Clinical Neurology and Neurosurgery 115S (2013) S6–S11
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Adherence to disease-modifying therapies and attitudes regarding disease in patients with multiple sclerosis a,∗ ˇ Ana Oˇzura a , Lea Kovaˇc b , Saˇsa Sega a b
Division of Neurology, University Medical Centre Ljubljana, Zaloˇska 2, 1000 Ljubljana, Slovenia Medical Faculty, University of Ljubljana, Vrazov trg 2, 1104 Ljubljana, Slovenia
a r t i c l e
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Keywords: Multiple sclerosis Patient adherence Disease-modifying treatment Side effects Attitudes
a b s t r a c t Although currently there is no cure for MS the course of the disease can be influenced by disease modifying therapy (DMT). For therapy to be sufficiently efficient, it is crucial that patients take their medication regularly as prescribed. Adherence describes the extent to which a patient acts in accordance with the prescribed timing, dosing, and frequency of medication administration. To date, there are no known data about adherence rates among patients with MS in Slovenia. We wanted to assess adherence in patients with MS, who are treated with first line DMTs and discover reasons for non-adherence. A number of 451 patients were invited to participate. They received two questionnaires via post mail. The adherence rate and putative reasons for non-adherence were assessed by the use of standardized self-report Multiple Sclerosis Treatment Experience Questionnaire (MSTEQ). Patients’ attitudes regarding disease, therapy and relationship with their physician were assessed by another questionnaire. The analysis of results included 299 patients. Among the patients 18.5% missed at least one medication dose in the past 28 days. Patients taking Avonex were significantly more adherent then patients on other DMTs (p = 0.005). Our study showed a higher then expected adherence among Slovenian patients with MS (81.5%). Our research did not confirm the influence of side effects or patients’ attitudes regarding illness and therapy on adherence. However we found unexpectedly high percentage (71.8%) of patients belief that psychological factors are involved in MS aetiology. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease associated with central nervous system (CNS) demyelination, affecting primarily young adults. Depending on the site of demyelinating lesions, it manifests clinically as a broad spectrum of physical, cognitive and emotional symptoms [1]. MS has three main phenotypes. The commonest form is relapsing–remitting MS, which is encountered in around 80% of the patients at an early stage of the disease [2]. It is characterised by an individual frequency of relapses followed by complete or incomplete remissions [3]. In around 65% of patients, RRMS eventually evolves to secondary progressive MS (SPMS) with continuous progression of disability independent of relapses, which also may occur. Primary progressive MS is a form that is progressive from onset without relapses and remissions and accounts for 20% of cases [3]. Although the disease itself remains incurable, the course of MS with relapses can be managed by so called Disease Modifying Therapy (DMT). Currently licensed as the first line immunomodulatory medications
∗ Corresponding author. Tel.: +386 15224320. ˇ E-mail address: [email protected] (S. Sega). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.09.013
are preparations of interferon -1a [Avonex®, Rebif®], interferon -1b [Betaferon®, Extavia®] and glatiramere acetate [Copaxone®]. Avonex® is injected intramuscularly once a week, Rebif® is injected 3 times per week subcutaneously, Betaferon® and Extavia® every second day subcutaneously and Copaxone® every day subcutaneously. Early treatment with DMT decreases the frequency of relapses, reduces disability progression [4] and lowers the incidence of hospitalisations [5]. It has been shown that DMT might not be effective in the long term in those MS patients with a poor level of adherence [6]. Adherence is defined as “the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen” [7]. Adherence has been studied across many chronic illnesses, such as HIV infection, hypertension, diabetes, epilepsy, asthma, and psychiatric illnesses. Overall, an average adherence rate of only 50% is indicated by The World Health Organization among patients with chronic diseases [8]. Rates of adherence are often variable and in some cases low also among DMT treated patients, in spite of the apparent benefits of DMT use. Different surveys report nonadherence rate among DMT treated patients to be between 6% and 46% [9,10], with an average nonadherence rate of nearly 25% [10]. Approximately half of the patients discontinue their treatment with DMT completely after 2 years [11]. Adherence
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Table 1 Patient demographic characteristics. Gender (%)
Age M (SD)
Disease duration M (SD)
DMT treatment duration M (SD)
m = 23.9; f = 76.1
42.0 (9.3)
10.6 (7.1)
6.0 (3.9)
N = 293. All data, except gender, expressed in years. M—arithmetic mean; SD—standard deviation; m—male; f—female; DMT—disease modifying treatment.
rate is difficult to measure accurately and so far none of the measurement methods is considered a golden standard. Adherence can be ascertained through a pill count, lab test, medical chart, collateral report, or electronic monitor. Most frequently used is still self-report method, although the patients tend to over-report their adherence [12]. Unfortunately, criteria for adequate adherence are not strictly defined, but rather depend on the particular survey. Some authors thus define adherence as taking at least 75% [13], 80% [4] or 85% [14] of prescribed medication doses over a longer period of time, whereas others define it as taking every dose of medication in the past 4 weeks [15,16]. To date there is no data on adherence rate in Slovenian MS patients. The aim of our study was to examine adherence to first line DMT in patients with MS at our MS center in Slovenia and potential factors that could influence it. We were also interested in attitudes patients have regarding the disease and treatment and their possible connection with adherence.
Fig. 1. Percentage of respective MS types. N (RR) = 246; N (SP) = 34; N (CIS) = 13. RRMS—relapsing–remitting MS; SPMS—secondary progressive MS; CIS—clinically isolated syndrome.
