CXCR4-PET/CT for the Detection of Inflammatory Activity in Systemic Sclerosis
Phase: NA
Conditions: Systemic Sclerosis (SSc)
Sponsor: Wuerzburg University Hospital

 
 
 
 
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CXCR4-PET/CT in SSc study protocol V4 vom 09.Feb.2022 
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CXCR4 PET/CT for detecting inflammatory activity in 
systemic sclerosis 
 
 
 
 
 
 
 
 
 
Protocol Version 
: 
 
Version 4 
Date:  
 
 
09.02.2022 
 
 

 
 
 
 
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Oberdürrbacher Str. 6-8, 97078 Würzburg 
 
 
 
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Content 
1. 
General information ........................................................................................................... 3 
1.1. 
Institutions involved and responsible persons ............................................................. 3 
2. 
Synopse .............................................................................................................................. 4 
3. 
Background ........................................................................................................................ 5 
4. 
Aims of the study ............................................................................................................... 6 
5. 
Study design and endpoints ................................................................................................ 6 
5.1. 
Design .......................................................................................................................... 6 
5.2. 
Endpoints ..................................................................................................................... 6 
6. 
Course of the study ............................................................................................................. 6 
6.1. 
Inclusion criteria .......................................................................................................... 6 
6.2. 
Exclusion criteria ......................................................................................................... 7 
6.3. 
Recruitment and study procedure ................................................................................ 7 
6.4. 
PET/CT scanning ......................................................................................................... 8 
6.5. 
Blood sampling ............................................................................................................ 9 
7. 
Adverse events and safety .................................................................................................. 9 
7.1. 
Adverse events ............................................................................................................. 9 
7.2. 
Safety ........................................................................................................................... 9 
8. 
Evaluation of data ............................................................................................................... 9 
8.1. 
Case number estimate .................................................................................................. 9 
8.2. 
Biometric analyses and data evaluation ....................................................................... 9 
9. 
Data protection, data storage ............................................................................................ 10 
10. 
Consent ......................................................................................................................... 11 
11. 
Ethics ............................................................................................................................ 11 
12. 
Publication of data ........................................................................................................ 11 
13. 
Literatur ........................................................................................................................ 11 
14. 
Abbreviations ............................................................................................................... 12 
15. 
Unterschriften ............................................................................................................... 13 
16. 
Appendix ...................................................................................................................... 15 
 
 
 

 
 
 
 
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1. General information 
1.1. 
Institutions involved and responsible persons 
 
Scientific Directors 
Dr. med. M. Gernert 
Medizinische Klinik und Poliklinik II 
Rheumatologie/Klinische Immunologie 
 
PD Dr. med. M. Schmalzing 
Medizinische Klinik und Poliklinik II.  
Rheumatologie/Klinische Immunologie 
 
Dr. med. S. Serfling 
Klinik und Poliklinik für Nuklearmedizin 
 
PD Dr. med. R. Werner 
Klinik und Poliklinik für Nuklearmedizin 
 
Participating 
clinics/institutions 
Medizinische Klinik und Poliklinik II 
Rheumatologie/Klinische Immunologie 
Direktor der Klinik: Prof. Dr. H. Einsele 
Schwerpunktleiter: Prof. Dr. H.-P. Tony 
Klinik und Poliklinik für Nuklearmedizin 
Direktor der Klinik: Prof. Dr. med. A. Buck 
Institut für diagnostische und interventionelle Radiologie 
Direktor des Instituts: Prof. Dr. med. T. A. Bley 
 

 
 
 
 
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2. Synopse 
 
TITLE 
CXCR4 PET/CT for detecting inflammatory activity in 
systemic sclerosis 
DATE VERSION 
09.FEB. 2022 Version 4 
AIMS 
 
