Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

J Kuhle; G Disanto; R Dobson; R Adiutori; L Bianchi; J Topping; JP Bestwick; UC Meier; M Marta; G (Giuseppe) Costa; Tessel Runia; E Evdoshenko; N Lazareva; E Thouvenot; P Iaffaldano; V Direnzo; M Khademi; F Piehl; M Comabella; M Sombekke; J Killestein; H Hegen; S Rauch; S D'Alfonso; JC Alvarez-Cermeno; P Kleinova; D Horakova; R Roesler; F Lauda; S Llufriu; T Avsar; U Uygunoglu; A Altintas; S Saip; T Menge; C Rajda; R Bergamaschi; N Moll; M Khalil; R Marignier; I Dujmovic; H Larsson; C Malmestrom; E Scarpini; C Fenoglio; S Wergeland; A Laroni; V Annibali; S Romano; AD Martinez; A Carra; M Salvetti; A Uccelli; O Torkildsen; KM Myhr; D Galimberti; K Rejdak; J Lycke; JL Frederiksen; J Drulovic; C Confavreux; D Brassat; C Enzinger; S Fuchs; I Bosca; J Pelletier; C Picard; E Colombo; D Franciotta; T Derfuss; RLP Lindberg; O Yaldizli; L Vecsei; BC Kieseier; HP Hartung; P Villoslada; A Siva; A Saiz; H Tumani; E Havrdova; LM Villar; M Leone; N Barizzone; F Deisenhammer; C Teunissen; X Montalban; M Tintore; T Olsson; M Trojano; S Lehmann; G Castelnovo; S Lapin; Rogier Hintzen; L Kappos; R Furlan; V Martinelli; G Comi; SV Ramagopalan; G Giovannoni

doi:10.1177/1352458514568827

Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

J Kuhle
, G Disanto
, R Dobson
, R Adiutori
, L Bianchi
, J Topping
, JP Bestwick
, UC Meier
, M Marta
, G (Giuseppe) Costa
, Tessel Runia
, E Evdoshenko
, N Lazareva
, E Thouvenot
, P Iaffaldano
, V Direnzo
, M Khademi
, F Piehl
, M Comabella
, M Sombekke

J Killestein, H Hegen, S Rauch, S D'Alfonso, JC Alvarez-Cermeno, P Kleinova, D Horakova, R Roesler, F Lauda, S Llufriu, T Avsar, U Uygunoglu, A Altintas, S Saip, T Menge, C Rajda, R Bergamaschi, N Moll, M Khalil, R Marignier, I Dujmovic, H Larsson, C Malmestrom, E Scarpini, C Fenoglio, S Wergeland, A Laroni, V Annibali, S Romano, AD Martinez, A Carra, M Salvetti, A Uccelli, O Torkildsen, KM Myhr, D Galimberti, K Rejdak, J Lycke, JL Frederiksen, J Drulovic, C Confavreux, D Brassat, C Enzinger, S Fuchs, I Bosca, J Pelletier, C Picard, E Colombo, D Franciotta, T Derfuss, RLP Lindberg, O Yaldizli, L Vecsei, BC Kieseier, HP Hartung, P Villoslada, A Siva, A Saiz, H Tumani, E Havrdova, LM Villar, M Leone, N Barizzone, F Deisenhammer, C Teunissen, X Montalban, M Tintore, T Olsson, M Trojano, S Lehmann, G Castelnovo, S Lapin, Rogier Hintzen, L Kappos, R Furlan, V Martinelli, G Comi, SV Ramagopalan, G Giovannoni

Neurology

Research output: Contribution to journal › Article › Academic

273 Citations (Scopus)

Abstract

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Original language	Undefined/Unknown
Pages (from-to)	1013-1024
Number of pages	12
Journal	Multiple Sclerosis
Volume	21
Issue number	8
DOIs	https://doi.org/10.1177/1352458514568827
Publication status	Published - 2015

