Vaskülitlerde B Hücresini Hedef Alan Tedaviler

Vaskülitlerde
B Hücresini Hedef Alan
Tedaviler
Sevil Kamalı
İ.Ü. İstanbul Tıp Fakültesi
İç Hastalıkları Anabilim Dalı
Romatoloji Bilim Dalı
AAV – Patogenez
B Hücreleri
• AAV’de B hücre
aktivasyonu ve BAFF
düzeyleri hastalık
aktivitesi ile korele
• GPA granülomlarındaki
tersiyer folikül yapılarında,
çok miktarda saptanabilen
proteinaz 3’e afinitesi olan
“otoreaktif hafıza B
hücreleri”
1.
2.
Specks U, et al. A&R, 2001
Jennette JC, Ann Rev Pathol Mech Dis, 2013
Anti-MPO Ig
Posiimmün GN, lökositoklastik angiitis,
hemorajik pulmoner kapillerit
Xiao H, et al. J Clin Investig, 2002
• >2001 – AAV’de RTX (Mayo Clinic1)
• Dirençli AAV’de %80-90 remisyon
• 2005-2006 – 9 kohort çalışması
• 2010 – NEJM / 2 RKÇ
• Nisan.2011 – AAV’de FDA onayı
Specks U, et al. 2001
YENİ, CİDDİ AAV1, 2
RTX %64
CYC %53
NÜKS AAV
RTX %67
CYC %42
RTX %42
CYC %36
Jones R, et al., NEJM, 2010
Stone JH, et al., NEJM, 2010
CİDDİ, NÜKS EDEN AAV2
RTX %76
CYC %82
Specks U, RAVE-ITN Research Group, NEJM, 2013
P<0.001 %20 “noninferiority” sınırı
RAVE-ITN – RTX-Rİ – 12. 18. ay
Nüks
(%)
Nükse Kadar Geçen Süre
RTX
32
176±91.2
SF
29
142±99.2
Nüks – B Hücre Geri Dönüşü
RTX %88, 80.2±85.1 gün (1-286)
SF-AZA %55 101.8±98.2
ANCA Titresi Artışı/Nüks - İlişkisiz
• Kronik nüks eden GPA- CYC direnci / intoleransı
• 53 GPA (52 PR3ANCA)
• %40 granülomatöz
• %60 vaskülitik
• RTX- 4/w, 375 mg/m2, ≥2 kür
• 1. kür RI
• 2. kür
• Nüks (+PRD)
• RS (-PRD)
• B hücre rekonstitüsyonu / ANCA 
• B hücre rekonstitüsyonu /ANCA (-) (başından beri)
• B hücre rekonstitüsyonu (nükse öncülük eden) / ANCA
Cartin-Ceba R, et al., A&R, 2012
Nüks
RS
Standart RTX Tekrarı
Stratejisi
İS (-) / Standart PRD dozu
Nüks / B lenfosit Rekonstitüsyonu / PR3ANCA 
Hastalar Arasında Değişken
Aynı Bireyde Oldukça Tutarlı
B hücre rekons. medyan 8.3 ay (6-11)
Nüks (%100)
B hücre rekons.
Öncülük/eşlik eden ANCA 
ADVERS OLAY
OLAY
SAYISI
AML
P. Jirovechii
pnömonisi
1
1
İnfeksiyon
Üsye
Bronşit
Üriner
Pnömoni
H zoster
Selülit
9
6
3
5
4
3
İnfüzyon
Reaksiyon
u
Hipertansiyon
Hipotansiyon
Titreme
Diyare
Wheezing
Boğazda sıkışma
Göğüste sıkışma
Ateş
1
4
2
1
2
1
1
4
Ölüm
Serum Ig
Hasta
Sayısı
Bazal
Median (IQR)
Post-RTX
Median (IQR)
p
IgA, mg/dl
(61–356)
18
147
(69–202)
86
(60–181)
0.006
IgG, mg/dl
(767–1,590)
19
840 (678–949)
574
(427–739)
<0.001
IgM, mg/dl
(50–300)
18
51
(41–77)
26
(13–48)
<0.001
IgG – İnfeksiyon İlişkisi Gösterilememiş
Tüm Hastalar PCP Proflaksisi Almakta!
