Magnetic Resonance Enterography as a Screening Tool for Axial Spondyloarthritis in Crohn's Disease: A Prospective Single-center Cross-sectional Observational Study Using MRE Screening Followed by Clinical Assessment
Conditions: Axial Spondyloarthritis, Crohn Disease
Sponsor: Cambridge University Hospitals NHS Foundation Trust

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ProSpA-CD, Protocol, v4, 08/01/2019 
 
 
Research Study Protocol 
 
Department of Rheumatology, Cambridge University Hospitals NHSFT 
  
 
Magnetic resonance enterography as a screening tool for axial spondyloarthritis in 
Crohn’s disease: A prospective single-center cross-sectional observational study 
using MRE screening followed by clinical assessment (ProSpA-CD) 
 
 
 
 
Chief Investigator 
Dr Deepak Jadon  
MBBCh MRCP PhD 
Consultant Rheumatologist & Director of the Rheumatology Research Unit 
Associate Principle Investigator, Department of Medicine, University of Cambridge 
 
Principal Investigator 
Dr Jobie Evans 
BMBS MRCP 
Research Fellow 
 
 
Research Institution: 
 
Cambridge University Hospitals NHS Foundation Trust 
Addenbrooke’s Hospital 
Hills Road 
Cambridge 
U.K. 
CB2 0QQ 
 
Study Sponsor:  
Cambridge University Hospitals NHSFT 
 
IRAS Ref:  
 
249724

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ProSpA-CD, Protocol, v4, 08/01/2019 
SIGNATURES PAGE 
 
Protocol Version 3; 18 Sept 2018 
 
Written and approved by the following 
 
 
____________________ 
 
____________________ 
Dr Deepak Jadon 
 
 
Date 
 
 
 
 
 
Chief Investigator (consultant rheumatologist) 
 
 
____________________ 
 
____________________ 
Dr Jobie Evans 
 
 
Date 
 
 
 
 
 
 
Principal Investigator (rheumatology SpR and clinical research fellow) 
 
 
____________________ 
 
____________________ 
Dr Tim Raine  
 
 
Date 
 
 
 
 
 
 
Co-investigator (consultant gastroenterologist) 
 
 
____________________ 
 
____________________ 
Dr Scott McDonald 
 
 
Date 
 
 
 
 
 
 
Co-investigator (consultant radiologist) 
 
 
____________________ 
 
____________________ 
Professor Richard Samworth  
Date 
 
 
 
 
 
 
Co-investigator (University of Cambridge, Statistician) 
 
 
____________________ 
 
____________________ 
Dr Kenneth Poole 
 
 
Date 
 
 
 
 
 
 
Academic Supervisor (honorary consultant rheumatologist) 
 
 
__________________ 
____________________ 
Dr Gavin Clunie 
 
 
Date 
 
 
 
 
 
 
Co-investigator (consultant rheumatologist) 
 
 
____________________ 
 
____________________ 
Dr Miles Parkes 
 
 
Date 
 
 
 
 
 
 
Co-investigator (consultant gastroenterologist) 
 
 
 
 
 

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ProSpA-CD, Protocol, v4, 08/01/2019 
KEY CONTACTS 
 
Chief Investigator: 
 
Dr Deepak Jadon 
 
 
 
 
Consultant Rheumatologist 
 
 
 
 
Rheumatology Research Unit, Level E6 (Box 194) 
Addenbrooke’s Hospital 
Hills Road  
Cambridge 
U.K. 
CB2 0QQ 
 
Tel. 
    01223 217457 
Fax. 
    01223 257120 
 
Email.     deepak.jadon@addenbrookes.nhs.uk 
 
 
Principal Investigator:  
Dr Jobie Evans 
 
 
 
 
Research Fellow Rheumatology 
 
 
 
 
Rheumatology Research Unit, Level E6 (Box 194) 
Addenbrooke’s Hospital 
Hills Road  
 
 
 
 
Cambridge 
U.K. 
CB2 0QQ 
 
Tel. 
    01223 349360 
Fax. 
    01223 257120 
 
Email.     jobie.evans@addenbrookes.nhs.uk 
 
 
 

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ProSpA-CD, Protocol, v4, 08/01/2019 
TABLE OF CONTENTS 
 
TITLE PAGE 
SIGNATURES PAGE 
KEY CONTACTS 
TABLE OF CONTENTS 
1.0 
PROTOCOL SUMMARY 
2.0 
INTRODUCTION 
3.0 
STUDY AIM AND OBJECTIVES 
3.1 
AIM 
3.2 
OBJECTIVES  
4.0 
STUDY DESIGN 
4.1 
GENERAL 
4.2 
PROSPA-CD-SCREEN PHASE:  
4.2.1 MAGNETIC RESONANCE ENTEROGRAGRAPHY (MRE) REVIEW 
4.3 
PROSPA-CD-ASSESS PHASE: 
4.3.1 ASSESSMENT OF PATIENTS WITH LESIONS ON MRE CONSISTENT WITH AXSPA 
(CASES)  
4.3.2 ASSESSMENT OF SUBJECTS WITH NO LESIONS ON MRE CONSISTENT WITH 
AXSPA (CONTROLS) 
4.3.3 AXIAL MRI SCAN 
5.0 
STUDY SUBJECT SELECTION 
5.1 
ELIGIBILITY CRITERIA 
5.2 
RECRUITMENT, CONSENT AND RANDOMISATION PROCESSES 
6.0 
STUDY SCHEDULE 
7.0 
DATA COLLECTION, SOURCE DATA AND CONFIDENTIALITY 
7.1 
GENERAL 
7.2 
ARCHIVING 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
POWER ANAYLSIS 
8.2 
STATISTICAL ANALYSIS 
8.3 
MISSING DATA 
9.0 
ETHICAL CONSIDERATIONS 
10.0 
STATEMENT OF INDEMNITY 
11.0 
SAFETY 
12.0 
COSTINGS 
13.0 
APPENDICES 
14.0 
REFERENCES 
 
 

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ProSpA-CD, Protocol, v4, 08/01/2019 
1.  
Protocol summary 
 
 
1.1 
Title of study 
 
 
Magnetic resonance enterography as a screening tool for axial spondyloarthritis in Crohn’s disease: a 
prospective single-center cross-sectional observational study using MRE screening followed by 
clinical assessment. 
 
1.2 
Aim 
 
The aim of this study is to determine the sensitivity and specificity of magnetic resonance 
enterography (MRE) as a screening tool for axial spondyloarthritis (axSpA) in a cohort of adult 
patients with Crohn’s disease (CD) in a secondary-care hospital, using dedicated axial magnetic 
resonance imaging (MRI) with clinical assessment as the gold standard. 
 
1.3 
Objectives 
 
We hypothesise that existing cross-sectional imaging (MRE) from the routine NHS care of patients 
with CD can be used to screen patients for evidence of axSpA,  thereby prompting onward referral to 
the rheumatology department for further management.  
The objectives of this study are therefore to determine: 
1. the validity, sensitivity, specificity and area under the receiver operating characteristic (ROC) 
curve (AUC) of MRE as a screening tool for axSpA in CD, using dedicated axial MRI scans with 
clinical assessment as the gold standard. 
2. the proportion of patients with evidence of axSpA on MRE imaging who fulfill the 2009 
Assessment of Spondyloarthritis International Society (ASAS) criteria for axSpA, modified New 
York criteria for ankylosing spondylitis (AS) and the classification criteria for psoriatic arthritis 
(CASPAR). 
3. the proportion of these patients proceeding to non-pharmacological and pharmacological 
treatment of their axSpA, as a surrogate measure of change in clinical care as a result of MRE 
screening. 
4. the extra-articular features associated with axSpA in CD, in order to better characterise the 
clinical phenotype of enteropathic spondyloarthritis (eSpA).  
5. whether the site of CD (colon, ileum, etc.) predicts the occurrence of axSpA. 
 
 
1.4 
Design   
 
Prospective single-center cross-sectional observational study 
 
 
1.5 
Study group  
 
The ProSpA-CD study will be divided into two parts: 
 
ProSpA-CD-Screen Phase: Review of the patients MRE scan for evidence of axSpA 
The gastroenterology team (Drs Raine and Parkes) at Cambridge University Hospitals (CUH) will write 
to approximately 1100 patients with a diagnosis of CD (male and female patients aged 18 years or 
above) who have had a MRE scan since 2015, asking for their consent to retrospectively review the 
MRE scans for evidence of axSpA. CD subjects with a known diagnosis of SpA (AS, axSpA, eSpA or 

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ProSpA-CD, Protocol, v4, 08/01/2019 
psoriatic arthritis) will be eligible and invited to enter the study. Subjects who consent to this will 
then have their MRE scans reviewed for this purpose. 
 