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EMC MM-02-72-02

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10.1177/1352458514568827

Cite this

Kuhle, J., Disanto, G., Dobson, R., Adiutori, R., Bianchi, L., Topping, J., Bestwick, JP., Meier, UC., Marta, M., Costa, G., Runia, T., Evdoshenko, E., Lazareva, N., Thouvenot, E., Iaffaldano, P., Direnzo, V., Khademi, M., Piehl, F., Comabella, M., ... Giovannoni, G. (2015). Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study. Multiple Sclerosis, 21(8), 1013-1024. https://doi.org/10.1177/1352458514568827

@article{d35da35af6da4df785f8ee04c4e5f2f6,

title = "Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study",

abstract = "Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95\% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95\% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95\% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95\% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.",

author = "J Kuhle and G Disanto and R Dobson and R Adiutori and L Bianchi and J Topping and JP Bestwick and UC Meier and M Marta and Costa, \{G (Giuseppe)\} and Tessel Runia and E Evdoshenko and N Lazareva and E Thouvenot and P Iaffaldano and V Direnzo and M Khademi and F Piehl and M Comabella and M Sombekke and J Killestein and H Hegen and S Rauch and S D'Alfonso and JC Alvarez-Cermeno and P Kleinova and D Horakova and R Roesler and F Lauda and S Llufriu and T Avsar and U Uygunoglu and A Altintas and S Saip and T Menge and C Rajda and R Bergamaschi and N Moll and M Khalil and R Marignier and I Dujmovic and H Larsson and C Malmestrom and E Scarpini and C Fenoglio and S Wergeland and A Laroni and V Annibali and S Romano and AD Martinez and A Carra and M Salvetti and A Uccelli and O Torkildsen and KM Myhr and D Galimberti and K Rejdak and J Lycke and JL Frederiksen and J Drulovic and C Confavreux and D Brassat and C Enzinger and S Fuchs and I Bosca and J Pelletier and C Picard and E Colombo and D Franciotta and T Derfuss and RLP Lindberg and O Yaldizli and L Vecsei and BC Kieseier and HP Hartung and P Villoslada and A Siva and A Saiz and H Tumani and E Havrdova and LM Villar and M Leone and N Barizzone and F Deisenhammer and C Teunissen and X Montalban and M Tintore and T Olsson and M Trojano and S Lehmann and G Castelnovo and S Lapin and Rogier Hintzen and L Kappos and R Furlan and V Martinelli and G Comi and SV Ramagopalan and G Giovannoni",

year = "2015",

doi = "10.1177/1352458514568827",

language = "Undefined/Unknown",

volume = "21",

pages = "1013--1024",

journal = "Multiple Sclerosis",

issn = "1352-4585",

publisher = "SAGE Publications Ltd",

number = "8",

}

Kuhle, J, Disanto, G, Dobson, R, Adiutori, R, Bianchi, L, Topping, J, Bestwick, JP, Meier, UC, Marta, M, Costa, G, Runia, T, Evdoshenko, E, Lazareva, N, Thouvenot, E, Iaffaldano, P, Direnzo, V, Khademi, M, Piehl, F, Comabella, M, Sombekke, M, Killestein, J, Hegen, H, Rauch, S, D'Alfonso, S, Alvarez-Cermeno, JC, Kleinova, P, Horakova, D, Roesler, R, Lauda, F, Llufriu, S, Avsar, T, Uygunoglu, U, Altintas, A, Saip, S, Menge, T, Rajda, C, Bergamaschi, R, Moll, N, Khalil, M, Marignier, R, Dujmovic, I, Larsson, H, Malmestrom, C, Scarpini, E, Fenoglio, C, Wergeland, S, Laroni, A, Annibali, V, Romano, S, Martinez, AD, Carra, A, Salvetti, M, Uccelli, A, Torkildsen, O, Myhr, KM, Galimberti, D, Rejdak, K, Lycke, J, Frederiksen, JL, Drulovic, J, Confavreux, C, Brassat, D, Enzinger, C, Fuchs, S, Bosca, I, Pelletier, J, Picard, C, Colombo, E, Franciotta, D, Derfuss, T, Lindberg, RLP, Yaldizli, O, Vecsei, L, Kieseier, BC, Hartung, HP, Villoslada, P, Siva, A, Saiz, A, Tumani, H, Havrdova, E, Villar, LM, Leone, M, Barizzone, N, Deisenhammer, F, Teunissen, C, Montalban, X, Tintore, M, Olsson, T, Trojano, M, Lehmann, S, Castelnovo, G, Lapin, S, Hintzen, R, Kappos, L, Furlan, R, Martinelli, V, Comi, G, Ramagopalan, SV & Giovannoni, G 2015, 'Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study', Multiple Sclerosis, vol. 21, no. 8, pp. 1013-1024. https://doi.org/10.1177/1352458514568827

