Pilot Study Characterizing Aerobic Exercise in Women With Systemic Lupus Erythematosus (Exercise SLE Pilot).
Phase: NA
Conditions: Systemic Lupus Erythematosus, Lupus, Autoimmune Disease, Rheumatic Disease
Sponsor: National Institutes of Health Clinical Center (CC)

 
SLE and Exercise 
 
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Leighton Chan 
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CLINICAL RESEARCH PROJECT 
 
 
 
 
 
 
 
Date: September 23, 2019 
To: 
Richard Cannon, MD, Chair, General Medicine 1 IRB 
Protocol Title:   
Pilot Study Characterizing Aerobic Exercise in Women with Systemic Lupus 
Erythematosus (Exercise SLE Pilot).  
 
Principal and Administratively Accountable Investigator:   
Leighton Chan, MD, MPH (E) * 
Chief, NIH Clinical Center, Rehabilitation Medicine Department 
301.496.4733 chanle@cc.nih.gov 
 
Building 10 Room 1-1469 
 
 
Collaborations: 
George Mason University 
Department of Rehabilitation Science 
4400 University Drive 
Fairfax, VA 22030 
 
Medical Monitor: 
Dr. Michael M. Ward M.D. 
Building 10-CRC Room 4-1339 
10 Center Drive 
Bethesda, Maryland 20814 
Wardm1@mail.nih.gov 
 
Estimated Duration of Study:  36-60 Months 
Estimated Completion Date of Study:  December 2022 
 
 
Subjects of study: 
 
Number 
 
 
Sex 
 
Age range 
                                              
20 evaluable subjects 
 
F               
21-80 years 
 
 
 
30 subjects with Systemic Lupus Erythematosus will be recruited in order to accrue 20 evaluable 
subjects. Enrollment will remain open until 20 subjects have completed the study.  

 
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Project involves ionizing radiation? 
 
 
No 
 
Offsite project?                                                                 No 
 
 
Multi-Institutional project? 
Yes, NIH (medical and research testing, and 
exercise and educational training), George 
Mason University (collaborating research 
institution) 
 
 
DSMB involvement?  
 
 
 
No 
 
 
 
 
Tech Transfer: CRADA, MTA 
 
 
No 
 
 
Identifying Words:  Exercise, Systemic Lupus Erythematosus, Rehabilitation 
 
 
 
 
 
 
 
 
Table of Contents 
 
Précis .................................................................................................................................... 4 
Study Impact: ................................................................................................................................5 
Background .......................................................................................................................... 5 
Specific Aims ........................................................................................................................ 7 
Study Overview .................................................................................................................... 7 
Inclusion Criteria .......................................................................................................................... 10 
Exclusion Criteria ......................................................................................................................... 10 
Methods ...................................................................................................................................... 11 
Study Procedures ......................................................................................................................... 11 
Treadmill Exercise Training: .......................................................................................................... 17 
Statistical Analysis ............................................................................................................. 18 
Subject Withdrawal ........................................................................................................... 18 
Risks and Discomforts to Subjects: .................................................................................... 19 
1. 
CPET: ................................................................................................................................... 19 
2. 
PROMIS and FSS: .................................................................................................................. 19 
3. 
Square wave CPET (swCPET): ................................................................................................. 19 
4. 
Fatigability Tests: .................................................................................................................. 20 

 
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5. 
NIRS Test with Arterial Occlusion Muscle Oxygenation Capacity Test: ...................................... 20 
6. 
Bioimpedance Cardiography (ZCG) Test: ................................................................................ 20 
7. 
Treadmill Exercise Training: ................................................................................................... 20 
8. 
Echocardiography: ................................................................................................................ 21 
9. 
PFT with DLCO: ..................................................................................................................... 21 
10. 
Blood draw: ..................................................................................................................... 21 
11. 
Electrocardiogram: ........................................................................................................... 21 
12. 
Vascular function studies: ................................................................................................. 21 
Benefits to Subjects: ........................................................................................................... 22 
Human Subject Research Protections (HSRP) ................................................................... 22 
Subject Selection ......................................................................................................................... 22 
Exclusions: ................................................................................................................................... 23 
Participation of NIH employees ......................................................................................... 24 
Data and Safety Monitoring Plan ....................................................................................... 25 
NIH IRB and CD reporting: .............................................................................................. 25 
Conflicts of Interest ............................................................................................................ 25 
Travel and Compensation .................................................................................................. 25 
Informed Consent: ............................................................................................................. 26 
Management of Data and Samples ..................................................................................... 26 
Sample Storage: ........................................................................................................................... 27 
References: ......................................................................................................................... 29 
Appendices ......................................................................................................................... 31 
Appendix 1 – Study Protocol Timeline Checklist ............................................................................ 31 
Appendix 2. Fatigue Severity Scale (FSS) ....................................................................................... 42 
Appendix 3: SELENA SLEDAI .......................................................................................................... 43 
Appendix 4: SLICC/ACR DAMAGE INDEX FOR SLE .......................................................................... 45 
Appendix 5: PROMIS–57 Profile v2.0 ............................................................................................ 47 
Appendix 6: Fatigue Severity Score (Spanish) ................................................................................ 51 
Appendix 7: PROMIS 57 v2 (Spanish) ............................................................................................ 52 
 
 
 

 
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Précis 
We propose a single-arm exploratory study to characterize the responses and adaptations to 
aerobic exercise in women who have mild to moderate systemic lupus erythematosus (SLE) 
uncomplicated by organ damage that would limit participation. This is a pilot study to provide 
additional preliminary data to support a future U01 application.  Persistent, excessive fatigue is 
among the three most debilitating symptoms of SLE and is cited by as many as 50% of patients 
as the single most debilitating symptom. We have observed, in women with mild SLE, 
significant relationships among deficits in work capacity and oxygen consumption obtained 
during treadmill exercise and patient reported measures of fatigue severity 8. Clinically 
significant functional aerobic impairment was present in these women, suggesting an underlying 
pathophysiological limitation that restricted cardiorespiratory capacity to well below that 
expected to occur as a result of normal deconditioning due to a sedentary lifestyle and lack of 
physical activity.  We have also observed prolonged rest to steady state metabolic transition 
during even submaximal exercise in women with SLE 10.  At peak exercise, muscle oxygenation 
deficiency was apparent despite normal increases in central circulatory oxygen delivery to the 
active muscles. Muscle tissue studies in other laboratories have implicated muscle capillary basal 
lamina thickening as an oxygen diffusion barrier, which could possibly diminish the rate of 
tissue oxygen uptake and restrict cardiorespiratory capacity.  Aerobic exercise training could 
improve cardiorespiratory capacity in women with SLE and with that improvement precipitate a 
reduction in their fatigability, particularly if that fatigability is mediated by impaired 
cardiorespiratory function.  
Our research team is uniquely qualified to undertake this research and is one of the few teams 
possessing the experience and background necessary for contributing to this novel, understudied, 
yet critical field of rehabilitation research.  For example, in addition to Dr. Keyser’s studies on 
cardiorespiratory dysfunction in women with SLE, our team has studied the effects of an intense 
aerobic exercise-training program in individuals who have pulmonary hypertension (PH) 24,25 or 
interstitial lung disease (ILD) 26,27, two conditions associated with autoimmune diseases such as 
SLE. In fact, several of the subjects had SLE and the majority had autoimmune diseases of 
somewhat similar etiology. Our results demonstrated improved cardiorespiratory function and 
diminished fatigability in these patients, without serious adverse events, following a 10-week 
regimen of intense aerobic exercise training. Adherence to the protocol was over 90% in both 
subject subsets and there were no serious adverse events in either of these groups. 
Subjects of the proposed research will be between 21 and 80 years of age and living within a 
reasonable travel distance from the greater Washington D.C. area. Subjects will be recruited 
from the NIH/NIAMS IRP Lupus Clinics. All tests and exercise training will be conducted at the 
NIH Clinical Center. There will be a single treatment condition consisting of 12-weeks of 
supervised treadmill walking, three times a week, for 30 minutes per session, at an intensity of 
70-80% of the subject’s heart rate reserve.  
The primary outcome measure for our trial will be the time taken to attain the anaerobic 
threshold, which is a performance marker of fatigability that is unaffected by patient motivation 
or perception.  Secondary outcome variables will include other measures of cardiorespiratory 
capacity measured during a cardiopulmonary exercise test (CPET) with accompanying 
pulmonary gas exchange, central circulatory function (including heart function and an optional 
measures of peripheral blood flow) and muscle oxygenation analyses. A number of 

 
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questionnaires will also be completed including: Fatigue Severity Scale, Patient Reported 
Outcomes Measurement Information System (PROMIS).  All of these data will be obtained 
before and after aerobic exercise training.  
 
Study Impact: Aerobic exercise is generally safe, inexpensive, and can easily be made available 
and accessible to almost everyone. It requires no approval by regulatory agencies and is thus 
available as a medically prescribed and supervised intervention almost immediately following 
confirmation of its safety and efficacy. Effective use of aerobic exercise training as a 
cardiorespiratory, rehabilitative intervention could have a high degree of impact on personal and 
public health outcomes. 
Background 
As many as 1.5 million Americans are living with systemic lupus erythematosus (SLE).1, 2  The 
disease is most prevalent in young African American women3, 4, although there is significant 
prevalence in all races. The SLE population is indeed aging.  Moreover, SLE is similar in 
etiology and symptoms to more than 100 other autoimmune diseases collectively effecting 1 in 5 
individuals living in the U.S.  One of the most debilitating symptoms of SLE is excessive fatigue 
(SLE-fatigue), which persists even during periods of negligible disease activity or remission. 
Nearly all patients who have SLE identify fatigue among their three most debilitating symptoms 
and as many as half report it to be their single most debilitating symptom.2, 6, 7 SLE-fatigue is 
associated with functional limitations such as physical activity intolerance8, 9 and poor 
cardiorespiratory fitness8. Management of SLE-fatigue and the resultant physical debilitation has 
become a clinical and social challenge that spans the entire course of the disease and lifespan.  
Despite the centrality of this symptom to a patient’s experience of the disease, a full 
understanding of the phenomenon has been hampered by dichotomous scientific perspectives 
depending on whether “fatigue” is regarded as either a subjective perception of tiredness or as a 
decrement in performance.  The NIH/NIA has defined fatigue as “a subjective lack of physical 
and/or mental energy that is perceived by the individual to interfere with usual or desired 
activities” (NIH/NIA PA-08-161). Fatigability was defined as a phenotype that associates the 
degree of fatigue with activity of any kind.  Physically active people reporting any given level of 
fatigue are generally less fatigable than their less active counterparts even if those who are less 
active report the same level of fatigue. Offering additional clarity, the NIH/NIA further defined 
perceived fatigability as “the change in the feeling of tiredness as a function of duration, intensity 
and/or frequency of activity” and performance fatigability as “the decline in performance as a 
function of frequency, intensity, and/or duration of activity” (NIH/NIA PA-12-227).  Several 
methods have been proposed to measure perceived and performance fatigability.  A better 
understanding of the complex phenomenon of SLE-fatigue will require integration of knowledge 
derived from measuring both performance and perceived fatigability. However, it remains that 
performance fatigability is the most objectively measureable subtype and that certain 
performance fatigability measurements can link mechanistic functions to acute declines in 
performance, for example, links between exercise-induced fatigue and cardiorespiratory 
dysfunction.   

 
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Cardiorespiratory function supports all physical activity and is the primary support for engaging 
in strenuous activities, when these activities are prolonged or when repetitions are frequent. 
Tench and coworkers,9 reported that peak total body oxygen consumption (VO2) and physical 
function scores were significantly lower and fatigue was more severe in 93 patients with mild 
SLE compared to 41 healthy controls. Peak VO2 correlated significantly with physical function 
but not with fatigue, whereas fatigue severity and physical function were indirectly associated. 
Conversely, in a later study of 18 women with mild SLE and 16 healthy controls, Keyser and 
associates8 reported that the severity of cardiorespiratory impairment, decline in physical 
performance, and severity of fatigue were all strongly related. In the women with SLE, 
cardiorespiratory function was insufficient for sustaining even instrumental activities of daily 
living and the diminished cardiorespiratory capacity appeared to be linked to an underlying 
pathomechanism. A subset of the same group demonstrated protracted responsiveness of the 
cardiorespiratory system to both moderate and vigorous energy demands.10 These findings 
provide strong evidence for a potentially mediating influence of cardiorespiratory impairment on 
performance fatigability in women with SLE.  
Three studies have reported improvements in cardiorespiratory function, fatigue and/or physical 
activity following aerobic exercise training. Robb Nicholson and coworkers11 reported a 
significant increase in cardiopulmonary exercise test (CPET) duration over controls following 
aerobic exercise training. The improvement was associated with decreased patient-reported 
fatigue severity. A significant within group improvement in cardiorespiratory capacity was 
present after training, but this was not significant over controls. De Carvalho and associates12 
reported significant exercise training-induced increases in cardiorespiratory fitness that were 
associated with increases in physical activity in women with SLE. Patient-reported fatigue 
neither increased nor decreased as a result of training. A third, pilot study with a sample of only 
six subjects13 found that aerobic exercise training resulted in improvement in SF-36 vitality score 
in all six women with SLE. Four of the six had increases in peak VO2 ranging between 2.5 and 
3.6 ml/kg/min. The findings of these studies implicated cardiorespiratory fitness as a potential 
mediator/modulator of performance fatigability in women with SLE and suggested that aerobic 
exercise may be a sufficient stimulus for evoking a training adaptation in these patients. 
However, neither performance nor perceived fatigability was directly measured in any of these 
studies. 
The investigators (Drs. Keyser, Chan, and Chin) from the NIH Clinical Center, Rehabilitation 
Medicine Department have been involved in a clinical trial entitled titled “The NIH Exercise 
Therapy for Advanced Lung Disease Trials (HEALD: 08-CC-0133 and14-CC-0027). HEALD 
examined the effects of vigorous exercise training on cardiorespiratory function and health 
related quality of life (including fatigue severity and physical activity) in patients with 
pulmonary hypertension (PH) and/or interstitial lung disease (ILD). Most of the subjects in 
HEALD had an advanced lung condition associated with an autoimmune/collagen vascular 
disease similar to SLE. Several of them had SLE. The preliminary findings of HEALD (24-27) 
suggested that vigorous aerobic exercise training, similar to that proposed in this pilot study, was 
well tolerated with a high degree of adherence and safe with no serious adverse events, even in 
these subjects with advanced pulmonary complications associated with autoimmunity.  
Furthermore, the exercise-training regimen was effective for improving cardiorespiratory 
function, exercise tolerance, fatigue and fatigability in a subset of patients.  The findings of 

 
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HEALD so far have linked the improvements in fatigue and fatigability to increases in 
cardiorespiratory capacity.  In this pilot study we intend to examine the feasibility of translating 
the methodology used in HEALD to women with SLE who do not have overt cardiac, pulmonary 
or other systemic complications. 
Specific Aims 
 