• 59 GPA / 75 RTX kürü – Retrospektif
• Yanıt %61 (%52 düzelme, %9 stabil
seyir), %9 tam remisyon
• Orbital granülom ve pakimenenjit gibi
granülomatöz bulgular, RTX’e vaskülitik
bulgulardan dirençli
• GN - %89 vs Orbital kütle %44 (p= 0.03)
• Median 13 ayda %44 nüks
• Advers olay %30
• Pnömoni %15 (%3 ölüm)
Holle JU, et al., ARD, 2012
• Grup A (n=28) Rİ - 375 mg/m2 X4
veya 1 g X2, nükste
Nüksü Öngörme
B Hücre ve ANCA Duyarsız
• Grup B (n= 45) Rİ – 1 g X2 – 2 yıl 1g
X4
• Grup C (n= 19) – Grup A/Nüks – 2 yıl
• Yanıt - %93 (A), %96 (B), %95 (C)
• Nüks (2. yıl) – (p<0.001)
• %73 - Med 12 ay (5-76) (A)
• %12 - Med 29 ay (5-48) (B)
• %11 - Med 34.5 (5-53) (C)
• Son vizitte med 44 ayda nüks %85
(A) %26 (B) %56 (C)
GK (-) / 2. Yıl
%21 (A) %38 (B) % 47 (C)
Smith RM, et al. A&R, 2012
•
80 refrakter / nüks eden AAV (%88 GPA, %11 MPA, %1 CSS)
•
%50 ENT, %40 AC, %20 Böbrek - %91 Rİ, %9 RS (takipte %90) - %25
+İS
Yanıt
Pre-RTX
(n= 80)
Post-RTX
6 ay (n=77) 12 ay (n=77)
Aktif Hastalık %
91
9
18
Tam Remisyon %
9
66
71
Kısmi Remisyon
%
0
25
14
DEI
median (IQR)
2 (2-4)
0 (0-0)
0 (0-0)
BVAS
median (IQR)
7 (5-12)
0 (0-1)
0 (0-0)
VDI
median (IQR)
0 (0-1)
1 (0-1)
0 (0-1)
PRD doz (mg)
median (IQR)
20 (9.544)
• %15 Ciddi infeksiyon
- %50 akciğer
10 (5-12)
5 (5-10)
• %50 ölüm
Charles P, FVSG. Rheumatology, 2013
• Nüks AAV – yeniden RTX
– RAVE – 6-18 ay nüks edenler (ciddi)
– 16 hasta – 2 kür / ort. 1 yıl takip / ort. 158
günde %43 komplet remisyon
• RAVE - ≥ vs < 65 yaş ciddi AAV – SF
vs RTX ile total ve ciddi yan etki oranı
benzer
Miloslavsky E, La Presse Médicale QMR, 2013, P229
Miloslavsky E, La Presse Médicale QMR, 2013, P231
• Açık etiketli Faz 3 RKÇ– AAV RS - RTX vs AZA
• Primer sonlanma – 18 ay tedavi + 10 ay takip
sonunda major nüks (BVAS>10) sayısı
• RI tedavisinden 1 ay sonra randomizasyon
• 18 ay X5 500 mg RTX (J1 J 15, M6 M12 M18) vs 22 ay
2 mg/kg/g AZA
• 28. ayda RTX > AZA
• Median 34. ayda ≥1 major nüks %10.7 (RTX) vs %45.3
(AZA)
Terrier B, et al, Miloslavsky E, La Presse Medicale QMR, 2013,
P230
• 190 Nüks AAV – RTX/GK ile Rİ
• 4. ayda randomizasyon
RITAZAREM
rituximab (RTX) or azathioprine (AZA) for remission after RTX induction
190
GPA/MPA
relapse
Induction
RTX
375mg/m2x4
Induction
0-4 months
RTX group
1000mg / 4 months
AZA group
2mg/kg/d
Remission treatment
4-24 months
Follow-up
24-48 months
Jayne D, et al. , , La Presse Medicale QMR, 2013, P205
CD19+CD20-CD27highHLADR+
CD19+ CD20- CD27high
CD19+ CD27high
Akitf TA n=11
İnaktif TA n= 6
SLE n=9
SK n= 9
- Aktif TA’da dolaşan
plazmablast sayısı 
B lenfosit sayısı 
IL6, BAFF ile ilişki?