TY - JOUR

T1 - Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

AU - Kuhle, J

AU - Disanto, G

AU - Dobson, R

AU - Adiutori, R

AU - Bianchi, L

AU - Topping, J

AU - Bestwick, JP

AU - Meier, UC

AU - Marta, M

AU - Costa, G (Giuseppe)

AU - Runia, Tessel

AU - Evdoshenko, E

AU - Lazareva, N

AU - Thouvenot, E

AU - Iaffaldano, P

AU - Direnzo, V

AU - Khademi, M

AU - Piehl, F

AU - Comabella, M

AU - Sombekke, M

AU - Killestein, J

AU - Hegen, H

AU - Rauch, S

AU - D'Alfonso, S

AU - Alvarez-Cermeno, JC

AU - Kleinova, P

AU - Horakova, D

AU - Roesler, R

AU - Lauda, F

AU - Llufriu, S

AU - Avsar, T

AU - Uygunoglu, U

AU - Altintas, A

AU - Saip, S

AU - Menge, T

AU - Rajda, C

AU - Bergamaschi, R

AU - Moll, N

AU - Khalil, M

AU - Marignier, R

AU - Dujmovic, I

AU - Larsson, H

AU - Malmestrom, C

AU - Scarpini, E

AU - Fenoglio, C

AU - Wergeland, S

AU - Laroni, A

AU - Annibali, V

AU - Romano, S

AU - Martinez, AD

AU - Carra, A

AU - Salvetti, M

AU - Uccelli, A

AU - Torkildsen, O

AU - Myhr, KM

AU - Galimberti, D

AU - Rejdak, K

AU - Lycke, J

AU - Frederiksen, JL

AU - Drulovic, J

AU - Confavreux, C

AU - Brassat, D

AU - Enzinger, C

AU - Fuchs, S

AU - Bosca, I

AU - Pelletier, J

AU - Picard, C

AU - Colombo, E

AU - Franciotta, D

AU - Derfuss, T

AU - Lindberg, RLP

AU - Yaldizli, O

AU - Vecsei, L

AU - Kieseier, BC

AU - Hartung, HP

AU - Villoslada, P

AU - Siva, A

AU - Saiz, A

AU - Tumani, H

AU - Havrdova, E

AU - Villar, LM

AU - Leone, M

AU - Barizzone, N

AU - Deisenhammer, F

AU - Teunissen, C

AU - Montalban, X

AU - Tintore, M

AU - Olsson, T

AU - Trojano, M

AU - Lehmann, S

AU - Castelnovo, G

AU - Lapin, S

AU - Hintzen, Rogier

AU - Kappos, L

AU - Furlan, R

AU - Martinelli, V

AU - Comi, G

AU - Ramagopalan, SV

AU - Giovannoni, G

PY - 2015

Y1 - 2015

N2 - Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

AB - Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

U2 - 10.1177/1352458514568827

DO - 10.1177/1352458514568827

M3 - Article

C2 - 25680984

SN - 1352-4585

VL - 21

SP - 1013

EP - 1024

JO - Multiple Sclerosis

JF - Multiple Sclerosis

IS - 8

ER -