2. Methods 2.1. Participants All the patients diagnosed with MS, who were listed in the registry of the Centre for MS in Ljubljana and had been previously treated for at least one month with one of the first-line DMTs Betaferon®, Avonex®, Rebif®, Copaxone® or Extavia® were recruited to participate in this survey. On the basis of the registry demographic data about the patients (age, MS type, duration of illness, DMT type and duration of treatment), 451 patients meeting the above stated survey criteria were selected. They were invited to participate in the research by sending them two questionnaires and an explanatory letter to their home address by regular post. The patients were asked to answer both questionnaires and return the signed questionnaires via post to a given address. The returned questionnaires were collected and the data were transferred into a SPSS file for further analysis. All patients signed an informed consent at the start of the study. Our study was approved by the Slovenian ethic committee. A number of 15 patients did not receive the questionnaires due to an incorrect postal address; out of remaining 436 patients, that presumably received the questionnaires, 308 patients responded (response rate was 70.4%). After revising filled out questionnaires, 9 patients were excluded from the survey because they had not been taking any of the investigated medications in the previous 28 days (2 because of pregnancy, 4 switched therapies, 1 completely discontinued the therapy, 2 did not state any reason). In the result analysis 68.6% (299/436) of invited patients were included. Also 26 incomplete and 6 unsigned questionnaires were included in the analysis. It was not possible to analyse the unsigned questionnaires demographically, so demographic analysis was only done for the remaining 293 respondents. Demographic characteristics of the patients are shown in Table 1, Figs. 1 and 2.
Fig. 2. DMT type. N (Avonex®) = 44; N (Betaferon®) = 98; N (Copaxone®) = 65; N (Rebif®) = 88; N (Extavia®) = 4.
Fig. 3. Percentage of adherent patients on different DMT according to both criteria.
2.2. Material Two separate questionnaires were used to collect data. Each participant was asked to answer both questionnaires (Figs. 3 and 4).
Fig. 4. Attitudes of patients regarding MS aetiology.
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Table 2 Differences in demographic and disease variables between adherent and non-adherent groups.
Sex Age Disease type Disease duration Treatment duration
Nonadherent (N = 54)
Adherent (N = 294)
M
SD
M
SD
Testing differences M–W
2
p
/ 40.41 / 10.98 6.39
/ 9.291 / 7.173 4.341
/ 42.42 / 10.48 5.84
/ 9.337 / 7.082 3.718
/ 5610.000 / 6114.500 6151.000
0.139 / 0.112 / /
0.710 0.145 0.945 0.578 0.622
M—arithmetic mean; SD—standard deviation; M–W—Mann–Whitney test; 2 —Chi square test for nominal variables. Table 3 Differences in DMT type between adherent and non-adherent groups. DTM type
Estimated applications in 28 days
Nonadherent
Adherent
2
p
Avonex (IFN-1a) Betaferon (IFN-1b) Extavia (IFN-1b) Copaxone (GA) Rebif (IFN-1a)
4 14 14 28 12
2 21 0 15 17
42 77 4 49 71
0.01 0.857 / 1.344 0.062
0.005 0.427 / 0.276 0.87
IFN—interferon ; GA—glatiramer acetate. Table 4 Differences between the adherent and nonadherent group in side effects of injection.
Bleeding at injection site Pain, stinging, burning, or soreness at the injection sire during administration of treatment Have itching or irritation at the injection sire during administration of treatment Feel nervous or anxious during administration of treatment Have pain, stinging, burning, or soreness at the injection site after administration of treatment Have itching or irritation at the injection site after administration of treatment Have swelling, welts, or lumps at the injection site after administration of treatment Have abnormal redness of the skin or rash at the injection site after administration of treatment Have bruises at the injection site after administration of treatment Have chills, headaches, or flu-like symptoms after treatment Sum of all side effects
Nondherent (N = 55)
Adherent (N = 243)
Testing differences
M
SD
M
SD
M–W
p
0.87 1.44 0.42 1.02 1.24 0.80 1.56 0.98 0.86 1.05 10.24
0.883 1.183 0.854 1.240 1.217 1.177 1.198 1.080 0.893 1.353 7.279
0.94 1.62 0.37 1.01 1.10 0.59 1.50 1.13 1.02 1.10 10.37
0.789 1.119 0.758 1.182 1.203 1.017 1.248 1.229 1.062 1.363 7.048
6204.000 5938.500 6539.500 6626.000 6148.500 5929.500 6419.500 6378.500 6275.500 6442.000 6580.500
0.378 0.168 0.793 0.917 0.327 0.156 0.632 0.579 0.471 0.729 0.859
M—arithmetic mean, SD—standard deviation, M–W—Mann–Whitney test. Table 5 Reasons for missing injections in the nonadherent group.
Too busy Did not want taking medication to interfere with activities Memory problems Side effects of medication Tired of taking medication Did not feel like taking medication Feeling anxious, depressed or nervous about taking medication Side effects of injection Away from home and could not access medication Fear of needles Dissatisfaction with medication Ran out of medication or could not refill prescription Needing someone to help me take medication
Not important at all (%)
A little important (%)
46.3 51.9 59.3 59.3 55.6 63 66.7 64.8 70.4 79.6 81.5 85.2 88.9
33.3 24.1 18.5 20.4 27.8 20.4 14.8 14.8 13 7.4 5.6 7.4 5.6
Moderately important (%) 11.1 13 11.1 9.3 7.4 5.6 9.3 16.7 7.4 3.7 7.4 1.9 0
Extremely important (%)
M
SD
9.3 11.1 11.1 11.1 9.3 11.1 9.3 3.7 9.3 9.3 5.6 5.6 5.6
0.83 0.83 0.74 0.72 0.70 0.65 0.61 0.59 0.56 0.43 0.37 0.28 0.22
0.966 1.042 1.049 1.036 0.964 1.012 0.998 0.901 0.984 0.944 0.853 0.763 0.718
N = 54, M—arithmetic mean; SD—standard deviation. Table 6 Differences between the adherent and nonadherent group in attitudes regarding disease and treatment.
Belief in genetic cause of MS Belief in autoimmune cause of MS Belief in infection as cause of MS Belief in psychological factors as cause of MS Belief in one’s influence on disease course Satisfaction with neurologist Belief in efficacy of alternative methods of treatment
Neadherentni (N = 55)
Adherentni (N = 293)
Preverjanje razlik
M
SD
M
SD
M–W
p
2.61 3.80 2.39 3.10 3.52 4.27 2.51
0.763 0.595 0.712 0.890 0.720 0.616 0.979
2.61 3.87 2.39 2.98 3.42 4.27 2.51
0.763 0.713 0.846 0.974 0.873 0.690 0.838
6459.000 6428.000 6255.000 6116.500 5855.000 6545.000 6125.000
0.965 0.620 0.645 0.443 0.052 0.338 0.336
M—arithmetic mean; SD—standard deviation; M–W—Mann–Whitney test.
