An Observational Study of Bone Erosion Determination and Progression in Rheumatoid Arthritis Assessed by HR-pQCT and Conventional X-ray
Conditions: Arthritis, Rheumatoid
Sponsor: Aarhus University Hospital

 
 
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PROTOCOL FOR  
THE CENTRAL DENMARK REGION COMMITTEE ON  
HEALTH RESEARCH ETHICS 
 
ADMINISTRATIVE INFORMATION 
1 TITLE  
RACTX – An observational study of bone erosion determination and progression in Rheumatoid Arthritis 
assessed by HR-pQCT and conventional X-ray. 
 
2 TRIAL REGISTRATION 
The trial is registered at Clinicaltrails.gov. This protocol is structured according to SPIRIT 2013 checklist.1 
 
3 PROTOCOL VERSION  
Version 1.19.01.2018 
 
4 ROLES AND RESPONSIBILITIES 
Principal investigator:  
MD. PhD student Rasmus Klose Jensen, Aarhus University Hospital, Department of Rheumatology,  
Nørrebrogade 44, 8000 Aarhus C, E-mail: raujen@rm.dk  Tlf: 31672106 
 
Sponsor-investigator & Head supervisor  
Head of the department, clinical Professor, PhD Ellen-Margrethe Hauge, Aarhus University Hospital, 
Department of Rheumatology. Nørrebrogade 44, 8000 Aarhus C, E-mail: ellen.hauge@aarhus.rm.dk  Tlf: 
25775154 
 
Co-Supervisor  
MD. PhD Kresten Krarup Keller, Aarhus University Hospital, Department of Rheumatology. Nørrebrogade 44, 
8000 Aarhus C 
 
Collaborators 
MD, PhD student Anne-Birgitte Garm Blavnsfeldt, Aarhus University Hospital, Department of Rheumatology 
Professor, DMSc. Bente Langdahl, Aarhus University Hospital, Department of Endocrinology 

 
 
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TABLE OF CONTENTS 
ADMINISTRATIVE INFORMATION ......................................................................................................................................................1 
1 TITLE..................................................................................................................................................................................................1 
2 TRIAL REGISTRATION......................................................................................................................................................................1 
3 PROTOCOL VERSION ......................................................................................................................................................................1 
4 ROLES AND RESPONSIBILITIES ......................................................................................................................................................1 
TABLE OF CONTENTS .............................................................................................................................................................................2 
INTRODUCTION ......................................................................................................................................................................................4 
5 BACKGROUND AND RATIONALE ..................................................................................................................................................4 
6 OBJECTIVES ......................................................................................................................................................................................5 
6.1 Perspectives.............................................................................................................................................................................5 
6.2 Objectives ................................................................................................................................................................................6 
6.3 Hypothesis ...............................................................................................................................................................................7 
METHODS: PARTICIPANTS, INTERVENTIONS, AND OUTCOMES ..................................................................................................8 
7 TRIAL DESIGN...................................................................................................................................................................................8 
8 STUDY SETTING ...............................................................................................................................................................................8 
9 ELIGIBILITY CRITERIA ......................................................................................................................................................................9 
9.1 RA patients ..............................................................................................................................................................................9 
9.2 Pre-RA patients .......................................................................................................................................................................9 
9.3 Healthy subjects................................................................................................................................................................... 10 
10 INTERVENTIONS......................................................................................................................................................................... 10 
11 OUTCOMES................................................................................................................................................................................. 10 
11.1 Primary outcomes ............................................................................................................................................................. 10 
11.2 Secondary outcomes......................................................................................................................................................... 11 
12 PARTICIPANT TIMELINE ............................................................................................................................................................ 12 
13 SAMPLE SIZE ............................................................................................................................................................................... 12 
14 RECRUITMENT............................................................................................................................................................................ 12 
14.1 RA and pre-RA patients .................................................................................................................................................... 12 
14.2 Healthy subjects ................................................................................................................................................................ 13 
METHODS: DATA COLLECTION, MANAGEMENT, AND ANALYSIS............................................................................................. 13 
15 DATA COLLECTION METHODS ................................................................................................................................................. 13 
15.1 HR-pQCT.............................................................................................................................................................................. 13 
15.2 Conventional X-ray............................................................................................................................................................ 13 
15.4 Physical examination........................................................................................................................................................ 14 
15.5 Recording of patient demography and clinical information...................................................................................... 14 
15.6 DXA ...................................................................................................................................................................................... 15 
15.7 Practical feasibility............................................................................................................................................................ 15 
16 DATA MANAGEMENT ............................................................................................................................................................... 15 
17 STATISTICAL METHODS ............................................................................................................................................................ 16 
ETHICS AND DISSEMINATION........................................................................................................................................................... 18 
18 RESEARCH ETHICS APPROVAL ................................................................................................................................................. 18 
19 PROTOCOL AMENDMENTS ...................................................................................................................................................... 19 
20 CONSENT OR ASSENT................................................................................................................................................................ 19 
20.1 RA and Pre-RA patients .................................................................................................................................................... 19 
20.2 Healthy subjects ................................................................................................................................................................ 19 

 
 
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21 CONFIDENTIALITY...................................................................................................................................................................... 20 
22 DECLARATIONS OF INTEREST & FUNDING............................................................................................................................. 20 
23 ACCESS TO DATA........................................................................................................................................................................ 20 
24 ANCILLARY AND POST-TRIAL CARE ......................................................................................................................................... 20 
25 DISSEMINATION POLICY ........................................................................................................................................................... 21 
REFERENCES ......................................................................................................................................................................................... 22 
 
