April 15, 2016

Two studies by MS Society-funded researcher shine the spotlight on comorbidity in multiple sclerosis


Many people living with multiple sclerosis may also be affected by other chronic diseases. When someone is living with more than one condition, those conditions are termed “comorbidities”. Last year, MS Society Dr. Donald Paty Career Development Award and Operating Grant holder Dr. Ruth Ann Marrie (University of Manitoba) and collaborators undertook a review of the latest scientific literature and found that some of the most common comorbidities experienced by people living with MS include hypertension, hyperlipidemia (high cholesterol and other fats in the blood), chronic lung disease, depression and anxiety. Furthermore, a handful of other studies have shown evidence that comorbidities in MS are linked to disability progression, formation of brain lesions, increased hospitalizations and mortality.

Several important unresolved questions related to comorbidity and MS remain. Firstly, there is limited information on how comorbidities impact MS-related treatment, such as the decision to treat, the selection of a particular treatment, or evaluation of effectiveness, safety, tolerability and adherence of the treatment. This is of particular concern when considering the design of clinical trials for experimental therapies, which often exclude individuals with specific comorbidities from their inclusion criteria, therefore limiting the findings of the trial to people living with MS who do not have comorbidities.

Secondly, although people living with MS generally experience a lower health-related quality-of-life (HRQL) compared to the general population, it is unknown to what extent comorbidities play a direct and/or indirect role in contributing to the decline in HRQL in people living with MS. Addressing this knowledge gap is important because it will allow clinical practitioners to focus their attentions on specific comorbidities as part of the treatment plan for people living with MS and have the greatest impact on improving HRQL.

Dr. Marrie and colleagues recently published two studies aimed at shedding light on these important and unresolved questions. The first study, titled ‘The challenge of comorbidity in clinical trials for multiple sclerosis’, was based on the discussions and recommendations emerging from a group of expert investigators who attended the International Workshop on Comorbidity in Multiple Sclerosis, hosted in Toronto on March 27-28, 2015. The second study – ‘Health-related quality of life in multiple sclerosis: Direct and indirect effects of comorbidity’ – was funded in part by the MS Society of Canada. Both studies were published in the journal Neurology.

The Challenge of Comorbidity in Clinical Trials for MS

The expert group attending the International Workshop on Comorbidity in MS set out to identify research priorities for studying comorbidity, with a strong emphasis on how comorbidity can be appropriately integrated into clinical trial design. The group based their analyses on a systematic review of the body of scientific literature about the rates of comorbidity in MS.

They found that those with comorbidities are underrepresented or, in many cases, excluded from clinical trials across the health and disease spectrum and in MS trials in particular, and those trials that do include people with comorbidities often don’t report on them in great detail. While the reason for this trend is to ensure participant safety and to remove any confounding variables that could complicate interpretation of results, the consequence is that there is little information about the efficacy, safety and tolerability of experimental treatments in people with comorbidities who represent a sizeable portion of the MS population. These arguments were considered when weighing the benefits and drawbacks of explanatory trials – those that test the efficacy of an intervention under ideal conditions where every variable can be tightly controlled – and pragmatic trials – which mirror “real world” conditions more closely and capture the heterogeneity of people living with MS more closely.

The expert group developed a series of recommendations based on their analyses. These include:

  • Establish estimates for the rate of comorbidities among people living with MS based on both age and sex;
  • Shift phase III clinical trials of new therapies in MS from explanatory towards more pragmatic trial designs;
  • Clearly and consistently describe any comorbidities in MS clinical trial participants;
  • Evaluate treatment response, tolerability, and safety in clinical trials based on the presence of specific comorbidities;
  • People with comorbidities should be enrolled in phase IV, post-approval studies that monitor long-term safety data.

Health-Related Quality of Life in MS: Direct and Indirect Effects of Comorbidity

The researchers recruited 949 adults living with MS from four MS clinics across Canada in Alberta, British Columbia, Manitoba and Nova Scotia. The researchers used medical records to capture demographic and clinical information, including sex, age, race, age of MS symptom onset, disease course and disability status as measured by the Expanded Disability Status Scale (EDSS). Measures of HRQL were assessed using participant-reported questionnaires. Both physical and psychiatric comorbidities were determined based on the total number of physical illnesses other than MS ever diagnosed according to a self-reported questionnaire.

Based on the collected information, the researchers were able to measure both direct and indirect effects of disability, depression, anxiety, fatigue and physical comorbidity on HRQL in MS. All of the measured variables were significantly associated with HRQL; in particular, disability status and depressive symptoms had the strongest effects on diminishing HRQL. Although physical comorbidity and anxiety had a relatively small direct effect on HRQL, when the researchers considered how they might be acting indirectly through factors like depression and fatigue, the association became much stronger.


These two studies join a mounting body of scientific evidence that demonstrates a greater need to consider how comorbidities can impact the overall health, wellbeing, treatment and management of people living with MS. Information about how comorbidities influence the safety and efficacy of experimental treatments being evaluated in clinical trials will ensure that trials capture a greater proportion of the MS population in “real world” settings. Similarly, a greater awareness of the interactions between comorbidity and health related quality of life will inform treatment strategies that place a greater focus on managing other health factors like depression, anxiety and fatigue to optimize quality of life alongside conventional, disease-modifying therapies.


  1. Marrie RA et al. The challenge of comorbidity in clinical trials for multiple sclerosis. Neurology. 2016. pii: 10.1212/WNL.0000000000002471. [Epub ahead of print]
  2. Berrigan LI et al. Health-related quality of life in multiple sclerosis: Direct and indirect effects of comorbidity. Neurology. 2016. pii: 10.1212/WNL.0000000000002564. [Epub ahead of print]