BACKGROUND

Patients with multiple sclerosis (MS) receiving disease-modifying therapies (DMT) show published adherence rates of 27.0% to 93.8% and published persistence rates of 49.7% to 96.5%. Improvements in DMT adherence and persistence are key to optimizing MS care, and enhanced understanding could improve MS disease management and identify research gaps. This scoping literature review aims to examine the nature and findings of the literature evaluating factors associated with DMT adherence and persistence in patients with MS.

METHODS

Eligible articles included in the literature review were quantitative clinical studies written in English, included adherence or persistence as primary outcomes, and accounted for covariates/confounders. The articles were assessed to identify factors associated with adherence/persistence and analyzed according to DMT type (self-injectable, oral, infusion).

RESULTS

Fifty-eight studies (103,450 patients) were included. Study distribution by DMT type was self-injectable only (n = 41), oral only (n = 2), infusion only (n = 1), and more than 1 type (n = 14). Older age and previous DMT use were associated with increased adherence and/or persistence. Increased alcohol consumption, DMT adverse events, higher education, and higher body mass index were negatively associated with adherence and/or persistence. Greater number and severity of relapses was associated with increased adherence but decreased persistence.

CONCLUSIONS

Most studies examined factors associated with adherence and persistence to self-injectable DMTs. These factors should be evaluated further for oral and infusion DMTs. Insights into the modifiable factors associated with adherence and persistence could guide treatment decisions and help improve adherence and clinical outcomes.

Adherence and persistence have often been used interchangeably in the management of disease-modifying therapies (DMT) in multiple sclerosis (MS). However, in recent years, there has been greater differentiation between the terms in published medical literature.1  Medication adherence is the degree or extent of conformity to the day-to-day treatment recommendations regarding the timing, dosage, and frequency of a medication.1  Medication persistence is the act of continuing treatment for the prescribed duration, from initiation to discontinuation.1  The degree of adherence and persistence is often situation specific (ie, treatment, individual, disease), resulting in a large degree of variability.

Similar to studies of patients with other chronic medical conditions,2,3  studies of adherence and persistence to DMTs in people with MS have found that a substantial percentage do not conform to recommendations about their prescribed therapies.414  Published adherence rates range from 27.0% to 93.8%,414  and published persistence rates range from 49.7% to 96.5%.46,810,12  The rates of adherence and persistence observed varied depending on the patient population, the type of DMT, the study duration, and the definitions of adherence and persistence.414  Adherence and persistence to MS DMTs are important to achieve the best clinical outcomes. Patients adherent to DMTs have been shown to have a reduced risk of relapse, emergency department visits, severe relapses, hospitalizations, and neuropsychological issues; lower costs; and increased quality of life compared with nonadherent patients.10,12,15,16  Persistence to DMTs has been associated with a lower likelihood of emergency department visits and inpatient admissions and with lower costs.17,18 

An improved understanding of the factors associated with DMT adherence and persistence could enhance the overall planning of MS disease management and improve patient outcomes. These factors include those associated with the patient, treatment regimen, patient-provider relationship, clinical setting, and disease.19  The present study explores how the factors associated with adherence and persistence to DMTs in MS have been evaluated in the current literature. We determined that a scoping review2022  was the most appropriate approach. To our knowledge, this is the first scoping review of the literature summarizing all studies evaluating adherence and persistence to DMTs in patients with MS, regardless of the definitions of outcomes used, the types of patients included, the study design, or the types of DMTs received.

A scoping review of the literature was performed given the heterogeneous nature of the body of literature and our desire to systematically synthesize the research evidence and group it in terms of its nature, features, and volume.22  The scoping review also enabled us to identify research gaps and make recommendations for future research.22  The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMAScR) Checklist was used to conduct the literature review.23 

We searched the PubMed database in March 2020 using the following search terms and strategy: multiple sclerosis AND (adherence OR compliance OR persistence) AND (factors affect OR predict OR associated with) AND limits to “human” and “English.” PubMed was used because of its ease of accessibility and comprehensiveness. There were no limits on publication date. Only studies that had primary data (ie, review articles and editorials were excluded), evaluated factors associated with adherence/persistence, and accounted for covariates and confounders were included. Two reviewers (author N.C.E and researcher Roger Edwards) screened the titles and abstracts of the articles from the literature search results to identify those that met the inclusion criteria. They also searched the reference lists of identified review articles to identify additional relevant studies.

Of 402 records identified through the PubMed database search, 341 were excluded due to a lack of primary data (n = 102) or because they did not measure factors associated with adherence or persistence (n = 239). The full text of the remaining articles was then assessed for eligibility, and a further 11 articles were excluded because they did not account for confounders or covariates. An additional 8 articles were identified from reference lists of previous literature reviews that met the inclusion criteria and were included. Overall, 58 studies were eligible for inclusion (FIGURE 1).

FIGURE 1.

Overview of Studies

FIGURE 1.

Overview of Studies

Close modal

The information extracted and summarized from the screened articles included journal citation; publication date; country of analysis; study design; data source; duration of follow-up; years of data collection; study population (baseline demographic and clinical characteristics); sample size; DMTs evaluated; definition of adherence/persistence; factors associated with adherence/persistence that were evaluated; and factors positively, negatively, or not associated with DMT adherence/persistence.8,16,17,2474 

The factors associated with adherence/persistence were summarized as frequency of collection and directional findings. Studies were stratified by type of DMT evaluated (self-injectable, oral, infusion) and the definitions of adherence/persistence used (adherence, discontinuation, treatment initiation), creating 9 different groupings. Studies that included more than 1 type of DMT and did not present their findings by type of DMT were included in the scoping review; however, they were not included in the evaluation of the factors associated with adherence/persistence given the differences in assessing adherence/persistence across DMT types, and, hence, the stratification by type of DMT.

