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Eurofever Project: update on enrollment
after 3 years
Silvia Federici, MD
UO Pediatria II and Department
of Pediatrics, “G. Gaslini”
Institute and University of
Genoa, Italy
The new world of the inherited
Autoinflammatory diseases
- Monogenic inflammatory diseases caused by
mutations of genes involved in the innate
immune response
- First gene identified in 1997
Inherited autoinflammatory diseases
3
Disease
(Identification)
Gene
Chromosome
Protein
Inheritance
Gene
Identification
Periodic Fevers
FMF (1945) MEFV 16p13.3 Pyrin AR 1997
Hyper IgD (1984) MVK 12q24 MVK AR 1998
TRAPS (1982) TNFRSF1A 12p13 TNFR1 AD 1999
NLRPs-related
diseases
FCAS, MWS, CINCA
(1940, 1962, 1982)
NLRP3 1q44 Cryopyrin AD 2000
FCAS 2 (2008) NLRP12 14p35 NLPR12 AD 2008
Granulomatous
disorders
Blau’s syndrome
(1985)
CARD15/NOD2
16q12
CARD15 AD 2001
Proteasome
deficency
Nakajo-Nishimura (1993)
JMP (2010)
CANDLE (2010)
PSMB8
PSMB8
AD
2010
Pyogenic
disorders
PAPA syndrome (1997) PSTPIP 15q24 PSTPIP1 AD 2002
Majeed syndrome (1989) LPIN2 18p LPIN2 AR 2005
DIRA (2009) IL1RN 2p22 IL1Ra AR 2009
DITRA (2011) IL36RN 2q13 IL36Ra AD 2011
MKD registry www.hids.net
Meta FMF http://fmf.igh.cnrs.fr/metaFMF
PFAPA registry www.pfapa.net
Blau’s disease
EuroTRAPS linked to Eurofever
CAPS
? PAPA
NLRP3 12
DIRA
CRMO
UNDEFINED PATIENTS/
INFORMATIVE FAMILIES
Existent autoinflammatory diseases registries
MKD registry www.hids.net
Meta FMF http://fmf.igh.cnrs.fr/metaFMF
PFAPA registry www.pfapa.net
Blau’s disease
EuroTRAPS linked to Eurofever
CAPS
? PAPA
NLRP 12
DIRA
CRMO
UNDEFINED PATIENTS/
INFORMATIVE FAMILIES
Existent autoinflammatory diseases registries
pediatric
rheumatology
european
society
Autoinflammatory Diseases’ Working Party
The PRES network for Autoinflammatory diseases in childhood
“EuroFever” (Grant. N. 2007332 Public Health Program 2008)
The Eurofever Project
6
2.1. General objectives
The main aim of the present project is to build a network on autoinflammatory diseases to stimulate the exchange of information among different centres dealing with these disorders.
Final goal: to improve the general knowledge, standard of care and possibility of early diagnosis for these patients.
2.2. Specific objectives
i) A web survey will be evaluate the number of already diagnosed and suspected patients in the context of different centers dealing with Autoinflammatory diseases.
ii) A web-based registry will be created for all known Autoinflammatory diseases (in collaboration with the Eurotraps project)
iii) Informative web-pages on Autoinflammatory diseases to families and general Pediatricians
iv) A Consensus conference for the identification of criteria for disease activity (in collaboration with AIMAI project)
The Eurofever Project - Objectives
7
Building the registry
PRINTO members (51 countries, 331 Centers)
9
A network of registries or a unique registry?
Pros
• More specific
• Avoid unnecessary variables (i.e. bone deformities in PFAPA)
• Less time consuming
Cons
• Different forms (12!)
