REGISTRO INTERNAZIONALE DELLE FORME RICORRENTI E FAMILIARI DI SEU E PTT

1. REGISTRO INTERNAZIONALE DELLE FORME
RICORRENTI E FAMILIARI DI SEU E PTT
Erica Daina
Centro di Ricerche Cliniche
per le Malattie Rare
Aldo e Cele Daccò
Istituto Mario Negri
22 Gennaio 2009
Torino

2. PROBLEMS FOR PATIENTS WITH RARE DISORDERS
• Timely diagnosis and treatment
– 36% remain undiagnosed for one year or more
– 68% of patients take three months or longer to
obtain a diagnosis
– one-in-seven remain undiagnosed for six or more
years
• Accessible source of understandable, reliable
information on their disorders
• Information about research studies
The National Organization for Rare Disorders
(NORD) Survey
January 14, 2003
http://www.rarediseases.org/

3. DIFFICULTIES TO OVERCOME
• Scientific understanding of the disease (know-how) is
lacking
• Number of patients with a specific rare disease is low
• Interest of (big) pharmaceutical industry is lacking
• Interest of society is lacking
• Infrastructure and exchange of information
Van Weely S, Leufkens HGM (2004) Orphan diseases.
In: Priority medicines for Europe and the world
“A public health approach to innovation”.
Geneva (Switzerland): World Health Organization.

4. ARE REGISTRIES FOR RARE DISEASES NEEDED?

5. Patients are very difficult to localize
Patients must be recruited through numerous Centers to
obtain a suitable numerosity
REGISTRY ANALYSES
Complex questions
Rare events

6. THROMBOTIC MICROANGIOPATHY
Hemolytic Uremic Syndrome (HUS)/Thrombotic
Thrombocytopenic Purpura (TTP)
HUS and thrombotic TTP are rare
syndromes of microangiopathic hemolytic
anemia and thrombocytopenia, which
have in common thrombotic occlusion of
the microvasculature of various organs.

7. DIAGNOSIS OF HUS AND TTP
• HUS
laboratory findings of thrombotic microangiopathy
associated with acute renal failure without specific
neurologic signs except those caused by uremic
encephalopathy
• TTP
laboratory findings of thrombotic microangiopathy
with or without renal involvement, in whom specific
neurologic signs not attributable to uremic
encephalopathy dominated the picture

8. HEMOLYTIC UREMIC SYNDROME
In its typical presentation, HUS manifests as an acute
disease with watery or bloody diarrhea, most commonly
triggered by gastrointestinal infection with verotoxin
producing Escherichia coli (Stx-HUS)
Acute renal failure manifests in 55%-70% of these
cases, but renal function recovers in most of them
(up to 70% in various series)

9. HEMOLYTIC UREMIC SYNDROME
Forms of HUS not caused by Stx-producing E. coli
(non-Stx-HUS) are rarer (5 to 10% of all cases)
and may be familial or sporadic
It may manifest at all ages, but is more frequent in
adults
Non-Stx-HUS forms have a much poorer outcome
Up to 50% of cases progress to end-stage renal disease
(ESRD) or have irreversible brain damage, and 25%
may die during the acute phase of the disease

10. FAMILIAL HUS
Familial forms accounts for fewer than 3% of all cases
of HUS
Both autosomal dominant and autosomal recessive
forms of inheritance have been noted
The prognosis is poor, with a mortality rate of 60-70%
Recurrences are very frequent

11. SHORT-TERM OUTCOME OF HUS
ESRF (%) DEATH (%)
Typical, D+ childhood HUS 5 5
Atypical, D- childhood HUS 50 27
Adult HUS 25 16
Familial HUS 90 65
Noris and Remuzzi, JASN, 2005

12. THROMBOTIC THROMBOCYTOPENIC PURPURA
Incidence of TTP estimated at 4 cases per 1 million/year
TTP is more frequent among women
(female/male ratio 3:2)
The most commom form of TTP is acquired ( “sporadic”)
Relapses following an initial episode of acquired TTP are
described, with about one third of cases becoming recurrent
Familial TTP usually manifests in the postnatal period or
during infancy, although in some cases the onset is later at
20-30 years
Patients with familial TTP tipically exhibit a relapsing course

13. ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI
CENTRO DI RICERCHE CLINICHE PER LE MALATTIE RARE
ALDO E CELE DACCO’
Villa Camozzi – 24020 Ranica (BG)
Telefono 035-4535304 Fax 035-4535373 E-mail:
raredis@marionegri.it
INTERNATIONAL REGISTRY OF RECURRENT AND FAMILIAL
Hemolytic Uremic Syndrome
and Thrombotic Thrombocitopenic Purpura