1. Generate data that can be used for the planning of larger randomized controlled studies (RCT). 
This is the primary aim of this pilot study. Specifically, this pilot study is preliminary to the 
submission of a U01 clinical trial on exercise training, fatigability and physical 
functioning in women with SLE.  
2. Preliminary characterization of the performance fatigability and cardiorespiratory adaptation 
to aerobic exercise training in women with SLE. The data to be used in the development of 
the RCT are the results of the CPET and square wave cardiopulmonary exercise test 
(swCPET), which provide physiological markers of performance fatigability. The change in 
performance fatigability following aerobic exercise training will be the primary outcome 
variable. Specific markers characterizing performance fatigability are the time taken to attain 
the anaerobic threshold on the CPET and the oxygen kinetics time constant taken from the 
swCPET. In addition, we will further characterize the adaptation by evaluating exercise 
training-induced changes in muscle oxygenation and cardiac function (and optional limb 
blood flow), measured non-invasively.    
3. Preliminary assessment of stability of disease activity and effects of training on disease 
severity. Disease activity will be monitored at baseline, training mid-point, and after training 
by physical exam, symptom review, and serology. These assessments will contribute to the 
Safety of Estrogen in Lupus Erythematosus, National Assessment modification of Systemic 
Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI), which will be calculated 
at each of the pertinent data points. We will also track the number of flares and medication 
changes during subjects’ participation. Here our non-inferiority hypothesis is that the training 
regimen will have no observable effect on disease activity/severity in this group of women 
with mild SLE. 
4.  Assessment of feasibility and patient motivation to participate.  We will track and monitor the 
number of patients participating in the Pathogenesis and Natural History of SLE study, who 
indicate interest and willingness to participate.  We will also monitor compliance and 
attendance with the exercise sessions as well as adherence to the prescribed intensity and 
duration of exercise during the training sessions.  We will query all participants who drop out 
of the training regimen in order to compile a list of reasons that may affect participation.   
Study Overview 
We propose to enroll 30 sedentary, adult, women with negligible to mild SLE disease activity 
(SELENA-SLEDAI ≤ 4) in this pilot study with the goal of accruing 20 evaluable subjects. 
Subjects must also have a Fatigue Severity Scale (FSS) composite score ≥ 3. We will restrict our 
recruitment to women with SLE as this is a small pilot study and would like to eliminate possible 

 
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gender-biased confounders of physical activity (approximately 90% of patients with SLE are 
women).  
1. Visit 1: During this visit, subjects will sign the informed consent. To determine 
eligibility, subjects will first undergo medical history, physical exam, echocardiogram, 
electrocardiogram, pulmonary function tests, and complete the FSS questionnaire to 
ensure meeting of the inclusion criteria and absence of an exclusion criterion (below). 
Blood and urine samples for the evaluation of safety and SLE disease activity, and serum 
or urine pregnancy tests will be drawn at this visit. Research samples will also be 
collected at this visit. We will do SELENA-SLEDAI, Systemic Lupus International 
Collaborating Clinics/American College of Rheumatology damage index (SLICC/ACR-
DI) at this visit. This visit will require up to four hours to complete. Pre-screening 
procedures performed within the past 30 days under the Studies of the Pathogenesis and 
Natural History of Systemic Lupus Erythematosus protocol (94-AR-0066) may be 
included in this study. This is to avoid patient inconvenience and repeat testing. Research 
data from the same subject may also be shared directly with NIAMS investigators on 
protocol 94-AR-0066. Pre-screening assessments may be collected on multiple days to 
accommodate the patient’s schedule.  
2. Visit 2:  This visit will occur within 14 days of completion of all pre-screening 
assessments (Visit 1). All eligible subjects will complete a treadmill CPET to volitional 
exhaustion to evaluate cardiorespiratory capacity and to obtain anaerobic threshold and 
peak heart rate measures from which the work rate for the VO2 on-kinetics tests and the 
exercise training target heart range can be determined. Bioimpedance cardiography 
(ZCG) and arterial occlusion with near-infrared spectroscopy (NIRS) will be performed 
before the CPET. The subjects will also complete the PROMIS instrument. The visit will 
require three hours to complete. 
3. Visit 3: Subjects will undergo one submaximal swCPET, treadmill VO2 on-kinetics test, 
which is a submaximal, moderate exercise intensity test. Arterial occlusion with NIRS 
will be performed before the swCPET. Bioimpediance cardiography (ZCG) will be 
measured during the swCPET. The VO2 on-kinetics tests will be used to evaluate how 
readily the oxidative metabolic pathway can respond to increased work rates and energy 
demands. The VO2 on-kinetics test will take place 1-7 days after Visit 2 and will require 
about two hours to complete.  
4. Visit 4 and Exercise Training Session 1: This visit will be conducted between 1-7 days 
after the completion of Visit 3, and may be performed over multiple days to 
accommodate the patient’s schedule.  This visit will also include the first exercise session 
of the 36-session aerobic exercise-training regimen.  Subjects who would like to 
participate in the optional non-invasive vascular studies to examine the effect of exercise 
on vascular function in patients with SLE will do so at this visit. The methods for these 
studies are described in the research testing section and will take an additional 1.5 hours 
to complete. After the vascular studies and a light breakfast (since a 3-8 hour fast is 
required before vascular study testing), there will be a timed walk test to evaluate 
performance fatigability by measuring how far the subject can walk over a 10-minute 
interval (10-minute timed walk test). After another brief rest, subjects will complete 20 
additional minutes of treadmill walking exercise at the target heart rate to be used for 
exercise training (70-80% heart rate reserve calculated from CPET). Target heart rate will 

 
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be monitored by Polar® monitor. If the vascular studies, baseline 10-minute walk test, 
exercise training are all performed at this visit, it will take up to 3 hours to complete.  
5. Exercise Training Sessions 2-35:  All subsequent exercise sessions will be scheduled 1-
7 days after the first exercise session and 10-minute walk test (Visit 4). All sessions will 
be scheduled at regular intervals to achieve a goal of 3 visits per week for 12 weeks. 
Subjects will undergo a treadmill exercise-training program at an intensity of 70 to 80% 
of the heart rate reserve calculated from the CPETs for 30 minutes during each of the 
exercise training sessions. 
6. Visit 5:  During exercise training session 13, 14, or 15, Dr. Hasni or a member of the 
medical team will reevaluate the subjects, including performing a brief review of medical 
history and physical exam. Samples for research studies, including serum or urine 
pregnancy and clinical samples for safety and SLE disease activity, will be drawn. The 
SELENA-SLEDAI will be repeated. Subjects participating in the optional non-invasive 
vascular studies will do so at this visit.  With the medical evaluations, labs, exercise, and 
vascular studies, this visit will take up to 4 hours to complete.    
7. Visit 6 and Exercise Training Session 36: This visit will also include the final exercise 
session of the 36-session aerobic exercise-training regimen. This visit will be scheduled 
1-7 days after the previous training session, and may be performed over multiple days to 
accommodate the patient’s schedule. Subjects participating in the optional non-invasive 
vascular studies will do so at this visit. After vascular study testing and a light breakfast, 
subjects will then complete a 10-minute timed walk followed by an additional 20 minutes 
of treadmill exercise. If the vascular studies, 10-minute walk test, and exercise training 
session are all performed this visit will require about 3 hours to complete. 
8. Visit 7:  This visit will be scheduled 1-7 days after the final exercise session. The 
subjects will be evaluated by Dr. Hasni or a member of the medical team, including a 
brief review of medical history and a physical exam. The subjects will also complete the 
PROMIS instrument during this visit. Blood and urine samples for safety, SLE disease 
activity and pregnancy will be drawn at this visit.  Research blood will also be collected 
during this visit. The FSS, SELENA-SLEDAI, SLICC/ACR-DI will also be completed 
on this visit. After a resting electrocardiogram, subjects will complete a CPET with ZCG 
and arterial occlusion with NIRS during this visit. This visit will require three hours to 
complete. Components of this visit may be performed on multiple days to accommodate 
the patient’s schedule. 
9. Visit 8:   This visit will be scheduled 1-7 days after Visit 7.  Subjects will undergo a 
swCPET treadmill VO2 on-kinetics test with ZCG and arterial occlusion with NIRS at the 
work rate identical to the baseline swCPET*. This visit will require two hours to 
complete.  
10. Visit 9:  This visit will be scheduled 1-7 days after Visit 8.  Subjects will undergo a 
swCPET treadmill VO2 on-kinetics test with ZCG and arterial occlusion with NIRS at a 
work rate calculated from the CPET performed during Visit 7*.  This visit will require 
two hours to complete. 
*The two work rates for Visits 8 and 9 will be randomized.  

 
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Inclusion Criteria 
• Fulfilling 4 of the 11 American College of Rheumatology Criteria for the Classification 
of Systemic Lupus Erythematosus  
• Age 21 to 80 
• Female Gender 
• BMI less than 40 
• No primary or secondary medical conditions that would limit aerobic capacity or make 
exercise participation unsafe.  These conditions are found under the exclusion criteria 
listed below and include cardiovascular disease and cardiomyopathy, pulmonary and 
pulmonary vascular disease, stroke, significant hepatic or renal dysfunction, most 
cancers, diabetes mellitus, HIV infection, and peripheral vascular disease. 
• SELENA-SLEDAI score ≤ 4, maintained for at least three months. (C3 and C4 levels are 
measured as markers for stability and included in the SELENA-SLEDAI score if 
abnormal).  
• No increase in doses of immunosuppressive medications (hydroxychloroquine, 
mycophenolate mofetil, azathioprine, methotrexate) for at least three months at the time 
of screening.  
• No increase in the dose of prednisone or equivalent steroid in the past 3 months at the 
time of screening.  
• Physically inactive, not participating in aerobic exercise training at heart rate above 60% 
maximum heart rate, 20 min/session or more, 2 or more days per week, within the last 6 
months at the time of screening.  
• FSS composite score ≥ 3 indicating the presence of clinically significant fatigue 
• Subjects must be able to walk on a treadmill. 
Exclusion Criteria 
• Prednisone ≥ 15 mg daily (or equivalent) 
• Have started azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide or 
biologics within 3 months  
• Rituximab infusion within 6 months 
• Present symptoms of ischemic heart disease, right- or left-sided heart failure, cor 
pulmonale or pulmonary hypertension, dilated or hypertrophic cardiomyopathy or non-
idiopathic cardiomyopathy 
• Significant pulmonary dysfunction (obstructive, restrictive, or infectious pulmonary 
disease) 
• Significant hepatic (LFT > 2 times of upper limit of normal) or renal dysfunction 
(GFR<45 ml/min) 
• Deep vein thrombosis  
• Chronic anticoagulation, (with the exception of low dose aspirin), or a history of a 
bleeding disorder  
• History or presence of any form of cancer other than skin cancer or cervical in-situ cancer 
• History of cerebrovascular accident  

 
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• Orthopedic conditions that would limit performance of treadmill exercise tests or 
treadmill exercise training 
• Current smoker or active substance abuse  
• HIV infection  
• Any medication that limit exercise capacity or the ability to adapt to aerobic exercise 
training 
o (e.g. beta-blockers, anti-retroviral therapy for the treatment of HIV infection) 
• Diabetes Mellitus  
• Fibromyalgia determined at Visit 1, as per 2010 ACR criteria for diagnosis of 
fibromyalgia31  
• Uncontrolled or untreated thyroid dysfunction: Determined by abnormal Thyroid 
Stimulating Hormone (TSH) level checked at the time of screening or within 3 months 
before screening visit.  
• Currently pregnant, nursing or plan to become pregnant during the duration of the study 
• Anemia (hemoglobin < 9 g/dl) 
• Significant peripheral vascular disease 
• Severe Raynaud’s phenomenon 
• Individuals unable to give informed consent 
Methods 
Study Procedures: 
Subjects will undergo initial evaluation as an outpatient in either OP-9 outpatient clinical or the 
5SW Day hospital at the clinical center of the NIH; to ensure meeting inclusion criteria and 
absence of an exclusion criterion. The evaluation will consist of a medical history, physical 
examination, serological evaluation, and completion of the SELENA-SLEDAI, SLICC/ACR-DI 
and the FSS questionnaire.  
Subjects will undergo pulmonary function tests with DLCO to rule out obstructive and restrictive 
lung disease, and doppler echocardiography to rule out left ventricular dysfunction, cor 
pulmonale and pulmonary arterial hypertension, and an electrocardiogram to rule out abnormal 
cardiac rhythm and myocardial injury.  Subjects meeting inclusion criteria and not meeting an 
exclusion criterion will be qualified for participation in the study.  Participating subjects will 
then complete the aerobic exercise training regimen, interim tests, medical evaluations, and post-
training tests, which are similar to those completed at baseline. 
Medical Tests: 
Blood Draw:  Patients will undergo a blood draw in the National Institutes of Health Phlebotomy 
Laboratory or the Department of Rehabilitation Medicine.  Nine tests will be run with 
approximately 5 tablespoons of blood taken via a standard blood draw technique.  Additionally, 
approximately 6 tablespoons of blood will be collected via PAX gene, Serum Separator Tube, 
sodium heparin and CPT tubes and used for research purposes.  1) Nt ProBNP: N-terminal pro b-
type natriuretic peptide assays will be performed before and after the intervention period to 
objectively monitor for potential myocardial damage.  Recent data suggests that high levels of 
NT-proBNP indicate acute heart failure.  This test is used as a standard of care in many 

 
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emergency departments when patients exhibit symptoms of heart failure such as shortness of 
breath and fatigue. 2) Complete Blood Count with Differential:  Using the same sample of blood 
we will perform a test to separate the red blood cells, white blood cells and platelets from the 
plasma which will help us learn more about the oxygen carrying capacity of the blood. 3) SLE 
disease activity markers: This includes testing for complement proteins C3, C4, anti-ds-DNA 
antibody (anti-double stranded DNA), ESR (erythrocyte sedimentation rate) and hs-CRP (high 
sensitivity C-reactive protein levels), urinalysis, and urine protein creatinine ratio. 4) Lipid panel 
(preferably fasting 8-10 hours). 5) Chemistry panel including electrolytes, mineral panel, acute 
care panel, and hepatic panel. 6) Coagulation (PTT, PT/INR) 7) TSH (thyroid stimulating 
hormone, evaluate thyroid function as part of exclusion criteria). 8) Hemoglobin A1C to evaluate 
diabetes mellitus as part of the exclusion criteria. 9) HIV Antibody 
Pregnancy Testing:  Female patients of childbearing potential will undergo serum or urine dip-
stick pregnancy testing at the National Institutes of Health Phlebotomy Laboratory during 
baseline testing following blood draw.  Follow-up pregnancy tests will be performed at 
subsequent testing visits to the National Institutes of Health.  In order for a patient to be enrolled 
or continue with this study, this test must be negative.   
Electrocardiogram:  All subjects will be screened for signs/symptoms of coronary artery disease, 
cardiomyopathy, or any other underlying cardiovascular diseases that may increase the subject’s 
risk of performing an exercise-based intervention by screening all patients with a 12 lead 
electrocardiogram (EKG).  This will be performed in the National Institutes of Health 
Electrocardiography Laboratory prior to the subject’s inclusion in the study.  Subjects will be 
required to lay supine on an examination table while 12 electrodes are placed on the subject’s 
chest and then connected to an electrocardiogram by an EKG technician.  A cardiologist will 
interpret all electrocardiograms prior to the performance of any exercise testing. 
Echocardiogram:  Cardiac echo is required for this protocol.  Subjects must not have pulmonary 
hypertension (PH) and have an estimated left ventricular ejection fraction (LVEF) of ≥50%.  To 
evaluate both of these measures, all subjects will be required to undergo a Doppler 
echocardiogram prior to inclusion in the study.  This may be performed at the National Institutes 
of Health Echocardiogram Laboratory.  A transducer placed on the subject’s chest will allow us 
to measure the subject’s right ventricular size/thickness and systolic pressure.  1) PH causes a 
retrograde flow of blood from the pulmonary arteries into the right ventricle (RV) which, when 
chronic, results in ventricular remodeling, increasing the size and thickness of the myocardium, 
thus increasing the chronic RV systolic pressure. To determine the probability of PH we will use 
the guidelines as presented in the 2015 ESC/ERS guidelines for the diagnosis and treatment of 
PH.29 These guidelines suggest using tricuspid regurgitation velocity (TRV) at rest and the 
presence of additional pre-specified echocardiographic variables suggestive of PH.  The 
probability of PH may then be judged as low, intermediate, or high (Table A).  
Echocardiographic ‘PH signs’ used in addition to criteria based on TRV provide an assessment 
of the RV size and pressure overload, the pattern of blood flow velocity out of the RV, the 
diameter of the PA and an estimate of RAP (Table B).   Based on echocardiogram interpretation, 
the patient will be admitted to the study if the probability of pulmonary hypertension is low or 
intermediate. 
Table A 

