Background/Purpose:  The rationale for this prospective, biomarker-driven, open-label clinical trial of rapamycin (ClinicalTrials.gov Identifier: NCT00779194) has been based on growing evidence for involvement of the mechanistic target of rapamycin (mTOR) in abnormal T-cell activation and preliminary results of clinical efficacy in mice (Arthritis Rheum. 37:289-97) and patients with SLE (Arthritis Rheum. 54:2983-8; J Immunol.191:2236-46).

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. British Isles Lupus Assessment Group (BILAG; Rheumatology 44:902-6) scores, SLE disease activity index (SLEDAI; Arthritis Rheum. 35:630-40), and routine laboratory and immunological assessments were performed before 1st rapamycin dose and 1 month, 3 months, 6 months, 9 months, and 12 months after initiation of treatment. At each study visit, blood samples were obtained from healthy controls matched for patients’ age, gender, and ethnicity for parallel analyses 665 flow cytometry biomarkers. Patients having active disease with SLEDAI of 10.2±0.8 (mean±SEM), prednisone dose of 23.7±4.9 mg/day, and proteinuria <0.5 g/day, who were unresponsive or intolerant to conventional immunosuppressants, were enrolled. Prednisone dose was titrated to control disease activity during the study.

Results: Therapeutic rapamycin plasma levels were achieved between months 1 (6.9 ng/ml) through 12 (7.8 ng/ml). 11 patients dropped out due to non-compliance. Among safety outcomes, fasting lipid profile, liver function, platelet and lymphocyte counts were unchanged, while neutrophil counts (from 5,100/µl to 3,900/µl) and haemoglobin (from 13.5 to 12.9 g/dl) were moderately reduced in 12 months. As primary clinical efficacy endpoint, reduction of SLEDAI (≥4) and BILAG disease activity scores (≥2) over 12 months was met in 16 of 29 patients (55%). Among 29 patients, 19 achieved ≥4-point drop of SLEDAI, no BILAG A flare and only one BILAG B flare, indicating a 65.5% SLE Responder Index (Arthritis Care Res. 61:1143-51). SLEDAI was reduced from baseline of 10.2±0.8 to 7.5±0.9 at 1 month (p=0.04) and 4.8±0.8 at 12 months (p=0.00002). Within the SLEDAI components, arthritis, rash, and hypocomplementemia were significantly improved after 12 months. BILAG was reduced from baseline of 28.9±1.9 to 23.8±2.2 at 1 month (p=0.005) and 17.4±1.9 at 12 months (p=0.00003).Within BILAG components, fatigue, cardiopulmonary, musculoskeletal and mucocutaneous organ-domain scores were significantly reduced after 12 months. Daily prednisone use was reduced from 23.7±4.9 mg to 7.2±2.3 mg after 12 months (p=0.02). Rapamycin blocked the activity of mTOR complex 1 in all T cells, expanded CD4⁺CD25⁺FoxP3⁺ regulatory, CD4⁺ central-memory (CD62L⁺CD197⁺), and CD8⁺ effector-memory (CD62L^–CD197^–) T cells and inhibited the pro-inflammatory necrosis and IL-4 production of CD4^–CD8^– double-negative T cells after 12 months.

Conclusion:  Rapamycin elicits rapid, progressive, and sustained improvement of disease activity via correcting abnormal T-cell lineage specification in patients with active SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/rapamycin-elicits-rapid-and-lasting-improvement-of-disease-activity-through-blocking-pro-inflammatory-t-cell-lineage-specification-in-patients-with-active-sle/