Relazione Ardissino

La gestione clinica della SEUa
Gianluigi Ardissino
Fondazione IRCCS Ca’ Granda
Ospedale Maggiore Policlinico
Milano, Italy
Milano, 25 Ottobre 2014
Centro SEU di Milano: le basi del nostro sapere
(casi prevalenti 2000-2014; n: 226)
STEC-SEU
aSEU
Children 46%
Adults 54%
STEC
149
Pneumococcal
AIDS
Complement disregulation
CFH mutation
AntiFHAb
CFI
MCP
C3
CFB
Multiple
Unknown
Transcianocobalamin C deficiency
3
1
HELP
18
5
10
6
3
1
5
18
5
German epidemics of STEC-HUS – 2011
No: 845 (88% adults)
Frank C. te al., N Engl J Med 2011; 365:: 1171–80
HUS: a disease of the
endothelium
Danno Endoteliale
Trombosi nel Microcircolo
Consumo
piastrinico
Emolisi
meccanica
Danno
ipossico/ische
mico degli
organi
Pathogenesis and role of low circulating volume in
TMA-associated tissue damage
Proteinuria
Onchotic Endothelial
pressure
damage
Capillary leackage
Blood
flow
thrombi
formation
Hypovolemia
Blood
viscosity
Reduced tissue
perfusion,
increased tissue
hypoxia and
ischemia
Stroke volume in patients with HUS
3
S tro ke V o lu me (mL /kg )
2,5
2
Normal range
1,5
1
,5
0
Observati ons
Efficacia di
PLASMAEXCHANGE in aHUS
(33 patients)
PEX
30.3%
RESPONDERS
NON RESPONDERS
69.7%
End-point: disease remission with preserved (any degree)
renal function
Eculizumab
(Anti C5 Ab)
2009 the
Changeover
Eculizumab (Anti C5 Ab)
The changeover
Efficacia di
PLASMAEXCHANGE vs ECULIZUMAB
IN aHUS
(33 vs 26)
PEX
ECULIZUMAB
11.5%
30.3%
69.7%
RESPONDERS
RESPONDERS
NON RESPONDERS
NON RESPONDERS
88.5%
End-point: disease remission with preserved (any degree)
renal function
EFFICACY OF
PEX vs ECULIZUMAB
FHD (n: 18 vs 13)
81%
PEX
Eculizumab
PEX
19%
FID (n: 5 vs 5)
20%
RESPONDERS
NO
RESPONDERS
RESPONDERS
80%
PEX
15
%
Eculizumab
75%
NO
RESPONDERS
80%
Eculizumab
PEX
RESPONDERS
28.6%
RESPONDERS
33.3%
RESPONDERS
100%
RESPONDERS
Eziologia non nota (n: 6 Vs 7)
RESPONDERS
NO
RESPONDERS
20%
NO
RESPONDERS
100%
MCP (n: 4 Vs 1)
RESPONDERS
Eculizumab
66.7%
NO
RESPONDERS
71.4%
NO
RESPONDERS
End-point: disease remission with preserved (any degree)
renal function
Very slow and persistent recovery of renal function
following eculizumab treatment
ECULIZUMAB
RB, Female
aHUS negative for gene mutations on
CFH, CFI, CFB, MCP, C3 and THBD
and for antiCFH antibodies
The earlier is the better!
(16 patients with aHUS treated with eculizumab)
Time to the nadir of sCr
vs. sCr at treatment start
Nadir of sCr vs. sCr at
treatment start
Treatment with Eculizumab should be started as early as possible
WARNING:
SERIOUS MENINGOCOCCAL INFECTIONS
• Soliris® (eculizumab) increases the risk of meningococcal infection.
Meningococcal infection may become rapidly life-threatening or fatal
if not recognised and treated early
• Vaccinate patients with a meningococcal vaccine, preferably tetravalent, at
least 2 weeks prior to receiving the first dose of Soliris. Patients treated with
Soliris less than 2 weeks after receiving a meningococcal vaccine must receive
treatment with appropriate prophylactic antibiotics until 2 weeks after
vaccination.
• Monitor patients for early signs of meningococcal infection; evaluate
immediately if infection is suspected and treat with antibiotics if necessary
Our experience in minimizing the
costs for Eculizumab with
treatment discontinuation or
interval extension
The rational:
improve the patient’s quality of life
reduce the risk of meningococcal infection
reduce the risk of other adverse events
reduce the cost of treatment
Mean annual cost (70 kg):
based on standard schedule
470.700 Euro
DISCONTINUATION OF ECULIZUMAB MAINTENANCE
TREATMENT FOR ATYPICAL HEMOLYTIC-UREMIC
SYNDROME
Gianluigi Ardissino1 MD, Sara Testa1 MD, Ilaria Possenti1 MD, Francesca Tel1 MD, Fabio Paglialonga1 MD,
Stefania Salardi1 BS, Silvana Tedeschi1 MD, Mirco Belingheri1 MD, Massimo Cugno1 MD.
sCr (mg/dl)
0.8
1
FHD
2
FHD, FID, THBDD
3
FID
4
FID
5
FID
6
Idiopathic
7
AbAntiFH + KTx
8
MCP
9
AbAntiFH
2.8
0.8
1.4
2.3
1.3
1.0
2.5
2013: 3 relapses/96 mos.
cumul. observation period
0.4
0.3
1.2
0.5
0.6
CFHR3-R1 + Ab antiFH
10 0.7
0
0.6
3.4
2
4
6
8
Relapse
10
12
14
Eculizumab
16
18
20
22
24
Stop Eculizumab
26
28
30 32
months
2014:4 relapses/216 mos.