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To assess adherence rate and determine the reasons for potential nonadherence, we used a translated and adapted version of Multiple Sclerosis Treatment Experience Questionnaire (MSTEQ) [17]. For the use in this study we also developed and used a survey on attitudes regarding MS and treatment (Tables 2–6). 2.3. Statistical analysis Statistical analysis was performed using SPSS version 17.0 (IBM Corporation, Somers, NY, USA). Normality of distribution was tested using Kolmogorov–Smirnoff test. Since all the statistics apart from patients’ age were not normally distributed, we used nonparametric tests for further analysis. Group comparisons were computed using Mann–Whitney test for two independent samples with ordinal and interval variables, and with 2 test for nominal variables. We considered the differences statistically significant where p value was p ≤ 0.05. 3. Results 3.1. Defining adherence In previous research with the MSTEQ instrument patients were identified as non-adherent if they missed 1 or more injections in the 28 days prior to completing the survey [6,18]. DMTs differ in the frequency of injection administration as described in the Introduction. That is why 1 missed injection cannot be evaluated in the same way in different DMTs. In the 28 days included in the MSTEQ analysis the expected number of Avonex injection administrations would be only 4 (once weekly) and 1 missed injection would represent 25% of all injections, while the excepted number of Copaxone injections would be 28 (daily administration) and 1 missed injection would represent 3.5% of all injections. To evaluate all DMTs equally we decided to also use a second criterion where patients would be identified as non-adherent when they miss at least 25% of the chosen DMT. The criteria would be quantified as ≥1 injection of Avonex, ≥3 injections of Rebif, Betaferon or Extavia or ≥7 injections of Copaxone. The overall adherence in our sample was 81.5% according to the 1st criteria (missed ≥1 injection), and 96.6% according to the 2nd criteria (missed ≥25% injections). Only 10 patients missed ≥25% of injections according to criteria 2. This group was too small therefore we used the criteria of missing ≥1 injection in the subsequent analysis. We can see that the adherent and the nonadherent group did not differ significantly in the demographic and disease variables. In the group on Extavia the adherence rate was 100%, however only four patients were receiving this therapy so statistical analysis was not possible. Testing the differences between the other 4 DMT’s showed that patients on Avonex were significantly more adherent then patients on other DMT’s. Side effects of treatment did not differ statistically significantly between the group of adherent and nonadherent. Among the patients 34.9% were using only classical type of injection application while 56.7% were using an autoinjector. Both types of injecting were used by 8.4% of patients. Only 19.3% of patients needed regular help with injecting, while 82.6% needed help only occasionally or never. Neither type of application (classical or use of autoinjector) or help of another person was significantly different between the adherent and nonadherent group. We also assessed reasons for missing injections. The most common self-reported reasons for nonadherence were being too busy, not wanting the medication to interfere with other activities, memory problems and side effects.
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Next we assessed the attitudes regarding disease and their influence on adherence. We can see the attitudes regarding aetiology of MS, one’s influence on the disease course, satisfaction with one’s neurologist and belief in alternative methods of treatment were not statistically significantly different between the adherent and non-adherent group. We can see that almost the whole sample believed that MS is an autoimmune disease and two thirds believed that psychological factors are important cause of MS. However, only around half of the patients regarded genetic and infectious factors as important.
4. Discussion The aim of our study was to examine adherence to DMT in patients with MS and potential factors that could influence it. We were also interested in attitudes patients have regarding the disease and treatment and their possible connection with adherence. Overall our study showed a high self-reported adherence rate (81.5%). Other studies with using self-report measures and the same a criterion (missing one or more injections) showed similar or lower rates of adherence—around 63% [13], 80% [4], between 84% to 49% [17] and 85.4% overall adherence [6]. Studies with an indirect criterion using rates of refilling prescriptions (≥80% medication possession ratio) found 59.6% adherence [19] and 81.1% adherence [20]. However a study using a novel electronic monitoring device showed 80% adherence (defined as missing less than 20% of their prescribed DMT), while only 40.3% of patients had perfect adherence [21]. Our study therefore showed similar results as previous research; however it is important to note that self-reported adherence rates such as the one we used might be underestimating non-adherence. Our results also showed that patients on Avonex® were significantly more adherent then patients on other DMT’s. The same was also found in other studies [1,13,16,22,23]. There is no general agreement up to date on whether type of DMT actually influences adherence [4]. In our case we believe that results showed this difference in adherence due to different frequency of DMT administration. Avonex is taken only once weekly, while other therapies are taken more often. Patients on Avonex therefore had to take the therapy only four times in order to be adherent, which is three to seven times less often then patients on other DMTs. Therefore adherence could be higher in patients on Avonex because they had to take the medication less often. However the study from Kleinman et al. [18] showed that adherence to Avonex was higher in comparison to other DMTs even when looking at it annually. It could be that simpler regimes which include less frequent administration of the drug increase adherence. Patients in our sample used the auto-injector 1.6 times more often than classical application. Nevertheless in our study there was no connection between injector type and adherence. Up till now there is no date on auto-injectors improving adherence in MS, its use however has been shown to reduce side effects and discomfort [24]. In addition there was no connection between the need for help of another person during the application of DMT and adherence. Other studies similarly found that the help of other person was among least important reasons for missing injections [15,17]. Next we looked at the reasons for nonadherence. The most common self-reported reason for missing an injection was being too busy and doing other activities. The third most common reason was memory problems (forgetting to take the injection) followed by the side effects of the medication and being tired of taking medication. The least common reasons were needing help of others and being out of medication. These results are somewhat different from the previous studies where patients as the most common reason for