As pilot study, visualization of inflammatory activity in 
systemic sclerosis using CXCR4-PET/CT. 
RATIONALE FOR THE STUDY Systemic sclerosis (SSc) is a heterogeneous disease 
characterized by inflammatory, vasculopathic, and fibrotic 
changes. Initially, inflammatory changes usually occur, 
which progress to fibrosis. Various organ systems such as 
the lungs, skin, heart, and gastrointestinal tract are affected. 
Early detection of inflammatory activity is therefore important 
in order to prevent consequential damage, in particular 
irreversible fibrosis. Since the inflammatory foci can spread 
throughout the entire body, there is a need to be able to 
detect inflammatory activity over a large area. The 68Ga-
Pentixafor-based imaging of the CXCR4 chemokine 
receptor, which is expressed on immune system cells such 
as lymphocytes and macrophages, offers a useful approach 
here, as it allows specific inflammatory cells to be visualized 
that migrate to inflammatory lesions via the corresponding 
ligand (CXCL12) and are involved in the pathogenesis of 
SSc. To date, only chest CT has been used to diagnose and 
monitor the progression of pulmonary fibrosis in SSc. This 
non-functional 
imaging 
technique makes 
it 
virtually 
impossible to assess inflammatory activity. 
NUMBER OF PARTICIPANTS 
12 patients (pilotstudy)  
STUDY POPULATION 
Patients with SSc, with a disease duration of less than 5 
years and with interstitial lung disease (ILD) 
STUDY DESIGN 
Explorative, prospective pilotstudy, not blinded, not 
randomized 
PRIMARY ENDPOINT 
Measurement of the maximum measurable 68Ga-pentixafor 
tracer activity in CXCR4-PET/CT 
DURATION 
Ca. 1 year 
NUMBER OF CENTERS 
Monocentric at the University Hospital Würzburg 
 
 
 

 
 
 
 
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3. Background 
Interstitial lung disease (ILD) is the most common cause of death in patients with 
systemic sclerosis (SSc). With regard to the pathogenesis of ILD, but also of other 
manifestations of SSc, it is postulated that leukocytes initially migrate into the tissue 
and cause an inflammatory reaction, which subsequently leads to fibrosis. Active 
inflammation can be treated much more effectively with medication than fibrosis. 
The distinction between fibrosis that has already occurred, i.e., is usually irreversible, 
and the active stage with inflammation is therefore of great therapeutic importance. 
Stromal cell-derived factor 1 (SDF-1 or synonymously CXCL12) and its receptor C-X-
C motif chemokine receptor 4 (CXCR4) are involved in angiogenesis and the mediation 
of leukocyte migration, which is an important pathomechanism in SSc. Consistent with 
this, high SDF-1 and CXCR4 expression is found in the skin of SSc patients, especially 
in the early stages of the disease, which decreases with increasing disease duration 
(Cipriani et al. 2006). 
SSc patients may have antibodies against CXCR4. Higher antibody titers are 
associated with more severe lung involvement and poorer lung function. CXCR4-
positive mononuclear cells from peripheral blood are found to be reduced in SSc 
(Weigold et al. 2018).  
The consideration of the CXCR4/CXCL12 axis in SSc therefore appears promising. 
The Clinic and Polyclinic for Nuclear Medicine at Würzburg University Hospital has a 
manufacturing license (issued by the Regional Council of Upper Franconia) for the 
production of 68Ga-Pentixafor for imaging the chemokine receptor CXCR4. CXCR4 is 
expressed by many cells of the hematopoietic system, such as stem cells, neutrophil 
granulocytes, monocytes, T lymphocytes, B lymphocytes, pre-B cells, dendritic cells, 
and macrophages. It is also detectable on most malignant cells. 
During inflammatory processes, CXCL12, the ligand of CXCR4, is upregulated in the 
affected tissue. The chemotactic effect of this ligand leads to the migration of CXCR4-
positive cells into the inflamed area, which can be visualized in PET using the CXCR4-
specific tracer 68Ga-Pentixafor. A significant advantage over the previous standard 
tracer F-18 deoxyglucose is its independence from glucose metabolism. 
Based on experience gained in the use of CXCR4-PET/CT in malignant diseases in 
studies conducted at the University Hospital of Würzburg, it can be assumed that this 
new tracer should enable sensitive visualization of inflammatory processes in SSc and 
thus functional imaging. This assumption is supported by the fact that CXCR4 can be 
visualized using PET/CT in idiopathic pulmonary fibrosis (IPF) – a clinical picture that 
is very similar to ILD in SSc in terms of clinical presentation, prognosis, and treatment 
(Derlin et al. 2021). 
To date, only non-functional cross-sectional imaging using chest CT, which is routinely 
performed every 1-2 years, has been established for the diagnosis and monitoring of 
pulmonary fibrosis in SSc. 