ProSpA-CD-Assess Phase: Clinical assessment of case and control subjects for evidence of axSpA in 
the clinic setting 
Patients with lesions on their MRE scan consistent with axSpA (regarded as ‘cases’), but who do not 
have a known diagnosis of SpA, will be referred for further clinical assessment in the NHS 
rheumatology spondyloarthritis (SpA) clinic for evidence of axSpA (Dr Jadon’s NHS SpA clinic, but 
assessed by Dr Evans in a supernumerary capacity). Patients will also be invited to participate in the 
ProSpA-CD-Assess phase of the study at this stage.  
 
CD subjects with a known diagnosis of SpA who are already under review by rheumatology and who 
have lesions on MRE consistent with axSpA will be considered as cases but will instead be invited to 
attend the rheumatology SpA research clinic to be assessed for axSpA as this will be considered 
outside of their routine NHS care (Dr Jadon’s SpA research clinic, but assessed by Dr Evans in a 
supernumerary capacity). 
 
CD subjects (including those with a known diagnosis of SpA) who had consented to have their MRE 
scans reviewed, but do not have evidence of axSpA on MRE will also be invited to participate in this 
phase of the study as ‘control’ subjects and consenting subjects will be referred for further clinical 
assessment in the rheumatology SpA research clinic for evidence of axSpA (Dr Jadon’s SpA research 
clinic, but assessed by Dr Evans in a supernumerary capacity). Cases and controls will be matched for 
sex and age, with a cases : control ratio of 1:1.  
 
1.6 
Study schedule  
 
The MRE scans of consenting patients will be reviewed for evidence of axSpA in the ProSpA-CD-
Screen phase of the study. Case and control subjects meeting the inclusion criteria and giving 
informed consent as per section 5.2.2 will then be recruited in to the ProSpA-CD-Assess phase of the 
study. Consented subjects will complete the following patient reported outcome measures (PROM); 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional 
Index (BASFI), a Visual Analogue Score for back pain (VASbp), Ankylosing Spondylitis Disease Activity 
Score (ASDAS) and Stanford Health Assessment Questionnaire Disability Index (HAQ-DI). Each subject 
will be examined in the SpA clinic using the Bath Ankylosing Spondylitis Metrology Index (BASMI), 68 
tender joint count, 66 swollen joint count, the spondyloarthritis research consortium of Canada 
(SPARCC) enthesitis index, and for skin or nail psoriasis.   
 
The following investigations will also be performed as per standard of care for the patients with axial 
skeleton abnormalities on their MRE (MRE+) and no known diagnosis of SpA, if clinically indicated 
and if not been performed in the preceding month; full blood count (FBC), renal function, liver 
function tests (LFTs), C-reactive protein level (CRP), erythrocyte sedimentation rate (ESR) and faecal 
calprotectin. HLA-B27 testing will also be requested if not previously performed. These investigations 
will also be performed for the control subjects and the group of CD subjects with a known diagnosis 
of SpA who are MRE+ (if not performed in the preceding month and if HLA-B27 not previously 
performed) but will be funded by the research grant, unless clinically indicated. 
 
A dedicated axial MRI scan of the spine and sacroiliac joints will be performed in all case and control 
subjects if indicated by the clinical assessment as part of their standard NHS care. Subjects in whom a 
dedicated axial MRI scan is not clinically indicated, or those who have had one performed previously 
for a known diagnosis of SpA, will be consented to undertake the MRI scan for research purposes and 
the MRI scan will be funded by the research grant.  
 
All subjects (cases and controls) will be asked to further consent to provide research samples, 
including whole blood and stool, for storage and future analysis (serum for biomarker analysis, 
plasma for proteomic analysis, DNA for genotyping, and stool for microbiome analysis). Collection of 

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ProSpA-CD, Protocol, v4, 08/01/2019 
these samples will be funded by the existing research grant, and analysis will be funded by research 
grants that are currently being applied for.  
 
The control group will receive no further follow up unless clinically indicated. CD subjects in this 
group with a known history of SpA will be followed up as planned by their primary rheumatology 
team.   
 
The cases (excluding CD subjects with known SpA who are MRE+ and already under rheumatology 
review) will be followed up for their second review in the NHS rheumatology SpA clinic 
approximately 6 months later and will complete the following PROMs; BASDAI, BASFI, VASbp, ASDAS 
& HAQ-DI. Each patient will also be examined using the BASMI, 68 tender joint count, 66 swollen 
joint count, the SPARCC enthesitis index, and for skin or nail psoriasis. The following investigations 
will also be performed as per standard of care if not performed within the preceding month; FBC, 
renal function, LFTs, CRP and ESR. The patients will also be reviewed in the SpA clinic at an earlier 
date if indicated for treatment or clinical reasons. However, subjects who already have a diagnosis of 
SpA and are already under review by a rheumatology team will be followed up as planned by their 
primary rheumatology team. 
 
Further details of how subjects will be approached, classified as cases or controls, and how the 
various assessments (clinical, imaging, laboratory) are being funded are detailed in Appendix 1. 
 
1.7 
Study timelines & accrual  
 
Study set up:   
 
 
Up to November 2018 
Recruitment and data collection:  
December 2018 to February 2020 
Analysis and publication of data: 
March 2020 to August 2020 
 
Please see Appendix 2 (Schedule of Procedures) and Appendix 3 (Gantt time chart for research 
timeline). 
 
1.8 
End of the study 
August 2020 
 
 
 
 

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ProSpA-CD, Protocol, v4, 08/01/2019 
2. 
Introduction 
 
2.1 
Background and rationale for the proposed study 
 
Spondyloarthritis (SpA) is a term used to describe a group of chronic inflammatory musculoskeletal 
diseases that can present with axial and / or peripheral joint disease. SpA encompasses non-
radiographic axial spondyloarthritis (nr-axSpA), AS and psoriatic arthritis (PsA). The prevalence of SpA 
has been estimated to range between 0.01% (Japan) and 2.5% (Alaska and Russia) of the general 
population [1]. There is an association with the Human Leucocyte Antigen B27 (HLA-B27) which is 
estimated to be present in 50-95% of patients with SpA [2]. Patients with SpA have an excess burden 
of inflammatory bowel disease (IBD), which primarily includes CD and ulcerative colitis (UC). It is 
estimated that up to 40% of patients with PsA also have axial disease (PsSpA) [3]. The estimated 
prevalence of diagnosed IBD in patients with PsSpA is 12% and in patients with AS is 10% [3]. 
However, few studies have investigated the presence of undiagnosed SpA in patients with IBD.  SpA 
can have a significant negative impact on various aspects of quality of life including employment, 
social life and sexual relations [4-6]. PsA has been found to be associated with relatively high levels of 
unemployment (20%–50%) with some improvement following conventional or biologic disease 
modifying anti-rheumatic drugs (DMARDs) [7, 8]. Timely diagnosis and treatment is therefore 
potentially crucial.  
Novel biologic therapies for SpA have been developed to target the dysregulated innate and adaptive 
immune systems which underpin its pathophysiological and inflammatory processes. Such targets 
include pathways involving the cytokines interleukin (IL)-17, IL12/23 and tumour necrosis factor 
(TNF).  These cytokine pathways are also common to the pathophysiological processes of IBD [9-12]. 
There have subsequently been a number of biological therapies that have emerged over the last 
decade with a license to treat IBD and SpA, including anti-tumour necrosis factor (anti-TNF), anti-IL-
23 and anti-IL 17 agents. Whilst these treatments are not equally efficacious for both conditions, if 
used appropriately and early in the course of the disease, they can have a significant impact on the 
burden of disease [13, 14]. 
Sacroiliitis (inflammation of the sacroiliac joints) is the radiological hallmark of axSpA, but other 
spinal lesions include spondylitis (inflammation of the vertebral bodies) spondylodiscitis 
(inflammation of the vertebral discs), enthesitis (inflammation of the spinal ligament insertion 
points) and the formation of syndesmophytes in chronic disease. Historically, axSpA has been 
diagnosed using plain radiographs of the sacroiliac joints to assess for sacroiliitis according to the 
1984 modified New York criteria for AS [15]. However, over the last 20 to 30 years, cross-sectional 
imaging with computed tomography (CT) and magnetic resonance imaging (MRI) has become 
increasingly utilised. CT scans can better detect chronic bony changes in axSpA, including erosions, 
sclerosis and ankylosis, compared with radiographs [16-19]. However unlike MRI, they are unable to 
identify acute inflammatory changes related to bone marrow oedema or chronic changes related to 
fatty atrophy and MRI is much more effective at detecting early signs of axSpA [16, 20-22]. CT scans 
also pose higher ionising radiation exposure. MRI does not pose an ionising radiation risk and has 
therefore been recommended for the assessment of SpA in the 2009 ASAS guidelines [16]. Regarding 
PsA, this can be diagnosed using the CASPAR criteria [23]. 
The acute inflammatory changes of axSpA are best seen on MRI using dedicated fluid sensitive 
sequences such as a fat saturated T2-weighted sequence or a short tau inversion recovery (STIR) 
sequence. The typical active inflammatory lesions of the sacroiliac joint on MRI include bone marrow 
oedema, capsulitis, enthesitis and synovitis, and the chronic lesions include sclerosis, erosions and 
ankylosis [24].  The typical axSpA MRI spinal lesions include spondylitis, spondylodiscitis, enthesitis 
and syndesmophytes [16].  
MRE imaging has been shown to be a useful tool in the diagnosis and assessment of potential 
complications for patients with CD [25, 26]. The majority of CD patients will have been reviewed by 
secondary care specialists in gastroenterology, and most will have had cross-sectional imaging in the 
form of MRE imaging to assess the extent of their CD. These scans also capture the axial (spine and 

