Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

F Barzaghi; LC Amaya Hernandez; B Neven; S Ricci; ZY Kucuk; JJ Bleesing; Z Nademi; MA Slatter; ER Ulloa; A Shcherbina; A Roppelt; A Worth; J Silva; A Aiuti; L Murguia-Favela; C Speckmann; M Carneiro-Sampaio; JF Fernandes; S Baris; A Ozen; E Karakoc-Aydiner; A Kiykim; A Schulz; S Steinmann; LD Notarangelo; E Gambineri; P Lionetti; WT Shearer; LR Forbes; C Martinez; D Moshous; S Blanche; A Fisher; FM Ruemmele; C Tissandier; M Ouachee-Chardin; F Rieux-Laucat; M Cavazzana; W Qasim; B Lucarelli; MH Albert; I Kobayashi; L Alonso; C Diaz De Heredia; H Kanegane; A Lawitschka; JJ Seo; M Gonzalez-Vicent; MA Diaz; RK Goyal; MG Sauer; A Yesilipek; M Kim; Y Yilmaz-Demirdag; M Bhatia; J Khlevner; EJ Richmond Padilla; S Martino; D Montin; O Neth; A Molinos-Quintana; J Valverde-Fernandez; A Broides; V Pinsk; A Ballauf; F Haerynck; V Bordon; C Dhooge; ML Garcia-Lloret; RG Bredius; K Kałwak; E Haddad; MG Seidel; G Duckers; SY Pai; CC Dvorak; S Ehl; F Locatelli; F Goldman; AR Gennery; MJ Cowan; MG Roncarolo; R Bacchetta; on behalf of the Primary Immune Deficiency Treatment Consortium (PIDTC); the Inborn Errors Working Party (IEWP) of the European Society for Blood; Marrow Transplantation (EBMT)

doi:10.1016/j.jaci.2017.10.041

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

F Barzaghi, LC Amaya Hernandez, B Neven, S Ricci, ZY Kucuk, JJ Bleesing, Z Nademi, MA Slatter, ER Ulloa, A Shcherbina, A Roppelt, A Worth, J Silva, A Aiuti, L Murguia-Favela, C Speckmann, M Carneiro-Sampaio, JF Fernandes, S Baris, A OzenE Karakoc-Aydiner, A Kiykim, A Schulz, S Steinmann, LD Notarangelo, E Gambineri, P Lionetti, WT Shearer, LR Forbes, C Martinez, D Moshous, S Blanche, A Fisher, FM Ruemmele, C Tissandier, M Ouachee-Chardin, F Rieux-Laucat, M Cavazzana, W Qasim, B Lucarelli, MH Albert, I Kobayashi, L Alonso, C Diaz De Heredia, H Kanegane, A Lawitschka, JJ Seo, M Gonzalez-Vicent, MA Diaz, RK Goyal, MG Sauer, A Yesilipek, M Kim, Y Yilmaz-Demirdag, M Bhatia, J Khlevner, EJ Richmond Padilla, S Martino, D Montin, O Neth, A Molinos-Quintana, J Valverde-Fernandez, A Broides, V Pinsk, A Ballauf, F Haerynck, V Bordon, C Dhooge, ML Garcia-Lloret, RG Bredius, K Kałwak, E Haddad, MG Seidel, G Duckers, SY Pai, CC Dvorak, S Ehl, F Locatelli, F Goldman, AR Gennery, MJ Cowan, MG Roncarolo, R Bacchetta, on behalf of the Primary Immune Deficiency Treatment Consortium (PIDTC), the Inborn Errors Working Party (IEWP) of the European Society for Blood, Marrow Transplantation (EBMT)

IRCCS Ospedale San Raffaele

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P =.035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen. © 2017 The Authors

Original language	English
Pages (from-to)	1036-1049.e5
Journal	Journal of Allergy and Clinical Immunology
Volume	141
Issue number	3
DOIs	https://doi.org/10.1016/j.jaci.2017.10.041
Publication status	Published - 2018