 
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Peak tricuspid 
regurgitation velocity (m/s) 
Presence of other echo ‘PH 
signs’* 
Echocardiographic probability 
of pulmonary hypertension 
≤2.8 or not measurable 
No 
Low 
≤2.8 or not measurable2.9-3.4 
Yes 
No 
Intermediate 
2.9-3.4 
>3.4 
Yes 
Not required 
High 
Table B 
A.  The ventricles a 
B. Pulmonary artery 
C:  Interior vena cava and right 
atrium 
Right ventricle/left ventricle 
basal diameter ratio > 1.0 
Right ventricular outflow 
Doppler acceleration time 
<105 msec and/or midsystolic 
notching 
Inferior cava diameter >21 mm with 
decreased inspiratory collapse (<50% 
with a sniff or <20% with quiet 
inspiration) 
Flattening of the 
interventricular septum (left 
ventricular eccentricity index 
>1.1 in systole and/or 
diastole) 
Early diastolic pulmonary 
regurgitation velocity >2.2 
m/sec 
Right atrial area (end-systole) >18 
cm² 
 
PA diameter >25 mm. 
 
a. Echocardiographic signs from at least two different categories (A/B/C) from the list 
should be present to alter the level of echocardiographic probability of pulmonary 
hypertension. 
LVEF will be estimated through echocardiogram volumetric measurements of the left ventricle.  
Placing the transducer over the subject’s left ventricle allows for the measurement of the 
chamber’s size in end-systolic and end-diastolic states thus giving an estimation of LVEF by 
comparing the difference in size.  Subjects in this protocol will be required to have an estimated 
LVEF of ≥50%, because a decreased LVEF will increase the risk of exercise testing/training in 
this study population.  
Pulmonary Function Test:  Forced Vital Capacity (FVC), Maximal Voluntary Ventilation 
(MVV), and Diffusion Capacity (DLCO) tests will be assessed for all subjects.  These tests will 
be performed at the National Institutes of Health Pulmonary Function Laboratory prior to 
inclusion in the study.  FVC is used to evaluate the degree of obstructive and restrictive lung 
disease.  MVV is used to evaluate the subject’s ventilatory limitation.  Both tests will be obtained 
while the subject is at rest.  We will determine whether the subject’s exercise capacity is limited 
by ventilation by computing the ratio between expired minute ventilation (Ve) measured at 
maximum exercise and MVV (Ve / MVV must not exceed 0.90).  To perform the FVC and the 

 
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MVV test the subject will be instructed to stand, plug their nose with their free hand (or wear a 
nose clip) and create an airtight seal over the mouth piece.  For the FVC, the subject will be 
asked to take in three regular breaths, followed by a deep inhalation and a quick and complete 
exhalation, blowing air until there is nothing left to expire.  This test will be performed 2-3 times.  
Completion of the test will be when two test results are within 5% of each other.  For the MVV, 
the subject will be asked to breathe in and out normally three times followed by breathing in and 
out rapidly (90-100 breaths·minˉ¹) for 12-15 seconds.  The teeth and tongue must refrain from 
blocking airflow.  A DLCO test is used to determine the lungs’ ability to exchange gases across 
this respiratory membrane wall.  Using a mouthpiece and nose clip, the subject will be required 
to inhale air containing a small amount of carbon monoxide and then exhale rapidly for 10 
seconds.  Exhaled air is then measured to determine the amount of carbon monoxide that is 
absorbed by the lung tissue and as such determine the subject’s diffusion capacity. 
  
Research Tests: 
Fatigability Tests: For this measure, subjects will complete a 10-minute timed walk test. Subjects 
are instructed to walk as far as they can, in ten minutes. Velocity measurements are taken each 
minute and at 2.5 minutes. Two fatigability types, perceived and performance, are measured 
during a 10-minute walk test.  Fatigability is best defined as the change in physical performance 
or/and feelings of tiredness over the duration of a particular intensity, duration or frequency of 
activity (NIH/NIA PAR-12-227). Performance fatigability is the decline in physical performance 
over time and is measured directly in the laboratory or as a field test in the clinic by measuring 
physical performance over, in our case, work intensity sustained for a given duration. A 
performance fatigability index is calculated by dividing the average velocity of the entire 10-
minutes of the test into the average velocity over the first 2.5 minutes (decline in performance) 
and further dividing the previous quotient in performance by the total distance walked (an index 
of intensity).  Perceived fatigability is simultaneously evaluated by having the subject rate 
perceived changes in the feeling of tiredness over the 10-minutes of the test on a numerical 
visual response scale and dividing the change by the total distance walked. This test will take 
approximately 20 minutes to complete.  
Treadmill Cardiopulmonary Exercise Test (CPET): We will be measuring time to anaerobic 
threshold (AT-time) during this test. The anaerobic threshold is a physiological measure that is 
unaffected by motivation or the perception of fatigue, which indexes the metabolic intensity at 
which intracellular buffering capacity is exceeded. For activity intensities above the anaerobic 
threshold, oxidative metabolism is insufficient for supplying all of the ATP needed to sustain the 
work rate resulting in increased glycolytic supplementation. The by-products of anaerobic 
glycolysis and insufficient buffering, particularly free ions and metabolic acids, mediate fatigue. 
Above the anaerobic threshold, glycolytic supplementation intensifies as the energy demand 
increases. Measuring the AT-time during CPET further scales the index to exercise duration. 
Thus, AT-time is a physiological measure of performance fatigability in which its prolongation 
reflects low fatigability and shortening reflects proportionally higher levels. This test will also 
include muscle oxygenation and cardiac function measurements described below. Ratings of 
Perceived Exertion (RPE) will be measured incrementally throughout the CPET.  Each CPET 
will take about 120 minutes to complete and one CPET will be performed at baseline and one 
will be performed after exercise training (for pre to post-training comparison). 

 
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Square Wave CPET (swCPET): The swCPET is a submaximal, moderate treadmill test of 3 
moderate bouts of continuous work rate exercise alternated with longer bouts of active rest at 
low intensity. The bouts are comprised of an initial stabilization period of treadmill walking at 
0.7 mph for 3 minutes. The stabilization bout is followed by an increase in walking velocity to 
that corresponding to 85% of the anaerobic threshold measured on the CPET sustained for six 
minutes. The 6-minute interval is followed by an 8-minute active rest period.  The 6-minute 
exercise, 8-minute recovery sequence is repeated a total of three times. This test is used to 
measure VO2 on-kinetics. VO2 on-kinetics is a measure of the rapidity with which the 
cardiorespiratory and oxidative metabolic systems can respond to increases in energy demand. 
Prolonged VO2 on-kinetics contributes to increased fatigability whereas more rapid VO2 on-
kinetics is associated with lower levels of fatigability. Muscle oxygenation and cardiac function 
measurements will also be made during this test, as will RPE.  One of these tests will be 
completed at baseline and since the work intensity is based on CPET performance, two will be 
performed after completing the exercise training regimen: one at the original baseline intensity 
and one at a new intensity established from the post-training CPET. These tests will each take 
about 45 minutes to complete.  
Near Infrared Spectroscopy: Near infrared spectroscopy (NIRS) will be used to assess 
microvascular reactivity and muscle oxygen extraction. Both of these components are necessary 
for optimized cardiorespiratory function. Diminished muscle oxygenation capacity is associated 
with exercise intolerance and performance and perceived fatigability. The NIRS test will be 
performed during a gastrocnemius total arterial occlusion to assess muscle oxygenation capacity 
test just prior to the CPET and swCPET.  The NIRS light emitters and sensors will be left in 
place to assess the muscle oxygenation during the swCPET and CPET. The NIRS analysis will 
help to determine the relative contribution of muscle oxygenation to overall oxygen kinetics in 
these women with SLE. Times for preparation and making the occlusion measurements are 
included in the time estimates for both the CPET and swCPET. 
Arterial Occlusion Muscle Oxygenation Capacity Test:  NIR light source and receiving sensors 
will be placed on the belly of the dominant gastrocnemius muscle to record muscle oxygen-
hemoglobin flux.  A blood pressure cuff will be placed around the distal hamstrings of the 
dominant leg. Using a Hokanson® rapid inflation vascular testing system, the cuff will be 
rapidly inflated to a pressure that totally occludes blood flow into the gastrocnemius, typically 
between 60 and 80 mmHg above systolic pressure. The occlusion will be maintained for up to 10 
minutes and tissue saturation will be measured over the time course. The tissue saturation index 
will be calculated as STI= [O2-Hb] / Tot-Hb. The rate of decline in STI will be the main muscle 
tissue saturation measure. 
Bioimpedance Cardiography (ZCG) Test: Bioimpedance cardiography will be used to measure 
changes in cardiac function at rest and during exercise and the cardiodynamics associated with 
VO2 on-kinetics. Data will be collected before and after the 12-week aerobic exercise-training 
regimen. The primary variables for this test are cardiac output and stroke volume however, 
other cardiac function variables will also be available. The ZCG analysis will be performed 
during both the CPET and the swCPET. Aluminum/aluminum chloride (Ag/AgCl) electrodes 
will be placed on the sternum at the level of the heart and another to the standard precordial V6 
position. Two Ag/AgCl electrodes will also be placed on the lateral triangle of the neck and 
two directly over the spine at the level of the xiphoid process. Data will be measured prior to 
each CPET after subjects rest for at least 10 minutes in a semi-recumbent position. 
Measurements will subsequently be taken in the standing position on the treadmill and then 

 
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continuously during both the CPETs and the swCPETs. Time requirements have been included 
in the estimates for both CPET and swCPET. 
Biomarkers and Mitochondrial Profile: We will collect samples of whole blood, serum CPT and 
PAX gene tubes for future exploration biomarkers with fatigability.  These include serum 
cytokine markers such as but not limited to IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12, IL-15, IL-
17, IL-23, IFNα, IFNγ, TNF-α and TGF-β, and interferon gene signature.30 They also include 
analysis to look for alterations in the “interferon signature” and the “granulocyte signature” in 
PBMCs using nanostring and measures of CD3+ T cell expression of IFN regulatory factor-
related genes using RNAseq and/or NanoString. 
We will collect whole blood samples to assess mitochondrial profile of the PBMCs. This 
includes testing for the maximum respiratory capacity, spare respiratory capacity, and ATP 
production of PBMCs. 
The amount of blood drawn for clinical care indication and research purposes will be kept within 
the NIH guidelines of 10.5 mL/kg or 550 mL, whichever is smaller, over any 8-week period for 
adults.  We plan to collect samples during Visits 1, 5 and 7.  
Non-Invasive Vascular Function Testing (Optional): 
Changes in vascular function, as assessed by the reactive hyperemia index (RHI) using Endopat 
device, arterial stiffness using cardio-ankle vascular index (CAVI), and by using SphygmoCor 
device to determine central blood pressures and arterial stiffness. Patients with SLE have 
vascular endothelial dysfunction and premature atherosclerosis. To date there are no studies 
looking at effect of exercise on vascular function in patients with SLE. These are surrogate 
markers of vascular damage and future atherosclerosis development which may be amenable to 
change within the timeframe of this study. 
 
Pulse wave analysis (SphygmoCor):  This optional procedure will be performed duringVisits 4, 5 
and 6.  SphygmoCor is a set of non-invasive tools used to determine central blood pressures and 
arterial stiffness.  It (1) derives the pressure wave from the ascending aorta to the carotid artery 
and (2) gives an accurate measurement of pressure at the heart, brain, and kidneys.  However, it 
cannot be used on patients who may suffer from heart arrhythmias or arterial stenosis. The 
SphygmoCor consists of the following:  
SphygmoCor Px Pulse Wave Analysis System – a diagnostic tool to measure central blood 
pressure. 
SphygmoCor Pulse Wave Analysis System – an algorithm used to determine central aortic 
pressure and visualize ventricular- vascular interactions.  
SphygmoCor Pulse Wave Velocity System- a tool that derives a pressure pulse waveform 
using the pressure tonometer and an ECG signal simultaneously. Arterial tonometry uses 
a pressure sensor to detect the speed of a pulse wave and may indicate a problem in the 
arteries.    
SphygmoCor Pulse Wave Monitoring System– a tool that provides an estimated pressure 
waveform from the ascending aorta. 
Cardio-ankle vascular index (CAVI):  This optional procedure will be performed the morning of 
Visits 4, 5 and 6.  For this procedure, placement of ECG electrodes on both wrists and a 
microphone for phonocardiograph on second intercostal space and 4 blood pressure cuffs 
wrapped around 4 extremities.  Arterial stiffness is calculated followed specified formulas. Main 
advantage of this procedure versus other procedures to measure arterial stiffness is that it is not 
altered by blood pressure. In addition, it is simple to perform. All vasodilators, antihypertensives 

 
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and statins will be held the morning of the test and will be restarted after the procedures are 
completed.  This is in order to avoid having additional variables interfering with the readings of 
the vascular measurements. The test takes approximately 20 minutes to be performed. 
Peripheral arterial tonometry (Endopat):   This optional procedure will be performed the 
morning of Visits 4, 5 and 6.  EndoPAT™ quantifies the endothelium-mediated changes in 
vascular tone, elicited by a 5-minute occlusion of the brachial artery (using a standard blood 
pressure cuff). When the cuff is released, the surge of blood flow causes an endothelium-
dependent.  Flow Mediated Dilatation (FMD). The dilatation, manifested as Reactive 
Hyperemia, is captured by EndoPAT as an increase in the PAT Signal amplitude. A post-
occlusion to pre-occlusion ratio is calculated by the EndoPAT software, providing the EndoPAT 
index. The test takes approximately 15 minutes to complete, is very easy to perform, and is both 
operator and interpreter independent. It is a noninvasive test, providing automatic analysis, 
office-based procedure. The five-minute blood pressure cuff inflation is an accepted standard test 
to cause reactive hyperemia (the increase of blood flow after a temporary restriction in blood 
supply) for the assessment of endothelial function. While the occlusion may cause some minor 
discomfort, and tingling in the fingers, the test is absolutely harmless.  It is recommended that 
the patient fast 3 to 8 hours before the test. Subjects will be requested to hold all medications 
including but not limited to all vasodilator, antihypertensive and statin on the morning of the test.  
Subjects will be requested to bring their medication with them on the day of the procedure they 
will resume their medications right after the completion of procedures. This is in order to avoid 
any possible confounding variables interfering with the readings of the vascular measurements. 
Heart rate variability (HRV): HRV may be calculated during rest and exercise using the ECG and 
HR data collected during the CPET, swCPET, exercise sessions and/or vascular function tests to 
examine autonomic functioning. Patients with SLE have been reported to have decreased HRV at 
rest, suggesting autonomic dysfunction in this population. There have been no studies that 
examined HRV during exercise and as a result of exercise training in patients with SLE. 
 
