A scoping review of comorbidity aetiology in multiple sclerosis

Individuals with multiple sclerosis (MS) have a higher risk of comorbidities, such as depression and hypertension, than those without MS, although the underlying mechanisms remain poorly understood. We conducted a scoping review to map the existing literature regarding the aetiological mechanisms linking MS and comorbidities.

We searched PubMed from inception to March, 2025, including studies of adult participants diagnosed with MS that focused on comorbidity aetiology. Studies estimating the risk or prevalence of comorbidities without investigating aetiology were excluded. For each study, we classified the proposed aetiological mechanism separately for Mendelian randomization (MR) and non-MR studies using an existing mechanistic framework. The categories were: chance/artifactual, causative, resultant, shared risk factors, and bidirectional effects.

We identified, 7224 articles, of which 311 underwent full-text review; 141 underwent data extraction. The most common comorbidities were depression (n = 20 studies), diabetes (n = 9), and epilepsy (n = 8). MR was a common study design (n = 57, 40.4%). MR studies were classified as chance/artifactual (n = 26), causative (comorbidity was proposed to cause MS) (n = 9), resultant (MS or its treatment were proposed to cause the comorbidity) (n = 20); or bidirectional (n = 2). Non-MR studies were classified as: resultant (comorbidity was proposed to result from MS or its treatment) (n = 19), shared risk factors (n = 44), or association only (temporality could not be established) (n = 21).

Evidence suggests MS comorbidities arise from shared risk factors or from MS pathology or its treatment, with few demonstrating clear causal relationships. This review highlights important gaps in our understanding of the aetiology of comorbidity in MS.

The protocol for this rapid review was registered on the Open Science Framework: https://doi.org/10.17605/OSF.IO/HK7A5.