Clinical efficacy and safety of sirolimus in systemic lupus erythematosus: a real-world study and meta-analysis

Therapeutic Advances in Musculoskeletal

Sun

2022

It has been reported that the mammalian target of rapamycin (mTOR) pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE), and increasing evidence has shown the effect of mTOR-targeted therapies with sirolimus in SLE. The objective of this study was to report the successful treatment of sirolimus in a Chinese patient with refractory lupus nephritis (LN) and anti-phospholipid antibody syndrome (APS). A 44-year-old female with a previous diagnosis of autoimmune hemolytic anemia (AIHA) and APS secondary to SLE presented with lupus nephritis refractory to cyclophosphamide and mycophenolate. Renal biopsy met the criteria of WHO class III LN complicated by acute tubular injury and immunofluorescence confirmed the activation of the mTOR pathway. Treatment with the mTOR inhibitor sirolimus was initiated in this patient. Complete remission (CR) was achieved after 6 months, and flare-free remission was maintained for the next 3.5 years. The literature on the efficacy of sirolimus in patients with LN was reviewed. Although the available evidence is limited to retrospective studies with small sample sizes, sirolimus appeared to be efficacious in some patients with refractory LN. Well-designed clinical trials are warranted, and pathology-guided precision medicine might assist in guiding physicians’ treatment decisions.

Section: Introductionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Successful treatment of sirolimus in a Chinese patient with refractory LN and APS: a case report

Therapeutic Advances in Musculoskeletal

Sun

2022

“…Its effectiveness and safety in SLE treatment have been reported in uncontrolled studies. [13][14][15][16] However, a comparison of sirolimus with other classic immunosuppressants has not been reported. In our study, tacrolimus was chosen as the positive control due to its structural similarities with sirolimus and its proven effectiveness as a medication recommended for SLE treatment according to several guidelines.…”

Section: Discussionmentioning

confidence: 99%

“…Studies show that it has both mechanical and clinical therapeutic effects on SLE. [10][11][12][13][14][15][16] However, as a newly used medicine for SLE, more evidence and comparisons with other immunosuppressants are necessary to prove its efficacy and safety.…”

Section: Introductionmentioning

confidence: 99%

Sirolimus versus tacrolimus for systemic lupus erythematosus treatment: results from a real-world CSTAR cohort study

Jiang

et al. 2022

Lupus Sci Med

Self Cite

ObjectiveThe effectiveness and safety of sirolimus for SLE treatment have been shown in some uncontrolled studies. However, a comparison of sirolimus with other classic immunosuppressants has not been reported. We conducted the study to compare the effectiveness and safety of sirolimus versus tacrolimus for SLE treatment.MethodsA real-world cohort study was conducted. Patients with clinically active SLE who were prescribed sirolimus or tacrolimus were enrolled. Propensity score matching was used to ensure equivalent disease conditions and background medications. SLE disease activity indices, serological parameters, steroid doses, modification of other immunosuppressants, renal effectiveness and adverse events were compared between the two groups at 3-month, 6-month, 9-month and 12-month follow-up visits.ResultsData from 52 patients in each of the sirolimus and tacrolimus groups were analysed. Indices regarding the effectiveness of sirolimus, including Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, physician’s global assessment (PhGA) scores, and proportion of patients with SLEDAI-2K reduction of ≥4 and PhGA increase of <0.3, were equivalent to those of tacrolimus at all follow-up timepoints (all p≥0.05). Greater improvements in complement levels were observed in the sirolimus group at 3 and 6 months. Higher percentages of patients with prednisone doses ≤7.5 mg/day were observed in the sirolimus group at all timepoints. Seventeen adverse events in the sirolimus group were recorded. None was severe or led to drug discontinuation.ConclusionsOverall, sirolimus was as effective as tacrolimus in the treatment of SLE. Sirolimus had better effects on serological improvement and glucocorticoid tapering. Sirolimus was well tolerated in patients with SLE.

“…The activated mTOR pathway has been detected in LN and has emerged as a central pathway for pathogenesis and treatment with rapamycin or other mTOR inhibitors, displaying protective and beneficial effects for LN [ 15 , 16 ]. In our previous study, ADSC (passage 4) transplantation prevented LN development and ameliorated already-established disease via the mTOR/HIF-1 α signal pathway [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

miR-20a Overexpression in Adipose-Derived Mesenchymal Stem Cells Promotes Therapeutic Efficacy in Murine Lupus Nephritis by Regulating Autophagy

Wei

Stem Cells International

Liu

et al. 2021

Objective. Lupus nephritis is the most common and severe complication of systemic lupus erythematosus. The aim of our study was to investigate the efficacy of miR-20a overexpressing adipose-derived stem cell (ADSC) transplantation in murine lupus nephritis (LN) and explore potential molecular mechanisms. Methods. Mouse ADSCs were transfected with a miR-20a lentiviral vector to obtain miR-20a overexpression ADSCs (miR-20a-ADSCs). We first observed the influence of miR-20a on ADSC viability and apoptosis in vitro. B6.MRL/lpr mice were administered ADSC/miR-20a-ADSC intravenously every week from age 30 to 33 weeks, and the lupus and normal control groups received PBS on the same schedule. Results. miR-20a expression increased in miR-20a-ADSC-derived exosomes, and miR-20a overexpression promoted ADSC proliferation and inhibited apoptosis. Compared with ADSCs, miR-20a-ADSC treatment significantly improved serologic and histologic abnormalities, as evidenced by reduced serum creatinine, anti-dsDNA antibody, 24 h urine protein levels, nephritis scores, and C3/IgG deposits. Furthermore, miR-20a-ADSC treatment resulted in downregulated Akt, mTOR, and p62 expression and upregulated miR-20a, Beclin 1, and LC3 II/I expression compared with ADSC treatment. After treatment with miR-20a-ADSC, a significant increase in the number of autophagosomes within podocytes was observed, along with upregulated expression of podocin and nephrin, compared with the ADSC group. Conclusions. miR-20a-ADSC transplantation prevents the development of lupus nephritis and significantly ameliorates already-established disease, and its mechanism is related to autophagy by targeting the miR-20a-regulated mTOR pathway.