 
 

 
 
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INTRODUCTION 
5 BACKGROUND AND RATIONALE 
Rheumatoid arthritis (RA) is the most common autoimmune joint disease, afflicting about 35,000 people in 
Denmark. Morbidity and mortality are significant and result in multiple joint destruction and disability and 
reduce life expectancy by ten years. Bone destruction (erosion) occurs in the early disease course and is seen 
in about half of patients at diagnosis2. Early treatment with disease modifying anti-rheumatic drugs 
(DMARDs) in mono- or combination therapy in a treat-to-target regime improves prognosis3. In case of long-
term disease remission without radiological progression, it may be considered to terminate biological 
DMARD therapy, but identifying patients with low risk of progression of bone erosion is not trivial. Bone 
erosion is usually considered an irreversible damage. Some studies show that regression of the radiographic 
erosion score may happen4,5.However, bone formation may be prevalent in bone tissue of arthritic joints6. 
Bone resorption and formation are uncoupled in RA7; true healing may therefore not occur. Longitudinal 
assessment of these lesions with respect to repair is, however, scarce, and more sensitive methods than 
convention X-ray are needed.  
Several factors are prognostic for the progressions of joint destruction, such as the presence of rheumatoid 
factor (RF), anti-citrullinated protein antibody (ACPA), genetics, smoking, age and gender. Apart from the 
patient’s risk profile, treatment escalation is based on the radiographic progression of joint erosions, disease 
activity score (DAS28-CRP) using the number of tender and swollen joints, acute phase reactants, and patient-
reported outcomes. However, no prognostic factors exist that at an early stage can reliably predict the 
disease course at the individual level.  
Bone erosion is present in approximately 40% of Danish RA patients already at diagnosis2. Knowledge of what 
happens in the joints in the period up to the clinical diagnosis is sparse, and bone changes are particularly 
poorly described. Studies have demonstrated that ACPA may be present in patients for many years before 
diagnosis8,9. Therefore, individuals with positive ACPA may be ideal candidates for prospectively studying the 
period before a clinical diagnosis can be established (pre-RA phase).  A single study has demonstrated a shift 
in serum biomarkers in pre-RA patients, which may indicate that bone changes occur before clinical disease10. 
Another minor study found thinner and more porous cortical bone in the metacarpophalangeal joint (MCP 
joint) of individuals with positive ACPA, but no symptoms of rheumatoid arthritis11. Our research group, 
however, has previously found no change in the cortical bone, but thinner trabecular bone in the MCP joint 
of individuals with positive ACPA compared with individuals with negatively ACPA12. 
The treat-to-target escalation algorithms for RA have reduced the amount of bone destruction that is allowed 
before treatment is instituted. The changes in the radiographic score during the first 2 years of the disease is 
less than 1% of the maximal radiographic score used for conventional X-ray examination13,14. Therefore, more 

 
 
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sensitive imaging methods could be a valuable factor to prognosticate development of bone erosion and shift 
treatment towards a more personalised medicine approach. 
The Danish multi-centre study on early RA (CIMESTRA) showed that bone marrow oedema as seen by 
magnetic resonance imaging (MRI) was a predictor of progression of joint destruction15. Bone marrow 
oedema is associated with inflammation16; and in experimental arthritis, bone resorption is prominent 
adjacent to inflammatory cells in the bone marrow6. Before the appearance of destructive bone erosion, a 
more diffuse loss of bone may occur12, but this parameter is not included in the scoring system for 
conventional X-ray examination used in research and the clinic14.  
Conventional X-ray examination is the gold standard for detecting progression of joint destruction, but even 
at moderate resolutions (voxel size 400×400×1000 microns), CT systems have higher sensitivity for detecting 
erosions than conventional X-ray and MRI17. Ultrasound is used in daily clinical practice for assessing joint 
effusion and synovitis, but observer dependence is prominent, and the specificity for bone erosions is low18.  
The areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry(DXA), is used 
clinically in diagnosis and monitoring of osteoporosis. The aBMD by DXA is also a  useful measure of disease 
activity and progression in RA, although, it is seldom used clinically19,20. The DXA scan, however, has its 
disadvantages. Firstly, the bone mineral density by DXA is only a two-dimensional estimate of the bone loss. 
Secondly, the bone mineral density by DXA is systemic and not juxta-articular; and, finally, DXA gives no 
information of the bone’s microarchitecture. The imaging method high-resolution peripheral quantitative 
computed tomography (HR-pQCT), however, has a high resolution with voxel size 82×82×82 microns. Still, 
scan time is short and radiation exposure low, equaling that of conventional X-ray. The HR-pQCT scanner has 
been used in osteoporosis research for measuring juxta-articular volumetric bone mineral density (vBMD) 
and bone microarchitecture21. Patients with RA have an increased risk of osteoporosis and fragility 
fractures22.  Lately, the HR-pQCT-scanner has also been used for detecting erosions, bone loss and possible 
healing in RA joints23–28. The HR-pQCT has been shown to be a promising technique capable of providing a 
quantitative assessment of hand bone loss in RA patients29. Further studies are needed, however, to examine 
the diagnostic and prognostic value of minimal erosions and loss of bone mineral density (BMD) as measured 
by HR-pQCT imaging. 
 
