Type 1 Interferon Induced Changes to Exercise Adaptations in Systemic Lupus
Phase: NA
Conditions: Systemic Lupus Erythematosus, Interferon Deficiency
Sponsor: Rigshospitalet, Denmark

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1 Title Page:  
Type 1 interferon induced changes to exercise adaptations in systemic 
lupus erythematosus patients 
Date: 27/09/2023 
Protocol Version: 2.0 
Protocol Journal Number: H-21039032 
Principal investigator 
Malte Lund Adamsen (MLA), MD (a, c) 
Research team 
Regitse Højgaard Christensen (RHC) (a,d) 
Simon Jønck (SJØ), MD (a) 
Ronan M. G. Berg (RMB), MD, DMSc (a,b) 
Iben Elmerdahl Rasmussen (IER), MSc (a) 
Philip Hasbak (PHA), MD DMSc (b) 
Laura Langkjær Johnsen (LLJ), MD, (e) 
Kanwal Zahid Siddiqi (KZ), MSc, (c) 
Helga Ellingsgaard (HEL), MSc PhD (a) 
Pil Højgaard (PHØ), MD PhD (c) 
Louise Diederichsen (LD), MD PhD(a) 
Bente Klarlund Pedersen (BKP), MD DMSc (a) 
Søren Jacobsen (SJA), MD DMSc (c) 
(a) Centre for Physical Activity Research, Rigshospitalet, Capital Region of Copenhagen, The Faculty of 
Health and Medical Sciences, University of Copenhagen, Denmark 
(b) Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Capital Region of 
Copenhagen, Denmark 
(c) Department of Rheumatology, Rigshospitalet, Capital Region of Copenhagen, Denmark 
(d) Department of Cardiology, Rigshospitalet, Capital Region of Copenhagen, Denmark 
(e) Department of Rheumatology, Gentofte Hospital, Capital Region of Copenhagen, Denmark. 
 
 

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Place of study execution 
Centre for Physical Activity Research (CFAS), Rigshospitalet, section 7641  
Ole Maaløes vej 26, 2200 Copenhagen, Denmark (study address)  
Blegdamsvej 9, dept. 7641, 2100 Copenhagen, Denmark (postal address)  
Telephone: +45 3545 7617 
Correspondance: 
Malte Lund Adamsen 
Email: Malte.Lund.Adamsen.02@regionh.dk 
Telephone: +45 23278105 
 
 

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Table of Contents 
1 
Title Page: ..................................................................................................................................... 1 
2 
Introduction and background ........................................................................................................ 5 
2.1 
General objective .................................................................................................... 5 
2.2 
Overall aim ............................................................................................................. 6 
2.2.1 
Primary aim .................................................................................................................... 6 
2.2.2 
Secondary aims .............................................................................................................. 7 
2.3 
Trial registration ...................................................................................................... 7 
2.4 
Hypotheses ............................................................................................................. 7 
3 
Methods ........................................................................................................................................ 7 
3.1 
Study design and study settings ............................................................................. 7 
3.2 
Eligibility criteria ...................................................................................................... 8 
3.2.1 
Inclusion criteria ............................................................................................................ 8 
3.2.2 
Exclusion criteria ........................................................................................................... 8 
3.3 
Intervention ............................................................................................................. 9 
3.4 
Criteria for discontinuation .................................................................................... 10 
3.5 
Concomitant care .................................................................................................. 11 
3.6 
Outcomes ............................................................................................................. 11 
3.6.1 
Primary Outcome: ........................................................................................................ 11 
3.6.2 
Co-Primary Outcome: .................................................................................................. 11 
3.6.3 
Secondary Outcomes: .................................................................................................. 11 
3.7 
Recruitment plan ................................................................................................... 12 
3.8 
Patient visits.......................................................................................................... 13 
3.8.1 
Visit 1 – Informed Consent .......................................................................................... 13 
3.8.2 
Visit 2 - Thorough medical examination - Baseline .................................................... 13 
3.8.3 
Visit 3 - 82Rb PET Scan - Baseline .............................................................................. 13 
3.8.4 
Visit 4 - Acute Exercise bout - Baseline ...................................................................... 14 
3.8.5 
Visit 5 – Medical examination - Follow-up ................................................................. 15 
3.8.6 
Visit 6 - 82Rb PET Scan – Follow-up ........................................................................... 15 
3.8.7 
Visit 7 - Acute Exercise bout – Follow-up .................................................................. 15 
3.9 
Assessment of study outcome .............................................................................. 16 
3.9.1 
Medical assessment ...................................................................................................... 16 
3.9.2 
Maximal aerobic capacity ............................................................................................ 16 
3.9.3 
Acute Exercise Bout..................................................................................................... 16 
3.9.4 
Transthoracic echocardiography .................................................................................. 17 

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3.9.5 
Body composition ........................................................................................................ 18 
3.9.6 
Blood samples .............................................................................................................. 18 
3.9.7 
Biochemical analyses ................................................................................................... 19 
3.9.8 
mRNA expression analyses ......................................................................................... 19 
3.9.9 
Urine Samples .............................................................................................................. 41 
3.9.10 
SLE disease activity measures ..................................................................................... 41 
3.9.11 
82Rb-PET Scan ............................................................................................................. 41 
3.9.12 
Oral glucose tolerance test ........................................................................................... 41 
3.9.13 
Lung function ............................................................................................................... 42 
3.9.14 
Nailfold Capillaroscopy ............................................................................................... 42 
3.9.15 
Muscle biopsies ............................................................................................................ 42 
3.9.16 
Data analysis ................................................................................................................ 42 
4 
Ethical considerations ................................................................................................................. 43 
4.1 
General information .............................................................................................. 43 
4.2 
Initiative for the project .......................................................................................... 44 
4.3 
Access to patient information ................................................................................ 44 
4.4 
Novelty and importance ........................................................................................ 44 
4.5 
Risks and disadvantages of interventions ............................................................. 44 
4.6 
Risks and disadvantages of baseline and follow-up tests ..................................... 44 
4.7 
Radiation exposure ............................................................................................... 45 
4.8 
Safety and precautions ......................................................................................... 45 
4.8.1 
Safety evaluation .......................................................................................................... 45 
4.9 
Procedure for recording and handling AEs and SAEs .......................................... 46 
4.10 
Dissemination of study results ........................................................................... 46 
4.11 
Withdrawal from study ....................................................................................... 46 
4.12 
Insurance ........................................................................................................... 47 
4.13 
Practical setups ................................................................................................. 47 
4.14 
Economy ........................................................................................................... 47 
4.15 
Biobank & Data Storage .................................................................................... 47 
5 
References ................................................................................................................................... 48 
 
 
 

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2 Introduction and background 
2.1 General objective 
Systemic lupus erythematosus (SLE) is a rare chronic autoimmune disease with a varied phenotype 
and multisystemic involvement1. SLE shows a predilection for women of childbearing age in which 
the prevalence in Denmark is 20-40/100.0002. The disease involves a complex interplay of 
immunopathogenic pathways that is yet to be fully elucidated3. Notably, these patients often suffer 
from reduced exercise capacity and a related up to 50-fold increased risk of cardiovascular disease 
(CVD)3,4. The cause of impaired exercise capacity has been debated for decades4,5, and remains to 
be fully elucidated, but likely reflects the unique link between immune function and exercise 
capacity.  
SLE is characterised by an activation of the interferon (IFN) system with increased expression of 
IFN-regulated genes6. There are three types of IFNs that can be further divided into several 
subtypes and classes that affect distinct receptors6. Key subtypes of type 1 IFN are IFNα and 
IFNβ7,8. These subtypes display a high degree of homology and biological effects9. In healthy 
individuals, IFNα and IFNβ constitute an important part of the barriers against viral infections and 
modulation and activation of the innate and adaptive immune system7. The activation of IFNs are 
tightly regulated by several mechanisms7, but in SLE patients, the balance between activation and 
regulation becomes skewed with a concomitant over-expression of IFNs10. Since IFNs in peripheral 
blood are measured in the order of picograms per millilitre, and they are incredibly short lived as 
they constantly interact with blood and endothelial cells, no method has produced effective 
measurements of this constant varying amount of IFN. Instead robust assessments of the underlying 
IFN gene signature (IFNGS) have been developed, by measuring the pool of transcribed mRNA 
related to prolonged IFN exposure. The individual patient’s IFNGS has been linked to the 
subsequent clinical presentation and pathophysiology of disease11,12. 
These gene signatures can be differentiated between genes related to type 1 (like IFNα and IFNβ), 
type 2 (like IFNγ) and type 3 (like IFNλ) IFNs. Which creates type 1, type 2 and type 3 IFNGSs. 
These major groups have multiple subgroups, and these subgroups interfere and crosstalk with 
eachother, therefore single genes, or small gene groups coding to just one of these IFNs are hard to 
define.  
Ex vivo studies have shown, that IFNα and IFNβ, which are both types of type 1 IFN interfere with 
the interleukin (IL)-6 induced transducer and activator of transcription 3 (STAT3), leading to an 
abrogation of IL-6 activated intracellular pathways13,14. IL-6 is a pleiotropic cytokine with both pro- 
and anti-inflammatory effects. During exercise, IL-6 is released from skeletal muscle resulting in 
increased circulating levels of IL-615. Recently we found that the IL-6 receptor antibody 
tocilizumab (TCZ) completely abolish exercise-induced reductions in visceral and cardiac adipose 
tissue in healthy individuals as well as reducing the left ventricular mass growth of the TCZ treated 
group to match the non-exercising controls16,17. Thus, IL-6 is an important signalling molecule 
stimulating both cardiac and non-cardiac adaptations to exercise training.  
Evidence suggests that the type 1 IFN largely regulates a chronic pathological process and is less 
involved in the acute disease manifestations11,12. 
Chaussabel et al. attempted to define a unifiable IFNGS for SLE18 by dividing genes from pediatric 
SLE patients into multiple modular subset of gene signatures related to interferon profile. Defining 
260 different modules of coclustered genesets that were upregulated in SLE. 

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Chiche et al. further defined three of these modules (see 3.9.9); M1.2, M3.4 and M5.1219, relating 
M1.2 to IFNα, M3.4 to signalling by both IFNα and β but also some degree of IFNγ signalling and 
M5.12 to IFNα, β and γ.  
M1.2 had no increase with increasing SLEDAI score, and likely represents a baseline characteristic 
of the SLE disease as noted by the type 1 IFNGS representing a chronic pathological process11,12. 
Increasing M3.4 and M5.12 scores correlated with increased SLEDAI scores19. Furthermore, 
Chiche et al. showed that in order to have M5.12 activity; SLE patients needed M3.4 activity 
creating a dose-response correlation of these modules. Measuring the levels of these genetic 
modules and correlating them to our primary outcomes will allow us to evaluate whether patients 
with more active type 1 IFN system have fewer benefits from exercise.  
Based on our previous studies combining exercise training and IL-6 receptor blockade, we 
hypothesize that exercise-induced cardiac, metabolic and muscle adaptations are impaired in SLE 
patients with high- compared to low- IFNGS.  
Exercise capacity in patients with SLE has previously been studied, in those studies focus was on 
fatigue severity and quality of life measures (QoLs), showing a non-significant improvement in 
fatigue scores, and a slightly significant increase in VO2Max20,21. Only few studies have 
investigated the cardiac benefits, such as decreased sympathetic tonus, of exercise training in SLE 
patients22, showing an overall, but reduced compared to healthy controls, positive effect of exercise 
in this patient group. 
Studies have shown that endurance high intensity interval training (HIIT) is superior to resistance 
training with respect to improving QoLs in patients with SLE23. Exercise-induced IL-6 is intensity-
dependent, thus, HIIT will lead to a higher release of IL-6 compared to exercise at lower intensity. 
It is tempting to speculate that SLE patients with high IFNGS will experience increased exercise-
related fatigue due to the supressed IL-6 signalling24.To the best of our knowledge, an exercise 
intervention study in patients with SLE regarding the differing effects for IFNGS has not been 
performed.  
Thus, the aim of the present study is to compare the effects of regular supervised exercise training 
on cardiac adaptations, exercise tolerance and fatigue in SLE patients who will have measured their 
IFNGS before and after exercise intervention, so that post hoc analysis can show whether increases 
to any of the three IFNGS modules affect their outcomes. Changes in IL-6 signalling in the immune 
system will also be assessed. 
2.2 Overall aim 
The overall aim of this project is to understand whether patients with differing IFNGS differ in their 
cardiac, metabolic and muscle adaptations to exercise training, notably cardiac pump function and 
perfusion. Furthermore, to study the impact of exercise on patient-reported outcomes including 
measures of fatigue and SLE disease activity according to IFNGS. 
We anticipate that the results will provide insight into the fundamental mechanisms of severe 
fatigue and exercise capacity in patients with SLE, this may improve and personalize physical 
rehabilitation and medical treatment strategies in this rare disease. 
2.2.1 Primary aim 
We aim to investigate whether maximal oxygen uptake adaptation to 12 weeks of regular 
supervised exercise training differs between SLE patients with increasing IFNGS. 

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In addition to this, we aim to investigate as a co-primary endpoint whether patients with increasing 
IFNGS will have less benefit of exercise on their fatigue severity scores. 
2.2.2 Secondary aims 
To investigate whether the cardiac and metabolic adaptations to 12 weeks of regular supervised 
exercise training differ between SLE patients with increasing IFN gene signature. Cardiac function 
will be assessed by left ventricular ejection fraction, ventricular muscle mass, and coronary 
perfusion reserve. Metabolic adaptations include changes in visceral adipose tissue mass, lean body 
mass, and various metabolic blood samples as well as lung function.  
To investigate the effects of regular supervised exercise training on measures of SLE disease 
activity and patient-reported outcomes including but not limited to SLEDAI/SRI-50, FSS and SF-
36.  
2.3 Trial registration 
We intend to register the trial at ClinicalTrials.Gov following acceptance by the regional ethics 
committee. 
2.4 Hypotheses 
We hypothesize that exercise-induced cardiac and metabolic adaptations are impaired and exercise 
intolerance and fatigue is aggravated in SLE patients with high compared to low IFNGS.  
We hypothesize that improvements in peak oxygen uptake following 12 weeks of high intensity 
exercise is less pronounced in SLE patients with increasing IFNGS. 
3 Methods 
3.1 Study design and study settings  
The study is designed as an investigator-blinded randomized controlled trial consisting of 12 weeks 
of endurance exercise (Figure 1). A total of 60 patients will be randomized to intervention in a 1:1 
fashion, a total of 30 patients will follow an exercise intervention, while the remaining will be 
encouraged to maintain current exercise habits for the duration of the study (see Figure 1).   
 
