Sleep and Immunity in Rheumatoid Arthritis : Remicade Substudy

Abnormal sleep is reported by more than half of rheumatoid arthritis patients, in addition to
the traditional symptoms associated with the disease, such as morning stiffness, pain, and
functional debility. When recording brain activity during sleep using electroencephalography
or EEG. Sleep abnormalities have been found independent of pain and thus the mechanisms to
account for disordered sleep in this population are unknown. The immune system, via
pro-inflammatory cytokines, plays a major role in the development of rheumatoid arthritis.
Pro-inflammatory cytokines are molecules that act as signals to stimulate activity of
different arms of the immune system. New medications such as remicade (infliximab) have been
developed which slow disease activity by blocking the activity of these pro-inflammatory
cytokines. This is done by binding to the cytokine TNF and rendering it biologically
inactive. Pro-inflammatory cytokines also appear to play a role in sleep. A number of basic
and human studies have found that cytokines and sleep exhibit a bi-directional relationship.
However, no study to date has explored this relationship in a rheumatoid arthritis
population. Thus, this research study has the potential to test whether cytokines influence
sleep in rheumatoid arthritis. We will determine if a single dose of a pro-inflammatory
cytokine blocking medication (remicade) affects sleep in rheumatoid arthritis patients.
Interested participants will undergo an eligibility interview to review in-depth subject
participation, RA diagnosis, written Consent. Following eligibility, patients will undergo a
single overnight sleep assessment lasting four nights at the General Clinical Research
Center. After the adaption and baseline nights, on day 3, patients will be randomized to
receive either 10 mg/kg of remicade or placebo and their sleep will be subsequently monitored
for two additional nights ( post-infusion 1 and post-infusion 2).

Inclusion Criteria:

1. Rheumatoid arthritis patients will meet American College of Rheumatology revised
criteria (Arnett, Edworthy et al. 1988). This requires at least four of the following
seven criteria: 1) morning joint stiffness; 2) arthritis in 3 or more joint areas; 3)
arthritis of hand joints; 4) symmetric arthritis; 5) rheumatoid nodules; 6) presence
of serum rheumatoid factor and 7) changes on posteroanterior hand and wrist
radiographs. In addition, criteria 1-4 must be present for at least four weeks.
Subjects must be between 18 and 85 years of age.

2. If rheumatoid arthritis patients are receiving treatment with traditional disease
modifying antirheumatic drugs (DMARD), such as methotrexate, sulfasalazine or
hydroxychloroquine, they must be on a stable regime for one month before study and
stable throughout study.

3. If rheumatoid arthritis patients have received treatment with a TNF antagonist or
other biologic medication, they must be drug free for greater than 3 months.

Exclusion Criteria:

1. Steroids - Individuals currently taking greater than an equivalent of 10 mg of
prednisone will be excluded given the potent anti-inflammatory effects of such
medications.

2. Opioids - Individuals using multiple daily dosage schedule of opioid agents such as
oxycodone (Percocet), hydrocodone (Vicodin), morphine, Dilaudid will be excluded.

3. Co-morbid medical disorders - the presence of active unstable and uncontrolled
co-morbid medical conditions such as diabetes, cardiovascular diseases, and cancer
will be exclusionary criteria. In particular, individuals with co-morbid inflammatory
disorders such as Crohn's disease and ulcerative colitis and other autoimmune
disorders will be excluded. Any uncontrolled medical condition that is deemed by the
investigators to interfere with the proposed study procedures, or put the study
participant at undue risk will also be considered exclusionary criteria.

4. Chronic infections - individuals with chronic infections will also be excluded because
of effects on immune markers measured in study.

5. Co-morbid pain disorders - individuals with co-morbid pain disorders such as
fibromyalgia will also be excluded. Individuals with fibromyalgia have been found to
have sleep abnormalities as well as daytime fatigue and pain and thus could confound
findings.

6. Psychiatric disorders - current conditions such as major depressive disorder, bipolar
disorder and risk for suicide will also be considered exclusionary criteria.

7. Gender-based criteria - pregnant or breast-feeding women will also be excluded because
of their effects on neuroendocrine systems and sleep