Proefschrift Zwikker

All about beliefs

Exploring and intervening on beliefs about medication to

improve adherence in patients with rheumatoid arthritis

Hanneke Zwikker

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All about beliefsExploring and intervening

on beliefs about medication to improve adherence in patients with rheumatoid

arthritis

op woensdag 2 december 2015 om 14.30 uur precies

in de aula van de Radboud Universiteit Nijmegen,

Comeniuslaan 2, 6525 HP, Nijmegen

U bent van harte welkom bij deze plechtigheid en de

aansluitende receptie

Hanneke ZwikkerDe Hoper 23

1511 HK [email protected]

ParanimfenAgnes Smink

(06-190 673 91)Joke Vriezekolk (06-253 143 03)

Laat u via [email protected]

uiterlijk 18 november weten of u aanwezig bent?

Dank u wel!

All about beliefs Exploring and intervening on beliefs about medication to improve

adherence in patients with rheumatoid arthritis

Hanneke Zwikker

Colofon ISBN: 978-90-9029228-1 Lay-out: Doortje Saya, NIVEL (Netherlands institute for health services research), Utrecht Gildeprint, Enschede, The Netherlands Cover design and printing: Gildeprint Cover photos: Damiano Poli/Shutterstock.com The studies presented in this thesis were conducted at the departments of Rheumatology and Pharmacy of the Sint Maartenskliniek in Nijmegen. Publication of this thesis was financially supported by the Sint Maartenskliniek, NIVEL, and the Radboud University Nijmegen, The Netherlands. 2015 by Hanneke Zwikker. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the author.

All about beliefs

Exploring and intervening on beliefs about medication to improve

adherence in patients with rheumatoid arthritis

Proefschrift

ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen

op gezag van de rector magnificus, volgens besluit van het college van decanen

in het openbaar te verdedigen op woensdag 2 december 2015 om 14.30 uur precies

door

Hanneke Elisabeth Zwikker

geboren op 16 april 1981 te Zaandam

Promotor: Prof. dr. A.M. van Dulmen Copromotoren: Dr. B.J.F. van den Bemt (St. Maartenskliniek, Nijmegen) Dr. C.H.M. van den Ende (St. Maartenskliniek, Nijmegen) Manuscriptcommissie: Prof. dr. D.M. Burger Prof. dr. J.M.W. Hazes (Erasmus MC, Rotterdam) Prof. dr. P.A.G.M. de Smet

CONTENTS Chapter 1 General introduction 7 Part one Intervening on beliefs about medication to improve adherence in patients with rheumatoid arthritis

Chapter 2 Medication adherence in patients with rheumatoid arthritis: a 27 critical appraisal of the existing literature

Chapter 3 Development and content of a group-based intervention to 63 improve medication adherence in non-adherent patients with

rheumatoid arthritis

Chapter 4 Effectiveness of a group-based intervention to change 89 medication beliefs and improve medication adherence in

patients with rheumatoid arthritis: a randomized controlled trial

Part two Exploring on beliefs about medication to improve adherence in

patients with rheumatoid arthritis

Chapter 5 Psychosocial predictors of non-adherence to chronic 121 medication: systematic review of longitudinal studies

Chapter 6 Perceived need to take medication is associated with 209 medication non-adherence in patients with rheumatoid arthritis

Chapter 7 Rheumatologists beliefs about medication barely differ from 233 patients medication beliefs Chapter 8 Summary and general discussion 8.1. Summary 249 8.2. General discussion 255 Nederlandstalige samenvatting (Summary in Dutch) 273 Dankwoord (Acknowledgments) 279 About the author 287 List of publications and conference abstracts 289

Promotor: Prof. dr. A.M. van Dulmen Copromotoren: Dr. B.J.F. van den Bemt (St. Maartenskliniek, Nijmegen) Dr. C.H.M. van den Ende (St. Maartenskliniek, Nijmegen) Manuscriptcommissie: Prof. dr. D.M. Burger Prof. dr. J.M.W. Hazes (Erasmus MC, Rotterdam) Prof. dr. P.A.G.M. de Smet

CONTENTS Chapter 1 General introduction 7 Part one Intervening on beliefs about medication to improve adherence in patients with rheumatoid arthritis

Chapter 2 Medication adherence in patients with rheumatoid arthritis: a 27 critical appraisal of the existing literature

Chapter 3 Development and content of a group-based intervention to 59 improve medication adherence in non-adherent patients with

rheumatoid arthritis

Chapter 4 Effectiveness of a group-based intervention to change 85 medication beliefs and improve medication adherence in

patients with rheumatoid arthritis: a randomized controlled trial

Part two Exploring on beliefs about medication to improve adherence in

patients with rheumatoid arthritis

Chapter 5 Psychosocial predictors of non-adherence to chronic 117 medication: systematic review of longitudinal studies

Chapter 6 Perceived need to take medication is associated with 205 medication non-adherence in patients with rheumatoid arthritis

Chapter 7 Rheumatologists beliefs about medication barely differ from 229 patients medication beliefs Chapter 8 Summary and general discussion 8.1. Summary 245 8.2. General discussion 251 Nederlandstalige samenvatting (Summary in Dutch) 269 Dankwoord (Acknowledgments) 277 About the author 287 List of publications and conference abstracts 291

Chapter 1General introduction

Although medication is the cornerstone of the treatment of rheumatoid arthritis (RA), patients do not always take their medication as recommended by the rheumatologist. Medication non-adherence can have serious consequences for the patients health and for societal costs. Therefore, effective interventions to improve adherence are warranted. As beliefs about medication seem to play an important role in predicting non-adherence in RA patients, they could be promising intervention targets. This thesis is about exploring and intervening on generic and RA-specific medication beliefs. Living with rheumatoid arthritis Rheumatoid arthritis is a chronic, progressive and systemic autoimmune disease. It is characterized by joint inflammation that (if untreated) leads to irreversible joint damage, fatigue and decreased physical abilities [1,2]. RA can occur at any age but is most common among those aged 40-70 years [3]. The disease affects approximately 0.5-1% of the European and North American adults, with the prevalence being higher among women than among men (overall gender ratio 3:1) [3-5]. Distal joints in hands and feet are most often affected, and inflammation in the joints is associated with (morning) stiffness, swelling, and pain. RA can also affect organs such as periarticular tissue, skin, eyes, and lungs [3,4].

Having RA has major effects on a patients health-related quality of life in both physical and mental domains of well-being [6,7], because RA limits activities in daily living, household management, social participation and work [1,2,8-10]. The death incidence from cardiovascular disease, infection and malignancies is also significantly higher for patients with RA compared to the general population [11-13]. Treatment of rheumatoid arthritis Patients receive non-pharmacological and pharmacological treatment for RA. Non-pharmacological treatment includes, amongst others, exercise therapy and manual therapy, provision of aids and devices (e.g., special jar openers, customized beds), orthoses, self-management interventions, psychological support and patient education [14]. However, the key to minimize joint damage and functional decline is early pharmacological treatment with disease-modifying antirheumatic drugs (DMARDs) [15-17].

Traditionally, RA has been treated with non-steroidal anti-inflammatory drugs (NSAIDs) like diclofenac, ibuprofen and naproxen, and synthetic DMARDs like

Although medication is the cornerstone of the treatment of rheumatoid arthritis (RA), patients do not always take their medication as recommended by the rheumatologist. Medication non-adherence can have serious consequences for the patients health and for societal costs. Therefore, effective interventions to improve adherence are warranted. As beliefs about medication seem to play an important role in predicting non-adherence in RA patients, they could be promising intervention targets. This thesis is about exploring and intervening on generic and RA-specific medication beliefs. Living with rheumatoid arthritis Rheumatoid arthritis is a chronic, progressive and systemic autoimmune disease. It is characterized by joint inflammation that (if untreated) leads to irreversible joint damage, fatigue and decreased physical abilities [1,2]. RA can occur at any age but is most common among those aged 40-70 years [3]. The disease affects approximately 0.5-1% of the European and North American adults, with the prevalence being higher among women than among men (overall gender ratio 3:1) [3-5]. Distal joints in hands and feet are most often affected, and inflammation in the joints is associated with (morning) stiffness, swelling, and pain. RA can also affect organs such as periarticular tissue, skin, eyes, and lungs [3,4].

Having RA has major effects on a patients health-related quality of life in both physical and mental domains of well-being [6,7], because RA limits activities in daily living, household management, social participation and work [1,2,8-10]. The death incidence from cardiovascular disease, infection and malignancies is also significantly higher for patients with RA compared to the general population [11-13]. Treatment of rheumatoid arthritis Patients receive non-pharmacological and pharmacological treatment for RA. Non-pharmacological treatment includes, amongst others, exercise therapy and manual therapy, provision of aids and devices (e.g., special jar openers, customized beds), orthoses, self-management interventions, psychological support and patient education [14]. However, the key to minimize joint damage and functional decline is early pharmacological treatment with disease-modifying antirheumatic drugs (DMARDs) [15-17].