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Barzaghi, F., Amaya Hernandez, LC., Neven, B., Ricci, S., Kucuk, ZY., Bleesing, JJ., Nademi, Z., Slatter, MA., Ulloa, ER., Shcherbina, A., Roppelt, A., Worth, A., Silva, J., Aiuti, A., Murguia-Favela, L., Speckmann, C., Carneiro-Sampaio, M., Fernandes, JF., Baris, S., ... (EBMT), M. T. (2018). Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. Journal of Allergy and Clinical Immunology, 141(3), 1036-1049.e5. https://doi.org/10.1016/j.jaci.2017.10.041

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. / Barzaghi, F; Amaya Hernandez, LC; Neven, B; Ricci, S; Kucuk, ZY; Bleesing, JJ; Nademi, Z; Slatter, MA; Ulloa, ER; Shcherbina, A; Roppelt, A; Worth, A; Silva, J; Aiuti, A; Murguia-Favela, L; Speckmann, C; Carneiro-Sampaio, M; Fernandes, JF; Baris, S; Ozen, A; Karakoc-Aydiner, E; Kiykim, A; Schulz, A; Steinmann, S; Notarangelo, LD; Gambineri, E; Lionetti, P; Shearer, WT; Forbes, LR; Martinez, C; Moshous, D; Blanche, S; Fisher, A; Ruemmele, FM; Tissandier, C; Ouachee-Chardin, M; Rieux-Laucat, F; Cavazzana, M; Qasim, W; Lucarelli, B; Albert, MH; Kobayashi, I; Alonso, L; Diaz De Heredia, C; Kanegane, H; Lawitschka, A; Seo, JJ; Gonzalez-Vicent, M; Diaz, MA; Goyal, RK; Sauer, MG; Yesilipek, A; Kim, M; Yilmaz-Demirdag, Y; Bhatia, M; Khlevner, J; Richmond Padilla, EJ; Martino, S; Montin, D; Neth, O; Molinos-Quintana, A; Valverde-Fernandez, J; Broides, A; Pinsk, V; Ballauf, A; Haerynck, F; Bordon, V; Dhooge, C; Garcia-Lloret, ML; Bredius, RG; Kałwak, K; Haddad, E; Seidel, MG; Duckers, G; Pai, SY; Dvorak, CC; Ehl, S; Locatelli, F; Goldman, F; Gennery, AR; Cowan, MJ; Roncarolo, MG; Bacchetta, R; (PIDTC), on behalf of the Primary Immune Deficiency Treatment Consortium; Blood, the Inborn Errors Working Party (IEWP) of the European Society for; (EBMT), Marrow Transplantation.

In: Journal of Allergy and Clinical Immunology, Vol. 141, No. 3, 2018, p. 1036-1049.e5.

Research output: Contribution to journal › Article › peer-review

Barzaghi, F, Amaya Hernandez, LC, Neven, B, Ricci, S, Kucuk, ZY, Bleesing, JJ, Nademi, Z, Slatter, MA, Ulloa, ER, Shcherbina, A, Roppelt, A, Worth, A, Silva, J, Aiuti, A, Murguia-Favela, L, Speckmann, C, Carneiro-Sampaio, M, Fernandes, JF, Baris, S, Ozen, A, Karakoc-Aydiner, E, Kiykim, A, Schulz, A, Steinmann, S, Notarangelo, LD, Gambineri, E, Lionetti, P, Shearer, WT, Forbes, LR, Martinez, C, Moshous, D, Blanche, S, Fisher, A, Ruemmele, FM, Tissandier, C, Ouachee-Chardin, M, Rieux-Laucat, F, Cavazzana, M, Qasim, W, Lucarelli, B, Albert, MH, Kobayashi, I, Alonso, L, Diaz De Heredia, C, Kanegane, H, Lawitschka, A, Seo, JJ, Gonzalez-Vicent, M, Diaz, MA, Goyal, RK, Sauer, MG, Yesilipek, A, Kim, M, Yilmaz-Demirdag, Y, Bhatia, M, Khlevner, J, Richmond Padilla, EJ, Martino, S, Montin, D, Neth, O, Molinos-Quintana, A, Valverde-Fernandez, J, Broides, A, Pinsk, V, Ballauf, A, Haerynck, F, Bordon, V, Dhooge, C, Garcia-Lloret, ML, Bredius, RG, Kałwak, K, Haddad, E, Seidel, MG, Duckers, G, Pai, SY, Dvorak, CC, Ehl, S, Locatelli, F, Goldman, F, Gennery, AR, Cowan, MJ, Roncarolo, MG, Bacchetta, R, (PIDTC), OBOTPIDTC, Blood, TIEWPIEWPOTESF & (EBMT), MT 2018, 'Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study', Journal of Allergy and Clinical Immunology, vol. 141, no. 3, pp. 1036-1049.e5. https://doi.org/10.1016/j.jaci.2017.10.041