 
 
 
 
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4. Aims of the study 
Testing the hypothesis that tracer activity in 68Ga-pentixafor PET/CT correlates with 
disease activity in the lungs (heart, and skin) and that activity is associated with disease 
progression, i.e., worsening fibrosis in the corresponding organ. 
 
Another objective of the study is to characterize CXCR4 expression in monocytes, 
granulocytes, and lymphocytes in peripheral blood using flow cytometry and, if 
necessary, cell culture analysis, as well as to measure CXCL12 and CXCR4 antibodies 
in peripheral blood. The leukocyte populations mentioned above are particularly 
important for the pathogenesis of inflammatory changes in SSc. A correlation with 
68Ga-pentixafor uptake will be investigated. 
A further objective is to correlate 68Ga-pentixafor uptake with routinely available 
clinical, imaging, and laboratory parameters. 
The aim is to use the data collected to perform a well-founded case number calculation 
for a subsequent prospective study. 
5. Study design and endpoints 
5.1. 
Design 
The project is designed as a monocentric, exploratory, and prospective pilot study that 
is neither blinded nor randomized. The pilot study will take approximately one year to 
complete. For individual participating patients, participation in the study ends with the 
planned CXCR4 PET/CT examination. The parameters routinely collected after 6 and 
12 months will be included in the evaluation. 
5.2. 
Endpoints 
The primary endpoint of the pilot series is to determine the maximum measurable 
68Ga-Pentixafor uptake in CXCR4-PET/CT in the area of fibrotic pulmonary changes. 
 
Secondary endpoints:  
•    Determination of the maximum measurable 68Ga-Pentixafor uptake in CXCR4-
PET/CT in the heart 
•    Correlation of the measured tracer activity with clinical, laboratory, and imaging 
findings. 
 
The secondary endpoints serve to classify the measured tracer activities should 
significant fluctuations occur within the group. 
6. Course of the study 
6.1. 
Inclusion criteria 
• Confirmed diagnosis of SSc based on the 2013 ACR/EULAR criteria 
• Disease duration less than 5 years (onset of the first non-Raynaud's symptom within 
the last 5 years) 

 
 
 
 
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•    Evidence of ILD in computed tomography 
•    Patient's ability to understand the information provided 
•    Patient of legal age 
•    Exclusion of contraindications for performing a PET/CT examination (see below) 
 
Patients are informed in detail, both in writing and verbally, about the purpose of the 
examination and the risks of participating in the pilot study. The information is provided 
with sufficient time for consideration before the planned PET/CT scan. The Declaration 
of Helsinki and the guidelines of Good Clinical Practice are observed in all respects. 
Consent to participate in the pilot study and any questions/special circumstances are 
documented in writing by the patient's signature on the consent form, which must also 
be signed by the physician providing the information. 
6.2. 
Exclusion criteria 
•    Following autologous stem cell transplantation 
•    Presence of pulmonary hypertension 
•    Contraindications for performing a PET/CT scan 
•    Pregnancy 
•    Breastfeeding 
•    Allergies to 68Ga-Pentixafor 
•    Patient's inability to understand and give informed consent 
 
6.3. 
Recruitment and study procedure 
Timeline of the pilot study: 
a.    Screening of patients during their appointment at the rheumatology outpatient 
clinic 
b.    Review of inclusion and exclusion criteria 
c. 
Inclusion in the pilot study 
d.    Determination of baseline parameters: 
i.    mRSS 
ii.    Troponin/NT-pro-BNP 
iii.    Leukocyte differentiation (flow cytometry/cell culture), CXCL12 determination, and 
CXCR4 antibody determination 
iv.    Echocardiography 
v.    Lung function with 6-minute walk test 
vi.    Collection of indices for probability of progression (analogous to the INBUILD 
study, Flaherty et al. 2019), extent of lung involvement (according to Goh et al. 2008) 
and activity index according to EUSTAR (Valentini et al. 2017). 
vii.    ANA/ENA, fibrillarin, RNA polymerase III, myositis line blot 
e.    Performance of a CXCR4 PET/CT scan 
f.    Routine clinical check-ups are performed after 6 and 12 months, including points 
i.-vi. Follow-up checks of ILD using chest CT are performed after 12 months, in 
accordance with routine clinical practice. 

