Publications

GLORIA project

List of publications: planned, in preparation, submitted/under review, published.

 

Version 22-08-2021: status update of manuscripts and publications.

 

1. GLORIA Trial protocol.
   Published.

Hartman L, Rasch LA, Klausch T, Bijlsma HWJ, Christensen R, Smulders YM, Ralston SH, Buttgereit F, Cutolo M, Da Silva JAP, Opris D, Rovensky J, Szamosi S, Middelink LM, Lems WF, Boers M. Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial): study protocol for a randomised controlled trial. Trials 2018;19:67.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785876/

Abstract:

Background. Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called "JAK/STAT inhibitors") have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA.

Methods. The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions.

Discussion. Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA.

Trial registration: ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015.

 

 

2. GLORIA main trial results: effectiveness and safety.

            In Publication

1. authors: Boers M, Hartman L, Opris D, Bos R, Kok MR, Da Silva JAP, Griep E.N., Klaasen R, Allaart CF, Baudoin P,  Raterman HG,  Szekanecz Z, Buttgereit F, Masaryk P, Klausch LT (statistician), Paolino S, Schilder AM, Lems WF, Cutolo M, for the GLORIA Consortium.
2. Apart from the listed authors the GLORIA Consortium comprises:

L.M. Middelink, Middelinc BV The Netherlands, Operational Lead;

V. Dekker, Amsterdam UMC, Vrije Universiteit, Financial Lead;

•  

Trial operations: N. van den Bulk, CR2O BV, The Netherlands;

Study Medication (Development, Manufacturing & Supply): R.M.A. Pinto, Bluepharma – Indústria Farmacêutica, S.A., Portugal;

Data management: L. Doerwald, Linical Netherlands B.V., The Netherlands;

Adherence monitoring: J. Redol, BeyonDevices LDA, Portugal;

Safety monitoring: K. Prinsen, Clinfidence BV, The Netherlands;

Patient partner: M. Scholte-Voshaar, Stichting Tools (Tools2Use), The Netherlands.

Investigators (recruiting centers):

T.L.T.A. Jansen, VieCuri – location Venlo, The Netherlands;

C. Codreanu, Clinical Center for Rheumatic Diseases, Bucarest, Rumania;

R.M.Zandhuis-Mooij, MSc, Gelre Ziekenhuis, Apeldoorn, The Netherlands;

E. Molenaar, Groene Hart Ziekenhuis, Gouda, The Netherlands;

J.M. van Laar, UMC Utrecht, The Netherlands;

Y.P.M. Ruiterman, Haga Ziekenhuis, Den Haag, The Netherlands;

A.E.R.C.H. Boonen, MUMC, Maastricht, The Netherlands;

M. Micaelo, Instituto Português de Reumatologia, Lisboa, Portugal;

J. Costa, Hospital de Ponte Lima, Portugal;

M. Sieburg, Rheumatologische Facharztpraxis Magdeburg, Germany;

J.P.L. Spoorenberg, UMC Groningen, The Netherlands;

U. Prothmann, Knappschaftsklinikum Saar GbmH, Puettlingen, Germany;

M.J. Saavedra, Hospital de Santa Maria, Lisboa, Portugal;

I. Silva, Hospital de Egas Moniz, Lisboa, Portugal;

M.T. Nurmohamed, Reade, Amsterdam, The Netherlands;

J.W.G. Jacobs, UMC Utrecht, The Netherlands; and

S.W. Tas, Amsterdam UMC, University of Amsterdam, The Netherlands.

Scientific Advisory Committee:

J.W.J. Bijlsma, UMC Utrecht, The Netherlands;

R. Christensen, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark;

Y.M. Smulders, Amsterdam UMC, VU University, The Netherlands; and

S.H. Ralston, University of Edinburgh, Edinburgh, UK.

Radiographic assessment:

D.M.F.M. van der Heijde (Imaging Rheumatology BV, the Netherlands)coordinated the reading of the hand and foot x-rays.