6 OBJECTIVES 
6.1 Perspectives 
If the HR-pQCT imaging system turns out to be a reliable candidate for individual disease monitoring, it may 
establish a basis for precision medicine in the treatment of RA. The perspective is that appropriate 
immunosuppressive treatment can be initiated at an earlier stage to improve the prognosis for patients at 

 
 
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risk of developing severe bone destruction and disability and that the immunosuppressive treatment can be 
omitted or stopped in those patients not at risk, thus avoiding excessive health cost and patient adverse 
events.  
6.2 Objectives 
The overall objective of this observational study is to detect erosive changes in patients with RA and pre-RA 
earlier than conventional X-ray, using the new image diagnostic method HR-pQCT. Specifically, the following 
are investigated: 
• 
The number, size and volume of bone erosions, determined by HR-pQCT imaging, compared with 
erosion score by conventional X-ray examination at baseline. In RA patients, pre-RA patients and 
healthy subjects. 
• 
The number, size and volume of bone erosions, determined by HR-pQCT imaging, compared with 
erosion score by conventional X-ray examination at one-year follow-up. In RA patients, pre-RA 
patients and healthy subjects. 
• 
The progression of number, size and volume of bone erosions, determined by HR-pQCT imaging, 
versus the progression in radiographic erosion score determine by conventional X-ray examination 
throughout the trial period. In RA patients, pre-RA patients and healthy subjects.  
• 
Correlation between changes in radiographic erosion score, determined by conventional X-ray, 
throughout the trial period, and the mean disease activity, assessed by DAS28-CRP, HAQ and VAS, 
throughout the trial period, as well as serological markers for bone metabolism and inflammation 
(see 11.2) throughout the trial period. In RA patients, pre-RA patients and healthy subjects.  
• 
Correlation between changes in radiographic erosion score, determined by conventional X-ray, and 
the mean disease activity, assessed by DAS28-CRP, HAQ and VAS, throughout the RA patients’ entire 
disease duration. 
• 
Correlation between change in number, size, and volume of erosions, determined by HR-pQCT 
imaging, throughout the trial period, and the mean disease activity, assessed by DAS28-CRP, HAQ 
and VAS, throughout the trial period, as well as serological markers for bone metabolism and 
inflammation (see 11.2) throughout the trial period. In RA patients, pre-RA patients and healthy 
subjects.  
• 
Correlation between change in number, size, and volume of erosions, determined by HR-pQCT 
imaging, throughout the trial period, and the mean disease, assessed by DAS28-CRP, HAQ and VAS, 
throughout the RA patients’ entire disease duration. 
 

 
 
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• 
The regression of the articular vBMD and bone architecture by HR-pQCT imaging throughout the trial 
period. In RA patients, pre-RA patients and healthy subjects. 
• 
Correlation between articular vBMD by HR-pQCT imaging and systemic aBMD by DXA, at both 
baseline and one-year follow-up in patients with RA. 
• 
Correlation between change in the articular vBMD, determined by HR-pQCT imaging, throughout the 
trial period, and the mean disease activity assessed by assessed by DAS28-CRP, HAQ and VAS, 
throughout the trial period, as well as biomarkers for bone metabolism and inflammation (see 11.2), 
throughout the trial period. In RA patients, pre-RA patients and healthy subjects.  
• 
Correlation between change in the articular vBMD, determined by HR-pQCT imaging, throughout the 
trial period, and the mean disease activity, assessed by DAS28-CRP, HAQ and VAS, throughout the 
RA patients’ entire disease duration. 
 
6.3 Hypothesis 
1. The progression of number, size and volume of bone erosions, determined by HR-pQCT imaging, 
throughout the trial period are higher in RA patients compared with pre-RA patients and healthy 
subjects. 
2. The progression of the number, size and volume of bone erosions, determined by HR-pQCT imaging, 
throughout the trial period are correlated with a higher disease activity score, assessed by DAS28-
CRP, HAQ and VAS, throughout the trial period in RA patients, pre-RA patients and healthy subjects. 
3. The progression of the number, size and volume of bone erosions, determined by HR-pQCT, 
throughout the trial period are correlated with changes in biomarkers for bone metabolism and 
inflammation (see 11.2) 
4. The progression in the radiographic erosion score throughout the trial period, determined by 
conventional X-ray, is higher in RA patients compared with pre-RA patients and healthy subjects. 
5. The progression in the radiographic erosion score throughout the trial period, determined by 
conventional X-ray, is correlated with a higher disease activity score, assessed by DAS28-CRP, HAQ 
and VAS, throughout the trial period in RA patients, pre-RA patients and healthy subjects. 
6. The progression in the radiographic erosion score throughout the trial period, determined by 
conventional X-ray, is correlated with changes in biomarkers for bone metabolism and inflammation 
(see 11.2) 
7. The regression of articular vBMD and bone architecture throughout the trial, determined by HR-pQCT 
imaging, are higher in RA patients compared with pre-RA patients and healthy subjects. 