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missing injections reported memory problems [13,15,18] or side effects of medication [25]. One of the reasons for this could be the time frame of the investigation. During a longer time period memory problems become more pronounced. Other studies that used a shorter time frame (28 days) like we did also did not identify memory problems as the main reason for missing injections [13,17]. Another possible reason could be that our sample included patients who were in average younger and had shorter disease duration. Therefore they could have had less memory problems and were more active and busy in their daily lives. Among the nonadherent patients 40.7% reported side effects as one of the reasons for missing an injection. However the difference in side effects between the adherent and nonadherent group did not reach statistical significance. The study by Wicks et al. [17] using the same questionnaire as us also did not find significant differences, while other studies found side effects to be one of the most important reasons for nonadherence [13,16,18,25]. Furthermore we were interested in patients’ attitudes regarding illness and their connection to adherence. Previous research showed that belief in perceived benefits provided by the Health Beliefs Model predicted adherence [4]. We found that attitudes regarding disease aetiology, one’s influence on disease course, in efficacy of alternative methods of treatment and satisfaction with neurologist did not differ significantly between the groups of adherent or nonadherent patients. Only 1.3% of patients were not satisfied with their neurologists, therefore the number was not sufficient for reliable statistical analysis. Relationship with the neurologist was shown to be an important factor in adherence in other studies and seems to be the key in leading patients through treatment [26]. Next we were interested in the influence of the belief in efficacy of alternative treatments and how that relates to adherence as this field has not been included in previous research. We found that close to 50% of our sample believed these methods could be effective help in MS. At the same time these attitudes did not differ in the adherent and nonadherent group. Patients tend to choose alternative treatments due to unavailability of DMTs and its limited long term efficacy [27]. Moreover almost all patients believed MS to be an autoimmune disease, 71.8% believed psychological factors are important, while only 57.3% believed that genetic factors are significant in disease aetiology. Interestingly more patients believed in psychological factors involved in MS disease development then in genetic factors. Meta-analytical research showed that studies consistently find association between psychological stress and relapses in MS [28], however there is no data that stress increases risk for the development of MS [29]. Still, it is important to note that in patients’ attitudes psychological factors are perceived as important in disease aetiology. Patients who believe their disease was caused by psychological factors might feel they do not need to take medication. However our results did not confirm that hypothesis. Nevertheless they did indicate that patients in our sample were not very well informed about their disease which could be important. It was shown that unmet needs in education regarding disease influence adherence [30]. Our study had several limitations. We used a self-report questionnaire which is an indirect and subjective measure and can overestimate adherence [13]. Questionnaires were sent by post and the response rate was 70.4% which is similar to other studies [4,17]. Nevertheless it is probable that our sample included patients who were more ready to respond, while non-adherent patients might have refused to respond. This can again lead to overestimation of adherence. Also the time frame of the questionnaire we used (MSTEQ) for measuring adherence was short (one month). Other studies with time frames of several months or even years reported lower rates of adherence [11,26]; then studies using short time frames [9,13,17]. The described problem of underestimated nonadherence lead to a small number of identified nonadherent
patients. The comparison of groups (adherent vs. nonadherent) was therefore less reliable. This was the first study looking at adherence in Slovenia and it showed a high self-reported adherence rate (81.5%). Patients were most adherent to least frequently administered DMT. The most common self-reported reason for missing an injection was being too busy and doing other activities, memory problems were on third place. There were no differences in side effects between adherent and nonadherent patients. Patients’ attitudes regarding illness had no influence on adherence. Conflict of interest statement All authors report no actual or potential conflict of interest. Author’s contribution ˇ Study concept and design was performed by Saˇsa Sega and Ana Oˇzura, acquisition of data by Lea Kovaˇc, analysis and interpretation of data by Ana Oˇzura and Lea Kovaˇc, drafting of the manuscript ˇ and Lea Kovaˇc, critical revision of the by Ana Oˇzura, Saˇsa Sega ˇ manuscript for important intellectual content by Saˇsa Sega and administrative, technical and material support was performed by ˇ Saˇsa Sega. References [1] Barten LJ, Allington DR, Procacci KA, Rivey MP. New approaches in the management of multiple sclerosis. Drug Des Devel Ther 2010;4:343–66. [2] Nicholas R, Chataway J. Multiple sclerosis. Clin Evidence (Online) 2009:1202. [3] Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502–17. [4] 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):1146–452. [5] 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. ˜ O, GAP Study Group. [6] Arroyo E, Grau C, Ramo-Tello C, Parra J, Sánchez-Solino Adherence to disease-modifying therapies in spanish patients with relapsing multiple sclerosis: two-year interim results of the global adherence project. Eur Neurol 2011;65(2):59–67. [7] Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, Wong PK. Medication compliance and persistence: terminology and definitions. Value Health 2008;11(1):44–7. [8] Sabate E. Adherence to long-term therapies: evidence for action. Switzerland: World Health Organization; 2003. [9] Lugaresi A, Florio C, Brescia-Morra V, Cottone S, Bellantonio P, Clerico M, Centonze D, et al. Patient adherence to and tolerability of self-administered interferon -1a using an electronic autoinjection device: a multicentre, openlabel, phase IV study. BMC Neurol 2012;12:7. [10] Klauer T, Zettl UK. Compliance, adherence, and the treatment of multiple sclerosis. J Neurol 2008;255:687–92. [11] Wong J, Gomes T, Mamdani M, Manno M, O’Connor PW. Adherence to multiple sclerosis disease-modifying therapies in Ontario is low. Can J Neurol Sci 2011;(38):429–33. [12] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353(5):487–97. [13] Treadaway K, Cutter G, Salte A, Lynch S, Simsarian J, Corboy J, Jeffery D, et al. Factors that influence adherence with disease-modifying therapy in MS. J Neurol 2009;256(4):568–76. [14] 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 Invest 2010;30(2):89–100. [15] Devonshire V, Lapierre Y, Macdonell R, Ramo-Tello C, Patti F, Fontoura P, Suchet L, Hyde R, Balla I, Frohman EM, Kieseier BC. The Global Adherence Project (GAP): a multicenter observational study on adherence todisease-modifying therapies in patients with relapsing–remitting multiple sclerosis. Eur J Neurol 2011;18(1):69–77. [16] Beer K, Müller M, Hew-Winzeler AM, Bont A, Maire P, You X, Foulds P, Mårlind J, Curtius D. The prevalence of injection-site reactions with disease-modifying therapies and their effect on adherence in patients with multiple sclerosis: an observational study. BMC Neurol 2011;11:144. [17] 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):12.