A.F. Marsman and W.F. Lems scored the spine X-rays.

3. target journal: NEJM, Lancet, JAMA, ARD.

 

3. GLORIA cost-effectiveness and cost utility.

      In Preparation

1. authors: Hartman L, Coupé VMH (C/E expert), Cutolo M, Opris D, Da Silva JAP, Szekanecz Z, Buttgereit F, Masaryk P, Bos R, Kok MR, Paolino S, Klausch LT, Lems WF, Boers M, for the GLORIA Consortium.
2. Apart from the listed authors the GLORIA Consortium comprises: see 2.c; added:
   E.N. Griep, R. Klaasen, C.F. Allaart, P. Baudoin, H.G. Raterman.
3. target journal: Arthritis & Rheumatology or ARD, depending on where publication #1 ends up.

 

4. GLORIA adherence substudy RCT.

      In Preparation

1. authors: Hartman L, Kok MR, Molenaar E, Griep EN, Van Laar JM, Van Woerkom JM, Allaart CF, Raterman HG, Ruiterman YPM, Voshaar MJH (Tools), Redol J (Beyond), Aguiar Pinto R (Bluepharma), Klausch LT, Lems WF, Boers M.
2. Acknowledgments:
3. J.W.J. Bijlsma, R. Christensen, Y.M. Smulders and S.H. Ralston are members of the scientific advisory committee of the GLORIA trial. 
4. target journal: ARD.

 

5. GLORIA adherence data.

Published.
 

Hartman L, Cutolo M, Bos R, Opris-Belinski D, Kok MR, Griep-Wentink HRM, et al. Medication adherence in older people with rheumatoid arthritis is lower according to electronic monitoring than according to pill count. Rheumatology 2021 Mar 2;keab207.

doi: 10.1093/rheumatology/keab207. Online ahead of print.

 

LINK: https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keab207/6158038

 

Abstract:

Objectives. Suboptimal medication adherence is a serious problem in the treatment of chronic inflammatory diseases. To measure medication adherence, electronic monitoring is regarded as superior to pill count. GLORIA is an ongoing two-year trial on the addition of low-dose (5 mg/d) prednisolone or placebo to standard care in older people (65+ years) with RA. During the entire trial, adherence is measured with electronic caps, and with pill counts. The objective is to describe medication adherence patterns, and to compare the adherence results of the two methods.

Methods. The recorded adherence patterns of patients (blinded for treatment group) were classified according to descriptive categories. The cutoff for good adherence was set at 80% of prescribed pills taken.

Results. Trial inclusion closed in 2018 at 451 patients, but trial follow-up is ongoing; the current dataset contains adherence data of 371 patients. Mean number of recorded 90-day periods per patient was 4 (range 1–8). Based on pill count over all periods, 90% of the patients had good adherence; based on cap data, only 20%. Cap data classified 30% of patients as non-user (<20% of days an opening) and 40% as irregular user (different adherence patterns, in or between periods).

Conclusion. In our trial of older people with RA, the majority appeared to be adherent to medication according to pill count. Results from caps conflicted with those of pill counts, with patterns suggesting patients did not use the bottle for daily dispensing, despite specific advice to do so.

Trial registration

NCT02585258. ClinicalTrials.gov (https://www.clinicaltrials.gov/)

 

 

 

6. GLORIA prediction model.

In Preparation

1. authors: Hartman L, Da Silva JAP, Buttgereit F, Cutolo M, Opris D, Szekanecz Z, Masaryk P, Voshaar MJH, Klausch LT, Lems WF, Van der Heijde DMFM, Boers M.
2. Acknowledgments: BeyonDevices LDA, Portugal; Bluepharma – Industria Farmaceuticasa, Portugal; Clinfidence, The Netherlands; Curve Clinical BV The Netherlands; Linical Accelovance Europe B.V., The Netherlands; Middelinc BV, The Netherlands; and Stichting Tools (Tools2Use), The Netherlands were partners in the GLORIA trial.