14. INTERNATIONAL REGISTRY OF
RECURRENT AND FAMILIAL HUS and TTP
COORDINATING
CENTRE
BIOLOGICAL
CLINICAL DATA SAMPLES

16. RESEARCH PROTOCOL
GENETIC AND BIOCHEMICAL ABNORMALITIES IN
HEMOLYTIC UREMIC SYNDROME
AND THROMBOTIC THROMBOCYTOPENIC PURPURA
Ranica, November 2th 2006
Prepared by
Elena Bresin, Jessica Caprioli, Miriam Galbusera, Roberta
Donadelli, Erica Daina, Marina Noris
and Giuseppe Remuzzi
Istituto di Ricerche Farmacologiche Mario Negri
Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò
Villa Camozzi, Via Camozzi, 3
24020 RANICA (Bergamo)
Tel.: 035-4535304 Fax: 035-4535373
E-mail: raredis@marionegri.it
Web site: www.marionegri.it

20. #04 HUS
#03
#01 HUS #02 HUS/TTP
HUS
I I
F63
I 34y 33y
*
F83 F82 F81
* 22y 25y
I II II
F43 F40 F42 F41 F39 F56 F57
F49
F45 HUS F46 F48 TTP F50 F51
II
F35 F36
F70 F37 F38 26y
°
°
° °
III III
II F58
F59 F60 F61 F44
6m 8y 1y F47 F54 F55 F52 F53
died after F27 F32 F31
III F34 5 hours
III ° intrauterine death 25y 3y
*= vWF-cleaving IV
protease activity =0
F28 F30 F80 F33
#15 HUS
#08 HUS
#05 HUS #19 HUS/TTP
#06 TTP
I
I
I F76
I F4
*
*
F72 F71 F69 FS2 FS1 FS3
II
II
II F102 F101
F103
F78 F74
F77 F75
HUS
F3 F2 TTP
F1
41y
II
F66
III
F67
III
III 8m 6m
p p
p p
F111 F5 F6 F7 F8 F9 F110 F109 F100
III *= vWF-cleaving
F64
protease activity =0
#34 HUS
#33 HUS/TTP #36 TTP
#24 HUS #29 HUS
I I
I F127
I F122
35y
20y
F104 F105
II I
25y
3y 3.5y
II II F88 F89 F93 F94 F99 F116
6y
II F121 F120 F123
HUS F119
F126
III
F107 F106 F108
18m III
22y F118
?
II
III
IV F90 F91 F95 F96 F97 F98 F117
F87
F86 F125 F124 F128
F73 F79 TTP
HUS
p p p p p p p p p p
V
F29 F84 F85
male female
#45 HUS
#42 HUS
#37 TTP/DIC #38 HUS
I = dead
FZ FP FM
I F148
24y 22y
F131
I
II II = unaffected to date
F129 F130
F134 F133 F135
TTP DIC FF
F145 F149
F147
III II
F132
III p p
= affected
F146
= probably affected
= spontaneous abortion

21. INTERNATIONAL REGISTRY OF
RECURRENT AND
FAMILIAL HUS/TTP Denmark Germany Esthonia Czech R.
3 cases 15 cases 1 case 10 cases
Switzerland
11 cases
Trento
Bergamo
UK Varese Serbia
Brescia Treviso
9 cases 3 cases
Monza
Milano Vicenza
Torino Padova
Greece
Genova Pavia Parma
Belgium 3 cases
1 case
Firenze
Canada Turkey
3 cases 1 case
Italy
Roma
376 cases
Sassari Foggia
S. Arabia
USA Salerno
Portugal Bari 4 cases
49 cases 4 cases
Israel
Cagliari
10 cases
Spain
Reggio Calabria
5 cases
Palermo
IRAN
11 cases
South Africa Australia
Japan Malaysia
1 case
Argentina 1 case
1 case 1 case
15 cases

22. INTERNATIONAL REGISTRY OF
RECURRENT AND FAMILIAL HUS and TTP
Participating Centers: 180 overall
100 from Italy
80 from Europe/extra-Europe
Patients with HUS/TTP
Total cases: 538
Italian cases: 376 (266 HUS, 110 TTP)
Foreign cases: 162 (154 HUS, 8 TTP)
Familial form: 82 HUS (40 families)
18 TTP (10 families)

25. REGISTRY ANALYSES
Complex questions
Rare events

26. Outcome of Renal Transplantation
in patients with non-Stx-HUS
Analysis of reports with >10 patients who had
non-Stx-HUS and underwent RT showed that:
> 50% of patients lost the graft for HUS recurrence
<1yr post-RT, despite treatment with plasma
exchange and/or infusion
No clinical prognostic factors that correlate with graft
outcome emerge from literature
Bresin et al, CJASN, 2006

27. Atypical hemolytic uremic syndrome (non-Stx-HUS)
is a disease of complement dysregulation
In approximately 50% of patients, mutations have
been described in the genes encoding the
complement regulators factor H, MCP, factor I, the
activator factor B and the central component of the
complement cascade C3