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Adherence to disease-modifying therapies and attitudes regarding disease in patients with multiple sclerosis a,∗ ˇ Ana Oˇzura a , Lea Kovaˇc b , Saˇsa Sega a b
Division of Neurology, University Medical Centre Ljubljana, Zaloˇska 2, 1000 Ljubljana, Slovenia Medical Faculty, University of Ljubljana, Vrazov trg 2, 1104 Ljubljana, Slovenia
a r t i c l e
i n f o
Keywords: Multiple sclerosis Patient adherence Disease-modifying treatment Side effects Attitudes
a b s t r a c t Although currently there is no cure for MS the course of the disease can be influenced by disease modifying therapy (DMT). For therapy to be sufficiently efficient, it is crucial that patients take their medication regularly as prescribed. Adherence describes the extent to which a patient acts in accordance with the prescribed timing, dosing, and frequency of medication administration. To date, there are no known data about adherence rates among patients with MS in Slovenia. We wanted to assess adherence in patients with MS, who are treated with first line DMTs and discover reasons for non-adherence. A number of 451 patients were invited to participate. They received two questionnaires via post mail. The adherence rate and putative reasons for non-adherence were assessed by the use of standardized self-report Multiple Sclerosis Treatment Experience Questionnaire (MSTEQ). Patients’ attitudes regarding disease, therapy and relationship with their physician were assessed by another questionnaire. The analysis of results included 299 patients. Among the patients 18.5% missed at least one medication dose in the past 28 days. Patients taking Avonex were significantly more adherent then patients on other DMTs (p = 0.005). Our study showed a higher then expected adherence among Slovenian patients with MS (81.5%). Our research did not confirm the influence of side effects or patients’ attitudes regarding illness and therapy on adherence. However we found unexpectedly high percentage (71.8%) of patients belief that psychological factors are involved in MS aetiology. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease associated with central nervous system (CNS) demyelination, affecting primarily young adults. Depending on the site of demyelinating lesions, it manifests clinically as a broad spectrum of physical, cognitive and emotional symptoms [1]. MS has three main phenotypes. The commonest form is relapsing–remitting MS, which is encountered in around 80% of the patients at an early stage of the disease [2]. It is characterised by an individual frequency of relapses followed by complete or incomplete remissions [3]. In around 65% of patients, RRMS eventually evolves to secondary progressive MS (SPMS) with continuous progression of disability independent of relapses, which also may occur. Primary progressive MS is a form that is progressive from onset without relapses and remissions and accounts for 20% of cases [3]. Although the disease itself remains incurable, the course of MS with relapses can be managed by so called Disease Modifying Therapy (DMT). Currently licensed as the first line immunomodulatory medications
∗ Corresponding author. Tel.: +386 15224320. ˇ E-mail address: [email protected] (S. Sega). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.09.013
are preparations of interferon -1a [Avonex®, Rebif®], interferon -1b [Betaferon®, Extavia®] and glatiramere acetate [Copaxone®]. Avonex® is injected intramuscularly once a week, Rebif® is injected 3 times per week subcutaneously, Betaferon® and Extavia® every second day subcutaneously and Copaxone® every day subcutaneously. Early treatment with DMT decreases the frequency of relapses, reduces disability progression [4] and lowers the incidence of hospitalisations [5]. It has been shown that DMT might not be effective in the long term in those MS patients with a poor level of adherence [6]. Adherence is defined as “the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen” [7]. Adherence has been studied across many chronic illnesses, such as HIV infection, hypertension, diabetes, epilepsy, asthma, and psychiatric illnesses. Overall, an average adherence rate of only 50% is indicated by The World Health Organization among patients with chronic diseases [8]. Rates of adherence are often variable and in some cases low also among DMT treated patients, in spite of the apparent benefits of DMT use. Different surveys report nonadherence rate among DMT treated patients to be between 6% and 46% [9,10], with an average nonadherence rate of nearly 25% [10]. Approximately half of the patients discontinue their treatment with DMT completely after 2 years [11]. Adherence
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Table 1 Patient demographic characteristics. Gender (%)
Age M (SD)
Disease duration M (SD)
DMT treatment duration M (SD)
m = 23.9; f = 76.1
42.0 (9.3)
10.6 (7.1)
6.0 (3.9)
N = 293. All data, except gender, expressed in years. M—arithmetic mean; SD—standard deviation; m—male; f—female; DMT—disease modifying treatment.
rate is difficult to measure accurately and so far none of the measurement methods is considered a golden standard. Adherence can be ascertained through a pill count, lab test, medical chart, collateral report, or electronic monitor. Most frequently used is still self-report method, although the patients tend to over-report their adherence [12]. Unfortunately, criteria for adequate adherence are not strictly defined, but rather depend on the particular survey. Some authors thus define adherence as taking at least 75% [13], 80% [4] or 85% [14] of prescribed medication doses over a longer period of time, whereas others define it as taking every dose of medication in the past 4 weeks [15,16]. To date there is no data on adherence rate in Slovenian MS patients. The aim of our study was to examine adherence to first line DMT in patients with MS at our MS center in Slovenia and potential factors that could influence it. We were also interested in attitudes patients have regarding the disease and treatment and their possible connection with adherence.
Fig. 1. Percentage of respective MS types. N (RR) = 246; N (SP) = 34; N (CIS) = 13. RRMS—relapsing–remitting MS; SPMS—secondary progressive MS; CIS—clinically isolated syndrome.
