunity 48-49 (2014) 94e98 • 50 a 100 autopsias en judíos al mes • Año 2007: Destitución de titulo de Master por ACCP
  • 9. Jacob Churg – Lotte Strauss • 1951: 13 necropsias en pacientes con asma y vasculitis sistémica. • Chumbley y Lanham han cambiado los criterios. Diagnosis and classication of eosinophilic granulomatosis with polyangiitis (formerly named Churge Strauss syndrome) Journal of Autoimmunity 48-49 (2014) 99e103
  • 11. Clasificación Chapel Hill Consensus Conference 2012 Vasculitis de pequeño vaso 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Vol. 65, No. 1, January 2013, pp 1–11
  • 12. Clasificación Chapel Hill Consensus Conference 2012 Vasculitis ANCA positivo 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Vol. 65, No. 1, January 2013, pp 1–11 Vasculitis necrotizante Sin o muy poco depósitos inmunes Afectación de pequeño vaso Asociado a ANCA Mieloperoxidasa o Proteinasa 3 Poliangeítis microscópica Glomerulonefritis necrotizante Capilaritis pulmonar es frecuente No inflamación granulomatosa Poliangeítis granulomatosa Inflamación granulomatosa necrotizante Compromiso respiratorio alto o bajo Glomerulonefritis necrotizante Poliangeítis granulomatosa eosinofílica Inflamación granulomatosa necrotizante y rica en eosinófilos Asociada a asma con eosinofilia Afectación del tracto respiratorio
  • 13. Epidemiología Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant (2015) 30: i14–i22 Por millón de habitantes
  • 15. Fisiopatología Diagnosis and classication of eosinophilic granulomatosis with polyangiitis (formerly named Churge Strauss syndrome) Journal of Autoimmunity 48-49 (2014) 99e103
  • 17. Manifestaciones Clínicas Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis PA Merkel1, DD Cuthbertson2, B Hellmich3, GS Hoffman4, DRW Jayne5, CGM Kallenberg6, JP Krischer2, R Luqmani7, AD Mahr8, EL Matteson9, U Specks9, and JH Stone10 for the Vasculitis Clinical Research Consortium 1Boston University School of Medicine, Boston, Massachussets, USA 2University of South Florida, Tampa, Florida, USA 3Kreiskrankenhaus Plochingen, Plochingen, Germany 4Cleveland Clinic, Cleveland, Ohio, USA 5Addenbrookes Hospital, Cambridge, UK 6University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 7University of Oxford, Oxford, UK 8Hospital Cochin, Paris, France 9Mayo Clinic, Rochester, Minnesota, USA 10Massachusetts General Hospital, Boston, Massachussets, USA Abstract Aim—Currently, several different instruments are used to measure disease activity and extent in clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading to division among investigative groups and difficulty comparing study results. An exercise comparing six different vasculitis instruments was performed. Methods—A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in the literature of Wegener granulomatosis or microscopic polyangiitis using 6 disease assessment NIH Public Access Author Manuscript Ann Rheum Dis. Author manuscript; available in PMC 2011 July 19. Published in final edited form as: Ann Rheum Dis. 2009 January ; 68(1): 103–106. doi:10.1136/ard.2008.097758. Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis PA Merkel1, DD Cuthbertson2, B Hellmich3, GS Hoffman4, DRW Jayne5, CGM Kallenberg6, JP Krischer2, R Luqmani7, AD Mahr8, EL Matteson9, U Specks9, and JH Stone10 for the Vasculitis Clinical Research Consortium 1Boston University School of Medicine, Boston, Massachussets, USA 2University of South Florida, Tampa, Florida, USA 3Kreiskrankenhaus Plochingen, Plochingen, Germany 4Cleveland Clinic, Cleveland, Ohio, USA 5Addenbrookes Hospital, Cambridge, UK 6University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 7University of Oxford, Oxford, UK 8Hospital Cochin, Paris, France 9Mayo Clinic, Rochester, Minnesota, USA 10Massachusetts General Hospital, Boston, Massachussets, USA Abstract Aim—Currently, several different instruments are used to measure disease activity and extent in clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading to division among investigative groups and difficulty comparing study results. An exercise comparing six different vasculitis instruments was performed. Methods—A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in NIH Public Access Author Manuscript Ann Rheum Dis. Author manuscript; available in PMC 2011 July 19. Published in final edited form as: Ann Rheum Dis. 2009 January ; 68(1): 103–106. doi:10.1136/ard.2008.097758. 