Dose Reduction and Discontinuation of Prednisolone Using Structured Treat-to-target Taper in Patients With Polymyalgia Rheumatica
Phase: NA
Conditions: Polymyalgia Rheumatica
Sponsor: Aarhus University Hospital

1 
 
Dose reduction and discontinuation of prednisolone using 
structured treat-to-target taper in patients with polymyalgia 
rheumatica: 
Protocol for an open label, parallel-group, multi-centre trial 
1 Administrative information 
1.1 Title 
Dose reduction and discontinuation of prednisolone using structured treat-to-target taper in patients with 
polymyalgia rheumatica 
1.2 Trial Registration 
The trial will be registered at Clinicaltrials.gov. This protocol is structured according to the SPIRIT 2013 
checklist. 
1.3 Protocol Version 
Version 1.2; 2022-11-08 
1.4 Funding 
The initiator of this study is MD, PhD Kresten Keller. Principal investigator Christoffer Søvsø Våben has 
received an introductory scholarship from Institute of Clinical Medicine, Aarhus University (65.000 DKR) to 
prepare this protocol and further prepare the study. Christoffer Søvsø Våben has received a scholarship from 
The Danish Rheuamtism Association (1.000.000 DKR) for VIP-salary for the two first years of the PhD 
project. Kresten Keller has received a grant from Independent Research Fond Denmark (2.000.000 DKR) 
covering the last year of PhD Salary as well as operating expenses. 
There is a continuous search for funding. If funding is granted, an amendment to the protocol will be 
submitted to The Central Denmark Region Committee on Health Research Ethics. The financial contributors 
have no influence on design, conduct, and publication of the results. 
 
1.5 Roles and responsibilities 
Principal Investigator: 
 
 
Main supervisor: 
Christoffer Søvsø Våben 
 
 
Kresten Krarup Keller 
MD 
 
 
 
MD, PhD, Associate Professor 

2 
 
Department of Rheumatology 
 
Department of Rheumatology 
Aarhus University Hospital  
 
Aarhus University Hospital 
chrmoa@rm.dk 
 
 
kreskell@rm.dk 
+45 22840838  
 
 
+45 40384984 
Research group 
Christoffer Søvsø Våben, MD, Department of Rheumatology, Aarhus University Hospital 
Kresten Krarup Keller, MD, PhD, Associate Professor, Main supervisor, Department of Rheumatology, 
Aarhus University Hospital.  
Andreas Wiggers, MD, PhD student, Department of Rheumatology, Aarhus University Hospital 
Ib Tønder Hansen, MD, PhD, Department of Rheumatology, Aarhus University Hospital 
Ellen-Margrethe Hauge, MD, PhD, Professor, Department of Rheumatology, Aarhus University Hospital 
Berit Dalsgaard Nielsen, MD, PhD, Department of Rheumatology, Horsens Regional Hospital  
Jesper Blegvad Nissen, MD, Department of Rheumatology, Silkeborg Regional Hospital 
Line Thorndal Moll, MD, PhD, Department of Rheumatology, Gødstrup Regional Hospital 
Sidsel Aabo, MD, Department of Rheumatology, Randers Regional Hospital 
Stavros Chrysidis, MD, Department of Rheumatology, Esbjerg Regional Hospital 
Salome Kristensen, MD, PhD Department of Rheumatology, Aalborg University Hospital 
Caroline Marie Andreasen, MD, PhD, Department of Rheumatology, Vejle Regional Hospital 
Lone Holm Hansen, MD, Department of Rheumatology, North Denmark Regional Hospital, Hjørring 
Robin Christensen, MSc, PhD; Professor of Biostatistics and Clinical Epidemiology, Department of Clinical 
Research, University of Southern Denmark, Odense University Hospital 
 
International scientific advisory board 
Elisabeth Brouwer, MD, PhD, Professor, Department of Rheumatology and Clinical Immunology, 
University of Groningen, Netherlands 
Sarah Mackie, MD, PhD, Associate Professor in Vascular Rheumatology, University of Leeds, 
Honorary Consultant Rheumatologist, Leeds Teaching Hospital NHS Trust, UK 
 
 
 
 

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Table of Contents 
 
1 Administrative information ............................................................................................................................ 1 
1.1 
Title.................................................................................................................................................... 1 
1.2 
Trial Registration ............................................................................................................................... 1 
1.3 
Protocol Version ................................................................................................................................ 1 
1.4 
Funding .............................................................................................................................................. 1 
1.5 
Roles and responsibilities .................................................................................................................. 1 
Table of Contents .......................................................................................................................................... 3 
2 
Introduction ............................................................................................................................................... 5 
2.1 Background and Rationale....................................................................................................................... 5 
2.2 
Aim and Objective(s)......................................................................................................................... 6 
2.2.1 Hypotheses ....................................................................................................................................... 8 
2.3 
Trial Design ....................................................................................................................................... 8 
3 
Methods ..................................................................................................................................................... 9 
3.1 Participants, Interventions and Outcomes ............................................................................................... 9 
3.1.1 Study Setting .................................................................................................................................... 9 
3.1.2 Eligibility Criteria ............................................................................................................................. 9 
3.1.3 Interventions ..................................................................................................................................... 9 
3.1.4 Outcomes ........................................................................................................................................ 12 
3.1.5 Participant timeline ......................................................................................................................... 13 
3.1.7 Recruitment .................................................................................................................................... 15 
3.2 Assignment of Interventions .................................................................................................................. 16 
3.2.1 Allocation Sequence generation ..................................................................................................... 16 
3.2.2 Allocation concealment mechanism ............................................................................................... 16 
3.2.3 Implementation ............................................................................................................................... 16 
3.2.4 Blinding .......................................................................................................................................... 16 
3.3 Data collection, management and analysis ............................................................................................ 16 
3.3.1 Data collection methods ................................................................................................................. 16 
3.3.2 Data Management ........................................................................................................................... 19 
3.3.3 Statistical methods .......................................................................................................................... 19 
3.3 
Monitoring ....................................................................................................................................... 20 
3.3.1 
Data monitoring ....................................................................................................................... 20 