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ProSpA-CD, Protocol, v4, 08/01/2019 
pelvis) skeleton but radiological assessment of this aspect of the scan is often overlooked and 
deemed beyond the remit of the initial MRE request. However, these scans contain valuable 
unreported data, which could be used to screen for the presence of axSpA in patients with CD.  
To our knowledge, there have been only 12 studies assessing this in practice; the presence of axSpA 
features (sacroiliitis) in IBD patients as defined by cross-sectional imaging. Only two of these 12 
studies have used MRE imaging for this purpose, with the majority using CT scans, and most of the 
studies had a small-medium sample size.   
Leclerc-Jacob et al. (2014) assessed the MRE scans of 186 patients with IBD (131 patients with CD 
and 55 with UC) and found evidence of sacroiliitis in 16.7% of patients [27]. The incidence of 
sacroiliitis was found to be equal within the CD and UC group. Gotler et al. (2015) had similar findings 
with 15% of 286 IBD patients having evidence of sacroiliitis on MRE. However, there was no 
correlation between MRE score and inflammatory back pain [28]. A smaller study by Orchard et al. 
using dedicated MRI images of the sacroiliac joints found sacroiliitis in 17 of 44 (39%) patients with 
established CD, the majority of which had inflammatory back pain [29]. Bandyopadhyay et al. (2015) 
assessed 120 patients with IBD and found 24 patients (20%) to have sacroiliitis on dedicated MRI of 
the sacroiliac joints, with 21 of these patients having inflammatory back pain [30]. Chan et al. 
assessed the CT images of 216 patients with IBD compared to 108 controls. They found a significantly 
higher proportion of sacroiliitis in the IBD patients (15.5 vs. 5.6%) [31]. Other studies have found 
evidence of sacroiliitis on CT scans of patients with IBD ranging from 17% to 68% of the study group 
[18, 19, 32-36].  
Currently, there is limited knowledge on the true prevalence of axSpA in CD patients and there is no 
reliable screening tool available. Undiagnosed and untreated axSpA can impact significantly on 
quality of life, but there are a number of potentially effective treatments which could have a 
significant impact on symptom burden if started in a timely fashion. The development of an effective 
screening tool for use within the gastroenterology clinic is therefore highly desired by the clinical and 
research community. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ProSpA-CD, Protocol, v4, 08/01/2019 
3.  
Study aim and objectives 
 
3.1 
Aim 
 
The aim of this study is to determine the sensitivity and specificity of MRE as a screening tool for 
axSpA in a cohort of adult patients with CD in a secondary-care hospital, using dedicated axial MRI 
with clinical assessment as the gold standard. 
 
3.2 
Objectives  
 
 
We hypothesise that existing cross-sectional imaging (MRE) from the routine NHS care of patients 
with CD can be used to screen patients for evidence of axSpA,  thereby prompting onward referral to 
the rheumatology department for further management.  
The objectives of this study are therefore to determine: 
1. the validity, sensitivity, specificity and area under the ROC curve of MRE as a screening tool for 
axSpA in CD, using dedicated axial MRI scans with clinical assessment as the gold standard. 
 
2. the proportion of patients with evidence of axSpA on MRE imaging who fulfill the 2009 ASAS 
criteria for axSpA, modified New York criteria for AS and the CASPAR criteria for PsA. 
 
3. the proportion of these patients proceeding to non-pharmacological and pharmacological 
treatment of their axSpA, as a surrogate measure of change in clinical care as a result of MRE 
screening. 
 
4. the extra-articular features associated with axSpA in CD, in order to better characterise the 
clinical phenotype of eSpA.  
 
5. whether the site of CD (colon, ileum, etc.) predicts the occurrence of axSpA. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ProSpA-CD, Protocol, v4, 08/01/2019 
4.  
Study design 
 
4.1  
General 
 
 
The ProSpA-CD study will be divided in to two phases: 
 
1. The ProSpA-CD-Screen phase: The review of the patients MRE scan for evidence of axSpA. 
 
2. The ProSpA-CD-Assess phase: The clinical assessment of case and control subjects for evidence 
of axSpA in the clinic setting (including clinical examination, PROMs, blood tests, stool sample 
testing and a dedicated MRI of the spine) followed by comparison of the two groups. 
 
A prospective single-center observational study will be conducted. For the ProSpA-CD-Screen phase 
of the study, the gastroenterology team at CUH (Drs Raine and Parkes) will write to approximately 
1100 patients with a diagnosis of CD (male and female patients aged 18 years or above) who have 
had a MRE scan since 2015, asking for their consent to retrospectively review the MRE scans for 
evidence of axSpA.  CD subjects with a known diagnosis of SpA will be eligible and invited to enter 
the study. Subjects who consent to this will then have their MRE scans reviewed and those with 
lesions consistent with axSpA (regarded as cases), but who do not have a known diagnosis of SpA, 
will be referred for further clinical assessment in the NHS rheumatology SpA clinic for evidence of 
SpA (Dr Jadon’s NHS SpA clinic, but assessed by Dr Evans in a supernumerary capacity). At this stage 
they will also be invited to participate in the ProSpA-CD-Assess phase of the study. 
 
CD subjects with a known diagnosis of SpA who are already under review by rheumatology and who 
have lesions on MRE consistent with axSpA will be considered as cases and also invited to participate 
in the ProSpA-CD-Assess phase of the study. However, they will instead be asked to attend the 
rheumatology SpA research clinic to be assessed for axSpA as this will be considered to be outside of 
their routine NHS care (Dr Jadon’s SpA research clinic, but assessed by Dr Evans in a supernumerary 
capacity). 
 
CD subjects (including those with a known diagnosis of SpA) who had consented to have their MRE 
scans reviewed, but do not have evidence of axSpA on MRE will also be invited to participate in the 
ProSpA-CD-Assess phase of the study as control subjects and will be referred for further clinical 
assessment in the rheumatology SpA research clinic for evidence of axSpA (Dr Jadon’s SpA research 
clinic, but assessed by Dr Evans in a supernumerary capacity). Cases and controls will be matched for 
sex and age, with a cases : control ratio of 1:1.  
 
Subjects meeting the inclusion criteria and giving informed consent as per section 5.2.2 will then be 
recruited in to the ProSpA-CD-Assess phase of the study. Consented subjects will complete the 
following PROMs; BASDAI, BASFI, VASbp, ASDAS and HAQ-DI [37-40]. Each subject will be examined 
in the SpA clinic using the BASMI, 68 tender joint count, 66 swollen joint count, the SPARCC 
enthesitis index, and for skin or nail psoriasis. The following investigations will also be performed as 
per standard of care for the patients with axial skeleton abnormalities on their MRE (MRE+) and no 
known diagnosis of SpA, if clinically indicated and if not been performed in the preceding month; 
FBC, renal function, LFTs, CRP, ESR and faecal calprotectin. HLA-B27 testing will also be requested if 
not previously performed. These investigations will also be performed for the control subjects and 
the group of CD subjects with a known diagnosis of SpA who are MRE+ (if not performed in the 
preceding month and if HLA-B27 not previously performed) but will be funded by the research grant 
unless clinically indicated. 
A dedicated axial MRI scan of the spine and sacroiliac joints will be performed in all case and control 
subjects if indicated by the clinical assessment. Subjects in whom a dedicated axial MRI scan is not 
clinically indicated, or those who have had one performed previously for a known diagnosis of SpA,  
will be consented to undertake the MRI scan for research purposes and the MRI scan will be funded 
by the research grant.  