2009 Poliangeítis microscópica 82% compromiso glomerular Piel, Articulaciones y pulmonar Poliangeítis granulomatosa 80% compromiso glomerular 90% compromiso pulmonar (Alto o bajo) Poliangeítis granulomatosa eosinofílica 50% frecuente compromiso glomerular 100% Asma 72% Sistema nervioso periférico
  • 19. Diagnóstico Estudio inicial Exámenes iniciales Hemograma tipo IV Creatinina Nitrógeno ureico en sangre Uroanálisis Anticuerpos antinucleares Función hepática Clínica ANCAs Comprenhensive Clinical Nephrology 4th Edition
  • 20. Diagnóstico ANCA dirigido a auto-antígenos Clinical features and diagnosis of small-vessel vasculitis. doi:10.3949/ccjm.79.s3.01 Mejor prueba para la evaluación de los ANCA Valor pronóstico de los ANCA Implicación clínica del tipo de ANCA toemphasizethat t usedintheselabora whereIFTwithor w A variety of dif tionof ANCAshav includingthird-ge based multiplex a for analysingANC summarizesthem methodologyand testinginvasculitis applyingthesetech Automated ana Despitetheemerge IFTremainstherec ingin vasculitis. H dependsonanum conjugatesandfixa cells,storagecond andwashing.7 Furt consuming,requir performance compared with conventional assays and can be used for PR3-ANCA and MPO-ANCAdetection The new methods for ANCAdetection and evaluation in ANCA-associated vasculitis should be urgentlyevaluated in multicentre studies, in anticipation of updating of standardization processes and a revision of existing strategies a b Figure 1 | ANCAIIFpattern differentiation byautomated signal intensityanalysis. IIFimages, taken automatically byAKLIDES®, can discriminate a | P-ANCA-specific and b | C-ANCA-specific staining of neutrophils byuse of mathematical algorithms for pattern differentiation. Chromatin is stained byDAPI (blue) and specific ANCA
  • 21. Diagnóstico ANCA dirigido a auto-antígenos Clinical features and diagnosis of small-vessel vasculitis. doi:10.3949/ccjm.79.s3.01 Mejor prueba para la evaluación de los ANCA Inmunofluorescencia Pruebas antígeno- específicas
  • 22. Diagnóstico ANCA dirigido a auto-antígenos Current and emerging techniques for ANCA detection in vasculitis Nat. Rev. Rheumatol. 10, 494–501 (2014) rapidANCA testing.35 In thisassay,IFT iscombinedwitha dot-blot test for PR3-ANCA and MPO-ANCA. However, theresultsobtained areonly qualitativeand should be confirmed and quantified by other ANCA assays. patientswith suspected vasculitisneedstobeevaluated in prospectivestudies. Clinical usefulness of ANCA testing Table 1 | Comparison of methods for testing for PR3-ANCA and MPO-ANCA in ANCA-associated vasculitis Patient population (n) vs comparison group (n) Method Sensitivity (%) Specificity (%) PPV (%) NPV (%) AUC/ ROC Comments GPA (86) vs non-vasculitic disease (450)28 IFT Direct PR3-ANCA ELISA Capture ELISA Anchor ELISA 92 60 72 96 99 99 99.3 98.5 Nd Nd 0.96 (0.94–0.98) 0.80 (0.76–0.83) 0.86 (0.82–0.89) 0.96 (0.94–0.98) Histological diagnosis Retrospective study GPA (232) vs in ammatory diseases (661)29 IFT Anchor ELISA 77.9 80.4 90.9 97.4 73 88 93 93 Nd Histological diagnosis Prospective study GPA (59* ) vs in ammatory and infectious diseases (585)30 Hn–hr PR3-ANCA ELISA Capture ELISA Direct (hn) PR3-ANCA 94 66 64 99 (prede ned) Nd Nd Nd Histological diagnosis Retrospective study GPA (34) vs SLE (65)31 Direct PR3-ANCA Anchor ELISA 97.1 98.4 Nd Nd 0.999 (0.947–1.00) Clinical diagnosis Retrospective study GPA (40) vs RA or SLE (20)32 IFT Direct PR3-ANCA (n= 5 kits) Capture ELISA (n=2 kits) Anchor ELISA (n= 4 kits) 62.5 45–55 60–62.5 60–62.5 