Thirty-six studies evaluated adherence16,2629,3134,3741,4347,5356,58,59,62,6467,70,71,7376  and 30 studies evaluated persistence8,17,24,25,29,30,3539,42,44,4852,56,57,5961,63,64,68,69,72,77,78  (not mutually exclusive; total of 58 studies, 103,450 patients) (TABLE S1, available online at IJMSC.org). The studies were mostly conducted in the United States (n = 27)8,17,24,27,3235,3840,43,45,47,52,5658,60,62,63,6567,70,73,75,77  or Europe (n = 20),25,26,28,31,36,37,41,44,46,4851,53,54,68,71,72,74,78  with the rest in Canada (n = 4),29,30,59,76  Australia (n = 2),42,64  or multinational (n = 4).16,55,61,69  The duration of follow-up ranged from a minimum of 1 month75  to a maximum of 14 years,30  and 11 studies had any or non-specified follow-up24,32,33,36,44,47,48,58,68,74,78  (Table S1).

The types of studies included were prospective and retrospective cohort studies (level IV), prospective patient surveys (level IV), analyses of randomized controlled trials (level II), and retrospective administrative claims database analyses (level IV) (FIGURE 2). Prospective and retrospective cohort studies and retrospective claims database evaluations were the most common types of studies conducted. Retrospective claims database analyses typically included large samples of patients. The year of publication for included studies ranged from 2001 to 2019. Clusters of studies were published in 2011, 2016, and 2017 (Figure 2).

FIGURE 2.

Study Selection Flow Diagram

FIGURE 2.

Study Selection Flow Diagram

Close modal

Most studies examined self-injectable DMTs only (n = 41; interferon [IFN] β-1a intramuscular, IFN β-1a subcutaneous, IFN β-1b, glatiramer acetate)16,17,2437,3941,4345,47,5357,6468,7074,7678 ; 2 examined oral DMTs only (dimethyl fumarate, fingolimod, terif lunomide),51,59  1 examined infusion DMTs (natalizumab) only,48  and 13 examined more than 1 type of DMT8,38,42,46,49,50,52,58,6062,69,75  (FIGURE S1). Thirty studies evaluated adherence through patient self-reported outcomes (n = 15),16,28,37,40,44,58,63,65,67,68,70,73,7577  medication possession ratio (n = 6),27,38,39,43,57,62  proportion of days covered (n = 5),29,45,47,56,59  or device reports (n = 4),31,40,53,71  and 36 studies evaluated persistence through discontinuation (n = 30),8,17,24,25,29,35,36,41,42,48,49,51,52,5557,60,61,6469,72,7476  noninitiation (n = 5),35,36,63,73,77  or switching (n = 1)50  (Figure S1). The studies were not mutually exclusive, as some evaluated both discontinuation and adherence.

Self-injectable DMTs

The 41 studies involving only self-injectable DMTs evaluated adherence (n = 25),16,26,27, 28,29,31,34,37,39,40,43,44,47,53,54,55,64,65,66,67,70,71,73,74,76  discontinuation (n = 17),17,24, 25,26,30,35,36,37,39,41,44,56, 57,64,68,72,78  and treatment initiation (n = 3).35,36,77  The factors associated with self-injectable DMT adherence and/or persistence in at least 3 of the studies are presented in TABLE S2. There was substantial variability across studies in which factors showed positive, neutral, or negative associations with adherence. Increasing age was evaluated in 16 studies26,27,29,39,47,53,56,6468,70,7678  and was found to be positively associated with adherence in half of the studies.26,27,39,47,56,65,67,77  The effect of number or severity of relapses was evaluated in 7 studies31,40,57,64,72,77,78  and was found to be positively associated with adherence in half of the studies (Table S2). Higher educational level, higher body mass index (BMI), greater alcohol consumption, and DMT adverse events were negatively associated with adherence in half or more of the studies in which they were assessed (Table S2). Perceived benefits of the DMT had a positive association with persistence, while being in the South US Census region, lower educational level, greater number/severity of relapses, greater alcohol consumption, and more recent year of DMT initiation had a negative association with persistence in half or more of the studies in which they were assessed. Overall, associations between adherence and/or persistence and cognitive issues, anxiety, or depression were not apparent (Table S2).

Three studies evaluated factors associated with self-injectable DMT initiation.35,36,77  Two of them evaluated prescription abandonment, defined as the patient never taking possession of a prescribed medication. Gleason et al35  found that greater out-of-pocket expenses for DMTs were associated with a greater likelihood of prescription abandonment (odds ratio [OR], 6.1-7.3 for out-of-pocket expense groups greater than $200). Grytten et al36  found that the risk of not starting a DMT was associated with increasing age at diagnosis (OR, 1.04), geographic region (OR, 0.07-0.27), and disease-related stress and avoidant trauma coping (OR, 1.03). The third, Minden et al,77  evaluated the factors associated with ever use of self-injectable DMTs. Age (OR, 0.09-0.38), annual family income (OR, 0.38-0.69), perceived health status (OR, 1.69), seeing a neurologist for usual MS care (OR, 0.14-0.54), time since diagnosis (OR, 0.59-2.37), level of disability (OR, 2.79-3.68), disease course (OR, 0.55), and number of relapses (OR, 1.46-2.01) were associated with ever use of self-injectable DMTs.

Oral DMTs

Of the 2 studies that examined only oral DMTs,51,59  1 study evaluated the factors associated with DMT adherence,59  both evaluated the factors associated with DMT persistence, and neither evaluated DMT initiation. Setayeshgar et al59  found that patients with MS who had previously used another DMT had higher odds of optimal adherence to their oral DMT (OR, 2.4). In addition, patients with MS with higher neighborhood-level socioeconomic status had higher odds of discontinuation within 6 months (OR, 2.2).59  Lattanzi et al51  reported variation in discontinuation rates by oral DMT (OR, 2.89-3.26) and suggested that the reason for these observed differences in persistence may be a combination of drug efficacy and drug tolerability; however, this was not specifically evaluated in the study.

