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

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.; Sombekke, M.; Killestein, J.; Hegen, H.; Rauch, S.; Dalfonso, S.; Alvarez-Cermeno, J. C.; 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, A. D.; Carra, A.; Salvetti, M.; Uccelli, A.; Torkildsen, O.; Myhr, K. M.; Galimberti, D.; Rejdak, K.; Lycke, J.; Frederiksen, J. L.; Drulovic, J.; Confavreux, C.; Brassat, D.; Enzinger, C.; Fuchs, S.; Bosca, I.; Pelletier, J.; Picard, C.; Colombo, E.; Franciotta, D.; Derfuss, T.; Lindberg, R. L. P.; Yaldizli, O.; Vecsei, L.; Kieseier, B. C.; Hartung, H. P.; Villoslada, P.; Siva, A.; Saiz, A.; Tumani, H.; Havrdova, E.; Villar, L. M.; 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, S. V.; Giovannoni, G.

doi:10.1177/1352458514568827

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.

Conversion from clinically isolated syndrome to multiple sclerosis: A large multicantre study / 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.; Sombekke, M.; Killestein, J.; Hegen, H.; Rauch, S.; Dalfonso, S.; Alvarez-Cermeno, J. C.; 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, A. D.; Carra, A.; Salvetti, M.; Uccelli, A.; Torkildsen, O.; Myhr, K. M.; Galimberti, D.; Rejdak, K.; Lycke, J.; Frederiksen, J. L.; Drulovic, J.; Confavreux, C.; Brassat, D.; Enzinger, C.; Fuchs, S.; Bosca, I.; Pelletier, J.; Picard, C.; Colombo, E.; Franciotta, D.; Derfuss, T.; Lindberg, R. L. P.; Yaldizli, O.; Vecsei, L.; Kieseier, B. C.; Hartung, H. P.; Villoslada, P.; Siva, A.; Saiz, A.; Tumani, H.; Havrdova, E.; Villar, L. M.; 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, S. V.; Giovannoni, G.. - In: MULTIPLE SCLEROSIS. - ISSN 1352-4585. - 21:8(2015), pp. 1013-1024. [10.1177/1352458514568827]