Figure 1 Study Design 

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The enrolment period is planned to start in early 2022 and run for approximately two years or when 
30 patients are recruited to each group. Follow-up is estimated to be completed in the spring of 
2023. All baseline and follow-up tests will be carried out at Centre for Physical Activity Research 
(CFAS), Rigshospitalet, Denmark. 82Rb-PET scans will be performed at the Department of Clinical 
Physiology, Nuclear Medicine & PET, Rigshospitalet, Denmark. All data will be collected and 
analysed in Denmark.  
3.2 Eligibility criteria 
3.2.1 Inclusion criteria 
• Age ≥ 18 years by inclusion. 
• Able to provide informed consent. 
• Diagnosed SLE and fulfilling the classification criteria for SLE based on the American 
College of Rheumatology/EULAR criteria25 (SLICC) 
3.2.2 Exclusion criteria 
• Health conditions that prevent participating in the exercise intervention determined by the 
Research Coordinator these include but are not limited to 
o Major bone fracture at inclusion 
o Significant myalgias exacerbated by physical exercise 
o Active infectious disease such as Covid-19 
o Severe symptomatic pleuritis or pericarditis 
• Corticosteroid use > 10mg/day at baseline 
• Diagnosed with diabetes mellitus by physician 
• Pregnancy 
• SLEDAI-2k26 (with the SELENA modifications to Proteinuria changes so as to not exclude 
patients with chronic proteinuria27) > 10 
• Contraindications to 82Rb-PET with adenosine stress (according to local guidelines at the 
Dept. of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, which are in 
accordance with the recommendations of the European Association of Nuclear Medicine)28 
o Fever, myocarditis or endocarditis 
o Previous heart transplantation 
o Dysregulated atrial or ventricular tachyarrhythmias  
o Severe chronic obstructive pulmonary disease with a FEV1 of less than 50% of 
predicted 
o Second or third degree sinoatrial or atrioventricular block 
o Active bronchospasm at the time of the scan 
o Systolic blood pressure <90 or >200 mmHg at the time of the scan 

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o Treatment with theophyllin within 7 days of the scan 
3.3 Intervention 
The exercise training program includes three sessions per week over a 12-week period and will take 
place at CFAS or a local collaborator. The exercise intervention will start when baseline visits have 
been completed.  
Figure 2 Flowchart of study. SLE; Systemic Lupus Erythematosus. 

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Figure 3 Exercise intervention, HRMax = Maximal Heart Rate. 
The program consists of high intensity endurance training on ergometer bicycles. The intensity will 
progress throughout the 12 weeks of training. The training consists of 10 minutes of warm up at 40-
60% maximum heart rate (HRmax), followed by 4 sets of 4 minutes of high intensity interval 
training (HR>85%HRmax) followed by 4 sets of 3 minutes of medium intensity (40-60% HRmax), 
for a total of 28minutes, and finally a 10 min cool-down of 50% HRmax fading to exercise 
cessation (see sFigure 3 Exercise intervention), for a total exercise time of 38-45 minutes. Previous 
studies in our centre have had significant results following this training program17. Strenuous 
exercise is considered beneficial for SLE patients, and not considered harmful29.   
All sessions will be supervised and administered by CFAS personnel or local collaborators with 
experience in handling endurance exercise. To ensure proper intensity, all patients will be wearing a 
heart rate monitor. The maximal heart rate (HRmax) will be measured as the peak heart rate during 
the final minute of the VO2max test (see 3.9.2)30. To evaluate the precise amount of exercise 
completed for every patient, each training session will be documented (attendance, total time of 
HRmax > 85%, total time of exercise, average watt, average heart rate, and perceived exertion 
(BORG scale)). 
The exercise session will be counted as successful if more than half of the high intensity training is 
above 85% of HRmax (so 8 minutes of the session), this is similar to previous studies. The time in 
each HR span of the patient for each training session will then be recorded to be measured for 
further compliance parameters. 
Control groups will be encouraged to maintain current exercise habits for the duration of the study, 
and both groups will do a dietary and activity record at study baseline and followup. 
3.4 Criteria for discontinuation 
Prior to each exercise session, the patient will be assessed regarding chest pain (acute or recurring). 
The termination criteria during exercise include onset of angina, confusion, nausea, severe pain in 
joints or muscles that prohibit further exercise, physical signs of profound fatigue, and verbal 

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communication of profound fatigue. If chest pain is present prior to exercise or any of the above- 
mentioned criteria occurs during exercise, the instructors are obliged to call one of the study-
affiliated medical doctors immediately.  If a patient experiences increased joint or muscle pain 
during the exercise, the medical doctor will be called to decide (in dialog with the patient) whether 
the exercise can continue or not. 
3.5 Concomitant care 
The patients will follow standardized clinical care at their respective physician. The patients will be 
urged to continue their normal day-to-day activities and diet outside of this study. The patients will 
be advised to inform the study personnel about any new prescription or over-the-counter drugs used 
one month prior to, and during the study. All information regarding changes in medicine will be 
documented. We do not anticipate complications from participation in this study.  
3.6 Outcomes 
3.6.1 Primary Outcome:  
Changes in maximal aerobic capacity (VO2max) 
3.6.2 Co-Primary Outcome: 
Patient reported Fatigue, measured by Fatigue Severity Scale (FSS)31 
3.6.3 Secondary Outcomes:  
Physician evaluated measures of SLE, such as the year 2000 updated SLE disease activity 
(SLEDAI-2K)26, with the SELENA modifcations27, SLEDAI Responder Index-50 (SRI-50)32 and 
Visual Analog Scale (VAS) of global disease by Physician. 
Transcriptomic analysis of blood samples related to IFN-I signalling. 
3.6.4 Exploratory Outcomes:  
Patient reported outcome measures (PROMs) including VAS fatigue, VAS pain and Short Form 
(SF)-36 Health Survey33. 
Cardiac adaptations, including left ventricular mass, stroke volume, left ventricular and atrial end-
diastolic volume, global longitudinal strain, left ventricular ejection fraction, and coronary perfusion 
reserve by echocardiography. 
Metabolic adaptations, such as fat distribution, waist-to-height and waist-to-hip ratio, total fat mass, 
visceral fat mass, gynecoid fat mass, android fat mass and lean body mass, measured by DXA scan.  
Blood samples analysed for markers related to exercise, metabolism, inflammation and 
cardiovascular function. 
Transcriptomic analysis of blood samples related to IFN-II, IFN-III, IL-6, and TNF signalling. 
Peripheral capillaries of the nailfold assessed by capillaroscopy. 
Autonomic nervous system measurements by RR interval changes. 

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Change in physical activity measured by activity measurements and dietary changes will serve to 
help alleviate possible confounders 
 
3.7 Recruitment plan 
Patients will be recruited from the out-patient clinic at the Department of Rheumatology, 
Rigshospitalet. If determined eligible for the study by one of the nurses or the treating 
rheumatologist, patients will be informed about the possibility of participating in the current study. 
The patient will be informed that interest in this study will allow one of the Study MDs to screen 
their electronic and physical medical journal for inclusion criteria before contacting the patient. 
If the patient shows interest, the nurse or rheumatologist will inform one of the CFAS investigators 
who will contact the patient by telephone and perform pre-screening. 
In order to assess for inclusion and exclusion criteria, so as to not contact patients that would be 
excluded from the study, a study MD will pre-screen the patient based on the information accessed 
through the medical journal.  
This information will include: Name, Social Security Number (Including age and sex), 
pharmaceutical products used (to assess for corticosteroid and other anti-rheumatic drugs for the 
treatment of SLE use), medical history (to rule out DM and check for other diagnoses that could 
pose an exercise risk), recent blood samples and the entries from the rheumatologic department at 
RH to asses for the classification criteria for SLE based on the American College of 
Rheumatology/EULAR criteria25. 
Alternatively, a clinician employed at the out-patient clinic at the Department of Rheumatology will 
provide a list of patients eligible for the study, who will then be contacted by the study personnel. 
If the patient fulfils the inclusion criteria and none of the exclusion criteria at prescreening and the 
patient accepts; written information including (“Deltagerinformation om deltagelse I et 
videnskabeligt forsøg”) a consent form (“Informeret samtykke til deltagelse I et 
sundhedsvidenskabeligt forskningsprojekt”), and the pamphlet “Forsøgspersoners rettigheder i et 
sundhedsvidenskabeligt forskningsprojekt” will be emailed, and a telephone call approximately 3 
days later will be planned.  
Through this the patient will be informed that further participation in the study will require access to 
the medical electronic and physical journal for investigator, the sponsor and her representatives 
(Bente Klarlund Pedersen and CFAS), and controlling instances that ascertain correct ethical 
conduct of this study. They will furthermore be informed that this consent can be recalled at any 
time with termination of study participation, and with no further effects on their future treatment of 
their disease. 
If the patient still shows interest in participating by the second telephone call, the patient will be 
invited to CFAS for visit 1, if the prospective participant prefers so and cannot make time for a 
physical visit 1 it can be done by video call.  
If, for any reason, the patient wishes additional time to consider participation, a telephone call will 
be planned within 3-5 days.  
Informed consent will always be obtained prior to medical- and baseline assessments by a medical 
doctor or a delegated experienced study personnel working under supervision. 

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Following this oral and written information and written consent visit 1; visit 2 of the baseline visit 
will be planned (see 3.8.1 below), patients will be asked to arrive fasting at visit 2. 
3.8 Patient visits 
Following the visit to obtain consent all patients will undergo a total of six assessment visits. Four 
of the visits will take place at CFAS (visits 1, 3, 4 and 6) and two will take place at the Department 
of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet (visits 2 and 5).  
The exercise intervention will take place at CFAS or one of our local collaborators. Baseline visits 
1, 2, and 3 will take place prior to intervention. During follow-up visits 4, 5, and 6, patients will be 
met by staff blinded to the intervention. An overview of visits is presented in Table 1.  
3.8.1 Visit 1 – Informed Consent 
At CFAS or if the participant prefers, another setting such as video conference: 
The patient will be informed about the possibility of bringing a trustee along. In a quiet setting 
without external interruptions, the patient will receive thorough information regarding purpose, 
procedure, potential side-effects and possible withdrawal of the study by one of the medical doctors 
or a delegated experienced study personnel.  
The patient will be offered to use at least 24 hours or as long time as is needed for contemplation 
and explained that SLE treatment will not be jeopardized in any way by declination to join the 
study. 
If the patient wishes to continue, a consent form will be signed. If the patient requests to consider 
their participation further; a new appointment about one week later will be scheduled.  
Prior to this initial information, the patient has the opportunity to contact one of the study 
investigators, with contact information clearly listed on the written material they have received by 
email. 
3.8.2 Visit 2 - Thorough medical examination - Baseline 
At CFAS: 
Patients will arrive fasted at CFAS. The patient will then undergo a medical assessment. If, for any 
reason, the examining medical doctor finds reason to exclude the patient, no further assessments 
will take place. The patient will be informed about the decision, and if deemed necessary, the 
patient will be informed to contact his/her general practitioner or rheumatologist.  
Further OGTTs, DXA scan, VO2-Max test, medical history and more as described in table 1 will 
then be done on visit 1. 
Blood Samples including Pax Gene tubes for IFNGS are collected. These blood samples are the 
characterization and outcome packages of blood samples as specified in 3.9.7 as well as the IFNGS 
analysis as described in 3.9.9. 
3.8.3 Visit 3 - 82Rb PET Scan - Baseline 
At Dept. of Clinical Physiology, Nuclear medicine & PET, Rigshospitalet: 

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Rest-adenosine stress 82Rb-PET/CT scan. The patient will be informed to pause nitroglycerin for 1 
hour, other long-lasting nitrite-based drugs, betablockers and persantin for 24 hours, prior to the 
82Rb-PET scan (if appropriate). Furthermore, the patient must refrain from consuming any 
methylxantin-containing drugs, foods or drinks for 18 hours prior to the scan. Methylxantins 
encompass theophyllin, caffeine, and theobromine, and are present in e.g. coffee, tea, chocolate, and 
cocoa. 
3.8.4 Visit 4 - Acute Exercise bout - Baseline 
At CFAS:  
Patients will be asked to arrive fasting. 
Acute exercise bout as specified in 3.9.3 and Figure 4 with the exercise related markers of 
inflammation as specified in 3.9.7.3. 
1. Patient waits in a relaxed environment for at least 20 minutes. 
2. During this time they will complete the autonomic nerve function test as described in 3.9.16. 
3. Baseline ECG and Blood Pressure will be measured. 
4. Blood tests as specified in the acute exercise bout package at 3.9.7 will be drawn twice, this 
is defined as t=-5 and t=0 
5. Acute exercise bout of 45 minutes of acute exercise. As described below 
6. Following warm up at 10 minutes, first bout at 14 minutes, final bout at 35 minutes, and 
total exercise at 45 minutes, (t=10, 14, 35, and 45 respectively) blood tests as specified in 
the small package at 3.9.7 will be drawn. 
7. Exercise ceases and further blood tests as specified in the small package at 3.9.7 will be 
drawn at 15 (t=60), 45(t=90), and 60 (t=105) minutes after exercise 
8. After these blood tests participants will be offered a light meal. 
9. Participants will be instructed in dietary diaries and have applied activity axial 
accelerometer-based physical activity monitors (AX3; Axivity, Newcastle upon Tyne, UK) 
for a 3-to-5-day period. 
 