Health Related Quality of Life Measures 
PROMIS and FSS-: These are validated patient reported outcome measures. The fatigue, 
physical function, mental and sleep domains will be scored for each of these scales. Use of 
PROMIS and FSS, will permit an assessment of the relative contributions of factors, other than 
cardiorespiratory fitness and physical activity, such as mental and social functioning, to fatigue. 
Examining the relationships among fatigue and physical function provides an index of general 
fatigability.  PROMIS will provide a venue for characterizing health related quality of life. These 
questionnaires are estimated to take 30 minutes to complete.  
 
Treadmill Exercise Training: After the above baseline tests are completed, subjects will 
undergo aerobic exercise training. The training regimen used in this project is known to elicit 
improvements in cardiorespiratory function in healthy cohorts and in those who have chronic 
illnesses in general. This training regimen has been shown to improve cardiorespiratory function 
and fatigue/fatigability in patients with autoimmune disease comorbid with pulmonary 
hypertension and/or interstitial lung disease, with subject adherence to the protocol at over 90% 
in both subject subsets and with no serious adverse events in either group. The target training 
heart rate range is 70-80% of heart rate reserve, computed as: 0.7 and 0.80 (peak heart rate minus 
resting heart rate) + resting heart rate. This method allows for the target heart rate range to be 
determine relative to each subject’s own capacity since it accounts for both the resting as well as 

 
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the measured maximum heart rate.  The 70-80% range defines performance of physical activity 
that is within the recommendations for prescription of safe, effective, and enjoyable exercise put 
forth by the American College of Sports Medicine (ACSM).28 The frequency of the visits will be 
on average three times per week, unless make up visits are needed in order to attend 80% or 29 
visits in 12 weeks.   During the training session, heart rate, treadmill speed, treadmill inclination, 
and RPE will be recorded. In the event that subjects cannot sustain 30 minutes of continuous 
treadmill walking at the target intensity, an interval approach will be used in which walking at 
the target will be sustained at smaller training interval durations of no shorter than 5 minutes 
followed by an active rest interval that is no longer than 1.5 times the training interval until the 
subject achieves a total exercise time of 30 minutes, excluding the rest intervals. Each of these 
sessions will last about 60 minutes but slightly longer if an interval approached is used. 
 
Post Training Protocol:  After completing the 12-week aerobic exercise training regimens, 
subjects will repeat the medical examinations, 10 MWT, vascular studies, CPET with muscle 
oxygenation and cardiac function measures, swCPET, fatigability tests, PROMIS, Fatigue 
Severity Scale, SELENA-SLEDAI, and SLICC/ACR-DI. Pre-post differences in the outcome 
measures will then be compared between the groups and analyzed for clinical and biological 
relevance.  
 
Statistical Analysis 
 
Pre-post differences in the outcome measures will be analyzed for clinical and biological 
relevance using t tests or ANCOVA to control for confounding or intervening modulators if 
discovered. The primary outcome variable for this study is the change in performance fatigability 
as determined by pre to post exercise training changes in the time taken to attain the anaerobic 
threshold on the CPET and oxygen kinetics time constant measured during the swCPET. We also 
assess changes in the performance fatigability index (PFI) and the perceived fatigability index.  
Secondary outcome measures will include exercise training induced changes in muscle 
oxygenation and cardiac function, as well as changes in questionnaire responses, including the 
PROMIS and Fatigue Severity Scale. Changes in disease activity and severity will be assessed 
by comparing post-training to baseline scores on the SELENA-SLEDAI and SLICC/ACR-DI. As 
change in these measures are expected to be small, Chi-square tests or logistic regression after 
dichotomizing changes into categories of up to no change and increase by at least 3 points will 
be used. 
 
Subject Withdrawal 
Subjects may withdraw voluntarily anytime during the study. Any subject who misses more than 
7 exercise training sessions without making them up before the end of the study or missing more 
than 2 consecutive weeks of exercise at the NIH Clinical Center will be withdrawn. Subjects who 
develop a SLE flare, defined as an increase in SELENA-SLEDAI score of ≥4 compared to 
baseline during the study or any other medical condition as determined by the clinician that will 
impair their ability to participate in the study will be withdrawn.  In addition, the emergence of 
any of the exclusion criteria after subject enrollment or any changes in medications that may 
make subject participation unsafe or interfere with the study interpretation will lead to that 
subject’s withdrawal.  Any subject withdrawn after completion of more than 12 visits will not be 
replaced.  

 
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Risks and Discomforts to Subjects:  
1. CPET: The most serious risks of participating in vigorous exercise are cardiovascular 
abnormalities including sudden cardiac arrest, myocardial infarction, angina and 
electrocardiographic abnormalities, shortness of breath, dizziness, early fatigue onset and 
exhaustion. These risks are slight and the likelihood of their occurrence is small even in 
individuals with known coronary atherosclerosis or chronic heart failure during maximal 
exercise testing. The general risk of serious adverse events during CPET is low at 0.0 to 
8.3 per 10,000 tests.14-23 Pre-screening minimizes the risk to almost negligible levels.  
Exercising at submaximal intensities, such as during aerobic exercise training, carries 
with it an even lower risk of serious adverse events that is not greater than that occurring 
during routine activities or exercising in unsupervised settings.  
To minimize risk and maximize safety, subjects will be evaluated by medical history and 
physical examination, ECG, Doppler cardiac echocardiography, and pulmonary function 
tests with DLCO, to exclude those with contraindications to exercise prior to initial 
CPET. During CPETs, subjects will be monitored by continuous 12-lead EKG and before 
beginning the tests subjects will be informed of the signs and symptoms of heart disease 
and questioned frequently during the test regarding their presence. Staff with training 
appropriate for exercise testing and training will supervise CPET and training sessions for 
individuals with chronic illnesses, credentialed by the NIH Clinical Center, Rehabilitation 
Medicine Department, in which the testing and training procedures will take place.  
2. PROMIS and FSS: These questionnaires are generally not provocative and used to 
describe overall domains relative to health quality of life. The major risk associated with 
their use is accidental identification of the data.  To avoid this, no names or other 
personal identification information will be written or attached to the questionnaire forms.  
To de-identify the data, the completed questionnaires will be linked to other study data 
only by a study identifier, which will be a number assigned to each subject’s information. 
The identification key will be kept in secure files in the offices of Dr. Chin, Dr. Keyser 
and Dr. Hasni and available only to Drs. Chin, Keyser and Hasni.   
3. Square wave CPET (swCPET):  This test does not require vigorous levels of exertion, 
is of moderate intensity and does not use an exercise intensity greater than that 
encountered in routine daily activities. As such the risk to patients is minimal. The major 
risk of this test is tripping and falling on a moving treadmill belt or falling off the 
treadmill. This could result in contusions and bruising, lacerations, abrasions from the 
treadmill belt, concussion, and sprains, strains and fractures. Again these risks are 
minimal.  
To optimize safety, swCPETs will be conducted after first completing the CPETs as 
described above. Thus, subjects will have demonstrated their ability to safely exercise at 
a severe intensity that is much higher than the moderate intensity used for the swCPET. 
The tests will be conducted by trained and experienced staff all of whom are credentialed 
to supervise cardiopulmonary testing in the NIH Clinical Center, Rehabilitation Medicine 
Department after physician clearance of the subject for testing. The treadmill itself is 
equipped with 2/3 length handrails to enable the subject to maintain balance or catch 
herself in the event of a stumble. At least two staff members will be present for the 
swCPET and subjects will have been pre-screened for all exercise and tests by a 
physician prior to participation. 

 
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4. Fatigability Tests: Subjects are instructed to walk as far as possible around an 80-meter 
circular corridor  in 10 minutes.  The major risks to this test are stumbles and falls, which 
could result in sprains, strains, fractures, contusions, and concussion. Additional risks 
include chest pain, shortness of breath, nausea, pallor, diaphoresis, heart attack, cardiac 
arrest and sudden death similar to the CPET.  
To maintain the safety of participation in this test, all Fatigability tests will be conducted 
after the CPET, which imposes volitionally maximum cardiovascular stress. Only 
subjects able to tolerate the CPET without clinical signs and symptoms of cardiovascular 
disease will be enrolled in the study. Therefore, subjects will have demonstrated their 
ability to tolerate exercise intensities and stress greater than that imposed by the 10-
minute walk test. Credentialed staff with expertise in exercise testing will conduct the 10-
minute walk test. Subjects will sit immediately following the test to avoid falling in the 
event they would become dizzy after strenuous exercise. 
5. NIRS Test with Arterial Occlusion Muscle Oxygenation Capacity Test: The near 
infrared spectroscopy (NIRS) test involves placing infrared light emitters and sensors on 
the belly of the gastrocnemius (calf) muscle. These are held in place by a sticky cement 
and are often covered with an elastic wrap to help hold them in place. The light itself 
does not cause burns and we could find no reports of any untoward events regarding the 
use of NIRS. Some very minor risk may be due to minor skin breakdown under the 
emitter/sensor patches. This usually resolves in a few hours to several days and is usually 
not painful or uncomfortable.   
This test also involves total occlusion of blood flow just above the knee. Subjects may 
experience pain, tingling, and/or numbness in the lower leg during the test. To diminish 
these effects, occlusion time will be kept minimal, after observing complete 
deoxygenation of the gastrocnemius muscle (not more than 10 minutes).  No ischemic 
injury is associated with this test due to the high anaerobic capacity of skeletal muscle 
and the short occlusion time. 
Arterial occlusion for measures of reactive hyperemia is a non-invasive and safe 
technique commonly used in patients with peripheral vascular disease. We are using 
arterial occlusion in our current interstitial lung disease (ILD) protocol. Of the 16 
participants who have completed the ILD study, three participants did not participate in 
the arterial occlusion due to Raynaud’s Syndrome and one requested to stop due to 
discomfort. All participants fully recovered within minutes of cuff removal with no 
reports of residual pain or discomfort after leaving our facility. There have been no 
adverse events from arterial occlusion in our lab. It is a well-accepted procedure deemed 
safe and tolerable.  
6. Bioimpedance Cardiography (ZCG) Test: This test involves passing a small, 
unnoticeable electrical current between electrodes of known distance on the thorax and 
back. The voltage and amperage of the current is below the threshold for perception or 
stimulation of action potentials in skeletal, smooth, or cardiac muscle and sensory, motor 
or CNS neurons. We could find no reports of adverse events due to use of the ZCG. Risks 
are basically those associated with skin breakdown due to sliver/silver chloride electrode 
patch contact with the skin. Some slight itching has been reported in some subjects. 
These symptoms are minimal and last only for a few hours to a few days.  
7. Treadmill Exercise Training:  The risks are those associated with aerobic exercise and 
treadmill walking in general. These are the risks of provocation of signs and symptoms of 

 
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cardiovascular disease including chest pain, shortness of breath, dizziness/syncope, 
diaphoresis, sweating, nausea, heart attack and sudden death. Risks also include 
contusions, abrasions, concussion, sprains, strains and fractures associated with falling on 
a moving treadmill. Subjects are likely to experience immediate or delayed muscle 
soreness due to initiating an exercise-training program after having been sedentary. The 
onset of muscle soreness typically occurs immediately or within 48 hours and lasts a few 
days to a week.   
As a method of establishing her exercise training regimen is within the ranges 
recommended for safe and effective exercise by the ACSM and as a safety precaution, 
subjects will have undergone CPET prior to beginning exercise training. The intensity for 
training will be well below the maximum attained on the CPET and subjects presenting 
clinical signs and symptoms on the CPET will be excluded from the study. All subjects 
will be pre-screened and approved for participation by a medical staff member before 
beginning participation. In addition, treadmills used for training will have handrails and 
an emergency stop button easily accessible for the subject in the event they begin to fall 
or need to stop immediately. The stop button is linked to a clip worn on the subject’s 
clothing and in the event she falls the treadmill will stop immediately preventing further 
abrasions from a moving treadmill belt. Subjects’ treadmill exercise training sessions will 
be overseen and monitored by staff specifically credentialed for the supervision of 
aerobic exercise.  
8. Echocardiography: The use of diagnostic transthoracic ultrasound is not associated with 
significant risk. There is however the possibility of an allergic response to the gel used to 
optimize contact of the ultrasound transducer with the skin in a few people. The allergy 
may present as a rash and/or itching localized to the area of contact and subsides after a 
few hours to a few days.  
9. PFT with DLCO: Serious risks are not associated with pulmonary function tests or lung 
diffusion tests. Patients may experience perceptions associated with exertion on the PFT 
and may feel dizzy and short of breath for a short time after completion of the test. 
Patients may also experience slight dizziness and shortness of breath during and shortly 
after the DLCO procedure. In both cases these symptoms are not specific to any emergent 
condition, unless severe and persistent, and should only last a few minutes following the 
tests. 
10. Blood draw: The risks are those associated with routine blood draws. These include 
infection, vein collapse, and the need for multiple sticks. These risks will be minimized 
by personal credentialed at the Clinical Center for obtaining and handling blood samples. 
On occasion, some subjects may be come dizzy, nauseous, or may faint at the sight of 
their own blood. We will instruct subjects to face a different direction during the draws if 
they are prone to these reactions. If these reactions do occur, subjects will be given 
appropriate instructions for managing them by the trained technician acquiring the 
sample. 
11. Electrocardiogram: There is no clinically significant risk associated with this procedure. 
There may be minor discomfort, when the ECG electrodes taped to chest are removed.  
Rarely, a reaction to the electrodes may cause redness or swelling of the skin. 
12. Vascular function studies:  SphygmoCor, CAVI, and Endopat, (optional).  These 
procedures are very well tolerated. Other than potential transient minimal discomfort with 
blood pressure cuff, no side effects are expected. 