 
 
 
 
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6.4. 
PET/CT scanning 
The PET/CT examination is performed in accordance with the current guidelines of the 
German Society of Nuclear Medicine and the European Association of Nuclear 
Medicine. Patients are informed about the planned examination by the responsible 
study physician and give their written consent to the examination. The explanatory 
discussion takes place with sufficient time for consideration before the start of the 
examination. 
 
Patient preparation 
Patients do not need to fast before imaging with the tracer 68Ga-Pentixafor. A venous 
cannula is inserted to administer the tracer. Before the start of image acquisition, 
patients should empty their bladder completely so that they do not become restless 
during the examination due to a possible urge to urinate. 
After the examination, patients should drink plenty of fluids and empty their bladder 
frequently to support the renal excretion of 68Ga-Pentixafor and thus minimize 
radiation exposure. 
 
Image acquisition 
The clinical examinations are performed using a PET/CT hybrid scanner (Siemens 
mCT, Knoxville, TN). The dose coefficient for 68Ga-Pentixafor is 1.56·10-2 mSv/MBq. 
The radiation exposure for a PET examination with an application of 100-130 MBq is 
therefore 2.3 mSv. In comparison, the radiation dose for an adult human from natural 
and civilizational radiation exposure is approximately 2.1 mSv per year; This means 
that the examination corresponds approximately to the dose of natural radiation 
received by an adult in Germany (Federal Office for Radiation Protection, accessed on 
February 9, 2022).  
Image acquisition for 68Ga pentixafor PET takes place 45 minutes after injection. The 
measurement range extends from the neck to the pelvis. In 3D mode, measurements 
are taken for 2 minutes per bed position, and image reconstruction is performed using 
an OSEM algorithm (attenuation-weighted ordered subsets expectation maximization 
algorithm; 4 iterations, 8 subsets). 
 
Low-dose CT protocol  
After PET has been performed, the CT series is acquired immediately afterwards using 
a Siemens mCT Biograph 64. CT acquisition for PET involves low-dose CT (30 mAseff, 
120 kV, 0.5 s/rotation, 5 mm layer thickness, pitch = 0.8). An effective dose of 1.7 mSv 
is to be expected for a low-dose CT of the thorax (scan length approx. 30 cm). The 
total additional radiation exposure of the PET/CT for the patient is 4 mSv (calculated 
with CT-EXPO v2.1). 
 
Image evaluation 
All CT and PET examinations are initially evaluated visually to determine the intensity 
and extent of the inflammatory processes. For semi-quantitative assessment of 
regional inflammatory activity, regions of interest (ROI) are placed in areas of increased 
[68Ga]-pentixafor uptake using TrueD software (Siemens Medical Solutions, Knoxville, 
TN). The SUV(mean/max/peak) is calculated within the ROI according to the formula: 

 
 
 
 
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SUV = specific activity concentration (Bq/g) x body weight (in g) / injected activity (Bq). 
In addition to the SUV, other standard quantification parameters, such as the CXCR4-
positive volume or mathematically extracted items (e.g., radiomics parameters, 
Interview Fusion, Mediso Medical Imaging, Hungary), are determined. In [68Ga]-
pentixafor PET/CT, the SUVs are correlated with tracer uptake in the background (e.g., 
in the liver) and a ratio is formed. 
 
 
6.5. 
Blood sampling 
A venous cannula is inserted for the application of the tracer (see section 6.4). This 
cannula is used to collect 20 ml of EDTA blood and 5 ml of serum to determine the 
leukocyte profile, CXCL12, and CXCR4 antibodies (see section 4). 
7. Adverse events and safety 
7.1. 
Adverse events 
Adverse events are recorded in the electronic case report form (eCRF) created for 
each patient (see Chapter 9) and, if clinically relevant, communicated to the patient 
and appropriate measures initiated. If desired, the patient's family doctor can also be 
informed. Any necessary follow-up checks or further measures are primarily carried 
out by the attending physician in the rheumatology outpatient clinic or are initiated by 
them. 
 