R. Bos, M.R. Kok, E.N. Griep, R. Klaasen, C.F. Allaart, G.A.W. Bruyn, H.G. Raterman, T.L.T.A. Jansen, C. Codreanu, R.M. Zandhuis-Mooij, E. Molenaar, J.M. van Laar, Y.P.M. Ruiterman, A.E.R.C.H. Boonen, M. Micaelo, J. Costa, M. Sieburg, J.P.L. Spoorenberg, U. Prothmann, M.J. Saavedra and I. Silva included patients in the GLORIA trial.

J.W.J. Bijlsma, R. Christensen, Y.M. Smulders and S.H. Ralston are members of the scientific advisory committee of the GLORIA trial.

3. target journal: Rheumatology (Oxford).

 

7. Implementation of Low-Intervention Trial Procedures: a case study on feasibility and operational gains.

In Preparation

1. authors: Middelink LM, vd Bulk N (Curve), Doerwald L (Linical), Prinsen K (Linical), Redol J, Aguiar Pinto R, Bijlsma J.W., Christensen R, Smulders Y.M., Ralston S.H., Tas S.W., <selected sites>, Boers M.

 

 

WP 7: Guidelines and regulatory guidance: F. Buttgereit lead, MD student (Yannick Palmowski)

PhD student (Thomas Buttgereit), with named involvement of VUmc, CHUC, UNIGE, UMFCDB, Tools, C. Dejaco and the <Clinical partners> which provide significant input.
WP 8: Education, Dissemination, Communication: J. da Silva lead, with named involvement of VUmc, CH, UMFCDB, UNIGE and Tools.
 

 

8. Assessment of current recommendations.

Published.

1. Palmowski Y, Buttgereit T, Dejaco C, Bijlsma JW, Matteson EL, Voshaar M, Boers M, Buttgereit F. "Official View" on Glucocorticoids in Rheumatoid Arthritis: A Systematic Review of International Guidelines and Consensus Statements. Arthritis Care Res (Hoboken) 2017;69:1134-41.

LINK: https://onlinelibrary.wiley.com/doi/epdf/10.1002/acr.23185​

 

Objective. To describe the perception of the current role of systemic glucocorticoids in the management of rheumatoid arthritis (RA) by examining their importance and the current level of evidence in recent guidelines, and to identify open questions to be addressed in future guidelines and research projects.

Methods. We conducted a systematic literature review using the databases Ovid Embase, PubMed Medline, and Cochrane Library for guidelines on the pharmacologic treatment of RA. Retrieved articles were evaluated regarding their quality using the Appraisal of Guidelines for Research and Evaluation II tool and scrutinized for all relevant information concerning the use of glucocorticoids.

Results. All guidelines agree that glucocorticoids, especially if given at low doses and for a short duration, are an appropriate option in the treatment of RA. However, many recommendations remain vague, as reliable and detailed evidence is scarce. Important aspects of glucocorticoid therapy are partially or completely neglected, and the existing nomenclature is not used uniformly. Quality evaluation revealed flaws in many articles, concerning not only glucocorticoid-specific recommendations but also guideline quality in general.

Conclusion. Current recommendations for use of glucocorticoids in the management of RA are suboptimal. More rigorous evaluation of doses, timing, and duration of their use is needed. Existing nomenclature on glucocorticoid therapy should be used uniformly.

 

2. Palmowski Y, Boers M, Buttgereit F. Low-dose glucocorticoids in rheumatoid arthritis: blurring the line between therapeutic dose and substitution therapy? Arthritis Care Res (Hoboken) 2017. (reply to letter to the editor)

LINK: https://onlinelibrary.wiley.com/doi/epdf/10.1002/acr.23452

 

 

9. Current status of involvement of elderly in trials. (I)

Published.