Hoyer BF, et al, ARD, 2012
• HCV-KV / Esansiyel mixt kriyoglobulinemi – RKÇ (59 hasta)
• Cilt ülseri, akut glomerülonefrit, periferik nöropati
• GK + AZA/SF/PEX vs RTX (1/2 kür) – 24 ay / Primer sonlanma –
12. ayda tedavi sağkalımı
Faktör
Yaş
HR (%95 CI)
p
0.99
0.499
Kadın
1
Erkek
1.92 (0.93-3.98)
Cilt Ülseri
0.077
1
Nefrit
3.6 (0.85-15.27)
0.082
Nöropati
4.05 (0.91-18.03)
0.066
Non-RTX Grubu
RTX Grubu
1
8.21 (3.77-17.87)
<0.0001
De Vita S, A&R, 2012
RTX – İVİG Replasmanı
Impact of Rituximab on Immunoglobulin Concentrations
and B Cell Numbers after Cyclophosphamide Treatment
in Patients with ANCA-Associated Vasculitides
•
Nils Venhoff 1. , Nora M. Effelsb erg 1. , Ulrich Salzer 1,2, Klaus Warnat z 1,2, Hans Hart m ut Pet er 1,2,
Dirk Lebrecht 1, Michael Schlesi er 1,2, Reinhar d E. Voll 1,2, Jens Thiel 1,2*
AAV (%80 GPA, ¾ AC-üsy, %50 böbrek, %40 PSS, %13
MSS)
1 Department of Rheumatology and Clinical Immunology, University Hospit al Freiburg, Freiburg, Germany, 2 Centre for Chronic Immunodeficiency (CCI), University
Hospital Freiburg, Freiburg, Germany
%21 İVİG replasmanı ihtiyacı
Abst ract
Serum
Ig
(median
)
PrePostp
Pre-CYCPost-CYCObjective: To assess
the impact of immunosuppressive
therapy
with cyclophosphamide (CYC)
and rituximab (RTX) on
serum immunoglobulin (Ig) concentrations and B lymphocyte counts in patients with ANCA-associated vasculitides (AAVs).
CYC
CYC
RTX
RTX
Methods: Retrospective
analysis of Ig concentrations and peripheral
B cell counts in 55 AAV patients.
IgG
12.8
IgM
1.05
0.83
0.046
0.84
0.35 A subsequent
Conclusions: In patients
with AAVs, treatment
with CYC leads to
a decline in immunoglobulin concentrations.
IgA
Results: CYC treatment resulted in a decrease in Ig levels (median; interquartile range IQR) from IgG 12.8 g/L (8.15-15.45) to
9.17 g/L (8.04-9.90) (p = 0.002), IgM 1.05 g/L (0.70-1.41) to 0.83 g/L (0.60-1.17) (p = 0.046) and IgA 2.58 g/L (1.71-3.48) to
1.58 g/L (1-31-2.39) (p = 0.056) at a median follow-up time of 4 months. IgG remained significantly below the initial value at
14.5 months and 30 months analyses. Subsequent RTX treatment in patients that had previously received CYC resulted in
a further decline in Ig levels from pre RTX IgG 9.84 g/L (8.71-11.60) to 7.11 g/L (5.75-8.77; p = 0.007), from pre RTX IgM
0.84 g/L (0.63-1.18) to 0.35 g/L (0.23-0.48; p, 0.001) and from pre RTX IgA 2.03 g/L (1.37-2.50) to IgA 1.62 g/L (IQR0.84-2.43;
p = 0.365) 14 months after RTX. Treatment with RTX induced a complete depletion of B cells in all patients. After a median
observation time of 20 months median B lymphocyte counts remained severely suppressed (4 B-cells/ml, 1.25-9.5, p, 0.001).
Seven patients (21%) that had been treated with CYC followed by RTX were started on Ig replacement because of severe
bronchopulmonary infections and serum IgG concentrations below 5 g/L.
9.17
0.002
9.84
7.11
p
0.007
<0.001
RTX therapy aggravates the decline in serum immunoglobulin concentrations and results in a profoundly delayed B cell
repopulation. Surveying patients with AAVs post CYC and RTX treatment for serum immunoglobulin concentrations and
persisting hypogammaglobulinemia is warranted.
2.58 CYC
1.58
Median
7.88 g0.056
Median 4 ay
Median CYC1.62
14.45 g
2.03
0.365
Median RTX
2
g
Serum Immunoglobulins after RTX in AAV Patients
Median 14 ay
Citat ion: Venhoff N, Effelsberg NM, Salzer U, Warnatz K, Peter HH, et al. (2012) Impact of Rituximab on Immunoglobulin Concentrations and B Cell Numbers after
Cyclophosphamide Treatment in Patients with ANCA-Associated Vasculitides. PLoS ONE 7(5): e37626. doi:10.1371/journal.p one.0037626
Editor: Pierre Bobe´, Institut Jacques Monod, France
Received October 25, 2011; Accepted April 23, 2012; Published May 21, 2012
Copyright: ß 2012 Venhoff et al. This is an open-access article distributed under the terms of the Creative Commons Attribut ion License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Compet ing Interest s: The authors have declared that no competing interests exist.