 
 
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8. The regression of articular vBMD and bone architecture throughout the trial, determined by HR-pQCT 
imaging, is correlated with a higher disease activity score, assessed by DAS28-CRP, HAQ and VAS, 
throughout the trial period in RA patients, pre-RA patients and healthy subjects. 
9. The regression of articular vBMD and bone architecture throughout the trial, determined by HR-pQCT 
imaging, is correlated with changes in biomarkers for bone metabolism and inflammation (see 11.2) 
10. The articular vBMD, determined by HR-pQCT imaging, correlates with the systemic aBMD, 
determined by DXA scan, in RA patients  
 
METHODS: PARTICIPANTS, INTERVENTIONS, AND OUTCOMES 
7 TRIAL DESIGN 
The design of the trial is an observational study with three distinct groups. At the start of the trial period and 
at one-year of follow-up, the trial subject will have their hand X-rayed by conventional radiography, and their 
metacarpophalangeal (MCP) joint and wrist scanned by HR-pQCT-Imaging. The 28-joint Disease Activity 
Score(DAS28-CRP)30, Health Assessment Questionnaire (HAQ)31, Visual analogue scale(VAS)-score for pain, 
fatigue and quality of life are performed to investigate the correlation between radiographic changes and 
disease activity. Blood samples are collected to investigate serological markers of bone metabolism and 
inflammation and the radiographic changes. The following groups are investigated: 
RA patients: Patients with RA ≥5 years according to the ACR/EULAR 2010 classification criteria32 or the 
American Rheumatism Association 1987 revised criteria33 are recruited from the outpatient clinic at the 
Department of Rheumatology, Aarhus University Hospital. Treatment will be adjusted according to the 
patient’s need and according to national guidelines. (n=450) 
Pre-RA patients: Patients with pre-RA, (joint pain, but now swelling and ACPA 3 times above the upper limit) 
are recruited from the outpatient clinic at the Department of Rheumatology, Aarhus University Hospital. 
(n=75) 
Healthy subjects:  Healthy age- and sex-matched Individuals are recruited, as a control group, by posting at 
libraries in Aarhus, Aarhus University, Aarhus University Hospital and postings on the websites 
www.forsøgsperson.dk and www.Sundhed.dk.  (N=100) 
 
8 STUDY SETTING 
Aarhus University Hospital, Department of Rheumatology. Nørrebrogade 44, 8000 Aarhus C, Denmark.  
 

 
 
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9 ELIGIBILITY CRITERIA  
9.1 RA patients 
Inclusion criteria  
• 
Patients (> 18 years) with rheumatoid arthritis ≥5 years according to the ACR/EULAR (2010) 
classification criteria32 or American Rheumatism Association 1987 revised criteria33 for the patients 
who were diagnosed before 2010. 
• 
Patients who are receiving treatment on an outpatient basis. 
• 
Ability and willingness to give written informed consent and to meet the requirements of the trial 
protocol. 
Exclusion criteria 
• 
Patients who have previously suffered trauma in the form of fracture or luxation of the hand are 
excluded. 
• 
Evidence of active malignant disease. 
• 
Hypo- or hyperthyroidism. 
• 
Hypocalcaemia. 
• 
Impaired renal function (eGFR <35ml/min). 
• 
Pregnancy. 
 
9.2 Pre-RA patients 
Inclusion criteria  
• 
Age over 18 years. 
• 
ACPA 3 times the upper limit of the reference interval. 
• 
Arthralgia. 
• 
Ability and willingness to give written informed consent and to meet the requirements of the trial 
protocol. 
Exclusion criteria 
• 
Pregnancy. 
• 
Swelling of joints. Verified by clinical ultrasound. 
• 
Patients who have previously suffered trauma in the form of fracture or luxation of the hand are 
excluded. 
• 
Evidence of malignant disease. 
• 
Hypo- or hyperthyroidism. 
• 
Hypocalcaemia. 

 
 
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• 
Impaired renal function (eGFR <35ml/min). 
• 
Earlier or present rheumatological disease or bone metabolic disease. 
 
9.3 Healthy subjects 
 Inclusion criteria  
• 
Age over 18 years. 
• 
No joint complaints. 
• 
Ability and willingness to give written informed consent and to meet the requirements of the trial 
protocol. 
Exclusion criteria 
• 
Patients who have previously suffered trauma in the form of fracture or luxation of the hand are 
excluded. 
• 
Evidence of malignant disease. 
• 
Hypo- or hyperthyroidism. 
• 
Hypocalcaemia. 
• 
Impaired renal function (eGFR <35ml/min). 
• 
Earlier or present rheumatological disease or bone metabolic disease. 
• 
Positive anti-CCP. 
• 
Pregnancy. 
 
10 INTERVENTIONS 
The study is an observational study. This study does not perform any Interventions on any of the groups. 
 
11 OUTCOMES 
11.1 Primary outcomes  
a) Changes in bone erosion number, size and volume by HR-pQCT-imaging from baseline to one-year 
follow-up, in the three groups. 
b) Change in radiographic erosion score from baseline to one-year follow-up, in the three groups. 
c) Changes in vBMD in cancellous and trabecular bone respectively from baseline to one-year follow-
up by the HR-pQCT, in the three groups. 
• 
Average bone density (Dtotal). 
• 
Trabecular bone density (Dtrab).  
• 
Cortical bone density (Dcort) in milligrams of hydroxyapatite (HA) per centimetre cubed.  

 
 
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• 
Mean cortical thickness (Ct.Th, millimetres).  
• 
Trabecular bone volume fraction (BV/TV). 
• 
Trabecular number (Tb.N, 1 mm). 
• 
Trabecular thickness (Tb.Th, millimetre). 
• 
Trabecular spacing (Tb.Sp, millimetre). 
 