cumul. observation period
Home urine dip-stick for hemoglobinuria is
a simple and highly sensitive method to
screen patients for HUS relapses
Global complement activity (AP50) and interval extension of
Eculizumab maintenance treatment in aHUS
Eculizumab maintenance treatment in aHUS and
interval extension based on global complement activity
sCr (mg/dl)
CFH + KTx
0.7
FH
0.8
FH + KTx
1.8
C3 + KTx
0.7
FH
2,1
FH + KTx
1.0
FH + KTx
2.1
FH
0 relapses/396 mos. cumulative
observation period
FH
3.9
2.7
1.8
Idiopathic
months
Eculiz 2 wks
Eculiz 3 wks
Eculiz 4 wks
Annual cost of maintenance treatment of aHUS with Eculizumab in a cohort of 10 patients
(50% children) according to the standard schedule vs a body weight-tailored (WT) schedule
vs WT + interval extension (IE) schedule (on the basis of global complement function) (1)
vs WT + IE + treatment discontinuation (2) (whenever possible, based on the genetic
pattern) as regularly done at HUS Center in Milano
4
3,5
Treatment schedule currently
used at the Center for
HUS PCM in Milano
3
Euro (milions)
2,5
2
1,5
1
0,5
0
Standard
Weight taloired (WT)
WT + Interval Extension (IE)
WT + IE + Discontinuation
1-
Cugno M, Gualtierotti R, Possenti I, Testa S, Tel F, Griffini S, Grovetti E, Tedeschi S, Salardi S, Cresseri D, Messa P, Ardissino G.
Complement Functional Tests For Monitoring Eculizumab Treatment In Patients With Atypical Hemolytic Uremic Syndrome. J Thromb
Haemost. 2014 May 23. doi: 10.1111/JTH.12615.
2-
Ardissino G, Testa S, Possenti I, Tel F, Paglialonga F, Salardi S, Tedeschi S, Belingheri M, Cugno M. Discontinuation of Eculizumab
Maintenance Treatment for Atypical Hemolytic Uremic Syndrome: A Report of 10 Cases. Am J Kidney Dis. 2014 Mar 19. pii: S02726386(14)00528-9. doi: 10.1053/j.AJKD.2014.01.434.
Obs & Ginec. Vol 122, No 2, Part 2, Aug 2013
Eculizumab for atypical uremic syndrome in pregnancy
Ardissino G, Ossola MW, Baffero GM, Rigotti A, Cugno M.
Take-home message
In tutte le forme di MAT deve essere attentamente
valutata la volemia per il rischio di aggravamento del
danno ipossico/ischemico in caso di ipovolemia
La terapia con Eculizumab e’ il trattamento di prima
scelta per la SEUa
Take-home message II
Il trattamento di mantenimento con Eculizumab puo’
essere sospeso o modulato sulla base delle specifiche
diagnostiche e/o della funzione globale del
complemento
Il paziente in stop terapia puo’ essere efficacemente
monitorato mediante stick urine a domicilio per uHb
Grazie a tutti e soprattutto grazie a….
Asola: S. Sardini
Bergamo: M. D'Agostino, A. Gervasoni
Bollate: C. Verdura, M. Fusi
Busto Arsizio: A. Pellegatta
Carate B.za: A. Sterpa, D. Fossati
Cinisello B.mo: A. Reciputo, R. Malberti
Cittiglio: C. Baldioli
Como: A. Di Cesare Merlone, A. Noè
Cremona: P.Caruso, E. Milanesi, G. Mazzei
Desenzano del Garda: A. Corti, E. Cama
Desio: F. Russo, M.R. Sala
Esine: B. Balduzzi, S. Poli
Garbagnate Milanese: A. Rosco, L. Re
Gavardo: C. Messa
Lecco: C. Sciuto
Lodi: C.Zambetti, F. Sanfilippo, M.E. Vimercati
Magenta: L. Parola, C. Cucchi, M. Bellini, B. Osnaghi
Manerbio: A. Bonomini, P. Pedroni
Mantova: M.L. Casciana, S. Fasoli, R. Ceruti
Melegnano: P. Bruni
Melzo: I. Frugnoli
Merate: A. Bettinelli
Milano Buzzi: P. Tommasi, G. Pattarino, M. Frediani, M. Facchini
Milano San Raffaele: P. Sgaramella, R. Rovelli, C. Ossi
Milano Sacco: P. Carlucci, V. Pivetti
Milano FBF: V. Goj, S. Grosso
Milano San Paolo: F. Salvini, D. Ghisleni
Monza: M. Milani, M.L. Melzi, B. Scicchitano, F. Cichello
Pieve di Coriano: P. Accorsi
Rho: D. Casnaghi, G. Trifirò, M. Re
Saronno: S. Mariani, L. Cafarelli, M. Musmanno
Sesto San Giovanni: N. Altamura, M. Mella
Tradate: A. Bussolini, P. Erba
Varese: A. Negri, J. Berini, S. Binda, S. Pierdomenico
Vigevano : C. Deicher, F. Schepis
Vimercate: B. Roman, P. Casella
Voghera: P. Perotti, P. Troupioti
Pediatra di Base: A. Grassi
R. Colombo
D. Cresseri
M. Cugno
L. Daprai
F. Paglialonga
I. Possenti
S. Salardi
S. Tedeschi
F. Tel
S. Testa
E. Torresani
A. Caprioli
S. Morabito
G. Scavia
M.V. Luini
S. Lauzi
N. Borsa-Ghiringhelli
R. Smith
M. Brigotti
P. Tazzari

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