Relationship between cognition and treatment adherence to disease-modifying therapy in multiple sclerosis: a prospective, cross-sectional study

Less than half of patients with chronic diseases, including multiple sclerosis (MS), adhere to their prescribed medications. Treatment selection is essential for patient adherence. The aim of this study was to explore the potential factors influencing nonadherence to disease-modifying therapies (DMTs) in MS. This prospective, cross-sectional study was performed at the Multiple Sclerosis Center between 2018 and 2021. In total, 85 patients were eligible for final analysis. Forty-one patient (48.2%) with MS were non-adherent to DMT. Male sex, oral administration of drugs, and longer treatment duration were associated with nonadherence. The mean Expanded Disability Status Scale score did not differ between the adherent and non-adherent patients (p > 0.05). Patients with a higher score on the Symbol Digit Modalities Test, who were receiving self-injection therapy, had shorter treatment duration, and higher disability, were more likely to be adherent to DMT than those without. To minimize nonadherence in patients with MS, the patient’s information processing speed should be considered before DMT initiation, and appropriate treatment options should be discussed.

. Flowchart of patient selection. DMT, disease-modifying therapy. Relationship between demographic, disease characteristics, and adherence to DMT. According to the study data of 85 patients with MS who were taking an injectable or oral DMT, the proportion of days covered (PDC) was < 80 in 41 (48.2%) patients. The adherence range was the same in patients up to 45 and older than 45 years of age (p > 0.05). The nonadherence rate was significantly higher in men than in women (p < 0.05).
No differences in adherence rates were detected according to disease duration, education level, and professional activity (all, p > 0.05). Oral administration showed a greater lack of adherence, also longer treatment duration (> 12 months) p < 0.05). Non-adherent patients were associated with an increased frequency of relapse in the post-index 12-month period (p < 0.05) ( Table 2).
Neurological disability, cognitive impairment, and adherence to DMT. The mean Expanded Disability Status Scale (EDSS) score did not differ between the adherent and non-adherent patients (p > 0.05). The scores of information processing speed and visuospatial memory were significantly lower in non-adherent patients than in adherent patients (p < 0.05), whereas the scores for verbal learning did not differ between the groups (p > 0.05) ( Table 3).   Table 4 shows the results of the binary logistic regression analysis, which identified significant factors that predict nonadherence to DMT in patients with MS. Patients with a higher SDMT score, self-injection therapy, shorter treatment duration, and higher disability were more likely to be adherent to DMT.

Discussion
In this study, overall adherence to DMT was low, with approximately 48% of patients not meeting the adherence criteria (PDC ≥ 0.8). The rate of adherence (52%) at 12 months was lower than that (60-77%) reported by other authors [17][18][19] , who applied the PDC criteria to larger samples. The disparate findings may have been due to differences between study populations (in other studies, investigators included patients with disability claims or patients before and after the first DMT claim date) or the DMTs analyzed 17,18 . Adherence rates vary among studies according to study sample and methods 11,13,17,18 , and it is apparent that adherence remains suboptimal in patients with MS initiating DMTs, and measures to improve adherence are warranted.
This study found several associations between patient characteristics and DMT adherence. Compliance and adherence levels to DMT were lower in men with MS than in women with MS. Other studies have provided mixed evidence regarding the difference in adherence between sexes 5,19,20 . Although MS is more prevalent in women than in men, it is important to focus on patient-centered care that can be used by health care practitioners to aid in enhancing adherence to DMT in men.
In the present study, oral DMT administration, a lower EDSS score, and longer treatment duration were associated with a greater lack of adherence. Many studies have compared adherence by type of DMT 5,19,21,22 . There is no consensus on which DMT patients have a higher compliance with: some studies have shown that patients using self-injected therapy, predominantly IFNβ, are more adherent than those not using such therapy 5,19 , other studies have indicated that patients using oral therapy, predominantly fingolimod, are more adherent than those not using such therapy 21,22 . Likewise, a study assessed three oral and five self-injected DMTs and found that the route of administration was not a significant predictor of nonadherence 23 . Given the equivocal evidence of the studies 5,19,21-23 , the difference in adherence between injectable and oral DMT remains unclear. In many studies, treatment adherence was found to be related to the duration of the treatment and neurological disability 24,25 . Similarly, in our study, patients with a longer treatment duration and lower EDSS score were also non-adherent to DMT.
Patients adherent to DMT (PDC > 80) in our study had a significantly decreased likelihood of relapse. The observed association between nonadherence and a higher probability of severe relapse (p < 0.05) coincides with the evidence demonstrated in other studies that nonadherence is a significant predictor of relapse 7,18,26-28 . Therefore, clues that promote adherence may improve the overall outcomes for patients with MS receiving DMT by reducing the frequency of relapses and disease progression.
Cognitive impairment in patients with MS as an important indicator of safe medication use should be assessed in patients with MS. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) was selected for cognition assessment in our study, as the BICAMS was recognized as a short, highly sensitive, and easily administered battery for patients with MS 29,30 . We found an association between a lower score of information processing speed and PDC < 80. There are no published data about adherence and the SDMT score, so this study is the first to examine the relationship between information processing speed and DMT adherence. The SDMT assessment, which is a quick and effective assessment of cognition 29,30 can be performed before DMT initiation and can help improve adherence to DMT. The patients with impaired information processing speed on the oral or injectable DMT should be closer monitored during routine visits. Some studies have shown that patient support programs have a positive impact on adherence to DMT independent of the treatment duration on DMT 31,32 . It is important that the majority of patients also believe in this positive effect 31 . E-pills or e-injection medication devices (e.g., timers or alarm watches) also can help improve medication compliance in these patients 32 . After all efforts are taken, if the patient still remains non-adherent, other treatment options should be considered. www.nature.com/scientificreports/ The present study has several limitations. First, cognition was only tested with the BICAMS, so other cognitive domains were not assessed. However, most cognitive tests, despite their sensitivity to MS, are time consuming and not routinely used in clinical settings. The aim of this study was to estimate and assess the impact of a cognitive tool that is readily available in most countries. Second, fatigue and depression, which are common comorbid conditions that have a great impact on cognition, were not assessed in the study. However, patients with severe fatigue and depression were excluded from the study.