Timeline 
Baseline 
Intervention 
(12 weeks) 
Follow-up 
Visit 
1 
2 
3 
4 
 
5 
6 
7 
Study day 
1 
2 
3 
4 
93 
94 
95 
Written consent 
X 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Questionnaires 
 
X 
 
 
X 
 
 
Clinical examination  
(Vital signs, BP, ECG) 
 
X 
 
X 
X 
 
X 
Blood Sample1 
 
X 
 
X 
X  
 
X 

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3.8.5 Visit 5 – Medical examination - Follow-up 
At CFAS:  
Follow-up assessments identical to Visit 2. 
3.8.6 Visit 6 - 82Rb PET Scan – Follow-up 
Dept. of Clinical Physiology, Nuclear medicine & PET, Rigshospitalet:  
Follow-up assessments Identical to visit 3.  
3.8.7 Visit 7 - Acute Exercise bout – Follow-up 
CFAS:  
Follow-up assessments Identical to visit 4 
PAX-Gene tube for 
IFNGS 
 
X 
 
 
X 
 
 
DXA scan and 
anthropometrics  
(weight, BMI) 
 
X 
 
 
X 
 
 
VO2 max test 
X 
X 
 
 
X 
 
 
82Rb-PET scan 
 
 
X 
 
 
X 
 
Echocardiography 
 
X 
 
 
X 
 
 
OGTT 
 
X 
 
 
X 
 
 
Lung function 
 
X 
 
 
X 
 
 
Acute Exercise Bout 
 
 
 
X 
 
 
X 
Muscle Biopsy 
 
X 
 
 
X 
 
 
Activity and Dietary 
record initiation 
 
 
 
X 
 
 
X 
Nailfold 
Capillaroscopy 
 
X 
 
X 
X 
 
X 
Autonomic Nerve 
Function tests 
 
 
 
X 
 
 
X 
Table 1 Overview of the visits. BMI; Body mass index, BP; blood pressure, DXA; dual energy X-ray absorptiometry, ECG; 
Electrocardiogram, rubidium-82 positron emission tomography; 82Rb-PET scan, VO2 max; maximal oxygen consumption. 
1Blood samples will be drawn as specified in 3.9.7 Blood samples 

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3.9 Assessment of study outcome 
All study outcomes will be collected after written signed consent.  
3.9.1 Medical assessment 
Prior to enrolment and at follow-up, each patient will undergo a medical examination and interview 
that includes auscultation of heart and lungs, a brief medical history, electrocardiogram, and blood 
pressure. 
3.9.2 Maximal aerobic capacity 
Patients will perform a graded exercise test on a bicycle ergometer (Monark LC4, Monark Exercise 
AB, Vansbro, Sweden) at CFAS, to determine the maximal oxygen consumption (VO2 max).  
Maximal workload (watt-max) will be estimated based on baseline physical activity, resting heart 
rate, weight, gender, age and waist circumference as per the method described by Nes et al34. 
Using this estimation participants will warm up for 5 minutes at 15% of their watt-max (rounded to 
nearest 10) and increase in steady increments of 1 minute each to reach their estimated 100% watt-
max at 15 minutes (so an increase of 8,5% watt-max per minute). Following these 15 minutes, watt 
will be added in the same increments until exhaustion. 
The patients will be encouraged to perform at their maximal effort by CFAS staff. The ventilation 
rate and expired CO2 and O2 will be measured by indirect calorimetric measurements (Quark b2, 
Cosmed, Rome, Italy.) The peak HR measured will serve as reference for relative intensity during 
the study. 
This test will be done immediately following consent, and again at the first baseline day and at 
follow-up, to alleviate for habituation in the exercise group. 
If for some reason the participant cannot do more than 7 minutes on this maximal aerobic capacity 
or they cannot increase their maximal heart rate above 120 minutes at the first test; another test will 
be done which is reduced to this new watt-max (reached at 15 minutes). This test will be done with 
a stress ECG monitoring to evaluate whether the participant suffers from a cardiac condition that 
limits their potential. 
3.9.3 Acute Exercise Bout 
At baseline and follow-up all patients, both control and intervention patients will perform an acute 
symptom-limited exercise bout on a bicycle ergometer (Monark LC4, Monark Exercise AB, 
Vansbro, Sweden) at CFAS. This exercise bout will be identical to the exercise interventions and 
consist of 10 minutes of warm up at 40-60% maximum heart rate (HRmax), followed by 4 sets of 4 
minutes of high intensity interval training (HR>85%HRmax) these sets are followed by 4 sets of 3 
minutes of medium intensity (40-60% HRmax), for a total of 28minutes, and finally a 0-7 min cool-
down of 40-60% HRmax or below. This gives a total exercise of 38-45 minutes. 
These acute exercise bouts are identical to the intervention and gives us an opportunity to study the 
changes in cytokine activity during exercise for patients with SLE following intervention. 

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Figure 4 Acute Exercise Bout, HRMax = Maximal Heart Rate 
During and following this bout, the small package of blood samples will be drawn to assess for 
markers of inflammation, as described in 3.9.7.3, for a total of 10 times, as described in 3.8.4 (see 
Figure 4). 
3.9.4 Activity Measures and Dietary Diaries 
At baseline and followup, patients will have applied axial accelerometers monitors (AX3; Axivity, 
Newcastle upon Tyne, UK) for a 3 to 5 day period, to study their Free-Living physical activity. 
In addition to this dietary diaries will be handed out as questionnaires at baseline and follow-up for 
patients to fill in. 
3.9.5 Transthoracic echocardiography 
Transthoracic echocardiography (TTE) will be performed at CFAS to assess changes in cardiac 
function and structure. The images will be acquired and analyzed with GE Vivid E95 (GE Vingmed 
Ultrasound, Horten, Norway) and GE Echopac software. Patients will be examined in the left lateral 
decubitus position. All echocardiograms will be obtained and analyzed by one of the study 
clinicians and validated by a cardiologist who is blinded to the allocated study group. The 
acquisition of images will be done according to the American Society of Echocardiography and the 
European Association of Cardiovascular Imaging 35. In parasternal long axis view, the left 
ventricular wall thicknesses will be determined at end-diastole at the level of the mitral valve leaflet 
tips. Ventricular mass will be calculated by the formula: 0.8 · 1.04 · [(interventricular septu m + LV 
internal diameter + posterior wall thickness)3 – (LV internal diameter)3] + 0.6 g. LV ejection 
fraction will be determined by Simpson’s biplane method. Left atrial volume will be determined by 
the biplane area-length method. The early (E) to late (A) ventricular filling velocity ratio (E/A), will 
be determined by Pulsed-wave doppler in apical 4-chamber view. The early mitral annular diastolic 

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velocity (e’) will be determined in both the septal and lateral region using the 4-chamber view. 
Global longitudinal strain measurements and ejection fraction will be performed by the semi-
automatized algorithms in the GE software. 
3.9.6 Body composition 
To analyze fat and lean body mass, patients will undergo a dual x-ray absorptiometry (DXA) (Lunar 
Prodigy GE Heathcare, Madison, Wisconsin, USA. enCORE software version 14, 10, 022), under 
the supervision of experienced staff. Patients will be asked to empty their bladder prior to scanning.  
3.9.7 Blood samples 
Blood Samples will be taken at multiple times throughout the study, all samples, including the ones 
specified in 3.9.8 and 3.9.9, will be analyzed at Rigshospitalet unless otherwise noted.  
Samples taken in this way will be accessible through the patients medical record at “Labka”, and 
earlier data collected by other physicians will have been needed at the point of drawing these blood 
tests in order to assess for the SLICC criteria, as described under recruitment. 
Blood samples will be referred in the protocol as the “Characterization Package”, the “Outcome 
Package” and the “Exercise Package” in this protocol. A total of 200mL of blood will be drawn at 
baseline tests and at follow-up tests. For a total of 400mL of blood withdrawn within the 12 weeks 
of study. 
3.9.7.1 Characterization package 
Blood samples of approximately 25mL necessary to characterize type and severity of SLE, and also 
required for the SLICC since the characterization package will only be taken along with the 
outcome package at baseline (3.8.2), blood tests that are in the outcome package will not be 
included in the characterization package. 
These include: 
Antinuclear Antibodies by immunofluorescence, Sjögren Antibodies (SSA & SSB), Anti-
Phospholipid antibodies, Anti-Smith Antibodies, Anti U1RNP, and Direct Antiglobulin test (DAT). 
3.9.7.2 Outcome package 
Fasting (minimum of 10 hours) blood samples of approximately 75mL will be drawn in the 
morning at CFAS at baseline and follow-up visits 1 and 4 respectively. 
They will include 
1. Markers of inflammation (Leukocyte differential counts, thrombocytes count and plasma 
measurements of highly sensitive C-Reactive Protein(hsCRP), ferritin, IL-1, IL-6, soluble 
IL-6 receptor, IL-10, TNF, IFNα, and IFNγ) 
2. Specialized SLE markers of inflammation (Complement C3 and C4, Antibodies to double-
stranded DNA, and β2-microglobulin). 
3. Metabolic Markers (Glucose, Hba1c) and Lipid status (Total Cholesterol, Nonesterified 
Fatty Acids (NEFAs), low density lipoproteins (LDL), small dense LDL(sdLDL), 
triglycerides, high density lipoproteins (HDL)) 
4. Markers of hydration status (Hematocrit, Sodium, Potassium, Hemoglobin, Creatinine) 
5. Liver and Muscle Biomarkers (ALAT, Creatine-Kinase, Myoglobin) 

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6. Cardiac markers (Troponin T, Troponin I, NT-ProBNP and ANP) 
7. Markers of endothelial damage (VCAM, Tissue Plasminogen Activation Factor and von 
Willebrand Factor). 
8. Peripheral whole blood cell mRNA expressions as specified under 3.9.9 (below) 
9. Biobank blood test for the CFAS biobank. 
3.9.7.3 Exercise Package 
Blood sample of approximately 5-10ml to be drawn multiple times during the acute exercise bout: 
analyzed for markers of inflammation, such as HS-CRP, ferritin, Leukocyte Differential, Il-1, Il-6, 
soluble Il-6-receptor, Il-10, IFNα, IFNγ, hemoglobin, thrombocytes, sodium, potassium, and 
hematocrit. 
3.9.7.4 OGTT Package 
Two blood samples of approximately 5-10 ml to be drawn twice during OGTT, these samples will 
be analyzed for glucose, insulin, and c-peptide. 
3.9.8 Biochemical analyses 
Blood sampling will be conducted at baseline and at post-intervention by standard procedures. 
Blood sampling will include markers for inflammation as above, metabolites, haematology, 
electrolytes, liver- and renal status, endocrinology, and lipid status. White blood cells will be 
separated and flow cytometry by a 10-colored antibody panel consisting of seven prefabricated 
customized DuraClone tubes from Beckman Coulter (Beckman Coulter, Brea, CA, USA) with 
freeze dried antibodies will be used to analyse surface markers and cytokine expression levels in 
various white blood cell subpopulations, focusing primarily on IL-6 signalling in monocytes and B 
lymphocytes. 
3.9.9 mRNA expression analyses 
During withdrawal of whole blood from patients, 10mL will be transferred to a PAXgene Blood 
RNA tube (PreAnalytiX, Switzerland), which will then be incubated overnight at room temperature 
before processing, to complete lysis of nucleated blood cells.  
RNA will then be isolated without external stimuli using the PAXgene Blood RNA Kit (Qiagen), 
following manufacturer instructions. The samples will then be spun in a Sigma 4k10 centrifuge to 
pellet the nucleic acids, which will then be resuspended, transferred to a PAXgene Shredder spin 
column and incubated in optimized buffers and Proteinase K to digest proteins. The shredder spin 
column will then be centrifuged again to homogenize the cell lysate and remove cell debris.  
The supernatant of the flow-through fraction will then be transferred to a fresh microcentrifuge tube 
and ethanol will be added. 
Then the lysate will be transferred to a PAXgene RNA spin column and spinned briefly. This will 
cause RNA to bind to the spin column membrane and with several following wash steps, 
contaminants will be removed. In between these wash steps the spin column membrane will be 
treated with DNAase I to remove trace amounts of DNA. Hereafter RNA will be eluted in a buffer 
(BR5) and heat denatured. Whereafter RNA will be stored at -80°C. 
When ready for analysis, these tubes will be thawed on ice and total RNA will be quantified using 
RT-qPCR or Nanostring (Thermo Fisher, Waltham, MA, USA) technology.  

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We will then analyze these samples for mRNA gene expression analysis for IFNGS, TNF-related 
genes, IL-6-Related genes as well as housekeeping genes. In total we will analyze mRNA 
expression for around 100 different genes. The abbreviations and types of genes as well as their 
function have been looked up using Genecards.org36. 
The expression of each transcript will be normalized to an average expression of housekeeping 
genes. We plan to analyze the mRNA expression of three housekeeping genes. 
Afterwards, like the process described by Kim et al. we will determine both a Z-score and a 
Geomean mRNA expression score for all subjects37: 
3.9.9.1 Standardized mRNA expression scores 
Samples will be compared to samples from 10 healthy in-house volunteers, to give a Z-Score: 
 𝑍−𝑆𝑐𝑜𝑟𝑒𝐺𝑒𝑛𝑒=
[𝐺𝑒𝑛𝑒 𝐶𝑜𝑢𝑛𝑡−𝑀𝑒𝑎𝑛 (𝐻𝐶 𝑔𝑒𝑛𝑒 𝑒𝑥𝑝𝑟𝑒𝑠𝑠𝑖𝑜𝑛)]
[𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝐷𝑒𝑣𝑖𝑎𝑡𝑖𝑜𝑛 (𝐻𝐶 𝐺𝑒𝑛𝑒 𝑒𝑥𝑝𝑟𝑒𝑠𝑠𝑖𝑜𝑛)] 
This Z-Score can then be averaged for each module to give a standardized mRNA expression score 
for all of the modalities below. 
3.9.9.2 Geomean mRNA expression Score 
Alternatively, the geometric mean of mRNA expressed genes can be calculated as: 
 𝐺𝑒𝑜𝑚𝑒𝑎𝑛−𝐼𝐹𝑁𝑆𝑐𝑜𝑟𝑒= √𝑔1 ∙𝑔2 ∙𝑔3(… ) ∙𝑔𝑛 
𝑛
  
So for example: 
𝐺𝐸𝑂𝑀𝐸𝐴𝑁, 𝑀5.12
= √[ADAR] ∙[BST2] ∙[GBP2] ∙[IRF9] ∙[ISG20] ∙[SP100] ∙[TRIM21] ∙[TRIM25]
8
 
Which gives a score for M5.12 that can be compared across patients with SLE. 
This geomean score can be done in absence of healthy volunteers and could be useful for further 
clinical practice. 
3.9.9.3 Interferon Gene Signature Analysis 
To analyse the interferon gene signature we will use both the methods by Chaussabel et al. and El-
Sherbiny et al. 
In summation we will analyse 58 genes for mRNA expression related to IFN. 
3.9.9.3.1 Chiche and Chaussabel et al. method 
The Chiche and Chaussabel et al. method will be done in WB of modules defined by them as 
related to IFNGS for SLE; M1.2, M3.4 and M5.12 (see Table 2). 
These genes are the same as defined in the modular gene expression by Chaussabel et al. and have 
been used for SLE patients18,19. 
3.9.9.3.1.1 M1.2 20 Genes 
Abbreviation 
Gene 
Function36,38 (according to Genecards.org) 
CXCL10 
chemokine (C-X-
C motif) ligand 
10 
Protein Coding gene. Diseases associated with CXCL10 include 
Periapical Periodontitis and Viral Encephalitis. Among its related 
pathways are Innate Immune System and PEDF Induced Signaling. 
Gene Ontology (GO) annotations related to this gene include 