4 
 
3.3.2 
Harms ...................................................................................................................................... 20 
4 
Ethics and dissemination ......................................................................................................................... 21 
4.1 Research ethics approval ....................................................................................................................... 21 
4.2 Consent or assent ................................................................................................................................... 22 
4.3 Confidentiality ....................................................................................................................................... 22 
4.3 
Declaration of interests .................................................................................................................... 22 
4.4 
Access to data .................................................................................................................................. 23 
4.5 
Ancillary and post-trial care ............................................................................................................ 23 
4.7 Dissemination policy ............................................................................................................................. 23 
5 References ................................................................................................................................................ 23 
 
 
 
 

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2 Introduction 
2.1 Background and Rationale 
Polymyalgia Rheumatica (PMR) is one of the most common inflammatory diseases of the elderly [1]. It is 
characterised by symmetrical pain in the proximal muscles, morning stiffness and raised inflammatory 
markers. Prednisolone remains a cornerstone in the treatment of PMR [2], even though it carries several 
significant adverse effects such as osteoporosis, diabetes and increased infection risk [3-5]. Methotrexate as a 
glucocorticoid sparing agent is rarely used because of limited evidence and potential side effects [6]. 
Therefore, prednisolone remains the standard drug of choice, and dose as well as treatment duration should 
be reduced as much as possible [7]. PMR is associated with giant cell arteritis (GCA), which is treated with a 
much higher prednisolone dosage than PMR [8]. Approximately 20% of PMR patients develop GCA during 
the course of their disease and some studies have shown that up to 1/3 of PMR patients have an undiagnosed 
GCA [1, 9, 10]. Since treatment regimens for GCA and PMR differ significantly in prednisolone dose and 
tapering, there is a rationale to screen PMR patients for GCA. Ultrasonography is a cheap, non-invasive and 
precise method to diagnose GCA [11, 12]. 
Danish National PMR guidelines as well as European League Against Rheumatism (EULAR) 
guidelines, suggests a starting dose of prednisolone from 12,5-25 mg daily and hereafter a gradually and 
individualised taper over approximately one year but these recommendations are not based on evidence. [13, 
14]. Furthermore, the national guidelines states that PMR patients can be diagnosed and treated either by 
their general practitioner (GP) or a rheumatological department, but one is not recommended over the other 
[14]. Therefore, further research is necessary to determine where and how these patients are managed most 
successfully. 
In other rheumatic diseases such as rheumatoid arthritis and axial spondyloarthritis, a treat-to-
target approach has proven beneficial to control disease activity [15, 16]. Treat-to-target is characterized by 
setting a specific treatment goal corresponding to disease remission or low activity and then systematically 
trying to reach this goal. Leading experts have suggested that a treat-to-target strategy may be effective in 
PMR and proposed further studies in this field [17, 18]. Recently our research group published a 
retrospective study demonstrating that a systematic approach to prednisolone taper in PMR more effectively 
brings patients in prednisolone free remission, but the results must be confirmed in a prospective setting [19]. 
 
Perspectives 
It is anticipated that this trial will improve the current treatment strategy for PMR patients. By using an 
evidence-based treat-to-target approach, patients will reach a faster prednisolone free remission, which 
results in less PMR related morbidity and less patients developing prednisolone adverse effects. By 
following PMR patients in a hospital setting, a larger proportion of GCA patients will be found. It is 

6 
 
expected that the rheumatological driven treat-to-target taper will overall be an improvement for PMR 
patients regarding symptom relief and quality of life and be a cheaper way to treat PMR patients in a long-
term health-economic perspective.  
 
2.2 Aim and Objective(s) 
The overall aim of this study is to investigate benefits and harms associated with a systematic “treat-to-
target” prednisolone taper strategy compared to usual care in newly diagnosed, treatment naïve patients with 
PMR.  
Primary objective:  
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on the proportion of 
patients in prednisolone free remission after 52 weeks, in patients with PMR. 
Key secondary objectives: 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in the 
patient-reported prednisolone dose from baseline to week 52, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on the proportion of 
patients diagnosed with GCA during 52 weeks, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on number of relapses 
from baseline to week 52, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in the 
patient reported global VAS from baseline to week 52, in patients with PMR. 
Secondary objectives: 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in PMR-
Activity Score (PMR-AS) from baseline to week 52, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on the proportion of 
patients with an undiagnosed vasculitis verified by ultrasound at the 52-week visit, in patients with 
PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in SF-36 
MCS from baseline to week 52, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in SF-36 
PCS from baseline to week 52, in patients with PMR 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in HAQ-
DI from baseline to week 52, in patients with PMR. 

7 
 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in PMR 
VAS from baseline to week 52, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in fatigue 
VAS from baseline to week 52, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in stiffness 
VAS from baseline to week 52, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in morning 
stiffness duration (min) from baseline to week 52, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on frequency of 
adverse effects and comorbidities related to prednisolone treatment after 13, 26, 39 and 52 weeks, in 
patients with PMR. 
Other (exploratory) objectives: 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on 13 weeks sustained 
prednisolone free remission after 65 and 104 weeks, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on the patient reported 
accumulated prednisolone dosage after 13, 26, 39, 52, 65, 78, 91 and 104 weeks, in patients with 
PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on prednisolone dose 
at 13, 26, 39, 52, 65, 78, 91 and 104 weeks, only in GCA free PMR patients. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in PMR-
AS from baseline to 104 weeks, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in SF-36 
MCS and PCS, HAQ-DI, PMR VAS, fatigue VAS, stiffness VAS, global VAS and morning stiffness 
duration (min) from baseline to week 65, 78, 91 and 104, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on number of relapses 
after 65, 78, 91 and 104 weeks, in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on the proportion of 
patients diagnosed with GCA during 104 weeks (incidence), in patients with PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on the proportion of 
patients with an undiagnosed GCA verified by ultrasound at the 104-week visit, in patients with 
PMR. 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on changes in 
inflammatory and cardiovascular biochemical markers from baseline to 13, 26, 39, 52, 65, 78, 91 and 
104 weeks, in patients with PMR. 