7.2. 
Safety 
A request was submitted to HDI-Gerling to register patient insurance as soon as a final 
positive vote from the ethics committee is available. 
8. Evaluation of data 
8.1. 
Case number estimate 
The case number estimate was carried out in collaboration with Dr. Mügge and resulted 
in a total number of 12 participants. The complete case number estimate is attached 
to the study protocol. 
8.2. 
Biometric analyses and data evaluation 
Due to the number of cases, the statistical evaluation mainly comprises exploratory 
analysis methods. The primary question (maximum tracer uptake in the ILD area 
versus normal lung tissue) is evaluated using Kendall's tau correlation coefficient. 
If possible, subgroups could be examined in relation to limited vs. extensive ILD (Goh 
et al. 2008) with regard to stratification analogous to the INBUILD study (Flaherty et al. 
2019) and with regard to the EUSTAR activity index (Valentini et al. 2017). 

 
 
 
 
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CXCR4-PET/CT in SSc study protocol V4 vom 09.Feb.2022 
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9. Data protection, data storage 
Personalized data will be collected as part of the study. External cooperation partners, 
such as the statistician conducting the analysis, will only receive personal data in 
pseudonymized form. The data will be anonymized for the purpose of scientific 
publication in a peer-reviewed journal. 
The data will be stored in locked rooms at the rheumatology outpatient clinic (A3, -1, 
ZIM) and on the UKW servers. At the end of the evaluation, but no later than after 10 
years, the data collected as part of the study will be anonymized and personal data will 
be deleted. Any remaining sample material will be destroyed. 
Until the data is anonymized, patient-related data records can be deleted and any 
samples that may be available can be destroyed if the patient revokes their consent.  
 
All data is subject to the data protection regulations applicable throughout the clinic. 
Test subject data will not be passed on to third parties. The names of the test subjects 
and all other confidential information are subject to confidentiality and the provisions of 
the Federal Data Protection Act (BDSG). The pilot study is for research purposes only 
and its data will not be used (even in the future) for a consultation evaluation procedure. 
 
All patient-related data is recorded in pseudonymized form, and an Excel-based eCRF 
is created for each patient. Each patient is uniquely identified by a patient number 
assigned during registration. Dr. M. Gernert maintains a confidential patient list in which 
the pseudonyms are linked to the full patient names. The evaluation of the collected 
image data is stored in SAP as a findings document. The data collected for the 
evaluation of the pilot series is also stored as a pseudonymized Excel file, which 
contains only the data and the study code of the respective patient. 
 
The blood samples of the participating patients are generally used directly for analysis 
and then destroyed. In the event that a new analysis is necessary, which only occurs 
during the course of the study, part of the blood is frozen and stored in pseudonymized 
form in our in-house immunological laboratory in the rheumatology department. After 
completion of the study, but no later than ten years, the blood samples will be 
destroyed. Only physicians and medical-technical assistants involved in the study have 
access to the blood samples. 
 
The data protection provisions in accordance with the EU General Data Protection 
Regulation (GDPR) are complied with. The legal basis for data processing is the 
consent of the study participants (Art. 6 (1a) and Art. 9 (2a) of the GDPR). Participants 
may request information about the stored data from the UKW within the framework of 
the legal requirements; if incorrect personal data is processed, participants have the 
right to have it corrected. They may request the deletion of personal data or the 
restriction of processing or data transfer. If these rights are asserted against the UKW, 
it will be examined whether these rights are subject to any restrictions. 
 

 
 
 
 
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10. Consent 
Participation in this study is voluntary; consent can be withdrawn at any time without 
giving reasons (see also “Data protection”). There is no connection between the 
treatment of patients and participation in the study. 
11. Ethics 
The project complies with the Declaration of Helsinki (as of October 2013, Fortaleza, 
Brazil) and Good Clinical Practice. 
 
The protocol and patient information with consent form will be submitted to the local, 
independent ethics committee of the Medical Faculty of the University of Würzburg. 
12. Publication of data 
The results or parts of the results of the study are to be published in peer-reviewed 
scientific journals in anonymized form. 
13. Literatur 
Bundesamt für Strahlenschutz, Natürliche Strahlung in Deutschland (letztmalig 
abgerufen am 9.2.2022): https://www.bfs.de/DE/themen/ion/umwelt/natuerliche-
strahlung/natuerliche-strahlung_node.html 
 
Cipriani P et al. Differential expression of stromal cell-derived factor 1 and its receptor 
CXCR4 in the skin and endothelial cells of systemic sclerosis patients: 
Pathogenetic implications. Arthritis Rheum. 2006 Sep;54(9):3022-33. doi: 
10.1002/art.22047. 
 
