Table 3.

Examples of the bidirectional relationship between comorbidities and the disease-modifying therapies used to treat MS.

Direction and summary of effect	Observed effect of the comorbidity	Specific examples from the literature	Examples of key outstanding issues and/or directions for future work
Comorbidity → DMTs
Comorbidity may affect DMT use	Delay or prevent initiation of a DMT	• ≥3 vs. no comorbidities present at MS diagnosis associated with a 25% lower risk (hazard) of starting a DMT (83) • specific comorbidities present at diagnosis - anxiety or ischemic heart disease - associated with a 22-28% lower risk (hazard) of starting a DMT (83) • only the injectable DMTs were studied (IFNB, GA)	Information is limited: • for the more recently approved DMTs (including orals and infusions) • across many world regions and healthcare settings (most cited studies are from Canada/N. Europe & universal health care settings)
	Lower DMT adherence	• Alcohol dependence associated with two-fold higher odds of poor adherence (<80% expected doses in last 30 days) to DMTs over 2-year study period (87) • only the injectable DMTs were studied (IFNB, GA)
	Earlier DMT discontinuation	• Mental health disorders or antidepressant use associated with a 47-51% higher risk (hazard) for earlier DMT discontinuation (84)
	Earlier DMT switch or escalation	• Presence of any comorbidity associated with a 42% higher risk of earlier safety or tolerability-related switch from first DMT used; findings differed by DMT (86) • Higher cardiovascular risk score associated with earlier escalation of DMT (36)
DMTs → comorbidity
DMTs may affect subsequent comorbidity burden	DMT triggers/causes onset of new disease‡	• alemtuzumab-associated autoimmune disease (affects 1 in 3 users) (88, 89) • mitoxantrone-associated cardiotoxicity and acute myeloid leukemia • several DMTs associated with severe hepatoxicity • several DMTs associated with risk of hypertension	DMT use and cancer risk largely unknown; long-term follow-up in large cohorts needed
	DMT worsens/re-activates an existing comorbidity or underlying comorbidity increases risk of another comorbidity‡	• Ofatumumab may reactivate hepatitis B virus • Macular oedema associated with several DMTs; presence of diabetes may increase risk
	DMT improves an existing comorbidity	• Emerging work suggests that some DMTs (e.g., fingolimod) may improve underlying depression (unclear if direct or indirect effect) (90)	Limited work in this area. Inclusion of persons with comorbidities in clinical trials offers opportunity to provide further insights

DMT, disease-modifying therapy; IFNB, beta-interferon; GA, glatiramer acetate; MS, multiple sclerosis.

‡ for a complete summary of potential effects of the DMTs, see each DMTs product monograph, in addition to a recent review (91).