8 
 
 
To compare the effect of a treat-to-target taper strategy, relative to usual care, on the frequency of 
adverse effects and comorbidities related to prednisolone treatment after 65, 78, 91 and 104 weeks, 
in patients with PMR. 
Other information: 
 
The proportion of GCA patients at baseline 
2.2.1 Hypotheses 
 
More patients will be in prednisolone free remission after one and two years in PMR patients 
receiving a treat-to-target prednisolone taper vs. usual care. 
 
No difference will be seen in changes in PMR-AS after one and two years in PMR patients receiving 
a treat-to-target prednisolone taper vs. usual care. 
 
No difference will be seen in outcomes related to patient reported outcome measures (SF-36 MCS 
and PCS, HAQ-DI, PMR VAS, fatigue VAS, stiffness VAS, global VAS and morning stiffness 
duration (min)) in PMR patients receiving a treat-to-target prednisolone taper vs. usual care. 
 
The absolute dosage of prednisolone will decrease faster in PMR patients receiving a treat-to-target 
prednisolone taper vs. usual care. 
 
The total accumulated prednisolone dose will be lower after one and two years in PMR patients 
receiving a treat-to-target prednisolone taper vs. usual care. 
 
Fewer patients will have an undiagnosed GCA after one and two years when comparing a treat-to-
target prednisolone taper with usual care.  
 
No difference is seen in the total number of GCA patients found with vascular ultrasound after one 
and two years when comparing a treat-to-target prednisolone taper to usual care. 
 
No difference is seen in inflammatory and cardiovascular biochemical markers after one and two 
years in PMR patients receiving a treat-to-target prednisolone taper vs. usual care. 
 
Less adverse effects to prednisolone will occur in PMR patients receiving a treat-to-target 
prednisolone taper vs. usual care. 
 
Following a treat-to-target taper in a hospital setting will be a more cost-effective approach than 
treatment in general practise. 
 
2.3 Trial Design 
It is a 1-year open label randomised trial, with a planned 1-year extension. Study population is 120 patients 
with newly diagnosed treatment naïve PMR. Patients will be randomised to either structured treat-to-target 

9 
 
prednisolone taper in a hospital setting according to a standard tapering scheme, or to usual care by general 
practitioners. Treatment effect is evaluated every 3 months. 
 
3 Methods 
3.1 Participants, Interventions and Outcomes 
3.1.1 Study Setting 
The study is a multicentre study and patients will be included from rheumatological departments in the 
Central Denmark Region (Aarhus University Hospital, Silkeborg Regional Hospital, Horsens Regional 
Hospital, Randers Regional Hospital, and Gødstrup Regional Hospital), Southern Denmark Region (Esbjerg 
Regional Hospital, Vejle Regional Hospital) and Northern Denmark Region (Aalborg University Hospital, 
North Denmark Regional Hospital, Hjørring). The primary research group will be located at the Department 
of Rheumatology, Aarhus University Hospital. 
3.1.2 Eligibility Criteria 
Inclusion criteria 
 
Patients newly diagnosed with PMR according to the EULAR criteria for PMR [20]. 
 
No sign of GCA on ultrasonography of the temporal and axillary arteries. 
 
Age over 50 years. 
 
Danish spoken and written language skills sufficient to fill out questionnaires.  
Exclusion criteria 
 
Peroral, intraarticular or intramuscular application of glucocorticoids within the last month.  
 
Previous prednisolone treatment for GCA/PMR. 
 
Unable to give consent. 
 
Symptoms of GCA (newly onset-headache, tenderness of the temporal artery, jaw claudication, 
vision disturbances). 
 
Active malignant cancers within the last 5 years (except basal cell carcinoma). 
 
Other inflammatory rheumatic diseases (eg. rheumatoid arthritis, polymyositis, spondyloarthritis, 
psoriatic arthritits, gout). 
 
Uncontrolled diseases (eg severe active asthma, cardiac disease with NYHA class IV) 
3.1.3 Interventions 
Both groups are diagnosed by a rheumatologist according to the inclusion and exclusion criteria. Hereafter 
treatment with prednisolone is started with 15 mg as a morning dose according to the standard starting dose 

10 
 
advised in national as well as EULAR guidelines [13, 14]. All patients will receive a thorough information 
about PMR and what symptoms to be aware of including GCA symptoms. 
Usual Care 
Patients randomized to “usual care” are dismissed from the hospital after the diagnosis and the prednisolone 
taper are subsequently performed by the patient’s general practitioner. A letter is sent to the general 
practitioner informing that the patient is included in a scientific study, guidance for prednisolone tapering 
according to national guidelines, and where to find further information (See appendix 1). 
Rereferral of patients if general practitioners need rheumatological assistance, is part of normal clinical 
practise. During this trial, patients rereferred to rheumatological assessment from general practice will 
receive a treatment similar to other patients seen in the outpatient clinic according to standard care but will 
not receive the structured treat-to-target taper.   
Treat-to-target Prednisolone Taper 
Patients randomized to the “Treat-to-target” group is prescribed with a systematic prednisolone taper 
according to the Table 1 below, which adhere to the Danish national guidelines[14]. The starting dose can be 
increased if remission is not reached initially. Preferably dosage should be increase to a maximum of 25 mg 
daily according to Danish and EULAR guidelines [13, 14]. If prednisolone dosage is increased, Table 2 
below is followed until a daily dosage of 15 mg is reached. Hereafter Table 1 is followed. 
 