 
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Benefits to Subjects: 
This research involves greater than minimal risk with the prospect of direct benefit to individual 
subjects. Potential benefits of participation include improvements in cardiorespiratory capacity 
that may enable individuals to accomplish a given amount of activity or work at a lower 
percentage of maximum capacity and with less fatigue. Moreover, improvement of exercise 
tolerance generally increases quality of life by permitting individuals to engage more easily in 
daily physical activities and perhaps full or part time employment. Improved cardiorespiratory 
fitness may also decrease the risk for cardiovascular disease, stroke, cancer, obesity and diabetes 
mellitus.  
Human Subject Research Protections (HSRP) 
Subject Selection 
Rationale:  Patients referred from the Baltimore/Washington/Northern Virginia area will be 
potential subjects for this study.  All subjects will be classified by SELENA-SLEDAI score, which 
measures Lupus disease activity.   No participants will be excluded based on race or ethnicity. 
Recruitment:  Subjects will be primarily recruited from the pool of subjects available at National 
Institute of Health’s, National Institute of Arthritis, Musculoskeletal, and Skin Diseases clinic. The 
majority of these subjects are enrolled in the Pathogenesis and Natural History of Systemic Lupus 
Erythematosus (SLE) study, which has been ongoing since the early 1990’s and currently has 
approximately 1100 enrollees. Other recruitment efforts may be directed toward presentations to 
Lupus support groups and an introductory study letter for local private rheumatology practices.  
We may also utilize NIH Clinical Center-sponsored digital media resources such as Twitter, 
Facebook, CC Radio, CC TV, Photo Gallery; databases such as NIH Search the Studies, 
ClinicalTrials.gov, and Research Match; and local newspapers such as the Washington Post to 
disseminate information about the study to potential participants and their healthcare providers. 
The recruitment strategy offered by the NIH/CC Office of Patient Recruitment, including sample 
recruitment messages and advertisements in the form of study flyers will be used. IRB-approved 
flyers may be left with clinics for interested treating physicians to refer subjects to this study with 
approval of the venue or in accord with their policy; self-referral is also permitted. Recruitment 
flyers may also be given directly or sent electronically to those requesting study information. Flyers 
may be made available at outreach exhibits, speaking engagements, support group meetings, 
professional meetings or association/trade meetings with approval of the venue or in accord with 
their policy. 
Pre-Screening Process in the NIAMS Clinic 
 

 
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Leighton Chan 
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If any physicians in NIAMS feel they have a patient that may be an appropriate candidate for 
enrollment based on inclusion/exclusion criteria, then an associate investigator will be introduced 
to the patient after a brief overview of the study. If she is interested, they will be consented at 
that time or make an appointment for a future date in order to be consented and tested.  
If the NIH Study Coordinator or Associate Investigator interviews a potential subject from 
any source the following script will be followed: 
“Thank you for your interest regarding the research we are conducting to determine the benefits 
of an exercise program on Lupus.  We are accepting volunteers 21-80 years of age who have 
been diagnosed with Lupus, with moderate to severe fatigue, and are currently stable in their 
disease and treatments.  If you are enrolled in the study we would ask that you come to NIH for 3 
days of testing, which do not have to be in a row, which would include a test to determine how 
far you can walk in 10 minutes, breathing tests and a treadmill exercise test.  During the 
treadmill test you will have 16 electrodes on your chest, we will ask that you wear a neoprene 
mask to collect data on the amount of oxygen you breathe in and out, as well as an electrode on 
your calf to determine the amount of oxygen your muscle utilizes for energy. After testing you 
will begin an exercise regimen that will include 36 exercise training sessions over 12 weeks. 
Does this sound like something that you would like to participate in?” 
If they answer “yes,” we ask if they have time to answer a short questionnaire that would allow 
us to evaluate their eligibility and safety for inclusion into the study.   
If, based on this interaction, we think the subject might meet the inclusion criteria for the study, 
we will request medical records such as (recent history, medication list, pulmonary function test, 
resting EKG, six-minute walk and echocardiogram) to further evaluate their eligibility for the 
study. Their medical records will be reviewed and, if it appears that the patient meets the 
inclusion criteria, we will set up an appointment for the patient to come to the NIH Clinical 
Center for consent and testing.  If, after obtaining a patient’s medical records it is clear that the 
patient does not meet inclusion criteria, the information may be used to refine our inclusion and 
exclusion criteria; however, these medical records will not be used for any research purposes. 
Upon arriving at the NIH, the patient will proceed through admissions and then consented to the 
study, followed by a history and physical examination, blood draw, ECG, transthoracic 
echocardiogram, pulmonary function testing, arterial occlusion muscle oxygenation capacity test, 
cardiopulmonary exercise test, questionnaires, and ten minute walk test.  
Exclusions: 
Exclusion of Children:  Individuals younger than 21 years will not be included in the protocol 
because reference ranges for normative aerobic capacity and aerobic fitness have not been 
established for children and adolescents.  The objectives of this project do not include 
establishing these normative reference ranges.  Moreover, far less is understood about Lupus in 
children and the mechanisms by which it occurs. This lack of information could introduce 
critical levels of bias into the interpretation and cause the interpretation of our results to be 

 
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Leighton Chan 
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misleading.  Exercise response and adaptation in children with Lupus should be studied in 
separate and specific protocols. 
Exclusion of Males:  Males account for less than 10% of those diagnosed with Lupus and this 
accounts for less understanding of Lupus as it relates to males. Due to the limited access of male 
patients and decreased likelihood to find willing male subjects we chose to exclude them because 
they will not be a viable comparison for this study.   
Exclusion of Pregnant Women:  Women of childbearing age will undergo urine pregnancy 
testing during screening and follow-up visits and will be excluded from the study should results 
be positive.   Pregnant women will necessarily be excluded from the study for safety reasons.  
Women who do not exercise before pregnancy should not begin a rigorous exercise during 
pregnancy and would not be able to achieve the target heart rate required as part of the testing 
and training.   
Exclusion of Those Who Are Unable to Provide Informed Consent:  Individuals unable 
to give informed consent will necessarily be excluded from the study because of the risk to 
subject safety and the need to maintain integrity of the study.  Subjects must be able to 
comprehend and follow directions, and express their own needs adequately during all testing and 
retesting procedures, and exercise and educational training sessions.   
Participation of NIH employees: 
We anticipate eligible NIH employees may participate in this study.  We will follow the 
Guidelines for the Inclusion of Employees in NIH Research Studies and will give each employee 
a copy of the “NIH information sheet on Staff Research Participation” as per NIH SOP 14F, 
“Research Involving NIH Staff as Subjects.” If the employee is within the same branch, section, 
or unit such that the individual obtaining consent is a supervisor then independent monitoring of 
the consent process through Clinical Center Department of Bioethics Consultation Service will 
be requested. Study staff will be trained that communication of any personal or medical 
information about an NIH employee, including the fact that they are participating in this study, 
should be restricted to those investigators who need to know this information, and such 
information will not be discussed with anyone outside of the study without permission from the 
subject. 
We will discuss the following applicable safeguards to the eligible NIH employee: 
- 
Unbiased participation for protocol integrity and participant risk assessment. 
- 
Ensure there is no perceived workplace pressure or expectation on either participation or 
deciding not to participate on the protocol in regards to a benefit or adverse effect on their 
NIH employment or staff position.   
- 
Protection of privacy and confidentiality will be maintained, but also with acknowledgement 
of the limits due to sensitive information that may be in their NIH file.   
- 
Discussion of time commitments of the study and compensation in accordance with NIH 
policy 2300-630-3, Leave Policy for NIH Employees Participating in NIH Medical Research 
Studies. 
 

 
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Data and Safety Monitoring Plan: As the PI, Dr. Chan will closely monitor patient safety 
throughout the duration of the study.  As the medically responsible physician, Dr. Sarfaraz 
Hasni, will monitor the patient’s condition as it relates to their Lupus disease activity.     
Since the risk of performing several exercise tests on patients with SLE is unknown, our plan 
may need more than just PI monitoring, but fails to meet the criteria for the involvement of a full 
DSMB. We suspect that the risk is a minor increase over minimal risk, but we are not sure.  For 
this reason, we have enlisted the assistance of Michael M. Ward M.D., Senior Investigator in the 
Clinical Trials and Outcomes Branch of NIAMS, as the independent medical monitor (IMM) for 
this study. He will be apprised of all significant adverse events.  In addition, this monitor will 
also have access to the study data. RMD’s Epidemiology and Biostatistics Department will 
examine the results on an interim basis. If, at any point, they feel that the study should be 
stopped because of concern for safety of study subjects, they will inform the PI, the IRB, and the 
clinical and scientific directors of CC and NHLBI.   
NIH IRB and CD reporting: 
Adverse events, non-compliance, protocol deviations, unanticipated problems (UP), and serious 
adverse events are defined as described in NIH HRPP SOP Policy 801 (“Reporting Research 
Events”).  All adverse events and deviations occurring during the study, including those 
observed by or reported to the research team, will be recorded. Reporting research events to the 
IRB will conform to the reporting requirements and timeframes as specified in Policy 801. 
Specifically, any actual or suspected non-compliance, major deviations, or UPs will be reported 
within 7 calendar days. Deaths that are possibly, probably or definitely related to the research 
will be reported to the IRB within 24 hours of an investigator becoming aware of the death. 
Minor deviations, adverse events and SAEs that are not UPs will be summarized and reported to 
IRB at the time of continuing review, or when otherwise requested by IRB or OHSRP office of 
Compliance and Training.  
 
Conflicts of Interest:  This study does not include any commercial interests, technology 
transfer, or any products made by a commercial interest.  No conflicts of interest have been 
identified for any NIH employees associated with this study. 
 
Travel and Compensation: No travel reimbursement will be provided.  
Subjects will receive a total of $2015 upon completion of the protocol as compensation for the 
following research activities and interventions*:   
 
Prescreening visit 
$140 
Baseline Exercise Testing Visit 1 
  110 
Baseline Exercise Testing Visit 2 
    90 
Exercise Training Visit #1 (including 10- 
minute-walk test and vascular studies 
  110 
Interim Evaluation Study Visit (including 
exercise training session and vascular studies 
  125 

 
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Leighton Chan 
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Final Exercise Training Session (including 
10-minute-walk test and vascular studies 
  110 
Post-Exercise Testing Visit #1 
  160 
Post-Exercise Testing Visit #2 
    90 
Post-Exercise Testing Visit #3 
    90 
33 Exercise Training Visits at $30/visit 
  990 
TOTAL 
$2015 
 
*Subjects withdrawn before completing the study will be pro-rated for the portion of the study 
completed.  Subjects will be compensated for the total number of exercise training sessions 
attended. 
Informed Consent: 
 Consenting:  NIH research staff will interview interested candidates.  Those deemed 
appropriate will both read and sign the NHLBI NIH approved consent form.  A copy of the 
signed informed consent shall be given to the individual signing the consent and the original 
consent document will be retained in the medical record.  Upon giving consent, the subject will 
undergo a full examination by a physician, and a review of available medical records will be 
performed to confirm their suitability for the trial. Additionally, they will undergo an 
echocardiogram, EKG, PFT with DLCO and a pregnancy test to ensure the patient is safe to 
exercise and do not meet any exclusion criteria. After this, they will begin the baseline research 
tests including: treadmill cardiopulmonary exercise test, arterial occlusion muscle oxygenation 
capacity test, pulmonary gas exchange analysis, heart rate measurement, bioelectrical impedance 
plethysmography, near infrared spectroscopy, six-minute walk and fatigability tests, and patient 
self-report instruments.  All tests will be performed again post rehabilitation for outcome 
comparisons. 
 
Management of Data and Samples:  Data will be collected using appropriately calibrated 
computer-assisted instrumentation, commercial software programs, data collection sheets and 
self-reported outcome questionnaires.   
Clinical Trials Survey System (CTSS) will be used to manage data collection of the following 
subject self-reported outcome questionnaires and subjects will have the choice of using an NIH 
mobile device or paper format to complete the questionnaires. All digital CTDB forms will be 
considered source documentation. 
 
CTDB 
Source 
Fatigue Severity Scale 
Digital or Paper 
PROMIS 
Digital or Paper 
Clinical Trials Database (CTDB) will be used to manage data collection and tracking of the 
intervention through the use of an NIH mobile device.   Paper source may be used should 
capability of digital entry not be available.    All Digital CTDB forms will be considered source 
documentation. 

 
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Leighton Chan 
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Upon enrollment, subjects will be assigned a protocol number that will be used as a subject 
identifier for all subject files and data collection sheets.  All computer software with associated 
data files is kept on password-protected computers that are off-network and are stored in a 
locked laboratory with restricted access.  Paper data collection sheets will be kept in de-
identified subject folders in locked filing cabinets in secure areas.  Patient consent forms and 
other relevant medical records with patient names and other identifiable data are kept in separate 
folders and locked in separate filing cabinets.  No information will be kept in either folder that 
could be used to link a subject’s medical record file to a subject’s study data file.   
Electronic data collected in the laboratory will be transferred to a restricted access folder on the 
Clinical Center network with appropriate firewall protection.  Only study PIs and AIs will have 
access to this folder. A password protected USB device will be used to transfer data.  Email 
communication with patient information or data will be transmitted via encrypted email as per 
NIH guidelines. 
Data will be analyzed as discussed in the Data Analysis section of this document. Analysis will 
be conducted using an assigned protocol number as the subject identifier described above. 
Analysis of de-identified data may be performed at George Mason University by approved 
associate investigators on this protocol. This includes de-identified data from the treadmill 
exercise tests, 10 MWT, fatigability tests, exercise training data and questionnaires. 
Sample Storage:  
As described under the biomarkers section we will collect samples of whole blood, serum CPT 
and PAX gene tubes for future exploration biomarkers with fatigability and other related 
research studies.  These include serum cytokine markers such as but not limited to IL-2, IL-6, IL-
10, TNF-α and TGF-β, and interferon gene signature.30  
The amount of blood drawn for clinical care indication and research purposes will be kept within 
the NIH guidelines of 10.5 mL/kg or 550 mL, whichever is smaller, over any 8 week period for 
adults.  
Research samples collected from subjects consenting to this protocol will be stored in locked 
secure freezers belonging to NIAMS.  The freezers are located in Building 10 at the NIH.  Only 
study investigators and participating research personnel will have access to the samples. Samples 
will be kept indefinitely unless there is a significant justification for destroying them.  The 
Principal Investigator will report the loss or destruction of samples collected under this protocol 
to the Institutional Review Board (IRB). 
All samples will be coded and will not have personal identifiers.  The codes for identifiers will 
be contained in a secure electronic database (CTDB) and a subject code log that is maintained in 
secure research files.    An electronic record log with identifiers of all collected research 
specimens will be kept.  These will be stored in secure NIH computers.   
Coded samples may be shared with collaborators within and outside the NIH.  Any remaining 
samples will be stored in the NIAMS locked freezers.  Stored samples may be used for studies 

 
SLE and Exercise 
 
28 
Leighton Chan 
9/23/2019 
related to systemic lupus erythematosus.  Approval from the IRB will be obtained prior to any 
research use of stored samples beyond the scope of this study. 
All patient samples will be coded and used for research purposes without sharing identifying 
information and all collaborators will follow federal rules for clinical research. 
 