Derlin T, Jaeger B, Jonigk D et al. Clinical Molecular Imaging of Pulmonary CXCR4 
expression to predict outcome of pirfenidone treatment in idiopathic pulmonary 
Fibrosis. Chest2021;159(3):1094-1106 
 
Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in Progressive fibrosing interstitial 
lung diseases. N Engl J Med 2019;381: 1718–27. 
 
Goh NS, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic 
sclerosis: a simple staging system. Am J Respir Crit Care Med 2008; 177: 1248–
54. 
 
Kircher M, et al. Imaging Inflammation in Atherosclerosis with CXCR4-Directed 
68Ga-Pentixafor PET/CT: Correlation with 18F-FDG PET/CT. J Nucl Med. 2020 

 
 
 
 
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Oberdürrbacher Str. 6-8, 97078 Würzburg 
 
 
 
CXCR4-PET/CT in SSc study protocol V4 vom 09.Feb.2022 
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May;61(5):751-756. doi: 10.2967/jnumed.119.234484. Epub 2019 Oct 25. PMID: 
31653710. 
 
Kircher M, et al. CXCR4-directed theranostics in oncology and inflammation. Ann Nucl 
Med. 2018 Oct;32(8):503-511. doi: 10.1007/s12149-018-1290-8. Epub 2018 Aug 
13. PMID: 30105558; PMCID: PMC6182637. 
 
Valentini G, Iudici M, Walker UA, et al. The European Scleroderma Trials and 
Research group (EUSTAR) task force for the development of revised activity 
criteria for systemic sclerosis: derivation and validation of a preliminarily revised 
EUSTAR activity index. Ann Rheum Dis 2017; 76: 270–76. 
 
Weigold et al. Antibodies against chemokine receptors CXCR3 and CXCR4 predict 
progressive deterioration of lung function in patients with systemic sclerosis. 
Arthritis Res Ther. 2018 Mar 22;20(1):52. doi: 10.1186/s13075-018-1545-8 
 
14. Abbreviations 
 
ACR        American College of Rheumatology 
CT        Computed tomography 
CXCR4    C-X-C motif chemokine receptor 4 
CXCL12    C-X-C motif chemokine 12 
eCRF        Electronic case report form 
EULAR    European League against Rheumatism 
FDG        Fluorine 18 deoxyglucose 
ILD        Interstitial lung disease 
IPF        Idiopathic pulmonary fibrosis 
PET        Positron emission tomography 
SSc        Systemic sclerosis 
SUV        Surface under the curve 
 
 
 
 

 
 
 
 
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15. Unterschriften 
 
Unterschriften wissenschaftliche Leitung 
 
 
 
___________________________ 
Dr. med. M. Gernert 
Medizinische Klinik und Poliklinik II, 
Schwerpunkt Rheumatologie/Klinische Immunologie 
 
 
 
___________________________ 
PD Dr. med. M. Schmalzing 
Medizinische Klinik und Poliklinik II, 
Schwerpunkt Rheumatologie/Klinische Immunologie 
 
 
 
___________________________ 
Dr. med. S. Serfling 
Klinik und Poliklinik für Nuklearmedizin 
 
 
 
___________________________ 
PD Dr. med. R. Werner 
Klinik und Poliklinik für Nuklearmedizin 
 
 

 
 
 
 
Medizinische Klinik und Poliklinik II 
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Unterschriften Klinikdirektoren 
 
 
 
___________________________ 
Prof. Dr. med. T. A. Bley 
Institut für diagnostische und interventionelle Radiologie 
 
 
 
___________________________ 
Prof. Dr. med. A. Buck 
Direktor der Klinik und Poliklinik für Nuklearmedizin 
 
 
 
___________________________ 
Prof. Dr. med. H. Einsele 
Direktor der Medizinischen Klinik und Poliklinik II 
 
 
 

 
 
 
 
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16. Appendix