Infusion DMTs

Only 1 study examined the factors associated with infusion DMT persistence: Krämer et al48  found that discontinuing an infused DMT was associated with physicians’ judgment on treatment continuation, patients’ perception of personal progressive multifocal leukoencephalopathy risk, and John Cunningham virus seroconversion (R2 = 0.31; P < .05).48  No studies evaluated the factors associated with only infusion DMT adherence or initiation.

The present research summarizes the breadth of studies that sought to evaluate factors associated with DMT adherence and persistence in MS and identifies potential research opportunities to help improve adherence and clinical outcomes. There is a scarcity of studies evaluating adherence and persistence in oral and infusion DMTs. As oral and infusion DMTs have emerged in the MS treatment landscape in recent years, understanding the unique factors that may influence adherence and persistence to these therapies has become increasingly important.14,59 

Factors affecting adherence and persistence differed among the types of DMTs. Increasing age and greater number and severity of relapses may be associated with higher levels of self-injectable DMT adherence, whereas higher educational level, higher BMI, greater alcohol consumption, and DMT adverse events may be negatively associated with self-injectable adherence. Perceived benefits of a self-injectable DMT may have a positive association with persistence, whereas region (South US Census region), lower educational level, greater number and severity of relapses, greater alcohol consumption, and more recent DMT initiation had a negative association with persistence. Only previous use of another DMT was associated with increased adherence to oral DMTs. Socioeconomic status and the specific DMT used were associated with oral DMT discontinuation. Physicians’ judgment, patients’ perception of personal progressive multifocal leukoencephalopathy risk, and John Cunningham virus seroconversion were associated with infusion DMT discontinuation.

The identification of modifiable factors associated with adherence and persistence may inform the design of programs and policies that can optimize DMT treatment.76,79  Modifiable factors found to have a positive association with adherence and/or persistence included the type of DMT and patient and provider perception of the treatment. Modifiable factors found to have a negative association with adherence and/or persistence included BMI, alcohol consumption, and DMT adverse events. Although nonmodifiable factors cannot be reasonably altered by patients or providers, they can inform possible subgroups of patients who warrant special attention regarding potential interventions or the optimal timing of an intervention.76,79  Older age and previous DMT use were the nonmodifiable factors found to have a positive association with adherence and/or persistence, and region (South US Census region), higher educational level, and more recent DMT initiation were the nonmodifiable factors found to have a negative association. Greater number and severity of relapses was found to be positively associated with adherence but negatively associated with persistence. Patients who experience relapses may be more motivated to adhere to their treatment regimen to control their disease activity,40,75  but they may also be more likely to discontinue or switch from their current medication if it is perceived to be ineffective.64,69,78  The present analysis did not find an association between adherence and/or persistence and cognitive issues, anxiety, or depression.

There is no clear consensus as to why higher educational level has been found to be negatively associated with adherence16,28,41  and persistence36  in some studies of self-injectable DMTs. The 3 studies that found a negative association between higher educational level and adherence all used a strict definition of adherence (ie, not missing any doses of DMT),16,28,41  and 2 of the studies assessed adherence over a relatively short period compared with most published studies evaluating adherence.16,28  Devonshire et al16  evaluated factors associated with adherence through a global phase 4 study and defined nonadherence as missing at least 1 dose of DMT in the previous 4 weeks. Duchovskiene et al28  evaluated factors associated with adherence using an observational survey from a referral center in Lithuania and defined nonadherence as missing at least 1 dose of DMT during the previous 3 months. Jernas et al41  evaluated patients treated at the Medical University of Lublin and found that the risk of omitting a dose during 2 years of therapy increased in patients who were working or studying. Regarding persistence, Grytten et al36  showed that patients with more education were more likely to initiate DMTs (although not statistically significantly different) but also more likely to discontinue after the first-prescribed DMT. Hence, some patients with greater education who initiated a DMT may have been less motivated to continue.

To effectively address nonadherence, it is important that providers understand each patient’s treatment challenges, including specific reasons for nonadherence and dose-skipping patterns.80  This information will enable clinicians to more effectively discern the patient’s needs and how they may encourage adherence. Most patients with MS prefer to take an active role in decision-making; hence, a shared decision-making process, including a collaborative approach to treatment decisions between the provider and the patient, is expected to be an important factor in DMT adherence.82  Patients are more likely to adhere to treatment regimens if they view their relationship with their clinician as high-quality.83  Shared decision-making is also an opportunity to improve health literacy.84  According to American Academy of Neurology guidelines for good clinical practice, treatment discussions should occur when the patient is receptive and should be a continuing dialogue throughout a patient’s treatment because ensuring adherence and carefully monitoring DMTs are important aspects of cost-effective care in MS.85 

Several interventions for improving adherence and persistence among the patient subgroups warranting special attention (ie, having nonmodifiable factors associated with adherence and persistence, such as age, previous DMT use, relapse rate and severity, US Census region, educational level, and year of DMT initiation) have been shown to be effective. Motivational interviewing has been effectively used to improve communication with and education of patients with MS,86  and telephone-based counseling has improved adherence and persistence in the treatment of MS.86  Technologies that offer timely support and reminders to patients (eg, text messaging) are effective for patients with MS.83  Integrated delivery networks that include their own specialty pharmacies offering patient counseling services and that have MS clinical pharmacists available may assist in addressing barriers to adherence. Specialty pharmacies routinely call patients for their refills and can determine whether there may be an issue that could be impacting adherence or signal a potential lack of efficacy and need for a change in therapy to refer to a prescriber.87  Specialty pharmacies have been shown to increase adherence to specialty drugs and may help enable early identification of potential barriers, such as cost, disease/treatment education, prior authorizations, appeals processing, and close patient follow-up.87,88 