Traditionally, RA has been treated with non-steroidal anti-inflammatory drugs (NSAIDs) like diclofenac, ibuprofen and naproxen, and synthetic DMARDs like

General introduction | 9

1

methotrexate (MTX), sulfasalazine and hydroxychloroquine [18]. Whereas NSAIDs provide symptomatic relief, they do not alter the course of the disease. In contrast to NSAIDs, DMARDs do modify the underlying systemic inflammatory process of RA by their impact on synovitis and bone and joint destruction [19]. The newest class of DMARDs (biological DMARDs like etanercept, adalimumab or infliximab) target pro-inflammatory cytokines and immune-cellular targets (B- and T-cells) [18].

(Inter)national guidelines recommend to start DMARD therapy very early in the treatment of RA, because it slows joint destruction more effectively than a delayed start of DMARD therapy, and because joint damage and irreversible disability are a consequence of time exposed to high disease activity [16,18] (Figure 1).

Figure 1 Effect of DMARD therapy. DMARDs will interfere with the disease process at any time point, and will lead to a deflection of the slope of progression from its natural course. The ideal situation would be to diagnose and treat rheumatoid arthritis early; at best, before damage has occurred [16]

Especially synthetic DMARDs do not have an immediate effect on reducing disease activity. It may take several weeks or even months before patients experience symptom reductions. Still, patients must closely follow treatment regimens to fully benefit from DMARD therapy [20]. Some patients, as a consequence, have to take multiple medicines during the day which might conflict with other activities like food consumption, social life and work [1]. So, effective medication use requires continuous personal investment of time and effort of RA patients [21].

Ambivalence about taking medication It is well-known that RA patients (like other chronic patients) perceive taking medication not only as beneficial but also as a burden [21,22]. Apart from the patients investment of time and effort to use medication effectively, pharmacological treatment can also initiate side effects [21]. Amongst others, DMARD use is associated with an increased risk of toxicity like gastro-intestinal complaints, infections, hypertension and abnormal liver function tests [1,3,23].

The benefits and harm of RA medication can promote tension, ambivalence and sometimes dissatisfaction in RA patients [21,22]. Participants of focus groups expressed ambivalence most clearly about taking DMARDs: most RA patients described side effects which could, at times, be severe and could outweigh the (perceived) benefits of taking the medication [21].

The ambivalence and challenges that RA patients face in taking medication may evoke insufficient use or even non-use of medication (i.e., non-adherence). Before we discuss the consequences of non-adherence in RA patients, we first present some definitions and measurements of (non)-adherence. Medication (non-)adherence The term adherence comprises three different components, each referring to different phases in medication intake behavior [24]: the initiation phase (when a patient takes the first dose of prescribed medication), the implementation phase (the extent to which a patients actual dosing corresponds to the prescribed dosing regimen: from initiation to the last dose taken) and the discontinuation phase (when the next dose to be taken is omitted and no more doses are taken thereafter). The empirical studies in this thesis are focusing on the implementation phase (Figure 2).

Within the implementation phase, many types of aberrations in taking medication can be identified. Over a defined period of time, patients, for instance, might take a suboptimal proportion of prescribed tablets, might take a proportion of prescribed tablets at the wrong time of the day, or might take drug holidays (the deliberate interruption of pharmacotherapy for a defined period) [24,25].

Patients are prescribed doses, and non-adherent if they take

Figure 2 European consensus taxonomy of patient adherence [24]

Adherence measurement in this thesis Because a gold standard to measure adherence is still lacking and every measurement method has advantages and disadvantages [34], it is important to triangulate different measures to assess robustness of study findings [35]. Therefore, we used multiple adherence measures within two empirical studies of this thesis (chapters 4 and 6 [32,33]).

In these studies, the Compliance Questionnaire Rheumatology (CQR) is the main outcome measure for adherence. The CQR has 19 items which reflect statements about drug-taking behavior (e.g., If the rheumatologist tells me to take the medicines, I do so) an prescribed medication with a sensitivity of 62% and a specificity of 95%. The CQR is validated against an objective adherence measure: electronic monitoring (Medication Event Monitoring System (MEMS) [30,36]).

In addition to the CQR, we used the five item Medication Adherence Report Scale [37]. The MARS has been widely used in a range of long term conditions, including RA, asthma/COPD, cardiovascular diseases, diabetes, inflammatory bowel disease and depression [38-46], and a 9-item version of the MARS was recently (partly) validated in a sample of RA patients [45]. In addition, we used pharmacy refill data [47] as an objective adherence measure by calculating the medication

possession ratio: days of DMARD supply divided by the number of days within an observation period [31]. Consequences of non-adherence in RA patients As stated, medication adherence in RA patients is suboptimal and varies from 22% (underuse) to 107% (overuse) [48-52]. DMARD non-adherence results in more disease activity/radiological damage, loss of function and a lower quality of life [20,29,53-55]. Pascual-Ramos et al. demonstrated that 83% of RA patients who continued DMARD/corticosteroid therapy had a sustained remission of the disease over six months follow-up compared with 47% of patients who discontinued therapy. Patients continuing therapy also had a better functional status according to the Health Assessment Questionnaire during a two-year period [54]. Moreover, Waimann et al. demonstrated that RA patients non-adherent to oral DMARD and steroid therapy had higher disease activity scores across 2 years follow-up, with an additional trend towards increased radiographic damage (see Figures 3 and 4) [29]. Figure 3 Comparison of Disease Activity Score in 28 joints (DAS28) values between patients with > 80% adherence and patients with

Figure 4 Comparison of modified Sharp/van der Heijde radiographic score progression between patients with >80% adherence and patients with

help patients to make sense of the illness and are believed to be directly related to beliefs about the necessity of taking medication [41]. RA patients who perceive their illness as having minimal personal consequences may be less likely to perceive the need for regular use of DMARDs, for instance.

Background beliefs about medication in general are supposed to influence specific concerns about prescribed medication [41,64]. Even before illness occurs, a significant proportion of individuals have strong, general, negative beliefs about medication: that they are harmful, chemical, and could better be avoided. Many individuals also believe that doctors are far too willing to prescribe medications. These ideas make some patients turn towards natural remedies that are perceived to be a safer option [66].

Many earlier and recent (empirical) studies underline the importance of addressing necessity and concern beliefs about medication to improve adherence, in- and outside the field of RA [1,46,63,65,71-80]. Necessity beliefs and concern beliefs about medication can be measured using the Beliefs about Medicines Questionnaire (BMQ), a validated instrument in patients with somatic chronic illnesses [74] and with sufficient to good psychometric properties in RA samples [33,79,80].

In a recent meta-analysis with studies using the BMQ, both stronger perceptions of necessity of treatment and fewer concerns about treatment were associated with better medication adherence (ORnecessity = 1.7, 95% CI: 1.6-1.9, ORconcerns = 0.5, 95% CI: 0.5-0.6) [73]. In RA patients, necessity beliefs about medication were found to be among the most relevant determinants of non-adherence according to a recent systematic review [78]. Thus, beliefs about medication might be a promising intervention target to improve medication adherence in RA patients. Therefore, this thesis is focusing on the patient-related domain of the WHO classification of determinants of adherence. Existing interventions to improve adherence in RA patients Existing interventions to improve medication adherence in chronic diseases are mostly complex and have limited effect [81,82]. Moreover, although beliefs about medication have been identified as a promising intervention to improve medication in chronically ill patients, most interventions did not (systematically) address such beliefs. Only one study suggested that a short, individual, patient-centered telephone advice in chronically ill patients resulted in more positive beliefs about

medication and higher levels of adherence than a control condition. However, these findings should be interpreted with caution as baseline data were not reported [71].

So far, three studies have assessed the effectiveness of a medication adherence intervention in RA [83-85]. Only one of these studies demonstrated a slight improvement in adherence to D-penicillamine following a patient education program [85]. However, this program was (time) intensive as 51 individual patients were provided seven education sessions of 30 minutes each, and was intended for both adherent and non-adherent patients. So far, interventions targeting the medication beliefs in non-adherent RA patients have not been developed. Aim and outline of this thesis Given the central role of beliefs about medication in adherence literature and the absence of time-efficient interventions to improve adherence in RA patients, the main aim of this thesis is to explore and to intervene on beliefs about medication to improve medication adherence in RA patients. In part one, relevant targets for improving medication adherence in RA patients are identified. Subsequently, a short intervention is developed and tested for its effectiveness in changing medication beliefs and improving adherence. Chapter 2 comprises a narrative review of adherence literature. Herein, some

elements of this general introduction are further elaborated: non-adherence terminology and measurements, the extent of non-adherence in RA patients, risk factors for non-adherence, interventions to improve adherence among RA patients, and what is needed to develop those interventions are being discussed.

