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

J. Kuhle; G. Disanto; R. Dobson; R. Adiutori; L. Bianchi; J. Topping; J. P. Bestwick; U. C. Meier; M. Marta; G. Dalla Costa; T. 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. Dalfonso; J. C. Alvarez-Cermeño; P. Kleinová; D. Horáková; 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; A. D. Martínez; A. Carra; M. Salvetti; A. Uccelli; Torkildsen; K. M. Myhr; D. Galimberti; K. Rejdak; J. Lycke; J. L. Frederiksen; J. Drulovic; C. Confavreux; D. Brassat; C. Enzinger; S. Fuchs; I. Bosca; J. Pelletier; C. Picard; E. Colombo; D. Franciotta; T. Derfuss; R. L.P. Lindberg; Yaldizli; L. Vécsei; B. C. Kieseier; H. P. Hartung; P. Villoslada; A. Siva; A. Saiz; H. Tumani; E. Havrdová; L. M. Villar; M. Leone; N. Barizzone; F. Deisenhammer; C. Teunissen; X. Montalban; M. Tintoré; T. Olsson; M. Trojano; S. Lehmann; G. Castelnovo; S. Lapin; R. Hintzen; L. Kappos; R. Furlan; V. Martinelli; G. Comi; S. V. Ramagopalan; G. Giovannoni

doi:10.1177/1352458514568827

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

J. Kuhle
, G. Disanto
, R. Dobson
, R. Adiutori
, L. Bianchi
, J. Topping
, J. P. Bestwick
, U. C. Meier
, M. Marta
, G. Dalla Costa
, T. 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. Dalfonso, J. C. Alvarez-Cermeño, P. Kleinová, D. Horáková, 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, A. D. Martínez, A. Carra, M. Salvetti, A. Uccelli, Torkildsen, K. M. Myhr, D. Galimberti, K. Rejdak, J. Lycke, J. L. Frederiksen, J. Drulovic, C. Confavreux, D. Brassat, C. Enzinger, S. Fuchs, I. Bosca, J. Pelletier, C. Picard, E. Colombo, D. Franciotta, T. Derfuss, R. L.P. Lindberg, Yaldizli, L. Vécsei, B. C. Kieseier, H. P. Hartung, P. Villoslada, A. Siva, A. Saiz, H. Tumani, E. Havrdová, L. M. Villar, M. Leone, N. Barizzone, F. Deisenhammer, C. Teunissen, X. Montalban, M. Tintoré, T. Olsson, M. Trojano, S. Lehmann, G. Castelnovo, S. Lapin, R. Hintzen, L. Kappos, R. Furlan, V. Martinelli, G. Comi, S. V. Ramagopalan, G. Giovannoni

Department of Health Sciences

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

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	English
Pages (from-to)	1013-1024
Number of pages	12
Journal	Multiple Sclerosis Journal
Volume	21
Issue number	8
DOIs	https://doi.org/10.1177/1352458514568827
Publication status	Published - 11 Jul 2015

Keywords

Clinically definite multiple sclerosis (CDMS)
Epstein-Barr nuclear antigen 1 (EBNA-1)
clinically isolated syndrome (CIS)
oligoclonal bands (OCBs)
serum 25-hydroxyvitamin D3 (25-OH-D)

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10.1177/1352458514568827

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Kuhle, J., Disanto, G., Dobson, R., Adiutori, R., Bianchi, L., Topping, J., Bestwick, J. P., Meier, U. C., Marta, M., Dalla 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 multicantre study. Multiple Sclerosis Journal, 21(8), 1013-1024. https://doi.org/10.1177/1352458514568827

@article{5739f2a8a40d43fe83e0e343cef273e0,

title = "Conversion from clinically isolated syndrome to multiple sclerosis: A large multicantre 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.",

keywords = "Clinically definite multiple sclerosis (CDMS), Epstein-Barr nuclear antigen 1 (EBNA-1), clinically isolated syndrome (CIS), oligoclonal bands (OCBs), serum 25-hydroxyvitamin D3 (25-OH-D)",

author = "J. Kuhle and G. Disanto and R. Dobson and R. Adiutori and L. Bianchi and J. Topping and Bestwick, \{J. P.\} and Meier, \{U. C.\} and M. Marta and \{Dalla Costa\}, G. and T. 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. Dalfonso and Alvarez-Cerme{\~n}o, \{J. C.\} and P. Kleinov{\'a} and D. Hor{\'a}kov{\'a} 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 Mart{\'i}nez, \{A. D.\} and A. Carra and M. Salvetti and A. Uccelli and Torkildsen and Myhr, \{K. M.\} and D. Galimberti and K. Rejdak and J. Lycke and Frederiksen, \{J. L.\} 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 Lindberg, \{R. L.P.\} and Yaldizli and L. V{\'e}csei and Kieseier, \{B. C.\} and Hartung, \{H. P.\} and P. Villoslada and A. Siva and A. Saiz and H. Tumani and E. Havrdov{\'a} and Villar, \{L. M.\} and M. Leone and N. Barizzone and F. Deisenhammer and C. Teunissen and X. Montalban and M. Tintor{\'e} and T. Olsson and M. Trojano and S. Lehmann and G. Castelnovo and S. Lapin and R. Hintzen and L. Kappos and R. Furlan and V. Martinelli and G. Comi and Ramagopalan, \{S. V.\} and G. Giovannoni",

