Predictors of early disability accumulation in newly diagnosed multiple sclerosis: clinical, imaging and cerebrospinal fluid measures

Abstract

Background: A growing arsenal of treatment options for relapsing multiple sclerosis (RMS) emphasises the need for early prognostic biomarkers. While evidence for individual markers exists, comprehensive analyses at the time of diagnosis are sparse.

Methods: Brain and spinal cord lesion numbers, cerebrospinal fluid parameters, initial symptoms, and Expanded Disability Status Scale (EDSS) score were determined at the time of diagnosis. Confirmed disability accumulation (CDA), defined as a sustained EDSS increase over 6 months, was determined during a 5-year follow-up. All-subsets multivariable logistic regression was performed to identify predictors of CDA. Model performance was assessed via receiver operating characteristic analysis, and individual risks were calculated. Analyses were repeated with progression independent of relapse activity (PIRA) as an outcome.

Results: 113/417 (27.1%) people with RMS experienced CDA on follow-up. Intrathecal IgG synthesis, a higher number of spinal cord lesions, age and polysymptomatic manifestation were identified as independent predictors of CDA. The resulting prediction model yielded an area under the curve (AUC) of 0.75 with a 95% CI of 0.70 to 0.80. Individuals exceeding the optimal thresholds for the three most significant predictors had a 61.8% likelihood of experiencing CDA, whereas those below all three thresholds had a CDA rate of 4.5%. The only significant baseline predictor differentiating PIRA from relapse-associated worsening was a higher number of spinal cord lesions (AUC=0.64, 95% CI 0.54 to 0.74).

Conclusions: Intrathecal IgG synthesis, spinal cord lesion number, age and polysymptomatic manifestation are independent predictors of early CDA in newly diagnosed RMS.

Keywords: CLINICAL NEUROLOGY; CSF; MRI; MULTIPLE SCLEROSIS; NEUROIMMUNOLOGY.

Figure 1. Participant flow chart. CDA, confirmed disability accumulation; CSF, cerebrospinal fluid; PIRA, progression independent of relapse activity; RAW, relapse-associated worsening; RMS, relapsing multiple sclerosis.

Figure 2. Receiver operating characteristic curves for different prediction models with confirmed disability accumulation as an outcome. Full model: including all 12 potential predictors; reduced model: including only significant predictors identified by all-subsets regression (number of spinal cord lesions, intrathecal IgG synthesis, age, polysymptomatic manifestation). A curve for IgG index as a surrogate for intrathecal IgG synthesis was added since the latter’s dichotomous nature prevents it from being displayed this way. AUC, area under the curve; n, number.

Figure 3. Survival curves based on optimal thresholds for the three main predictors of CDA. (A) Survival curves of four subgroups based on the number of threshold values exceeded. RRs were calculated in reference to the group without any predictor above threshold. (B) Survival curves of the one and two thresholds groups further stratified by the specific predictors exceeding their respective threshold. + and − denote whether individuals in a group exceed the respective threshold for a variable or not (or are positive for an attribute or not in the case of intrathecal IgG synthesis). The y-axis has been cropped for better discrimination of the curves. Threshold values were calculated using Youden’s method: SC lesion number >1, age >38 years. CDA, confirmed disability accumulation; ref., reference; RR, relative risk; SC, spinal cord.