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ProSpA-CD, Protocol, v4, 08/01/2019 
All subjects (cases and controls) will be asked to further consent to provide research samples, 
including whole blood and stool, for storage and future analysis (serum for biomarker analysis, 
plasma for proteomic analysis, DNA for genotyping, and stool for microbiome analysis). Collection of 
these samples will be funded by the existing research grant, and analysis will be funded by research 
grants that are currently being applied for. 
The control group will receive no further follow up unless clinically indicated. CD subjects in this 
group with a known history of SpA will be followed up as planned by their primary rheumatology 
team. 
The cases (excluding CD subjects with known SpA who are MRE+ and already under rheumatology 
review) will then be followed up for their second review in the NHS rheumatology SpA clinic 
approximately 6 months later and will complete the following PROMs; BASDAI, BASFI, VASbp, ASDAS 
& HAQ-DI. Each patient will also be examined using the BASMI, 68 tender joint count, 66 swollen 
joint count, the SPARCC enthesitis index, and for skin or nail psoriasis. The following investigations 
will also be performed as per standard of care if not performed within the preceding month; FBC, 
renal function, LFTs, CRP and ESR. The patients will also be reviewed in the SpA clinic at an earlier 
date if indicated for treatment or clinical reasons. However, subjects who already have a diagnosis of 
SpA and are already under review by a rheumatology team will be followed up as planned by their 
primary rheumatology team. 
Please see Appendix 1 for study flow chart, Appendix 2 for schedule of procedures and Appendix 3 
for Gantt chart of the research timeline.  
4.2 
ProSpA-CD-Screen phase 
4.2.1 MRE review  
The MRE scans at CUH are typically performed using both an oral contrast agent and intravenous 
Gadolinium to diagnose and assess the extent of CD. The images also capture the lower thoracic 
spine/ thoracolumbar junction and lumbar spine in the coronal plane and sacroiliac joints in coronal 
and axial planes. It is the coronal and axial images of the sacroiliac joints that we will be using to 
assess for evidence of axSpA (sacroiliitis). There are a number of different sequences included for the 
MRE scans at Addenbrookes hospital including the SSFSE FS (single shot fast spin echo fat 
suppressed) and LAVA FLEX sequences which are fat suppressed (the complete list of MRE sequences 
used can be found in Appendix 4).  
For the subjects who consented to have their MRE imaging reviewed, two trained scorers (one 
musculoskeletal radiologist, Dr Elliott Rees; one rheumatologist, Dr Jobie Evans) will assess MRE 
imaging (sacroiliac joints) for evidence of axSpA using a specifically designed scoring system (see 
below). The MRE assessors will be blinded to the subjects co-morbidities (other than CD). Training 
sessions for this will be delivered by a consultant musculoskeletal radiologist (Dr McDonald). This 
scoring system was developed by an expert musculoskeletal radiologist (Dr McDonald) for this study 
to specifically identify features of sacroiliitis on both MRE and dedicated MRI spine images, and 
should permit reliable intergroup comparisons. It has not yet been used in clinical practice due to a 
lack of previous research on this topic. Scores will be compared and discrepancies decided by 
consensus. If the two assessors (ER and JE) are unable to reach a consensus for a particular subject, 
Dr McDonald (considered the ‘gold-standard’ scorer) will be asked to review and score the images. 
Dr McDonald will be one of the two expert consultant musculoskeletal radiologists who will be 
reviewing and scoring the subsequent dedicated axial MRI scans and therefore to prevent any 
scoring bias, the MRE images reviewed by Dr McDonald in the ProSpA-CD-Screen phase will be 
anonymised (patient identifiable data removed). The site of CD involvement in the gut will also be 
reviewed and documented, for further analysis.  
Training will also be provided to identify significant sacral fractures and significant infiltrative bone 
lesions. If an unexpected finding of this sort should arise, the imaging will be reviewed by the 

13 
ProSpA-CD, Protocol, v4, 08/01/2019 
consultant musculoskeletal radiologist (Dr McDonald) and appropriate onward referrals and 
communication with the patient will be made. 
Prior to the commencement of MRE screening, both scorers will score the same ten MREs to 
determine inter-rater agreement. Both scorers will then score the same ten MREs on two separate 
occasions a month apart, to determine intra-rater agreement.  
The scoring system for sacroiliac joints on MRE imaging will be divided into two sections as follows: 
i) 
Joint margins and contour (score range 0 – 2; 0=normal, 1=mildly abnormal, 
2=severely abnormal) 
ii) 
Juxta-articular bone marrow signal (score range 0 – 3; 0=normal, 1=mild, 
2=moderate, 3=severe) 
4.3  
ProSpA-CD-Assess phase 
4.3.1 Assessment of patients with lesions on MRE consistent with axSpA (cases) 
Patients with lesions on MRE consistent with axSpA (and no known diagnosis of SpA) will be 
informed by telephone and letter by the gastroenterology team and referred to Dr Jadon’s NHS 
rheumatology SpA clinic. They will also be sent separately an invitation letter, participant information 
sheet (PIS) and reply slip (study interest form with a stamped-addressed envelope for returns) for the 
ProSpA-CD-Assess phase of the study by the gastroenterology team. CD subjects with a known 
diagnosis of SpA who are already under review by rheumatology and who have lesions on MRE 
consistent with axSpA will also be considered as cases and will be sent an invitation letter, PIS and 
study interest form.  However, they will instead be invited to attend the rheumatology SpA research 
clinic to be assessed for axSpA (with the control group) as this will be considered to be outside of 
their routine NHS care.  
In the NHS SpA clinic, the patients will be assessed by a single rheumatologist (Dr Evans, in a 
supernumerary capacity with salary funded by the research grant) for clinical evidence of axSpA as 
per standard of care using the 2009 ASAS criteria for axSpA, modified New York criteria for AS and 
CASPAR criteria for PsA (see Appendices 5, 6 & 7). The assessment will include a clinical history, 
examination (including BASMI, 68 tender joint count, 66 swollen joint count, the SPARCC enthesitis 
index and for skin or nail psoriasis), PROMs (BASDAI, BASFI, VASbp, ASDAS and HAQ-DI), blood 
samples (FBC, renal function, LFTs, CRP and ESR unless performed in the preceding month, and HLA-
B27 unless previously performed) and stool samples (the monitoring of IBD luminal activity with 
faecal calprotectin is well established [41, 42]; stool samples will therefore also be collected to 
measure faecal calprotectin concentrations unless performed in the preceding month). During the 
consultation, the ProSpA-CD-Assess phase of the study will also be discussed further and patients will 
be provided with the opportunity to ask any questions they may have regarding the study. If they 
agree to participate in the study and meet the inclusion criteria, then written informed consent will 
be taken. The blood and stool tests will be performed as per standard of care if clinically indicated or 
for research and funded by the research grant if not clinically indicated. 
If considered to be clinically indicated as per the above assessments, a dedicated axial MRI scan of 
the spine and sacroiliac joints will be requested (NHS funded) as per standard of care. If considered 
not to be clinically indicated as per these assessments, consenting subjects will undertake a 
dedicated axial MRI scan of the spine and sacroiliac joints for research (research grant funded).  
As part of the ProSpA-CD-Assess phase of the study, all participants will be asked and consented to 
have blood (20mls) and stool samples taken for research. These will be stored and undergo analysis 
at a later date for biomarkers (serum, genotyping, proteomics, microbiome) of axial SpA occurrence 
and phenotype. Requests for research grants to fund these analyses are currently in progress.  
The NHS SpA clinic encounter will be summarised by letter to the patient and copies will also be sent 
to the patients GP and gastroenterology consultant . The cases (excluding CD subjects with known 