11.2 Secondary outcomes 
d) aBMD in the lumbar spine, and the left hip by DXA, in RA patients 
e) Changes from baseline to one-year follow-up in the following serological markers of bone 
metabolism and inflammation, in the three groups: 
• 
C-terminal telopeptide (CTX). 
• 
Procollagen type 1 N-terminal propeptide (P1NP). 
• 
Bone-specific alkaline phosphatase, (BAP). 
• 
Tumor necrosis factor-alfa (TNF-α). 
• 
RANK-Ligand (RANK-L). 
• 
Osteoprotegerin (OPG). 
• 
Osteocalcin (BGLAP). 
• 
Sclerostin(SCL). 
• 
Dickkopf-related protein 1 (Dkk-1). 
• 
Interleukins 1, 6, 15, 16, 17, 22, and 33 (IL-1, IL-6, IL-15, IL-16, IL-17, IL-22, and IL-33). 
• 
Chemokine ligand 11 (CCL11). 
• 
Chemokine (C-X-C) motif ligand (CXCL13). 
• 
C-reactive protein (CRP). 
• 
Tartrate-resistant acid phosphatase 5b (TRACP 5b). 
f) Clinical information. 
• 
DAS28-CRP. 
• 
HAQ. 
• 
VAS-pain, fatigue and quality of life. 
 

 
 
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12 PARTICIPANT TIMELINE  
 
Visit 
1 
2 
3 
4 
Month 
0 
3 
6 
12 
Information Meeting 
X 
 
 
 
Informed consent 
X 
 
 
 
Demography 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Medical history 
X 
 
 
 
Physical examination 
X 
 
 
X 
HR-pQCT 
X 
 
 
X 
DXA1 
X 
 
 
 
DAS 28-CRP 
X 
 
 
X 
X-Ray of hand 
X 
 
 
X 
Blood samples2 
X 
(X) 
(X) 
X 
1Only RA Patients without a recent DXA scan (< 2 years) will be referred to a DXA scan at the time of baseline. 
2Blood samples at the 3rd and 6th month are only collected from RA and pre-RA Patients. 
 
13 SAMPLE SIZE  
Data on relevant study populations on which sample size can be calculated is not available. The planned 
population size is estimated based on the following. Statistical significance is 0.05. Sensitivity, specificity, 
positive and negative predictive values could be estimated in a group of only 17 patient using low-resolution 
CT4. Progression in the radiographic score is however much less sensitive. The changes in the radiographic 
score during the first two years of the disease is less than 1% of the maximal radiographic score used for 
conventional X-ray examinations13,14. Therefore, a substantially higher number of patients are needed. Our 
study includes a study group of 450 patients with RA ≥5 years, and a group of 75 patient with pre-RA, not it 
medical treatment, where we expect a higher initial change in the articular bone. A group of 100 healthy 
individuals are included as a control group, which we assess, are sufficient. 
 
14 RECRUITMENT 
14.1 RA and pre-RA patients 
Patients are recruited from the outpatient clinic at the Department of Rheumatology, Aarhus University 
Hospital. The Department of Rheumatology treats about 1400 patients with RA. In the present study, we 
include 450 patients with RA. Patients participating in the trial are subjected to the same procedures as their 
annual doctor’s visit, which includes a physical examination, blood samples and questionnaires. At the annual 
doctor's visit, the patients are also examined with DXA scans and conventional X-ray according to clinical 
status. In this trial, the patients are also subjected to HR-pQCT imaging, at the start and one-year follow-up, 

 
 
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and extra blood samples at the 3rd and 6th month. We, therefore, do not expect any trouble with the 
recruitment of the patients, owing to the large patient population to recruit from, and because the patients 
only have to participate in a few additional procedures compared to their annual physical. 
 
14.2 Healthy subjects 
Healthy controls are recruited by posting at libraries in Aarhus, Aarhus University, Aarhus University Hospital, 
and postings on the website www.forøgsperson.dk and www.sundhed.dk. Contact information in the form 
of the principal investigator's email address is listed on the postings. Interested subjects can subsequently 
contact the trial investigator for further information. The healthy subjects are compensated 500 DKK for the 
disadvantages that may be associated with the trial. The healthy subjects are compensated after their last 
examination at the one-year follow-up. In case of exclusion or absence, the healthy subjects do not receive 
compensation. In previous studies, our research group has, under similar trial settings, not experienced any 
problems with recruiting healthy subjects. We, therefore, do not expect problems with recruiting.  
 
METHODS: DATA COLLECTION, MANAGEMENT, AND ANALYSIS 
15 DATA COLLECTION METHODS 
15.1 HR-pQCT 
All Patients will be scanned at baseline and one year after using the HR-pQCT scanner (Xtreme CT, Scanco 
Medical AG, Switzerland). The hand is scanned in a 2.7 cm long region corresponding to the 2. and 3. 
metacarpophalangeal joint, being the joints most commonly involved in RA34. The wrist is scanned over a 0.9 
cm long region starting at the most proximal joint surface of the radius. The number, size and volume of bone 
erosions are estimated. Structural parameters for cortical and trabecular bone are calculated.  
 
15.2 Conventional X-ray       
All patients will be examined at baseline and a year after with conventional X-ray using the standard 
dorsopalmar (PA) projection of the hands and wrist, a focus distance of 100-115 cm, and an exposure of 50-
55 kV and 2-12 mAs. Erosions score is appraised by the Sharp-van-der-Heijde method14, among other 
methods. If a conventional X-ray of hand and wrist has been performed within the last three months or is 
scheduled in the three months following inclusion, this will be recorded as the baseline scan. 
 