 

11 
 
Table 1 
 
 
Table 2 
Treatment 
Week 
Daily 
Prednisolone 
dosage 
1-2 
15.00 mg 
3-4 
12.50 mg 
5-9 
10.00 mg 
10-14 
10.00/7.50 mg 
15-19 
7.50 mg 
20-24 
7.50/5.00 mg 
25-29 
5.00 mg 
30-34 
5.00/2.50 mg 
35-39 
2.50 mg 
40-44 
2.50/0.00 mg 
45 
0.00 mg 
Table 1: Where two dosages is separated by an /, it refers to alternating dosages every other day. 
Furthermore, as part of their out-patient monitoring and treat-to-target approach, this group of patients will 
be monitored with blood samples four weeks after the first visit and hereafter every 4th week (including 
HgbA1C, after 1 and 3 months), which adhere to clinical practice. A nurse will subsequently make a 
minimum of 5 phone consultations at approximately week 3-5, 11-16, 24-32, 38-42, 52, and hereafter 
minimum every 3 months where the focus will be on symptoms, medical compliance, medical adverse 
effects and results of the blood samples. When the patient reaches prednisolone free remission, a last phone 
consultation is planned 2-3 months after and if the patient is still in remission further consultations is not 
necessary according to clinical practice. The patient will still receive the study questionnaires and come to 
the two-year study visits. 
 The nurse will consult a rheumatologist if one of the following occurs: 
 
The patient reports cranial symptoms of GCA 
 
If a second relapse occurs 
 
If CRP is not normalized or the patient still has symptoms after the first month of treatment 
If the patient is not in remission at the first phone consultation after 3-5 weeks or at the phone consultation 
one month after a relapse, additional phone consultations will be added monthly until the patient is deemed 
in remission and hereafter the above mentioned structure will be followed.  
Treatment 
week after 
prednisolone 
increase 
Daily 
prednisolone 
dose 
1-2 
25.00 mg 
3-4 
20.00 mg 
5-6 
15.00 mg 

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After consultation with a rheumatologist, it can be determined if the patient should proceed in the nurse-
managed care or be transferred to doctor-managed care. On clinical indication the doctor can furthermore 
decide to change the tapering scheme for the patient and plan additional visits for the patient and repeat the 
vascular ultrasound if it is deemed necessary.  
No widely accepted scoring system for PMR relapse exists [21]. In this study relapse is defined as the 
reappearance of signs and symptoms of PMR, accompanied by an increase in C-reactive protein level 
attributable to disease activity [22]. Between visits relapse is defined as symptoms leading to an increase in 
prednisolone dose determined by the treating physician. If relapse occur, prednisolone dosage will be 
increased to the previous level where symptoms were under control and tapering resume according to Table 
1 from here.  
This group of patients are also referred to a DXA and initiation of alendronate is recommended on clinical 
indication in all patients with a T-score of less than -1.0 at baseline or in case of low energy fractures in hip 
or spine. Treatment and further DXA scans are performed according to national guidelines [23]. 
3.1.4 Outcomes 
Primary Outcome 
 
Proportion of patients in prednisolone free remission 52 weeks from baseline 
Key Secondary Outcomes 
 
Change in prednisolone dose from baseline to week 52 
 
Proportion of GCA patients diagnosed during the first 52 weeks 
 
Self-reported number of relapses during the first 52 weeks (assessed by increase in symptoms and an 
increase in prednisolone dosage) 
 
Change in patient-reported global VAS from baseline to week 52 
 
Secondary Outcomes 
 
Change in PMR-AS from baseline to week 52 
 
Proportion of patients with an undiagnosed vasculitis assessed by ultrasound at week 52 
 
Changes in SF-36 MCS from baseline to week 52 
 
Changes in SF-36 PCS from baseline to week 52 
 
Changes in HAQ-DI from baseline to week 52 
 
Changes in patient reported PMR VAS from baseline to week 52 
 
Changes in patient reported fatigue VAS from baseline to week 52 
 
Changes in patient reported stiffness VAS from baseline to week 52 

13 
 
 
Changes in patient reported duration of morning stiffness from baseline to week 52 
 
Proportion of patients where baseline DXA scan are performed during the first 3 months after 
baseline visit 
 
Proportion of patients where HgbA1C blood samples are taken during the first 52 weeks 
 
Frequency of patient reported adverse effects and comorbidities related to prednisolone treatment 
after 13, 26, 39 and 52 weeks 
 
Proportion of patients with patient reported infections during the first 52 weeks 
 
Changes in inflammatory and cardiovascular biochemical markers from baseline to week 52 
Other (Exploratory) Outcomes 
 
Proportion of patients in 13 weeks sustained prednisolone free remission after 65 and 104 weeks 
 
Accumulated prednisolone dosage after 13, 26, 39, 52, 65, 78, 91 and 104 weeks  
 
Proportion of patients receiving prednisolone 65, 78, 91, and 104 weeks after diagnosis 
 
Changes in prednisolone dose from baseline to 104 weeks 
 
Changes in PMR-AS from baseline to 104 weeks 
 
Changes in PROMs from baseline to 65, 78, 91 and 104 weeks 
 
Self-reported number of relapses from baseline to week 104 
 
Percentage of GCA patients found during the 104 weeks (incidence) 
 
Percentage of GCA patients found with ultrasound at the 104 week visit 
 
Changes in inflammatory and cardiovascular biochemical markers from baseline to week 104 
 
Frequency of adverse effects and comorbidities related to prednisolone treatment after 65, 78, 91 and 
104 weeks 
Other information 
 
Proportion of GCA patients found at baseline 
 
3.1.5 Participant timeline 
Table 3 below presents the study-timeline for all study visits. The group randomised to “Treat-to-target” will 
have additional telephone consultations and clinical blood samples as described in section 3.1.3. The group 
randomised to usual care will have additional consultations and clinical blood samples as decided by the 
general practitioner. 
 
 

14 
 
Table 3, Participant timeline 
 
Inclusion 
Ramdomisation 
Questionnaire + Blood 
samples 
Questionnaire + Blood 
samples 
Questionnaire + Blood 
samples 
1 year visit 
Questionnaire + Blood 
samples 
Questionnaire + Blood 
samples 
Questionnaire + Blood 
samples 
Termination Visit 
Months 
0 
0-2 
weeks 
3 
6 
9 
12 
15 
18 
21 
24 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
PMR diagnosis 
X 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
Sex 
X 
 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
X 
 
 
 
X 
Comorbidity 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Medicine (incl 
Prednisolone information) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
PROMs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
PMR Symptoms 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
PMR Activity Score 
X 
 
 
 
 
X 
 
 
 
X 
Adverse effects to 
prednisolone 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
X 
 
 
 
X 
Blood sample, biobank 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vascular US 
X 
 
 
 
 
X 
 
 
 
X 
 
3.1.6 Sample size and power considerations 
One retrospective study have been conducted in this field, where the control group comprised usual care in a 
hospital setting [19]. Assuming a 30% points difference (between proportions), an alpha of 0.05, and a good 
statistical power of 90%, a sample size calculation based on the guestimated proportions of patients 
successfully withdrawn from prednisolone and also in remission after one year (80% vs 50%), yields 52 
patients in each group. Since this estimation is highly uncertain, we will aim for inclusion and randomisation 
(1:1) of 120 participants (approximately 60 patients in each group). 
 

