Background/Purpose: Anti-phospholipid antibodies (aPL) constitute a diagnostic criterion and source of morbidity, termed anti-phospholipid syndrome (APS), in patients with or without systemic lupus erythematosus (SLE). Oxidization causes the immunogenicity of phospholipid antigens, such as β₂GPI and cardiolipin (Arthritis Rheumatol. 63, 2774-82). Mitochondrial dysfunction-connected mechanistic target of rapamycin complex 1 (mTORC1) activation has been recently found to trigger aPL in mice (Arthritis Rheumatol. 68, 2728). Blockade of mTORC1 with rapamycin (Arthritis Rheum. 54:2983-8; J Immunol.191:2236-46) and the antioxidant, N-acetylcysteine (NAC) has shown clinical efficacy in SLE (Arthritis Rheum. 64:2937-46). Therefore, we measured aPL levels in sera collected during clinical trials with rapamycin and NAC (ClinicalTrials.gov Identifiers: NCT00779194 and NCT00775476).

Methods: 40 SLE patients meeting eligibility criteria were started on 2 mg of rapamycin (sirolimus) with the dose adjusted to tolerance and trough levels of 6-15 ng/ml, and sera were collected before 1st rapamycin dose and 1 month, 3 months, 6 months, 9 months, and 12 months after initiation of treatment. 36 patients were enrolled in the NAC trial, and sera were collected before 1st NAC dose and 1 month, 2 months, and 3 months after initiation of treatment. At each study visit, blood samples were obtained from 42 healthy controls (HC) matched for patients’ age, gender, and ethnicity for parallel analyses. IgA, IgG, and IgM antibodies to β₂GPI (anti-β₂GPI) and cardiolipin (ACLA) were measured by ELISA (Arthritis Rheumatol. 63, 2774-82). Statistical analyses of drug efficacy was assessed relative to pretreatment samples with paired t-test using GraphPad. Patients and HC were compared with unpaired t-test. For hypothesis testing, differences were considered significant at p <0.05.

Results: IgG, but not IgM or IgA, anti-β₂GPI (unpaired t-test p=0.014) and ACLA were elevated in untreated SLE patients relative to HC (unpaired t-test p=0.029). With respect to baseline, NAC, but not placebo, reduced IgG and IgM anti-β₂GPI levels after 1 month intervention. NAC also reduced IgM, but not IgG or IgA, ACLA after 1 month intervention. Rapamycin reduced IgM and IgA, but not IgG, anti-β₂GPI and ACLA production after 1 month, which was sustained after treatment for 12 months.

Conclusion: These ancillary studies suggest that rapamycin and NAC limit aPL production which should be included as an efficacy outcome in clinical trials of mTORC1 blockade in patients with SLE and APS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mtorc1-blockade-with-rapamycin-and-n-acetylcysteine-reduces-anti-phospholipid-antibody-levels-in-controlled-clinical-trials-of-patients-with-sle/