15.3 Blood samples       
A research biobank for blood samples will be established for the project, with an expected start on the 1st 
of January 2018 and which expires d. 31st of December 2026. The standard set of blood samples are stored 

 
 
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nine years in the research biobank, three years for inclusion, one-year of follow-up, and the last five years 
for the analysis.  The standard set of blood samples (see 11.2) is collected from all the RA and pre-RA 
patients at the beginning of the trial, at the 3rd month, at the 6th month, and after one-year. A total of 300 
ml is collected throughout the experiment. The standard set of blood samples is collected from the healthy 
subjects at the beginning of the trial, and after one-year. A total of 150 ml is collected throughout the 
experiment. 
The standard set of 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 
Molecular Medical Department (MOMA), AUH Skejby, where they are handled, registered and stored in 
DRB. Material for analysis in the project is then provided by DRB to the project's research biobank. At the 
end of the project period, nine years after the project start, the research biobank ceases. Excess material is 
requested to be transferred to a biobank for future research. Participants may withdraw any commitment 
to participate in the project, or for storage of the standard blood samples in RBGB at any time. If the 
participant only agrees to the research project, but not to RBGB, or if the consent to RBGB is withdrawn, 
the material in RBGB will be destroyed. The Central Denmark Region Committee on  
Health Research Ethics and Regional Data Protection Authorities are applied for permission before use of 
the standard set of blood samples from the for biobank for future research use in any ancillary studies. 
 
15.4 Physical examination 
The patients and healthy subjects are examined with a focus on their joints at the beginning of the trial and 
one-year later. The following twenty-eight joints, which also are included in DAS28-CRP are examined for 
swelling and tenderness: shoulders, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal 
joints and the knees. In addition, a general joint examination with a focus on remaining joints is made. 
 
15.5 Recording of patient demography and clinical information 
Demographic and clinical information is retrieved from the electronic patient journal (EPJ), which stores 
patient information indefinitely. The demographic and clinical information: Gender, age height, weight, 
duration of disease, menarche, menopause, pregnancies, births, medication, comorbidity, alcohol 
consumption, tobacco consumption, dietary calcium intake, which might not be obtainable from the journal, 
are retrieved directly from the patient in cooperation with the trial investigator. The following biomarkers 
are also extracted from EPJ: Creatinine, calcium ion (Ca+2), potassium ion(K+), magnesium ion(Mg+2), 
rheumatoid factor (RF), anti-citrullinated protein antibodies (anti-CCP), 25-OH-vitamin D, parathyroid 
hormone (PTH). 

 
 
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From the clinical database DanBio under The Danish Clinical Registries (RKKP) the following information is 
extracted; 28-joint Disease Activity Score (DAS28-CRP), Health Assessment Questionnaire (HAQ), C-reactive 
protein (CRP) and Visual analogue scale(VAS)-score for pain, fatigue and quality of life. 
 
15.6 DXA 
Patients with RA, but without a recent DXA scan (< 2 years) will be referred to a DXA scan according to clinical 
guidelines. Patients with osteoporosis, defined by a T-score <-2.5 according to DXA imaging, are treated 
according to National guidelines.  
To ensure comparative results, the same machine is used for each participant at each scan. Lumbar spine 
anterior-posterior and left hip pictures are recorded following local guidelines. In brief, the lumbar spine is 
scanned with the patient positioned on his/her back, with legs bent 90 degrees at both hip and knee. Then, 
the subject is placed flat on his/her back, and the left leg is rotated inward and fixated to position the femoral 
neck for the total hip scan. BMD in g/cm2 and Z- and T-scores are calculated using the built-in software. 
 
15.7 Practical feasibility 
In this study, cooperation with experienced and key persons in the relevant departments has been 
established, ensuring both recruitment of patients and subsequent imaging and blood sample. Our research 
group has initiated this line of clinical studies focusing on the early diagnosis of joint destruction in 
rheumatoid arthritis based on results from experimental arthritis6,12. We have experience with HR-pQCT 
imaging from a previous PhD project35,36 and more than 300 scans of RA and pre-RA patients completed at 
Aarhus University Hospital. In addition, the first publication on the pre-RA patients has been published12. 
Since 2013 our group has been participating in the international research group SPECTRA, which has recently 
become a Special Interest Group of the OMERACT initiative, an international initiative to improve outcome 
measurement in rheumatology28. The Department of Rheumatology at Aarhus University Hospital is currently 
the only Danish department investigating HR-pQCT imaging in RA patient for precision medicine.  
 
16 DATA MANAGEMENT 
All of the data mentioned above are considered source data. HR-pQCT-scans, X-rays and demographic 
information are documented in Research Electronic Data Capture (REDCap). The clinical information is 
extracted from DanBio and stored in REDcap. The standard set of blood samples (see 11.2) are stored at 
RBGB. The remaining data can be retrieved using the patients’ medical records, the electronic patient journal 
(EPJ), which stores patient information indefinitely. All data is anonymised, with the code of anonymisation 
stored separately.  

