Abstract
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<0.0009). Sirolimus expanded CD4+CD25+FoxP3+ Tregs and CD8+ memory T cells and inhibited IL-4 and IL-17 production by CD4+ and CD4-CD8- double-negative T cells after 12 months. CD8+ memory T cells were selectively expanded in SRI-responders.
Conclusions Sirolimus elicits rapid, progressive, and sustained improvement of disease activity by correcting pro-inflammatory T-cell lineage specification in patients with active SLE.
Metabolic control of pro-inflammatory T-cell lineage specification in SLE. Schematic molecular order of pathways upstream and downstream of activation of the mechanistic target of rapamycin (mTOR) in SLE. mTOR is activated on the surface of lysosomes in a state of amino acid sufficiency (V/L/I/Q/Kyn).1 Oxidative stress, in particular cysteine oxidation, also activates mTORC1 through association with Rheb.2 Given the results of our randomized double-blind placebo-controlled clinical trial showing that therapeutically effective reversal of GSH depletion by NAC blocks mTORC1 in vivo,3 GSH depletion will be considered the primary metabolic checkpoint of pro-inflammatory T-cell lineage specification in SLE. The depletion of GSH will be mechanistically connected to the depletion of cysteine (Cys) and NADPH and to the accumulation of kynurenine (Kyn) which have been uncovered by comprehensive metabolome studies of PBL from SLE and healthy subjects matched for age, gender, and ethnicity and processed in parallel.4 Blockade of mTOR with rapamycin reverses the depletion of effector-memory CD8 T cells and Tregs and the expansion of pro-inflammatory CD4-CD8- double-negative T cells in patients with active SLE in vivo 5. Red and blue arrows reflect direction of changes in 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.
