Treatment of Systemic Lupus Erythematosus (SLE) With N-acetylcysteine

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease which often has
debilitating and potentially life-threatening consequences. The cause of SLE is unknown and
current therapies lack specificity and carry significant side-effects. Existing data in the
literature provide evidence that a natural antioxidant, glutathione, is depleted in T cells
of patients with SLE. This may be a key factor underlying abnormal activation and
predisposition of T lymphocytes to pro-inflammatory cell death via necrosis. Administration
of N-acetylcysteine (NAC), that serves as a precursor of glutathione (GSH), improves the
clinical outcome of murine lupus, and limits the toxicity of pro-oxidant/immunosuppressant
medications commonly used in patients with SLE. NAC is widely available in health food
stores and large doses (up to 8 g/day) can be safely administered to humans. In a one-year
study of patients with inflammatory lung disease treated with prednisone and azathioprine,
addition of NAC (1.8 g/day) diminished disease severity and reduced drug toxicity in
comparison to placebo. Moreover, oral NAC has been found to improve muscle fatigue which is
reported to be the most disabling symptom in 53% of patients with SLE. Thus, establishing a
dose ranging between 1.2-7.2 g/day that is well tolerated and capable of raising
intracellular GSH in lupus patients and determining its immunological and therapeutic impact
in SLE appears to be well justified.

The study will consist of two parts, Aim 1 and Aim 2.

AIM 1:

The purpose of Aim 1 was to establish the optimal daily oral dose of NAC that can be well
tolerated without side effects and can normalize or moderate the depletion of GSH in lupus T
cells.

36 SLE subjects and 42 healthy controls (matched by age and sex) were studied.

The 36 SLE subjects were divided into 3 groups of 12. Each group received a different dose
of NAC (N-acetylcysteine)or placebo as follows:

Group 1: 9 received 600mg of NAC two times a Day, 3 received placebo; Group 2: 9 received
1200mg of NAC two times a Day, 3 received placebo; Group 3: 9 received 2400mg of NAC two
times a Day, 3 received placebo;

To account for attrition 12 subjects were randomized in each group (9 active, 3 placebo).

At each subject visit, blood from a healthy donor was drawn and used as control. The control
blood was used for flow cytometry measurements of GSH and in vitro immunological studies. In
addition to GSH measurements and immunologic studies, routine labs., ASRS self-reporting
assessment questionnaire, and SLEDAI/BILAG/Fatigue scores were obtained for the SLE
subjects. The healthy control subjects also answered the ASRS self-reporting questionnaire.
The ASRS questionnaire was incorporated into the study procedures in October, 2009. It is
designed to assess a patient's ability to concentrate which could be affected by the
involvement of the Central Nervous System (CNS) in lupus. There were up to 5 study visits
per SLE subjects in a period of four months.

At each visit up to 100 ml of blood were drawn from each subject. 20 ml are needed for
routine labs. and up to 80 ml are needed for the GSH and immunological tests.

Dose comparisons were based on continuous monitoring of adverse events and drug tolerance.

AIM 2:

Aim 2 will determine the tolerance and impact of two NAC doses on disease activity and
prednisone use in 165 subjects with SLE in a double-blind placebo-controlled 12-month study.
It is designed to detect clinically meaningful differences in disease activity in the
patient population.

It was determined by statistical analysis that each group must have 55 subjects. SLE
subjects will be randomized into 3 groups of 55 subjects to receive 1.2 g of NAC twice a
day, 2.4 g of NAC twice a day, or placebo. There will be up to seven study visits per SLE
subject, including the screening and wash out visits. Visits 1-5 will be scheduled three
months apart. The study will last 13 months with the wash out visit. Each subject will
donate approximately 80 ml of blood for research at each visit. Healthy control subjects
will donate blood at the same time. They will be matched to the SLE subjects by gender, age
within 10 years, and ethnicity. Their blood will be used as reference for research assays.

The inclusion and exclusion criteria will be the same as in Aim 1 and the same subjects may
continue to participate. There is a new consent form required to participate in the second
phase.