Chapter 3 describes the development of a short, group-based intervention to improve adherence to DMARDs in adult, non-adherent RA patients. It aims to improve adherence by changing the balance between necessity and concern beliefs about medication and by resolving practical barriers to take medication. Chapter 4 describes the effectiveness of the intervention, which is tested using a

randomized clinical trial design. 123 non-adherent patients are randomly assigned to the intervention arm (two group sessions + brochure about DMARDs) or control arm (only brochures about

16 | Chapter 1

help patients to make sense of the illness and are believed to be directly related to beliefs about the necessity of taking medication [41]. RA patients who perceive their illness as having minimal personal consequences may be less likely to perceive the need for regular use of DMARDs, for instance.

Background beliefs about medication in general are supposed to influence specific concerns about prescribed medication [41,64]. Even before illness occurs, a significant proportion of individuals have strong, general, negative beliefs about medication: that they are harmful, chemical, and could better be avoided. Many individuals also believe that doctors are far too willing to prescribe medications. These ideas make some patients turn towards natural remedies that are perceived to be a safer option [66].

Many earlier and recent (empirical) studies underline the importance of addressing necessity and concern beliefs about medication to improve adherence, in- and outside the field of RA [1,46,63,65,71-80]. Necessity beliefs and concern beliefs about medication can be measured using the Beliefs about Medicines Questionnaire (BMQ), a validated instrument in patients with somatic chronic illnesses [74] and with sufficient to good psychometric properties in RA samples [33,79,80].

In a recent meta-analysis with studies using the BMQ, both stronger perceptions of necessity of treatment and fewer concerns about treatment were associated with better medication adherence (ORnecessity = 1.7, 95% CI: 1.6-1.9, ORconcerns = 0.5, 95% CI: 0.5-0.6) [73]. In RA patients, necessity beliefs about medication were found to be among the most relevant determinants of non-adherence according to a recent systematic review [78]. Thus, beliefs about medication might be a promising intervention target to improve medication adherence in RA patients. Therefore, this thesis is focusing on the patient-related domain of the WHO classification of determinants of adherence. Existing interventions to improve adherence in RA patients Existing interventions to improve medication adherence in chronic diseases are mostly complex and have limited effect [81,82]. Moreover, although beliefs about medication have been identified as a promising intervention to improve medication in chronically ill patients, most interventions did not (systematically) address such beliefs. Only one study suggested that a short, individual, patient-centered telephone advice in chronically ill patients resulted in more positive beliefs about

medication and higher levels of adherence than a control condition. However, these findings should be interpreted with caution as baseline data were not reported [71].

So far, three studies have assessed the effectiveness of a medication adherence intervention in RA [83-85]. Only one of these studies demonstrated a slight improvement in adherence to D-penicillamine following a patient education program [85]. However, this program was (time) intensive as 51 individual patients were provided seven education sessions of 30 minutes each, and was intended for both adherent and non-adherent patients. So far, interventions targeting the medication beliefs in non-adherent RA patients have not been developed. Aim and outline of this thesis Given the central role of beliefs about medication in adherence literature and the absence of time-efficient interventions to improve adherence in RA patients, the main aim of this thesis is to explore and to intervene on beliefs about medication to improve medication adherence in RA patients. In part one, relevant targets for improving medication adherence in RA patients are identified. Subsequently, a short intervention is developed and tested for its effectiveness in changing medication beliefs and improving adherence. Chapter 2 comprises a narrative review of adherence literature. Herein, some

elements of this general introduction are further elaborated: non-adherence terminology and measurements, the extent of non-adherence in RA patients, risk factors for non-adherence, interventions to improve adherence among RA patients, and what is needed to develop those interventions are being discussed.

Chapter 3 describes the development of a short, group-based intervention to improve adherence to DMARDs in adult, non-adherent RA patients. It aims to improve adherence by changing the balance between necessity and concern beliefs about medication and by resolving practical barriers to take medication. Chapter 4 describes the effectiveness of the intervention, which is tested using a

randomized clinical trial design. 123 non-adherent patients are randomly assigned to the intervention arm (two group sessions + brochure about DMARDs) or control arm (only brochures about


1

DMARDs). The primary outcome measures are the BMQ and CQR questionnaires.

To further explore beliefs about medication as possible intervention target, different aspects of medication beliefs in relation to medication non-adherence are examined in part two. Chapter 5 comprises a systematic review about longitudinal associations

between beliefs about medication, other psychosocial predictors and non-adherence to chronic medication.

Chapter 6 reports a cross-sectional study, which examines if beliefs about medication are independent associates of non-adherence to DMARDs when controlling for potential important demographical, clinical and psychological confounders (anxiety/depression, self-efficacy and illness cognitions).

Chapter 7 describes rheumatologists beliefs about medication and compares them with beliefs about medication of RA patients. Finally, the results of the thesis are summarized and discussed within a broader perspective in chapter 8. Recommendations for future research and clinical practice are also provided.

REFERENCES [1] Elliott RA. Poor adherence to medication in adults with rheumatoid arthritis: Reasons

and solutions. Dis Manag Health Out 2008;13-29. [2] Flurey CA, Morris M, Richards P, Hughes R, Hewlett S. It's like a juggling act: rheumatoid

arthritis patient perspectives on daily life and flare while on current treatment regimes. Rheumatology (Oxford) 2014;53:696-703.

[3] Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001;358:903-11. [4] Kvien TK, Scherer HU, Burmester GR. Rheumatoid Arthritis. In: Bijlsma JWJ, editor.

EULAR compendium on Rheumatic Diseases. London: BMJ Publishing Group; 2009. p. 61-80.

[5] van Vollenhoven RF. Sex differences in rheumatoid arthritis: more than meets the eye.. BMC Med 2009;7:12.

[6] Uhlig T, Loge JH, Kristiansen IS, Kvien TK. Quantification of reduced health-related quality of life in patients with rheumatoid arthritis compared to the general population. J Rheumatol 2007;34:1241-7.

[7] Matcham F, Scott IC, Rayner L, Hotopf M, Kingsley GH, Norton S et al. The impact of rheumatoid arthritis on quality-of-life assessed using the SF-36: a systematic review and meta-analysis. Semin Arthritis Rheum 2014;44:123-30.

[8] Song J, Chang RW, Dunlop DD. Population impact of arthritis on disability in older adults. Arthritis Rheum 2006;55:248-55.

[9] Verbrugge LM, Juarez L. Profile of arthritis disability: II. Arthritis Rheum 2006;55:102-13. [10] Keenan AM, Tennant A, Fear J, Emery P, Conaghan PG. Impact of multiple joint

problems on daily living tasks in people in the community over age fifty-five. Arthritis Rheum 2006;55:757-64.

[11] Cibere J, Sibley J, Haga M. Rheumatoid arthritis and the risk of malignancy. Arthritis Rheum 1997;40:1580-6.

[12] Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 2002;46:2287-93.

[13] Mutru O, Laakso M, Isomaki H, Koota K. Cardiovascular mortality in patients with rheumatoid arthritis. Cardiology 1989;76:71-7.

[14] Vliet Vlieland TP. Non-drug care for RA--is the era of evidence-based practice approaching? Rheumatology (Oxford) 2007;46:1397-404.

[15] Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet 2009;373:659-72. [16] Smolen JS, Aletaha D, Grisar J, Redlich K, Steiner G, Wagner O. The need for

prognosticators in rheumatoid arthritis. Biological and clinical markers: where are we now? Arthritis Res Ther 2008;10:208.

[17] Smolen JS, Aletaha D. Developments in the clinical understanding of rheumatoid arthritis. Arthritis Res Ther 2009;11:204.

18 | Chapter 1

DMARDs). The primary outcome measures are the BMQ and CQR questionnaires.

To further explore beliefs about medication as possible intervention target, different aspects of medication beliefs in relation to medication non-adherence are examined in part two. Chapter 5 comprises a systematic review about longitudinal associations

between beliefs about medication, other psychosocial predictors and non-adherence to chronic medication.

Chapter 6 reports a cross-sectional study, which examines if beliefs about medication are independent associates of non-adherence to DMARDs when controlling for potential important demographical, clinical and psychological confounders (anxiety/depression, self-efficacy and illness cognitions).

Chapter 7 describes rheumatologists beliefs about medication and compares them with beliefs about medication of RA patients. Finally, the results of the thesis are summarized and discussed within a broader perspective in chapter 8. Recommendations for future research and clinical practice are also provided.

REFERENCES [1] Elliott RA. Poor adherence to medication in adults with rheumatoid arthritis: Reasons

and solutions. Dis Manag Health Out 2008;13-29. [2] Flurey CA, Morris M, Richards P, Hughes R, Hewlett S. It's like a juggling act: rheumatoid

arthritis patient perspectives on daily life and flare while on current treatment regimes. Rheumatology (Oxford) 2014;53:696-703.