2. Methods 2.1. Participants All the patients diagnosed with MS, who were listed in the registry of the Centre for MS in Ljubljana and had been previously treated for at least one month with one of the first-line DMTs Betaferon®, Avonex®, Rebif®, Copaxone® or Extavia® were recruited to participate in this survey. On the basis of the registry demographic data about the patients (age, MS type, duration of illness, DMT type and duration of treatment), 451 patients meeting the above stated survey criteria were selected. They were invited to participate in the research by sending them two questionnaires and an explanatory letter to their home address by regular post. The patients were asked to answer both questionnaires and return the signed questionnaires via post to a given address. The returned questionnaires were collected and the data were transferred into a SPSS file for further analysis. All patients signed an informed consent at the start of the study. Our study was approved by the Slovenian ethic committee. A number of 15 patients did not receive the questionnaires due to an incorrect postal address; out of remaining 436 patients, that presumably received the questionnaires, 308 patients responded (response rate was 70.4%). After revising filled out questionnaires, 9 patients were excluded from the survey because they had not been taking any of the investigated medications in the previous 28 days (2 because of pregnancy, 4 switched therapies, 1 completely discontinued the therapy, 2 did not state any reason). In the result analysis 68.6% (299/436) of invited patients were included. Also 26 incomplete and 6 unsigned questionnaires were included in the analysis. It was not possible to analyse the unsigned questionnaires demographically, so demographic analysis was only done for the remaining 293 respondents. Demographic characteristics of the patients are shown in Table 1, Figs. 1 and 2.
Fig. 2. DMT type. N (Avonex®) = 44; N (Betaferon®) = 98; N (Copaxone®) = 65; N (Rebif®) = 88; N (Extavia®) = 4.
Fig. 3. Percentage of adherent patients on different DMT according to both criteria.
2.2. Material Two separate questionnaires were used to collect data. Each participant was asked to answer both questionnaires (Figs. 3 and 4).
Fig. 4. Attitudes of patients regarding MS aetiology.
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Table 2 Differences in demographic and disease variables between adherent and non-adherent groups.
Sex Age Disease type Disease duration Treatment duration
Nonadherent (N = 54)
Adherent (N = 294)
M
SD
M
SD
Testing differences M–W
2
p
/ 40.41 / 10.98 6.39
/ 9.291 / 7.173 4.341
/ 42.42 / 10.48 5.84
/ 9.337 / 7.082 3.718
/ 5610.000 / 6114.500 6151.000
0.139 / 0.112 / /
0.710 0.145 0.945 0.578 0.622
M—arithmetic mean; SD—standard deviation; M–W—Mann–Whitney test; 2 —Chi square test for nominal variables. Table 3 Differences in DMT type between adherent and non-adherent groups. DTM type
Estimated applications in 28 days
Nonadherent
Adherent
2
p
Avonex (IFN-1a) Betaferon (IFN-1b) Extavia (IFN-1b) Copaxone (GA) Rebif (IFN-1a)
4 14 14 28 12
2 21 0 15 17
42 77 4 49 71
0.01 0.857 / 1.344 0.062
0.005 0.427 / 0.276 0.87
IFN—interferon ; GA—glatiramer acetate. Table 4 Differences between the adherent and nonadherent group in side effects of injection.
Bleeding at injection site Pain, stinging, burning, or soreness at the injection sire during administration of treatment Have itching or irritation at the injection sire during administration of treatment Feel nervous or anxious during administration of treatment Have pain, stinging, burning, or soreness at the injection site after administration of treatment Have itching or irritation at the injection site after administration of treatment Have swelling, welts, or lumps at the injection site after administration of treatment Have abnormal redness of the skin or rash at the injection site after administration of treatment Have bruises at the injection site after administration of treatment Have chills, headaches, or flu-like symptoms after treatment Sum of all side effects
Nondherent (N = 55)
Adherent (N = 243)
Testing differences
M
SD
M
SD
M–W
p
0.87 1.44 0.42 1.02 1.24 0.80 1.56 0.98 0.86 1.05 10.24
0.883 1.183 0.854 1.240 1.217 1.177 1.198 1.080 0.893 1.353 7.279
0.94 1.62 0.37 1.01 1.10 0.59 1.50 1.13 1.02 1.10 10.37
0.789 1.119 0.758 1.182 1.203 1.017 1.248 1.229 1.062 1.363 7.048
6204.000 5938.500 6539.500 6626.000 6148.500 5929.500 6419.500 6378.500 6275.500 6442.000 6580.500
0.378 0.168 0.793 0.917 0.327 0.156 0.632 0.579 0.471 0.729 0.859
M—arithmetic mean, SD—standard deviation, M–W—Mann–Whitney test. Table 5 Reasons for missing injections in the nonadherent group.
Too busy Did not want taking medication to interfere with activities Memory problems Side effects of medication Tired of taking medication Did not feel like taking medication Feeling anxious, depressed or nervous about taking medication Side effects of injection Away from home and could not access medication Fear of needles Dissatisfaction with medication Ran out of medication or could not refill prescription Needing someone to help me take medication
Not important at all (%)
A little important (%)
46.3 51.9 59.3 59.3 55.6 63 66.7 64.8 70.4 79.6 81.5 85.2 88.9
33.3 24.1 18.5 20.4 27.8 20.4 14.8 14.8 13 7.4 5.6 7.4 5.6
Moderately important (%) 11.1 13 11.1 9.3 7.4 5.6 9.3 16.7 7.4 3.7 7.4 1.9 0
Extremely important (%)
M
SD
9.3 11.1 11.1 11.1 9.3 11.1 9.3 3.7 9.3 9.3 5.6 5.6 5.6
0.83 0.83 0.74 0.72 0.70 0.65 0.61 0.59 0.56 0.43 0.37 0.28 0.22
0.966 1.042 1.049 1.036 0.964 1.012 0.998 0.901 0.984 0.944 0.853 0.763 0.718
N = 54, M—arithmetic mean; SD—standard deviation. Table 6 Differences between the adherent and nonadherent group in attitudes regarding disease and treatment.
Belief in genetic cause of MS Belief in autoimmune cause of MS Belief in infection as cause of MS Belief in psychological factors as cause of MS Belief in one’s influence on disease course Satisfaction with neurologist Belief in efficacy of alternative methods of treatment
Neadherentni (N = 55)
Adherentni (N = 293)
Preverjanje razlik
M
SD
M
SD
M–W
p
2.61 3.80 2.39 3.10 3.52 4.27 2.51
0.763 0.595 0.712 0.890 0.720 0.616 0.979
2.61 3.87 2.39 2.98 3.42 4.27 2.51
0.763 0.713 0.846 0.974 0.873 0.690 0.838
6459.000 6428.000 6255.000 6116.500 5855.000 6545.000 6125.000
0.965 0.620 0.645 0.443 0.052 0.338 0.336
M—arithmetic mean; SD—standard deviation; M–W—Mann–Whitney test.