 
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References: 
 
1. 
Helmick CG, Felson DT, Lawrence, et al. Estimates of the prevalence of arthritis and other 
rheumatic conditions in the United States. Part I. Arthritis Rheum. Jane 2008;58(1):15-25. 
2. 
Lahita RG. Systemic lupus erythematosus. 4th ed. San Diego, Calif: Academic Press; 2004 
3. 
Pisetsky D, Buyon J, S M, eds. Systemic Lupus Erythematosus. 12 ed. Atlanta Arthritis 
Foundation; 2001. Klippel J, Crofford L, Stone J, Weyland C, eds. Primer on the Rheumatic 
Diseases 
4. 
Rus V, Hajeer A, Hochberg MC, eds. Systemic Lupus Erythematosus. 2 ed. New YorkL 
Oxford University Press; 2001. Silman A, Hochberg MC, eds: Epidemiology of the 
Rheumatic Disease.  
5. 
Panopalis P, Yazdany J, Gillis J, et al. Health care costs associated with changes in work 
productivity among persons with systemic lupus erythematosus. Arthirits Care Res.  
2001;59(12):1788-1795. 
6. 
Fatigue AHCoSLERCf.  Measurement of fatigue in systemic lupus erythematosus: A 
systematic review. Arthritis Rheum. Dec 15 2007:57(8):1348-1357. 
7. 
Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application 
to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. Oct 
1989;46(10):1121-1123. 
8. 
Keyser RE, Rus V, Cade WT, Kalappa N, Flores RH, Handwerger BS. Evidence for aerobic 
insufficiency in women with systemic Lupus erythematosus. Arthritis Rheum, Feb 15 
2003:49(1):16-22. 
9. 
Tench C, Bentley D, Vleck V, McCurdie I, White P, D’Cruz D. Aerobic fitness, fatigue, and 
physical disability in systemic lupus erythematosus. J Rheumatol. Mar 2002;29(3):474-481. 
10. Keyser RE, Rus V, Mikdashi JA, Handwerger BS. Exploratory study on oxygen 
consumption on-kinetics during treadmill walking in women with systemic lupus 
erythematosus. Arch Phys Med Rehabil. Sep 201;91(9):1402-1409. 
11. Robb-Nicholson LC, Daltroy L, Eaton H, et al. Effects of aerobic conditioning in lupus 
fatigue: a pilot study. Br J Rheumatol. Dec 1989;28(6):500-505. 
12. Carvalho MR, Sato El, Tebexreni AS, Heidecher RT, Schenkman S, Neto TL. Effects of 
supervised cardiovascular training program on exercise tolerance, aerobic capacity, and 
quality of life in patients with systemic lupus erythematosus. Arthritis Rheum. Dec 15 
2005;53(6):838-844. 
13. Clarke-Jenssen AC, Fredriksen PM, Lilleby V, Mengshoel AM. Effects of supervised 
aerobic exercise in patients with systemic lupus erythematosus: a pilot study. Arthritis 
Rheum. Apr 15 2005;53(2):308-312. 
14. Atterhog JH, Jonsson B, Samuelsson R. Exercise testing: a prospective study of 
complication rates. Am Heart J. Nov 1979;98(5):572-579. 
15. Franklin B, Hellerstein H, Gordon S, Timmis G. Exercise Testing: Basic Principles. New 
York: Churchill Livingstone; 1992. 
16. Gibbons L, Blair SN, Kohl HW, Cooper K. The safety of maximal exercise testing. 
Circulation. Oct 1989;80(4):846-852. 
17. Gibbons LW, Mitchell TL, Gonzalez V. The safety of exercise testing. Prim Care. Sep 
1994;21(3):611-629. 
18. Hamm LF, Crow RS, Stull GA, Hanna P. Safety and characteristics of exercise testing early 
after acute myocardial infarction. Am J Cardiol. May 15 1989;63(17):1193-1197. 

 
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19. Modesto KM, Moller JE, Freeman WK, Shub C, Bailey KR, Pellikka PA, Safety of exercise 
stress testing in patients with abnormal concentration of serum potassium. Am J Cardiol. 
Apr 15 2006;97(8):1247-1249. 
20. Squires RW, Allison TG, Johnson BD, Gau GT. Non-physician supervision of 
cardiopulmonary exercise testing in chronic heart failure: safety and results of a preliminary 
investigation.  J Cardiopulm Rehabil.  Jul-Aug 1999;19(4):249-253. 
21. Stuart RJ, Jr., Ellestad MH. National survey of exercise stress testing facilities. Chest. Jan 
1980;77(1):94-97. 
22. Vacanti LJ, Sespedes LB, Sarpi Mde O. Exercise stress testing is useful, safe, and efficient 
even in patients aged 75 years or older. ARq Bras Cardiol, Feb 2004;82(2):151-154, 147-
150. 
23. Young DZ, Lampert S, Graboys TB, Lown B. Safety of maximal exercise testing in patients 
at high risk for ventricular arrhythmia. Circulation. Aug 1984l70(2):184-191. 
24. Chan L, Chin LM, Kennedy M, Keyser RE. Benefits of intensive treadmill exercise training 
on cardiorespiratory function and quality of life in patients with pulmonary hypertension. 
Chest 2013 Feb 1;143(2):333-43 
25. Weinstein AA1, Chin LM, Keyser RE, Chan L. Effect of aerobic exercise training on 
fatigue and physical activity in patients with pulmonary arterial hypertension. Respir Med. 
2013 May; 107(5):778-84 
26. Keyser RE, Woolstenhulme JG, Chin LM, Chan L. Cardiorespiratory function before and 
after aerobic exercise training in patients with interstitial lung disease. J Cardiopulm Rehabil 
Prev. 2015 Jan-Feb; 35(1):47-55. 
27. Keyser RE, Christensen EJ, Nathan SD, Chan LE. Changes in fatigability following intense 
aerobic exercise training in patients with interstitial lung disease. Respir Med. 2015 Apr; 
109(4):517-25. 
28. ACSM’s Guidelines for Exercise Testing and Prescription, 9thEdition. Thompson WR 
Editor, Lippincott Williams and Wilkins, Philadelphia, 2014. 
29. Galie, N, Humbert, M, Vachiery, J, Gibbs, S, Lang, I, Torbicki, A, Simonneau, G, Peacock, 
A, Noordegraaf, A, Beghetti, M, Ghofrani, A, Gomez Sanchez, M, Hansmann, G, Klepetko, 
W, Lancellotti, P, Matucci, M, McDonagh, T, Pierard, L, Trindade, P, Zompatori, M, 
Hoeper, M.  2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary 
hypertension.  European Heart Journal  Jan 2016, 37 (1) 67-119 
30. Ahn GE, Ramsey-Goldman R. Fatigue in systemic lupus erythematosus. International 
journal of clinical rheumatology. 2012;7(2):217-227.  
31. Bob Wolfe, F., Clauw, D. J., Fitzcharles, M.-A., Goldenberg, D. L., Katz, R. S., Mease, P., 
… Yunus, M. B. (2010). The American College of Rheumatology Preliminary Diagnostic 
Criteria for Fibromyalgia and Measurement of Symptom Severity. Arthritis Care & 
Research, 62(5), 600–610. https://doi.org/10.1002/acr.20140 
32. Bernal Vargas, L., Riveros Munévar, F., Vinaccia Alpi, S., & Quiceno Sierra, J. M. (2017). 
Estructura factorial y consistencia interna de la Escala de severidad de fatiga en población 
colombiana con enfermedades crónicas. Enfermería Global, 16(2), 37. 
https://doi.org/10.6018/eglobal.16.2.255821 
 

 
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Appendices 
Appendix 1 – Study Protocol Timeline Checklist 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4/Exercise Training 1 
Time Frame 
Consent Form 
X 
 
Medical History and Physical Exam 
X 
Inclusion/Exclusion Criteria 
X 
SELENA-SLEDAI 
X 
ACR Damage Index (SLICC/ACR-DI) 
X 
Labs and Imaging: 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene 
X 
 
2) Doppler Echocardiogram 
X 
3) Pulmonary Function Test with DLCO 
X 
4) Electrocardiogram 
X 
5) Serum or Urine Pregnancy test 
X 
 
6) Clinical labs and urine 
X 
Questionnaires: 
1) Fatigue Severity Scale (FSS) 
X 
2) PROMIS 
X 
Procedures: 
Cardio Pulmonary Exercise Test (CPET) 
X 
Arterial Occlusion Muscle Oxygenation Capacity Test 
X 
X 
Square Wave CPET (swCPET) 
X 
Fatigability Test (10 minutes) 
X 
Near Infrared Spectroscopy (NIRS) 
X 
X 
Bioimpedance Cardiography Test (ZCG) 
X 
X 
Modified Treadmill Exercise Training 20 minutes 
X 
Treadmill Exercise Training 30 minutes 
Non-Invasive Vascular Function Testing (Optional) 
 
X 

 
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Leighton Chan 
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Exercise Training 2 
Exercise Training 3 
Exercise Training 4 
Exercise Training 5 
Time Frame 
Consent Form 
Medical History and Physical Exam 
Inclusion/Exclusion Criteria 
SELENA-SLEDAI 
ACR Damage Index (SLICC/ACR-DI) 
Labs and Imaging: 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene tubes) 
2) Doppler Echocardiogram 
3) Pulmonary Function Test with DLCO 
4) Electrocardiogram 
5) Serum or Urine Pregnancy test 
6) Clinical labs and urine 
Questionnaires: 
1) Fatigue Severity Scale (FSS) 
- 
2) PROMIS 
Procedures: 
Cardio Pulmonary Exercise Test (CPET) 
Arterial Occlusion Muscle Oxygenation Capacity Test 
Square Wave CPET (swCPET) 
Fatigability Test (10 minutes) 
 
Near Infrared Spectroscopy (NIRS) 
Bioimpedance Cardiography Test (ZCG) 
Modified Treadmill Exercise Training 20 minutes 
 
Treadmill Exercise Training 30 minutes 
X 
X 
X 
X 
Non-Invasive Vascular Function Testing (Optional) 
 
 
 
 

 
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Leighton Chan 
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Exercise Training 6 
Exercise Training 7 
Exercise Training 8 
Exercise Training 9 
Time Frame 
Consent Form 
Medical History and Physical Exam 
Inclusion/Exclusion Criteria 
SELENA-SLEDAI 
ACR Damage Index (SLICC/ACR-DI) 
Labs and Imaging: 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene tubes) 
2) Doppler Echocardiogram 
3) Pulmonary Function Test with DLCO 
4) Electrocardiogram 
5) Serum or Urine Pregnancy test 
6) Clinical labs and urine 
Questionnaires: 
1) Fatigue Severity Scale (FSS) 
2) PROMIS 
Procedures: 
Cardio Pulmonary Exercise Test (CPET) 
Arterial Occlusion Muscle Oxygenation Capacity Test 
Square Wave CPET (swCPET) 
Fatigability Test (10 minutes) 
Near Infrared Spectroscopy (NIRS) 
Bioimpedance Cardiography Test (ZCG) 
Modified Treadmill Exercise Training 20 minutes 
Treadmill Exercise Training 30 minutes 
X 
X 
X 
X 
Non-Invasive Vascular Function Testing (Optional) 
 
 
 
 

 
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Leighton Chan 
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Exercise Training 10 
Exercise Training 11 
Exercise Training 12 
Exercise Training 13 
Time Frame 
Consent Form 
Medical History and Physical Exam 
Training Visit 13, 14 or15 
Inclusion/Exclusion Criteria 
SELENA-SLEDAI 
Training Visit 13, 14or 15 
ACR Damage Index (SLICC/ACR-DI) 
Labs and Imaging: 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene tubes) 
Training Visit 13, 14or 15 
2) Doppler Echocardiogram 
3) Pulmonary Function Test with DLCO 
4) Electrocardiogram 
5) Serum or Urine Pregnancy test 
Training Visit 13, 14 or 15 
6) Clinical labs and urine 
Training Visit 13, 14 or 15 
Questionnaires: 
1) Fatigue Severity Scale (FSS) 
2) PROMIS 
Procedures: 
Cardio Pulmonary Exercise Test (CPET) 
Arterial Occlusion Muscle Oxygenation Capacity Test 
Square Wave CPET (swCPET) 
Fatigability Test (10 minutes) 
Near Infrared Spectroscopy (NIRS) 
Bioimpedance Cardiography Test (ZCG) 
Modified Treadmill Exercise Training 20 minutes 
Treadmill Exercise Training 30 minutes 
X 
X 
X 
X 
Non-Invasive Vascular Function Testing (Optional) 
 
 
 
Training Visit 13, 14 or 15 

 
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Leighton Chan 
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Exercise Training 14 
Exercise Training 15 
Exercise Training 16 Exercise Training 17 
Time Frame 
 
Consent Form 
Medical History and Physical Exam 
Training Visit 13, 14 or 15 Training Visit 13, 14 or 15 
Inclusion/Exclusion Criteria 
SELENA-SLEDAI 
Training Visit 13, 14 or 15 Training Visit 13, 14 or 15 
ACR Damage Index (SLICC/ACR-DI) 
Labs and Imaging: 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene tubes) Training Visit 13, 14 or 15 Training Visit 13, 14 or15 
2) Doppler Echocardiogram 
3) Pulmonary Function Test with DLCO 
4) Electrocardiogram 
5) Serum or Urine Pregnancy test 
Training Visit 13, 14 or 15 Training Visit 13, 14 or 15 
6) Clinical labs and urine 
Training Visit 13, 14 or 15 Training Visit 13, 14 or 15 
Questionnaires: 
1) Fatigue Severity Scale (FSS) 
2) PROMIS 
Procedures: 
Cardio Pulmonary Exercise Test (CPET) 
Arterial Occlusion Muscle Oxygenation Capacity Test 
Square Wave CPET (swCPET) 
Fatigability Test (10 minutes) 
Near Infrared Spectroscopy (NIRS) 
Bioimpedance Cardiography Test (ZCG) 
Modified Treadmill Exercise Training 20 minutes 
Treadmill Exercise Training 30 minutes 
X 
X 
X 
X 
Non-Invasive Vascular Function Testing (Optional) 
Training Visit 13, 14 or 15 Training Visit 13, 14 or 15 
 
 

 
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Leighton Chan 
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Exercise Training 18 
Exercise Training 19 
Exercise Training 20 
Exercise Training 21 
Time Frame 
Consent Form 
Medical History and Physical Exam 
Inclusion/Exclusion Criteria 
SELENA-SLEDAI 
ACR Damage Index (SLICC/ACR-DI) 
Labs and Imaging: 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene tubes) 
2) Doppler Echocardiogram 
3) Pulmonary Function Test with DLCO 
4) Electrocardiogram 
5) Serum or Urine Pregnancy test 
6) Clinical labs and urine 
Questionnaires: 
1) Fatigue Severity Scale (FSS) 
2) PROMIS 
Procedures: 
Cardio Pulmonary Exercise Test (CPET) 
Arterial Occlusion Muscle Oxygenation Capacity Test 
Square Wave CPET (swCPET) 
Fatigability Test (10 minutes) 
Near Infrared Spectroscopy (NIRS) 
Bioimpedance Cardiography Test (ZCG) 
Modified Treadmill Exercise Training 20 minutes 
Treadmill Exercise Training 30 minutes 
X 
X 
X 
X 
Non-Invasive Vascular Function Testing (Optional) 
 
 
 
 

 
SLE and Exercise 
 
37 
Leighton Chan 
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Exercise Training 22 
Exercise Training 23 
Exercise Training 24 
Exercise Training 25 
Time Frame 
Consent Form 
Medical History and Physical Exam 
Inclusion/Exclusion Criteria 
SELENA-SLEDAI 
ACR Damage Index (SLICC/ACR-DI) 
Labs and Imaging: 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene tubes) 
2) Doppler Echocardiogram 
3) Pulmonary Function Test with DLCO 
4) Electrocardiogram 
5) Serum or Urine Pregnancy test 
6) Clinical labs and urine 
Questionnaires: 
1) Fatigue Severity Scale (FSS) 
2) PROMIS 
Procedures: 
Cardio Pulmonary Exercise Test (CPET) 
Arterial Occlusion Muscle Oxygenation Capacity Test 
Square Wave CPET (swCPET) 
Fatigability Test (10 minutes) 
Near Infrared Spectroscopy (NIRS) 
Bioimpedance Cardiography Test (ZCG) 
Modified Treadmill Exercise Training 20 minutes 
Treadmill Exercise Training 30 minutes 
X 
X 
X 
X 
Non-Invasive Vascular Function Testing (Optional) 
 