* E-mail: [email protected]
. These authors contributed equally to this work.
Int roduct ion
The group of ANCA-associated vasculitides (AAVs) comprises
granulomatosis with polyangiitis (GPA, Wegener’s granulomatosis), microscopic polyangiitis (MPA) and Churg-Strauss syndrome
(CSS). Since 1971 cyclophosphamide (CYC) hasbeen the standard
treatment for severe, life-threatening AAVs [1]. These diseases are
histologically characterized by a necrotizing inflammation of small
vessel walls mediated by ANCAs and cytokine primed neutrophils
[2]. Cytokine-primed neutrophils, antineutrophil cytoplasmic
antibodies (ANCA) and B lymphocytes play a significant role in
the pathogenesis of AAVs [3]. The pathogenic role of B
lymphocytes in AAVs is emphasized by the observation of
increased concentrations of BAFF in the serum of patients with
GPA [4]. Furthermore, B lymphocyte targeted therapy with
rituximab (RTX) has been shown to be effective in the induction
therapy of AAVs, as well as in the treatment of relapsing AAV
disease activity [5–7]. The standard induction therapy regimen
with CYC bears the risk of infections, infertility and malignancy.
Only very limited data are available evaluating the effect of
a combined therapy with CYC and RTX on peripheral B
lymphocyte counts and immunoglobulin concentrations over
a prolonged observation period. Such data are of considerable
interest since both therapies can potentially induce hypogammaglobulinemia leading to an increased risk of infections [8].
Microbial factors in turn may induce vasculitic flares, worsening
the overall disease outcome [9,10]. Here, we report on changes in
serum Ig concentrations, peripheral B cell numbers and infectious
complications in AAV treated with CYC or CYC followed by
RTX.
Venhoff N, et al., PlosOne, 2012
Figure 1. Effect of CYC treatment and CYC treatment followed by RTX on serum Ig concentration s in AAV patients. Vertical dashed
lines indicate the time
treatment
with CYC (A) and CYC followed by
stand
IgG concentrations,
open circles for IgA
PLoSof
ONE
| www.plosone.org
1 RTX (B). Black circlesMay
2012for
| Volume
7 | Issue 5 | e37626
RTX – P Jirovechii
Proflaksisi?
EULAR Recommendations for the Management of Primary
Small and Medium Vessel Vasculitis (Recommendation 6)1
• AAV’de P. Jirovechii pnömonisi %1.2
• Otoimmün hastalıklarda P Jirovechii kolonizasyonu
%25-30
• >60 yaş, akciğer, böbrek tutulumu, KOAH, sigara,
mutlak lenfopeni, CD4 hücre sayısında azalma, 
serum Ig, PRD (>15 mg/g), MTX
• B hücreleri – PCP
• P. jirovechii’nin f. murine suşunun, antikora bağımlı
klirensi (CD4 T hücrelerine sunumu)
• B hücreleri, akciğere göç edebilen CD4 T effektör
hücrelerinin çoğalmasını sağlar (hafıza CD4 T
hücrelerinin oluşum ve çoğalmasını sağlayan)
• Kemoproflaksi
• TMP-SMX direnci
• TMP-SMX yan etkileri
1. Mukhtyar C, et al., ARD, 2010
• AAV’de optimum RTX dozu/doz
aralığı?
• Nüksü öngördüren biyogösterge yok (3)
• Doku nişlerinde (tersiyer folikül/erken
granülom) otoreaktif hafıza B hücreleri
• Rİ
• Yeni AAV (CYC direnci, kontrend.) (1b)
• İlk nüks (1b)
• Baş-boyun (2b/4)
• RS (1b)
• Alternatif RS ilaçlarına direnç
varlığında
• RTX ile RI sonrasında RTX ile RS (4)
• Uzun süreli güvenlilik
• PMLE – GPA’da 6 olgu!
• İnfeksiyon! - RTX’den 1 ay önce
aşılama
• Risk modifikasyonu – P. Jirovechii

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