 
 
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17 STATISTICAL METHODS 
A p-value <0.05 will be considered significant when comparing two study groups, or the change from baseline 
to the one-year follow-up in the same group. Significant differences are calculated with either student's t-
test if data is normally distributed. In case the data is not normally distributed the Mann–Whitney U test is 
used to calculate significant differences. Correlation is calculated with either Pearson correlation coefficient 
or Spearman's rank correlation coefficient. A p-value < 0.05 will be considered significant. The following 
comparison is made: 
1. Δerosion number, size and volume at baseline, determined by HR-pQCT imaging, in RA patients 
compared with pre-RA patients and healthy subjects. 
2. Δerosion number, size and volume at baseline, determined by HR-pQCT imaging, in pre-RA 
patients compared with healthy subjects. 
3. Δradiographic erosion score at baseline, determined by conventional X-ray, in RA patients 
compared with pre-RA patients and healthy subjects. 
4. Δradiographic erosion score at baseline, determined by conventional X-ray, in pre-RA patients 
compared with healthy subjects. 
5. Δerosion number, size and volume at one-year follow-up, determined by HR-pQCT imaging, in 
RA patients compared with pre-RA patients and healthy subjects. 
6. Δerosion number, size and volume at one-year follow-up, determined by HR-pQCT imaging, in 
pre-RA patients compared with healthy subjects. 
7. Δerosion number, size and volume, determined by HR-pQCT imaging, at baseline compared with 
one-year follow-up. In RA patients, pre-RA patients and healthy subjects. 
8. Δradiographic erosion score at one-year follow-up, determined by conventional X-ray, imaging 
in RA patients compared with pre-RA patients and healthy subjects. 
9. Δradiographic erosion score at one-year follow-up, determined by conventional X-ray, in pre-RA 
patients compared with healthy subjects. 
10. Δradiographic erosion score, determined by conventional X-ray, at baseline compared with one-
year follow-up. In RA patients, pre-RA patients and healthy subjects. 
11. Δarticular vBMD and bone architecture at baseline, determined by HR-pQCT imaging, in RA 
patients compared with pre-RA patients and healthy subjects. 
12. Δarticular vBMD and bone architecture at baseline, determined by HR-pQCT imaging, in pre-RA 
patients compared with healthy subjects. 

 
 
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13. Δarticular vBMD and bone architecture at one-year follow-up, determined by HR-pQCT imaging, 
in RA patients compared with pre-RA patients and healthy subjects. 
14. Δarticular vBMD and bone architecture at one-year follow-up, determined by HR-pQCT imaging, 
in pre-RA patients compared with healthy subjects. 
15. Δarticular vBMD and bone architecture, determined by HR-pQCT imaging, at baseline compared 
with one-year follow-up. In RA patients, pre-RA patients and healthy subjects. 
16. Δvalues of the serological markers of bone metabolism and inflammation (see 11.2) between 
RA patients and pre-RA patients at baseline. 
17. Δvalues of the serological markers of bone metabolism and inflammation (see 11.2) between 
RA patients and healthy subjects at baseline. 
18. Δvalues of the serological markers of bone metabolism and inflammation (see 11.2) between 
pre-RA patients and healthy subjects at baseline. 
19. Δvalues of the serological markers of bone metabolism and inflammation (see 11.2) between 
baseline and one-year follow-up. In RA patients, pre-RA patients and healthy subjects. 
20. Δvalues of the serological markers of bone metabolism and inflammation (see 11.2) between 
RA patients and pre-RA patients at 3rd-month follow-up 
21. Δvalues of the serological markers of bone metabolism and inflammation (see 11.2) between 
RA patients and pre-RA patients at 6th-month follow-up 
22. Δvalues of the serological markers of bone metabolism and inflammation (see 11.2) between 
RA patients and pre-RA patients at one-year follow-up 
23. Δvalues of the serological markers of bone metabolism and inflammation (see 11.2) between 
RA patients and healthy subjects at one-year follow-up 
24. Δvalues of the serological markers of bone metabolism and inflammation (see 11.2) between 
pre-RA patients and healthy subjects at one-year follow-up 
25. Correlation between Δnumber, size and volume of bone erosions, determined by HR-pQCT 
imaging, and Δvalues of the serological markers for bone metabolism and inflammation (see 
11.2) throughout the trial period. In RA patients, pre-RA patients and healthy subjects. 
26. Correlation between Δradiographic erosion score, determined by conventional X-ray, and 
Δvalues of the serological markers for bone metabolism and inflammation (see 11.2) throughout 
the trial period. In RA patients, pre-RA patients and healthy subjects. 
27. Correlation between Δnumber, size, and volume of erosions, determined by HR-pQCT imaging, 
throughout the trial period and the mean disease activity, assessed by DAS28-CRP, HAQ and 
VAS, throughout the RA patient’s entire disease duration. 

 
 
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28. Correlation between Δnumber, size, and volume of erosions, determined by HR-pQCT imaging, 
throughout the trial period, and the mean disease activity, assessed by DAS28-CRP, HAQ and 
VAS, throughout the trial period. In RA patients, pre-RA patients and healthy subjects 
29. Correlation between Δradiographic erosion score throughout the trial period, determined by 
conventional X-ray, and the mean disease activity, assessed by DAS28-CRP, HAQ and VAS, 
throughout the trial period. In RA patients, pre-RA patients and healthy subjects. 
30. Correlation between Δradiographic erosion score throughout the trial period, determined by 
conventional X-ray, and the mean disease activity, assessed by DAS28-CRP, HAQ and VAS, 
throughout the RA patient’s entire disease duration. 
31. Correlation between Δarticular vBMD and bone architecture, determined by HR-pQCT imaging, 
and Δvalues of the serological markers for bone metabolism and inflammation (see 11.2) 
throughout the trial period. In RA patients, pre-RA patients and healthy subjects. 
32. Correlation between Δarticular vBMD and bone architecture throughout the trial period, 
determined by HR-pQCT imaging, and the mean disease activity, assessed by DAS28-CRP, HAQ 
and VAS, throughout the RA patient’s entire disease duration. 
33. Correlation between systemic aBMD, determined by DXA scan, and articular vBMD, determined 
by HR-pQCT imaging, in RA patients. 
 