[3] Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001;358:903-11. [4] Kvien TK, Scherer HU, Burmester GR. Rheumatoid Arthritis. In: Bijlsma JWJ, editor.

EULAR compendium on Rheumatic Diseases. London: BMJ Publishing Group; 2009. p. 61-80.

[5] van Vollenhoven RF. Sex differences in rheumatoid arthritis: more than meets the eye.. BMC Med 2009;7:12.

[6] Uhlig T, Loge JH, Kristiansen IS, Kvien TK. Quantification of reduced health-related quality of life in patients with rheumatoid arthritis compared to the general population. J Rheumatol 2007;34:1241-7.

[7] Matcham F, Scott IC, Rayner L, Hotopf M, Kingsley GH, Norton S et al. The impact of rheumatoid arthritis on quality-of-life assessed using the SF-36: a systematic review and meta-analysis. Semin Arthritis Rheum 2014;44:123-30.

[8] Song J, Chang RW, Dunlop DD. Population impact of arthritis on disability in older adults. Arthritis Rheum 2006;55:248-55.

[9] Verbrugge LM, Juarez L. Profile of arthritis disability: II. Arthritis Rheum 2006;55:102-13. [10] Keenan AM, Tennant A, Fear J, Emery P, Conaghan PG. Impact of multiple joint

problems on daily living tasks in people in the community over age fifty-five. Arthritis Rheum 2006;55:757-64.

[11] Cibere J, Sibley J, Haga M. Rheumatoid arthritis and the risk of malignancy. Arthritis Rheum 1997;40:1580-6.

[12] Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 2002;46:2287-93.

[13] Mutru O, Laakso M, Isomaki H, Koota K. Cardiovascular mortality in patients with rheumatoid arthritis. Cardiology 1989;76:71-7.

[14] Vliet Vlieland TP. Non-drug care for RA--is the era of evidence-based practice approaching? Rheumatology (Oxford) 2007;46:1397-404.

[15] Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet 2009;373:659-72. [16] Smolen JS, Aletaha D, Grisar J, Redlich K, Steiner G, Wagner O. The need for

prognosticators in rheumatoid arthritis. Biological and clinical markers: where are we now? Arthritis Res Ther 2008;10:208.

[17] Smolen JS, Aletaha D. Developments in the clinical understanding of rheumatoid arthritis. Arthritis Res Ther 2009;11:204.


1

[18] Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492-509.

[19] Tugwell P, Singh JA, Wells GA. Biologicals for rheumatoid arthritis. BMJ 2011;343:d4027. [20] van den Bemt BJF. Optimizing Pharmacotherapy in Patients with Rheumatoid Arthritis:

An Individualized Approach [dissertation]. Nijmegen (The Netherlands): Radboud University Nijmegen; 2009.

[21] Townsend A, Backman CL, Adam P, Li LC. A qualitative interview study: patient accounts of medication use in early rheumatoid arthritis from symptom onset to early postdiagnosis. BMJ Open 2013;3.

[22] Ahlmen M, Nordenskiold U, Archenholtz B, Thyberg I, Ronnqvist R, Linden L et al. Rheumatology outcomes: the patient's perspective. A multicentre focus group interview study of Swedish rheumatoid arthritis patients. Rheumatology (Oxford) 2005;44:105-10.

[23] Hetland ML, Unkerskov J, Ravn T, Friis M, Tarp U, Andersen LS et al. Routine database registration of biological therapy increases the reporting of adverse events twentyfold in clinical practice. First results from the Danish Database (DANBIO). Scand J Rheumatol 2005;34:40-4.

[24] Vrijens B, de Geest S, Hughes DA, Przemyslaw K, Demonceau J, Ruppar T et al. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol 2012;73:691-705.

[25] Howland RH. Medication holidays. J Psychosoc Nurs Ment Health Serv 2009;47:15-8. [26] Andrade SE, Kahler KH, Frech F, Chan KA. Methods for evaluation of medication

adherence and persistence using automated databases. Pharmacoepidemiol Drug Saf 2006;15:565-74.

[27] Karve S, Cleves MA, Helm M, Hudson TJ, West DS, Martin BC. Good and poor adherence: optimal cut-point for adherence measures using administrative claims data. Curr Med Res Opin 2009;25:2303-10.

[28] Lesen E, Sandstrom TZ, Carlsten A, Jonsson AK, Mardby AC, Sundell KA. A comparison of two methods for estimating refill adherence to statins in Sweden: the RARE project. Pharmacoepidemiol Drug Saf 2011;20:1073-9.

[29] Waimann CA, Marengo MF, de Achaval S, Cox VL, Garcia-Gonzalez A, Reveille JD et al. Electronic monitoring of oral therapies in ethnically diverse and economically disadvantaged patients with rheumatoid arthritis: consequences of low adherence. Arthritis Rheum 2013;65:1421-9.

[30] de Klerk E, van der Heijde D, Landewe R, van der Tempel H, van der Linden S. The compliance-questionnaire-rheumatology compared with electronic medication event monitoring: a validation study. J Rheumatol 2003;30:2469-75.

[31] Grijalva CG, Chung CP, Arbogast PG, Stein CM, Mitchel EF Jr., Griffin MR. Assessment of adherence to and persistence on disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis. Med Care 2007;45:S66-S76.

[32] Zwikker HE, van den Ende CH, van Lankveld WG, den Broeder AA, van den Hoogen FH, van de Mosselaar B et al. Effectiveness of a group-based intervention to change medication beliefs and improve medication adherence in patients with rheumatoid arthritis: a randomized controlled trial. Patient Educ Couns 2014;94:356-61.

[33] Zwikker HE, van Dulmen S, den Broeder AA, van den Bemt BJ, van den Ende CH. Perceived need to take medication is associated with medication non-adherence in patients with rheumatoid arthritis. Patient Prefer Adherence 2014;8:1635-45.

[34] van den Bemt BJ, Zwikker HE, van den Ende CH. Medication adherence in patients with rheumatoid arthritis: a critical appraisal of the existing literature. Expert Rev Clin Immunol 2012;8:337-51.

[35] Pool R, Montgomery CM, Morar NS, Mweemba O, Ssali A, Gafos M et al. A mixed methods and triangulation model for increasing the accuracy of adherence and sexual behaviour data: the Microbicides Development Programme. PLoS One 2010;5:e11600.

[36] de Klerk E, van der Heijde D, van der Tempel H, van der Linden S. Development of a questionnaire to investigate patient compliance with antirheumatic drug therapy. J Rheumatol 1999;26:2635-41.

[37] Horne R. The Medication Adherence Report Scale (MARS): a new measurement tool for eliciting patients' report non-adherence. [Working paper]. Mayfield House, United Kingdom: University of Brighton; 2013.

[38] Clatworthy J, Price D, Ryan D, Haughney J, Horne R. The value of self-report assessment of adherence, rhinitis and smoking in relation to asthma control. Prim Care Respir J 2009;18:300-5.

[39] Cohen JL, Mann DM, Wisnivesky JP, Home R, Leventhal H, Musumeci-Szabo TJ et al. Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma. Ann Allergy Asthma Immunol 2009;103:325-31.

[40] George J, Kong DC, Thoman R, Stewart K. Factors associated with medication nonadherence in patients with COPD. Chest 2005;128:3198-204.

[41] Horne R, Weinman J. Self-regulation and self-management in asthma: Exploring the role of illness perceptions and treatment beliefs in explaining non-adherence to preventer medication. Psychol Health 2002;17[1], 17-32.

[42] Horne R, Parham R, Driscoll R, Robinson A. Patients' attitudes to medicines and adherence to maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis 2009;15:837-44.

[43] Mahler C, Hermann K, Horne R, Ludt S, Haefeli WE, Szecsenyi J et al. Assessing reported adherence to pharmacological treatment recommendations. Translation and evaluation of the Medication Adherence Report Scale (MARS) in Germany. J Eval Clin Pract 2010;16:574-9.

[44] Mora PA, Berkowitz A, Contrada RJ, Wisnivesky J, Horne R, Leventhal H et al. Factor structure and longitudinal invariance of the Medical Adherence Report Scale-Asthma. Psychol Health 2011;26:713-27.

20 | Chapter 1

[18] Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492-509.

[19] Tugwell P, Singh JA, Wells GA. Biologicals for rheumatoid arthritis. BMJ 2011;343:d4027. [20] van den Bemt BJF. Optimizing Pharmacotherapy in Patients with Rheumatoid Arthritis:

An Individualized Approach [dissertation]. Nijmegen (The Netherlands): Radboud University Nijmegen; 2009.

[21] Townsend A, Backman CL, Adam P, Li LC. A qualitative interview study: patient accounts of medication use in early rheumatoid arthritis from symptom onset to early postdiagnosis. BMJ Open 2013;3.