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signaling receptor binding and chemokine activity. An important 
paralog of this gene is CXCL9. 
DDX60 
DEAD (Asp-Glu-
Ala-Asp) box 
polypeptide 60 
Protein Coding gene. Diseases associated with DDX60 include Lip 
Cancer and Autosomal Recessive Alport Syndrome. Gene Ontology 
(GO) annotations related to this gene include nucleic acid binding 
and hydrolase activity. An important paralog of this gene is 
DDX60L. 
EPSTI1 
epithelial stromal 
interaction 1 
Protein Coding gene. Diseases associated with EPSTI1 include 
Lupus Erythematosus and Systemic Lupus Erythematosus. 
HERC5 
HECT and RLD 
domain 
containing E3 
ubiquitin protein 
ligase 5 
Protein Coding gene. Diseases associated with HERC5 include 
Influenza. Among its related pathways are RIG-I/MDA5 mediated 
induction of IFN-alpha/beta pathways and Innate Immune System. 
Gene Ontology (GO) annotations related to this gene include 
ubiquitin-protein transferase activity. An important paralog of this 
gene is HERC6. 
IFI44 
interferon-
induced protein 
44 
Protein Coding gene. Diseases associated with IFI44 include 
Hepatitis D and Potocki-Shaffer Syndrome. An important paralog 
of this gene is IFI44L. 
IFI44L 
interferon-
induced protein 
44-like 
Protein Coding gene. Diseases associated with IFI44L include 
Lymph Node Tuberculosis and Immunodeficiency 38 With Basal 
Ganglia Calcification. An important paralog of this gene is IFI44. 
IFIT1 
interferon-
induced protein 
with 
tetratricopeptide 
repeats 1 
Protein Coding gene. Diseases associated with IFIT1 include 
Microphthalmia With Limb Anomalies and Vasculopathy, Retinal, 
With Cerebral Leukoencephalopathy And Systemic Manifestations. 
Among its related pathways are Innate Immune System and 
Interferon gamma signaling. Gene Ontology (GO) annotations 
related to this gene include RNA binding. An important paralog of 
this gene is IFIT1B. 
IFIT3 
interferon-
induced protein 
with 
tetratricopeptide 
repeats 3 
Protein Coding gene. Diseases associated with IFIT3 include Lupus 
Erythematosus and Human Cytomegalovirus Infection. Among its 
related pathways are Innate Immune System and Interferon gamma 
signaling. Gene Ontology (GO) annotations related to this gene 
include identical protein binding. An important paralog of this gene 
is IFIT2. 
IFITM3 
interferon 
induced 
transmembrane 
protein 3 
Protein Coding gene. Diseases associated with IFITM3 include 
Influenza. Among its related pathways are Innate Immune System 
and Interferon gamma signaling. An important paralog of this gene 
is IFITM1. 
ISG15 
ISG15 ubiquitin-
like modifier 
Protein Coding gene. Diseases associated with ISG15 include 
Immunodeficiency 38 With Basal Ganglia Calcification and 
Influenza. Among its related pathways are RIG-I/MDA5 mediated 
induction of IFN-alpha/beta pathways and Innate Immune System. 

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Gene Ontology (GO) annotations related to this gene include 
protein tag. An important paralog of this gene is UBC. 
LAMP3 
lysosomal-
associated 
membrane 
protein 3 
Protein Coding gene. Diseases associated with LAMP3 include 
Syndromic Oculocutaneous Albinism and Rem Sleep Behavior 
Disorder. 
LY6E 
lymphocyte 
antigen 6 
complex, locus E 
Protein Coding gene. Diseases associated with LY6E include Acute 
Promyelocytic Leukemia and West Nile Virus. Among its related 
pathways are Ectoderm Differentiation and Metabolism of proteins. 
An important paralog of this gene is GPIHBP1. 
MX1 
myxovirus 
(influenza virus) 
resistance 1 
Protein Coding gene. Diseases associated with MX1 include 
Influenza and Viral Encephalitis. Among its related pathways are 
Innate Immune System and Interferon gamma signaling. Gene 
Ontology (GO) annotations related to this gene include GTP 
binding and GTPase activity. An important paralog of this gene is 
MX2. 
 
OAS1 
2'-5'-
oligoadenylate 
synthetase 1, 
40/46kDa 
Protein Coding gene. Diseases associated with OAS1 include 
Infantile-Onset Pulmonary Alveolar Proteinosis-
Hypogammaglobulinemia and Pulmonary Alveolar Proteinosis 
With Hypogammaglobulinemia. Among its related pathways are 
Interferon gamma signaling and Innate Immune System. Gene 
Ontology (GO) annotations related to this gene include RNA 
binding and transferase activity. An important paralog of this gene 
is OAS3. 
 
OAS2 
2'-5' 
oligoadenylate 
synthetase 2 
Protein Coding gene. Diseases associated with OAS2 include Tick-
Borne Encephalitis and Microphthalmia With Limb Anomalies. 
Among its related pathways are Interferon gamma signaling and 
Innate Immune System. Gene Ontology (GO) annotations related to 
this gene include RNA binding and transferase activity. An 
important paralog of this gene is OAS3. 
OAS3 
2'-5' 
oligoadenylate 
synthetase 3 
Protein Coding gene. Diseases associated with OAS3 include 
Chikungunya and Tick-Borne Encephalitis. Among its related 
pathways are Interferon gamma signaling and Innate Immune 
System. Gene Ontology (GO) annotations related to this gene 
include RNA binding and transferase activity. An important paralog 
of this gene is OAS2. 
OASL 
2'-5'-
oligoadenylate 
synthetase-like 
Protein Coding gene. Diseases associated with OASL include West 
Nile Fever and West Nile Virus Infection. Among its related 
pathways are Interferon gamma signaling and Innate Immune 
System. Gene Ontology (GO) annotations related to this gene 
include double-stranded RNA binding. An important paralog of this 
gene is OAS1. 
RSAD2 
radical S-
adenosyl 
Protein Coding gene. Diseases associated with RSAD2 include 
Yellow Fever and Chikungunya. Among its related pathways are 

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methionine 
domain 
containing 2 
Innate Immune System and Interferon gamma signaling. Gene 
Ontology (GO) annotations related to this gene include protein self-
association and iron-sulfur cluster binding. 
RTP4 
receptor 
transporter 
protein 4 
Protein Coding gene. Among its related pathways are Signaling by 
GPCR. An important paralog of this gene is RTP3. 
SERPING1 
serine (or 
cysteine) 
peptidase 
inhibitor, clade 
G, member 1 
Protein Coding gene. Diseases associated with SERPING1 include 
Type 1 Hereditary Angioedema and partial defiency of 
Complement Component 4. Among its related pathways are 
Immune response Lectin induced complement pathway and 
Formation of Fibrin Clot (Clotting Cascade). Gene Ontology (GO) 
annotations related to this gene include serine-type endopeptidase 
inhibitor activity. An important paralog of this gene is SERPINF2. 
3.9.9.3.1.2 M3.4 17 Genes 
Abbreviation 
Gene 
Function36,38 (according to Genecards.org) 
DDX58 
DEAD (Asp-Glu-
Ala-Asp) box 
polypeptide 58 
Protein Coding gene. Diseases associated with DDX58 include 
Singleton-Merten Syndrome 2 and Singleton-Merten Syndrome. 
Among its related pathways are RIG-I/MDA5 mediated induction 
of IFN-alpha/beta pathways and Cytosolic sensors of pathogen-
associated DNA. Gene Ontology (GO) annotations related to this 
gene include nucleic acid binding and hydrolase activity. An 
important paralog of this gene is ENSG00000288684. 
GBP1 
guanylate 
binding protein 1, 
interferon-
inducible 
Protein Coding gene. Diseases associated with GBP1 include 
Chronic Active Epstein-Barr Virus Infection and Aneurysmal Bone 
Cysts. Among its related pathways are Interferon gamma signaling 
and NF-kB (NFkB) Pathway. Gene Ontology (GO) annotations 
related to this gene include identical protein binding and enzyme 
binding. An important paralog of this gene is GBP3. 
GBP3 
guanylate 
binding protein 3 
Protein Coding gene. Diseases associated with GBP3 include 
Retinitis Pigmentosa 7. Among its related pathways are Interferon 
gamma signaling and Calcineurin-regulated NFAT-dependent 
transcription in lymphocytes. Gene Ontology (GO) annotations 
related to this gene include GTP binding and GTPase activity. An 
important paralog of this gene is GBP1. 
GBP5 
guanylate 
binding protein 5 
Protein Coding gene. Diseases associated with GBP5 include 
Chronic Active Epstein-Barr Virus Infection. Among its related 
pathways are Interferon gamma signaling and NF-kB (NFkB) 
Pathway. Gene Ontology (GO) annotations related to this gene 
include identical protein binding and GTPase activity. An important 
paralog of this gene is GBP3. 
HERC6 
HECT And RLD 
Domain 
Containing E3 
Ubiquitin Protein 
Ligase Family 
Member 6 
Protein Coding gene. Diseases associated with HERC6 include 
Marburg Hemorrhagic Fever. Among its related pathways are 
Innate Immune System and Class I MHC mediated antigen 
processing and presentation. Gene Ontology (GO) annotations 
related to this gene include ligase activity and ubiquitin-protein 

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transferase activity. An important paralog of this gene is 
ENSG00000287542. 
IFI35 
interferon-
induced protein 
35 
Protein Coding gene. Diseases associated with IFI35 include 
Stomatitis and Mouth Disease. Among its related pathways are 
Innate Immune System and Interferon gamma signaling. An 
important paralog of this gene is NMI. 
IFIH1 
interferon 
induced with 
helicase C 
domain 1 
Protein Coding gene. Diseases associated with IFIH1 include 
Singleton-Merten Syndrome 1 and Aicardi-Goutieres Syndrome 7. 
Among its related pathways are RIG-I/MDA5 mediated induction 
of IFN-alpha/beta pathways and Cytosolic sensors of pathogen-
associated DNA. Gene Ontology (GO) annotations related to this 
gene include nucleic acid binding and hydrolase activity. An 
important paralog of this gene is DDX58. 
IFIT2 
interferon-
induced protein 
with 
tetratricopeptide 
repeats 2 
Protein Coding gene. Diseases associated with IFIT2 include 
Japanese Encephalitis and Microphthalmia With Limb Anomalies. 
Among its related pathways are Innate Immune System and 
Interferon gamma signaling. An important paralog of this gene is 
IFIT3. 
IFIT5 
interferon-
induced protein 
with 
tetratricopeptide 
repeats 5 
Protein Coding gene. Gene Ontology (GO) annotations related to 
this gene include tRNA binding. An important paralog of this gene 
is IFIT1. 
IFITM1 
interferon 
induced 
transmembrane 
protein 1 
Protein Coding gene. Diseases associated with IFITM1 include 
West Nile Virus and Dengue Virus. Among its related pathways are 
Innate Immune System and Interferon gamma signaling. Gene 
Ontology (GO) annotations related to this gene include obsolete 
signal transducer activity, downstream of receptor. An important 
paralog of this gene is IFITM3. 
LGALS3BP 
lectin, 
galactoside-
binding, soluble, 
3 binding protein 
Protein Coding gene. Diseases associated with LGALS3BP include 
Henoch-Schoenlein Purpura and Varicose Veins. Among its related 
pathways are Response to elevated platelet cytosolic Ca2+. Gene 
Ontology (GO) annotations related to this gene include scavenger 
receptor activity. An important paralog of this gene is DMBT1. 
PARP9 
poly (ADP-
ribose) 
polymerase 
family, member 9 
Protein Coding gene. Diseases associated with PARP9 include B-
Cell Lymphoma and Lymphoma. Among its related pathways are 
Metabolism of water-soluble vitamins and cofactors and Nicotinate 
metabolism. Gene Ontology (GO) annotations related to this gene 
include NAD+ ADP-ribosyltransferase activity. An important 
paralog of this gene is PARP14. 
PLSCR1 
phospholipid 
scramblase 1 
Protein Coding gene. Diseases associated with PLSCR1 include 
Scott Syndrome. Among its related pathways are EGF/EGFR 
Signaling Pathway. Gene Ontology (GO) annotations related to this 
gene include calcium ion binding and proximal promoter DNA-
binding transcription activator activity, RNA polymerase II-
specific. An important paralog of this gene is PLSCR2. 