28. ROLE OF COMPLEMENT IN HUS
Alternative pathway Classical pathway
Gram+, gram-, bacteria, Antigen-antibody
bacterial toxins, LPS complexes
C3 C1
C4
factor B
C3a C4a
C3b C4b
C2
C2a
factor H
C3bBb C4b-2a
C3 convertase C3 convertase
factor H
Factor I C3
C3 MCP
C3a
C3a
C3b
C3b
(C3b) Bb C4b3b.2a
2
C5 convertase C5 C5 convertase
C5a
C5b
C5b-9 (MAC)

29. In most patients with Factor H mutation, the disease recurred
on the transplanted kidney within 1yr after surgery
Bresin et al, CJASN, 2006

30. MCP mut
Cumulative renal survival
CFH mut
Follow up (months)
Bresin et al, CJASN, 2006

31. Genotyping for CFH, MCP and IF should be performed in
patients with ESRD secondary to non-Stx-HUS before
transplantation
Patients with a CFH mutation are at high risk of graft failure
and the same applies to patients with an IF mutation
In contrast, graft outcome seems to be good in patients
with MCP mutations
Bresin et al, CJASN, 2006

32. FATTORE H E FATTORE I
Prodotti principalmente dalle cellule
del fegato raggiungono la
circolazione
Fattore H
Fattore I

33. Outcome del trapianto renale in pazienti con mutazione
del gene MCP (Membrane Cofactor Protein)
MCP
MCP è una proteina di
transmembrana altamente espressa
nel tessuto renale
La frequenza delle mutazioni del
gene MCP varia dal 5 al 14% dei Prodotto principalmente
pazienti dal rene e legato
all’endotelio
L’outcome del trapianto in pazienti
con mutazione del gene MCP è più
favorevole

35. • TTP is a rare disease characterized by
thrombocytopenia, microangiopathic hemolytic
anemia, neurological and renal involvement
• It may manifest once in the lifetime or may
relapse after complete recovery of the initial
episode, leading often to neurological sequelae
or death

36. • Deficiency of the von Willebrand Factor (VWF)-
cleaving protease, ADAMTS13, has been
reported in the majority of patients with TTP
• ADAMTS13 deficiency may be either
constitutive, due to mutations in the
ADAMTS13 gene, or acquired due to the
presence of circulating anti-ADAMTS13
autoantibodies

37. DIFFERENTIAL DIAGNOSIS BETWEEN TTP
ASSOCIATED WITH GENETIC OR IMMUNE-
MEDIATED ADAMTS13 DEFICIENCY IS IMPORTANT
TO GUIDE SPECIFIC TREATMENTS
• Genetic ADAMTS13 deficiency
replacement with plasma of the defective activity
• Immuno-mediated ADAMTS13 deficiency
• plasmapheresis to remove anti-ADAMTS13
autoantibodies and to replace the metalloprotease
• inhibition of the autoantibodies production
through treatment with glucocorticoids or
immunosuppressive

38. INTERNATIONAL REGISTRY OF
RECURRENT AND FAMILIAL HUS and TTP
• A congenital deficiency of ADAMTS13 was found in 10
patients
• Undetectable ADAMTS13 activity (<6%) due to the
presence of anti-ADAMTS13 inhibitors was found in 28 of 32
patients, in the acute phase, and in 14 of 53 patients,
during remission
• 9 patients with a severe and recurrent form of TTP showed
persistence of high titers of autoantibodies in remission

39. AIMS OF THE STUDY
• To verify if Rituximab, in patients with anti-ADAMTS13
antibodies, can induce remission of acute refractory TTP
and can prevent relapses of recurrent forms
• To restore a significant ADAMTS13 plasma activity
(>10%) with no detectable inhibitors
• To evaluate whether the reapparance of high titer of
ADAMTS13 inhibitors may be an indicator for
retreatment

40. CONCLUSIONS
• Our study confirmed that rituximab as adjunctive
therapy in patients with TTP not responding to
conventional therapies induced remission
• Rituximab can be used as preventive therapy in
patients at high risk of relapses
Trials are needed to evalute:
- parameters that should be used to predict relapse
and indicate retreatment
- response rate and long term side effects
In press, 2009

41. GENETIC AND BIOCHEMICAL ABNORMALITIES IN
HUS AND TTP INFLUENCE
• Clinical manifestations
• Response to treatment
• Long term outcome
• Genetic counselling to these patients and their family

42. EU DESIGNATION
ORPHAN DRUGS - EMEA
Designated Designation Authorisation
Product
Orphan Indication date date
Complement Treatment of atypical
26/01/07
factor H HUS
Recombinant
human ADAMTS- Treatment of TTP 03/12/08
13
Treatment of
paroxysmal
Eculizumab 7/10/03 20/06/07
nocturnal
haemoglobinuria