The studies included in this scoping review varied widely in design, sample size, and definitions of adherence and persistence. The quality of the included studies was not assessed. Furthermore, studies typically focused on predefined factors hypothesized to affect adherence and persistence and were not comprehensive in their assessment of all factors. Some studies were not fully documented and may not have reported factors that were not found to be associated with adherence and/or persistence. In addition, it is unclear how these factors may affect adherence and persistence over time. Because medication adherence and persistence are dynamic behaviors, and chronic diseases such as MS require long-term treatment, adherence and persistence should be consistently monitored using multiple modalities and with a focus on encounters between providers and patients.89  Finally, all the included studies evaluated daily or maintenance medications only. Future studies should consider newer medications that have unique dosing regimens.

PRACTICE POINTS
  • A greater understanding of the nature and volume of published literature evaluating factors affecting patient adherence and persistence across types of disease-modifying therapies (DMTs) in patients with multiple sclerosis is needed.

  • Investigations of the factors associated with adherence and persistence to DMTs in multiple sclerosis tend to focus on self-injectable DMTs; there is a paucity of data for oral and infusion DMTs.

  • Multiple factors were identified as potentially affecting adherence and/or persistence across the types of DMTs; although many factors (eg, age, socioeconomic status, previous DMTs) cannot be altered by patients or health care providers, the findings inform possible patient subgroups warranting attention and monitoring.

Writing and editorial support for the preparation of this manuscript was provided by Erich Junge and Phoebe Sadler of Ashfield MedComms, an Inizio company (New York, NY, USA); funding was provided by the study sponsor. We thank Elisabeth B. Lucassen, MD, for her input during early discussions of this manuscript and Roger Edwards for research support.