[22] Ahlmen M, Nordenskiold U, Archenholtz B, Thyberg I, Ronnqvist R, Linden L et al. Rheumatology outcomes: the patient's perspective. A multicentre focus group interview study of Swedish rheumatoid arthritis patients. Rheumatology (Oxford) 2005;44:105-10.

[23] Hetland ML, Unkerskov J, Ravn T, Friis M, Tarp U, Andersen LS et al. Routine database registration of biological therapy increases the reporting of adverse events twentyfold in clinical practice. First results from the Danish Database (DANBIO). Scand J Rheumatol 2005;34:40-4.

[24] Vrijens B, de Geest S, Hughes DA, Przemyslaw K, Demonceau J, Ruppar T et al. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol 2012;73:691-705.

[25] Howland RH. Medication holidays. J Psychosoc Nurs Ment Health Serv 2009;47:15-8. [26] Andrade SE, Kahler KH, Frech F, Chan KA. Methods for evaluation of medication

adherence and persistence using automated databases. Pharmacoepidemiol Drug Saf 2006;15:565-74.

[27] Karve S, Cleves MA, Helm M, Hudson TJ, West DS, Martin BC. Good and poor adherence: optimal cut-point for adherence measures using administrative claims data. Curr Med Res Opin 2009;25:2303-10.

[28] Lesen E, Sandstrom TZ, Carlsten A, Jonsson AK, Mardby AC, Sundell KA. A comparison of two methods for estimating refill adherence to statins in Sweden: the RARE project. Pharmacoepidemiol Drug Saf 2011;20:1073-9.

[29] Waimann CA, Marengo MF, de Achaval S, Cox VL, Garcia-Gonzalez A, Reveille JD et al. Electronic monitoring of oral therapies in ethnically diverse and economically disadvantaged patients with rheumatoid arthritis: consequences of low adherence. Arthritis Rheum 2013;65:1421-9.

[30] de Klerk E, van der Heijde D, Landewe R, van der Tempel H, van der Linden S. The compliance-questionnaire-rheumatology compared with electronic medication event monitoring: a validation study. J Rheumatol 2003;30:2469-75.

[31] Grijalva CG, Chung CP, Arbogast PG, Stein CM, Mitchel EF Jr., Griffin MR. Assessment of adherence to and persistence on disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis. Med Care 2007;45:S66-S76.

[32] Zwikker HE, van den Ende CH, van Lankveld WG, den Broeder AA, van den Hoogen FH, van de Mosselaar B et al. Effectiveness of a group-based intervention to change medication beliefs and improve medication adherence in patients with rheumatoid arthritis: a randomized controlled trial. Patient Educ Couns 2014;94:356-61.

[33] Zwikker HE, van Dulmen S, den Broeder AA, van den Bemt BJ, van den Ende CH. Perceived need to take medication is associated with medication non-adherence in patients with rheumatoid arthritis. Patient Prefer Adherence 2014;8:1635-45.

[34] van den Bemt BJ, Zwikker HE, van den Ende CH. Medication adherence in patients with rheumatoid arthritis: a critical appraisal of the existing literature. Expert Rev Clin Immunol 2012;8:337-51.

[35] Pool R, Montgomery CM, Morar NS, Mweemba O, Ssali A, Gafos M et al. A mixed methods and triangulation model for increasing the accuracy of adherence and sexual behaviour data: the Microbicides Development Programme. PLoS One 2010;5:e11600.

[36] de Klerk E, van der Heijde D, van der Tempel H, van der Linden S. Development of a questionnaire to investigate patient compliance with antirheumatic drug therapy. J Rheumatol 1999;26:2635-41.

[37] Horne R. The Medication Adherence Report Scale (MARS): a new measurement tool for eliciting patients' report non-adherence. [Working paper]. Mayfield House, United Kingdom: University of Brighton; 2013.

[38] Clatworthy J, Price D, Ryan D, Haughney J, Horne R. The value of self-report assessment of adherence, rhinitis and smoking in relation to asthma control. Prim Care Respir J 2009;18:300-5.

[39] Cohen JL, Mann DM, Wisnivesky JP, Home R, Leventhal H, Musumeci-Szabo TJ et al. Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma. Ann Allergy Asthma Immunol 2009;103:325-31.

[40] George J, Kong DC, Thoman R, Stewart K. Factors associated with medication nonadherence in patients with COPD. Chest 2005;128:3198-204.

[41] Horne R, Weinman J. Self-regulation and self-management in asthma: Exploring the role of illness perceptions and treatment beliefs in explaining non-adherence to preventer medication. Psychol Health 2002;17[1], 17-32.

[42] Horne R, Parham R, Driscoll R, Robinson A. Patients' attitudes to medicines and adherence to maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis 2009;15:837-44.

[43] Mahler C, Hermann K, Horne R, Ludt S, Haefeli WE, Szecsenyi J et al. Assessing reported adherence to pharmacological treatment recommendations. Translation and evaluation of the Medication Adherence Report Scale (MARS) in Germany. J Eval Clin Pract 2010;16:574-9.

[44] Mora PA, Berkowitz A, Contrada RJ, Wisnivesky J, Horne R, Leventhal H et al. Factor structure and longitudinal invariance of the Medical Adherence Report Scale-Asthma. Psychol Health 2011;26:713-27.


1

[45] Salt E, Hall L, Peden AR, Home R. Psychometric properties of three medication adherence scales in patients with rheumatoid arthritis. J Nurs Meas 2012;20:59-72.

[46] Tibaldi G, Clatworthy J, Torchio E, Argentero P, Munizza C, Horne R. The utility of the Necessity-Concerns Framework in explaining treatment non-adherence in four chronic illness groups in Italy. Chronic Illn 2009;5:129-33.

[47] Steiner JF, Prochazka AV. The assessment of refill compliance using pharmacy records: methods, validity, and applications. J Clin Epidemiol 1997;50:105-16.

[48] Blum MA, Koo D, Doshi JA. Measurement and rates of persistence with and adherence to biologics for rheumatoid arthritis: a systematic review. Clin Ther 2011;33:901-13.

[49] Brus H, van de Laar M, Taal E, Rasker J, Wiegman O. Determinants of compliance with medication in patients with rheumatoid arthritis: the importance of self-efficacy expectations. Patient Educ Couns 1999;36:57-64.

[50] Doyle DV, Perrett D, Foster OJ, Ensor M, Scott DL. The long-term use of D-penicillamine for treating rheumatoid arthritis: is continuous therapy necessary? Br J Rheumatol 1993;32:614-7.

[51] Koncz T, Pentek M, Brodszky V, Ersek K, Orlewska E, Gulacsi L. Adherence to biologic DMARD therapies in rheumatoid arthritis. Expert Opin Biol Ther 2010;10:1367-78.

[52] Pullar T, Peaker S, Martin MF, Bird HA, Feely MP. The use of a pharmacological indicator to investigate compliance in patients with a poor response to antirheumatic therapy. Br J Rheumatol 1988;27:381-4.

[53] Contreras-Yanez I, Ponce De LS, Cabiedes J, Rull-Gabayet M, Pascual-Ramos V. Inadequate therapy behavior is associated to disease flares in patients with rheumatoid arthritis who have achieved remission with disease-modifying antirheumatic drugs. Am J Med Sci 2010;340:282-90.

[54] Pascual-Ramos V, Contreras-Yanez I, Villa AR, Cabiedes J, Rull-Gabayet M. Medication persistence over 2 years of follow-up in a cohort of early rheumatoid arthritis patients: associated factors and relationship with disease activity and with disability. Arthritis Res Ther 2009;11:R26.

[55] Viller F, Guillemin F, Briancon S, Moum T, Suurmeijer T, van den Heuvel W. Compliance to drug treatment of patients with rheumatoid arthritis: a 3 year longitudinal study. J Rheumatol 1999;26:2114-22.

[56] Berg JS, Dischler J, Wagner DJ, Raia JJ, Palmer-Shevlin N. Medication compliance: a healthcare problem. Ann Pharmacother 1993;27:S1-24.

[57] McDonnell PJ, Jacobs MR. Hospital admissions resulting from preventable adverse drug reactions. Ann Pharmacother 2002;36:1331-6.

[58] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487-97. [59] Senst BL, Achusim LE, Genest RP, Cosentino LA, Ford CC, Little JA et al. Practical

approach to determining costs and frequency of adverse drug events in a health care network. Am J Health Syst Pharm 2001;58:1126-32.

[60] Behner P, Klink A, Visser S, Bcken J, Etgeton S. Unleashing the Potential of Therapy Adherence High-Leverage Changes in Patient Behavior for Improved Health and Productivity. Booz & Company; 2012.

[61] Sabat E. Adherence to long-term therapies: evidence for action [Internet]. Switzerland: World Health Organization; 2003 [cited 2015 Apr 4]. Available from: http://whqlibdoc.who.int/publications/2003/9241545992.pdf.