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To assess adherence rate and determine the reasons for potential nonadherence, we used a translated and adapted version of Multiple Sclerosis Treatment Experience Questionnaire (MSTEQ) [17]. For the use in this study we also developed and used a survey on attitudes regarding MS and treatment (Tables 2–6). 2.3. Statistical analysis Statistical analysis was performed using SPSS version 17.0 (IBM Corporation, Somers, NY, USA). Normality of distribution was tested using Kolmogorov–Smirnoff test. Since all the statistics apart from patients’ age were not normally distributed, we used nonparametric tests for further analysis. Group comparisons were computed using Mann–Whitney test for two independent samples with ordinal and interval variables, and with 2 test for nominal variables. We considered the differences statistically significant where p value was p ≤ 0.05. 3. Results 3.1. Defining adherence In previous research with the MSTEQ instrument patients were identified as non-adherent if they missed 1 or more injections in the 28 days prior to completing the survey [6,18]. DMTs differ in the frequency of injection administration as described in the Introduction. That is why 1 missed injection cannot be evaluated in the same way in different DMTs. In the 28 days included in the MSTEQ analysis the expected number of Avonex injection administrations would be only 4 (once weekly) and 1 missed injection would represent 25% of all injections, while the excepted number of Copaxone injections would be 28 (daily administration) and 1 missed injection would represent 3.5% of all injections. To evaluate all DMTs equally we decided to also use a second criterion where patients would be identified as non-adherent when they miss at least 25% of the chosen DMT. The criteria would be quantified as ≥1 injection of Avonex, ≥3 injections of Rebif, Betaferon or Extavia or ≥7 injections of Copaxone. The overall adherence in our sample was 81.5% according to the 1st criteria (missed ≥1 injection), and 96.6% according to the 2nd criteria (missed ≥25% injections). Only 10 patients missed ≥25% of injections according to criteria 2. This group was too small therefore we used the criteria of missing ≥1 injection in the subsequent analysis. We can see that the adherent and the nonadherent group did not differ significantly in the demographic and disease variables. In the group on Extavia the adherence rate was 100%, however only four patients were receiving this therapy so statistical analysis was not possible. Testing the differences between the other 4 DMT’s showed that patients on Avonex were significantly more adherent then patients on other DMT’s. Side effects of treatment did not differ statistically significantly between the group of adherent and nonadherent. Among the patients 34.9% were using only classical type of injection application while 56.7% were using an autoinjector. Both types of injecting were used by 8.4% of patients. Only 19.3% of patients needed regular help with injecting, while 82.6% needed help only occasionally or never. Neither type of application (classical or use of autoinjector) or help of another person was significantly different between the adherent and nonadherent group. We also assessed reasons for missing injections. The most common self-reported reasons for nonadherence were being too busy, not wanting the medication to interfere with other activities, memory problems and side effects.
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Next we assessed the attitudes regarding disease and their influence on adherence. We can see the attitudes regarding aetiology of MS, one’s influence on the disease course, satisfaction with one’s neurologist and belief in alternative methods of treatment were not statistically significantly different between the adherent and non-adherent group. We can see that almost the whole sample believed that MS is an autoimmune disease and two thirds believed that psychological factors are important cause of MS. However, only around half of the patients regarded genetic and infectious factors as important.
4. Discussion The aim of our study was to examine adherence to DMT in patients with MS and potential factors that could influence it. We were also interested in attitudes patients have regarding the disease and treatment and their possible connection with adherence. Overall our study showed a high self-reported adherence rate (81.5%). Other studies with using self-report measures and the same a criterion (missing one or more injections) showed similar or lower rates of adherence—around 63% [13], 80% [4], between 84% to 49% [17] and 85.4% overall adherence [6]. Studies with an indirect criterion using rates of refilling prescriptions (≥80% medication possession ratio) found 59.6% adherence [19] and 81.1% adherence [20]. However a study using a novel electronic monitoring device showed 80% adherence (defined as missing less than 20% of their prescribed DMT), while only 40.3% of patients had perfect adherence [21]. Our study therefore showed similar results as previous research; however it is important to note that self-reported adherence rates such as the one we used might be underestimating non-adherence. Our results also showed that patients on Avonex® were significantly more adherent then patients on other DMT’s. The same was also found in other studies [1,13,16,22,23]. There is no general agreement up to date on whether type of DMT actually influences adherence [4]. In our case we believe that results showed this difference in adherence due to different frequency of DMT administration. Avonex is taken only once weekly, while other therapies are taken more often. Patients on Avonex therefore had to take the therapy only four times in order to be adherent, which is three to seven times less often then patients on other DMTs. Therefore adherence could be higher in patients on Avonex because they had to take the medication less often. However the study from Kleinman et al. [18] showed that adherence to Avonex was higher in comparison to other DMTs even when looking at it annually. It could be that simpler regimes which include less frequent administration of the drug increase adherence. Patients in our sample used the auto-injector 1.6 times more often than classical application. Nevertheless in our study there was no connection between injector type and adherence. Up till now there is no date on auto-injectors improving adherence in MS, its use however has been shown to reduce side effects and discomfort [24]. In addition there was no connection between the need for help of another person during the application of DMT and adherence. Other studies similarly found that the help of other person was among least important reasons for missing injections [15,17]. Next we looked at the reasons for nonadherence. The most common self-reported reason for missing an injection was being too busy and doing other activities. The third most common reason was memory problems (forgetting to take the injection) followed by the side effects of the medication and being tired of taking medication. The least common reasons were needing help of others and being out of medication. These results are somewhat different from the previous studies where patients as the most common reason for