1.
Cramer
JA
,
Roy
A
,
Burrell
A
, et al.
Medication compliance and persistence: terminology and definitions
.
Value Health
.
2008
;
11
(
1
):
44
47
.
doi:
2.
Adherence to long-term therapies: evidence for action
.
World Health Organization
.
2003
.
3.
Jüngst
C
,
Gräber
S
,
Simons
S
,
Wedemeyer
H
,
Lammert
F
.
Medication adherence among patients with chronic diseases: a survey-based study in pharmacies
.
QJM
.
2019
;
112
(
7
):
505
512
.
doi:
4.
Brandes
DW
,
Callender
T
,
Lathi
E
,
O’Leary
S.
A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events
.
Curr Med Res Opin
.
2009
;
25
(
1
):
77
92
.
doi:
5.
Menzin
J
,
Caon
C
,
Nichols
C
,
White
LA
,
Friedman
M
,
Pill
MW
.
Narrative review of the literature on adherence to disease-modifying therapies among patients with multiple sclerosis
.
J Manag Care Pharm
.
2013
;
19
(
1
)(
suppl A
):
S24
S40
.
doi:
6.
Nicholas
JA
,
Edwards
NC
,
Edwards
RA
,
Dellarole
A
,
Grosso
M
,
Phillips
AL
.
Real-world adherence to, and persistence with, once- and twice-daily oral disease-modifying drugs in patients with multiple sclerosis: a systematic review and meta-analysis
.
BMC Neurol
.
2020
;
20
(
1
):
281
.
doi:
7.
Steinberg
SC
,
Faris
RJ
,
Chang
CF
,
Chan
A
,
Tankersley
MA
.
Impact of adherence to interferons in the treatment of multiple sclerosis: a non-experimental, retrospective, cohort study
.
Clin Drug Investig
.
2010
;
30
(
2
):
89
100
.
doi:
8.
Agashivala
N
,
Wu
N
,
Abouzaid
S
, et al.
Compliance to fingolimod and other disease modifying treatments in multiple sclerosis patients, a retrospective cohort study
.
BMC Neurol
.
2013
;
13
:
138
.
doi:
9.
Bergvall
N
,
Petrilla
AA
,
Karkare
SU
, et al.
Persistence with and adherence to fingolimod compared with other disease-modifying therapies for the treatment of multiple sclerosis: a retrospective US claims database analysis
.
J Med Econ
.
2014
;
17
(
10
):
696
707
.
doi:
10.
Yermakov
S
,
Davis
M
,
Calnan
M
, et al.
Impact of increasing adherence to disease-modifying therapies on healthcare resource utilization and direct medical and indirect work loss costs for patients with multiple sclerosis
.
J Med Econ
.
2015
;
18
(
9
):
711
720
.
doi:
11.
Higuera
L
,
Carlin
CS
,
Anderson
S
.
Adherence to disease-modifying therapies for multiple sclerosis
.
J Manag Care Spec Pharm
.
2016
;
22
(
12
):
1394
1401
.
doi:
12.
Burks
J
,
Marshall
TS
,
Ye
X
.
Adherence to disease-modifying therapies and its impact on relapse, health resource utilization, and costs among patients with multiple sclerosis
.
Clinicoecon Outcomes Res
.
2017
;
9
:
251
260
.
doi:
13.
Johnson
KM
,
Zhou
H
,
Lin
F
,
Ko
JJ
,
Herrera
V
.
Real-world adherence and persistence to oral disease-modifying therapies in multiple sclerosis patients over 1 year
.
J Manag Care Spec Pharm
.
2017
;
23
(
8
):
844
852
.
doi:
14.
Munsell
M
,
Frean
M
,
Menzin
J
,
Phillips
AL
.
An evaluation of adherence in patients with multiple sclerosis newly initiating treatment with a self-injectable or an oral disease-modifying drug
.
Patient Prefer Adherence
.
2017
;
11
:
55
62
.
doi:
15.
Ivanova
JI
,
Bergman
RE
,
Birnbaum
HG
,
Phillips
AL
,
Stewart
M
,
Meletiche
DM
.
Impact of medication adherence to disease-modifying drugs on severe relapse, and direct and indirect costs among employees with multiple sclerosis in the US
.
J Med Econ
.
2012
;
15
(
3
):
601
609
.
doi:
16.
Devonshire
V
,
Lapierre
Y
,
Macdonell
R
, et al.
The Global Adherence Project (GAP): a multicenter observational study on adherence to disease-modifying therapies in patients with relapsing-remitting multiple sclerosis
.
Eur J Neurol
.
2011
;
18
(
1
):
69
77
.
doi:
17.
Reynolds
MW
,
Stephen
R
,
Seaman
C
,
Rajagopalan
K
.
Healthcare resource utilization following switch or discontinuation in multiple sclerosis patients on disease modifying drugs
.
J Med Econ
.
2010
;
13
(
1
):
90
98
.
doi:
18.
Thomas
NP
,
Curkendall
S
,
Farr
AM
,
Yu
E
,
Hurley
D
.
The impact of persistence with therapy on inpatient admissions and emergency room visits in the US among patients with multiple sclerosis
.
J Med Econ
.
2016
;
19
(
5
):
497
505
.
doi:
19.
Ickovics
JR
,
Meisler
AW
.
Adherence in AIDS clinical trials: a framework for clinical research and clinical care
.
J Clin Epidemiol
.
1997
;
50
(
4
):
385
391
.
doi:
20.
Munn
Z
,
Peters
MDJ
,
Stern
C
,
Tufanaru
C
, Mc
Arthur
A
,
Aromataris
E
.
Systematic review or scoping review? guidance for authors when choosing between a systematic or scoping review approach
.
BMC Med Res Methodol
.
2018
;
18
(
1
):
143
.
doi:
21.
Arksey
H
,
O’Malley
L
.
Scoping studies: towards a methodological framework
.
Int J Soc Res Methodol
.
2005
;
8
(
1
):
19
32
.
doi:
22.
Peters
MD
,
Godfrey
CM
,
Khalil
H
,
McInerney
P
,
Parker
D
,
Soares
CB
.
Guidance for conducting systematic scoping reviews
.
Int J Evid Based Healthc
.
2015
;
13
(
3
):
141
146
.
doi:
23.
Tricco
AC
,
Lillie
E
,
Zarin
W
, et al.
PRISMA Extension for Scoping Reviews (PRISMA-ScR): checklist and explanation
.
Ann Intern Med
.
2018
;
169
(
7
):
467
473
.
doi:
24.
Berger
BA
,
Hudmon
KS
,
Liang
H
.
Predicting treatment discontinuation among patients with multiple sclerosis: application of the transtheoretical model of change