[62] ABC project team. Ascertaining barriers for compliance: policies for save, effective and cost-effective use of medicines in Europe. Final report of the ABC-Project (deliverable 7.1) [Internet]. 2012 [cited 2015 Apr 4]. Available from: http://abcproject.eu/img/abc%20final.pdf

[63] Clifford S, Barber N, Horne R. Understanding different beliefs held by adherers, unintentional nonadherers, and intentional nonadherers: application of the Necessity-Concerns Framework. J Psychosom Res 2008;64:41-6.

[64] Horne R. Representations of medication and treatment: advances in theory and assessment. In: Petrie K, Weinman J, editors. Perceptions of Health and Illness. Amsterdam: Harwood Academic; 1997.

[65] Horne R, Weinman J. Patients' beliefs about prescribed medicines and their role in adherence to treatment in chronic physical illness. J Psychosom Res 1999;47:555-67.

[66] Horne R. Compliance, adherence, and concordance: implications for asthma treatment. Chest 2006;130:65S-72S.

[67] Lorish CD, Richards B, Brown S. Missed medication doses in rheumatic arthritis patients: intentional and unintentional reasons. Arthritis Care Res 1989;2:3-9.

[68] Lorish CD, Richards B, Brown S Jr. Perspective of the patient with rheumatoid arthritis on issues related to missed medication. Arthritis Care Res 1990;3:78-84.

[69] Wroe A, Thomas M. Intentional and unintentional nonadherence in patients prescribed HAART treatment regimens. Psychol Health Med 2003;8:453-63.

[70] Wroe AL. Intentional and unintentional nonadherence: a study of decision making. J Behav Med 2002;25:355-72.

[71] Clifford S, Barber N, Elliott R, Hartley E, Horne R. Patient-centred advice is effective in improving adherence to medicines. Pharm World Sci 2006;28:165-70.

[72] de Thurah A, Norgaard M, Harder I, Stengaard-Pedersen K. Compliance with methotrexate treatment in patients with rheumatoid arthritis: influence of patients' beliefs about the medicine. A prospective cohort study. Rheumatol Int 2010;30:1441-8.

[73] Horne R, Chapman SC, Parham R, Freemantle N, Forbes A, Cooper V. Understanding patients' adherence-related beliefs about medicines prescribed for long-term conditions: a meta-analytic review of the Necessity-Concerns Framework. PLoS One 2013;8:e80633.

[74] Horne R, Weinman J, Hankins M. The Beliefs about Medicines Questionnaire: The development and evaluation of a new method for assessing the cognitive representation of medication. Psychol Health 1999;1-24.

22 | Chapter 1

[45] Salt E, Hall L, Peden AR, Home R. Psychometric properties of three medication adherence scales in patients with rheumatoid arthritis. J Nurs Meas 2012;20:59-72.

[46] Tibaldi G, Clatworthy J, Torchio E, Argentero P, Munizza C, Horne R. The utility of the Necessity-Concerns Framework in explaining treatment non-adherence in four chronic illness groups in Italy. Chronic Illn 2009;5:129-33.

[47] Steiner JF, Prochazka AV. The assessment of refill compliance using pharmacy records: methods, validity, and applications. J Clin Epidemiol 1997;50:105-16.

[48] Blum MA, Koo D, Doshi JA. Measurement and rates of persistence with and adherence to biologics for rheumatoid arthritis: a systematic review. Clin Ther 2011;33:901-13.

[49] Brus H, van de Laar M, Taal E, Rasker J, Wiegman O. Determinants of compliance with medication in patients with rheumatoid arthritis: the importance of self-efficacy expectations. Patient Educ Couns 1999;36:57-64.

[50] Doyle DV, Perrett D, Foster OJ, Ensor M, Scott DL. The long-term use of D-penicillamine for treating rheumatoid arthritis: is continuous therapy necessary? Br J Rheumatol 1993;32:614-7.

[51] Koncz T, Pentek M, Brodszky V, Ersek K, Orlewska E, Gulacsi L. Adherence to biologic DMARD therapies in rheumatoid arthritis. Expert Opin Biol Ther 2010;10:1367-78.

[52] Pullar T, Peaker S, Martin MF, Bird HA, Feely MP. The use of a pharmacological indicator to investigate compliance in patients with a poor response to antirheumatic therapy. Br J Rheumatol 1988;27:381-4.

[53] Contreras-Yanez I, Ponce De LS, Cabiedes J, Rull-Gabayet M, Pascual-Ramos V. Inadequate therapy behavior is associated to disease flares in patients with rheumatoid arthritis who have achieved remission with disease-modifying antirheumatic drugs. Am J Med Sci 2010;340:282-90.

[54] Pascual-Ramos V, Contreras-Yanez I, Villa AR, Cabiedes J, Rull-Gabayet M. Medication persistence over 2 years of follow-up in a cohort of early rheumatoid arthritis patients: associated factors and relationship with disease activity and with disability. Arthritis Res Ther 2009;11:R26.

[55] Viller F, Guillemin F, Briancon S, Moum T, Suurmeijer T, van den Heuvel W. Compliance to drug treatment of patients with rheumatoid arthritis: a 3 year longitudinal study. J Rheumatol 1999;26:2114-22.

[56] Berg JS, Dischler J, Wagner DJ, Raia JJ, Palmer-Shevlin N. Medication compliance: a healthcare problem. Ann Pharmacother 1993;27:S1-24.

[57] McDonnell PJ, Jacobs MR. Hospital admissions resulting from preventable adverse drug reactions. Ann Pharmacother 2002;36:1331-6.

[58] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487-97. [59] Senst BL, Achusim LE, Genest RP, Cosentino LA, Ford CC, Little JA et al. Practical

approach to determining costs and frequency of adverse drug events in a health care network. Am J Health Syst Pharm 2001;58:1126-32.

[60] Behner P, Klink A, Visser S, Bcken J, Etgeton S. Unleashing the Potential of Therapy Adherence High-Leverage Changes in Patient Behavior for Improved Health and Productivity. Booz & Company; 2012.

[61] Sabat E. Adherence to long-term therapies: evidence for action [Internet]. Switzerland: World Health Organization; 2003 [cited 2015 Apr 4]. Available from: http://whqlibdoc.who.int/publications/2003/9241545992.pdf.

[62] ABC project team. Ascertaining barriers for compliance: policies for save, effective and cost-effective use of medicines in Europe. Final report of the ABC-Project (deliverable 7.1) [Internet]. 2012 [cited 2015 Apr 4]. Available from: http://abcproject.eu/img/abc%20final.pdf

[63] Clifford S, Barber N, Horne R. Understanding different beliefs held by adherers, unintentional nonadherers, and intentional nonadherers: application of the Necessity-Concerns Framework. J Psychosom Res 2008;64:41-6.

[64] Horne R. Representations of medication and treatment: advances in theory and assessment. In: Petrie K, Weinman J, editors. Perceptions of Health and Illness. Amsterdam: Harwood Academic; 1997.

[65] Horne R, Weinman J. Patients' beliefs about prescribed medicines and their role in adherence to treatment in chronic physical illness. J Psychosom Res 1999;47:555-67.

[66] Horne R. Compliance, adherence, and concordance: implications for asthma treatment. Chest 2006;130:65S-72S.

[67] Lorish CD, Richards B, Brown S. Missed medication doses in rheumatic arthritis patients: intentional and unintentional reasons. Arthritis Care Res 1989;2:3-9.

[68] Lorish CD, Richards B, Brown S Jr. Perspective of the patient with rheumatoid arthritis on issues related to missed medication. Arthritis Care Res 1990;3:78-84.

[69] Wroe A, Thomas M. Intentional and unintentional nonadherence in patients prescribed HAART treatment regimens. Psychol Health Med 2003;8:453-63.

[70] Wroe AL. Intentional and unintentional nonadherence: a study of decision making. J Behav Med 2002;25:355-72.

[71] Clifford S, Barber N, Elliott R, Hartley E, Horne R. Patient-centred advice is effective in improving adherence to medicines. Pharm World Sci 2006;28:165-70.

[72] de Thurah A, Norgaard M, Harder I, Stengaard-Pedersen K. Compliance with methotrexate treatment in patients with rheumatoid arthritis: influence of patients' beliefs about the medicine. A prospective cohort study. Rheumatol Int 2010;30:1441-8.

[73] Horne R, Chapman SC, Parham R, Freemantle N, Forbes A, Cooper V. Understanding patients' adherence-related beliefs about medicines prescribed for long-term conditions: a meta-analytic review of the Necessity-Concerns Framework. PLoS One 2013;8:e80633.

[74] Horne R, Weinman J, Hankins M. The Beliefs about Medicines Questionnaire: The development and evaluation of a new method for assessing the cognitive representation of medication. Psychol Health 1999;1-24.


