Prognosis after clinically isolated syndrome

Jokubaitis VG, Spelman T, Kalincik T, Izquierdo G, Grand’Maison F, Duquette P, Girard M, Lugaresi A, Grammond P, Hupperts R, Cabrera-Gomez J, Oreja-Guevara C, Boz C, Giuliani G, Fernández-Bolaños R, Iuliano G, Lechner-Scott J, Verheul F, van Pesch V, Petkovska-Boskova T, Fiol M, Moore F, Cristiano E, Alroughani R, Bergamaschi R, Barnett M, Slee M, Vella N, Herbert J, Shaw C, Saladino ML, Amato MP, Liew D, Paolicelli D, Butzkueven H, Trojano M. Predictors of disability worsening in clinically isolated syndrome. Ann Clin Transl Neurol.;2(5):479-91

OBJECTIVE:To assess demographic, clinical, magnetic resonance imaging, and treatment exposure predictors of time to 3 or 12-month confirmed disability worsening in clinically isolated syndrome (CIS) and early multiple sclerosis (MS).
METHODS: We utilized the MSBase Incident Study (MSBasis), a prospective cohort study of outcome after CIS. Predictors of time to first 3 and 12-month confirmed expanded disability status scale worsening were analyzed using Cox proportional hazards regression.
RESULTS: About 1989 patients were analyzed, the largest seen-from-onset cohort reported to-date. A total of 391 patients had a first 3-month confirmed disability worsening event, of which 307 were sustained for 12 months. Older age at CIS onset (adjusted hazard ratio: aHR 1.17, 95% 1.06, 1.30), pyramidal (aHR 1.45, 95% CI 1.13, 1.89) and ambulation (HR 1.60, 95% CI 1.09, 2.34) system dysfunction, annualized relapse rate (aHR 1.20, 95% CI 1.18, 1.22), and lower proportion of observation time on treatment were associated with 3-month confirmed worsening. Predictors of time to 12-month sustained worsening included pyramidal system dysfunction (Hazard ratio: aHR 1.38, 95% CI 1.05, 1.83), and older age at CIS onset (aHR 1.17, 95% CI 1.04, 1.31). Greater proportion of follow-up time exposed to treatment was associated with greater reductions in the rate of worsening.
INTERPRETATION: This study provides evidence for a strong protective effect of disease-modifying treatment to reduce disability worsening events in patients with CIS and early MS, and confirms age and pyramidal dysfunction at onset as risk factors.

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  • I think that the results of this paper are not as easy to interpret as they may appear. The authors were looking at the time to disability progression from CIS. Importantly, they censored the data after the first clinical visit showing EDSS worsening. In other words, if you only started a DMT after clinical progression, then all of your time on a DMT was excluded from the analyses, and you were counted as part of the non-DMT group.

    This introduces the following possible selection bias. Patients with severe MS may be less likely to make it onto a DMT before EDSS worsening than patients with milder disease course. Suppose that you have two patients, one with a severe disease course and one with a milder one, who both plan to start a DMT 1 year after CIS. The severe patient is less likely to go a year without disease worsening than the milder patient, and as a result, will be less likely to make it onto a DMT before disease progression. This means that the patients labeled as DMT-takers in the study will be selected for milder disease course.

    The study actually acknowledges this, and says: "we performed a sensitivity analysis for time to either first 3- or 12-month sustained worsening including time to first DMT as an additional model covariate. Every 1-year increase in the time to first post-CIS treatment initiation was associated with a reduction in the risk of subsequent 3-month (HR 0.75, 95% CI 0.65, 0.87) and 12-month sustained worsening (HR 0.73, 95% CI 0.61, 0.87)."

    So delaying treatment is associated with a decreased risk of EDSS worsening! They don't say what analysis they performed here, so I don't know what the result means, but it suggests something weird is going on. It doesn't make me confident about the conclusion of the paper.

    They also say: "However, an increasing proportion of follow-up time on treatment remained associated with a reduction in the risk of worsening." I may be missing something, but I don't see how this eliminates the selection bias issue. This result also has a possible bias of its own: people who are doing poorly on a drug may be more likely to switch drugs (which may take time) or stop taking DMTs altogether.

    I wish that these observational studies would just post their raw data, so that we could look at it ourselves, rather than making us rely on opaque summary statistics.

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