Palmowski A, Buttgereit T, Palmowski Y, Nielsen SM, Boers M, Christensen R, Buttgereit F. Applicability of trials in rheumatoid arthritis and osteoarthritis: A systematic review and meta-analysis of trial populations showing adequate proportion of women, but underrepresentation of elderly people. Semin Arthritis Rheum 2019;48:983-9.

LINK: https://www.sciencedirect.com/science/article/abs/pii/S0049017218304876?via%3Dihub

 

Objectives. To evaluate whether elderly people and women are adequately represented in randomized controlled trials (RCT) in rheumatoid arthritis (RA) and osteoarthritis (OA).

Methods. Four systematic searches in MEDLINE yielded RCT in RA and OA on any intervention published in 2016 and 2017 and population-based studies (PBS) in RA and OA published between 2013 and 2017. Random effects meta-analyses estimated the pooled proportion of elderly people (defined as being ≥ 65 years old), the mean age, its standard deviation (SD), and the proportion of women stratified by disease (RA and OA) and study type (RCT and PBS). Stratified estimates were subsequently compared.

Results. 265 RCT comprising 51,240 participants and 53 PBS comprising 523,630 participants were included. In both RA and OA, RCT included lower proportions of elderly people than PBS: RA –0.18 (95% confidence interval –0.22 to –0.13); OA –0.20 (–0.30 to –0.09); had lower mean ages: RA –5.2 years (–6.8 to –3.5); OA –4.7 years (–7.5 to –2.0); and smaller SD: RA –1.9 years (–2.6 to –1.3); OA –2.7 years (–4.2 to –1.2); (all comparisons: p ≤ 0.001). Proportions of women were comparable in RCT compared to PBS in both RA and OA.

Conclusions. While women are adequately represented in RA and OA trials, the elderly are underrepresented, probably limiting applicability of current evidence to this growing subgroup. It is urgent to improve the inclusion of elderly people in clinical trials and study age as a determinant for outcome.

 

 

 

10. Current status of involvement of elderly in trials. (II)

Published.

Palmowski A, Nielsen SM, Buttgereit T, Palmowski Y, Boers M, Christensen R, Buttgereit F. Association between participant retention and the proportion of included elderly people in rheumatology trials: Results from a series of exploratory meta-regression analyses. Arthritis Care Res 2020;72:1490-6.

LINK: https://onlinelibrary.wiley.com/doi/epdf/10.1002/acr.24051

                   Abstract:

Objective: The elderly, a population defined by an age of ≥65 years, are underrepresented in rheumatology trials, possibly due to investigators' concerns of increased premature discontinuations in higher age groups. The present study was undertaken to evaluate whether the proportion of included elderly individuals (PE) is independently associated with participant retention in rheumatology trials.

Methods: Medline was searched for randomized controlled trials (RCTs) in rheumatoid arthritis (RA) and osteoarthritis (OA) of any intervention (years 2016 and 2017). PE was either extracted from the research manuscript or estimated from an assumed (truncated) normal distribution. We used mixed-effects meta-regression models including several covariates to assess whether there is an independent association between PE and participant retention. Using sensitivity analyses, we evaluated whether associations were connected to attrition due to lack of efficacy (LoE) or adverse events (AE).

Results: In total, 243 RCTs comprising >48,000 participants were included. Pooled participant retention was 88%. PE was not associated with retention in the unadjusted (P = 0.97) or adjusted (all: P ≥ 0.14) models. Of all covariates, only study duration and type of intervention were associated with retention (both: P < 0.001). Post hoc analyses allowing for interaction revealed a small but statistically significant positive association between PE and retention in pharmacologic interventions and a negative association in physical/physiotherapeutic interventions (overall P for interaction = 0.05). No associations were found for PE and attrition due to LoE or AE.