15 
 
 
 
Interpretation of an apparent null finding: A 2-sided 95% confidence interval excluding differences greater 
than 20%points between the group proportions will be interpreted as indicating the absence of a clinically 
meaningful difference. As indicated in the figure, we would have a reasonable precision (±20%points) 
around the null (RD=0.00), with 102 participants in the sample (i.e., approximately 51 per group). 
 
3.1.7 Recruitment 
Patients will be recruited from all departments of rheumatology in the Central Denmark Region (Aarhus 
University Hospital, Silkeborg Regional Hospital, Horsens Regional Hospital, Randers Regional Hospital, 
Gødstrup Regional Hospital) as well as Esbjerg Regional Hospital, Vejle Regional Hospital, North Denmark 
Regional Hospital, Hjørring and Aalborg University Hospital. Both patients seen at the outpatient clinic and 
hospitalized patients can be recruited. If one of the above-mentioned departments find eligible patients, but 
not have the resources for inclusion at that time, the patient can be referred to one of the other collaborating 
departments for inclusion after patient consent. Participant enrolment is expected to take 24 months. 
 

16 
 
3.2 Assignment of Interventions 
3.2.1 Allocation Sequence generation 
Participants will be randomly assigned to either “Usual care” or “Treat-to-target” with a 1:1 allocation as per 
a computer-generated randomisation schedule stratified by site, using permuted blocks of random sizes 
between 2-6. The block sizes will not be disclosed, to improve the allocation concealment. 
3.2.2 Allocation concealment mechanism 
Randomisation will be set via the “Randomisation module” in Research Electronic Data Capture (REDCap) 
[24]. Allocation concealment will be ensured, as the service will not release the randomisation code until the 
patient has been recruited into the trial, which takes place after all baseline measurements have been 
completed. 
3.2.3 Implementation 
All patients who give consent for participation and who fulfil the inclusion criteria will be randomized. 
Randomization will be implemented at the first visit after all initial information and examination has 
occurred. Randomization will be assigned by the attending physician at the study site via access to REDCap 
Randomization Module. 
 
3.2.4 Blinding 
This is an open-label study without blinding. 
 
3.3 Data collection, management and analysis 
3.3.1 Data collection methods 
Demographics 
At baseline information regarding sex, age, weight, height, other medication, comorbidity, previous history 
of shoulder and hip related pain, alcohol and tobacco consumption is obtained.  
Physical examination 
Physical examination including ability to raise arms, swollen and tender peripheral joints and hip mobility 
will be performed at baseline and after one and two years. 
EULAR criteria for PMR and criteria for remission 
At baseline EULAR criteria for PMR are recorded [20]. In addition, the PMR activity score is recorded at 
baseline and after one and two years [25]. Since no validated remission criteria for PMR exists, in this study, 
remission is defined as absence of PMR activity evaluated by the doctor based on symptoms and clinical 

17 
 
examination combined with a CRP level below 8.0 mg/l at the one- and two-year visit (exceptions can be 
made if an elevated CRP level is assessed to be explained by an ongoing infection at the sample time). 
Sustained prednisolone free remission at 65 months is assessed in patients who were in remission at the 1 
year visit. If these patients have not been in contact with the hospital nor their general practitioner with 
relapse of symptoms and prednisolone has not been resumed according to questionnaires, sustained 
remission is assumed.  
Vascular ultrasonography 
Vascular ultrasound is accessed at baseline and after one and two years. A high-end ultrasound scanner with a 
linear probe is used. The right and left common superficial temporal artery, its parietal and frontal branch, and 
axillary artery are evaluated. Vasculitis is defined as a hypo-echoic wall swelling in both longitudinal and 
transverse view and in cranial arteries vasculitis is confirmed by compression sign [26]. The one- and two-
year visit will either be performed at the inclusion study site or by the principal investigator at Aarhus 
University Hospital. 
Patient reported outcome measures/Questionnaires 
Every 3 months a questionnaire will be send electronically via REDCap, patients not able to fill out an online 
questionnaire will receive a phone questionnaire carried out by the principal investigator or a 
doctor/nurse/secretary assigned by the principal investigator. This questionnaire (See Appendix 2) will 
include: 
 
Current prednisolone dose 
 
Weekly prednisolone dosages since last questionnaire 
 
Weight 
 
New medications 
 
Adverse effects to prednisolone 
 
Duration of morning stiffness (minutes) 
 
PMR related symptoms including patient reported relapse 
 
Global-VAS, PMR-VAS, fatigue VAS, stiffness VAS 
 
SF-36 
 
HAQ-DI 
 
EQ-5D-5L 
Patients who fail to report back on the questionnaires within two weeks, will receive a phone call by the 
principal investigator/project nurse/secretary/doctor. 

