VASCULITES

02/05/2016
Atualização no diagnóstico
e tratamento das vasculites
pulmonares
CARMEN SÍLVIA VALENTE BARBAS
Professora Livre Docente em Pneumologia pela FMUSP
Coordenadora do Ambulatório de Vasculites da
Disciplina de Pneumologia HC-FMUSP
VASCULITES
Doenças que se caracterizam
pela inflamação e destruição
dos vasos acometidos podendo ocorrer espessamento,
trombose, dilatações aneurismáticas e até ruptura do vaso.
0s sintomas são consequência
de isquemia ou sangramento
nos órgãos acometidos
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ANCA–ASSOCIATED VASCULITIS- AAV
GROUP OF DISEASES CHARACTERIZED BY THE
PRESENCE OF ANTINEUTROPHIL CYTOPLASMIC
ANTIBODY ASSOCIATED WITH NECROTIZING
VASCULITIS OF SMALL AND
MEDIUM SIZE VESSELS.
ANCA:
C-ANCA
P-ANCA
J Rheumatology 2011, 38: 1480-1486.
Sens: 95%
Espec: 90%
J Rheumatology 2011, 38: 1480-1486.
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ANCA ASSOCIATED VASCULITIS-AAV
1. GRANULOMATOSIS WITH POLYANGIITIS
(GPA) - (WEGENER GRANULOMATOSIS)
2. MICROSCOPIC POLYANGIITIS (MPA)
3. EOSINOPHILIC GRANULOMATOSIS
WITH POLYANGIITIS (EGPA)
(CHURG-STRAUSS SYNDROME)
J Rheumatology 2011, 38: 1480-1486.
Granulomatose com Poliangeite
(Ex-Granulomatose de Wegener )
• Vasculite sistêmica necrozante
• Prevalência: 10: milhão - homem/mulher– 1:1
• ANCA (Anti-proteinase 3 e Anti-Mieloperoxidase)
• Acometimento sistêmico
1. Olhos-nariz e
ouvido
2. Pulmonar
3. Renal
4. Ocular
5. Musculoesqulético
6. Cutaneo
7. Neurologico
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Clin Rheumatol. 2010 Aug;29(8):855-60.
Wegener's granulomatosis: experience from a Brazilian tertiary center.
de Souza FH, Radu Halpern AS, Valente Barbas CS, Shinjo SK.
Source
Division of Rheumatology, Faculdade de Medicina da Universidade de São Paulo
134 patients with
Granulomatosis with Poliangiitis
Mean age : 43± 15 years
Males: 48%
Mean duration of the disease : 8 ± 6 years
Lungs involvement : 78%
ANCA positivity 62%
5-years survival: 79%
Case-control study of HLA region in Brazilian carriers of
Granulomatosis with Polyangiitis (Wegener’s) .
Tavares MS, Kawano-Dourado L, Pinaffi J, Antunes T, Barbas CSV.
Tese de Doutorado Marcos Tavares 2016.
ATS poster 2016.
X
Arthritis Rheumatol. 2016 Feb 11. doi: 10.1002/art.39620. [Epub ahead of print]
HLA-DPB1 as a risk factor for relapse in ANCA-associated vasculitis - a cohort study.
Hilhorst M1, Arndt F2, Kemna MJ1, Wieczorek S3, Donner Y4, Wilde B5, Epplen JT3, van Paassen
P1, Cohen Tervaert JW 1.
Case-control study of HLA region in Brazilian carriers of
Granulomatosis with Polyangiitis (Wegener’s) .
Tavares MS, Kawano-Dourado L, Pinaffi J, Antunes T, Barbas CSV.
Tese de Doutorado Marcos Tavares 2016.
ATS poster 2016.