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SOCS1 
suppressor of 
cytokine 
signaling 1 
Protein Coding gene. Diseases associated with SOCS1 include 
Autoinflammatory Syndrome, Familial, With Or Without 
Immunodeficiency and Lipoprotein Quantitative Trait Locus. 
Among its related pathways are Interferon gamma signaling and 
TGF-Beta Pathway. Gene Ontology (GO) annotations related to this 
gene include protein kinase binding and insulin-like growth factor 
receptor binding. An important paralog of this gene is SOCS7. 
STAT1 
signal transducer 
and activator of 
transcription 1 
Protein Coding gene. Diseases associated with STAT1 include 
Immunodeficiency 31B and Immunodeficiency 31C. Among its 
related pathways are CNTF Signaling and p70S6K Signaling. Gene 
Ontology (GO) annotations related to this gene include DNA-
binding transcription factor activity and protein homodimerization 
activity. An important paralog of this gene is STAT4. 
STAT2 
signal transducer 
and activator of 
transcription 2 
Protein Coding gene. Diseases associated with STAT2 include 
Pseudo-Torch Syndrome 3 and Immunodeficiency 44. Among its 
related pathways are CNTF Signaling and ERK Signaling. Gene 
Ontology (GO) annotations related to this gene include DNA-
binding transcription factor activity and identical protein binding. 
ZBP1 
Z-DNA binding 
protein 1 
Protein Coding gene. Diseases associated with ZBP1 include 
Herpes Simplex and Influenza. Among its related pathways are 
Cytosolic sensors of pathogen-associated DNA and Innate Immune 
System. Gene Ontology (GO) annotations related to this gene 
include RNA binding and left-handed Z-DNA binding. 
3.9.9.3.1.3 M5.12 8 Genes 
Abbreviation 
Gene 
Function36,38 (according to Genecards.org) 
ADAR 
adenosine 
deaminase, 
RNA-specific 
Protein Coding gene. Diseases associated with ADAR include 
Dyschromatosis Symmetrica Hereditaria and Aicardi-Goutieres 
Syndrome 6. Among its related pathways are Innate Immune 
System and Formation of editosomes by ADAR proteins. Gene 
Ontology (GO) annotations related to this gene include adenosine 
deaminase activity. An important paralog of this gene is ADARB1. 
BST2 
bone marrow 
stromal cell 
antigen 2 
Protein Coding gene. Diseases associated with BST2 include 
Stomatitis and Human Immunodeficiency Virus Type 1. Among its 
related pathways are Innate Immune System and Interferon gamma 
signaling. Gene Ontology (GO) annotations related to this gene 
include obsolete signal transducer activity. 
GBP2 
guanylate 
binding protein 2 
Protein Coding gene. Among its related pathways are Interferon 
gamma signaling and NF-kB (NFkB) Pathway. Gene Ontology 
(GO) annotations related to this gene include GTP binding and 
GTPase activity. An important paralog of this gene is GBP3. 
IRF9 
interferon 
regulatory factor 
9 
Protein Coding gene. Diseases associated with IRF9 include 
Immunodeficiency 65. Among its related pathways are Interferon 
gamma signaling and Jak/STAT Signaling Pathway. Gene Ontology 
(GO) annotations related to this gene include DNA-binding 

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transcription factor activity. An important paralog of this gene is 
IRF4. 
ISG20 
interferon 
stimulated 
exonuclease 
gene 20kDa 
Protein Coding gene. Diseases associated with ISG20 include 
Hepatitis C and Yellow Fever. Among its related pathways are 
Innate Immune System and Interferon gamma signaling. Gene 
Ontology (GO) annotations related to this gene include nucleic acid 
binding and 3'-5'-exoribonuclease activity. An important paralog of 
this gene is AEN. 
SP100 
nuclear antigen 
Sp100 
Protein Coding gene. Diseases associated with SP100 include 
Autoimmune Cholangitis and Primary Biliary Cholangitis. Among 
its related pathways are Interferon gamma signaling and 
SUMOylation. Gene Ontology (GO) annotations related to this gene 
include protein homodimerization activity and chromatin binding. 
An important paralog of this gene is SP140. 
TRIM21 
tripartite motif-
containing 21 
Protein Coding gene. Diseases associated with TRIM21 include 
Heart Block, Congenital and Sjogren Syndrome. Among its related 
pathways are Interferon gamma signaling and Cytosolic sensors of 
pathogen-associated DNA. Gene Ontology (GO) annotations related 
to this gene include identical protein binding and ligase activity. An 
important paralog of this gene is TRIM27. 
TRIM25 
tripartite motif-
containing 25 
Protein Coding gene. Diseases associated with TRIM25 include 
Swine Influenza and Middle East Respiratory Syndrome. Among its 
related pathways are RIG-I/MDA5 mediated induction of IFN-
alpha/beta pathways and Interferon gamma signaling. Gene 
Ontology (GO) annotations related to this gene include acid-amino 
acid ligase activity. An important paralog of this gene is TRIM7. 
Table 2 Genes needed to measure IFNGS in the M1.2, M3.4 and M5.12 modules; The interferome Database, Genecards.org and 
Chiche et al.s supplementals have been used to create this table19,38–40. 
3.9.9.3.2 El-Sherbiny et al. method 
In addition to these we will evaluate mRNA for IFNGS as per El-Sherbiny et al.41 Who has 
segregated two IFNGS based on the above measurements into a characterizing type 1 IFN related 
gene signature as well as an activity-dependent type 2 IFN related gene signature. 
3.9.9.3.2.1 Type 1 IFN relation 
13 genes (6 unique) 
Abbreviation 
Gene 
Included 
in 
Function36,38 (according to 
Genecards.org) 
ISG15  
ISG15 ubiquitin-
like modifier 
M1.2 
Protein Coding gene. Diseases associated 
with ISG15 include Immunodeficiency 38 
With Basal Ganglia Calcification and 
Influenza. Among its related pathways are 
RIG-I/MDA5 mediated induction of IFN-
alpha/beta pathways and Innate Immune 
System. Gene Ontology (GO) annotations 
related to this gene include protein tag. An 
important paralog of this gene is UBC. 

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IFI44  
interferon-
induced protein 
44 
M1.2 
Protein Coding gene. Diseases associated 
with IFI44 include Hepatitis D and Potocki-
Shaffer Syndrome. An important paralog of 
this gene is IFI44L. 
IFI27 
Interferon Alpha 
Inducible 
Protein 27 
- 
Protein Coding gene. Diseases associated 
with IFI27 include Hepatitis C and Oral 
Leukoplakia. Among its related pathways 
are Innate Immune System and Interferon 
gamma signaling. Gene Ontology (GO) 
annotations related to this gene include 
RNA polymerase II activating transcription 
factor binding and lamin binding. An 
important paralog of this gene is IFI27L2. 
CXCL10  
chemokine (C-
X-C motif) 
ligand 10 
M1.2 
Protein Coding gene. Diseases associated 
with CXCL10 include Periapical 
Periodontitis and Viral Encephalitis. Among 
its related pathways are Innate Immune 
System and PEDF Induced Signaling. Gene 
Ontology (GO) annotations related to this 
gene include signaling receptor binding and 
chemokine activity. An important paralog of 
this gene is CXCL9. 
RSAD2  
radical S-
adenosyl 
methionine 
domain 
containing 2 
M1.2 
Protein Coding gene. Diseases associated 
with RSAD2 include Yellow Fever and 
Chikungunya. Among its related pathways 
are Innate Immune System and Interferon 
gamma signaling. Gene Ontology (GO) 
annotations related to this gene include 
protein self-association and iron-sulfur 
cluster binding. 
IFIT1 
interferon-
induced protein 
with 
tetratricopeptide 
repeats 1 
M1.2 
Protein Coding gene. Diseases associated 
with IFIT1 include Microphthalmia With 
Limb Anomalies and Vasculopathy, Retinal, 
With Cerebral Leukoencephalopathy And 
Systemic Manifestations. Among its related 
pathways are Innate Immune System and 
Interferon gamma signaling. Gene Ontology 
(GO) annotations related to this gene 
include RNA binding. An important paralog 
of this gene is IFIT1B. 
IFI44L  
interferon-
induced protein 
44-like 
M1.2 
Protein Coding gene. Diseases associated 
with IFI44L include Lymph Node 
Tuberculosis and Immunodeficiency 38 
With Basal Ganglia Calcification. An 
important paralog of this gene is IFI44. 
CCL8  
C-C Motif 
Chemokine 
Ligand 8 
- 
Protein Coding gene. Diseases associated 
with CCL8 include Tenosynovitis and 
Tendinitis. Among its related pathways are 
p70S6K Signaling and TGF-Beta Pathway. 

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Gene Ontology (GO) annotations related to 
this gene include protein kinase activity and 
chemokine activity. An important paralog of 
this gene is CCL11. 
XAF1  
XIAP-Associated 
Factor 1 
- 
Protein Coding gene. Among its related 
pathways are Innate Immune System and 
Apoptosis and Autophagy. An important 
paralog of this gene is TRAFD1. 
IFI6 
Interferon Alpha 
Inducible Protein 
6 
- 
Protein Coding gene. Diseases associated 
with IFI6 include Dengue Virus. Among its 
related pathways are Innate Lymphoid Cells 
Differentiation and Innate Immune System. 
An important paralog of this gene is 
IFI27L2. 
GBP1 
guanylate 
binding protein 
1, interferon-
inducible 
M3.4 
Protein Coding gene. Diseases associated 
with GBP1 include Chronic Active Epstein-
Barr Virus Infection and Aneurysmal Bone 
Cysts. Among its related pathways are 
Interferon gamma signaling and NF-kB 
(NFkB) Pathway. Gene Ontology (GO) 
annotations related to this gene include 
identical protein binding and enzyme 
binding. An important paralog of this gene 
is GBP3. 
IRF7 
interferon 
regulatory factor 
7 
- 
Protein Coding gene. Diseases associated 
with IRF7 include Immunodeficiency 39 
and Predisposition To Severe Viral Infection 
Due To Irf7 Deficiency. Among its related 
pathways are Interferon gamma signaling 
and Regulation of nuclear SMAD2/3 
signaling. Gene Ontology (GO) annotations 
related to this gene include DNA-binding 
transcription factor activity. An important 
paralog of this gene is IRF6. 
CEACAM1 
Carcinoembryonic 
Antigen-Related 
Cell Adhesion 
Molecule 1 
- 
Protein Coding gene. Diseases associated 
with CEACAM1 include Acute Gonococcal 
Endometritis and Adenomatoid Tumor. 
Among its related pathways are Adhesion 
and Innate Immune System. Gene Ontology 
(GO) annotations related to this gene 
include protein homodimerization activity. 
An important paralog of this gene is 
CEACAM6. 

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3.9.9.3.2.2 Type 2 IFN relation 
14 genes 
(7 
unique) 
Abbreviation 
Gene 
Included 
in 
Function36,38 (according to 
Genecards.org) 
LAMP3 
Lysosomal 
Associated 
Membrane 
Protein 3 
M1.2 
Protein Coding gene. Diseases associated 
with LAMP3 include Syndromic 
Oculocutaneous Albinism and Rem Sleep 
Behavior Disorder. 
IFIH1 
interferon 
induced with 
helicase C 
domain 1 
M3.4 
Protein Coding gene. Diseases associated 
with IFIH1 include Singleton-Merten 
Syndrome 1 and Aicardi-Goutieres 
Syndrome 7. Among its related pathways 
are RIG-I/MDA5 mediated induction of 
IFN-alpha/beta pathways and Cytosolic 
sensors of pathogen-associated DNA. Gene 
Ontology (GO) annotations related to this 
gene include nucleic acid binding and 
hydrolase activity. An important paralog of 
this gene is DDX58. 
PHF11 
PHD Finger 
Protein 11 
- 
Protein Coding gene. Diseases associated 
with PHF11 include Asthma and Dermatitis. 
An important paralog of this gene is PHF6. 
SERPING1 
serine (or 
cysteine) 
peptidase 
inhibitor, clade G, 
member 1 
M1.2 
Protein Coding gene. Diseases associated 
with SERPING1 include Angioedema, 
Hereditary, 1 and Partial Deficiency Of 
Complement Component 4. Among its 
related pathways are Immune response 
Lectin induced complement pathway and 
Formation of Fibrin Clot (Clotting Cascade). 
Gene Ontology (GO) annotations related to 
this gene include serine-type endopeptidase 
inhibitor activity. An important paralog of 
this gene is SERPINF2. 
IFI16 
Interferon Gamma 
Inducible Protein 
16 
- 
Protein Coding gene. Diseases associated 
with IFI16 include Herpes Simplex and 
Genital Herpes. Among its related pathways 
are Senescence and Autophagy in Cancer 
and Cytosolic sensors of pathogen-
associated DNA. Gene Ontology (GO) 
annotations related to this gene include 
transcription factor binding. An important 
paralog of this gene is PYHIN1. 
BST2 
bone marrow 
stromal cell 
antigen 2 
M5.12 
Protein Coding gene. Diseases associated 
with BST2 include Stomatitis and Human 
Immunodeficiency Virus Type 1. Among its 
related pathways are Innate Immune System 
and Interferon gamma signaling. Gene 

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Ontology (GO) annotations related to this 
gene include obsolete signal transducer 
activity. 
SP100 
nuclear antigen 
Sp100 
M5.12 
Protein Coding gene. Diseases associated 
with SP100 include Autoimmune 
Cholangitis and Primary Biliary Cholangitis. 
Among its related pathways are Interferon 
gamma signaling and SUMOylation. Gene 
Ontology (GO) annotations related to this 
gene include protein homodimerization 
activity and chromatin binding. An 
important paralog of this gene is SP140. 
NT5C3B 
5'-Nucleotidase, 
Cytosolic III-Like 
- 
Protein Coding gene. Among its related 
pathways are Gene Expression and 
Deadenylation-dependent mRNA decay. 
Gene Ontology (GO) annotations related to 
this gene include nucleotide binding and 5'-
nucleotidase activity. An important paralog 
of this gene is NT5C3A. 
SOCS1 
suppressor of 
cytokine signaling 
1 
M3.4 
Protein Coding gene. Diseases associated 
with SOCS1 include Autoinflammatory 
Syndrome, Familial, With Or Without 
Immunodeficiency and Lipoprotein 
Quantitative Trait Locus. Among its related 
pathways are Interferon gamma signaling 
and TGF-Beta Pathway. Gene Ontology 
(GO) annotations related to this gene 
include protein kinase binding and insulin-
like growth factor receptor binding. An 
important paralog of this gene is SOCS7. 
TRIM38 
Tripartite Motif 
Containing 38 
- 
rotein Coding gene. Diseases associated 
with TRIM38 include Fanconi Renotubular 
Syndrome 2. Among its related pathways 
are Interferon gamma signaling and Innate 
Immune System. Gene Ontology (GO) 
annotations related to this gene include 
ligase activity and obsolete signal transducer 
activity. An important paralog of this gene is 
TRIM21. 
UNC93B1 
Unc-93 Homolog 
B1, TLR 
Signaling 
Regulator 
- 
Protein Coding gene. Diseases associated 
with UNC93B1 include Encephalopathy, 
Acute, Infection-Induced 1 and Herpes 
Simplex Encephalitis. Among its related 
pathways are Innate Immune System and 
Activated TLR4 signalling. Gene Ontology 
(GO) annotations related to this gene 
include Toll-like receptor binding. An 
important paralog of this gene is UNC93A. 

