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 1.2-9.6 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 is 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.

50 SLE subjects and 50 healthy controls (matched by age and sex) will be studied.

The 50 SLE subjects will be divided into 5 groups of 10. Each group will receive a different dose of NAC (N-acetylcysteine)or placebo as follows:

Group 1- 8 will receive 600mg of NAC/Two times a Day, 2 will receive placebo Group 2- 8 will receive 1200mg of NAC/Two times a Day, 2 will receive placebo Group 3- 8 Will receive 2400mg of NAC/Two times a Day, 2 will receive placebo Group 4- 8 Will receive 3600mg of NAC/Two times a Day, 2 will receive placebo Group 5- 8 will receive 4800mg of NAC/Two times a Day, 2 will receive placebo

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

At each subject visit, blood from a healthy donor will be drawn and used as control. The control blood will be used for flow cytometry measurements of GSH and in vitro immunological studies. In addition to GSH measurements and immunologic studies, routine labs and SLEDAI/BILAG will be performed for the SLE subjects. There will be a total of 5 visits per subject, including the screening visit, in a period of four months.

At the same time of their selection, the SLE subjects will be given a Krupp Fatigue Severity Scale (FSS) test. At each visit up to 100 ml of blood will be drawn from each subject. 20 ml are needed for routine labs. and up to 80 ml are needed for the GSH/Immunologic tests.

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

AIM 2:

Aim 2 will determine the impact of an optimal NAC dose on disease activity and prednisone use in 110 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. There will be 3 groups. Group 1 will consist of 110 controls, group 2 will consist of 55 SLE subjects assigned to placebo, and group 3 will consist of 55 SLE subjects assigned to the optimum dose of NAC/Day as determined in Aim 1. SLE subjects will be randomized into three strata according to their baseline SLEDAI scores (0-6, 7-12, 13+).

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

In addition to the routine and experimental blood test performed in Aim 1, Aim 2 will include muscle tests and fatigue testing for the SLE subjects at each visit. The study will last 13 months with a total of 7 visits, including the screening visit and a 1 month washout.