• Redundancy (clinical overlap)*
• Classification of patients with mutations of more than 1 gene*
• No possibility to compare different conditions
Pros
• A single form and unique strategy
• Many common manifestations (i.e. periodic fevers)*
• Possible enrolment of “uncertain” patients*
• Possibility to compare different diseases
Cons
• Unnecessary variables
• More time consuming to be specific enough
Network Single registry
* Touitou et al. Rheumatology 2009 10
Creating the CRFs (ask the experts)
Blau’s/Early onset sarcoidosis (C. Wouters, Belgium; C. Rose, USA)
Behçet disease (I. Kone-Paut, France)
Cryopyrin associated periodic syndrome (CAPS) (B. Neven, France; J. Kuemmerle-Deschner, Germany)
Chronic recurrent multifocal osteomyelitis (CRMO) (H. Girschick, Germany)
DIRA (J. Frenkel, The Netherlands)
Familial Mediterranean Fever (FMF) (S. Ozen, H. Ozdogan, Turkey)
Mevalonate kinase deficency (MKD) (J. Frenkel, in collaboration with A. Simon for Hyper IgD registry, The Netherlands)
NLRP12-associated periodic syndrome (M. Gattorno, Italy; V. Hentgen, France)
PAPA syndrome (F. De Benedetti, Italy)
PFAPA syndrome and undefined periodic fevers (M. Hofer, CH, S. Stojanov, Germany)
TRAPS (M. Gattorno, Italy; P. Woo, UK in coll. with H. Lachmann, UK)
Creating the CRFs
- On the web
- As complete as possible
- As fast as possible to be completed
Two Steps
1) Baseline Information (from patients’charts)
2) Clinical manifestations & response to treatment (with patients)
Baseline information
Clinical manifestations
Validation of patients
Update on enrollement
Results: Enrollment
( November 2009- May 2013)
89 Centres
2777 patients
Coming from
56 countries
2258 complete (81,3 %)
28
Italy 643
France 248
UK 238
NL 91 Germany 263 CH 85
DK 126
Spain 103 Turkey 164
Israel 163
Saudi A. 39
Oman 6
Czech R. 194
Romania 23
Russia 28
Latvia 5 Lithuania 6
Australia 11
Croatia 11 Georgia 9 Slovenia 9
Hungary 24
Albania 1
Greece 53
Slovakia 1
Armenia 101 Belgium 15
Chile 5
India 5
Serbia 3
Sweden 1
Brazil 10
Argentina 31
China 14
Japan 6 Poland 7
USA 6 Iceland 1 Norway 2
Algeria 1
Morocco 2
Tunisia 1 Egypt 3
Ireland 6
Cyprus 3
Uruguay 1
Martinica 1
Lebanon 1
Kuwait 3
Azerbaijan 1
Guadeloupe
2
Taiwan 1
0
100
200
300
400
500
600
700
800
Baseline Clinical manifestations
797/637
579/404
394/375
243/213
217/197
158/141
85/69 68/21
20/18 8/6 3/3
205/174
Baseline vs complete clinical manifestations
Paediatrics 61%
Completed 81,3%
Progression of enrollement
End of EAHC grant
0
500
1000
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2000
2500
3000
June 2010 September2010
January2011
June 2011 September2011
January2012
June 2012 May 2013
Baseline Clinical manifestations
Papers
Published Papers
- Periodic fever syndromes in Eastern and Central European countries: results of a pediatric
multinational survey. Toplak N, et al Pediatr Rheumatol Online J. 2010 Dec 2
- A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the
AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference. Piram M et al Ann Rheum
Dis. 2011 Feb;70(2):309-14
- TheEurofever Project: toward better care for autoinflammatory diseases. Ozen S et al Eur J Pediatr. 2011
Apr;170(4):445-52.
- An International registry in Autoinflammatory diseases: The Eurofever experience. Toplak N et al Ann
Rheum Dis. 2012 May 10.
- Results from a multicentre international registry of Familial Mediterranean Fever; impact of
environment on the expression of a monogenic disease in children. Ozen S. et al Ann Rheum Dis. 2013
- Treatment of Autoinflammatory diseases: results from the Eurofever registry and a literature review. Ter
Haar N. et al. Ann Rheum Dis. 2013 May;72(5):678
- Validation of the Auto-Inflammatory Diseases Activity Index (AIDAI) for hereditary recurrent fever
syndromes. Piram M. et al Ann Rheum Dis. 2013 Sep 11
- The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a
series of 158 cases from the Eurofever/EUROTRAPS international registry. Lachmann HJ et al. Ann
Rheum Dis. 2013 Aug 21.
Other papers in preparation
• First paper on CAPS (B. Neven, J. Kümmerle-
Deschner)
• Validation of pediatric FMF criteria (S. Ozen, H.
Ozgodan)
• Description of CRMO cohort (H. Girshick)
• Severity score for FMF (E. Demirkaya, S. Ozen)
• New evidence-based classification criteria (M.
Gattorno, S. Federici)
Proposed studies
• Validation of pediatric FMF criteria
• Male fertility in CAPS (T.Tran)
• MBP polymorphisms in CRMO (L. Lepore)
• Screeening for mosaicisms in genetically-
negative AIDs and vertical transmission of
mosaicisms (R. Nishikomori and J.
Argousteni)
Published Papers
- Periodic fever syndromes in Eastern and Central European countries: results of a pediatric
multinational survey. Toplak N, et al Pediatr Rheumatol Online J. 2010 Dec 2
- A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the
AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference. Piram M et al Ann Rheum
Dis. 2011 Feb;70(2):309-14
- TheEurofever Project: toward better care for autoinflammatory diseases. Ozen S et al Eur J Pediatr. 2011
Apr;170(4):445-52.
- An International registry in Autoinflammatory diseases: The Eurofever experience. Toplak N et al Ann
Rheum Dis. 2012 May 10.
- Results from a multicentre international registry of Familial Mediterranean Fever; impact of
environment on the expression of a monogenic disease in children. Ozen S. et al Ann Rheum Dis. 2013
- Treatment of Autoinflammatory diseases: results from the Eurofever registry and a literature review. Ter
Haar N. et al. Ann Rheum Dis. 2013 May;72(5):678
- Validation of the Auto-Inflammatory Diseases Activity Index (AIDAI) for hereditary recurrent fever
syndromes. Piram M. et al Ann Rheum Dis. 2013 Sep 11
- The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a
series of 158 cases from the Eurofever/EUROTRAPS international registry. Lachmann HJ et al. Ann
Rheum Dis. 2013 Aug 21.
Genotype/phenotype correlation
www.printo.it/eurofever
Page under construction
Advances
Advances
-New autoinflammatory diseases (CANDLE
syndrome, DITRA syndrome, Schnitzler
syndrome and Majeed Syndrome)
- Updated to latest diagnostic gene list *
- Updated to latest mutations list up to april
2013*
Next steps
Make it longitudinal
Every year:
1) New manifestations/complications
2) Ongoing treatment (dosage, side effects, AE,
efficacy)
3) AIDAI (Autoinflammatory disease activity
index)?
4) Quality of life?
Support
- PRINTO network
- 3 unrestricted educational grants
(Research assitant/webmasters/phD student)
Acknowledgement
- Eurofever associated and collaborating partners
C. Wouters (Belgium), I. Kone-Paut, B. Neven, V. Hentgen, I. Touitou (France),
H. Girschick, S. Stojanov, J. Kuemmerle-Deschner (Germany), S. Ozen, H. Ozdogan
(Turkey), J. Frenkel, A. Simon (The Netherlands) , F. De Benedetti (Italy), M. Hofer
(CH), P. Woo, H. Lachmann (UK), C. Rose (USA), P. Dolazelova (Czech Rep),
N.Toplak (Slovenia), R. Vasely (Slovack Rep), J. Arostegui, J. Anton (Spain).
- The Eurotraps project
- Enrolling centers
- The “Gaslini-team”
Anuela Kondi, Albania
Carmen De Cunto, Argentina
Ricardo Russo, Argentina
Graciela Espada, Argentina
Gayane Amaryan, Armenia
Christina Boros, Australia
Carine Wouters, Belgium
Sheila K. Oliveira, Brazil
Flavio Sztajnbok, Brazil
Arturo Borzutzky, Chile
Caifeng Li, China
Marija Jelusic-Drazic, Croatia
Pavla Dolezalova, Czech Republic
Susan Nielsen, Denmark
Troels Herlin, Denmark
Eric Hachulla, France
Isabelle Touitou, France
Veronique Hentgen, France
Djamal Djeddi, France
Pierre Quartier, France
Isabelle Koné-Paut, France
Marine Desjonqueres, France
Maka Ioseliani, Georgia
Silvia Stojanov, Germany
Rainer Berendes, Germany
Tobias Schwarz, Germany
Annette Jansson, Germany
Jasmin Kuemmerle-Deschner, Germany
Ralf Trauzeddel, Germany
Gerd Horneff, Germany
Kirsten Minden, Germany
Despoina Maritsi, Greece
Efimia Papadopoulou-Alataki, Greece
Elena Tsitsami, Greece
Florence Kanakoudi Tsakalidou, Greece
Olga Vougiouka, Greece
Tamàs Constantin, Hungary
Anand Prahalad Rao, India
Riva Brik, Israel
Liora Harel, Israel
Yosef Uziel, Israel
Grazia Bossi, Italy
Donato Rigante, Italy
Raffaele Manna, Italy
Giovanna Fabio, Italy
Laura Obici, Italy
Rolando Cimaz, Italy
Rita Consolini, Italy
Silvana Martino, Italy
Antonella Meini, Italy
Alma Nunzia Olivieri, Italy
Romina Gallizzi, Italy
Alberto Martini, Italy
Luca Cantarini, Italy
Patrizia Barone, Italy
Loredana Lepore, Italy
Luciana Breda, Italy
Maria Alessio, Italy
Fabrizio De Benedetti, Italy
Ryuta Nishikomori, Japan
Valda Stanevicha, Latvia
Skirmante Rusoniene, Lithuania
Anna Simon, Netherlands
Joost Frenkel, Netherlands
Esther Hoppenreijs, Netherlands
Safiya Al-Abrawi, Oman
Beata Wolska-Kusnierz, Poland
Nicolae Iagaru, Romania
Anna Kozlova, Russian Federation
Irina Nikishina, Russian Federation
Wafaa Mohammed Saad Sewairi, Saudi
Arabia
Sulaiman M. Al-Mayouf, Saudi Arabia
Gordana Susic, Serbia
Peter Ciznar, Slovakia
Tadej Avcin, Slovenia
Rosa Bou, Spain
Consuelo Modesto, Spain
Rosa Merino, Spain
Maria Jesus Rua Elorduy, Spain
Jordi Anton, Spain
Anders Fasth, Sweden
Daniela Kaiser, Switzerland
Michael Hofer, Switzerland
Erkan Demirkaya, Turkey
Guzide Aksu, Turkey
Seza Ozen, Turkey
Helen Lachmann, United Kingdom
Pat Woo, United Kingdom
Carlos Rose, USA
Active enrolling centre
For any information:
• www.printo.it/eurofever
