Comorbidity Burden Is Associated With Increased Adverse Events, DMT Discontinuation in MS Clinical Trials

Amber Salter, PhD

(Credit: UT Southwestern)

Among a large group of patients with multiple sclerosis (MS), a higher rate of discontinuation of disease-modifying therapies (DMTs) was associated with the presence of 2 or more existing comorbidities, with psychiatric and cardiometabolic disorders showing particularly increased rates of early discontinuation.¹ Additionally, data suggest that greater comorbidity burden was associated with higher rates of adverse events of interest (AESIs) such as infection, treatment-emergent autoimmune disease, cancer, elevated transaminases, and lymphopenia.

“Higher comorbidity burden is associated with [an] increased rate of adverse events of interest and early discontinuation among people with MS participating in phase 3 clinical trials of DMTs. Our findings highlight the important role of comorbidities in the safety and tolerability of DMTs,” study author Amber Salter, PhD, the Kenney Marie Dixon-Pickens Distinguished Professors in Multiple Sclerosis Research at UT Southwestern Medical Center, and colleagues wrote.¹ The conclusions were based on data from a collection of 17 clinical trials that included more than 16,000 patients that were presented at the 2025 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum, held February 27-March 1, in West Palm Beach, Florida.

All told, higher rates of early discontinuation were associated with a greater number of comorbidities when compared with those without comorbid conditions. The presence of 2 comorbidities resulted in a risk ratio (RR) of 1.23 (95% CI, 1.07-1.42), while 3 or more comorbidities resulted in an RR of 1.19 (95% CI, 1.01-1.40). Across all the included trials, early DMT discontinuations affected roughly 17% of participants (95% CI, 13.8-20.9; I² = 97.9).

Comorbidities are not uncommon in patients with MS, with some comorbidities specifically being more prevalent. Additional work done by this same group of authors, published in Neurology in 2024, suggests that nearly half of more than 17,000 clinical trial participants (46.5%) had at least 1 comorbidity (1 comorbidity: 25.0% [95% CI, 23.0-27.0; I² = 89.9]; 2 comorbidities: 11.4% [95% CI, 9.3-14.0; I² = 96.3]; 3 or more comorbidities: 6.0% [95% CI, 4.2-8.4; I² = 97.7]), with depression (16.45%) being the most prevalent, followed by hypertension (10.16%).² According to another comprehensive systematic review of 249 articles conducted by Ruth Ann Marrie, MD, PhD—one of the coauthors of this recent ACTRIMS presentation—and colleagues in 2015, the most prevalent comorbidities in patients with MS were depression (23.7%), anxiety (21.9%), hypertension (18.6%), hypercholesterolemia (10.9%), and chronic lung disease (10%).³

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Among these newly presented data, over the course of 2 years of follow-up in the 17 trials included, the pooled proportion of patients with an AESIs was 64% (95% CI, 59.4-68.9%; I² = 98.1). Infections, notably, made up the majority of AESIs.

Existing literature has suggested that patients with MS have a higher risk of infection—for example, a 2020 study from Persson et al suggested that, relative to patients without MS, those with MS had higher rates of any infection (US Department of Defense health system [US-DOD]: incidence rate ratio [IRR], 1.76 [95% CI, 1.72-1.80]; UK Clinical Practice Research Datalink GOLD system [UK CPRD]: IRR, 1.25 [95% CI, 1.21-1.29]) and a 2-fold higher rate of hospitalized infections (US-DOD: IRR, 2.43 [95% CI, 2.23-2.63]; UK-CPRD: IRR, 2.00 [95% CI, 1.84-2.17]).⁴

Another study from Brand et al in 2022 suggested that the rate of serious infection was 32.6 and 9.8 per 1000 person-years among patients with progressive and relapsing-remitting MS, respectively, compared with 6.75 per 1000 person-years in matched reference individuals without MS.⁵

The data that Salter et al presented at ACTRIMS showed that a greater comorbidity burden was associated with a higher rate of AESIs (RR: 1 comorbidity: RR, 1.13 [95% CI, 1.09-1.17]; 2 comorbidities: RR, 1.19 [95% CI, 1.14-1.23]; 3 or more comorbidities: RR, 1.25 [95% CI, 1.18-1.33]) compared with those with no comorbidity. Among those with 2 or more cardiometabolic conditions and 2 or more psychiatric conditions, a 15% increased risk of AESIs was observed (cardiometabolic: RR, 1.15 [95% CI, 1.10-1.21]; psychiatric: RR, 1.15 [95% CI, 1.08-1.23]).¹

“Some studies suggest that comorbidity is associated with reduced persistence to disease-modifying therapies (DMTs) in multiple sclerosis (MS). Less is known regarding the association of comorbidity with safety outcomes,” Salter and colleagues wrote. They wrote that the work they conducted included a 2-stage meta-analysis of participant data from phase 3 clinical trials of MS DMTs, noting that “trials were excluded if 2 years of follow-up on treatment were not available.”

The individual comorbidities that were considered for the study included: hypertension, hyperlipidemia, functional heart conditions, ischemic heart disease, cerebrovascular disease, peripheral vascular disease, diabetes, autoimmune thyroid, miscellaneous autoimmune conditions, migraine, lung, skin conditions, depression, anxiety, and other psychiatric disorders. Salter et al then created a composite sum of comorbidities as well as the number of cardiometabolic and psychiatric disorders to conduct their analysis.

Safety outcomes in the study were defined using adverse event (AE) data from each trial, which they reviewed to identify specific AESIs. Notably, nonpersistence was defined as “any early discontinuation from a trial based on study withdrawal forms.”

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REFERENCES
1. Salter A, Lancia S, Fitzgerald K, Kowalec K, Marrie R. Association of Comorbidities and Safety in Phase III Clinical Trials for Disease-Modifying Therapies in Multiple Sclerosis. Presented at: ACTRIMS Forum 2025; February 27-March 2; West Palm Beach, FL. CE1.4. https://www.abstractsonline.com/pp8/#!/20973/presentation/8
2. Salter A, Lancia S, Kowalec K, Fitzgerald K, Marrie R. Investigating the Prevalence of Comorbidity in Multiple Sclerosis Clinical Trial Populations. Neurology. 2024;102(5). doi:10.1212/WNL.0000000000209135
3. Marrie RA, Cohen J, Stuve O, Trojano M, Sørensen PS, Reingold S, et al. A systematic review of the incidence and prevalence of comorbidity in multiple sclerosis: overview. Mult Scler J. 2015;21:263–81. 10.1177/1352458514564491
4. Persson R, Lee S, Ulcickas Yood M, Wagner Usn Mc CM, Minton N, Niemcryk S, Lindholm A, Evans AM, Jick SS. Infections in patients diagnosed with multiple sclerosis: A multi-database study. Mult Scler Relat Disord. 2020;41:101982. doi: 10.1016/j.msard.2020.101982
5. Brand JS, Smith KA, Piehl F, Olsson T, Montgomery S. Risk of serious infections in multiple sclerosis patients by disease course and disability status: Results from a Swedish register-based study. Brain Behav Immun Health. 2022;22:100470. doi: 10.1016/j.bbih