1

[75] Menckeberg TT, Bouvy ML, Bracke M, Kaptein AA, Leufkens HG, Raaijmakers JA et al. Beliefs about medicines predict refill adherence to inhaled corticosteroids. J Psychosom Res 2008;64:47-54.

[76] Moshkovska T, Stone MA, Clatworthy J, Smith RM, Bankart J, Baker R et al. An investigation of medication adherence to 5-aminosalicylic acid therapy in patients with ulcerative colitis, using self-report and urinary drug excretion measurements. Aliment Pharmacol Ther 2009;30:1118-27.

[77] Neame R, Hammond A. Beliefs about medications: a questionnaire survey of people with rheumatoid arthritis. Rheumatology (Oxford) 2005;44:762-7.

[78] Pasma A, van 't Spijker A, Hazes JM, Busschbach JJ, Luime JJ. Factors associated with adherence to pharmaceutical treatment for rheumatoid arthritis patients: a systematic review. Semin Arthritis Rheum 2013;43:18-28.

[79] Treharne GJ, Lyons AC, Kitas GD. Medication adherence in rheumatoid arthritis: Effects of psychosocial factors. Psychol Health Med 2004;9:337-49.

[80] van den Bemt BJF, van den Hoogen FH, Benraad B, Hekster YA, van Riel PL, van Lankveld W. Adherence rates and associations with nonadherence in patients with rheumatoid arthritis using disease modifying antirheumatic drugs. J Rheumatol 2009;36:2164-70.

[81] Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2008;CD000011.

[82] Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A, Agoritsas T et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2014;11:CD000011.

[83] van den Bemt BJF, den Broeder AA, van den Hoogen FH, Benraad B, Hekster YA, van Riel PL et al. Making the rheumatologist aware of patients' non-adherence does not improve medication adherence in patients with rheumatoid arthritis. Scand J Rheumatol 2011;40:192-6.

[84] Brus HL, van de Laar MA, Taal E, Rasker JJ, Wiegman O. Effects of patient education on compliance with basic treatment regimens and health in recent onset active rheumatoid arthritis. Ann Rheum Dis 1998;57:146-51.

[85] Hill J, Bird H, Johnson S. Effect of patient education on adherence to drug treatment for rheumatoid arthritis: a randomised controlled trial. Ann Rheum Dis 2001;60:869-75.

Part oneIntervening on beliefs about medication

to improve adherence in patients with rheumatoid arthritis

24 | Chapter 1

[75] Menckeberg TT, Bouvy ML, Bracke M, Kaptein AA, Leufkens HG, Raaijmakers JA et al. Beliefs about medicines predict refill adherence to inhaled corticosteroids. J Psychosom Res 2008;64:47-54.

[76] Moshkovska T, Stone MA, Clatworthy J, Smith RM, Bankart J, Baker R et al. An investigation of medication adherence to 5-aminosalicylic acid therapy in patients with ulcerative colitis, using self-report and urinary drug excretion measurements. Aliment Pharmacol Ther 2009;30:1118-27.

[77] Neame R, Hammond A. Beliefs about medications: a questionnaire survey of people with rheumatoid arthritis. Rheumatology (Oxford) 2005;44:762-7.

[78] Pasma A, van 't Spijker A, Hazes JM, Busschbach JJ, Luime JJ. Factors associated with adherence to pharmaceutical treatment for rheumatoid arthritis patients: a systematic review. Semin Arthritis Rheum 2013;43:18-28.

[79] Treharne GJ, Lyons AC, Kitas GD. Medication adherence in rheumatoid arthritis: Effects of psychosocial factors. Psychol Health Med 2004;9:337-49.

[80] van den Bemt BJF, van den Hoogen FH, Benraad B, Hekster YA, van Riel PL, van Lankveld W. Adherence rates and associations with nonadherence in patients with rheumatoid arthritis using disease modifying antirheumatic drugs. J Rheumatol 2009;36:2164-70.

[81] Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2008;CD000011.

[82] Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A, Agoritsas T et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2014;11:CD000011.

[83] van den Bemt BJF, den Broeder AA, van den Hoogen FH, Benraad B, Hekster YA, van Riel PL et al. Making the rheumatologist aware of patients' non-adherence does not improve medication adherence in patients with rheumatoid arthritis. Scand J Rheumatol 2011;40:192-6.

[84] Brus HL, van de Laar MA, Taal E, Rasker JJ, Wiegman O. Effects of patient education on compliance with basic treatment regimens and health in recent onset active rheumatoid arthritis. Ann Rheum Dis 1998;57:146-51.

[85] Hill J, Bird H, Johnson S. Effect of patient education on adherence to drug treatment for rheumatoid arthritis: a randomised controlled trial. Ann Rheum Dis 2001;60:869-75.

Part oneIntervening on beliefs about medication

to improve adherence in patients with rheumatoid arthritis

Chapter 2Medication adherence in patients with rheumatoid arthritis: a critical appraisal of the existing literature

van den Bemt BJ, Zwikker HE, van den Ende CH.Published in: Expert Review Clinical Immunology 2012;8(4):337-51.

Review CME

SUMMARY Adherence to medication in patients with rheumatoid arthritis is low, varying from 30 to 80%. Improving adherence to therapy could therefore dramatically improve the efficacy of drug therapy. Although indicators for suboptimal adherence can be useful to identify nonadherent patients, and could function as targets for adherence-improving interventions, no indicators are yet found to be consistently and strongly related to nonadherence. Despite this, nonadherence behavior could conceptually be categorized into two subtypes: unintentional (due to forgetfulness, regimen complexity or physical problems) and intentional (based on the patients decision to take no/less medication). In case of intentional nonadherence, patients seem to make a benefit risk analysis weighing the perceived risks of the treatment against the perceived benefits. This weighing process may be influenced by the patients beliefs about medication, the patients self-efficacy and the patients knowledge of the disease. This implicates that besides tackling practical barriers, clinicians should be sensitive to patients personal beliefs that may impact medication adherence.

INTRODUCTION The prescription of a medicine is one of the most common interventions in the healthcare system. However, the full benefit of pharmacological interventions can only be achieved if patients follow drug regimens closely. Adherence is, however, low in chronic medical conditions: approximately 50% of all people with chronic medical conditions do not adhere to their prescribed medication regimens [1,2]. The implications of nonadherence are far reaching, as nonadherence may severely compromise the effectiveness of treatment and increase healthcare costs; for example, the cost of nonadherence in the USA has been estimated to reach US$100 billion annually [3]. The reduction of nonadherence is therefore thought likely to have a greater effect in health than further improvements in traditional biomedical treatment [4].

Medication nonadherence has negative consequences on the pharmacological treatment of rheumatoid arthritis (RA), as disease-modifying antirheumatic drugs (DMARDs) reduce disease activity and radiological progression and improve long-term functional outcome in patients with RA [5]. Nonadherence is associated with disease flares and increased disability, for example [6,7]. Despite this, adherence

CME Review

rates to prescribed medicine regimes in people with RA are low, varying from 30 to 80% [722]. Improving adherence to therapy could therefore dramatically improve the efficacy of medical treatments and reduce costs associated with RA.

The purpose of this critical narrative appraisal of the literature is to give a broad overview of the existing literature on medication nonadherence and adherence to disease-modifying drugs in RA, by addressing adherence terminology, measuring nonadherence, the extent of the problem and risk factors for nonadherence, and by providing a short overview of interventions to improve medication adherence among people with RA. Available studies published until July 2011 on medication adherence in RA were searched for using an electronic literature search in PubMed. The search strategy is described in Table 1.

Table 1 Search strategy in PubMed for retrieving studies on medication adherence in rheumatoid arthritis

Boolean operator

Text words and Medical Index Subject Headings

Arthritis, rheumatoid [mesh terms] or rheumatoid arthritis[tw]

AND Medication adherence [mesh terms] or patient compliance [mesh terms]-or-(medication[tw] or medicine[tw] or medicines[tw] or medical[tw] or therapy[tw] or therapie[tw] or drug[tw] or drugs[tw]) and (complian* or non-complian* or non complian* or noncomplian* or adher* or nonadher* or non adher* or nonadher* or persist* or non-persist* or non persist* or nonpersist*)

AND adult[mesh terms] or mature [tw] or adult [tw]

Adherence terminology: adherence, compliance & concordance The terminology used in the area of medicine-taking reflects the changing understanding of medicine-taking behavior and the changing relationships between healthcare professionals and patients. In the medical literature of the 1950s, the term compliance was used. This term, strongly led by a physician- based approach, was defined as the extent to which patients behavior coincides with medical advice [23]. However, the word compliance became quickly unpopular for its judgmental overtones. Therefore, the term adherence was introduced as an alternative to compliance. It comes closer to describing and emphasizing patient and clinician collaboration in decisions, rather than conveying the idea of obedience to a medical prescription [2426]. Medication adherence can be defined as the extent to which a patients behavior, with respect to taking medication, corresponds with agreed recommendations from a healthcare provider [101].