Barzaghi, F ; Amaya Hernandez, LC ; Neven, B ; Ricci, S ; Kucuk, ZY ; Bleesing, JJ ; Nademi, Z ; Slatter, MA ; Ulloa, ER ; Shcherbina, A ; Roppelt, A ; Worth, A ; Silva, J ; Aiuti, A ; Murguia-Favela, L ; Speckmann, C ; Carneiro-Sampaio, M ; Fernandes, JF ; Baris, S ; Ozen, A ; Karakoc-Aydiner, E ; Kiykim, A ; Schulz, A ; Steinmann, S ; Notarangelo, LD ; Gambineri, E ; Lionetti, P ; Shearer, WT ; Forbes, LR ; Martinez, C ; Moshous, D ; Blanche, S ; Fisher, A ; Ruemmele, FM ; Tissandier, C ; Ouachee-Chardin, M ; Rieux-Laucat, F ; Cavazzana, M ; Qasim, W ; Lucarelli, B ; Albert, MH ; Kobayashi, I ; Alonso, L ; Diaz De Heredia, C ; Kanegane, H ; Lawitschka, A ; Seo, JJ ; Gonzalez-Vicent, M ; Diaz, MA ; Goyal, RK ; Sauer, MG ; Yesilipek, A ; Kim, M ; Yilmaz-Demirdag, Y ; Bhatia, M ; Khlevner, J ; Richmond Padilla, EJ ; Martino, S ; Montin, D ; Neth, O ; Molinos-Quintana, A ; Valverde-Fernandez, J ; Broides, A ; Pinsk, V ; Ballauf, A ; Haerynck, F ; Bordon, V ; Dhooge, C ; Garcia-Lloret, ML ; Bredius, RG ; Kałwak, K ; Haddad, E ; Seidel, MG ; Duckers, G ; Pai, SY ; Dvorak, CC ; Ehl, S ; Locatelli, F ; Goldman, F ; Gennery, AR ; Cowan, MJ ; Roncarolo, MG ; Bacchetta, R ; (PIDTC), on behalf of the Primary Immune Deficiency Treatment Consortium ; Blood, the Inborn Errors Working Party (IEWP) of the European Society for ; (EBMT), Marrow Transplantation. / Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. In: Journal of Allergy and Clinical Immunology. 2018 ; Vol. 141, No. 3. pp. 1036-1049.e5.

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title = "Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study",

abstract = "Background: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P =.035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen. {\textcopyright} 2017 The Authors",

author = "F Barzaghi and {Amaya Hernandez}, LC and B Neven and S Ricci and ZY Kucuk and JJ Bleesing and Z Nademi and MA Slatter and ER Ulloa and A Shcherbina and A Roppelt and A Worth and J Silva and A Aiuti and L Murguia-Favela and C Speckmann and M Carneiro-Sampaio and JF Fernandes and S Baris and A Ozen and E Karakoc-Aydiner and A Kiykim and A Schulz and S Steinmann and LD Notarangelo and E Gambineri and P Lionetti and WT Shearer and LR Forbes and C Martinez and D Moshous and S Blanche and A Fisher and FM Ruemmele and C Tissandier and M Ouachee-Chardin and F Rieux-Laucat and M Cavazzana and W Qasim and B Lucarelli and MH Albert and I Kobayashi and L Alonso and {Diaz De Heredia}, C and H Kanegane and A Lawitschka and JJ Seo and M Gonzalez-Vicent and MA Diaz and RK Goyal and MG Sauer and A Yesilipek and M Kim and Y Yilmaz-Demirdag and M Bhatia and J Khlevner and {Richmond Padilla}, EJ and S Martino and D Montin and O Neth and A Molinos-Quintana and J Valverde-Fernandez and A Broides and V Pinsk and A Ballauf and F Haerynck and V Bordon and C Dhooge and ML Garcia-Lloret and RG Bredius and K Ka{\l}wak and E Haddad and MG Seidel and G Duckers and SY Pai and CC Dvorak and S Ehl and F Locatelli and F Goldman and AR Gennery and MJ Cowan and MG Roncarolo and R Bacchetta and (PIDTC), {on behalf of the Primary Immune Deficiency Treatment Consortium} and Blood, {the Inborn Errors Working Party (IEWP) of the European Society for} and (EBMT), {Marrow Transplantation}",

