Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre 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. D'Alfonso; J. C. 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; A. D. Martinez; A. Carra; M. Salvetti; A. Uccelli; O. 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; Oe Yaldizli; L. Vecsei; B. C. Kieseier; H. P. Hartung; P. Villoslada; A. Siva; A. Saiz; H. Tumani; E. Havrdova; L. M. Villar; M. Leone; N. Barizzone; F. Deisenhammer; C. Teunissen; X. Montalban; M. Tintore; 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 multicentre 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. SombekkeJ. Killestein, H. Hegen, S. Rauch, S. D'Alfonso, J. C. 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, A. D. Martinez, A. Carra, M. Salvetti, A. Uccelli, O. 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, Oe Yaldizli, L. Vecsei, B. C. Kieseier, H. P. Hartung, P. Villoslada, A. Siva, A. Saiz, H. Tumani, E. Havrdova, L. M. Villar, M. Leone, N. Barizzone, F. Deisenhammer, C. Teunissen, X. Montalban, M. Tintore, 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

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

210 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	English
Pages (from-to)	1013-1024
Number of pages	12
Journal	Multiple Sclerosis Journal
Volume	21
Issue number	8
Early online date	13 Feb 2015
DOIs	https://doi.org/10.1177/1352458514568827
Publication status	Published - 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)

Access to Document

10.1177/1352458514568827

Cite this

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 multicentre study. Multiple Sclerosis Journal, 21(8), 1013-1024. https://doi.org/10.1177/1352458514568827

@article{4902cb2d62124dd09a505b03a37400f5,

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.",

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 U-C Meier 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. D'Alfonso and Alvarez-Cermeno, {J. C.} 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 Martinez, {A. D.} and A. Carra and M. Salvetti and A. Uccelli and O. 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 Oe Yaldizli and L. Vecsei and Kieseier, {B. C.} and Hartung, {H. P.} and P. Villoslada and A. Siva and A. Saiz and H. Tumani and E. Havrdova and Villar, {L. M.} 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 R. Hintzen and L. Kappos and R. Furlan and V. Martinelli and G. Comi and Ramagopalan, {S. V.} and G. Giovannoni",

year = "2015",

month = jul,

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, 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, 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 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 multicentre 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 - D'Alfonso, S.

AU - Alvarez-Cermeno, J. C.

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, A. D.

AU - Carra, A.

AU - Salvetti, M.

AU - Uccelli, A.

AU - Torkildsen, O.

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, Oe

AU - Vecsei, L.

AU - Kieseier, B. C.

AU - Hartung, H. P.

AU - Villoslada, P.

AU - Siva, A.

AU - Saiz, A.

AU - Tumani, H.

AU - Havrdova, E.

AU - Villar, L. M.

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, R.

AU - Kappos, L.

AU - Furlan, R.

AU - Martinelli, V.

AU - Comi, G.

AU - Ramagopalan, S. V.

AU - Giovannoni, G.

PY - 2015/7

Y1 - 2015/7

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.webofscience.com/api/gateway?GWVersion=2&SrcApp=uab_pure&SrcAuth=WosAPI&KeyUT=WOS:000357738700009&DestLinkType=FullRecord&DestApp=WOS

U2 - 10.1177/1352458514568827

DO - 10.1177/1352458514568827

M3 - Article

C2 - 25680984

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 multicentre study

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this