14 
ProSpA-CD, Protocol, v4, 08/01/2019 
SpA who are MRE+ and already under rheumatology review) will then be followed up for their 
second review in the NHS rheumatology SpA clinic approximately 6 months later and will complete 
the following PROMs; BASDAI, BASFI, VASbp, ASDAS & HAQ-DI. Each patient will also be examined 
using the BASMI, 68 tender joint count, 66 swollen joint count, the SPARCC enthesitis index, and for 
skin or nail psoriasis. The following investigations will also be performed as per standard of care if 
not performed within the preceding month; FBC, renal function, LFTs, CRP and ESR. The patients will 
also be reviewed in the SpA clinic at an earlier date if indicated for treatment or clinical reasons.  
4.3.2 
Assessment of subjects with no lesions on MRE consistent with axSpA (controls) 
Subjects (including those with a known diagnosis of SpA) who have consented to having their MRE 
scans reviewed, but who do not have lesions consistent with axSpA, will be informed in writing of 
this by the gastroenterology team. They will also be advised that they may be invited to enter the 
study as a control subject if they are randomly selected through matching (age and sex) to the 
enrolled ‘MRE+ cases’ (1:1 ratio). Matched potential control subjects will then be sent an invitation 
letter, PIS and reply slip (study interest form with a stamped-addressed envelope for returns) by the 
gastroenterology team to attend the rheumatology SpA research clinic to be assessed by Dr Evans for 
clinical evidence of axSpA. CD subjects with a known diagnosis of SpA who are already under review 
by rheumatology and who have lesions on MRE consistent with axSpA will also be invited to attend 
this clinic for review outside of their routine NHS care but will be considered as cases. Informed 
consent for study participation in the SpA research clinic will be performed at the start of the 
consultation. The same clinical assessments, blood and stool samples and dedicated axial MRI scan of 
the spine and sacroiliac joints will be performed in this control group and in the group of CD subjects 
with a known diagnosis of SpA who are MRE+ as in the other cases, but will be funded by the 
research grant unless clinically indicated.  
Control subjects in whom there is no evidence of axSpA (by ASAS, modified New York or CASPAR 
classification criteria) will be informed by letter, which will also be copied to the subjects GP and 
gastroenterology consultant. Control subjects who do have evidence of axSpA will be informed by 
letter (also copied to GP and gastroenterology consultant) and asked to return to Dr Jadon’s NHS 
rheumatology SpA clinic for ongoing care. CD subjects who already have a diagnosis of SpA (both in 
the control group and cases group) and are already under review by a rheumatology team will be 
informed by letter of the research clinic outcome and will be followed up as planned by their primary 
rheumatology team. We will also send a copy of the clinic letter to their GP, gastroenterology 
consultant and named rheumatology consultant to inform them of the clinic findings and to notify 
them of any outstanding tests/ management plans that may need to be considered at the next clinic 
review. 
4.3.3 
Axial MRI Scan 
Non-contrast MRI imaging of the whole spine and sacroiliac joints, using a dedicated protocol 
including T1 weighted and fluid sensitive sequences, will be performed in both the cases and 
controls. Images will be reviewed by two independent expert musculoskeletal radiologists (Dr 
McDonald and a colleague musculoskeletal radiologist) and any discrepancies will be decided by 
consensus agreement. Since MRI review by a second radiologist is not standard of care, it is funded 
by the research grant for the clinically indicated axial MRI scans. The MRI review by both of the 
radiologists for the axial MRI scans performed for research purposes is funded by the research grant.  
These will be assessed and scored using the spondyloarthritis research consortium of Canada 
(SPARCC) MRI index criteria which is a validated scoring system for the assessment of spinal and 
sacroiliac joint inflammation on MRI [43, 44]. To calculate the SPARCC MRI index criteria score for the 
spine, the six most abnormal discovertebral levels on the STIR sequence are used. At each of the 6 
levels, 3 consecutive slices are included and each slice is divided into four quadrants with each 
quadrant being scored as normal (score 0) or increased signal (score 1). In addition, each slice is 
scored for intensity and depth of inflammation to give a total possible score of 108 (see Appendix 8). 
To calculate the SPARCC MRI index criteria score for the sacroiliac joints, six coronal slices of the 

15 
ProSpA-CD, Protocol, v4, 08/01/2019 
sacroiliac joints on the STIR sequence are chosen and each slice is divided in to four quadrants. Each 
quadrant is then scored as normal (score 0) or increased signal (score 1). In addition, each slice is 
scored for intensity and depth of inflammation to give a total possible score of 72 (see Appendix 9). 
The SPARCC MRI index criteria has been validated and reported to be the most reliable MRI 
inflammation scoring system in a number of studies due to its sensitivity to changes and high inter-
reader reliability [45-47]. The dedicated MRI scans will also be scored using the specifically designed 
scoring system as follows: 
i) 
Joint margins and contour (score range 0 – 2; 0=normal, 1=mildly abnormal, 2= 
severely abnormal) 
ii) 
Juxta-articular bone marrow signal (0 – 3; 0=normal, 1=mild, 2=moderate, 3=severe) 
The SPARCC MRI index criteria score will then be used to determine the validity of our specifically 
designed scoring system for the dedicated axial MRI scans. The scores of the dedicated MRI scans will 
then be compared to the MRE scores for each patient to determine the validity of using MRE as a 
screening tool for axSpA in patients with CD. The sensitivity, specificity and area under the ROC curve 
of using MRE as a screening tool will also be determined.  
If an unexpected finding is identified, such as a fracture or potential malignancy, then the 
gastroenterology team will be informed and appropriate onward referrals and communication (in-
person or telephone, as deemed clinically appropriate) to the patient will be made.  
 
5.  
Study subject selection 
 
5.1 
Eligibility criteria 
 
5.1.1 
Inclusion criteria 
 
5.1.1.1 
Subjects who are willing and able to give informed consent for participation in the 
study. 
 
5.1.1.2 
Male and female subjects aged 18 years or above. 
 
5.1.1.3 
Diagnosed by the gastroenterology team with Crohn’s disease (CD). 
 
5.1.1.4 
MRE imaging since 2015 for their CD.  
 
 
5.1.2 
Exclusion criteria 
 
 
 
5.1.2.1 
Subjects unwilling or unable to give informed consent. 
 
5.2 
Recruitment, consent and randomisation processes 
 
 
5.2.1 
Recruitment  
 
5.2.1.1 Recruitment for the ProSpA-CD-Screen phase: 
The gastroenterology team will write to patients with CD who have had MRE imaging since 2015 
(estimated to be approximately 1100 patients) to ask them for consent to review their MRE imaging 
for evidence of axSpA. CD subjects with a known diagnosis of SpA will be eligible and invited to enter 
the study. Subjects who consent to this will then have their MRE imaging reviewed by a 
musculoskeletal radiology specialist registrar (Dr Elliott Rees) and a rheumatology specialist registrar 
(Dr Jobie Evans).   
 

16 
ProSpA-CD, Protocol, v4, 08/01/2019 
5.2.1.2 Recruitment for the ProSpA-CD-Assess phase: 
Patients with lesions consistent with axSpA on the MRE (and no known diagnosis of SpA) will be 
informed by telephone and letter by the gastroenterology team and then be referred to Dr Jadon’s 
NHS SpA clinic as per standard of care. They will also be invited to enter the ProSpA-CD-Assess phase 
of the study at that time and consent will be taken during the clinic encounter.  
 
CD subjects with a known diagnosis of SpA who are already under the care of a rheumatology team 
and have lesions on MRE consistent with axSpA will also be contacted by telephone and letter by the 
gastroenterology team. However, since they are already receiving standard NHS care for their SpA, 
they will be sent a separate invitation letter, PIS and reply slip (study interest form) by the 
gastroenterology team to attend the rheumatology SpA research clinic for assessment of axSpA by Dr 
Evans outside of their routine NHS care. Informed consent for study participation will be performed at 
the start of the consultation. 
 
Subjects (including those with a known diagnosis of SpA) who have consented to having their MRE 
scans reviewed, but who do not have lesions consistent with axSpA on MRE, will be informed in 
writing of this by the gastroenterology team. They will also be advised that they may be invited to 
enter this part of the study as a control subject if they are randomly selected through matching (age 
and sex) to the enrolled ‘MRE+ cases’ (1:1 ratio). Matched potential control subjects will then be sent 
an invitation letter, PIS and reply slip (study interest form) by the gastroenterology team to attend 
the rheumatology SpA research clinic to be assessed by Dr Evans for clinical evidence of axSpA. Any 
CD subjects with a history of SpA who have been selected as a potential control subject will be sent a 
separate invitation letter, PIS and reply slip (study interest form) by the gastroenterology team. 
Informed consent for study participation will be performed at the start of the consultation in the SpA 
research clinic.  
 
5.2.2 
Consent 
 
There will be two separate stages of informed consent. 
 
5.2.2.1 Consent for retrospective review of the MRE scans (ProSpA-CD-Screen phase) 
 
The gastroenterology team will write to all patients with CD and MRE scans since 2015 to ask for 
consent to review the images for evidence of axSpA. This correspondence will include a PIS and 
consent form with a stamped-addressed envelope for returns. The pack will also contain a BASDAI 
questionnaire with six simple questions relating to symptoms of axial inflammatory pain. These six 
questions, answered on a 1-10 VAS will pose low burden on the subject and be optional to complete, 
but will markedly help the research team gauge the impact of selection bias on the study given that 
there may be a preponderance of patients with axial pain willing to participate in the study.  
 
5.2.2.2 Consent to enter the study as a case or control subject (ProSpA-CD-Assess phase) 
 
Patients with lesions on MRE consistent with axSpA (and no known diagnosis of SpA) will be informed 
of this by the gastroenterology team (by telephone and letter) and be referred to Dr Jadon’s NHS SpA 
clinic for further clinical assessment. Once informed, they will also be invited by post to enter the 
research element of the study, with an invitation letter, accompanying PIS and reply slip (study 
interest form) with a stamped-addressed envelope to permit the patient to express if they do or do 
not wish to participate in the study.  
 