.
J Am Pharm Assoc (2003)
.
2004
;
44
(
4
):
445
454
.
doi:
25.
Correia
I
,
Marques
IB
,
Sousa
M
, et al.
Predictors of first-line treatment persistence in a Portuguese cohort of relapsing-remitting multiple sclerosis
.
J Clin Neurosci
.
2016
;
33
:
73
78
.
doi:
26.
Degli Esposti
L
,
Piccinni
C
,
Sangiorgi
D
, et al.
Changes in first-line injectable disease-modifying therapy for multiple sclerosis: predictors of non-adherence, switching, discontinuation, and interruption of drugs
.
Neurol Sci
.
2017
;
38
(
4
):
589
594
.
doi:
27.
Dor
A
,
Lage
MJ
,
Tarrants
ML
,
Castelli-Haley
J
.
Cost sharing, benefit design, and adherence: the case of multiple sclerosis
.
Adv Health Econ Health Serv Res
.
2010
;
22
:
175
193
.
doi:
28.
Duchovskiene
N
,
Mickeviciene
D
,
Jurkeviciene
G
,
Dirziuviene
B
,
Balnyte
R
.
Factors associated with adherence to disease modifying therapy in multiple sclerosis: an observational survey from a referral center in Lithuania
.
Mult Scler Relat Disord
.
2017
;
13
:
107
111
.
doi:
29.
Evans
C
,
Marrie
RA
,
Zhu
F
, et al.
Adherence and persistence to drug therapies for multiple sclerosis: a population-based study
.
Mult Scler Relat Disord
.
2016
;
8
:
78
85
.
doi:
30.
Evans
C
,
Tam
J
,
Kingwell
E
,
Oger
J
,
University of British Columbia MS Clinic Neurologists
,
Tremlett
H.
Long-term persistence with the immunomodulatory drugs for multiple sclerosis: a retrospective database study
.
Clin Ther
.
2012
;
34
(
2
):
341
350
.
doi:
31.
Fernández
O
,
Arroyo
R
,
Martínez-Yélamos
S
, et al.
Long-term adherence to IFN beta-1a treatment when using RebiSmart device in patients with relapsingremitting multiple sclerosis
.
PLoS One
.
2016
;
11
(
8
):e0160313.
doi:
32.
Fraser
C
,
Hadjimichael
O
,
Vollmer
T
.
Predictors of adherence to Copaxone therapy in individuals with relapsing-remitting multiple sclerosis
.
J Neurosci Nurs
.
2001
;
33
(
5
):
231
239
.
doi:
33.
Fraser
C
,
Hadjimichael
O
,
Vollmer
T
.
Predictors of adherence to glatiramer acetate therapy in individuals with self-reported progressive forms of multiple sclerosis
.
J Neurosci Nurs
.
2003
;
35
(
3
):
163
170
.
doi:
34.
Fraser
C
,
Morgante
L
,
Hadjimichael
O
,
Vollmer
T
.
A prospective study of adherence to glatiramer acetate in individuals with multiple sclerosis
.
J Neurosci Nurs
.
2004
;
36
(
3
):
120
129
.
doi:
35.
Gleason
PP
,
Starner
CI
,
Gunderson
BW
,
Schafer
JA
,
Sarran
HS
.
Association of prescription abandonment with cost share for high-cost specialty pharmacy medications
.
J Manag Care Pharm
.
2009
;
15
(
8
):
648
658
.
doi:
36.
Grytten
N
,
Aarseth
JH
,
Espeset
K
, et al.
Stoppers and non-starters of disease-modifying treatment in multiple sclerosis
.
Acta Neurol Scand
.
2013
;
127
(
2
):
133
140
.
doi:
37.
Haase
R
,
Kullmann
JS
,
Ziemssen
T
.
Therapy satisfaction and adherence in patients with relapsing-remitting multiple sclerosis: the THEPA-MS survey
.
Ther Adv Neurol Disord
.
2016
;
9
(
4
):
250
263
.
doi:
38.
Halpern
R
,
Agarwal
S
,
Borton
L
,
Oneacre
K
,
Lopez-Bresnahan
MV
.
Adherence and persistence among multiple sclerosis patients after one immunomodulatory therapy failure: retrospective claims analysis
.
Adv Ther
.
2011
;
28
(
9
):
761
775
.
doi:
39.
Halpern
R
,
Agarwal
S
,
Dembek
C
,
Borton
L
,
Lopez-Bresnahan
M
.
Comparison of adherence and persistence among multiple sclerosis patients treated with disease-modifying therapies: a retrospective administrative claims analysis
.
Patient Prefer Adherence
.
2011
;
5
:
73
84
.
doi:
40.
Hancock
LM
,
Bruce
JM
, Lynch SG
.
Exacerbation history is associated with medication and appointment adherence in MS
.
J Behav Med
.
2011
;
34
(
5
):
330
338
.
doi:
41.
Jernas
Ł
,
Wencel
J
,
Wiak
A
,
Bieniek
M
,
Bartosik-Psujek
H
.
Risk factors for poor adherence to Betaferon® treatment in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome
.
PLoS One
.
2016
;
11
(
10
):e0157950.
doi:
42.
Jokubaitis
VG
,
Spelman
T
,
Lechner-Scott
J
, et al.
The Australian Multiple Sclerosis (MS) immunotherapy study: a prospective, multicentre study of drug utilisation using the MSBase platform
.
PLoS One
.
2013
;
8
(
3
):e59694.
doi:
43.
Jones
JL
,
Scheidt
DJ
,
Kaushal
RS
,
Carroll
CA
.
Assessing the role of patient support services on adherence rates in patients using glatiramer acetate for relapsing-remitting multiple sclerosis
.
J Med Econ
.
2013
;
16
(
2
):
213
220
.
doi:
44.
Jongen
PJ
,
Lemmens
WA
,
Hoogervorst
EL
,
Donders
R
.
Glatiramer acetate treatment persistence - but not adherence - in multiple sclerosis patients is predicted by health-related quality of life and self-efficacy: a prospective web-based patient-centred study (CAIR study)
.
Health Qual Life Outcomes
.
2017
;
15
(
1
):
50
.
doi:
45.
Kale
HP
,
Patel
AM
,
Carroll
NV
.
A comparison of pharmacy dispensing channel use and adherence to specialty drugs among Medicare Part D beneficiaries
.
J Manag Care Spec Pharm
.
2018
;
24
(
4
):
317
326
.
doi:
46.
Koudriavtseva
T
,
Onesti
E
,
Pestalozza
IF
,
Sperduti
I
,
Jandolo
B
.
The importance of physician-patient relationship for improvement of adherence to long-term therapy: data of survey in a cohort of multiple sclerosis patients with mild and moderate disability