year = "2018",

doi = "10.1016/j.jaci.2017.10.041",

language = "English",

volume = "141",

pages = "1036--1049.e5",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "3",

}

TY - JOUR

T1 - Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

AU - Barzaghi, F

AU - Amaya Hernandez, LC

AU - Neven, B

AU - Ricci, S

AU - Kucuk, ZY

AU - Bleesing, JJ

AU - Nademi, Z

AU - Slatter, MA

AU - Ulloa, ER

AU - Shcherbina, A

AU - Roppelt, A

AU - Worth, A

AU - Silva, J

AU - Aiuti, A

AU - Murguia-Favela, L

AU - Speckmann, C

AU - Carneiro-Sampaio, M

AU - Fernandes, JF

AU - Baris, S

AU - Ozen, A

AU - Karakoc-Aydiner, E

AU - Kiykim, A

AU - Schulz, A

AU - Steinmann, S

AU - Notarangelo, LD

AU - Gambineri, E

AU - Lionetti, P

AU - Shearer, WT

AU - Forbes, LR

AU - Martinez, C

AU - Moshous, D

AU - Blanche, S

AU - Fisher, A

AU - Ruemmele, FM

AU - Tissandier, C

AU - Ouachee-Chardin, M

AU - Rieux-Laucat, F

AU - Cavazzana, M

AU - Qasim, W

AU - Lucarelli, B

AU - Albert, MH

AU - Kobayashi, I

AU - Alonso, L

AU - Diaz De Heredia, C

AU - Kanegane, H

AU - Lawitschka, A

AU - Seo, JJ

AU - Gonzalez-Vicent, M

AU - Diaz, MA

AU - Goyal, RK

AU - Sauer, MG

AU - Yesilipek, A

AU - Kim, M

AU - Yilmaz-Demirdag, Y

AU - Bhatia, M

AU - Khlevner, J

AU - Richmond Padilla, EJ

AU - Martino, S

AU - Montin, D

AU - Neth, O

AU - Molinos-Quintana, A

AU - Valverde-Fernandez, J

AU - Broides, A

AU - Pinsk, V

AU - Ballauf, A

AU - Haerynck, F

AU - Bordon, V

AU - Dhooge, C

AU - Garcia-Lloret, ML

AU - Bredius, RG

AU - Kałwak, K

AU - Haddad, E

AU - Seidel, MG

AU - Duckers, G

AU - Pai, SY

AU - Dvorak, CC

AU - Ehl, S

AU - Locatelli, F

AU - Goldman, F

AU - Gennery, AR

AU - Cowan, MJ

AU - Roncarolo, MG

AU - Bacchetta, R

AU - (PIDTC), on behalf of the Primary Immune Deficiency Treatment Consortium

AU - Blood, the Inborn Errors Working Party (IEWP) of the European Society for

AU - (EBMT), Marrow Transplantation

PY - 2018

Y1 - 2018

N2 - Background: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P =.035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen. © 2017 The Authors

AB - Background: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P =.035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen. © 2017 The Authors

U2 - 10.1016/j.jaci.2017.10.041

DO - 10.1016/j.jaci.2017.10.041

M3 - Article

VL - 141

SP - 1036-1049.e5

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 3

ER -