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UBE2L6 
Ubiquitin/ISG15-
Conjugating 
Enzyme E2 L6 
- 
Protein Coding gene. Among its related 
pathways are RIG-I/MDA5 mediated 
induction of IFN-alpha/beta pathways and 
Innate Immune System. Gene Ontology 
(GO) annotations related to this gene 
include ligase activity and acid-amino acid 
ligase activity. An important paralog of this 
gene is UBE2L5. 
STAT1 
signal 
transducer and 
activator of 
transcription 1 
M3.4 
Protein Coding gene. Diseases associated 
with STAT1 include Immunodeficiency 31B 
and Immunodeficiency 31C. Among its 
related pathways are CNTF Signaling and 
p70S6K Signaling. Gene Ontology (GO) 
annotations related to this gene include 
DNA-binding transcription factor activity 
and protein homodimerization activity. An 
important paralog of this gene is STAT4. 
TAP1 
Transporter 1, 
ATP Binding 
Cassette 
Subfamily B 
Member 
- 
Protein Coding gene. Diseases associated 
with TAP1 include Immunodeficiency By 
Defective Expression Of Mhc Class I and 
Bare Lymphocyte Syndrome, Type I. 
Among its related pathways are 
Thrombopoetin signaling via JAK-STAT 
pathway and Innate Immune System. Gene 
Ontology (GO) annotations related to this 
gene include protein homodimerization 
activity and ATPase activity, coupled to 
transmembrane movement of substances. An 
important paralog of this gene is TAP2. 
Table 3 Genes related to type 1 and 2 IFN according to El-Sherbiny et al.41 
3.9.9.3.3 Siddiqi et al. method 
These genes will be analyzed due to the findings by Siddiqi et al.42 
3.9.9.3.3.1 Type 2 IFN relation 
3 genes 
(3 
unique) 
Abbreviation 
Gene 
Included 
in 
Function36,38 (according to Genecards.org) 
S100A9 
S100 Calcium 
Binding Protein 
A9 
Siddiqi 
et al 
Protein Coding gene. Diseases associated with 
S100A9 include Cystic Fibrosis and Juvenile 
Rheumatoid Arthritis. Among its related 
pathways are MyD88 dependent cascade 
initiated on endosome and Diseases of Immune 
System. Gene Ontology (GO) annotations 
related to this gene include calcium ion binding 

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and microtubule binding. An important paralog 
of this gene is S100A12. 
S100A8 
S100 Calcium 
Binding Protein 
A8 
Siddiqi 
et al. 
Protein Coding gene. Diseases associated with 
S100A8 include Peptic Ulcer Disease and 
Duodenal Ulcer. Among its related pathways 
are MyD88 dependent cascade initiated on 
endosome and Diseases of Immune System. 
Gene Ontology (GO) annotations related to this 
gene include calcium ion binding and RAGE 
receptor binding. An important paralog of this 
gene is S100A12. 
FCGR1A 
Fc Gamma 
Receptor Ia 
Siddiqi 
et al. 
Protein Coding gene. Diseases associated with 
FCGR1A include Peritonitis and Pharyngitis. 
Among its related pathways are ADORA2B 
mediated anti-inflammatory cytokines 
production and Regulation of actin dynamics 
for phagocytic cup formation. Gene Ontology 
(GO) annotations related to this gene include 
obsolete signal transducer activity, downstream 
of receptor and IgG binding. An important 
paralog of this gene is FCRLB. 
 
3.9.9.3.4 Assumed presentation of IFNGS 
Assuming our patient population is similar to the one described by Chiche et al. we should see three 
groups of increasing IFNGS in the M1.2 then the M3.4 and then the M5.12 modules as well as 
increasing SLEDAI-2K scores (see Figure 5)19, since our population is selected for a lower 
SLEDAI -2Kscore in order to tolerate the intervention better, we will likely see a skew towards 
fewer patients with a high M3.4 and M5.12 scores. But as our hypotheses is related to the activity of 
IFNα, all three groups with positive scores in any module should have reduced effect of exercise as 
described in the outcomes (see section 3.6).  
 
Figure 5 IFN score from Chiche et al.19  

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3.9.9.4 Analysis of Il-6 and TNFα related mRNA in peripheral blood 
In addition to the analysis for IFNGS we will analyse mRNA in peripheral blood for transcripts of 
mRNA induced by IL-6 and TNFα. In summation we will analyse 38 genes for mRNA expression 
related to IL-6 and TNFα. 
Whole blood will be procured and stored in a Pax-Gene tube as per 3.9.9 above, but will be 
analysed for mRNA transcripts for IL-6 and TNFα related genes as outlined below. 
3.9.9.4.1 IL-6 Related mRNA expression 
For Il-6 related gene expression, as done by other studies we will analyse Monocyte Chemotactic 
Protein 1 (MCP-1, which is also induced by IFN-γ)43, SOCS344 and the IL-6 responsive genes of 
circulating macrophages which are important drivers of the acute phase response denoted by Jura et 
al.45. 
In addition to this, Robson-Ansley et al. has done methylation evaluation on healthy volunteers and 
their DNA demethylation in peripheral blood (which increases the transcription of the gene) as a 
result of the myokine activity of Il-646, we will analyse these genes as well, knowing that we are 
analysing mRNA expression in contrast to the original study. 
For the list of genes will analyse and relate to IL-6 activity see Table 4. 
3.9.9.4.1.1 IL-6 
27 Genes (27 Unique) 
 
Abbreviation 
Gene 
From Study 
Function36,38 (according to Genecards.org) 
α2M 
Alpha-2-Macroglobulin 
Fey 199147 
Protein Coding gene. Diseases associated 
with A2M include Alzheimer Disease and 
Alpha-2-Macroglobulin Deficiency. Among 
its related pathways are A-beta Uptake and 
Degradation and IL6-mediated signaling 
events. Gene Ontology (GO) annotations 
related to this gene include signaling 
receptor binding and serine-type 
endopeptidase inhibitor activity. An 
important paralog of this gene is PZP. 
ADCY7 
Adenylate Cyclase 7 
Robson-Ansley 
201446 
Protein Coding gene. Diseases associated 
with ADCY7 include Inhalation Anthrax. 
Among its related pathways are Aquaporin-
mediated transport and Activation of cAMP-
Dependent PKA. Gene Ontology (GO) 
annotations related to this gene include 
phosphorus-oxygen lyase activity and 
adenylate cyclase activity. An important 
paralog of this gene is ADCY2. 
AER61/EOGT 
EGF Domain-Specific 
O-Linked N-
Acetylglucosamine 
(GlcNAc) Transferase 
Robson-Ansley 
201446 
This gene encodes an enzyme that acts in the 
lumen of the endoplasmic reticulum to 
catalyze the transfer of N-acetylglucosamine 
to serine or threonine residues of 
extracellular-targeted proteins. This enzyme 
modifies proteins containing eukaryotic 
growth factor (EGF)-like domains, including 
the Notch receptor, thereby regulating 

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developmental signalling. Mutations in this 
gene have been observed in individuals with 
Adams-Oliver syndrome 4. Alternative 
splicing results in multiple transcript 
variants. [provided by RefSeq, Aug 2015] 
Ar 45 
Androgen Receptor 
 
Protein Coding gene. Diseases associated 
with AR include Androgen Insensitivity, 
Partial and Spinal And Bulbar Muscular 
Atrophy, X-Linked 1. Among its related 
pathways are Coregulation of Androgen 
receptor activity and Integrated Breast 
Cancer Pathway. Gene Ontology (GO) 
annotations related to this gene include 
DNA-binding transcription factor activity 
and chromatin binding. An important 
paralog of this gene is NR3C2. 
BRCA2 
Breast And Ovarian 
Cancer Susceptibility 
Gene, Early Onset 
Robson-Ansley 
201446 
Protein Coding gene. Diseases associated 
with BRCA2 include Fanconi Anemia, 
Complementation Group D1 and Breast 
Cancer. Among its related pathways are Cell 
Cycle, Mitotic and Integrated Breast Cancer 
Pathway. Gene Ontology (GO) annotations 
related to this gene include protease binding 
and histone acetyltransferase activity. 
C10orf89/PSTK 
Phosphoseryl-TRNA 
Kinase 
Robson-Ansley 
201446 
Protein Coding gene. Diseases associated 
with PSTK include Ivic Syndrome and 
Ischiocoxopodopatellar Syndrome With Or 
Without Pulmonary Arterial Hypertension. 
Among its related pathways are Peptide 
chain elongation and Metabolism. Gene 
Ontology (GO) annotations related to this 
gene include kinase activity and tRNA 
binding. 
CD11a/ITGAL48,49 
Cluster of 
Differentiation 11a / 
Integrin Subunit Alpha 
L 
 
Protein Coding gene. Diseases associated 
with ITGAL include Immune-Complex 
Glomerulonephritis and Chronic Venous 
Insufficiency. Among its related pathways 
are Integrin cell surface interactions and 
ERK Signaling. Gene Ontology (GO) 
annotations related to this gene include 
protein heterodimerization activity and cell 
adhesion molecule binding. An important 
paralog of this gene is ITGAX. 
CD70/ TNFSF748,49 
Cluster of 
Differentiation 70 / 
Tumor Necrosis Factor 
Ligand Superfamily 
Member 7 
 
Protein Coding gene. Diseases associated 
with CD70 include Lymphoproliferative 
Syndrome 3 and Acute Myocarditis. Among 
its related pathways are TRAF Pathway and 
Innate Immune System. Gene Ontology 
(GO) annotations related to this gene include 

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signaling receptor binding and protease 
binding. 
CDK9 
Cyclin dependant kinase 
9 
Robson-Ansley 
201446 
Protein Coding gene. Diseases associated 
with CDK9 include Herpes Simplex and 
Human Cytomegalovirus Infection. Among 
its related pathways are HIV Life Cycle and 
Formation of HIV-1 elongation complex 
containing HIV-1 Tat. Gene Ontology (GO) 
annotations related to this gene include 
transferase activity, transferring phosphorus-
containing groups and protein tyrosine 
kinase activity. An important paralog of this 
gene is CDK13. 
CREB145 
Cyclic AMP-
Responsive Element-
Binding Protein 1 
 
Protein Coding gene. Diseases associated 
with CREB1 include Histiocytoma, 
Angiomatoid Fibrous and Melanoma Of 
Soft Tissue. Among its related pathways are 
PI3K/AKT activation and Activated TLR4 
signalling. Gene Ontology (GO) annotations 
related to this gene include DNA-binding 
transcription factor activity and enzyme 
binding. An important paralog of this gene is 
CREM. 
FCRL2 
Fc Receptor-Like 2 
Robson-Ansley 
201446 
Protein Coding gene. Diseases associated 
with FCRL2 include Spastic Paraplegia 62, 
Autosomal Recessive. Gene Ontology (GO) 
annotations related to this gene include 
SH3/SH2 adaptor activity. An important 
paralog of this gene is FCRL3. 
Foxq145 
Hepatocyte Nuclear 
Factor 3 Forkhead 
Homolog 1 
 
Protein Coding gene. Diseases associated 
with FOXQ1 include Anterior Segment 
Dysgenesis 3 and Ectodermal Dysplasia 5, 
Hair/Nail Type. Among its related pathways 
are Preimplantation Embryo. Gene Ontology 
(GO) annotations related to this gene include 
DNA-binding transcription factor activity 
and DNA-binding transcription factor 
activity, RNA polymerase II-specific. An 
important paralog of this gene is FOXD1. 
GADD45β45 
Growth Arrest and DNA 
Damage Inducible Beta 
 
Protein Coding gene. Among its related 
pathways are Development TGF-beta 
receptor signaling and miRNA Regulation 
of DNA Damage Response. An important 
paralog of this gene is GADD45A. 
GRP1/ CYTH3 
General receptor for 
phosphoinositides 1-
associated scaffold 
protein / Cytohesin-3 
Robson-Ansley 
201446 
Protein Coding gene. Among its related 
pathways are Arf6 signaling events and 
Vesicle-mediated transport. Gene Ontology 
(GO) annotations related to this gene include 
phosphatidylinositol-3,4,5-trisphosphate 

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binding and ARF guanyl-nucleotide 
exchange factor activity. An important 
paralog of this gene is CYTH1. 
HSP90AB1 
Heat Shock Protein 
90kDa Alpha 
(Cytosolic), Class B 
Member 1 
A. 
STEPHANOU et 
al. 199750 
Protein Coding gene. Among its related 
pathways are Cell Cycle, Mitotic and PI3K-
Akt signaling pathway. Gene Ontology 
(GO) annotations related to this gene include 
RNA binding and protein kinase binding. 
An important paralog of this gene is 
HSP90AA1. 
IER345 
Immediate Early 
Response 3 
 
Protein Coding gene. Diseases associated 
with IER3 include Cortical Dysplasia, 
Complex, With Other Brain Malformations 
6 and Gilles De La Tourette Syndrome. 
Among its related pathways are PI3K/AKT 
activation and RET signaling. 
IRAK3 
Interleukin‐1 receptor‐
associated kinase 
Robson-Ansley 
201446 
Protein Coding gene. Diseases associated 
with IRAK3 include Asthma-Related Traits 
5 and Asthma. Among its related pathways 
are IL-1 Family Signaling Pathways and 
ERK Signaling. Gene Ontology (GO) 
annotations related to this gene include 
protein homodimerization activity and 
protein kinase activity. An important paralog 
of this gene is IRAK1. 
JDP2 
Jun Dimerization 
protein 2 
Robson-Ansley 
201446 
Protein Coding gene. Diseases associated 
with JDP2 include Granulomatous Amebic 
Encephalitis and Primary Amebic 
Meningoencephalitis. Among its related 
pathways are IL-1 Family Signaling 
Pathways and Tacrolimus/Cyclosporine 
Pathway, Pharmacodynamics. Gene 
Ontology (GO) annotations related to this 
gene include DNA-binding transcription 
factor activity and protein 
heterodimerization activity. An important 
paralog of this gene is ATF3. 
LRG-151 
Leucine Rich Alpha-2-
Glycoprotein 1 
 
Protein Coding gene. Diseases associated 
with LRG1 include Appendicitis and 
Normal Pressure Hydrocephalus. Among its 
related pathways are Innate Immune System. 
Gene Ontology (GO) annotations related to 
this gene include transforming growth factor 
beta receptor binding. An important paralog 
of this gene is CHADL. 