Conclusion: Participant retention in RA and OA trials is high and not associated with PE. These findings should motivate investigators to include more elderly participants in rheumatology trials.

 

 

11. Current status of involvement of elderly in trials. (III)

Published.

Forsat ND, Palmowski A, Palmowski Y, Boers M, Buttgereit F. Recruitment and Retention of Older People in Clinical Research: A Systematic Literature Review. J Am Geriatr Soc 2020; 68:2955-63.

LINK: https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.16875

            Abstract.

Objective: To identify barriers and solutions for the recruitment and retention of older (aged ≥65 years) people in clinical trials.

Design: Systematic literature review.

Methods: Three databases (Medline, Embase, and CENTRAL) were searched for articles reporting on barriers or solutions regarding the recruitment or retention of older people. Only original research articles were included.

Results: Fifty eligible articles were identified. Exclusion criteria were the most common cause of poor recruitment of older adults (mainly age and comorbidities). Patients' families or physicians often advised against participation (22% of included studies). Lack of interest (18%) and problems with transportation (18%) were also commonly cited as challenges. Fourteen trials (28%) reported that monitoring and adapting their recruitment methods helped, along with a flexible research team (26%) and provision of transportation (24%). Retention was impaired by death (12%), illness (8%), and loss of interest (6%). Methods with a positive effect on retention included financial incentives and regular information about the progress of the study (12%), a low staff turnover (12%), flexibility in appointment making (10%), and expression of appreciation by the staff through letters, gifts, and cards to the participants (10%).

Conclusion: We identified several barriers and have listed potential solutions that may improve recruitment and lead to fewer dropouts in trials involving older populations. Implementation of our findings may help mitigate the manifold challenges that come with running a trial with older people.

Trial registration: ClinicalTrials.gov NCT02585258.

 

12. Current status of involvement of elderly in trials. (IV)

Published.

Palmowski A, Nielsen SM, Buttgereit T, Palmowski Y, Boers M, Christensen R, et al. Glucocorticoid-trials in rheumatoid arthritis mostly study representative real-world patients: A systematic review and meta-analysis. Seminars in Arthritis and Rheumatism 2020;50:1400-5.

LINK (not free for all): https://www.sciencedirect.com/science/article/abs/pii/S004901722030069X?via%3Dihub

Abtract

Objective: Randomized controlled trials (RCTs) are considered the gold standard in clinical research due to credible causality. Their results, however, may not be generalizable to real-world populations. While glucocorticoids (GCs) remain a mainstay of rheumatoid arthritis (RA) treatment, it is unclear whether the results of GC-RCTs are generalizable to current real-world RA patients.

Methods: MEDLINE was searched for RCTs and, as comparators, cohort studies (CSs) in RA evaluating systemic GCs. Random-effects meta-analyses were performed for descriptive baseline characteristics (including general demographics, comorbidities, and disease activity) that have been shown to be able to modify the benefit-risk-ratio of various RA therapeutics. These meta-analyses were stratified by study type (RCT and CS). Stratified estimates were subsequently compared. Further sensitivity analyses were performed stratifying by disease duration.

Results: 56 RCTs (7053 participants) and 10 CSs (14,688 participants) were included. 12 characteristics were reported frequently enough to allow for comparative analysis. In 10/12 characteristics (83%), RCT estimates did not appear to differ from CS estimates. However, RCT participants were younger (-4.7 years [95% CI -7.2 to -2.1]; p < 0.001) and had higher erythrocyte sedimentation rates (11.8 mm/h [5.7 to 17.8]; p < 0.001) than CS participants. Comorbidities could not be assessed due to insufficient reporting.

Conclusion: Our findings suggest that evidence from GC trials in RA is of acceptable generalizability to current real-world patients - especially compared to findings from biologic agents in RA. However, RCT participants were younger than real-world patients, potentially limiting the generalizability of trial results to elderly patients.

Systematic review registration: PROSPERO (CRD42019134675).