CD subjects with a known diagnosis of SpA who are already under the care of a rheumatology team 
and have lesions on MRE consistent with axSpA will also be contacted by telephone and letter by the 
gastroenterology team. The subjects will then be sent a separate invitation letter, PIS and reply slip 
(study interest form) with a stamped-addressed envelope to permit the subject to express if they do 
or do not wish to participate further. 
 

17 
ProSpA-CD, Protocol, v4, 08/01/2019 
Subjects (including those with a known diagnosis of SpA) without evidence of axSpA on MRE will be 
contacted by the gastroenterology team (by letter) to inform them of the results and will also be 
advised that they may be invited to enter the study as a control subject. Once the cases have been 
identified and enrolled, control subjects will then be randomly selected (age and sex-matched in a 
case : control ratio of 1:1) to enter the research element of the study. The gastroenterology team will 
then write to these subjects to invite them to enter the study, accompanied by a PIS and a reply slip 
(study interest form) with a stamped-addressed envelope to permit the subject to express if they do 
or do not wish to participate further. Any CD subjects with a history of SpA who have been selected as 
a potential control subject will be sent a separate invitation letter, PIS and reply slip (study interest 
form) by the gastroenterology team. 
 
During the clinic consultation for both cases and controls, the research study will be discussed further 
and the subject will be provided with the opportunity to ask any questions they may have regarding 
the study. If the subject subsequently agrees to take part in the study, then inclusion and exclusion 
criteria will be assessed and informed written consent will be taken. 
 
 
6.  
Study schedule 
 
6.1 
MRE Review 
 
Subjects who consent for the ProSpA-CD-Screen phase of the study will have their MRE 
images reviewed for evidence of axSpA 
 
Subjects who then consent for the ProSpA-CD-Assess phase of the study will immediately 
undergo the following assessments: 
 
6.2  
Clinical questionnaires 
 
BASDAI, BASFI, VASbp, ASDAS & HAQ-DI. 
 
6.3 
Clinical assessment and measurements 
 
BASMI, tender and swollen joints, SPARCC enthesitis index, presence of skin and nail 
psoriasis. 
 
6.4 
Blood sampling (total of 40ml) 
 
20ml for standard of care : FBC, LFTs, renal function, CRP and ESR (if not performed within 
the last one month). HLA-B27 if not previously performed.  
 
20ml if subjects consent to the research element of the study : for storage and later analysis 
(serum biomarkers, proteomics and genotyping). 
 
6.5 
Stool sample 
 
If subjects consent to the research element of the study, a stool collection kit for faecal 
calprotectin testing will be provided (if not performed within the last one month) and a 
further sample will be stored for future microbiome analysis. 
 
6.6 
Dedicated axial MRI Scan 
 
This will be requested during the first clinic consultation (cases and controls ; funded by the 
NHS or research grant as appropriate) 
 

18 
ProSpA-CD, Protocol, v4, 08/01/2019 
6.7 
Definition of the end of study 
 
This will be the date of the last visit of the last participant 
 
If a subject is unable to undertake these assessments immediately, a convenient future research 
clinic appointment will be made for them and associated travelling costs will be reimbursed. 
This study schedule will pose low burden and inconvenience to the subject. Blood sampling will take 
place at the time of clinical measurements, and are of low total volume (40ml). The subjects will be 
asked to return to have the dedicated axial MRI scan and to minimise inconvenience, they will be 
encouraged to return their stool samples when they attend for the scan. Control subjects will be 
reimbursed for travel and parking costs, and the case subjects will also be reimbursed for any extra 
travel or parking costs incurred through participating in the study.  
Clinical questionnaires are those that would be completed as per standard in usual clinical care 
(except for the control group). However, as we are asking questions in some of the PROMs about the 
subject’s experience of illness, this may cause a degree of upset. Therefore to minimise distress, the 
clinician (Dr Evans) will talk the subject through each questionnaire prior to completion at the initial 
clinic visit. In addition, our participation information sheets will stress that participation is voluntary 
and that the subject can withdraw from the study at any time without their care being affected. Our 
participation information sheets will also explain the processes taken to maintain anonymity and 
confidentiality. 
The correspondence (invitation letters and PIS) for CD subjects with and without known SpA will have 
different content to reflect this and to reduce any potential concern or anxiety. 
 
The MRI scan is a non-invasive procedure and the subjects will already have had the experience of 
having a MRI scan (MRE). However, some subjects may find it difficult to have the MRI scan if they 
suffer from claustrophobia. Therefore, the MRI scan procedure will be explained to the subject 
during the initial consultation and they will be provided with the opportunity to ask any questions. 
We will also emphasise that this is voluntary and that they have the right to decline this or any other 
part of the study. 
 
7.  
Data collection, source data and confidentiality 
 
7.1 
General 
 
All information collected during the course of the study will be kept strictly confidential.   
 
Each subject will be assigned a unique subject study identification code which will be linked to their 
hospital number on a secure password protected electronic Microsoft-Access database and stored 
on the Cambridge University Hospitals NHS Foundation Trust (CUH NHSFT) computer network.  
 
The clinic encounter for the cases in the NHS SpA clinic will be documented on to the CUH NHSFT 
electronic health record system (Epic) and a letter will be sent out to the patient, their GP and 
gastroenterology consultant to summarise this encounter. The clinic encounter for the controls and 
CD subjects with a known diagnosis of SpA in the SpA research clinic will also be documented on the 
Epic system and a letter will be generated from this clinic to the subject, GP, gastroenterology 
consultant and rheumatology consultant if appropriate. For the cases in the NHS SpA clinic, the 
PROMs will be labeled with the patient’s details (name, date of birth and hospital number) as this will 

19 
ProSpA-CD, Protocol, v4, 08/01/2019 
be part of their standard NHS care. PROMs for the control group and group of CD subjects with a 
known diagnosis of SpA in the SpA research clinic will be labeled with the subjects unique study 
identification code only as this will be outside of their routine NHS care. The blood tests (FBC, renal 
function, LFTs, CRP, ESR, HLA B27), stool sample for faecal calprotectin and dedicated axial MRI scan 
of the spine and sacroiliac joints for all subjects within the study will be labeled as per standard trust 
policy with subject details (name, date of birth, hospital number) and will be requested, reported 
and stored on the Epic system. Where these tests are performed for research purposes and not 
standard of care, we will receive written consent from the subject for this. The extra blood and stool 
samples taken for storage and future analysis for all subjects will be labeled with the unique subject 
study identification code only. When the subject data is transcribed on to the secure password 
protected electronic Microsoft-Access database (for all subjects in the study) it will be assigned to 
the appropriate unique subject study identification code which will be linked to the subject’s hospital 
number. All other identifiable data (such as name, date of birth and NHS ID number) will be 
removed. This will only be accessible to the investigator team. Michelle Ellerbeck is the ‘Data 
Protection Officer’ for CUH NHSFT. 
 
Cambridge University Hospitals NHSFT will comply with all aspects of the Data Protection Act 1998 
and operationally this will include: 
 
 
7.1.1  Consent from subject to record personal details including name, date of birth, address and 
telephone number, NHS identification number, hospital identification number, GP name and 
address. 
 
7.1.2 
Appropriate storage, restricted access and disposal arrangements for the subjects personal 
and clinical details. 
 
7.1.3 
Consent from subject for access to their medical records by responsible individuals from the 
research staff, the sponsor or from regulatory authorities, where it is relevant to study 
participation. 
 
7.1.4. Consent from subject for the data collected for the study to be used to evaluate safety and 
develop new research. 
 
7.2 
Archiving 
 
In line with the principles of Good Clinical Practice and UK Clinical trial Regulations guidelines, at the 
end of the study, data will be securely archived for a minimum of ten years.  Arrangements for 
confidential destruction will then be made. If a subject withdraws consent for their data to be used, 
it will be confidentially destroyed immediately.  
 