95–100 Nd Nd Nd Histological diagnosis Retrospective study MPA (40) vs RA or SLE (20)32 IFT Direct MPO-ANCA ELISA (n= 8 kits) Capture ELISA (n=2 kits) Anchor ELISA (n= 1 kit) 82.5 62.5–85 80 75 95–100 Nd Nd Nd Histological diagnosis Retrospective study GPA (55) vs suspected vasculitis (175)33 IFT Direct PR3-ANCA ELISA (n= 2 kits) Capture ELISA (n=2 kits) Anchor ELISA (n= 3 kits) Other assays (n=2) 69.1 61.8–72.7 70.9–72.7 61.8–72.7 72.7–74.5 100 95.4–96.4 95.9–99.5 98.5–99.0 95.9–97.9 Nd Nd Nd 0.856–0.879 0.862–0.878 0.833–0.881 0.878–0.902 Clinical diagnosis Retrospective study * 47 of 59 patients in the GPA group had a cytoplasmic ANCA pattern on IFT. Abbreviations: ANCA, antineutrophil cytoplasmic antibody; AUC, area under the curve; GPA, granulomatosis with polyangiitis; hn, human native; hr, human recombinant; IFT, indirect immunofluorescence technique; MPA, microscopic polyangiitis; MPO, myeloperoxidase; Nd, not determined; NPV, negative predictive value; PPV, positive predictive value; PR3, proteinase 3; RA, rheumatoid arthritis; ROC, receiver operating characteristics; SLE, systemic lupus erythematosus. REVIEWS
  • 23. Diagnóstico ANCA dirigido a auto-antígenos Valor pronóstico de los ANCA Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis PA Merkel1, DD Cuthbertson2, B Hellmich3, GS Hoffman4, DRW Jayne5, CGM Kallenberg6, JP Krischer2, R Luqmani7, AD Mahr8, EL Matteson9, U Specks9, and JH Stone10 for the Vasculitis Clinical Research Consortium 1Boston University School of Medicine, Boston, Massachussets, USA 2University of South Florida, Tampa, Florida, USA 3Kreiskrankenhaus Plochingen, Plochingen, Germany 4Cleveland Clinic, Cleveland, Ohio, USA 5Addenbrookes Hospital, Cambridge, UK 6University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 7University of Oxford, Oxford, UK 8Hospital Cochin, Paris, France 9Mayo Clinic, Rochester, Minnesota, USA 10Massachusetts General Hospital, Boston, Massachussets, USA Abstract NIH Public Access Author Manuscript Ann Rheum Dis. Author manuscript; available in PMC 2011 July 19. Published in final edited form as: AnnRheumDis. 2009 January ; 68(1): 103–106. doi:10.1136/ard.2008.097758. Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis PA Merkel1, DD Cuthbertson2, B Hellmich3, GS Hoffman4, DRW Jayne5, CGM Kallenberg6, JP Krischer2, R Luqmani7, AD Mahr8, EL Matteson9, U Specks9, and JH Stone10 for the Vasculitis Clinical Research Consortium 1Boston University School of Medicine, Boston, Massachussets, USA 2University of South Florida, Tampa, Florida, USA 3Kreiskrankenhaus Plochingen, Plochingen, Germany 4Cleveland Clinic, Cleveland, Ohio, USA 5Addenbrookes Hospital, Cambridge, UK 6University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 7University of Oxford, Oxford, UK 8Hospital Cochin, Paris, France 9Mayo Clinic, Rochester, Minnesota, USA 10Massachusetts General Hospital, Boston, Massachussets, USA NIH Public Access Author Manuscript Ann Rheum Dis. Author manuscript; available in PMC 2011 July 19. Published in final edited form as: Ann Rheum Dis. 2009 January ; 68(1): 103–106. doi:10.1136/ard.2008.097758. NIH-PAAuthorManuscriptNIH-P 2009 NO
  • 24. Diagnóstico ANCA dirigido a auto-antígenos Implicación clínica del tipo de ANCA 1995
  • 25. Diagnóstico Imágenes Pathogenesis of ANCA-Associated Vasculitis: New Possibilities for Intervention. Am J Kidney Dis. 62(6):1176-1187 Nódulos pulmonares múltiples Cavitaciones Patrón en vidrio esmerilado
  • 27. Diagnóstico Histopatología Histopathological classification of pauci-immune glomerulonephritis and its impact on outcome. Rheumatol Int (2014) 34:1721–1727
  • 28. Diagnóstico Clinical features and diagnosis of small-vessel vasculitis. doi:10.3949/ccjm.79.s3.01
  • 31. Tratamiento Treatment of ANCA-Associated Vasculitis: New Therapies and a Look at Old Entities. Advances in Chronic Kidney Disease, Vol 21, No 2 (March), 2014: pp 182-193 1. Ciclofosfamida 15 mg/Kg/dosis cada 2 semanas por 3 dosis. 2. Continuar con Ciclofosfamida 15 mg/Kg/dosis cada 3 semanas hasta la remisión de la enfermedad 3. Continuar hasta 3 meses posterior a remisión de la enfermedad con medicación oral o endovenosa (Mantenimiento) Ciclofosfamida