 

 

13. Current status of involvement of elderly in trials. (IV)

Published.

Buttgereit T, Palmowski A, Forsat N, Boers M, Witham M, Rodondi N,  Moutzouri7 E, Quesada Navidad AJ, Van’t Hof AWJ, Van Der Worp B, Coll-Planas L, Voshaar M, De Wit M, Da Silva JAP, Stegemann S, Bijlsma JW, Koeller M, Mooijaart S, Gussekloo J, Kearney PM, Buttgereit F.
Barriers and potential solutions in the recruitment and retention of the elderly in clinical trials – lessons learned from six large multi-centre randomized controlled trials.  Age Ageing 2021  Jul 29;afab147.

LINK (not free for all): https://academic.oup.com/ageing/advance-article-abstract/doi/10.1093/ageing/afab147/6329807?redirectedFrom=fulltext

Abstract

Background. Older people remain underrepresented in clinical trials, and evidence generated in younger populations cannot always be generalized to older patients.

Objective. To identify key barriers and to discuss solutions to specific issues affecting recruitment and retention of older participants in clinical trials based on experience gained from six current European randomised controlled trials (RCTs) focusing on older people.

Methods. A multidisciplinary group of experts including representatives of the six RCTs held two networking conferences and compiled lists of potential barriers and solutions. Every item was subsequently allocated points by each study team according to how important it was perceived to be for their RCTs.

Results. The six RCTs enrolled 7,612 older patients. Key barriers to recruitment were impaired health status, comorbidities and diverse health beliefs including priorities within different cultural systems. All trials had to increase the number of recruitment sites. Other measures felt to be effective included the provision of extra time, communication training for the study staff and a re-design of patient information. Key barriers for retention included the presence of severe comorbidities and the occurrence of adverse events. Long study duration, frequent study visits and difficulties accessing the study site were also mentioned. Solutions felt to be effective included spending more time maintaining close contact with the participants, appropriate measures to show appreciation and reimbursement of travel arrangements.

Conclusion. Recruitment and retention of older patients in trials requires special recognition and a targeted approach. Our results provide scientifically-based practical recommendations for optimizing future studies in this population.

 

 

14. Current status of involvement of elderly in trials. (V)

Experience from GLORIA trial.

In preparation.

Voshaar M, van den Bulk N, Middelink L, et al. Barriers and solutions in the recruitment and retention of older persons in clinical trials: experience in the Gloria trial.

 

15. Patients’ and Rheumatologists’ perspectives on glucocorticoid use.

Published.

Santiago T, Voshaar M, De Wit M, Carvalho PD, Buttgereit F, Cutolo M, Paolino S,  Castelar Pinheiro GR, Boers M, Da Silva JAP. Patients’ and rheumatologists’ perspectives on the efficacy and safety of low-dose glucocorticoids in rheumatoid arthritis – an international survey within the GLORIA study. Rheumatology 2021;60:3334-42.

LINK (not free for all): https://academic.oup.com/rheumatology/article-abstract/60/7/3334/6062102?redirectedFrom=fulltext

            Abstract

Objective: To evaluate the current perspectives of patients and health professionals regarding the efficacy and safety of low-dose glucocorticoids (GCs) in RA.

Methods: Two online surveys were disseminated to patients and health professionals, in their native language, through national patient organizations and national rheumatology medical societies, respectively. SurveyMonkey®, MediGuard.org and the Glucocorticoid Low-dose Outcome in RA Study (GLORIA) website were used to offer and deliver these surveys.

Results: A total of 1221 RA patients with exposure to GCs, and 414 rheumatologists completed the surveys. Patients and rheumatologists reported high levels of agreement regarding the efficacy of low-dose GCs: at least 70% considered that they are very rapid and effective in the control of signs and symptoms of RA. However, half of the patients also reported having suffered serious adverse events with GCs, and 83% described concerns about safety. The majority of rheumatologists estimated that endocrine, ophthalmologic and cutaneous adverse events affect >4% of all patients treated with low-dose GCs for 2 years, based on a heat map.