 
 
 

 
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Leighton Chan 
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Exercise Training 26 
Exercise Training 27 
Exercise Training 28 
Exercise Training 29 
Time Frame 
Consent Form 
Medical History and Physical Exam 
Inclusion/Exclusion Criteria 
SELENA-SLEDAI 
ACR Damage Index (SLICC/ACR-DI) 
Labs and Imaging: 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene tubes) 
2) Doppler Echocardiogram 
3) Pulmonary Function Test with DLCO 
4) Electrocardiogram 
5) Serum or Urine Pregnancy test 
6) Clinical labs and urine 
Questionnaires: 
1) Fatigue Severity Scale (FSS) 
2) PROMIS 
Procedures: 
Cardio Pulmonary Exercise Test (CPET) 
Arterial Occlusion Muscle Oxygenation Capacity Test 
Square Wave CPET (swCPET) 
Fatigability Test (10 minutes) 
Near Infrared Spectroscopy (NIRS) 
Bioimpedance Cardiography Test (ZCG) 
Modified Treadmill Exercise Training 20 minutes 
Treadmill Exercise Training 30 minutes 
X 
X 
X 
X 
Non-Invasive Vascular Function Testing (Optional) 
 
 
 
 

 
SLE and Exercise 
 
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Leighton Chan 
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Exercise Training 30 
Exercise Training 31 
Exercise Training 32 
Exercise Training 33 
Time Frame 
Consent Form 
Medical History and Physical Exam 
Inclusion/Exclusion Criteria 
SELENA-SLEDAI 
ACR Damage Index (SLICC/ACR-DI) 
Labs and Imaging: 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene tubes) 
2) Doppler Echocardiogram 
3) Pulmonary Function Test with DLCO 
4) Electrocardiogram 
5) Serum or Urine Pregnancy test 
6) Clinical labs and urine 
Questionnaires: 
1) Fatigue Severity Scale (FSS) 
2) PROMIS 
Procedures: 
Cardio Pulmonary Exercise Test (CPET) 
Arterial Occlusion Muscle Oxygenation Capacity Test 
Square Wave CPET (swCPET) 
Fatigability Test (10 minutes) 
Near Infrared Spectroscopy (NIRS) 
Bioimpedance Cardiography Test (ZCG) 
Modified Treadmill Exercise Training 20 minutes 
Treadmill Exercise Training 30 minutes 
X 
X 
X 
X 
Non-Invasive Vascular Function Testing (Optional) 
 
 
 
 

 
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Leighton Chan 
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Exercise Training 34 
Exercise Training 35 
Exercise Training 36 
/Visit 6 
Visit 7 
Time Frame 
Consent Form 
 
Medical History and Physical Exam 
X 
Inclusion/Exclusion Criteria 
 
SELENA-SLEDAI 
X 
ACR Damage Index (SLICC/ACR-DI) 
X 
Labs and Imaging: 
 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene tubes) 
X 
2) Doppler Echocardiogram 
 
3) Pulmonary Function Test with DLCO 
 
4) Electrocardiogram 
X 
5) Serum or Urine Pregnancy test 
X 
6) Clinical labs and urine 
X 
Questionnaires: 
 
1) Fatigue Severity Scale (FSS) 
X 
2) PROMIS 
X 
Procedures: 
 
Cardio Pulmonary Exercise Test (CPET) 
X 
Arterial Occlusion Muscle Oxygenation Capacity Test 
X 
Square Wave CPET (swCPET) 
 
Fatigability Test (10 minutes) 
X 
 
Near Infrared Spectroscopy (NIRS) 
X 
Bioimpedance Cardiography Test (ZCG) 
X 
Modified Treadmill Exercise Training 20 minutes 
X 
 
Treadmill Exercise Training 30 minutes 
X 
X 
 
 
Non-Invasive Vascular Function Testing (Optional) 
 
 
X 
 

 
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Leighton Chan 
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Visit 8 
Visit 9 
Time Frame 
Consent Form 
Medical History and Physical Exam 
 
Inclusion/Exclusion Criteria 
SELENA-SLEDAI 
 
ACR Damage Index (SLICC/ACR-DI) 
 
Labs and Imaging: 
1) Research Blood Tests (Whole Blood, Serum, CPT, PAX gene tubes) 
 
2) Doppler Echocardiogram 
3) Pulmonary Function Test with DLCO 
4) Electrocardiogram 
5) Serum or Urine Pregnancy test 
6) Clinical labs and urine 
 
Questionnaires: 
1) Fatigue Severity Scale (FSS) 
 
2) PROMIS 
 
Procedures: 
Cardio Pulmonary Exercise Test (CPET) 
 
Arterial Occlusion Muscle Oxygenation Capacity Test 
X 
X 
Square Wave CPET (swCPET) 
X 
X 
Fatigability Test (10 minutes) 
Near Infrared Spectroscopy (NIRS) 
X 
X 
Bioimpedance Cardiography Test (ZCG) 
X 
X 
Modified Treadmill Exercise Training 20 minutes 
Treadmill Exercise Training 30 minutes 
Non-Invasive Vascular Function Testing (Optional) 
 

 
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Leighton Chan 
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Appendix 2. Fatigue Severity Scale (FSS) 
 
Fatigue Severity Scale (FSS) 
 
Name ______________________________ Date ____________ 
 
The Fatigue Severity Scale (FSS) is a method of evaluating the impact of fatigue on you. The FSS is a 
short questionnaire that requires you to rate your level of fatigue. 
 
The FSS questionnaire contains nine statements that rate the severity of your fatigue symptoms. Read 
each statement and circle a number from 1 to 7, based on how accurately it reflects your condition during 
the past week and the extent to which you agree or disagree that the statement applies to you. A score of 1 
indicates you disagree and a score of 7 indicates you agree.  
 
FSS Questionnaire 
During the past week, I have found that: 
Disagree <--------> Agree 
My motivation is lower when I am fatigued. 
1 
2 
3 
4 
5 
6 
7 
Exercise brings on my fatigue. 
1 
2 
3 
4 
5 
6 
7 
I am easily fatigued. 
1 
2 
3 
4 
5 
6 
7 
Fatigue interferes with my physical functioning. 
1 
2 
3 
4 
5 
6 
7 
Fatigue causes frequent problems for me. 
1 
2 
3 
4 
5 
6 
7 
My fatigue prevents sustained physical 
functioning. 
1 
2 
3 
4 
5 
6 
7 
Fatigue interferes with carrying out certain duties 
and responsibilities. 
1 
2 
3 
4 
5 
6 
7 
Fatigue is among my three most disabling 
symptoms. 
1 
2 
3 
4 
5 
6 
7 
Fatigue interferes with my work, family, or social 
life. 
1 
2 
3 
4 
5 
6 
7 
 
 
The Fatigue Severity Scale is copyrighted by Lauren B. Krupps. Reproduced with permission of the 
author. 
 
 
 

 
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Appendix 3: SELENA SLEDAI 
LE-NUM:  
 
 
 
 
Name of Patient: 
MRN: 
 
Date SLEDAI Performed: 
 
/  
/ 
     
 
 
 
          mm/dd/year) 
 
 
 
Wt. Present 
Descriptor 
Definition 
8 
Seizure 
Recent onset (last 10 days). Exclude metabolic, infections or drug cause, or 
seizure due to past irreversible. 
8 
Psychosis 
Altered ability to function in normal activity due to severe disturbances in 
the perception of reality. Include hallucination, incoherence, marked loose 
associations, impoverished thought content, marked illogical thinking, 
bizarre, disorganized or catatonic behavior. Exclude uremia and drug 
causes. 
8 
Organic Brain 
Syndrome 
Altered mental function with impaired orientation, memory or other 
intellectual function, with rapid onset and Syndrome fluctuating clinical 
features. Include clouding of consciousness with reduced capacity to focus 
and inability to sustain attention to environment, plus at least two of the 
following: Perceptual disturbance, incoherent speech, insomnia or daytime 
drowsiness, or increased or decreased psychomotor activity. Exclude 
metabolic infectious or drug causes. 
8 
Visual Disturbance 
Retinal and eye changes of SLE. Include cytoid bodies, retinal hemorrhages, 
serous exudate or hemorrhages in the choroid, optic neuritis, scleritis or 
episcleritis. Exclude hypertension, infection, or drug causes. 
8 
Cranial Nerve 
Disorder 
New onset of sensory or motor neuropathy involving cranial nerves. Include 
vertigo due to lupus. 
8 
Lupus Headache 
Serve persistent headache: may be migrainous, but must be non- 
responsive to narcotic analgesia. 
8 
CVA 
New onset of cerebrovascular accident(s). Exclude arteriosclerosis or 
hypertensive causes. 
8 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual infarction, splinter 
hemorrhages, or biopsy or an angiogram proof of vasculitis. 
4 
Arthritis 
More than 2 joints with pain and signs of inflammation. 
4 
Myositis 
Proximal muscle aching weakness, associated with elevated creatine 
phosphokinase/adolase or electromyogram changes or a biopsy showing 
myositis. 
4 
Urinary Casts 
Cellular casts. 
4 
Hematuria 
>10 red blood cells/high power field. Exclude stone, infection or other 
cause. 
4 
Proteinuria 
New onset or recent increase of more than 0.5h/24hr. 
4 
Pyuria 
>5 white blood cells/high power field. Exclude infection. 
2 
Rash 
Ongoing inflammatory lupus rash. 
2 
Alopecia 
Ongoing abnormal, patchy or diffuse loss of hair due to active lupus. 
2 
Mucosal Ulcers 
Ongoing oral or nasal ulcerations due to active lupus. 
2 
Pleurisy 
Classic and Severe pleuritic chest pain or pleural rub or effusion, or new 
pleural thickening due to lupus. 
2 
Pericarditis 
Classic and Severe pericardial pain or pleural rub or effusion, or 
electrocardiogram confirmation. 
2 
Low Complement 
Decrease in C3 or C4 below the lower limit of normal for testing laboratory. 

 
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Leighton Chan 
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2 
Increased DNA 
Binding 
Above normal range for testing laboratory. 
1 
Fever 
>38 C. Excluding infectious causes. 
1 
Thrombocytopenia <100,000-platelets/mm3. 
1 
Leukopenia 
<3,000 white blood cells/mm3. Excluding drug causes. 
TOTAL SCORE 
(Sum of weights next to description marked present) 
 
Please Return To:   
 
 
 
 

 
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Leighton Chan 
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Appendix 4: SLICC/ACR DAMAGE INDEX FOR SLE 
Obs. Num: ______ 
Name of Patient:__________________________________________ MRN:_________________ 
Date SLICC Performed:______/_____/________ LE-Num:_________________ 
 
Wt 
Score 
Item 
1 
1 
Ocular (either eye, by clinical assessment) 
Any cataract ever 
Retinal change or optic atrophy 
1 
1 
1(2) 
1 
1 
Neuropsychiatric 
Cognitive impairment (e.g. memory deficit, difficulty with calculation, poor concentration,- 
-difficulty in spoken or written language, impaired performance level) OR major psychosis 
Seizures requiring therapy for 6 months 
Cerebrovascular accident ever (score 2 if >1) 
Cranial or peripheral neuropathy (excluding optic) 
Transverse myelitis 
1 
1 
3 
Renal 
Estimated or measured glomerular filtration rate < 50% 
Proteinuria > 3.5g/24h 
OR End-stage renal disease (regardless of dialysis or transplantation) 
1 
1 
1 
1 
1 
Pulmonary 
Pulmonary hypertension (right ventricular prominence, or loud P2) 
Pulmonary fibrosis (physical and radiograph) 
Shrinking lung (radiograph) 
Pleural fibrosis (radiograph) 
Pulmonary infarction (radiograph) 
1 
1(2) 
1 
1 
1 
Cardiovascular 
Angina OR coronary artery bypass 
Myocardial infarction ever (score 2 if > 1) 
Cardiomyopathy (ventricular dysfunction) 
Valvular disease (diastolic murmur or systolic murmur > 3/6) 
Pericarditis for 6 months, OR pericardectomy 
1 
1 
1(2) 
1 
Peripheral vascular 
Claudication for 6 months 
Minor tissue loss (pulp space) 
Significant tissue loss ever (e.g. loss of digit or limb)(score 2 if > 1 site) 
Venous thrombosis with swelling, ulceration, OR venous stasis 
1(2) 
1 
1 
1 
Gastrointestinal 
Infarction or resection of bowel below duodenum, spleen, liver or gallbladder ever, for any 
cause (score 2 if > 1 site) 
Mesenteric insufficiency 
Chronic peritonitis 
Stricture OR upper gastrointestinal tract surgery ever 
1 
1 
1 
1(2) 
1 
Musculoskeletal 
Muscle atrophy or weakness 
Deforming or erosive arthritis (including reducible deformities, excluding avascular necrosis) 
Osteoporosis with fracture or vertebral collapse (excluding avascular necrosis) 
Avascular necrosis (score 2 if > 1) 
Osteomyelitis 
1 
1 
Skin 
Scarring chronic alopecia 
Extensive scarring of panniculum other than scalp and pulp space 

 
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1 
Skin ulceration (excluding thrombosis for > 6 months) 
1 
Premature gonadal failure 
1 
Diabetes (regardless of treatment) 
1(2) 
Malignancy (exclude dysplasia) (score 2 if >1 site) 
TOTAL Score 
 
 
 

 
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Leighton Chan 
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Appendix 5: PROMIS–57 Profile v2.0  
 Please respond to each question or statement by marking one box per row. 
  
Physical Function 
Without 
any 
difficulty 
With a 
little 
difficulty 
With 
some 
difficulty 
With 
much 
difficulty 
Unable 
to do 
1 
Are you able to do chores such as 
vacuuming or yard work?...........................
 
 
 
 
 
2 
Are you able to go up and down stairs at a 
normal pace? .............................................. 
 
 
 
 
 
3 
Are you able to go for a walk of at least 15 
minutes? ................................................ 
 
 
 
 
 
4 
Are you able to run errands and shop? ....... 
 
 
 
 
 
 
Not at all 
Very little 
Somewhat 
Quite a lot 
Cannot do 
5 
Does your health now limit you in doing 
two hours of physical labor? ......................
 
 
 
 
 
 
6 
Does your health now limit you in doing 
moderate work around the house like 
vacuuming, sweeping floors or carrying in 
groceries? ................................................... 
 
 
 
 
 
7 
Does your health now limit you in lifting 
or carrying groceries?................................. 
 
 
 
 
 
 
8 
Does your health now limit you in doing 
heavy work around the house like 
scrubbing floors, or lifting or moving 
heavy furniture?......................................... 
 
 
 
 
 
  
Anxiety 
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
9 
I felt fearful................................................ 
 
 
 
 
 
 
10 
I found it hard to focus on anything other 
than my anxiety .......................................... 
 
 
 
 
 
11 
My worries overwhelmed me..................... 
 
 
 
 
 
12 
I felt uneasy ................................................ 
 
 
 
 
 
13 
I felt nervous............................................... 
 
 
 
 
 
14 
I felt like I needed help for my anxiety ...... 
 
 
 
 
 
 

 
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Anxiety 
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
15 
I felt anxious............................................... 
 