28 | Chapter 2

Review CME

SUMMARY Adherence to medication in patients with rheumatoid arthritis is low, varying from 30 to 80%. Improving adherence to therapy could therefore dramatically improve the efficacy of drug therapy. Although indicators for suboptimal adherence can be useful to identify nonadherent patients, and could function as targets for adherence-improving interventions, no indicators are yet found to be consistently and strongly related to nonadherence. Despite this, nonadherence behavior could conceptually be categorized into two subtypes: unintentional (due to forgetfulness, regimen complexity or physical problems) and intentional (based on the patients decision to take no/less medication). In case of intentional nonadherence, patients seem to make a benefit risk analysis weighing the perceived risks of the treatment against the perceived benefits. This weighing process may be influenced by the patients beliefs about medication, the patients self-efficacy and the patients knowledge of the disease. This implicates that besides tackling practical barriers, clinicians should be sensitive to patients personal beliefs that may impact medication adherence.

INTRODUCTION The prescription of a medicine is one of the most common interventions in the healthcare system. However, the full benefit of pharmacological interventions can only be achieved if patients follow drug regimens closely. Adherence is, however, low in chronic medical conditions: approximately 50% of all people with chronic medical conditions do not adhere to their prescribed medication regimens [1,2]. The implications of nonadherence are far reaching, as nonadherence may severely compromise the effectiveness of treatment and increase healthcare costs; for example, the cost of nonadherence in the USA has been estimated to reach US$100 billion annually [3]. The reduction of nonadherence is therefore thought likely to have a greater effect in health than further improvements in traditional biomedical treatment [4].

Medication nonadherence has negative consequences on the pharmacological treatment of rheumatoid arthritis (RA), as disease-modifying antirheumatic drugs (DMARDs) reduce disease activity and radiological progression and improve long-term functional outcome in patients with RA [5]. Nonadherence is associated with disease flares and increased disability, for example [6,7]. Despite this, adherence

CME Review

rates to prescribed medicine regimes in people with RA are low, varying from 30 to 80% [722]. Improving adherence to therapy could therefore dramatically improve the efficacy of medical treatments and reduce costs associated with RA.

The purpose of this critical narrative appraisal of the literature is to give a broad overview of the existing literature on medication nonadherence and adherence to disease-modifying drugs in RA, by addressing adherence terminology, measuring nonadherence, the extent of the problem and risk factors for nonadherence, and by providing a short overview of interventions to improve medication adherence among people with RA. Available studies published until July 2011 on medication adherence in RA were searched for using an electronic literature search in PubMed. The search strategy is described in Table 1.

Table 1 Search strategy in PubMed for retrieving studies on medication adherence in rheumatoid arthritis

Boolean operator

Text words and Medical Index Subject Headings

Arthritis, rheumatoid [mesh terms] or rheumatoid arthritis[tw]

AND Medication adherence [mesh terms] or patient compliance [mesh terms]-or-(medication[tw] or medicine[tw] or medicines[tw] or medical[tw] or therapy[tw] or therapie[tw] or drug[tw] or drugs[tw]) and (complian* or non-complian* or non complian* or noncomplian* or adher* or nonadher* or non adher* or nonadher* or persist* or non-persist* or non persist* or nonpersist*)

AND adult[mesh terms] or mature [tw] or adult [tw]

Adherence terminology: adherence, compliance & concordance The terminology used in the area of medicine-taking reflects the changing understanding of medicine-taking behavior and the changing relationships between healthcare professionals and patients. In the medical literature of the 1950s, the term compliance was used. This term, strongly led by a physician- based approach, was defined as the extent to which patients behavior coincides with medical advice [23]. However, the word compliance became quickly unpopular for its judgmental overtones. Therefore, the term adherence was introduced as an alternative to compliance. It comes closer to describing and emphasizing patient and clinician collaboration in decisions, rather than conveying the idea of obedience to a medical prescription [2426]. Medication adherence can be defined as the extent to which a patients behavior, with respect to taking medication, corresponds with agreed recommendations from a healthcare provider [101].

Medication adherence: a critical appraisal of the existing literature | 29

2

Review CME

Medication adherence can be divided into three major components: persistence (defined as the length of time a patient fills his/her prescriptions); initiation adherence (does the patient start with the indented pharmacotherapy); and execution adherence (the comparison between the prescribed drug dosing regimen and the real patients drug-taking behavior). Execution adherence includes dose omissions (missed doses) and the so-called drug holidays (3 or more days without drug intake). In the mid 1990s, the concept of concordance was born. The term concordance relates to a process of the consultation in which prescribing is based on partnership. In this process, healthcare professionals recognize the primacy of the patients decision about taking the recommended medication, and the patients expertise and beliefs are fully valued. The term concordance overtly recognizes that for optimal medication use, the patients opinion on medication should be taken into account and discussed throughout the therapy. This discussion will help to foster a patientphysician relationship in which the patient is able to communicate as a partner in the selection of treatment and the subsequent review of its effect. Therefore, compliance focuses on the behavior of one person (the patient), whereas concordance requires the participation of at least two people. Measuring nonadherence The validity of adherence assessment is based on the method of measurement. The minimum requirements of a gold standard for adherence measurement include: Validity: proving ingestion of the medication and giving a detailed overview about timing and ingestion; Reliability and sensitivity to change: stable results under stable adherence and differential results under variable adherence; Feasibility: the patient should not be aware of adherence measurement and should not be able to censor the result. Although it is ethically desirable that patients know that his/her medication use is being followed, the consciousness of being monitored may increase a patients adherence. Moreover, the assessment should be easy to use and the method should be noninvasive. Unfortunately, a single instrument fulfilling these properties is currently unavailable [27]. Despite the absence of a gold standard, adherence can be measured in a variety of ways, as depicted in Table 2 [9,10,28,29].

CME Review

Table 2 Methods to assess adherence

Method of assessment Advantage Disadvantage

Subjective

Self-report Easy to use Readily available Noninvasive Sensitive for nonadherence Inexpensive

No evidence that the drug is actually ingested Not accurate Patient aware of the measurement

Physicians estimation Easy to use Inexpensive Noninvasive

Not accurate

Direct

Biomarkers (drug concentration/metabolites)

Objectively proves ingestion of the medication Accurate

Sensitive for white coat adherence Invasive Expensive Varies with individual difference in metabolism

Indirect

Pharmacy refill Inexpensive Noninvasive Patient is not aware that they are being monitored

No evidence that the drug is actually ingested once filled

Tablet counts Easy to use Inexpensive Noninvasive

No evidence that the drug is actually ingested once filled

Electronic monitors Noninvasive Objective Provides additional information about dosing interval

Patient is aware of the measurement

Questionnaires Easy to use Noninvasive Validation possible

Patient is aware of the measurement

Subjective measurement The simplest assessment of medication adherence is frequently used, and involves asking the patient whether he or she is taking the medications as prescribed. Although patient self-report may be 100% specific for being nonadherent, this method is relatively insensitive for the detection of nonadherence (which is confirmed in several studies showing that the answers of the patient are not always accurate). In fact, patients claiming to be adherent may under-report their nonadherence to avoid caregiver disapproval [30]. Furthermore, self-report is time-dependent, since patients have the best recall for adherence in the last 24-h period.

30 | Chapter 2

Review CME

Medication adherence can be divided into three major components: persistence (defined as the length of time a patient fills his/her prescriptions); initiation adherence (does the patient start with the indented pharmacotherapy); and execution adherence (the comparison between the prescribed drug dosing regimen and the real patients drug-taking behavior). Execution adherence includes dose omissions (missed doses) and the so-called drug holidays (3 or more days without drug intake). In the mid 1990s, the concept of concordance was born. The term concordance relates to a process of the consultation in which prescribing is based on partnership. In this process, healthcare professionals recognize the primacy of the patients decision about taking the recommended medication, and the patients expertise and beliefs are fully valued. The term concordance overtly recognizes that for optimal medication use, the patients opinion on medication should be taken into account and discussed throughout the therapy. This discussion will help to foster a patientphysician relationship in which the patient is able to communicate as a partner in the selection of treatment and the subsequent review of its effect. Therefore, compliance focuses on the behavior of one person (the patient), whereas concordance requires the participation of at least two people. Measuring nonadherence The validity of adherence assessment is based on the method of measurement. The minimum requirements of a gold standard for adherence measurement include: Validity: proving ingestion of the medication and giving a detailed overview about timing and ingestion; Reliability and sensitivity to change: stable results under stable adherence and differential results under variable adherence; Feasibility: the patient should not be aware of adherence measurement and should not be able to censor the result. Although it is ethically desirable that patients know that his/her medication use is being followed, the consciousness of being monitored may increase a patients adherence. Moreover, the assessment should be easy to use and the method should be noninvasive. Unfortunately,

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