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Summary Background Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial. Methods We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6–15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194. Findings Between March 9, 2009, and Dec 8, 2014, 43 patients were enrolled, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). SLEDAI and BILAG disease activity scores were reduced during 12 months of treatment in 16 (55%) of 29 patients who completed treatment. Mean SLEDAI score decreased from 10·2 (SD 5·6) at enrolment to 4·8 (4·5) after 12 months of treatment (p + CD25 + FoxP3 + regulatory T cells and CD8 + memory T-cell populations and inhibited interleukin-4 and interleukin-17 production by CD4 + and CD4 − CD8 − double-negative T cells after 12 months. CD8 + memory T cells were selectively expanded in SRI-responders. Patient liver function and lymphocyte counts were unchanged. Although HDL-cholesterol ( Z =–2·50, p=0·012), neutrophil counts ( Z =–1·92, p=0·054), and haemoglobin ( Z =–2·83, p=0·005) were moderately reduced during treatment, all changes occurred within a range that was considered safe. Platelet counts were slightly elevated during treatment ( Z =2·06, p=0·0400). Interpretation These data show that a progressive improvement in disease activity is associated with correction of pro-inflammatory T-cell lineage specification in patients with active systemic lupus erythematosus during 12 months of sirolimus treatment. Follow-up placebo-controlled clinical trials in diverse patient populations are warranted to further define the role of mTOR blockade in treatment of systemic lupus erythematosus. Funding Pfizer, the National Institutes of Health, and the Central New York Community Foundation.

Background Systemic lupus erythematosus (SLE) patients exhibit T-cell dysfunction that has been attributed to mechanistic target of rapamycin activation. Therefore, safety, tolerance, and efficacy of rapamycin were examined in a prospective biomarker-driven open-label clinical trial. Methods 40 patients having active disease and unresponsive or intolerant to conventional medications were enrolled. Sirolimus was started at 2 mg/day with dosage adjusted to tolerance and 6–15 ng/ml trough levels. Disease activity was evaluated by BILAG, SLEDAI, and prednisone use over 12 months. Blood samples of 56 matched healthy subjects were obtained as controls for immunometabolic outcomes monitored at each visit. Results 11 patients dropped out, 9 for non-compliance and 2 for intolerance. Among safety outcomes, liver function and lymphocyte counts were unchanged. While HDL-cholesterol, neutrophil counts and haemoglobin were moderately reduced, all changes occurred within a range considered safe. Platelet counts were slightly elevated over 12 months. As primary clinical efficacy endpoint, SLEDAI and BILAG disease activity scores were reduced over 12 months in 16/29 patients (55%). 19/29 patients (65.5%) met criteria for SLE Responder Index (SRI). Arthritis, rash, pyuria, and hypocomplementemia improved among SLEDAI components, while cardiopulmonary, musculoskeletal, mucocutaneous, and vasculitis BILAG organ-domain scores also declined. Prednisone use diminished from 24.3±4.7 mg/day to 7.2±2.3 mg/day (p Conclusions Sirolimus elicits rapid, progressive, and sustained improvement of disease activity by correcting pro-inflammatory T-cell lineage specification in patients with active SLE. Acknowledgements This work was supported in part by an Investigator-Initiated Research Grant P0468 × 1–4470/WS1234172 from Pfizer and grants AI 048079, AI 072648, and AI 122176 from the National Institutes of Health and the Central New York Community Foundation. Trial registration Prospective Study of Rapamycin for the Treatment of SLE; ClinicalTrials.gov Identifier: NCT00779194. Treatment trial of SLE with N–acetylcysteine; ClinicalTrials.gov identifier: NCT00775476. References . Perl A. Mechanistic target of rapamycin pathway activation in rheumatic diseases. Nat. Rev. Rheumatol. 2016;12:169–82. . Yoshida S, et al. Redox regulates mammalian Target of Rapamycin Complex 1 (mTORC1) activity by modulating the TSC1/TSC2-Rheb GTPase pathway. J. Biol. Chem 2011;286:32651–60. . Lai Z-W, et al. N-acetylcysteine reduces disease activity by blocking mTOR in T cells of lupus patients. Arthritis Rheum2012;64:2937–46. . Perl A, et al. Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: Implications for activation of the mechanistic target of rapamycin. Metabolomics2015;11:1157–74. . Lai Z, et al. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: A single-arm, open-label, phase 1/2 trial. Lancet2018;391:1186–96.

The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T cell lineage development; however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. In this study, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBLs relative to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square–discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p < 0.0005); increased mitochondrial mass of CD3+/CD4−/CD8− double-negative (DN) T cells (p = 1.1 × 10−22) and FOXP3 depletion in CD4+/CD25+ T cells were top contributors (p = 6.7 × 10−7). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥ 4) relative to 61 visits of remission (SLEDAI decrease ≥ 4). mTOR activation in DN T cells was also noted at preflare visits of SLE patients relative to those with stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25+/CD19+ B cells. Rapamycin treatment in vivo blocked the IL-4 production and necrosis of DN T cells, increased the expression of FOXP3 in CD25+/CD4+ T cells, and expanded CD25+/CD19+ B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE.