Aerobic Exercise in Women With Systemic Lupus Erythematosus

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. 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 . 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 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) or interstitial lung disease (ILD), 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
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.

- 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 less than or equal to 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 greater than or equal to 3 indicating the presence of clinically
significant fatigue

- Subjects must be able to walk on a treadmill

EXCLUSION CRITERIA:

- Prednisone greater than or equal to 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

- 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

--(e.g. beta-blockers, anti-retroviral therapy for the treatment of HIV infection)

- Diabetes Mellitus

- Fibromyalgia: Determined at pre-screening visit, as per 2010 ACR criteria for
diagnosis of fibromyalgia

- 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