.
Neurol Sci
.
2012
;
33
(
3
):
575
584
.
doi:
47.
Kozma
CM
,
Phillips
AL
,
Meletiche
DM
.
Use of an early disease-modifying drug adherence measure to predict future adherence in patients with multiple sclerosis
.
J Manag Care Spec Pharm
.
2014
;
20
(
8
):
800
807
.
doi:
48.
Krämer
J
,
Tenberge
JG
,
Kleiter
I
, et al.
Is the risk of progressive multifocal leukoencephalopathy the real reason for natalizumab discontinuation in patients with multiple sclerosis?
PLoS One
.
2017
;
12
(
4
):e0174858.
doi:
49.
Lanzillo
R
,
Prosperini
L
,
Gasperini
C
, et al.
A multicentRE observational analysiS of PErsistenCe to Treatment in the new multiple sclerosis era: the RESPECT study
.
J Neurol
.
2018
;
265
(
5
):
1174
1183
.
doi:
50.
Laroni
A
,
Signori
A
,
Maniscalco
GT
, et al.
Assessing association of comorbidities with treatment choice and persistence in MS: a real-life multicenter study
.
Neurology
.
2017
;
89
(
22
):
2222
2229
.
doi:
51.
Lattanzi
S
,
Danni
M
,
Taffi
R
, et al.
Persistence to oral disease-modifying therapies in multiple sclerosis patients
.
J Neurol
.
2017
;
264
(
11
):
2325
2329
.
doi:
52.
Li
P
,
Hu
T
,
Yu
X
, et al.
Impact of cost-sharing increases on continuity of specialty drug use: a quasi-experimental study
.
Health Serv Res
.
2018
;
53
(
suppl 1
):
2735
2757
.
doi:
53.
Lugaresi
A
,
Florio
C
,
Brescia-Morra
V
, et al.
Patient adherence to and tolerability of self-administered interferon β-1a using an electronic autoinjection device: a multicentre, open-label, phase IV study
.
BMC Neurol
.
2012
;
12
:
7
.
doi:
54.
Paolicelli
D
,
Cocco
E
, Di
Lecce
V
, et al.
Exploratory analysis of predictors of patient adherence to subcutaneous interferon beta-1a in multiple sclerosis: TRACER study
.
Expert Opin Drug Deliv
.
2016
;
13
(
6
):
799
805
.
doi:
55.
Pozzilli
C
,
Schweikert
B
,
Ecari
U
,
Oentrich
W
;
BetaPlus Study group
.
Supportive strategies to improve adherence to IFN β-1b in multiple sclerosis: results of the βPlus observational cohort study
.
J Neurol Sci
.
2011
;
307
(
1-2
):
120
126
.
doi:
56.
Reynolds
MW
,
Stephen
R
,
Seaman
C
,
Rajagopalan
K
.
Persistence and adherence to disease modifying drugs among patients with multiple sclerosis
.
Curr Med Res Opin
.
2010
;
26
(
3
):
663
674
.
doi:
57.
Sabidó-Espin
M
,
Munschauer
R
.
Reasons for discontinuation of subcutaneous interferon β-1a three times a week among patients with multiple sclerosis: a real-world cohort study
.
BMC Neurol
.
2017
;
17
(
1
):
57
.
doi:
58.
Schwartz
CE
,
Grover
SA
,
Powell
VE
, et al.
Risk factors for non-adherence to disease-modifying therapy in pediatric multiple sclerosis
.
Mult Scler
.
2018
;
24
(
2
):
175
185
.
doi:
59.
Setayeshgar
S
,
Kingwell
E
,
Zhu
F
, et al.
Persistence and adherence to the new oral disease-modifying therapies for multiple sclerosis: a population-based study
.
Mult Scler Relat Disord
.
2019
;
27
:
364
369
.
doi:
60.
Shao
H
,
Stoecker
C
,
Monnette
AM
,
Shi
L
.
Cost sharing of disease-modifying treatments (DMTs) as policy lever to improve DMTs’ access in multiple sclerosis
.
Value Health
.
2018
;
21
(
9
):
1083
1089
.
doi:
61.
Spelman
T
,
Kalincik
T
,
Jokubaitis
V
, et al.
Comparative efficacy of first-line natalizumab vs IFN-β or glatiramer acetate in relapsing MS
.
Neurol Clin Pract
.
2016
;
6
(
2
):
102
115
.
doi:
62.
Tarrants
M
, Oleen-
Burkey
M
,
Castelli-Haley
J
,
Lage
MJ
.
The impact of comorbid depression on adherence to therapy for multiple sclerosis
.
Mult Scler Int
.
2011
;
2011
:
271321
.
doi:
63.
Thelen
J
,
Bruce
A
,
Catley
D
, et al.
Baseline predictors of DMT reinitiation among patients with multiple sclerosis following an MI-CBT intervention
.
J Behav Med
.
2018
;
41
(
2
):
253
260
.
doi:
64.
Tremlett
H
, Van der
Mei
I
,
Pittas
F
, et al.
Adherence to the immunomodulatory drugs for multiple sclerosis: contrasting factors affect stopping drug and missing doses
.
Pharmacoepidemiol Drug Saf
.
2008
;
17
(
6
):
565
576
.
doi:
65.
Turner
AP
,
Kivlahan
DR
,
Sloan
AP
,
Haselkorn
JK
.
Predicting ongoing adherence to disease modifying therapies in multiple sclerosis: utility of the health beliefs model
.
Mult Scler
.
2007
;
13
(
9
):
1146
1152
.
doi:
66.
Turner
AP
,
Roubinov
DS
,
Atkins
DC
,
Haselkorn
JK
.
Predicting medication adherence in multiple sclerosis using telephone-based home monitoring
.
Disabil Health J
.
2016
;
9
(
1
):
83
89
.
doi:
67.
Turner
AP
,
Williams
RM
,
Sloan
AP
,
Haselkorn
JK
.
Injection anxiety remains a long-term barrier to medication adherence in multiple sclerosis
.
Rehabil Psychol
.
2009
;
54
(
1
):
116
121
.
doi:
68.
Twork
S
,
Nippert
I
,
Scherer
P
,
Haas
J
,
Pöhlau
D
,
Kugler
J
.
Immunomodulating drugs in multiple sclerosis: compliance, satisfaction and adverse effects evaluation in a German multiple sclerosis population
.
Curr Med Res Opin
.
2007
;
23
(
6
):
1209
1215
.
doi:
69.
Warrender-Sparkes
M
,
Spelman
T
,
Izquierdo
G
, et al.
The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis
.
Mult Scler
.
2016
;
22
(
4
):
520
532
.
doi:
70.
Wicks
P
,
Massagli
M
,
Kulkarni
A
,
Dastani
H
.
Use of an online community to develop patient-reported outcome instruments: the Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ)
.