Conclusions: RA patients with self-reported exposure to GCs express high levels of satisfaction with low-dose GCs efficacy, as do rheumatologists. However, both expressed excessive concerns regarding the safety of GCs (greatly exceeding the published evidence data), which may compromise the optimal use of this medication. This study indicates that there is an unmet need for appropriately designed prospective trials that shed light on the real risk associated with low-dose GCs, as well as a need for renovated educational programs on the real benefits and harms of low-dose GCs, for both patients and physicians.

 

 

Published.

16. Hartman L, Lems W.F., Boers M. Outcome measures for adherence data from a medication event monitoring system: A literature review. J Clin Pharm Ther 2019;44:1–5.

LINK: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379515/

Abstract

What is known: Currently, medication bottles with an electronic cap are frequently used to measure medication adherence. This system is termed medication event monitoring system (MEMS). To our knowledge, the optimal method to summarize data from MEMS has not yet been determined.

Objective: Look for best practices on how to quantify adherence data from MEMS.

Methods: Review of PubMed, Embase and Cochrane databases for the articles on medication adherence with MEMS.

Results: Of 1493 identified articles, 207 were included in this review. The MEMS cap was used for a median of 3 months (IQR: 4; range: 1 week to 24 months) in various health conditions. Many different outcome measures were used. Most studies computed an adherence score, expressed as the percentage of days on which the correct dose of medication was taken. The threshold to mark people as adherent was most frequently, arbitrarily, set at 80% (range: 67%-95%). We found no data to support a specific threshold.

Discussion: Although the commonly used definition of adherence has face validity, we found no validation studies, and not all studies used the same cut-off for adherence. Ideally, a cut-off should be defined and validated in the context of the specific drug and its pharmacokinetic and dynamic characteristics, and perhaps other contextual factors, rather than generically. In addition, there was large heterogeneity in the definition of what "correct intake" of medication is.

What is new and conclusion: Outcome measures for MEMS data lacked standardization, and no demonstrable effort to validate any definition against a relevant clinical outcome is available. Consensus on the definition of adherence is urgently needed.

 

17. Hartman L, Bos R, Buttgereit F, Güler-Yuksel M, Ionescu R, Kok MR, Lems WF, Micaelo M, Opris-Belinski D, Pusztai A, Santos EJF, da Silva JAP, Szekanecz Z, Kim Zeiner K, Zhang D, Boers M. Remarkable international variability in reasons for ineligibility and non-participation in the GLORIA trial. Scand J Rheumatol 2019;48:340-1.

LINK: https://www.tandfonline.com/doi/abs/10.1080/03009742.2018.1559880?journalCode=irhe20

 

Data collection phase.

18. Güler-Yuksel M, …, Kok M.R. Effects of low dose prednisolone on body composition of elderly patients with rheumatoid arthritis. Subgroup analysis of a randomized placebo-controlled trial.
19. Spittuler LF, Hartman L, Bos R, Kok MR, IJzerman RG, Smulders YM, Boers M. Working title: Symptoms and signs of adrenal insufficiency following 2 years of low-dose prednisolone in rheumatoid arthritis: randomized comparison.

 

 

EULAR 2018

posters:

1. Carvalho PD, Goel N, Voshaar M, Boers M, Silva JAPD. Patients’ perspective on the efficacy and risks of glucocorticoids in RA – an initiative under the GLORIA project. Ann Rheum Dis 2018; 77 Suppl: A982.
2. Hartman L, Lems W, Boers M. Methods for the analysis of adherence data from a medication event monitoring system (MEMS): a systematic review. Ann Rheum Dis 2018;77 Suppl:A823.