  • 35. Tratamiento Inmunoglobulina Intravenousimmunoglobulin asadjuvant therapy for Wegener’sgranulomatosis(Review) Fortin PM, Tejani AM, Bassett K, Musini VM Figure 1. QUORUM (qualityof reportingmeta-analyses) flowchart of studyselection Included studies For detailsof theincluded study seeCharacteristicsof included studies. Thisstudywasaprospective,randomized,double-blind,placebo- controlled multicenter trial. Thirty four patientswererandomly assignedtoreceiveIVIg(total dose=2g/kg,n=17)or placebo(n patientseither relapsing on steroidsalone(or steroidsin combi- nation with immunosuppressant therapy) or thosethat did not achievefull remission on steroidsin combination with immuno- suppressant therapyfollowinginitial presentation. Patients were excluded from participating in the trial if they had any of the following characteristics: IVIg therapy during the previous three months, history of anaphylaxis to properly matchedbloodproducts,selectiveIgAdeficiency,rapidlyprogres- Main results WeincludedoneRCT with34participantswhowererandomlyassignedtoreceiveIVIgor placebooncedailyinaddition toazathioprine and prednisolone for remission maintenance. Therewere no significant differencesbetween adjuvant IVIg and adjuvant placebo in mortality, seriousadverseevents, timetorelapse, open-label rescuetherapy, and infection rates. Thefall in diseaseactivity score, derived from patient-reported symptoms, was slightly greater in the IVIg group than in the placebo group at one month (MD 2.30; 95% Confidenceinterval (CI) 1.12 to 3.48, P<0.01) and threemonths(MD 1.80; 95% CI 0.35 to 3.25, P=0.01). Therewasasignificant increasein total adverseeventsin theIVIggroup (relativerisk (RR) 3.50; 95% CI 1.44 to 8.48, P< 0.01). Authors’ conclusions Thereisinsufficient evidencefromoneRCT that IVIgadjuvant therapyprovidesatherapeuticadvantagecomparedwiththecombination of steroids and immunosuppressants for patients with WG. Given the high cost of IVIg (one dose at 2 g/kg for a 70 kg patient = $8,400), it should belimited to treat WG in thecontext of awell conducted RCT powered to detect patient-relevant outcomes. P L A I N L A N G U A G E S U M M A R Y Intravenousimmunoglobulin in addition to standard treatmentsfor Wegener’sgranulomatosis Wegener’sgranulomatosis isararedisorder that causesinflammation of theblood vessels. Thisinflammation restrictsblood flow to 2013
  • 36. Tratamiento Treatment of ANCA-Associated Vasculitis: New Therapies and a Look at Old Entities. Advances in Chronic Kidney Disease, Vol 21, No 2 (March), 2014: pp 182-193

Editor's Notes

  1. El Termino iniciamente introducido en 1919 por Goodpasture, las causas del sindrome pulmon riñon corresponden a: VA+, SAAF, Enfermedad de anticuerpos contra la membrana basal, Vasculitis por lupus, Vasculitis por IgA, Vasculitis crioglobulinemia, Vasculitis reumatoide, Enfermedad de Behcet, Glomerulonefritis postestreptococcica, Enfermedad mixta de tejido conectivo, Polimiositis y dermatomiositis Glomerulonefritis rápidamente progresiva: La proteinuria usualmente no es mayor a 3 gr/día Pauciimune: Corresponde en ese orden de ideas a las vasculitis ANCA positivo descartando las medidadas por inmunocomplejos y complemento que pueden ser causa de glomerulonefritis rapidamente progresiva
  2. - El estudio histopatologico no es necesario para efectuar el diagnostico de la entidad.
  3. - Vasculitis de pequeño vaso: Definido como el compromiso de arterias intraparenquimatosas, arteriolas, capilares y venulas. Las arterias medias y venas medias pueden estar comprometidas.
  4. Pueden incluso no tener positivos los ANCA La poliangeitis granulomatosa eosinofilica puede o no estar asociada a glomerulonefritis necrotizante, cuando se asocia a esta es frecuente que muestra ANCA positivo.