J Med Internet Res
.
2011
;
13
(
1
):e12.
doi:
71.
Zecca
C
,
Disanto
G
,
Mühl
S
,
Gobbi
C
.
Subjective patient-reported versus objective adherence to subcutaneous interferon β-1a in multiple sclerosis using RebiSmart: the CORE study
.
BMC Neurol
.
2017
;
17
(
1
):
171
.
doi:
72.
Zettl
UK
,
Schreiber
H
,
Bauer-Steinhusen
U
, et al.
Baseline predictors of persistence to first disease-modifying treatment in multiple sclerosis
.
Acta Neurol Scand
.
2017
;
136
(
2
):
116
121
.
doi:
73.
Zwibel
H
,
Pardo
G
,
Smith
S
,
Denney
D
,
Oleen-Burkey
M
.
A multicenter study of the predictors of adherence to self-injected glatiramer acetate for treatment of relapsingremitting multiple sclerosis
.
J Neurol
.
2011
;
258
(
3
):
402
411
.
doi:
74.
Moccia
M
,
Palladino
R
,
Russo
C
, et al.
How many injections did you miss last month? a simple question to predict interferon β-1a adherence in multiple sclerosis
.
Expert Opin Drug Deliv
.
2015
;
12
(
12
):
1829
1835
.
doi:
75.
Lulu
S
,
Julian
L
,
Shapiro
E
,
Hudson
K
,
Waubant
E
.
Treatment adherence and transitioning youth in pediatric multiple sclerosis
.
Mult Scler Relat Disord
.
2014
;
3
(
6
):
689
695
.
doi:
76.
McKay
KA
,
Tremlett
H
,
Patten
SB
, et al.
Determinants of non-adherence to disease-modifying therapies in multiple sclerosis: a cross-Canada prospective study
.
Mult Scler
.
2017
;
23
(
4
):
588
596
.
doi:
77.
Minden
S
,
Hoaglin
D
,
Jureidini
S
, et al.
Disease-modifying agents in the Sonya Slifka Longitudinal Multiple Sclerosis Study
.
Mult Scler
.
2008
;
14
(
5
):
640
655
.
doi:
78.
Moccia
M
,
Palladino
R
,
Carotenuto
A
, et al.
Predictors of long-term interferon discontinuation in newly diagnosed relapsing multiple sclerosis
.
Mult Scler Relat Disord
.
2016
;
10
:
90
96
.
doi:
79.
Fragoso
YD
.
Modifiable environmental factors in multiple sclerosis
.
Arq Neuropsiquiatr
.
2014
;
72
(
11
):
889
894
.
doi:
80.
Tintoré
M
,
Alexander
M
,
Costello
K
, et al.
The state of multiple sclerosis: current insight into the patient/health care provider relationship, treatment challenges, and satisfaction
.
Patient Prefer Adherence
.
2016
;
11
:
33
45
.
doi:
81.
Heesen
C
,
Kasper
J
,
Segal
J
,
Köpke
S
,
Mühlhauser
I
.
Decisional role preferences, risk knowledge and information interests in patients with multiple sclerosis
.
Mult Scler
.
2004
;
10
(
6
):
643
650
.
doi:
82.
Lizán
L
,
Comellas
M
,
Paz
S
,
Poveda
JL
,
Meletiche
DM
,
Polanco
C
.
Treatment adherence and other patient-reported outcomes as cost determinants in multiple sclerosis: a review of the literature
.
Patient Prefer Adherence
.
2014
;
8
:
1653
1664
.
doi:
83.
Remington
G
,
Rodriguez
Y
,
Logan
D
,
Williamson
C
,
Treadaway
K
.
Facilitating medication adherence in patients with multiple sclerosis
.
Int J MS Care
.
2013
;
15
(
1
):
36
45
.
doi:
84.
Cofield
SS
,
Thomas
N
,
Tyry
T
,
Fox
RJ
,
Salter
A
.
Shared decision making and autonomy among US participants with multiple sclerosis in the NARCOMS registry
.
Int J MS Care
.
2017
;
19
(
6
):
303
312
.
doi:
85.
Rae-Grant
AD
.
Incorporating clinical practice guidelines and quality measures into high-quality cost-effective care for patients with multiple sclerosis
.
Continuum (Minneap Minn)
.
2019
;
25
(
3
):
845
849
.
doi:
86.
Caon
C
,
Saunders
C
,
Smrtka
J
,
Baxter
N
,
Shoemaker
J
.
Injectable disease-modifying therapy for relapsing-remitting multiple sclerosis: a review of adherence data
.
J Neurosci Nurs
.
2010
;
42
(
5 Suppl
):
S5
9
.
doi:
87.
Tang
J
,
Bailey
J
,
Chang
C
, et al.
Effects of specialty pharmacy care on health outcomes in multiple sclerosis
.
Am Health Drug Benefits
.
2016
;
9
(
8
):
420
429
.
88.
Moore
JM
,
Matlin
OS
,
Lotvin
AM
, et al.
The adherence impact of a program offering specialty pharmacy services to patients using retail pharmacies
.
J Am Pharm Assoc (2003)
.
2016
;
56
(
1
):
47
53
.
doi:
89.
Neter
E
,
Wolkowitz
A
,
Glass-Marmor
L
, et al.
Multiple modality approach to assess adherence to medications across time in multiple sclerosis
.
Mult Scler Relat Disord
.
2020
;
40
:
101951
.
doi:

FINANCIAL DISCLOSURES: Dr. Ben-Zacharia has received consulting fees from Biogen, EMD Serono, Genentech, Greenwich Biosciences, Novartis, and TG Therapeutics. Mr. Walker has received consulting fees from Biogen, Celgene, EMD Serono, Novartis, and Sanofi Genzyme and is now an employee of EMD Serono, Rockland, MA, USA. Ms Ross has received consulting fees from Biogen, EMD Serono, Genzyme, Genentech, Roche, Alexion, Horizon, and Janssen. Dr Tornatore has received research funding from Biogen, Sanofi, and EMD Serono and was on advisory boards for Biogen, Genentech, Sanofi, EMD Serono, TG Therapeutics, and Atara. Ms Edwards is an employee of Health Services Consulting Corporation. Drs Lipman and Phillips are employees of EMD Serono, Rockland, MA, USA.

FUNDING/SUPPORT: This review was sponsored by EMD Serono, Rockland, MA, USA (CrossRef Funder ID: 10.13039/100004755), who reviewed and provided feedback on the manuscript. The authors had full editorial control of the manuscript and provided their final approval of all content.

Author notes

Note: Supplementary material for this article is available at IJMSC.org

Supplementary Material