 
8.  
Statistical considerations 
 
8.1 
Power analysis 
 
This study will aim to include all CD cases with MRE imaging since 2015; the estimated sample size is 
therefore 1100 cases.  
To our knowledge, there are no studies comparing the sensitivity and / or specificity of MRE scans 
with gold standard dedicated MRI for the detection of sacroiliitis. However, there have been some 
studies comparing CT imaging with MRI and these found MRI to be up to 17% more sensitive for the 
detection of sacroiliitis than CT [48, 49].  
Although MRE is expected to be more sensitive at detecting evidence of sacroiliitis than CT, our 
power calculation is based on the conservative estimate that MRE will detect at ≥60% (sensitivity) of 

20 
ProSpA-CD, Protocol, v4, 08/01/2019 
the cases of sacroiliitis, when compared with the gold standard dedicated axial MRI scan. Therefore 
with 80% power and a two-tailed alpha of 0.05, it is estimated that ≥60 control subjects (MRE 
normal) will be required for the study. It estimated that a sample of >60 cases (with abnormal MRE 
scans) would be needed since the sample size required to assess specificity for a screening test is less 
than that of sensitivity.  Case and controls will be recruited in a ratio of 1:1. From the 1100 MRE 
scans already performed, it is expected that ≥90% will have a diagnosis of CD, i.e. 990 subjects. We 
estimate that ≥50% of postally invited participants will consent to participate in the study, giving   
approximately 445 MRE scans for review.  
The two previous studies assessing IBD patients for evidence of sacroiliitis using MRE imaging 
estimated the prevalence to be 16.7% and 15% [27, 28]. We therefore estimate to recruit ≥66 
subjects with positive MRE scans (cases) and ≥66 matched controls. This is a conservative estimate, 
greater than the minimum number needed to recruit. 
8.2 
Statistical analysis 
 
Statistical input has been sought from the University of Cambridge Statistics Clinic (PhD student 
Benajmin Stokell and his supervisor Professor Richard Samworth) and will be supported by Dr Jadon. 
Inter- and intra-rater reliability testing will be performed for the MRE and axial MRI assessments 
using intra-class correlation coefficients (ICC). The proportion of CD cases with evidence of axSpA on 
MRE imaging who fulfil diagnostic criteria for axSpA will be expressed as a percentage. Further 
descriptive analyses will also be performed on study participants. Due to the possible preponderance 
of patients with axial pain willing to participate in the study and therefore selection bias, we will not 
be able to calculate the true prevalence of axSpA in CD patients.  
As it is expected that the majority of data collected will be count data with an excess of zero-values, 
a zero-inflated Poisson (ZIP) regression model will be used to test for association between the 
presence of axSpA, MRE score, PROMs, clinical indices, site of CD and blood biomarkers. In addition, 
ZIP regression will be used to test for association between MRE scores and those of dedicated axial 
MRI scans. Zero-inflated binomial regression will be used as appropriate, where the mean 
approximates the variance. Two-tailed tests will be performed, and the alpha set at 0.05.  
8.3 
Missing data 
 
If a subject is uncertain how to complete an outcome measure questionnaire correctly, a research 
professional will be present to provide support and ensure correct and full completion.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ProSpA-CD, Protocol, v4, 08/01/2019 
9.  
Ethical considerations 
 
The study will be performed in accordance with the recommendations guiding ethical research 
involving human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, 
amended at the 52nd World Medical Association General Assembly, Edinburgh, Scotland, October 
2000. Informed written consent will be obtained from the patients prior to registration into the 
study.   
 
Any treatments prescribed for patients within the study who have a diagnosis of axSpA will be in  
accordance to existing local and clinical commissioning group (CCG) treatment pathways, and will not 
in any way favour the funder’s (MSD) product, namely golimumab (Simponi; an anti-tumour necrosis 
factor alpha product). 
 
The study will be submitted for approval by the local Research Ethics Committee (REC) via the 
Integrated Research Application System (IRAS). Ethics approval from the (institutional review board) 
research and development department of CUH NHSFT will also be sought.  
 
The right of a patient to refuse participation without giving reasons will be respected. The patient will 
remain free to withdraw at any time from the study without giving reasons and without prejudicing 
his/her further treatment.  
 
 
10.  
Statement of indemnity 
 
Cambridge University Hospitals NHSFT is able to provide insurance to cover for liabilities and 
prospective liabilities arising from negligent harm. Insurance cover is not provided for claims arising 
from non-negligent harm.  Clinical negligence indemnification will rest with the CUH NHSFT under 
standard NHS arrangements.   
 
 
11.  
Safety 
 
Venepuncture is the only potential risk to patients in this study. The healthcare professionals 
performing this procedure are trained in venepuncture and will also be able to deal with any 
potential complications. There are no other significant potential risks from the study procedures.   
 
 
12.  
Costings 
 
The study will be funded by MSD (Merck, Sharp and Dohme corporation) who have committed 
£147,273 for the study. This will fund Dr Evans’ salary for the 24 months of the study, research axial 
MRI scans, research blood tests and stool sampling, consultant radiologist time to review the 
dedicated axial MRI scans twice, statistical support and office ancillaries. 
 
 
 
 
 
 
 
 
 
 
 
 

22 
ProSpA-CD, Protocol, v4, 08/01/2019 
13.  
Appendices 
 
 
Appendix 1: Study Flow Chart 
 
 
 
Research Clinic Pathway               
 
 
 
NHS Clinic Pathway 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Crohn’s disease patients with 
MRE imaging in the last 3 years; 
consented for MRE imaging 
review 
MRE images reviewed for 
evidence of axSpA 
No evidence of axSpA on MRE, or CD patients with known 
SpA who have evidence of axSpA on MRE (CD SpA MRE+):  
Evidence of axSpA on MRE (and 
no known diagnosis of SpA): 
Subjects contacted by 
Gastroenterology team, 
informed of MRE result and 
referred to Dr Jadon’s NHS 
Rheumatology SpA clinic 
Consent and clinical 
assessment in research clinic  
Clinical assessment in NHS clinic 
Blood tests (FBC, U&E, LFT, 
CRP, ESR and HLA-B27), stool 
sample & dedicated axial MRI 
scan funded by research grant 
(unless clinically indicated) 
Blood tests (FBC, U&E, LFT, CRP, 
ESR and HLA-B27), stool sample     
& dedicated axial MRI as per NHS 
standard of care; 
or, funded by research grant if 
not clinically indicated 
Axial MRI assessment by 2 
independent radiologists  
(2nd reviewer funded by research 
grant) 
 
Data analysis, thesis write-up and publication of results 
Study Objectives: 
1. 
the validity, sensitivity, specificity and area under the receiver operating characteristic (ROC) curve (AUC) of MRE as a screening 
tool for axSpA in CD, using dedicated axial MRI scans with clinical assessment as the gold standard. 
2. 
the proportion of patients with evidence of axSpA on MRE imaging who fulfill the 2009 Assessment of Spondyloarthritis 
International Society (ASAS) criteria for axSpA, modified New York criteria for ankylosing spondylitis (AS) and the classification 
criteria for psoriatic arthritis (CASPAR). 
3. 
the proportion of these patients proceeding to non-pharmacological and pharmacological treatment of their axSpA, as a surrogate 
measure of change in clinical care as a result of MRE screening. 
4. 
the extra-articular features associated with axSpA in CD, in order to better characterise the clinical phenotype of enteropathic 
spondyloarthritis (eSpA).  
5. 
whether the site of CD (colon, ileum, etc.) predicts the occurrence of axSpA. 
Axial MRI assessment by 2 
independent radiologists 
(funded by research grant) 
Subjects informed of MRE 
result. Age- and sex-matched 
controls invited to research 
clinic and willing to participate 
(aim to recruit same number as 
cases and assuming that 50% 
decline to participate). CD SpA 
MRE + patients invited as cases 
to research clinic 
Research tests for 
storage and future 
use: Blood sample for 
genotyping, serum 
biomarker and 
proteomic analysis. 
Stool sample for 
microbiome analysis 
Subjects informed of 
MRE result.  
 
Age- and sex-matched 
controls invited to 
research clinic, but not 
willing to participate.  
= No further 
participation 

23 
ProSpA-CD, Protocol, v4, 08/01/2019 
Appendix 2: Schedule of Procedures 
 
Procedure 
Timeline / visits 
Months 
0-6 
Months 
7-12 
(screening/ 
baseline) 
Months 
13-18 
(follow-up) 
Months 
19-24 
Patient consent for MRE 
image review and recruitment 
● 
 
 
 
MRE training and scoring  
● 
 
 
 
Systematic literature review 
● 
 
 
 
Demographics 
 
● 
● 
 
Medical history 
 
● 
● 
 
Clinical examination 
 
● 
● 
 
PROMs 
 
● 
● 
 
Blood tests as per standard of 
care or research 
 
● 
● 
 
‘Research’ tests (blood and 
stool samples) 
 
● 
 
 
Faecal calprotectin as per 
standard of care or research 
 
● 
● 
 
Dedicated axial MRI as per 
standard of care or research, 
with two expert scorers  
 
● 
 
 
Statistical analysis 
 
 
● 
● 
Write-up of MD thesis and 
associated papers 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ProSpA-CD, Protocol, v4, 08/01/2019 
Appendix 3: Gantt Chart for the Research Timeline 
 
Task 
Mar-Nov 
2018 
Dec 2018- 
Feb  2019 
Mar 2019- 
Feb 2020 
Mar 2020-
Aug 2020 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
 
 
Task: 
 