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Lung
19 Mar 2015
In Situ Evidence of Pulmonary Endothelial Activation in
Patients with Granulomatosis with Polyangiitis and Systemic
Sclerosis
Leticia Kawano-Dourado, Alexandre M. Ab’Saber, Vera Luiza Capelozzi, Carla Valeri,
Carmen Sílvia Valente Barbas
WEGENER -PATHOGENESIS
C-ANCA
NEUTROPHIL ACTIVATION
Giant cell
ANCA
Proteinase
-3
Adhesion molecule
TNF-a IL -1 IL -8
Adhesion molecule
receptor
FcgRIIa receptor
VESSEL
Granuloma formation
APOPTOSIS
Vasculitis
Apoptotic
cells
Vasculitis
Elastic fibers fragmentation
Antunes T, Capellozzi V, Barbas CSV.
Am J Respir Crit Care Med, A,2002.
J. M. Barros, E. R. Parras, A. M. Ab'Saber, E. R. Borges, T. Antunes, C. R. R. Carvalho, P. H. N. Saldiva, V. L. Capelozzi, C. S. V. Barbas. Elastic
fibers fragmentation of the pulmonary vessels in wegener granulomatosis: a quantitative study. Eur Respir J ,24(48),43S, 2004.
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Confocal microscopy
visualization of the pulmonary
arteries with CD 34 marker
Arterial lumen/ total
area of normal
controls
Arterial lumen/ total area of patients
with Wegener granulomatosis
Arterial Lumen area
Arterial Total area
Santana AN, Antunes T, Barbas CS. Treatment of ANCA-associated vasculitis.
JAMA. 2007 Dec 19;298(23):2739
GRANULOMATOSIS WITH POLIANGIITIS
Chest High-Resolution CT Findings At The Time Of Diagnosis Of
Granulomatosis With Polyangiitis (Wegener Granulomatosis)
L.B. Kawano-Dourado, M. Tavares, A.N.C. Santana, T. Antunes, C.S.V. Barbas
University of São Paulo Medical School - São Paulo/BR
119 PATIENTS
ATS, 2012
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TOMOGRAPHIC FINDINGS
GRANULOMATOSIS WITH POLIANGIITIS
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MICROSCOPIC POLIANGIITIS
• GLOMERULONEPHRITIS : 80%
• WEIGHT LOSS: >70%
•CUTANEOUS LESIONS: >60%
• PERIPHERIC NERVOUS SYSTEM :>60%
• FEVER:>55%
• ALVEOLAR HEMORRHAGE : 12%
• ANCA POSITIVITY : 75%
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G.P.
VESSEL SIZE
SMALL AND MEDIUM
VESSEL INVOL VED
ARTERIOLES AND VENULES
M.P.
SMALL AND MEDIUM
ARTERIOLES AND VENULES
GRANULOMATOUS INFLAMMATON
YES
NO
TISSUE NECROSIS
YES
YES
PULMONARY INVOLVEMENT
YES
YES
GLOMERULONEHRITIS
YES
YES
RARE
FREQUENT
CUTANEOUS LESIONS
YES
YES
GI SYMPTOMS
YES
YES
OCULAR INVOLVEMENT
YES
MONONEURITIS MULTIPLEX
YES
ANCA POSITIVITY
65-90%
75%
CONSTITUTIONAL SYMPTOMS
YES
YES
Granulomatose eosinofílica com poliangeite
( ex –Síndrome de CHURG-STRAUSS )
2.5 / million- Associated with HLA DRB4
Th2- CD4T+-IL4,IL5,IL13 response
Alergic and eosinophilic reactions (eotaxins)
• ASTHMA
• EOSINOPHILIA
• SYSTEMIC VASCULITIS
CHURG-STRAUSS SYNDROME
2 PHENOTYPES:
1.Vasculitic- P-ANCA associated.
( Purpura, mononeuritis multiplex and glomerulonephritis)
2. Eosinophilic:tissue eosinophilic infiltration (e.g.
pulmonary infiltrates, cardiomyopathy).