18 
 
Prednisolone dosage information 
The patient will weekly fill in the current prednisolone dose in a standard scheme. In relation to the 
questionnaires the patients will then report the weekly doses for the last 3 months.  
DXA 
DXA scan is performed according to usual clinical practice.  
Blood samples 
Routine samples 
Differential diagnostic evaluation at baseline: Creatine kinase, p-25-hydroxy vitamin D2+D3, Thyroid-
stimulating hormone, ca2+, M-component, kappa and lambda chains, immunoglobulin A, G and M, rheumatoid 
factor, anti citrullinated protein antibody, alkaline phosphatase, HgbA1C. 
Biochemical routine tests performed at baseline for both groups and hereafter every 4 weeks for the group 
receiving a structured taper: CRP, ESR, creatinine, alanine aminotransferase, platelet count, haemoglobin, 
white blood cells, absolute neutrophil count, absolute lymphocyte count. 
Research samples 
The blood samples are collected by the Danish Reuma Biobank (DRB) under the regional Bio-and Genome 
Bank Denmark (RBGB). Immediately after sampling, blood samples are sent to the nearest biochemical 
department with a collaboration agreement with DRB for processing. Afterwards the samples are handled, 
registered and stored in DRB. Material will be reserved for this project. Material for analysis in the project is 
then provided by DRB to the project's research biobank. 
A research biobank for blood samples will be established for the project, with an expected start on the 1st of 
March 2022 and an expected expire on the 31st of December 2028 at study termination.  The following will be 
evaluated: C-reactive protein, HgbA1c, Multiplex immunoassay for cardiovascular and inflammatory 
biomarkers (Olink, Upsala, Sweden). A total of 300 ml is collected throughout the study. Excess material from 
the research biobank is transferred to a biobank for future research at study termination. The material in the 
biobank for future research is stored until 31st of December 2040. At that time point the material is either 
destroyed or anonymised.  The biobank for future research is registered in the Danish Central Region internal 
list of research projects.  The research biobank and the biobank for future research both conforms to The 
Danish law concerning patient confidentiality (Databeskyttelsesloven) and the General Data Protection 
Regulation (Databeskyttelsesforordningen). 
 
Practical feasibility 
This project is planned to start in March 2022. Inclusion of subjects will begin when written permissions 
have been granted. The inclusion period is expected to last 24 months. The project is expected to end in 
January 2029. 

19 
 
3.3.2 Data Management 
Before informed consent, information from the patient journal concerning symptoms, blood tests, inclusion 
criteria, and exclusion criteria can be passed from a person designated by the investigator. The information 
will be passed to an investigator in order to determine if the patient may be suitable for the study.  After 
informed consent from the patient, information about demographic, comorbidities, medication, and results 
from the routine blood samples (incl. HgbA1C) and DXA scan is retrieved from the electronic patient journal 
(EPJ). Information about medications will also be retrieved from “Fælles Medicin Kort” (FMK). Informed 
consent gives the investigators, sponsor and representatives of the sponsor direct access to retrieve 
information in the patient journal etc., including the electronic patient journal, for the purpose of managing 
information regarding the patients general health data, which is necessary as part of completing the project as 
well as monitoring, including self-monitoring, quality control and general study monitoring in which they are 
obligated to perform. The study conforms to The Danish law concerning patient confidentiality 
(Databeskyttelsesloven) and the General Data Protection Regulation (Databeskyttelsesforordningen). All of 
the data mentioned above are considered source data. All information is documented in REDCap.  
 
3.3.3 Statistical methods 
All 95% confidence intervals and P values will be two sided. We will not apply explicit adjustments for 
multiplicity, rather we will analyse the key secondary outcomes in a prioritised order (i.e. “gatekeeping 
procedure”): The analyses of the key secondary outcomes will be performed in sequence until one of the 
analyses fails to show the statistically significant difference, or until all analyses have been completed at a 
statistical significance level of 0.05. The key secondary statistical tests will be reported with P values for 
hypothesis tests and claims of statistical significance.  P-values (two sided) less than 0.05 will be considered 
statistically significant. 
The primary analyses will be based on the Intention to Treat (ITT) population. The ITT principle asserts 
the effect of a treatment policy (that is, the planned treatment regimen), rather than the actual treatment given 
(i.e., it is independent of treatment adherence). Accordingly, participants allocated to a treatment group 
(taper vs usual care) should be followed up, assessed and analysed as members of that group, irrespective of 
their adherence to the planned course of treatment (i.e., independent of withdrawals and cross-over 
phenomena). 
The statistical objectives of a repeated measures design are to make inferences about the expected values 
of the observations, that is, about the means of the populations from which participants are sampled. This 
objective is achieved by taking into account treatment group and time effects in the model (Group×Time). 
Data will be analysed, with the particular outcome variable (Yi) at baseline level (Y0,i) as a covariate, using a 

20 
 
multilevel repeated measures mixed-effects model with participants as the random effects factor based on a 
restricted maximum likelihood (REML) model, while other covariates are handled as fixed effect factors. 
Missing Data and the Repeated Measurements Using Mixed Models: As stated above, our primary 
analyses will be based on the ITT population, including all randomised participants with available data at 
baseline. Missing data will be handled indirectly and statistically modelled using repeated-measures linear 
mixed models (see below). These models will be valid if data are ‘Missing at Random’ (MAR), where “Any 
systematic difference between the missing values and the observed values can be explained by differences in 
observed data” [27].Contrasts between groups will be estimated based on repeated-measures analysis of 
covariance applied in mixed effects linear models (i.e., at 52 weeks from baseline). 
For continuous outcomes (e.g., Yi score) will be the response (dependent) variable, and the baseline value 
(one for each participant), treatment group (two levels), and time will be included as covariates, as well as 
the interaction between treatment group and time; Patient ID will be handled as a random effects variable. As 
the study design was based on a stratified randomization technique, we will also adjust for the three 
stratification variables. This statistical model holds all between-group comparisons at all assessment points 
up to 52 weeks from baseline (including baseline) and allows for evaluation of the average effect, as well as 
the trajectory over time from baseline to the 52-week follow-up. 
Categorical outcomes for dichotomous endpoints will be analysed with use of logistic regression with the 
same fixed effect factors and covariates as the respective analysis of continuous endpoints. Since Odds 
Ratios (ORs) for outcomes of common incidence either over- or under-estimate the corresponding risk 
estimate, we will convert all the calculated OR values and 95% confidence intervals into approximate Risk 
Ratios (RR) in the text. This approach will also allow us to calculate numbers-needed-to-treat (NNTs) and 
numbers-needed-to-harm (NNHs) for efficacy and safety outcomes by dividing 1 by the risk difference that 
can guide clinicians in their decision making. 
 
