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Higher comorbidity burden among people with multiple sclerosis (MS) was associated with worse clinical outcomes, pooled trial data showed.

Over a 2-year follow-up, people with three or more comorbidities had a 14% increased risk (adjusted HR 1.14, 95% CI 1.02-1.28) of any evidence of MS disease activity compared with those who had no comorbidity, reported Amber Salter, PhD, of UT Southwestern Medical Center in Dallas, who presented the findings at the annual European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Copenhagen.

Evidence of disease activity was defined as confirmed disability worsening, relapse, or lesion activity. The results were published simultaneously in .

Several studies have suggested comorbidities may be tied to more severe MS at diagnosis or disability worsening rates, but not much is known about the relationship between comorbidity and relapses or lesion activity, Salter said.

"We don't think that people with comorbidities are generally included in clinical trials," Salter said. "But in a recent study we conducted, we found that over 40% of participants enrolled in these trials had at least one comorbid condition."

The analysis used individual participant-level data from 16,794 MS patients in 17 phase III trials of disease-modifying therapies conducted from November 2001 to March 2018.

The primary outcome was evidence of disease activity over 2 years of follow-up. This included confirmed disability worsening assessed by scores, relapse activity, or any new or enlarging lesions on MRI.

About two-thirds of participants were women. At trial enrollment, 45.4% of participants had one or more comorbidities including hypertension; hyperlipidemia; ischemic, cerebrovascular, or peripheral vascular disease; diabetes; autoimmune thyroid and other autoimmune conditions; migraine; lung and skin conditions; depression; anxiety; or other psychiatric disorders.

Over the 2-year follow-up period, 61% (95% CI 56.2%-66.3%, I²=97.9%) of the pooled trials had evidence of MS disease activity.

Two or more cardiometabolic conditions upped the risk of disease activity (adjusted HR 1.21, 95% CI 1.08-1.37) compared with no cardiometabolic comorbidity. The presence of one psychiatric disorder also was tied to disease activity (adjusted HR 1.07, 95% CI 1.02-1.14).

In a model that examined individual comorbidities, depression and ischemic heart disease were associated with an increased risk of any evidence of disease activity.

"Those with the highest burden of comorbidity had over a 30% increased risk of having disability worsening," Salter said. "In the individual comorbidity model, we found that depression, ischemic heart disease, and hyperlipidemia were associated with an increased risk of disability worsening," she added.

"For relapses, we saw an association with the burden of [total] comorbidity and with psychiatric comorbidity, but we did not see an association with cardiometabolic conditions and an increased risk of relapse."

The number of total comorbidities, cardiometabolic comorbidities, or psychiatric comorbidities was not associated with a higher risk of developing new lesions. An increased hazard of new lesion activity, however, emerged for ischemic heart disease and diabetes, after adjusting for other comorbidities and additional covariates.

"We all recognize that if anyone has a significant comorbidity, they're excluded from coming into these studies," said Mark Freedman, MD, MSc, of the University of Ottawa in Ontario, who wasn't involved with the analysis. Outcomes might be more clear-cut "if you were to gather the general population and focus on that," he observed.

The findings are likely an underestimate, Salter acknowledged. "The severity of these comorbidities is probably on the more mild side, even within this population," she said.

"That's when you think about the broader MS community -- the impact on an individual patient could actually be quite larger," she noted. "The prevention and management of comorbidities is a strong clinical need."

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