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TREATMENT OF CHURG-STRAUSS
5 - FACTORS SCORE:
1. RENAL FAILURE : Creatinine > 1.58 mg/dL
2. Proteinuria > 1gr/day
3. GI involvement : bleeding, perforation, infarction
or pancreatitis
4. Central nervous system involvement
5. Cardiomiopathy
F=0: CORTICOSTEROIDS: 1 a / A
F> 1: Corticosteroids + Cyclophosphamide: 1 a / A
J Rheumatology 2011, 38: 1480-1486.
Arthritis Rheumatol. 2016 Mar 4. doi: 10.1002/art.39663. [Epub ahead of print]
Anti-IgE monoclonal antibody (omalizumab) in refractory and
relapsing eosinophilic granulomatosis withpolyangiitis (Churg-Strauss): Data from 17
patients.
Jachiet M1, Samson M2, Cottin V3, Kahn JE4, Le Guenno G5, Bonniaud P6, Devilliers H2, Bouillet L7, Gondouin
A8, Makhlouf F7, Meaux-Ruault N9, Gil H9,Bienvenu B10, Coste A11, Groh M1, Giraud V12, Dominique S13, Godeau
B14, Puéchal X1, Khouatra C2, Ruivard M5, Le Jeunne C1, Mouthon L1, Guillevin L1,Terrier
B1; French Vasculitis Study Group (FVSG).
Author information
Abstract
OBJECTIVE:
To describe the efficacy and safety of omalizumab, an anti-IgE monoclonal antibody, in patients with refractory
and/or relapsingeosinophilic granulomatosis with polyangiitis (EGPA).
METHODS:
We conducted a nationwide retrospective study including EGPA patients who received omalizumab. Response
was defined as the absence of asthma and/or sinonasal exacerbations with a prednisone dose ≤7.5 mg/day
(complete response) or >7.5 mg/day (partial response).
RESULTS:
Seventeen patients (median age 45 years) received omalizumab for severe steroid-dependent asthma (88%)
and/or sinonasal involvement (18%). After a median follow-up of 22 months, 6 patients (35%) achieved a
complete response, 5 patients (30%) a partial response and 6 patients (35%) had no improvement. Median
BVAS dropped from 2.5 at baseline to 0.5 at 12 months. Median rate of exacerbations decreased from 1/month
at baseline to 0 at 12 months, and median forced expiratory volume in 1 second (FEV1) increased from 63% at
baseline to 85% of the average value at 12 months. Median prednisone dose decreased from 16 mg/day at
baseline to 11 and 9 mg/day at 6 and 12 months, respectively. Omalizumab was discontinued in 8 patients
because of remission (25%), refractory disease (25%), or relapse (50%). Relapses included retrobulbar optic
neuritis attributable to EGPA in 2 cases and severe asthma flare in 2 others.
CONCLUSION:
This study suggests that omalizumab may have corticosteroid-sparing effect in EGPA with asthmatic and/or
sinonasal manifestations, but reducing corticosteroid doses may also increase the risk of severe EGPA flares,
raising the question of its safety in this condition.
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Clin Exp Rheumatol. 2016 Mar 25. [Epub ahead of print]
Rituximab versus azathioprine for ANCA-associated vasculitides maintenance
therapy: impact on global disability and health-related quality of life.
Pugnet G1, Pagnoux C2, Terrier B3, Perrodeau E4, Puéchal X3, Karras A5, Khouatra C6, Aumaître O7, Cohen P3, Maurier F8, Decaux
O9, Ninet J10, Gobert P11,Quemeneur T 12, Blanchard-Delaunay C13, Godmer P14, Carron PL15, Hatron PY16, Limal N17, Hamidou
M18, Ducret M19, Daugas E20, Papo T 21, Bonnotte B22, Mahr A23, Ravaud P4, Mouthon L3, Guillevin L3; French Vasculitis Study Group.
Author information
Abstract
OBJECTIVES:
To investigate the effects on health-related quality of life (HRQOL) and functional capability of rituximab vs
azathioprine for ANCA-associated vasculitis (AAV) maintenance therapy.