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LDB2 
LIM Domain Binding 2 Robson-Ansley 
201446 
MCP-1/CCL243 
Monocyte Chemotactic 
Protein 1 / C-C Motif 
Chemokine Ligand 2 
 
Protein Coding gene. Diseases associated 
with CCL2 include Neural Tube Defects and 
Human Immunodeficiency Virus Type 1. 
Among its related pathways are p70S6K 
Signaling and A-beta Uptake and 
Degradation. Gene Ontology (GO) 
annotations related to this gene include 
protein kinase activity and heparin binding. 
An important paralog of this gene is CCL7. 
MGP 
Matrix GLA Protein 
Robson-Ansley 
201446 
Protein Coding gene. Diseases associated 
with MGP include Keutel Syndrome and 
Peripheral Pulmonary Stenosis. Among its 
related pathways are NOTCH1 regulation of 
human endothelial cell calcification and 
Validated transcriptional targets of AP1 
family members Fra1 and Fra2. Gene 
Ontology (GO) annotations related to this 
gene include calcium ion binding and 
structural constituent of bone. 
PLAUR45 
Plasminogen Activator, 
Urokinase Receptor 
 
Protein Coding gene. Diseases associated 
with PLAUR include Cancer of the Ureter 
and Paroxysmal Nocturnal Hemoglobinuria. 
Among its related pathways are Post-
translational modification- synthesis of GPI-
anchored proteins and Transcription 
Receptor-mediated HIF regulation. Gene 
Ontology (GO) annotations related to this 
gene include signaling receptor binding. An 
important paralog of this gene is LYPD3. 
RAG 152,53 
recombination 
activating gene 1 
 
Protein Coding gene. Diseases associated 
with RAG1 include Combined Cellular And 
Humoral Immune Defects With Granulomas 
and Alpha/Beta T-Cell Lymphopenia With 
Gamma/Delta T-Cell Expansion, Severe 
Cytomegalovirus Infection, And 
Autoimmunity. Among its related pathways 
are Interleukin-7 signaling and RET 
signaling. Gene Ontology (GO) annotations 
related to this gene include protein 
homodimerization activity and ubiquitin-
protein transferase activity. 
RAG 246,52,53 
recombination 
activating gene 2 
Robson-Ansley 
201446 
(downregulated) 
Protein Coding gene. Diseases associated 
with RAG2 include Omenn Syndrome and 
Combined Cellular And Humoral Immune 
Defects With Granulomas. Among its 
related pathways are Interleukin-7 signaling 
and RET signaling. Gene Ontology (GO) 

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annotations related to this gene include 
chromatin binding and methylated histone 
binding. 
RELA45 
RELA Proto-Oncogene, 
NF-KB Subunit / 
Nuclear Factor of Kappa 
Light Polypeptide Gene 
Enhancer In B-Cells 3 
 
Protein Coding gene. Diseases associated 
with RELA include Mucocutaneous 
Ulceration, Chronic and Rela Fusion-
Positive Ependymoma. Among its related 
pathways are Activated TLR4 signalling and 
TNFR1 Pathway. Gene Ontology (GO) 
annotations related to this gene include 
DNA-binding transcription factor activity 
and identical protein binding. An important 
paralog of this gene is REL. 
SOCS344,54 
Suppressor of cytokine 
signaling 3 
 
Protein Coding gene. Diseases associated 
with SOCS3 include Dermatitis, Atopic, 4 
and Overnutrition. Among its related 
pathways are Interferon gamma signaling 
and TGF-Beta Pathway. Gene Ontology 
(GO) annotations related to this gene include 
protein kinase inhibitor activity. An 
important paralog of this gene is CISH. 
VEGFA55 
Vascular Endothelial 
Growth Factor A 
 
Protein Coding gene. Diseases associated 
with VEGFA include Microvascular 
Complications Of Diabetes 1 and Poems 
Syndrome. Among its related pathways are 
ERK Signaling and VEGF ligand-receptor 
interactions. Gene Ontology (GO) 
annotations related to this gene include 
protein homodimerization activity and 
protein heterodimerization activity. An 
important paralog of this gene is PGF. 
STAT-3 
Signal Transducer and 
Activator of 
Transcription 3 
Suggested by 
Kanwal Siddiqi42 
Protein Coding gene. Diseases associated 
with STAT3 include Autoimmune Disease, 
Multisystem, Infantile-Onset, 1 and Hyper-
Ige Recurrent Infection Syndrome 1, 
Autosomal Dominant. Among its related 
pathways are IL-9 Signaling Pathways and 
Prolactin Signaling. Gene Ontology (GO) 
annotations related to this gene include 
DNA-binding transcription factor activity 
and sequence-specific DNA binding. An 
important paralog of this gene is STAT1. 
Table 4 Genes related to IL-6 to be tested for mRNA expression 
3.9.9.4.2 TNFα Related mRNA expression 
TNFα related genetic expression of mRNA were found from the study by Smiljanovic et al.56 who 
did in vitro stimulation of whole blood with TNFα to study the mRNA expression of circulating 
macrophages. As well as other authors, noted in Table 5. 

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Only the genes upregulated by Il-6 and TNFα respectively will be included in the geomean and 
standardised scores for these genes (see above) 
3.9.9.4.2.1 TNFα 
15 Genes (13 
Unique) 
Abbreviation 
Gene 
Function36,38 (according to Genecards.org) 
ADAM1756 
A Disintegrin And 
Metalloproteinase 
domain 17 
Protein Coding gene. Diseases associated with ADAM17 include 
Inflammatory Skin And Bowel Disease, Neonatal, 1 and 
Neonatal Inflammatory Skin And Bowel Disease. Among its 
related pathways are Signaling by NOTCH1 and NOTCH2 
Activation and Transmission of Signal to the Nucleus. Gene 
Ontology (GO) annotations related to this gene include SH3 
domain binding and integrin binding. An important paralog of 
this gene is ADAM10. 
ARNTL256 
Aryl Hydrocarbon 
Receptor Nuclear 
Translocator Like 2 
Protein Coding gene. Diseases associated with ARNTL2 include 
Hepatorenal Syndrome and Acute Kidney Failure. Among its 
related pathways are Circadian rythm related genes and BMAL1-
CLOCK,NPAS2 activates circadian gene expression. Gene 
Ontology (GO) annotations related to this gene include DNA-
binding transcription factor activity and protein dimerization 
activity. An important paralog of this gene is ARNTL. 
CASP356 
Caspase 3 
Protein Coding gene. Diseases associated with CASP3 include 
Oropharynx Cancer and Ischemia. Among its related pathways 
are TNFR1 Pathway and ERK Signaling. Gene Ontology (GO) 
annotations related to this gene include peptidase activity and 
cysteine-type peptidase activity. An important paralog of this 
gene is CASP7. 
CASP556 
Caspase 5 
Protein Coding gene. Diseases associated with CASP5 include 
Cowpox and Familial Mediterranean Fever. Among its related 
pathways are TRAF Pathway and Apoptosis and Autophagy. 
Gene Ontology (GO) annotations related to this gene include 
cysteine-type endopeptidase activity and scaffold protein 
binding. An important paralog of this gene is CASP4. 
CCR156 
C-C Motif 
Chemokine Receptor 
1 
Protein Coding gene. Diseases associated with CCR1 include 
Behcet Syndrome and Immune-Complex Glomerulonephritis. 
Among its related pathways are Innate Immune System and 
Chemokine Superfamily: Human/Mouse Ligand-Receptor 
Interactions. Gene Ontology (GO) annotations related to this 
gene include G protein-coupled receptor activity and chemokine 
receptor activity. An important paralog of this gene is CCR3. 
CD22/ SIGLEC2 
56 
Sialic Acid-Binding 
Ig-Like Lectin 2 
Protein Coding gene. Diseases associated with CD22 include 
Refractory Hematologic Cancer and Hairy Cell Leukemia. 
Among its related pathways are Antigen activates B Cell 
Receptor (BCR) leading to generation of second messengers and 
Innate Immune System. Gene Ontology (GO) annotations related 
to this gene include carbohydrate binding. An important paralog 
of this gene is SIGLEC1. 

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GJA356 
Gap Junction Protein 
Alpha 3 
Protein Coding gene. Diseases associated with GJA3 include 
Cataract 14, Multiple Types and Early-Onset Posterior Polar 
Cataract. Among its related pathways are Myometrial Relaxation 
and Contraction Pathways and Gap junction trafficking. Gene 
Ontology (GO) annotations related to this gene include gap 
junction channel activity. An important paralog of this gene is 
GJA8. 
GPR3556 
G Protein-Coupled 
Receptor 35  
Protein Coding gene. Diseases associated with GPR35 include 
Cholangitis, Primary Sclerosing and Short-Rib Thoracic 
Dysplasia 10 With Or Without Polydactyly. Among its related 
pathways are Peptide ligand-binding receptors and Signaling by 
GPCR. Gene Ontology (GO) annotations related to this gene 
include G protein-coupled receptor activity. An important 
paralog of this gene is GPR55. 
MAP3K7IP3/ 
TAB356 
Mitogen-Activated 
Protein Kinase Kinase 
Kinase 7 Interacting 
Protein /TGF-Beta 
Activated Kinase 1 
(MAP3K7)  
Protein Coding gene. Among its related pathways are Activated 
TLR4 signalling and MAP Kinase Signaling. An important 
paralog of this gene is TAB2. 
MCP-1/CCL243 
Monocyte 
Chemotactic Protein 1 
/ C-C Motif 
Chemokine Ligand 2 
Protein Coding gene. Diseases associated with CCL2 include 
Neural Tube Defects and Human Immunodeficiency Virus Type 
1. Among its related pathways are p70S6K Signaling and A-beta 
Uptake and Degradation. Gene Ontology (GO) annotations 
related to this gene include protein kinase activity and heparin 
binding. An important paralog of this gene is CCL7. 
PLAUR 
(downregulated) 56 
Plasminogen 
Activator, Urokinase 
Receptor 
Protein Coding gene. Diseases associated with PLAUR include 
Cancer of the Ureter and Paroxysmal Nocturnal Hemoglobinuria. 
Among its related pathways are Post-translational modification- 
synthesis of GPI-anchored proteins and Transcription Receptor-
mediated HIF regulation. Gene Ontology (GO) annotations 
related to this gene include signaling receptor binding. An 
important paralog of this gene is LYPD3. 
PPAP2A / PLPP1 
56 
Phospholipid 
Phosphatase 1 
Protein Coding gene. Diseases associated with PLPP1 include 
Myxosarcoma. Among its related pathways are Androgen 
receptor signaling pathway and triacylglycerol biosynthesis. An 
important paralog of this gene is PLPP2. 
PPP1CA56 
Protein Phosphatase 1 
Catalytic Subunit 
Alpha 
Protein Coding gene. Diseases associated with PPP1CA include 
Venezuelan Equine Encephalitis and Encephalitis. Among its 
related pathways are Circadian rythm related genes and 
Development Ligand-independent activation of ESR1 and ESR2. 
Gene Ontology (GO) annotations related to this gene include 
hydrolase activity and phosphoprotein phosphatase activity. An 
important paralog of this gene is PPP1CC. 
SPP156 
Secreted 
Phosphoprotein 1 
Protein Coding gene. Diseases associated with SPP1 include 
Pediatric Systemic Lupus Erythematosus and Urolithiasis. 
Among its related pathways are Integrin cell surface interactions 
and Development_Hedgehog and PTH signaling pathways in 

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bone and cartilage development. Gene Ontology (GO) 
annotations related to this gene include cytokine activity and 
extracellular matrix binding. 
SYNGR356 
Synaptogyrin 3 
Protein Coding gene. Diseases associated with SYNGR3 include 
Deafness, Autosomal Recessive 74 and Deafness, Autosomal 
Recessive 86. Gene Ontology (GO) annotations related to this 
gene include protein N-terminus binding and SH2 domain 
binding. An important paralog of this gene is SYNGR1. 
Table 5 Genes related to TNFa to be tested for mRNA expression 
3.9.10 Urine Samples 
Urine samples will be collected, and analyzed by dipstick at CFAS screening for hematuria, 
proteinuria, glucosuria, leukocyturia and nitrituria.  
3.9.11 SLE disease activity measures 
At baseline and follow-up, PROMs will be collected from questionnaires including Fatigue Severity 
Scale and VAS fatigue, VAS pain and Short Form (SF)-36 Health Survey33. 
Patients will be evaluated by a blinded study MD, using the SLEDAI-2K26 system (With the 
SELENA modifications), the SR-50, Q-SLAQ score57, as well as VAS Physician of overall disease 
at both inclusion and follow-up.  
3.9.12 82Rb-PET Scan 
A subgroup of patients, chosen from their Lupus Anticoagulant and Sjögren antibody status, up to 
40, will undergo a serial rest–stress imaging on a Biograph mCT 128-slice scanner (Siemens 
Healthcare) using list-mode 3D acquisition after 82Rb infusion (Bracco Diagnostics). Low-dose CT 
(0.4 mSv; 120 kVp; effective tube current, 26 mA [11-mAs quality reference]; 3.3 seconds) will be 
performed for attenuation correction during normal breathing. Stress will be induced with adenosine 
infused at 140 cg/kg/min for 6 minutes, with acquisition starting 2.5 minutes later. Coronary artery 
calcium score (CACS) images and the quantitation of pericardial fat will be acquired from a non-
contrast breath-hold CT at the first scan. Myocardial blood flow will be quantitated from dynamic 
rest and stress images with quantitative-gated nuclear imaging based on a single compartment 82Rb 
tracer kinetics model using syngo.MBF (Siemens Medical Solutions, Version VB15, Illinois, USA), 
and Corridor4DM v. 2015.0.0.44 (INVIA, LLC, Ann Abor, USA). The myocardial flow reserve, 
which may be used to unveil microvascular disease in these patients will be calculated as 
myocardial blood flow at adenosine-induced maximal hyperaemia divided by resting myocardial 
blood flow. Based on left ventricular contours, ventricular volumes and ejection fraction will be 
determined.  
3.9.13 Oral glucose tolerance test  
A standard 2-hour 75 g OGTT will be performed with a serial of blood drawn at baseline, after 60 
min and after 120 min. These samples will be analyzed for glucose, insulin, and c-peptide as per 
3.9.7.4. 