 

abstract book:

3. Carvalho PD, Buttgereit F, Boers M, Silva JAPD. Health professionals’ perspective on benefits and risks of low dose glucocorticoids in RA – an initiative under the GLORIA project. Ann Rheum Dis 2018; 77 Suppl: A1839.
4. Hartman L, Bos R, Buttgereit F, Güler-Yuksel M, Ionescu R, Kok M.R., et al. Remarkable international variability in reasons for non-participation in the GLORIA trial. Ann Rheum Dis 2018;77 Suppl:A1353.

 

ACR 2018

posters:

1. Andriko Palmowski, Thomas Buttgereit, Yannick Palmowski, Sabrina Mai Nielsen, Maarten Boers, Robin Christensen and Frank Buttgereit.  Representation of Elderly People and Women in Rheumatoid Arthritis and Osteoarthritis Trials: A Systematic Review and Meta-Analysis Comparing Clinical Trials with Population-Based Studies.

 

EULAR 2019

oral presentation:

1. Palmowski A, Nielsen SM, Buttgereit T, et al. No association between the proportion of elderly people and trial retention in rheumatoid arthritis and osteoarthritis trials: a systematic review with meta-regression analyses Ann Rheum Dis 2019;78:73. (OP0014).

 

 

EULAR 2020

poster:

1. Hartman L, Paolino S, Bos R, Opris-Belinski D, Kok MR, Griep-Wentink H, Klaasen R, Allaart C, Bruyn G, Raterman H, Voshaar M, Gomes N, Pinto R, Klausch T, Lems W, Boers M. In elderly patients, caps that record medication bottle openings are unreliable and thus not the gold standard for adherence. Ann Rheum Dis 2020; 79 Suppl:A894.

 

abstract book:

2. Hartman L, Alessandri E, Bos R, Opris-Bellinski D, Kok MR, Griep-Wentink H, Klaasen R, Allaart C, Bruyn G, Raterman H, Voshaar M, Gomes N, Pinto  R, Klausch T, Lems W, Boers M. Medication adherence data in a randomized trial: large challenges to come from raw data to a workable and reliable dataset. Ann Rheum Dis 2020; 79 Suppl:AB1165.
3. T. Santiago, M. Voshaar, M. De Wit, P. Carvalho, M. Boers, M. Cutolo, F. Buttgereit, J. A. P. Da Silva. Health professionals’ perspective on the benefits and risks of low-dose glucocorticoids in rheumatoid arthritis – an international survey of 444 health professionals.  Ann Rheum Dis 2020; 79 Suppl:AB1335-HPR.
4. T. Santiago, M. Voshaar, M. De Wit, P. Carvalho, M. Boers, M. Cutolo, F. Buttgereit, J. A. P. Da Silva. Patients’ perspective on the benefits and risks of low-dose glucocorticoids in rheumatoid arthritis – an international survey of 1344 patients.  Ann Rheum Dis 2020; 79 Suppl:PARE0004.
5. A. Palmowski, S. M. Nielsen, T. Buttgereit, Y. Palmowski, M. Boers, R. Christensen, F. Buttgereit. Rheumatoid arthritis patients included in glucocorticoid trials mostly resemble those seen in observational cohorts: a systematic review and meta-analysis. Ann Rheum Dis 2020; 79 Suppl:AB1223.

 

EULAR 2021

abstract book:

1. M. Boers, L. Hartman, D. Opris-Belinski, R. Bos, M. R. Kok, J. A. P. Da Silva, E. N. Griep, R. Klaasen, C. Allaart, P. Baudoin, H. Raterman, Z. Szekanecz, F. Buttgereit, P. Masaryk, T. Klausch, S. Paolino, A. Schilder, W. Lems, M. Cutolo. High number of concomitant medications and comorbidities at baseline in the glucocorticoid low-dose outcome in rheumatoid arthritis (gloria) study: an older population with rheumatoid arthritis. Ann Rheum Dis 2020; 80 Suppl:AB0160.