METHODS:
In a 24-month phase III randomised-controlled trial, 115 patients over time received rituximab or azathioprine for
AAV maintenance therapy. Mean changes of 36-item Short-form Health Survey (SF-36) and Health Assessment
Questionnaire (HAQ) scores from baseline were analysed.
RESULTS:
Mean improvements of HAQ scores, from baseline to month 24 were significantly better for the rituximab (0.16
points lower) than the azathioprine group (p=0.038). As demonstrated by SF-36, study patients' baseline HRQOL
was significantly impaired compared with age- and sex-matched US norms. At month 24, mean changes from
baseline of SF-36 physical component score tended to be better for the rituximab group (+3.95 points, p=0.067)
whereas mean changes from baseline of the SF-36 mental component score were significantly better for the
azathioprine group (+4.23 points, p=0.041).
CONCLUSIONS:
Azathioprine-treated patients' for AAV maintenance therapy showed a decline in
physical abilities when compared to RTX at M24 in the MAINRITSAN trial.
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Santana AN.......Barbas CSV. J Bras Pneumol, 2008 34(6):362-6
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TAKAYASU ARTERITIS
FEMALES 9:1 < 40 YEARS
SYSTEMIC PHASE:
FEVER
WEIGHT LOSS
PAINS
OCCLUSIVE PHASE :
HEADACHE
BLURRED VISION
SYNCOPES
ARTERIAL MURMUR
TAKAYASU ARTERITIS
TREATMENT:
PREDNISONE
IMUNOSSUPRESSORS
Clin Exp Rheumatol. 2016 Apr 6.
Tocilizumab in patients with Takayasu arteritis: a
retrospective study and literature review.
Loricera J1, Blanco R1, Hernández JL1, Castañeda S2, Humbría A2, Ortego N3, Bravo B4, Freire M5, Melchor
S6, Mínguez M7, Salvatierra J3, González-Vela C1, Calvo-Río V1, Santos-Gómez M1, Pina T1, González-Gay MA8.
Author information
Abstract
OBJECTIVES:
To assess the efficacy of tocilizumab (TCZ) in patients with Takayasu arteritis (TA).
METHODS:
Multicentre open-label retrospective study.
RESULTS:
Eight patients (all women) with a mean age of 34±16 years, median 36 years (range: 7-57) were assessed. The
main clinical features at TCZ therapy onset were: constitutional symptoms (n=4), fever (n=3), headache (n=2),
chest pain (n=1), abdominal pain (n=1), mesenteric ischaemia (n=1), myalgia involving the lower limbs (n=1),
cerebral vascular insufficiency (n=1), malaise (n=1), upper limb claudication (n=1) and nodular scleritis (n=1).
Besides corticosteroids and before TCZ treatment onset, 7 of 8 patients had also received several conventional
immunosuppressive and/or biologic agents. Seven patients experienced marked clinical improvement in the first 3
months after the onset of TCZ therapy. After a median follow-up of 15.5 [interquartile range-IQR: 12-24] months, 7
patients were asymptomatic. The median C-reactive protein decreased from 3.09 [IQR: 0.5-12] to 0.15 [IQR: 0.10.5] mg/dL (p=0.018), and median erythrocyte sedimentation rate from 40 [IQ range: 28-72] to 3 [IQR: 2-5] mm/1st
hour (p=0.012). The median dose of prednisone was also tapered from 42.5 [IQR: 25-50] to 2.5 [IQR: 0-7.5]
mg/day (p=0.011). However, TCZ had to be discontinued in 1 patient because she developed a systemic lupus
erythematosus, and in another patient due to inefficiency. TCZ dose was reduced in a patient because of mild
thrombocytopenia.
CONCLUSIONS:
TCZ appears to be effective in the management of patients with TA, in particular in patients refractory to
corticosteroids and/or conventional immunosuppressive drugs.
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