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3.9.14 Lung function 
Standardised lung function testing will be performed in accordance with consensus guidelines at 
using equipment at CFAS. This encompasses dynamic spirometry58, body plethysmography59, and 
diffusing capacity60.  Based on summary equations61,62, the expected values according to height, age 
and sex will be calculated.  
3.9.15 Nailfold Capillaroscopy 
Peripheral capillaries will be assessed at baseline and follow-up by nailfold capillaroscopy, a 
technique routinely used in the clinic for patients with systemic scleroderma, SLE or 
dermatomyositis. This is a non-invasive examination where a clinician uses a capillaroscope, in 
essence a powerful digital microscope, to examine the peripheral capillaries of the subjects 
nailfolds63. 
3.9.16 Autonomic Nerve Function tests 
Using a handheld external device that measured the first lead of an ECG, participants will be 
instructed to stand up from supine position, do a controlled breathing exercise and then a Valsalva 
manoeuvre while measuring the RR interval. 
3.9.17 Muscle biopsies 
Muscle biopsies will not be required for participation in the study and will be entirely optional. 
After anesthetising the skin with up to 10ml Lidocaine 20mg/Noradrenalin5microgram/ml, 
approximately 100-200 mg of skeletal muscle tissue will be extracted from the quadriceps muscle 
under sterile conditions. The samples are then immediately frozen in liquid nitrogen and stored at 
−80°C until analysis.  
Upon completion of the study, the samples will be analysed en bloc for fiber type, inflammatory 
markers, expression of multiple genes, including, but not limited to: NF-κB p65 DNA binding 
activity (ELISA), phosphorylated and total JNK, phosphorylated AMPK (p-AMPK) total AMPK 
(Western blotting), mRNA expression of genes as described in 3.9.9, as well as NF-κB binding 
activity (Western blotting). 
3.9.18 Data analysis 

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At least 10 participants in each intervention group and 10 
participants in each control group, will be included to obtain 
a significance level of 0.05 with a power of 80% to observe 
an increase in VO2max of 1.14ml/kg/min with a SD of 2.15 
in the control group and an increase in VO2max of 
3.80ml/kg/min with a SD of 3.34 in the intervention group 
based on a previous publication5. If we assume a drop-out 
rate of less than 30% with 15 participants in each group, we 
will have at least a power of 80% even with 30% drop-out. 
With 14 participants in each group, we will achieve a power 
of 90%. 
Similar results were gained when examining the study by 
Boström et al.64 were the control group had an increase in 
VO2max of 1.7ml/kg/min with an SD of 1.3 and the 
intervention group had an increase of 3.2ml/kg/min with an 
SD of 1.2. A significance of 0.05 and a power of 80% 
requires 12 subjects in each group. 
Since we hope to be able to part our groups into patients with 
higher IFNGS being the patients with M3.4 and M5.12 and we assume one third of our patients will 
be in this group, including 30 patients for intervention will give us 10 “high IFNGS intervention” 
patients in total for this power calculation. 
Results will be analysed according to a pre-defined statistical analysis plan and initial modelling of 
the primary outcome will be based on Analysis of Covariance (ANCOVA) performed with change 
(post-measure minus pre-measure) as the dependent outcome, with a fixed factor for group (two 
levels) and applying the value at baseline as a covariate. 
 
 
4 Ethical considerations 
4.1 General information 
This study will be conducted in accordance with Regional Ethics Committee (REC) and the 
Declaration of Helsinki. All participants must sign an informed consent form before enrolment. The 
protocol will be submitted to the Capital Regional Ethics Committee and to the Danish Data 
Protection Agency. Information regarding participants of the project will be protected in accordance 
with the applicable laws of Denmark including laws concerning the processing of personal data 
(“databeskyttelsesforordningen” and “databeskyttelsesloven”). Amendments and modifications to 
Sample Size  
Group 1 
10 
Group 2 
10 
Total  
20 
Study Parameters  
Mean, group 1 
1.14 
Mean, group 2 
3.8 
Alpha 
0.05 
Beta 
0.2 
Power 
0.8 

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the protocol will be sent to the Regional Ethics Comittee and the Danish Data Protection Agency 
for approval and no changes to the protocol will be established before approval.  
4.2 Initiative for the project 
The idea and development of the project was done by Center for Physical Activity Research by 
BKP as well as HEL, RHC, RMB collaborated with PHØ and SJA to formulate the foundation of 
the study. Since then MLA, SJØ, RHC, PHØ, HEL, RMB and SJA have adapted the study protocol. 
Further revisions have been done by MLA and SJA in collaboration. There are no economic 
interests in the study, funding has been sought by RMB, RHC, MLA and SJA. 
4.3 Access to patient information 
The medical doctors affiliated with this study, will seek access to the patients’ medical chart 
(“Sundhedsplatformen”), to obtain information regarding previous diagnoses that could jeopardize 
the participation in the study. The patients’ blood samples that are drawn as part of this study will 
be analyzed by the Department of Clinical Biochemistry at Rigshospitalet. Information regarding 
these blood samples will also be obtained through access to the patients’ medical chart. Any health 
information regarding the patient will only be obtained following informed oral and written consent 
from the patient.  
4.4 
Novelty and importance 
We expect this study to provide novel insight into the physiological response to exercise in SLE 
patients that differ in their IFN gene signature. As well as give clinicians an idea of the differing 
needs of patients in this heterogenous group of patients. Allowing physicians to further tailor 
medical practice to the individual. Furthermore, this research will help elucidate the complex 
relationship between auto-immune diseases and exercise. 
4.5 Risks and disadvantages of interventions 
Evidence shows that exercise for stable patients with SLE is safe5,20, and it has proven to be 
clinically beneficial on patient reported outcome measures of fatigue, but not necessarily on their 
SLE activity. Therefore, we are not asking our control group to seize their current physical 
activities, but rather we are adding on exercise in the intervention group.  
We believe that these 12 weeks of not increasing exercise hold little risk for the control groups, who 
after the study will be instructed in the exercise methods that the intervention group received. 
4.6 Risks and disadvantages of baseline and follow-up tests 
During the study, blood samples of up to 400 ml will be drawn from the patient. Half of this over 
multiple days on the baseline assessments and half of this 12 weeks after at follow-up assessments. 
The risks of dizziness, infections or anemia are minimal. Patients will be informed to contact one of 
the medical doctors affiliated with this study, if the patient suspects infection surrounding the 
penetrated skin (redness, swelling, fever, heat).  
A VO2max test is considered safe but may cause patients to feel dizzy immediately following the 
test. An oral glucose tolerance test is considered safe. A lung function test is considered safe but 
may cause patients to feel dizzy for a limited time. An echocardiography following standard clinical 
procedures is considered safe and does not in itself pose any risks. 82Rb-PET/CT will be performed 
by specialized medical technologists at the Dept. of Clinical Physiology, Nuclear Medicine and 
PET at Rigshospitalet, who routinely do this. The scan itself, including the injection of tracer, is not 
associated with any discomfort, but an intravenous line must be placed which is associated with the 
same risks as normal blood sampling as described above. Adenosine infusion may cause some 

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temporary discomfort, notably palpitations, breathlessness, headache, dizziness, and fatigue; 
adenosine has a half-life in the blood stream of less than 30 seconds, and these symptoms will cease 
within minutes after the 6-minute adenosine infusion is discontinued. The stress scan is performed 
under the immediate supervision of a nuclear medicine physician.  
Prior to the muscle biopsy, local anesthesia will be administered, which is associated with short-
lasting discomfort. After a few minutes, the area is numbed, and a small skin incision is made. The 
Bergstrom cannula is inserted in M. vastus lateralis and the biopsy is taken. This part of the 
procedure might be associated with slight pain. The procedure takes a few minutes and after the 
biopsy is taken, the wound will be closed with Steri-Strips, which must be kept on for five days. 
There will be an additional patch, which can be removed after two days. Subjects might experience 
some degree of muscle pain after the biopsy. Paracetamol,1000 mg, max. four times a day will be 
recommended as pain killers. The procedure can leave small bruises, but generally heals nicely. 
Temporary decreased sensation at the incision area or where the local anesthetic has been injected 
can be seen. Usually, nerve lesions and altered sensation at the incision area heals within months. In 
theory, infections can appear when piercing the skin. This occurs in 1 out of 25,000 times and can 
in some cases require treatment with antibiotics. In order to avoid infection all participants will be 
informed to abstain from swimming in seawater or swimming pools within the first five days. 
Furthermore, they will be informed to contact a project doctor in case of any signs of infection 
(heat, redness, swelling or fever). We believe that the potential outcome of this study to future SLE 
patients are significant, compared to any potential risk or disadvantages that patients must endure 
by participating. 
4.7 Radiation exposure 
A DXA scan will provide an effective radiation dose in the range of 3-30 µSv - equivalent of 3 days 
of background radiation in Denmark and is considered safe (Category I in “Appendiks 2: 
Retningslinjer om anvendelse af ioniserende stråling i sundhedsvidenskabelige forsøg”; NVK 
2011). The radiation exposure due to each rest-stress 82Rb-PET/CT scan is 4 mSv. The maximal 
total effective radiation exposure associated with participation in this study in thus less than 9 mSv 
and is thus risk category IIb according to the International Commission on Radiation Protection and 
the European Commission. Due to this radiation exposure, the lifetime risk of cancer is increased 
from 25% to 25.045%. As the current study is directly targeted at unveiling means of preventing 
and curing cardiovascular disease in patients with SLE, we consider this reasonable.  If pregnancy 
is deemed possible, a pregnancy test will be performed prior to the scans.  
4.8 Safety and precautions 
Patients will undergo a medical assessment to ensure eligibility and safety. At all patient 
interventions (including exercise) at CFAS, a medical doctor is present and reachable. During 
exercise at one of the local collaboration-centers a medical doctor will not be present but be 
reachable through telephone. The Department of Clinical Physiology, Nuclear Medicine & PET, 
Rigshospitalet has great experience in conducting PET scans and will perform the necessary 
precautions both prior to and after the scan.  
4.8.1 Safety evaluation 
All adverse events (AEs) and serious adverse events (SAEs) observed by the investigators will be 
reported in the case report form (CRF) and to REC as requested, from the start of the trial (after 
written consent) to the final day of protocol procedure. An AE is defined as any untoward medical 

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occurrence in a participant, which does not necessarily have a causal relationship with the trial 
intervention. AEs are graded as the following: 
Grade 1: The AE is noticeable to the subject but does not interfere with subject’s every day’s life 
activities; it may or may not require additional concomitant therapy.  
Grade 2: The AE interferes with the subject’s daily activities; it usually requires additional therapy.  
Grade 3: The AE is intolerable and requires additional therapy.  
Grade 4: The individual is at immediate risk of death at the time of the AE; it does not refer to an 
event which hypothetically might have caused death if it was more severe. Life-threatening events 
result in a SAE.  
An SAE is any untoward medical occurrence or effect that at any dose results in death, is life-
threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent 
or significant disability or incapacity, or is a congenital anomaly or birth defect. 
4.9 Procedure for recording and handling AEs and SAEs 
 
Full description of these procedures is attached in Appendix A. All AEs/SAEs related to the study 
assessments (including the exercise intervention) will be recorded immediately and notified in the 
CRF. All AEs/SAEs (both those that are anticipated and unanticipated) will be recorded on adverse 
event forms and published with study results. We will also collect patients’ self-report of 
AEs/SAEs, and report these in the CRF. These forms will include a description and classification of 
the event, date of onset, date resolved, whether the event was serious or not (ICH criteria), 
relationship of the event to the study (1=none, 2=unlikely, 3=possible, 4=probable, 5=definitely), 
action taken, and whether the study was suspended or not.  
All SAEs, regardless of causation, will be reported to REC within one week (in any SAE resulted in 
death, an immediate report within 24 hours will be sent.) Once a year the sponsor will summarize 
all SAEs and report these to REC. If at any point it is considered medically unsafe by the principal 
investigator for a patient to continue in the study, the patient will be excluded from the study and 
offered appropriate support.  
4.10 Dissemination of study results 
The results of the study, whether positive, negative or inconclusive, will be disseminated through a 
systematic dissemination and publication strategy. After registration on ClinicalTrials.org, the study 
protocol will be published in an international peer reviewed journal, and once the study has been 
completed and the data analysed, a preprint of the manuscript will be submitted to medRxiv. After 
this, the manuscript will then be submitted to peer reviewed scientific journals. After publication, 
the original data will be made available in a public repository. The results will also be presented at 
national and international conferences. Patients will be informed of the study and the results by 
public outreach in the form of layman articles, short study reports at websites and in newsletters and 
presentations. Authorships will be assigned according to the Vancouver rules as determined by the 
PI RHC. All participants are guaranteed access to more information about the project. In need of 
information, participants will be invited to contact the Research Coordinator Malte Lund Adamsen. 
4.11 Withdrawal from study 
A patient may choose to end their participation in the study at any time. The patient will not be 
obliged to provide a reason, and the termination of participation will not influence future medical 
treatment nor have any other consequences for that patient, and this will be made clear to the patient 
when obtaining oral and written informed consent. The reason for discontinuation will be 

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documented (including “unknown reason”). In exceptional circumstances, the study investigator 
may choose to withdraw a patient from the study due to safety reasons determined by the study 
investigator.  
The patient must have completed no less than 80% of the prescribed exercise (no less than 29 
session or less than 32 minutes per session on average). This will be assessed at two weeks 
intervals, and subjects will be given two weeks to catch up on the missed sessions.  
4.12 Insurance 
All patients will be covered by The Danish Patient Insurance Association for any injury that may 
occur as a direct consequence of study-related procedures. 
 
4.13 Practical setups  
The study related procedures will be performed at the following locations:  
1. Eligibility and recruitment: Department of rheumatology, Rigshospitalet and CFAS 
2. Enrolment and baseline testing including VO2 max, echocardiography, muscle biopsies, and 
DXA: CFAS 
3. PET scan: Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet 
4. Exercise intervention: CFAS or a local collaborator with experience in exercise therapy for 
patients. 
 
4.14 Economy 
The economy for this project will be maintained through a research fund created and maintained by 
center for activity research at Rigshospitalet by our economist Inge Holm. 
MLA is employed by CFAS, Rigshospitalet with a one-year guarantee of salary, through use of 
some of the Novo Nordisk Foundation grant (see below). The Danish Rheumatism Association 
(Gigtforeningen) has pledged 1,000,000DKK for payment of 2 more years of his salary, dependent 
on re-application after the first year (grant ID: R202-A7503). 
MD RHC has received a grant from “Region Hovedstadens Forskningsfond” for DKK540,000 for 
her salary. 
MD Simon Jønck has received a grant from Gangstedforeningen for DKK 500,000 for his salary for 
this project as well as another project. 
The project has received a grant from The Novo Nordisk Foundation (1,753,832 DKK, Grant ID: 
NNF20OC0065929). To cover all expenses new funding will be sought throughout the study and in 
case of further grants, the Regional Ethics Committee and participant information will be updated.  
 
Participants will not receive economic compensation. However, transport allowance may be granted 
at attendance (a maximum of DKK 4000). As well as payment for temporal disability and pain with 
muscle biopsies of 500 DKK per biopsy. 
None of the investigators involved in the research group have any financial interests in the project. 
 
4.15 Biobank & Data Storage 
Data and associated biological material will be stored in an individual database and research 
biobank during the study. At the end of the study remaining biological material will be transferred 
to the general research biobank of CFAS. The biological material will be stored in this research 
biobank for a maximum of 10 years. After that, it will be destroyed. If any later studies want to 
make use of the biological material, this will only take place following approval by the ethical 
committee. Confidentiality of the subjects will be maintained by assigning subjects a study number, 

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keeping identifiers separate from the data and storing data in a locked file and secure computer 
database. Scientific reports generated from the study will not contain information that would 
identify the participants. 
 
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