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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.
Lancet 2018; 391(10126):1186-1196Lct

Abstract

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<0·001) and the mean total BILAG index score decreased from 28·4 (12·4) at enrolment to 17·4 (10·7) after 12 months of treatment (p<0·001). The mean daily dose of prednisone required to control disease activity decreased from 23·7 mg (SD 9·6) to 7·2 mg (2·3; p<0·001) after 12 months of treatment. Sirolimus expanded CD4+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.

Authors+Show Affiliations

Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA.Division of Rheumatology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY, USA; Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, Syracuse, NY, USA. Electronic address: perla@upstate.edu.

Pub Type(s)

Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29551338

Citation

Lai, Zhi-Wei, 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." Lancet (London, England), vol. 391, no. 10126, 2018, pp. 1186-1196.
Lai ZW, Kelly R, Winans T, 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. Lancet. 2018;391(10126):1186-1196.
Lai, Z. W., Kelly, R., Winans, T., Marchena, I., Shadakshari, A., Yu, J., ... Perl, A. (2018). 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. Lancet (London, England), 391(10126), pp. 1186-1196. doi:10.1016/S0140-6736(18)30485-9.
Lai ZW, 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. Lancet. 2018 03 24;391(10126):1186-1196. PubMed PMID: 29551338.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Lai,Zhi-Wei, AU - Kelly,Ryan, AU - Winans,Thomas, AU - Marchena,Ivan, AU - Shadakshari,Ashwini, AU - Yu,Julie, AU - Dawood,Maha, AU - Garcia,Ricardo, AU - Tily,Hajra, AU - Francis,Lisa, AU - Faraone,Stephen V, AU - Phillips,Paul E, AU - Perl,Andras, Y1 - 2018/03/15/ PY - 2017/10/03/received PY - 2017/11/22/revised PY - 2017/11/28/accepted PY - 2018/3/20/pubmed PY - 2018/10/3/medline PY - 2018/3/20/entrez SP - 1186 EP - 1196 JF - Lancet (London, England) JO - Lancet VL - 391 IS - 10126 N2 - 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<0·001) and the mean total BILAG index score decreased from 28·4 (12·4) at enrolment to 17·4 (10·7) after 12 months of treatment (p<0·001). The mean daily dose of prednisone required to control disease activity decreased from 23·7 mg (SD 9·6) to 7·2 mg (2·3; p<0·001) after 12 months of treatment. Sirolimus expanded CD4+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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/29551338/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(18)30485-9 DB - PRIME DP - Unbound Medicine ER -