ETHICS AND DISSEMINATION 
18 RESEARCH ETHICS APPROVAL 
In this scientific study, joint destruction in rheumatoid arthritis patients is investigated with a new medical 
Imaging modality (HR-pQCT). Furthermore, data from the annual monitoring of patients' disease from the 
Department of Rheumatology are included. One risk/disadvantage for the patients in this trial is to have their 
hand fixated in 3 minutes, and 8 minutes, otherwise, no discomfort is related to HR-pQCT. The total radiation 
dose of HR-pQCT in the study is less than 0.1 mSv, which is about the same as in conventional X-ray of hands. 
Each DXA scan gives a radiation dose of 0,01mSv. Background radiation in Denmark is three mSv a year. The 
total radiation in the study enhances the risk of cancer with 1/1.000.000 compared to the overall lifetime risk 
of 1/4, which is considered as insignificant. Slight pain associated with blood sampling may occur but is 
deemed acceptable. The risk of infection is estimated to be very low. 
This trial does not benefit the individual patient with RA or pre-RA. The knowledge gained through the trial, 
however, will contribute with significant scientific information of importance to the future treatment of 
rheumatoid arthritis patients, and it is thus the investigator's opinion that the trial is relevant and ethical. It 
is estimated that potential risks for patients by participating in the experiment are insignificant. 

 
 
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Approval must be provided from The Central Denmark Region Committee on Health Research Ethics and 
Regional Data Protection Authorities before the recruitment of research subjects. 
 
19 PROTOCOL AMENDMENTS 
All Modifications to the protocol are reported to The Central Denmark Region Committee on Health Research 
Ethics and The Data Protection Authorities. 
 
20 CONSENT OR ASSENT 
20.1 RA and Pre-RA patients 
Patients are recruited from the outpatient clinic at the Department of Rheumatology, Aarhus University 
Hospital. Information about the trial is given at an already scheduled appointment in the outpatient clinic 
or by sending written information to the patient. All information is provided by the trial investigator or by a 
person designated by the trial investigator. Patients who are interested in participating in the trial will be 
invited to a meeting with the trial 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 be offered one 
weekto consider their decision. The informed consent form is signed and dated by both the trial subject 
and the investigator. Subsequently, it is reviewed by the investigator for the correct date, readable name 
and signature. A copy of the signed informed consent is offered to the trial subject. 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.  
 
20.2 Healthy subjects 
Healthy subjects, interested in participating in the trial after seeing the postings are encouraged to contact 
the trial investigator. A meeting between the healthy subject and the trial investigator are scheduled. Here, 
the subject will receive full oral and written information in uninterrupted surroundings and have the 
opportunity to ask questions. The subject is informed of the right to bring a friend or relative to the 
conversation beforehand and will be offered one week to consider his or her decision. The subject may, at 
any time and without giving a reason, withdraw his or her consent. The informed consent form is signed 
and dated by both the trial subject and the investigator. Subsequently, it is reviewed by the investigator for 
the correct date, readable name and signature. A copy of the signed informed consent is offered to the trial 
subject. The subject may, at any time and without giving a reason, withdraw his or her consent. Withdrawal 
of consent will not affect the further treatment.  

 
 
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21 CONFIDENTIALITY 
Information regarding previous medical history and treatment is gathered from the participants’ medical 
records. All information is recorded in 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 accordance with the Danish law concerning the processing of personal data. Approval must be 
provided by the Data Protection Authorities. The scan results are deleted or submitted to the state archives 
at the end of the study. 
 
22 DECLARATIONS OF INTEREST & FUNDING 
Aarhus University has awarded a fully financed PhD fellowship which includes both PhD-scholarship 
(1.350.000 DKK) and PhD-fee (180.000 DKK) for the trial investigator.  
The Novo Nordisk Foundation have donated 2.500.000 DKK for the conventional radiography and HR-pQCT-
imaging.  
The Danish Rheumatism Association have donated 140.000 DKK and “Fonden for lægevidenskabens fremme” 
have donated 40.000 DKK for which is earmarked for salary to a research nurse. 
Aarhus University Hospital administers all funds for salaries and imaging. 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 ACCESS TO DATA  
All source data will be accessible for Inspection by the Danish Health and Medicine Authority. All original 
informed consent forms and detailed records of medical disposition will be stored safely and destroyed after 
15 years. Original data including laboratory data can be retrieved from the electronic medical records (EPJ). 
Investigator will ensure that direct access to all source data is available for Inspection by Danish Health and 
Medicines Authority and other authorities. 
 
24 ANCILLARY AND POST-TRIAL CARE  
The Patient Compensation Association covers patients who against all expectations, should be injured in the 
study. 
 

 
 
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25 DISSEMINATION POLICY  
Positive, negative and inconclusive results will be published in high-ranking international peer-reviewed 
journals. We plan two publications related to the aims in Annals of Rheumatic Diseases, and 1 in Arthritis & 
Rheumatology. MD, PhD student Rasmus Klose Jensen will first author on all publications. Chief physician, 
Clinical Professor, PhD Ellen-Margrethe Hauge will be senior author. MD, PhD Kresten Krarup Keller, MD, 
PhD-student Anne-Birgitte Garm and Professor DMSc Bente Langdahl will be co-authors according to 
contributions. Authorship for other co-authors is awarded according to the Vancouver guidelines for 
authorship. This protocol will be published on ClinicalTrials.gov. 
 
 

 
 
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