note = "Funding Information: RLP Lindberg has received research support from the Roche Postdoc Fellowship Program, and unrestricted research grants from Novartis and Biogen. Funding Information: J Killestein has accepted consulting and speaker fees from Merck-Serono, Biogen Idec, Teva and Novartis. VU Medical Centre has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis and Teva. Funding Information: S Saip has received unrestricted research grants from Bayer-Schering AG and from Merck-Serono and travel and registration coverage for attending several national or international congresses or symposia from Merck Serono, Novartis and Teva. Funding Information: T Derfuss serves on scientific advisory boards for Novartis Pharma, Merck Serono, Biogen Idec, Genzyme, Mitsubishi Pharma, Teva Pharma and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen Idec, Novartis, Merck Serono and Bayer Schering Pharma; and receives research support from Novartis Pharma. ",

year = "2015",

month = jul,

day = "11",

doi = "10.1177/1352458514568827",

language = "English",

volume = "21",

pages = "1013--1024",

journal = "Multiple Sclerosis Journal",

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, Dalla 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, Dalfonso, S, Alvarez-Cermeño, JC, Kleinová, P, Horáková, 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, Martínez, AD, Carra, A, Salvetti, M, Uccelli, A, Torkildsen, 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, Vécsei, L, Kieseier, BC, Hartung, HP, Villoslada, P, Siva, A, Saiz, A, Tumani, H, Havrdová, E, Villar, LM, Leone, M, Barizzone, N, Deisenhammer, F, Teunissen, C, Montalban, X, Tintoré, 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 multicantre study', Multiple Sclerosis Journal, vol. 21, no. 8, pp. 1013-1024. https://doi.org/10.1177/1352458514568827

TY - JOUR

T1 - Conversion from clinically isolated syndrome to multiple sclerosis

T2 - A large multicantre study

AU - Kuhle, J.

AU - Disanto, G.

AU - Dobson, R.

AU - Adiutori, R.

AU - Bianchi, L.

AU - Topping, J.

AU - Bestwick, J. P.

AU - Meier, U. C.

AU - Marta, M.

AU - Dalla Costa, G.

AU - Runia, T.

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 - Dalfonso, S.

AU - Alvarez-Cermeño, J. C.

AU - Kleinová, P.

AU - Horáková, 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 - Martínez, A. D.

AU - Carra, A.

AU - Salvetti, M.

AU - Uccelli, A.

AU - Torkildsen,

AU - Myhr, K. M.

AU - Galimberti, D.

AU - Rejdak, K.

AU - Lycke, J.

AU - Frederiksen, J. L.

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, R. L.P.

AU - Yaldizli,

AU - Vécsei, L.

AU - Kieseier, B. C.

AU - Hartung, H. P.

AU - Villoslada, P.

AU - Siva, A.

AU - Saiz, A.

AU - Tumani, H.

AU - Havrdová, E.

AU - Villar, L. M.

AU - Leone, M.

AU - Barizzone, N.

AU - Deisenhammer, F.

AU - Teunissen, C.

AU - Montalban, X.

AU - Tintoré, M.

AU - Olsson, T.

AU - Trojano, M.

AU - Lehmann, S.

AU - Castelnovo, G.

AU - Lapin, S.

AU - Hintzen, R.

AU - Kappos, L.

AU - Furlan, R.

AU - Martinelli, V.

AU - Comi, G.

AU - Ramagopalan, S. V.

AU - Giovannoni, G.

N1 - Funding Information: RLP Lindberg has received research support from the Roche Postdoc Fellowship Program, and unrestricted research grants from Novartis and Biogen. Funding Information: J Killestein has accepted consulting and speaker fees from Merck-Serono, Biogen Idec, Teva and Novartis. VU Medical Centre has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis and Teva. Funding Information: S Saip has received unrestricted research grants from Bayer-Schering AG and from Merck-Serono and travel and registration coverage for attending several national or international congresses or symposia from Merck Serono, Novartis and Teva. Funding Information: T Derfuss serves on scientific advisory boards for Novartis Pharma, Merck Serono, Biogen Idec, Genzyme, Mitsubishi Pharma, Teva Pharma and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen Idec, Novartis, Merck Serono and Bayer Schering Pharma; and receives research support from Novartis Pharma.

PY - 2015/7/11

Y1 - 2015/7/11

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.

KW - Clinically definite multiple sclerosis (CDMS)

KW - Epstein-Barr nuclear antigen 1 (EBNA-1)

KW - clinically isolated syndrome (CIS)

KW - oligoclonal bands (OCBs)

KW - serum 25-hydroxyvitamin D3 (25-OH-D)

UR - https://www.scopus.com/pages/publications/84929479105

U2 - 10.1177/1352458514568827

DO - 10.1177/1352458514568827

M3 - Article

SN - 1352-4585

VL - 21

SP - 1013

EP - 1024

JO - Multiple Sclerosis Journal

JF - Multiple Sclerosis Journal

IS - 8

ER -

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

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