Systemic lupus erythematosus (SLE), a chronic and multisystem autoimmune disorder that is characterized by dysregulated immune responses and production of pathogenic autoantibodies by immune cells such as B-cells, T-cells and dendritic cells (1). The clinical presentations of SLE include rash, oral ulcers, fatigue and arthralgias, and the course of the disease is unpredictable, with periods of flares alternating with remission (1). The pathogenesis of SLE remains unclear, and autoantibodies, proinflammatory and anti-inflammatory cytokines, lymphocyte subset abnormalities as well as genetic predispositions may contribute to the development of SLE (2). The disease occurs more often in women, with an incidence about nine times higher compared to men, and is also more common in non-Caucasian descent (1). SLE can affect the majority of organs and tissues such as skin, joints, lungs, blood vessels and kidneys. Lupus nephritis (LN) is a sever consequence of SLE, and ∼ 40–70% of patients with SLE would develop LN (3).

At present, LN is primarily treated with corticosteroids and immunosuppressive drugs, but is often associated with high morbidity and suboptimal outcomes (4). As an inflammation of the kidney caused by systemic lupus erythematosus (SLE), LN has been documented to be closely associated with the imbalance between oxidative and antioxidative activities during the pathogenesis of LN (5,6). The few studies that have investigated the use of antioxidants in the treatment of LN have resulted in a satisfactory outcome (7,8). N-acetylcysteine (NAC) is a typical antioxidant that is often used during clinical treatments (9). It is believed that NAC primarily acts as a glutathione precursor to minimize the hepatic risk caused by paracetamol poisoning (10). The present report describes two cases of early-stage LN that were treated with NAC.

Two female patients were diagnosed with SLE in accordance with the criteria of the American College of Rheumatology (2009) (11): i) Polyarthritis, ii) leucopenia, iii) renal involvement and iv) positive for antinuclear antibodies (ANA+). As no serious damage in the target organs or obvious damage to the skin was evident, and considering the possible adverse effects of corticosteroids and immunosuppressive drugs, the two cases were treated with hydroxychloroquine (400 mg/day; Shanghai Zhongxi Pharmaceutical Co., Ltd., Shanghai, China), calcitriol (0.25 µg/day; Qingdao Haier Pharmaceutical Co., Ltd., Qingdao, China) and NAC (1.2 g/day; Zambon S.p.A., Bresso, Italy). The NAC effervescent tablet was dissolved in warm water and taken twice a day, at a dose of 600 mg each time. The 3-month (12-week) intervention was decided according to a previous study (8). The routine blood and urine, 24-h urine protein, liver and kidney function, erythrocyte sedimentation rate (ESR), glomerular filtration rate (GFR) and creatinine test results were examined. In addition, the levels of glutathione (GSH) and 8-iso-prostaglandin F2α (8-iso-PGF2α) in the whole blood were determined. The SLE disease activity index (SLEDAI) (12) and adverse effects were recorded and the therapeutic outcomes were evaluated at 8 and 12 weeks after treatment, respectively. Written informed consent was obtained from the patients.

The depletion of GSH in lymphocytes in patients with SLE was first reported in 2002 (13); thereafter, the increase in 8-iso-PGF2α (a biomarker of lipid peroxidation) and the reduction in GSH levels have been frequently observed in patients with SLE (5,6), suggesting that oxidative stress plays an essential role in the progression of SLE. Consistent with previous studies (5,6), the 8-iso-PGF2α level was high while the GSH level was low in both cases of early-stage LN in this report, indicating the existence of oxidative stress in the early stage of LN.

The treatment of LN with antioxidants has been rarely reported. A previous animal experiment showed that treatment with the antioxidant NAC in mouse models of SLE could reduce the rates of mortality (7). A study by Lai et al (14) indicated that NAC could improve SLE by blocking mammalian target of rapamycin (mTOR) activity in T cells. This is consistent with the results of the present study, which showed that NAC treatment could enhance the GSH levels in SLE and improve the disease outcome. It should be noted, however, that the dose of NAC used in the study by Lai et al (14) was very high (2.4 and 4.8 g daily), to a level that has rarely been reported previously, although the study declared that 2.4 g/day was safe and tolerate. A study by Garcia et al (15) has used similar doses to what was used by Lai et al (14). High doses of NAC have been demonstrated to frequently cause adverse effects (16), and the dose of 4.8 g/day used in the study by Lai et al (14) caused certain uncomfortable reactions. In a report by Tewthanom et al (8), NAC at the relatively high dose of 1.8 g/day was used to treat a patient with an LN-history of several years and achieved a satisfactory therapeutic outcome. In the present study, considering that the two cases were early-stage LN and that a high dose of NAC may have caused a higher risk of adverse effects (16), the moderate dose of NAC at 1.2 g/day was selected, to be administered in combination with the basic treatment using hydroxychloroquine and calcitriol (17,18). This dose of NAC achieved a good therapeutic effect in the present study and has been most widely used in the treatment of nephropathy (19,20), suggesting that it is effective for patients with early-stage LN.

The mechanism of NAC in the treatment of SLE is associated with its effect on oxidative stress. Studies have indicated that NAC can decrease the oxygen consumption in mitochondria (21) and block mTOR, a regulator of oxygen consumption and oxidative stress in mitochondria (22), which is consistent with the present finding that NAC increased the GSH and decreased the 8-iso-PGF2α levels in LN. Accordingly, after 12 weeks of treatment, the relative indexes, such as WBC, 24-h urine protein and ESR, were largely improved, and the SLEDAI was notably decreased, reflecting a satisfactory therapeutic outcome. In conclusion, this study suggests that the combination of NAC (1.2 g/day) with hydroxychloroquine and calcitriol may be suitable for the treatment of early-stage LN.