  5. Los antigenos mas comunmente asociados a los anticuerpos contra el citoplasma del neutrofilo son la proteinasa 3 (PR3) y la mieloperoxidasa (MPO). Han sido descubiertos anticuerpos contra las proteinas de la membrana asociada al lisosoma 2 (LAMP 2) los cuales se reportan frecuentemente en pacientes con MPO o PR3 positivo. La clave es que existe una fuerte asociación de los ANCA con estas formas distintivas de vasculitis de pequeño vaso, y la asociacion entre la severidad y los titulas de ANCA tambien apoya la teoria de su role patogenico. Sin embargo, algunos pacientes con hallazgos clinicos y patologicos de PM, PG y PGE muestran negatividad en estudios convencionales de serologia para ANCA. Esto puede estar en relación a la presencia de otros epitopes diferentes a los mencionados. El estimo de los neutrofilos con citoquinas incrementa la expresion de antigenos para ANCA en su superficie, los neutrofilos estimulados por las citoquinas y que intercatuan con los ANCAS, liberan IgG de sus granulos liberando metabolitos toxicos que favorecen a la muerte endotelial. Los complejos entre los ANCA y los antigenos premiten la adhesion a las celulas endoteliales y la liberacion de mas mediadores de la inflamación y daño celular. La activación de la via alterna del complemento juega un papel importante en la amplificación de la inflamación inducida por los ANCA, la activacion de los neutrofilos resulta en la generación de C5a, que es un fuerte quimiotactico para los neutrofilos y estimula a los mismos faciltando la expresion de sus antigenos
  6. El estudio tuvo como objetivo principal evaluar la validez externa de diferentes scores de actividad de la vasculitis ANCA positivo y tipifico el espectro clinico de cada una de las vasculitis. Poliangeitis microscopica: La hemorragia alveolar siendo particularmente importante como marcador de pronostico de la enfermedad. Poliangeitis granulomatosa: Solo el 20% de los pacientes debuta con compromiso renal, sin embago cerca del 80% de todos los que la presentan desarrollan compromiso glomerular. Los sintomas respiratorios altos son la principal forma de manifestación. Dentro del compromiso respiratorio alto se documenta ulceracion de la mucosa, engrosamiento de la misma, perforacion nasal o colapso del puente, estenosis subglotica. Poliangeitis granulomatosa eosinofilica: Usualmente cursa con 3 fases, prodromos, eosinofilica y vasculitica. Las fases no son secuenciales y pueden no estar siempre presentes. La fase prodromica asociada a asma y a rinitis sin pliposis, La fase eosinofilica es caracterizada por por eosinofilia en sangre y tejidos. La eosinofilia es fundamental en la identificacion de la enfermedad, pero puede ser normalizada con el uso de corticoides inhalados durante la fase de asma. La fase vasculitica puede comprometer todo tipo de organos. El compromiso del SNP corresponde mononeuritis
  7. C ANCA hace referencia a los anticuerpos contra la proteinasa 3 y tiene un patron de distribución de citoplasma granular mientras los anticuerpos contra la MPO muestran un patron perinuclear y correponden a los P ANCA. Fijacion con etanol. AKLIDES
  8. La utilidad diagnostica de los ANCA depende de la precision metodologica de la prueba y lo apropiada que sea su solicitud (Valoracion pretest). Definitivamente un diagnostico se hace mas probable si la inmunoflurecencia coincide con una prueba antigeno especifica, por ejemplo, cuando los c ANCA coinciden con la prueba especifica para la proteinasa 3. Cuando la inmunoflurencia muestra un patron cANCA o pANCA un test especifico para el antigeno se encuentra indicado. Estos ensayos son de fase solida y el mas reconocido es el ELISA. Pero puede haber ELISA por captura o ELISA por anclaje
  9. - La utilidad diagnostica de los ANCA depende de la precision metodologica de la prueba y lo apropiada que sea su solicitud (Valoracion pretest).
  10. - La utilidad diagnostica de los ANCA depende de la precision metodologica de la prueba y lo apropiada que sea su solicitud (Valoracion pretest).
  11. Patrón del vidrio despulido (Sensibilidad 100%) , especificidad (89%) pneumocistis pero en este caso corresponde a los hallazgos de una hemorragia alveolar. Si le hacemos una broncoscopia al paciente podemos encontrar estenosis endobronquial. Enfermedad pleural