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missing injections reported memory problems [13,15,18] or side effects of medication [25]. One of the reasons for this could be the time frame of the investigation. During a longer time period memory problems become more pronounced. Other studies that used a shorter time frame (28 days) like we did also did not identify memory problems as the main reason for missing injections [13,17]. Another possible reason could be that our sample included patients who were in average younger and had shorter disease duration. Therefore they could have had less memory problems and were more active and busy in their daily lives. Among the nonadherent patients 40.7% reported side effects as one of the reasons for missing an injection. However the difference in side effects between the adherent and nonadherent group did not reach statistical significance. The study by Wicks et al. [17] using the same questionnaire as us also did not find significant differences, while other studies found side effects to be one of the most important reasons for nonadherence [13,16,18,25]. Furthermore we were interested in patients’ attitudes regarding illness and their connection to adherence. Previous research showed that belief in perceived benefits provided by the Health Beliefs Model predicted adherence [4]. We found that attitudes regarding disease aetiology, one’s influence on disease course, in efficacy of alternative methods of treatment and satisfaction with neurologist did not differ significantly between the groups of adherent or nonadherent patients. Only 1.3% of patients were not satisfied with their neurologists, therefore the number was not sufficient for reliable statistical analysis. Relationship with the neurologist was shown to be an important factor in adherence in other studies and seems to be the key in leading patients through treatment [26]. Next we were interested in the influence of the belief in efficacy of alternative treatments and how that relates to adherence as this field has not been included in previous research. We found that close to 50% of our sample believed these methods could be effective help in MS. At the same time these attitudes did not differ in the adherent and nonadherent group. Patients tend to choose alternative treatments due to unavailability of DMTs and its limited long term efficacy [27]. Moreover almost all patients believed MS to be an autoimmune disease, 71.8% believed psychological factors are important, while only 57.3% believed that genetic factors are significant in disease aetiology. Interestingly more patients believed in psychological factors involved in MS disease development then in genetic factors. Meta-analytical research showed that studies consistently find association between psychological stress and relapses in MS [28], however there is no data that stress increases risk for the development of MS [29]. Still, it is important to note that in patients’ attitudes psychological factors are perceived as important in disease aetiology. Patients who believe their disease was caused by psychological factors might feel they do not need to take medication. However our results did not confirm that hypothesis. Nevertheless they did indicate that patients in our sample were not very well informed about their disease which could be important. It was shown that unmet needs in education regarding disease influence adherence [30]. Our study had several limitations. We used a self-report questionnaire which is an indirect and subjective measure and can overestimate adherence [13]. Questionnaires were sent by post and the response rate was 70.4% which is similar to other studies [4,17]. Nevertheless it is probable that our sample included patients who were more ready to respond, while non-adherent patients might have refused to respond. This can again lead to overestimation of adherence. Also the time frame of the questionnaire we used (MSTEQ) for measuring adherence was short (one month). Other studies with time frames of several months or even years reported lower rates of adherence [11,26]; then studies using short time frames [9,13,17]. The described problem of underestimated nonadherence lead to a small number of identified nonadherent
patients. The comparison of groups (adherent vs. nonadherent) was therefore less reliable. This was the first study looking at adherence in Slovenia and it showed a high self-reported adherence rate (81.5%). Patients were most adherent to least frequently administered DMT. The most common self-reported reason for missing an injection was being too busy and doing other activities, memory problems were on third place. There were no differences in side effects between adherent and nonadherent patients. Patients’ attitudes regarding illness had no influence on adherence. Conflict of interest statement All authors report no actual or potential conflict of interest. Author’s contribution ˇ Study concept and design was performed by Saˇsa Sega and Ana Oˇzura, acquisition of data by Lea Kovaˇc, analysis and interpretation of data by Ana Oˇzura and Lea Kovaˇc, drafting of the manuscript ˇ and Lea Kovaˇc, critical revision of the by Ana Oˇzura, Saˇsa Sega ˇ manuscript for important intellectual content by Saˇsa Sega and administrative, technical and material support was performed by ˇ Saˇsa Sega. References [1] Barten LJ, Allington DR, Procacci KA, Rivey MP. New approaches in the management of multiple sclerosis. Drug Des Devel Ther 2010;4:343–66. [2] Nicholas R, Chataway J. Multiple sclerosis. Clin Evidence (Online) 2009:1202. [3] Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502–17. [4] 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):1146–452. [5] 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. ˜ O, GAP Study Group. [6] Arroyo E, Grau C, Ramo-Tello C, Parra J, Sánchez-Solino Adherence to disease-modifying therapies in spanish patients with relapsing multiple sclerosis: two-year interim results of the global adherence project. Eur Neurol 2011;65(2):59–67. [7] Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, Wong PK. Medication compliance and persistence: terminology and definitions. Value Health 2008;11(1):44–7. [8] Sabate E. Adherence to long-term therapies: evidence for action. Switzerland: World Health Organization; 2003. [9] Lugaresi A, Florio C, Brescia-Morra V, Cottone S, Bellantonio P, Clerico M, Centonze D, et al. Patient adherence to and tolerability of self-administered interferon -1a using an electronic autoinjection device: a multicentre, openlabel, phase IV study. BMC Neurol 2012;12:7. [10] Klauer T, Zettl UK. Compliance, adherence, and the treatment of multiple sclerosis. J Neurol 2008;255:687–92. [11] Wong J, Gomes T, Mamdani M, Manno M, O’Connor PW. Adherence to multiple sclerosis disease-modifying therapies in Ontario is low. Can J Neurol Sci 2011;(38):429–33. [12] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353(5):487–97. [13] Treadaway K, Cutter G, Salte A, Lynch S, Simsarian J, Corboy J, Jeffery D, et al. Factors that influence adherence with disease-modifying therapy in MS. J Neurol 2009;256(4):568–76. [14] 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 Invest 2010;30(2):89–100. [15] Devonshire V, Lapierre Y, Macdonell R, Ramo-Tello C, Patti F, Fontoura P, Suchet L, Hyde R, Balla I, Frohman EM, Kieseier BC. The Global Adherence Project (GAP): a multicenter observational study on adherence todisease-modifying therapies in patients with relapsing–remitting multiple sclerosis. Eur J Neurol 2011;18(1):69–77. [16] Beer K, Müller M, Hew-Winzeler AM, Bont A, Maire P, You X, Foulds P, Mårlind J, Curtius D. The prevalence of injection-site reactions with disease-modifying therapies and their effect on adherence in patients with multiple sclerosis: an observational study. BMC Neurol 2011;11:144. [17] 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):12.
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