Comorbidities and their association with outcomes in the multiple sclerosis population: A rapid review

Introduction: Multiple sclerosis (MS) has a high comorbidity burden. Despite known associations with adverse outcomes, a comprehensive evaluation of the specific associations between individual comorbidities and disability, treatment initiation, and mortality remains underexplored. This study aimed to review and summarize existing evidence on the association between comorbidities and these three MS outcomes. Methods: A rapid review spanning the period from January 2002 to October 2023 was conducted following the Cochrane Rapid Review Methods Group recommendations. MEDLINE, Embase, and the grey literature were searched to identify studies examining the effects of comorbidities on disability, treatment initiation, and mortality among individuals with MS. Data extraction and risk of bias assessments were systematically performed, with the Newcastle-Ottawa scale and A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) criteria for observational studies and systematic reviews respectively. Results: The review included 100 primary studies, encompassing 88 different comorbidities. Most study populations were between 60-80% female, with an average age of 30-45 years at study start. The majority of included studies were conducted in Europe, North America, and Asia (specifically the Middle East). Over half (66%) of specific comorbidity-outcome relationships were examined within a single study only, and just two studies examined treatment initiation as an outcome. Methods used to assess comorbidities and outcomes varied widely and included self-report measures, medical records and diagnostic codes, and standardized clinical assessments. Depression was consistently associated with greater disability (adjusted hazard ratio (aHR): 1.50-3.59) and mortality (aHR: 1.62-3.55). Epilepsy was similarly associated with increased disability (aOR: 1.13-1.77) and increased mortality (aHR: 2.23-3.85). Diabetes was generally associated with increased mortality (aHR: 1.39-1.47), but results for disability were inconsistent. Most other conditions were examined in one or two studies only or findings varied across studies, unable to collectively indicate a clear association. Although the anxiety-disability relationship was assessed by 24 studies, the findings varied in terms of the presence, direction, and strength of a possible association, requiring nuanced interpretation. Conclusions: This study identifies relationships between various comorbidities and three outcomes in MS, providing a foundation for future research and clinical guidelines. People with psychiatric, metabolic, and neurological conditions may be at a higher risk of MS disease progression and may therefore benefit from the targeted treatment of their comorbidities. Overall, comorbidities have varying associations with MS outcomes and individual associations require further exploration. However, there is evidence that some comorbidities indicate worse disability and higher mortality risk, and present barriers to initiating MS treatment, making the prevention and management of comorbidities an integral piece of MS patient care.