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-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; Ø Torkildsen; K M Myhr; D Galimberti; K Rejdak; J Lycke; Jette Lautrup Fredriksen; J Drulovic; C Confavreux; D Brassat; C Enzinger; S Fuchs; I Bosca; J Pelletier; C Picard; E Colombo; D Franciotta; T Derfuss; Rlp Lindberg; Ö 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 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-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, Ø Torkildsen, K M Myhr, D Galimberti, K Rejdak, J Lycke, Jette Lautrup Fredriksen, J Drulovic, C Confavreux, D Brassat, C Enzinger, S Fuchs, I Bosca, J Pelletier, C Picard, E Colombo, D Franciotta, T Derfuss, Rlp Lindberg, Ö 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 Clinical Medicine

160 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
Journal	Multiple Sclerosis Journal
Volume	21
Issue number	8
Pages (from-to)	1013-24
Number of pages	12
ISSN	1352-4585
DOIs	https://doi.org/10.1177/1352458514568827
Publication status	Published - 11 Jul 2015

Keywords

Adult
Cohort Studies
Disease Progression
Female
Follow-Up Studies
Humans
Immunoglobulin G
Magnetic Resonance Imaging
Male
Multiple Sclerosis
Nuclear Proteins
Oligoclonal Bands
Predictive Value of Tests
Prognosis
Risk Assessment
Survival Analysis
Vitamin 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 multicentre study. Multiple Sclerosis Journal, 21(8), 1013-24. https://doi.org/10.1177/1352458514568827

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-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, Ø, Myhr, KM, Galimberti, D, Rejdak, K, Lycke, J, Fredriksen, JL, Drulovic, J, Confavreux, C, Brassat, D, Enzinger, C, Fuchs, S, Bosca, I, Pelletier, J, Picard, C, Colombo, E, Franciotta, D, Derfuss, T, Lindberg, R, Yaldizli, Ö, 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 multicentre study', Multiple Sclerosis Journal, vol. 21, no. 8, pp. 1013-24. https://doi.org/10.1177/1352458514568827

@article{0615fe86209748a2b0f5b5736ce51b7d,

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 = "Adult, Cohort Studies, Disease Progression, Female, Follow-Up Studies, Humans, Immunoglobulin G, Magnetic Resonance Imaging, Male, Multiple Sclerosis, Nuclear Proteins, Oligoclonal Bands, Predictive Value of Tests, Prognosis, Risk Assessment, Survival Analysis, Vitamin 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-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 {\O} Torkildsen and Myhr, {K M} and D Galimberti and K Rejdak and J Lycke and Fredriksen, {Jette Lautrup} 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 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 = "{\textcopyright} The Author(s), 2015.",

year = "2015",

month = jul,

day = "11",

doi = "10.1177/1352458514568827",

language = "English",

volume = "21",

pages = "1013--24",

journal = "Multiple Sclerosis Journal",

issn = "1352-4585",

publisher = "SAGE Publications",

number = "8",

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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-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, Ø

AU - Myhr, K M

AU - Galimberti, D

AU - Rejdak, K

AU - Lycke, J

AU - Fredriksen, Jette Lautrup

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, Ö

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

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 - Adult

KW - Cohort Studies

KW - Disease Progression

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Immunoglobulin G

KW - Magnetic Resonance Imaging

KW - Male

KW - Multiple Sclerosis

KW - Nuclear Proteins

KW - Oligoclonal Bands

KW - Predictive Value of Tests

KW - Prognosis

KW - Risk Assessment

KW - Survival Analysis

KW - Vitamin D

U2 - 10.1177/1352458514568827

DO - 10.1177/1352458514568827

M3 - Journal 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

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