3.3 Monitoring 
3.3.1 Data monitoring 
If questionnaires are left unreported by the study participants a reminder will be send via REDCap to the 
principal investigator who will then facilitate contact to the participants by phone to ensure all questionnaires 
are reported.  
3.3.2 Harms 
Harms are stated below in section 4.1 

21 
 
4 Ethics and dissemination 
4.1 Research ethics approval 
The study conforms to the Danish law concerning patient confidentiality (Databeskyttelsesloven) and the 
General Data Protection Regulation (Databeskyttelsesforordningen). Approval will be provided from the 
Central Denmark Region Committee on Health Research Ethics and the project registered in the Danish 
Central Region internal list of research projects before the recruitment of research subjects. Furthermore the 
study will be registered at ClinicalTrials.gov. 
Prednisolone treatment 
The treatment with prednisolone and the tapering strategy is in both groups prescribed in accordance to 
standard clinical practice described in national and EULAR guidelines [13, 14]. Both of the tapering 
strategies (hospital managed vs. general practitioner managed) is within what is currently offered at Danish 
hospitals. 
DXA scan and osteoporosis prophylaxis 
DXA are conducted in accordance with normal clinical practice. Vitamin D and Calcium are administered in 
accordance to standard clinical practise. If DXA scans reveals osteopenia or osteoporosis, alendronate 
treatment will be administered according to standard clinical practise. 
Blood samples 
Blood samples from the baseline visit as well as the 4th weekly blood samples in the “Treat-to-target 
prednisolone taper” group are conducted in accordance with normal clinical practise. The same applies to the 
blood samples conducted from general practitioners in the “usual care” group. 
Both groups will have blood samples conducted every 3 months for the study biobank. Obtaining these 
samples can be associated with minimal pain as well as minimal risk of infection. 
Ultrasound 
Ultrasound is often used as part of the diagnostic workup for both PMR and GCA but is usually not 
performed in all patients. In this study it is assessed a benefit that all patients undergo ultrasound 
examination, because of the more thorough examination. The examination lasts approximately 30 minutes. 
No known harms are associated with this examination.  
Based on the above, it is assessed that the risk of participating in the study is very limited. Both groups 
receive treatment according to normal clinical practice as well as following the current national guidelines. 
Yet the two approaches have never been compared and it is in the opinion of the investigators that this study 
will contribute to improve the clinical practice in this field in the future and any potential risks or side effects 

22 
 
are offset by the expected benefits of carrying out the study, which is therefore considered ethical and 
relevant. 
Protocol amendments 
All modifications to the protocol are reported to The Central Denmark Region Committee on Health 
Research Ethics and the Danish Central Region internal list of research projects. 
4.2 Consent or assent 
If the patient decline to participate it will not affect the further treatment of the patient. Information about the 
trial is given at an already scheduled appointment in the outpatient clinic or hospital ward. All information is 
provided by an investigator or by a person designated by the investigator. Patients who are interested in 
participating in the trial will be invited to a meeting with an investigator. Here, the patient will receive full 
oral and written information in uninterrupted surroundings and have the opportunity to ask questions. The 
patients are informed of their right to bring a friend or relative to the conversation beforehand and will at the 
meeting be offered 24 hours to consider their decision unless they do not want time to consider. The 
informed consent form is signed and dated by both the trial subject and the investigator. The participant 
receives a signed copy of the informed consent form and the original is kept in the participant’s case record 
form. The patient may, at any time and without giving a reason, withdraw his or her consent. Withdrawal of 
consent will not affect the further treatment of the patient. The informed consent grants the investigator and 
relevant control authorities direct access to relevant health information during conduct of the study and for 
control purposes. 
 
4.3 Confidentiality 
All data including patient information is recorded in Research Electronic Data Capture (REDCap). The law 
on the processing of personal data is followed. Patients’ informed written consent is collected before 
participation in the study. Patient information is protected in accordance with the Danish law concerning the 
processing of personal data. Approval must be provided by the Danish Central Region internal list of 
research projects. The research biobank conforms to the Danish law concerning patient confidentiality 
(Databeskyttelsesloven) and the General Data Protection Regulation (Databeskyttelsesforordningen).  
 
4.3 Declaration of interests 
Financial contributors do not influence the study implementation or publication of results. There is a 
continuous search for funding from other funds. If such funding is granted, an amendment to the protocol 
will be submitted to The Central Denmark Region Committee on Health Research Ethics. 

23 
 
The funds have no influence on study design, data handling, analyses, or presentation of data. The project 
manager has no financial association with the funds.  No investigators have any conflicts of interest. Patients 
included in the trial will not be honored for participation.  
The project was initiated on the initiative of the research group of this protocol.  
 
4.4 Access to data 
All source data will be accessible for Inspection by the Danish Health and Medicine Authority. Patient data 
and informed consent forms will be stored for 18 years and then destroyed, fully anonymized, or submitted 
to the State Archives.  The Data protection regulation and the Data Protection Act are complied with at all 
times.  
 
4.5 Ancillary and post-trial care 
The Patient Compensation Association covers patients who against all expectations, should be injured in the 
study. 
 
4.7 Dissemination policy 
Positive, negative, and inconclusive results will be published in high-ranking international peer-reviewed 
journals. The reporting of results will adhere to the CONSORT guidelines for RCT studies [28]. MD 
Christoffer Søvsø Våben will be the first author on all publications. MD, PhD Kresten Keller will be senior 
author. Ellen-Margrethe Hauge and Robin Christensen will be co-authors. Furthermore, each trial centre will 
be assigned 1 co-authorship per paper per 10 patients who completes the trial. Authorship for other co-authors 
is awarded according to the Vancouver guidelines for authorship. This protocol will be published on 
ClinicalTrials.gov. 
 
 5 References 
1. 
Buttgereit, F., et al., Polymyalgia Rheumatica and Giant Cell Arteritis: A Systematic Review. Jama, 
2016. 315(22): p. 2442-58. 
2. 
Dejaco, C., et al., Current evidence for therapeutic interventions and prognostic factors in 
polymyalgia rheumatica: a systematic literature review informing the 2015 European League 
Against Rheumatism/American College of Rheumatology recommendations for the management of 
po. Annals of the Rheumatic Diseases, 2015. 74(10): p. 1808-1817. 
3. 
Gabriel, S.E., et al., Adverse outcomes of antiinflammatory therapy among patients with 
polymyalgia rheumatica. Arthritis Rheum, 1997. 40(10): p. 1873-8. 