 
 
 
 
16 
I felt tense .................................................... 
 
 
 
 
 
 
Depression 
In the past 7 days... 
Never 
Rarely 
Sometimes 
Often 
Always 
17 
I felt worthless ............................................ 
 
 
 
 
 
18 
I felt helpless .............................................. 
 
 
 
 
 
19 
I felt depressed ........................................... 
 
 
 
 
 
20 
I felt hopeless ............................................. 
 
 
 
 
 
21 
I felt like a failure ....................................... 
 
 
 
 
 
22 
I felt unhappy ............................................. 
 
 
 
 
 
23 
I felt that I had nothing to look forward to . 
 
 
 
 
 
24 
I felt that nothing could cheer me up.......... 
 
 
 
 
 
 
Fatigue 
During the past 7 days… 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
25 
I feel fatigued ............................................. 
 
 
 
 
 
26 
I have trouble starting things because I am 
tired............................................................. 
 
 
 
 
 
 
In the past 7 days… 
27 
How run-down did you feel on average? ... 
 
 
 
 
 
28 
How fatigued were you on average? ......... 
 
 
 
 
 
29 
How much were you bothered by your 
fatigue on average?..................................... 
 
 
 
 
 
30 
To what degree did your fatigue interfere 
with your physical functioning? ................. 
 
 
 
 
 
  

 
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Leighton Chan 
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Fatigue 
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
31  
How often did you have to push yourself 
to get things done because of your 
fatigue?......................................................
 
 
 
 
 
32  
How often did you have trouble finishing 
things because of your fatigue? .................. 
 
 
 
 
 
  
Sleep Disturbance 
In the past 7 days… 
Very poor 
Poor 
Fair 
Good 
Very good 
33 
My sleep quality was.................................. 
 
 
 
 
 
 
In the past 7 days… 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
34 
My sleep was refreshing............................. 
 
 
 
 
 
35 
I had a problem with my sleep .................. 
 
 
 
 
 
36 
I had difficulty falling asleep .................... 
 
 
 
 
 
37 
My sleep was restless ................................ 
 
 
 
 
 
38 
I tried hard to get to sleep........................... 
 
 
 
 
 
39 
I worried about not being able to fall 
asleep ......................................................... 
 
 
 
 
 
40 
I was satisfied with my sleep...................... 
 
 
 
 
 
  
Ability to Participate in Social Roles 
and Activities 
Never 
Rarely 
Sometimes 
Usually 
Always 
41 
I have trouble doing all of my regular 
leisure activities with others.....................
 
 
 
 
 
42 
I have trouble doing all of the family 
activities that I want to do ....................... 
 
 
 
 
 
43 
I have trouble doing all of my usual work 
(include work at home) ............................ 
 
 
 
 
 
44 
I have trouble doing all of the activities 
with friends that I want to do ................... 
 
 
 
 
 
45 
I have to limit the things I do for fun with 
others ........................................................ 
 
 
 
 
 

 
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Leighton Chan 
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Ability to Participate in Social Roles 
and Activities 
Never 
Rarely 
Sometimes 
Usually 
Always 
46 
I have to limit my regular activities with 
friends.......................................................
 
 
 
 
 
47 
I have to limit my regular family activities .. 
 
 
 
 
 
48 
I have trouble doing all of the work that is 
really important to me (include work at 
home)........................................................ 
 
 
 
 
 
  
Pain Interference 
In the past 7 days… 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
49 
How much did pain interfere with your 
day to day activities?.................................
 
 
 
 
 
50 
How much did pain interfere with work 
around the home? ....................................... 
 
 
 
 
 
51 
How much did pain interfere with your 
ability to participate in social activities? ... 
 
 
 
 
 
52 
How much did pain interfere with your 
enjoyment of life?....................................... 
 
 
 
 
 
  
53 
How much did pain interfere with the 
things you usually do for fun?................... 
 
 
 
 
 
54 
How much did pain interfere with your 
enjoyment of social activities? ................... 
 
 
 
 
 
55 
How much did pain interfere with your 
household chores? ..................................... 
 
 
 
 
 
56 
How much did pain interfere with your 
family life? ................................................ 
 
 
 
 
 
 
 
  
Pain Intensity 
In the past 7 days… 
 
57  
How would you rate your pain on 
           
  
average? .......................................... 
0 
No 
pain 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst 
imaginable 
pain 
 
 
 
 
 
 

 
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Leighton Chan 
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Appendix 6: Fatigue Severity Score (Spanish) 
Escala de Intensidad del Cansancio  
Fatigue Severity Scale (FSS) (Spanish) 
 
Nombre ______________________________ Fecha____________ 
 
La Escala de Intensidad del Cansancio (FSS) es un método para evaluar el efecto del cansancio en usted. La FSS es un 
cuestionario corto para el que es necesario que califique su grado de cansancio. 
 
El cuestionario de la FSS contiene nueve oraciones con las que se evalúa la intensidad de sus síntomas de cansancio. Lea 
cada oración y marque con un círculo un número del 1 al 7, con base en qué tan exactamente refleja su situación en la 
última semana y hasta qué punto está de acuerdo o en desacuerdo con que la oración le concierne. Un puntaje de 1 indica 
que no está de acuerdo y un puntaje de 7 indica que está de acuerdo. 
 
 
Cuestionario FSS 
En la última semana, noté que: 
En desacuerdo <--------> De acuerdo 
Mi motivación es menor cuando estoy cansado(a). 
1 
2 
3 
4 
5 
6 
7 
El ejercicio me cansa. 
1 
2 
3 
4 
5 
6 
7 
Me canso con facilidad. 
1 
2 
3 
4 
5 
6 
7 
El cansancio interfiere con mi funcionamiento físico. 1 
2 
3 
4 
5 
6 
7 
El cansancio me causa problemas frecuentes. 
1 
2 
3 
4 
5 
6 
7 
El cansancio impide mi funcionamiento físico 
sostenido. 
1 
2 
3 
4 
5 
6 
7 
El cansancio interfiere con el cumplimiento de 
ciertos deberes y responsabilidades.  
1 
2 
3 
4 
5 
6 
7 
El cansancio está entre mis tres síntomas más 
incapacitantes. 
1 
2 
3 
4 
5 
6 
7 
El cansancio interfiere con mi trabajo, familia o 
vida social. 
1 
2 
3 
4 
5 
6 
7 
 
 
La Escala de Intensidad del Cansancio es propiedad intelectual de Lauren B. Krupps. Reproducida con permiso de la 
autora. 
 
 
 
 
 
 
 
 

 
SLE and Exercise 
 
52 
Leighton Chan 
9/23/2019 
Appendix 7: PROMIS 57 v2 (Spanish) 
PROMIS–57 Profile v2.0 
Responda a cada enunciado marcando una casilla por línea. 
  
Capacidad de funcionamiento físico 
Sin 
dificultad 
Con poca 
dificultad 
Con alguna 
dificultad 
Con mucha 
dificultad 
No puedo 
hacerlo 
1 
¿Puede realizar tareas, como pasar la 
aspiradora o trabajar en el jardín?.................
 
 
 
 
 
2 
¿Puede subir y bajar escaleras a un paso 
normal?.......................................................... 
 
 
 
 
 
3 
¿Puede salir a caminar durante 15 minutos 
por lo menos? ................................................ 
 
 
 
 
 
4 
¿Puede hacer mandados y compras? ............. 
 
 
 
 
 
  
Nada 
Poco 
Algo 
Mucho 
No puedo 
hacerlo 
5 
¿Limita su salud en este momento su 
capacidad para realizar dos horas de trabajo 
físico?............................................................
 
 
 
 
 
6 
¿Limita su salud en este momento su 
capacidad para realizar trabajos moderados 
en el hogar, como pasar la aspiradora, 
barrer el piso (suelo) o entrar a la casa las 
compras del mercado?................................... 
 
 
 
 
 
7 
¿Limita su salud en este momento su 
capacidad para levantar o llevar las bolsas 
del supermercado?......................................... 
 
 
 
 
 
8 
¿Limita su salud en este momento su 
capacidad para realizar trabajos pesados en 
el hogar, como fregar (restregar) los pisos 
(el suelo), o levantar o mover muebles 
pesados? ........................................................ 
 
 
 
 
 
  
Ansiedad 
En los últimos 7 días… 
Nunca 
Rara vez 
Algunas 
veces 
A menudo 
Siempre 
9 
Sentí miedo ................................................. 
 
 
 
 
 
 
10 
Tuve dificultad para concentrarme en otra 
cosa que no fuera mi ansiedad ...................... 
 
 
 
 
 
11 
Mis inquietudes  fueron demasiado para 
mí ................................................................. 
 
 
 
 
 
 
12 
Me sentí intranquilo/a ................................... 
 
 
 
 
 
13 
Me sentí nervioso/a ....................................... 
 
 
 
 
 

 
SLE and Exercise 
 
53 
Leighton Chan 
9/23/2019 
 
14 
Sentí que necesitaba ayuda para mi 
ansiedad......................................................... 
 
 
 
 
 
  
15 
Sentí ansiedad ............................................... 
 
 
 
 
 
 
  
Ansiedad 
En los últimos 7 días… 
Nunca 
Rara vez 
Algunas 
veces 
A menudo 
Siempre 
16  
Me sentí tenso/a ........................................... 
 
 
 
 
 
  
Depresión 
En los últimos 7 días... 
Nunca 
Rara vez 
Algunas 
veces 
A menudo 
Siempre 
17 
Sentí que no valía nada................................ 
 
 
 
 
 
18 
Me sentí indefenso/a (que no podía hacer 
nada para ayudarme).................................... 
 
 
 
 
 
 
19 
Me sentí deprimido/a ................................... 
 
 
 
 
 
20 
Me sentí desesperanzado/a ......................... 
 
 
 
 
 
21 
Me sentí fracasado/a .................................... 
 
 
 
 
 
22 
Me sentí descontento/a ................................ 
 
 
 
 
 
23 
Sentí que nada me ilusionaba ...................... 
 
 
 
 
 
24 
Sentí que nada me podía animar.................. 
 
 
 
 
 
  
Agotamiento 
En los últimos 7 días… 
Nada 
Un poco 
Algo 
Mucho 
Muchísimo 
25 
Me siento agotado/a .................................... 
 
 
 
 
 
26 
Tengo dificultad para comenzar las cosas 
porque estoy cansado/a ............................. 
 
 
 
 
 
 
En los últimos 7 días… 
27 
¿Qué tan rendido/a se sintió en promedio?... 
 
 
 
 
 
28 
¿Qué tan agotado/a estuvo en promedio?.... 
 
 
 
 
 
29 
¿En qué medida le molestó el agotamiento 
en promedio? ............................................... 
 
 
 
 
 
30 
¿En qué medida el agotamiento interfirió 
en su funcionamiento físico? ...................... 
 
 
 
 
 
  
En los últimos 7 días... 
Nunca 
Rara vez 
Algunas 
veces 
A menudo 
Siempre 

 
SLE and Exercise 
 
54 
Leighton Chan 
9/23/2019 
31  
¿Con qué frecuencia se tuvo que forzar 
para hacer sus actividades debido al 
agotamiento?................................................ 
 
 
 
 
 
  
  
Agotamiento 
En los últimos 7 días... 
Nunca 
Rara vez 
Algunas 
veces 
A menudo 
Siempre 
32  
¿Con qué frecuencia tuvo dificultad para 
terminar las cosas debido al agotamiento? .... 
 
 
 
 
 
  
Alteración del sueño 
En los últimos 7 días… 
Muy 
mala 
Mala 
Pasable 
Buena 
Muy 
buena 
33 
  
La calidad de mi sueño fue... ........................ 
 
 
 
 
 
  
En los últimos 7 días… 
Nada 
Un poco 
Algo 
Mucho 
Muchísimo 
34 
Mi sueño fue reparador.................................. 
 
 
 
 
 
35 
Tuve problemas para dormir ........................ 
 
 
 
 
 
36 
Tuve dificultad para dormirme. .................... 
 
 
 
 
 
37 
Tuve el sueño inquieto.................................. 
 
 
 
 
 
38 
Hice un gran esfuerzo por lograr dormirme .. 
 
 
 
 
 
39 
Me preocupó no poder quedarme dormido/a 
 
 
 
 
 
40 
Me sentí satisfecho/a con mi sueño .............. 
 
 
 
 
 
  
Capacidad para participar en roles y 
actividades sociales 
Nunca 
Rara vez 
Algunas 
veces 
A menudo 
Siempre 
41 
Tengo problemas para realizar con otras 
personas todas mis actividades habituales 
de tiempo libre..............................................
 
 
 
 
 
42 
Tengo problemas para realizar todas las 
actividades con mi familia que quiero hacer 
 
 
 
 
 
43 
Tengo problemas para realizar todo mi 
trabajo habitual (incluya el trabajo en el 
hogar)............................................................ 
 
 
 
 
 
44 
Tengo problemas para realizar todas las 
actividades con mis amigos/as que quiero 
hacer ............................................................. 
 
 
 
 
 
45 
Tengo que limitar las cosas que hago para 
divertirme con otras personas ....................... 
 
 
 
 
 
 
46 
Tengo que limitar mis actividades 
habituales con mis amigos/as ....................... 
 
 
 
 
 

 
SLE and Exercise 
 
55 
Leighton Chan 
9/23/2019 
 
47 
Tengo que limitar las actividades habituales 
con mi familia............................................... 
 
 
 
 
 
 
  
Capacidad para participar en roles y 
actividades sociales 
Nunca 
Rara vez 
Algunas 
veces 
A 
menudo 
Siempre 
48 
Tengo problemas para realizar todo el 
trabajo que es verdaderamente importante 
para mí (incluya el trabajo en el hogar)....... 
 
 
 
 
 
Efectos del dolor 
En los últimos 7 días… 
Nada 
Un poco 
Algo 
Mucho 
Muchísimo 
 
En promedio, ¿cómo calificaría su 
 
 
 
  
 
 
 
 
  
57 
dolor? ................................................ 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Ningún 
El peor 
  
dolor  
  dolor 
   imaginable 
49 
¿En qué medida el dolor interfirió en sus 
actividades diarias?...................................... 
 
 
 
 
 
50 
¿En qué medida el dolor interfirió en el 
 
 
 
 
 
 
trabajo en el hogar?...................................... 
 
¿En qué medida el dolor interfirió en su 
51 
capacidad para participar en actividades 
 
 
 
 
 
 
sociales?...................................................... 
52 
¿En qué medida el dolor interfirió en su 
 
 
 
 
 
 
capacidad para disfrutar de la vida? ............ 
 
¿En qué medida el dolor interfirió en las 
53 
actividades que hace habitualmente para 
 
 
 
 
 
 
divertirse? .................................................... 
 
¿En qué medida el dolor interfirió en su 
54 
capacidad para disfrutar de actividades 
 
 
 
 
 
 
sociales?....................................................... 
 
55 
¿En qué medida el dolor interfirió en sus 
tareas domésticas? ....................................... 
 
 
 
 
 
 
56 
¿En qué medida el dolor interfirió en su 
vida familiar? ............................................... 
 
 
 
 
 
  
Intensidad del dolor 
En los últimos 7 días…