Conclusions
Patients with a higher SDMT score or who were receiving self-injection therapy, or had a shorter treatment duration, or higher disability were more likely to be adherent to DMT. Improving patients' adherence level requires not only decision-making between patients and physicians and addressing side-effect profiles of medications, but it also requires cognition assessment before DMT administration. To minimize nonadherence in patients with MS, the patient's information processing speed should be considered before DMT initiation, and appropriate treatment options should be discussed.

Methods
Study design and population. This prospective, cross-sectional study was performed at the Multiple Sclerosis Center of Vilnius University Hospital Santaros Klinikos, Lithuania. Patients were enrolled and assessed between 2018 and 2021.
A total of 98 patients were enrolled in this study. All patients had relapsing MS and were on DMT (injectable or oral therapy).
Inclusion criteria for all patients were as follows: • Male or female patients older than 18 years of age; • Patients diagnosed with MS according to the McDonald criteria 33,34 ; • Patients with a relapsing disease course; • Patients receiving the same DMT at least 6 months before enrollment; • Patients who had not used any cognition-influencing medication (e.g., antidepressants, neuroleptics, and anticholinergic drugs) at least 3 months prior to enrollment and during the study; • Patients with no MS relapse or relapse treatment at least 3 months before enrollment and cognitive assessment; and • Patients with MS who were fluent Lithuanian speakers.
Exclusion criteria for all patients were as follows: • Patients with any neurologic or psychiatric disorders that could affect cognitive functions; • Patients with a history of clinically significant central nervous system disease (e.g., stroke, traumatic brain, or spinal injury) or neurological disorders that could mimic MS; • Patients with moderate or severe fatigue, anxiety, and/or depression; and • Patients with neurological signs that could interfere with cognitive performance (e.g., optic neuritis, upper dominant extremity weakness, or severe ataxia).
Neurological and cognitive assessment. The neurological assessment was performed in all participants, and neurological disability was assessed using the EDSS. The BICAMS was used for cognitive assessment 29,30 , which was performed by the same person in the same sequence: SDMT; BVMT-R, first three recall trials; and CVLT-II, first five trials. The Lithuanian version of the CVLT-II was used for assessment 35,36 . DMT and adherence. Eight different DMTs were identified and categorized into two groups: self-injected and oral. Self-injected therapies included IFNβ (Betaferon, Rebif, Avonex and Plegridy) and glatiramer acetate (Copaxone). Oral therapies included fingolimod, teriflunomide, and dimethyl fumarate. Adherence was measured using pills or injections counts, which were combined into PDC. PDC was calculated for all patients as the sum of days during the follow-up period that were covered by pills or injections, divided by the number of days in the follow-up period (365 days) 37 . Values for PDC ranged from 0 to 100% with higher values indicating higher adherence and "100%" indicating a patient who had complete DMT adherence. The percentages of patients with adherence levels of < 80% were considered as non-adherent and > 80% as adherent.
Statistical analysis. Descriptive statistics are presented as mean (m) and standard deviation. The Student t-test was used to compare means of the same variables between the two groups when the data distribution was normal. Categorical variables are expressed as absolute number and percentage. Categorical variables were analyzed using the chi-square test. To assess the normality of the distribution of quantitative variables, the Shapiro-Wilk test was used. In the regression analyses, adherence was modeled as a binary variable, with PDC ≥ 0.8 representing adherence and PDC < 0.8 indicating nonadherence. Explanatory variables (covariates) included