24 
 
4. 
Wu, J., S.L. Mackie, and M. Pujades-Rodriguez, Glucocorticoid dose-dependent risk of type 2 
diabetes in six immune-mediated inflammatory diseases: a population-based cohort analysis. BMJ 
Open Diabetes Res Care, 2020. 8(1). 
5. 
Wu, J., et al., Incidence of infections associated with oral glucocorticoid dose in people diagnosed 
with polymyalgia rheumatica or giant cell arteritis: a cohort study in England. Cmaj, 2019. 191(25): 
p. E680-e688. 
6. 
Wang, W., H. Zhou, and L. Liu, Side effects of methotrexate therapy for rheumatoid arthritis: 
A systematic review. Eur J Med Chem, 2018. 158: p. 502-516. 
7. 
Camellino, D. and C. Dejaco, Update on treatment of polymyalgia rheumatica. Reumatismo, 2018. 
70(1): p. 59. 
8. 
Hellmich, B., et al., 2018 Update of the EULAR recommendations for the management of large 
vessel vasculitis. Ann Rheum Dis, 2020. 79(1): p. 19-30. 
9. 
Blockmans, D., et al., Repetitive 18-fluorodeoxyglucose positron emission tomography in isolated 
polymyalgia rheumatica: a prospective study in 35 patients. Rheumatology (Oxford), 2007. 46(4): p. 
672-7. 
10. 
Schmidt, W.A. and E. Gromnica-Ihle, Incidence of temporal arteritis in patients with polymyalgia 
rheumatica: a prospective study using colour Doppler ultrasonography of the temporal arteries. 
Rheumatology (Oxford), 2002. 41(1): p. 46-52. 
11. 
Schäfer, V.S., L. Jin, and W.A. Schmidt, Imaging for Diagnosis, Monitoring, and Outcome Prediction 
of Large Vessel Vasculitides. Curr Rheumatol Rep, 2020. 22(11): p. 76. 
12. 
Schmidt, W.A., et al., Ultrasound of proximal upper extremity arteries to increase the diagnostic 
yield in large-vessel giant cell arteritis. Rheumatology (Oxford), 2008. 47(1): p. 96-101. 
13. 
Dejaco, C., et al., 2015 Recommendations for the management of polymyalgia rheumatica: a 
European League Against Rheumatism/American College of Rheumatology collaborative initiative. 
Annals of the Rheumatic Diseases, 2015. 74(10): p. 1799-1807. 
14. 
Ib Tønder Hansen, B.D.N., Kresten Krarup Keller, Uffe Døhn, Dzenan Masic, Mette Yde Matthiesen, 
Salome Kristensen, Stavros Chrysidis, Kathrine Hindborg Gade. Kæmpecellearterit & polymyalgia 
reumatika, NBV, Dansk Reumatologisk Selskab. 2019 14/08/2019 [cited 2020 07/12]; Available 
from: https://danskreumatologi.dk/nbv/sygdomme/kaempecellearterit-polymyalgia-reumatika/. 
15. 
Salomon-Escoto, K. and J. Kay, The "Treat to Target" Approach to Rheumatoid Arthritis. Rheum Dis 
Clin North Am, 2019. 45(4): p. 487-504. 
16. 
Nikiphorou, E. and X. Baraliakos, Treat to Target in Axial Spondyloarthritis. Rheum Dis Clin North 
Am, 2019. 45(4): p. 519-535. 
17. 
Camellino, D., et al., Monitoring and long-term management of giant cell arteritis and polymyalgia 
rheumatica. Nat Rev Rheumatol, 2020. 16(9): p. 481-495. 
18. 
Camellino, D., et al., Treat to Target: A Valid Concept for Management of Polymyalgia Rheumatica 
and Giant Cell Arteritis? Rheum Dis Clin North Am, 2019. 45(4): p. 549-567. 
19. 
Mørk, C., et al., The effect of a nurse-led prednisolone tapering regimen in polymyalgia rheumatica: 
a retrospective cohort study. Rheumatol Int, 2020. 
20. 
Dasgupta, B., et al., 2012 provisional classification criteria for polymyalgia rheumatica: a European 
League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann 
Rheum Dis, 2012. 71(4): p. 484-92. 
21. 
Dejaco, C., et al., Definition of remission and relapse in polymyalgia rheumatica: data from a 
literature search compared with a Delphi-based expert consensus. Ann Rheum Dis, 2011. 70(3): p. 
447-53. 
22. 
Lally, L., et al., Brief Report: A Prospective Open-Label Phase IIa Trial of Tocilizumab in the 
Treatment of Polymyalgia Rheumatica. Arthritis Rheumatol, 2016. 68(10): p. 2550-4. 
23. 
Rejnmark, L.A., B.; Ejersted, C.; Hyldstrup, L.; Jensen, J-E.; Rintek Madsen, O.; Mosekilde, L.; 
Schwarz, P.; Vestergaard, P.; Langdahl, B.;. Behandlingsvejledning for glukokortikoid induceret 
osteoporose.  [cited 2020 28/12]; Available from: http://wp.dkms.dk/?page_id=1081. 

25 
 
24. 
Harris, P.A., et al., Research electronic data capture (REDCap)--a metadata-driven methodology and 
workflow process for providing translational research informatics support. J Biomed Inform, 2009. 
42(2): p. 377-81. 
25. 
Leeb, B.F. and H.A. Bird, A disease activity score for polymyalgia rheumatica. Ann Rheum Dis, 2004. 
63(10): p. 1279-83. 
26. 
Chrysidis, S., et al., Definitions and reliability assessment of elementary ultrasound lesions in giant 
cell arteritis: a study from the OMERACT Large Vessel Vasculitis Ultrasound Working Group. RMD 
Open, 2018. 4(1): p. e000598. 
27. 
Detry, M.A. and Y. Ma, Analyzing Repeated Measurements Using Mixed Models. Jama, 2016. 
315(4): p. 407-8. 
28. 
Schulz, K.F., D.G. Altman, and D. Moher, CONSORT 2010 statement: updated guidelines for 
reporting parallel group randomised trials. Bmj, 2010. 340: p. c332.