1. 
Study setup: Protocol and Ethics approval 
2. 
Systematic literature review (on prevalence of axial spondyloarthritis in patients with 
Inflammatory Bowel Disease based upon cross-sectional imaging) 
3. 
Magnetic Resonance Enterography (MRE) score training and reliability exercise 
4. 
Patient consent for MRE imaging review and recruitiment (including control group) 
5. 
Scoring of MRE scans 
6. 
Clinical review of patients in spondyloarthritis clinic including completion of patient reported 
outcome measures and investigations 
7. 
Statistical analyses 
8. 
Thesis and publication of results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ProSpA-CD, Protocol, v4, 08/01/2019 
Appendix 4: List of sequences for the MRE protocol at Cambridge University Hospitals NHSFT 
 
MRE Sequence 
Fat Suppressed 
2D CORONAL FIESTA 
 
No 
2D AXIAL FIESTA 
 
No 
2D CORONAL SLAB MRCP 
 
No 
CORONAL SSFSE 
 
No  
CORONAL SSFSE FS 
 
Yes 
CORONAL DWI B=600 
 
No 
CORONAL FIESTA MULTI 
Dynamic 
 
No 
CORONAL 3D LAVA FLEX GAD  
 
Yes 
AXIAL 3D LAVA FLEX GAD  
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 5: Assessment of spondyloarthritis international society (ASAS) criteria for classification of axial 
spondyloarthritis (to be applied in patients with chronic back pain and age at onset of back pain < 45 years) 
[50]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     or 
    
#SpA Features 
 
Inflammatory back pain 
 
Arthritis  
 
Enthesitis (heel) 
 
Uveitis 
 
Dactylitis 
 
Psoriasis 
 
Crohn’s/ Colitis 
 
Good response to NSAIDs 
 
Family history for SpA 
 
HLA-B27 
 
Elevated CRP 
*Sacroiliitis on imaging 
 
Active (acute) inflammation on 
MRI highly suggestive of 
sacroiliitis associated with SpA 
 
Definite radiographic sacroiliitis 
according to modified New York 
criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sacroiliitis on imaging* plus ≥ 
1 SpA feature  
HLA B27 plus ≥2 other SpA 
features# 
ASAS classification criteria for axial spondyloarthritis (SpA) in patients with ≥ 3 
months back pain and age at onset < 45 years 

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Appendix 6: Modified New York Criteria for the diagnosis of ankylosing spondylitis [15]. 
 
Requires radiological criterion & ≥1 clinical criterion 
Radiological criterion  
Sacroiliitis grade ≥2 bilaterally or grade ≥3 unilaterally  
Clinical criterion  
1. Inflammatory low back pain & stiffness ≥30m that improves with exercise and is not relieved by 
rest  
2. Reduced motion of the lumbar-spine in both sagittal & frontal planes 
3. Limited chest expansion 
 
(having excluded spinal fracture, intervertebral disc disease & fibromyalgia.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 7: Classification Criteria for Psoriatic Arthritis (CASPAR) [23].  
 
To meet the CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria, a patient must have 
inflammatory articular disease (joint, spine, or entheseal) plus ≥3 points from the following 5 
categories: 
 
1. Evidence of current psoriasis, a personal history of psoriasis, or a family history of psoriasis. 
 
Current psoriasis is defined as psoriatic skin or scalp disease present today as judged by a 
rheumatologist or dermatologist. 
 
† A personal history of psoriasis is defined as a history of psoriasis that may be obtained from a 
patient, family physician, dermatologist, rheumatologist, or other qualified health care provider. 
 
A family history of psoriasis is defined as a history of psoriasis in a first- or second-degree relative 
according to patient report. 
 
2. Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis observed on 
current physical examination. 
 
3. A negative test result for the presence of rheumatoid factor by any method except latex but 
preferably by enzyme-linked immunosorbent assay or nephelometry, according to the local 
laboratory reference range. 
 
4. Either current dactylitis, defined as swelling of an entire digit, or a history of dactylitis recorded by 
a rheumatologist. 
 
5. Radiographic evidence of juxtaarticular new bone formation, appearing as ill-defined ossification 
near joint margins (but excluding osteophyte formation) on plain radiographs of the hand or foot. 
 
(The CASPAR criteria have specificity of 98.7% and sensitivity of 91.4%) 
 
(† Current psoriasis is assigned a score of 2; all other features are assigned a score of 1.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 8: The spondyloarthritis research consortium of Canada (SPARCC): Magnetic Resonance Imaging 
index for scoring inflammation in the spine[43]. 
 
 
SCORING METHODOLOGY  
 
1. All scores are dichotomous – present or absent.  
 
2. After scanning the entire spine, 6 discovertebral levels are selected for scoring. These levels are 
chosen as representing the 6 most abnormal levels on the STIR sequence. Levels scored at a second 
time point are the same as those on the first.  
 
3. After selecting levels, three consecutive sagittal slices are chosen for scoring at each level 
representing the most abnormal slices for that level.  
 
4. Only abnormalities on the STIR sequence are scored. T1 SE images are included for anatomical 
reference.  
 
5. Bone marrow signal in the centre of each vertebra constitutes the reference normal signal. If the 
entire vertebra is abnormal, closest normal level is used for reference. Do not score disc lesions.  
 
6. Each discovertebral level is divided into four quadrants: 1 upper anterior endplate, 2 upper 
posterior endplate, 3 lower anterior endplate, 4 lower posterior endplate. The presence of increased 
signal in each quadrant is recorded for each of the 3 sagittal slices. Maximum score is 12 per 
discovertebral level. Maximum score for 6 levels = 72  
 
7. A score for “intense” may be assigned to each level on each slice. High signal from cerebrospinal 
fluid acts as a reference for assigning an “intense” reading score to a bone lesion. A score of 1 is 
assigned if “intense” signal is seen in any quadrant on a single slice. Therefore maximum score per 
slice is 1, per level is 3 and for 6 levels = 18.  
 
8. A score for “deep” may be assigned to each level on each slice. A lesion is graded as “deep” if 
there is homogeneous and unequivocal increase in signal extending over a depth of at least 1 cm 
from the surface of the endplate. A score of 1 is assigned if “deep” signal is seen in any quadrant on a 
single slice. Therefore maximum score per slice is 1, per level is 3 and for 6 levels = 18.  
 
9. Pre- and post-treatment MR images are scored together with observer blinded to time sequence.  
 
 
Total maximum score is 108:  
Presence of “bone marrow oedema” = 72  
Presence of “intense oedema” = 18  
Presence of “deep oedema” = 18 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 9: The spondyloarthritis research consortium of Canada (SPARCC): Magnetic Resonance Imaging 
index for scoring inflammation in the sacroiliac joints[44]. 
 
 
SCORING METHODOLOGY 
 
1. All scores are dichotomous – present or absent, 1 or 0. 
 
2. Only 6 coronal slices are assessed. Slices 4-9 are usually selected as those representing the 
largest proportion of the synovial compartment of the SI joints. Images scored at a second time 
point are selected to correspond as closely as possible to the first time point – normally 4-9, 3-8 
or 5-10. 
 
3. Only abnormalities on the STIR sequence are scored. T1 SE images are included for anatomical 
reference. 
 
4. Score all lesions within the iliac bone. Within the sacrum, score lesions medially as far as the 
lateral border of the sacral foramina. 
 
5. Sacral inter-foraminal bone marrow signal is used as the reference for normal to determine a 
threshold for increased signal in periarticular bone. 
 
6. Each SI joint is divided into four quadrants: 1 upper iliac, 2 lower iliac, 3 upper sacrum, 4 lower 
sacrum. The presence of increased signal in each quadrant is recorded. Maximum score for two 
SI joints in each coronal slice is 8. Maximum score for 6 coronal slices = 48. 
 
7. A score for “intense” may be assigned to each SI joint on each slice. High signal from slow 
flowing venous blood within presacral veins acts as a reference for assigning an “intense” reading 
score to a bone lesion. A score of 1 is assigned if “intense” signal is seen in any quadrant of an SI 
joint on a single slice. Maximum score per slice is therefore 2, and for 6 slices = 12. 
 
8. A score for “deep” may be assigned to each SI joint on each slice. A lesion is graded as “deep” if 
there is homogeneous and unequivocal increase in signal extending over a depth of at least 1 cm 
from the articular surface. A score of 1 is assigned if “deep” signal is seen in any quadrant of an 
SI joint on a single slice. Maximum score per slice is therefore 2, and for 6 slices = 12. 
 
9. Pre- and post-treatment MR images are scored together with observer blinded to time sequence. 
 
 
Total maximum score is 72: 
Presence of “bone marrow edema” = 48 
Presence of “intense edema” = 12 
Presence of “deep edema” = 12 
 
 
 
 
 
 
 
 
 
 
 
 

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