Table 1 Characteristics of the included studies

Bissler [24] (2008) USA

N Engl J Med

Single-center, nonrandomized open-label phase 1–2 trial

LAM (n = 6),

TSC-LAM (n = 12),

TSC (n = 7),

1 year of treatment,

1 year of observation

Sirolimus (n = 25)

0.25 mg/m² body-surface area

Renal AMLs, lung function, lung cyst volume, 6MWD, AEs, neurologic assessment.

Harari [20] (2008) Italy

Chest

Single-center, prospective phase 1 trial

LAM (n = 11)

3 years of treatment

Triptorelin (n = 11)

11.25 mg IM

Hormonal assays, pulmonary function tests, 6MWD, bone mineral density.

Dabora [34] (2011) USA

PLoS ONE

Multicenter open-label, phase 2 trial, single-arm

TSC-LAM

(n = 21),

TSC (n = 15)

1 year of treatment

Sirolimus (n = 36)

2 mg/day

AMLs, kidney cysts, skin lesions, pulmonary function, VEGF-D.

McCormack [33] (2011) USA

N Engl J Med

Multicenter, randomized, placebo-controlled study

LAM (n = 81),

TSC-LAM (n = 8)

1 year of treatment,

1 year of observation

Sirolimus group

(n = 46);

Placebo group

(n = 43)

2 mg/day

Lung function, 6MWD, VEGF-D, QOL scores, AEs.

Davies [35] (2011) UK

Clin Cancer Res

Multicenter nonrandomized open label phase 2 trial

LAM (n = 6),

TSC-LAM (n = 3),

TSC (n = 7),

2 years of treatment

Sirolimus (n = 16)

0.5 mg/m² body-surface area

Renal AMLs, lung function, AEs and neurocognitive function.

Bissler [25] (2013) USA

Lancet

Multicenter, randomized, double-blind, placebo-controlled phase 3 trial

LAM (n = 5),

TSC-LAM (n = 24),

TSC (n = 89)

Median 38 weeks for everolimus;

median 34 weeks for placebo.

Everolimus group (n = 79);

Placebo group (n = 39)

10 mg/day

AMLs, skin lesion, pharmacokinetics of everolimus, pulmonary function, AEs, neuropsychological assessments, VEGF-D.

Piment a[22] (2013) Brazil

J Bras Pneumol

Single-center open-label, single-arm, interventional clinical trial

LAM (n = 31)

1 year of treatment

Doxycycline (n = 31)

100 mg/day

Pulmonary function, 6MWD, QOL, MMP-2, MMP-9, VEGF-D

Chang [23] (2014) UK

Eur Respir J

Single-center randomized placebo-controlled trial

LAM (n = 23)

2 years of treatment

Doxycycline group (n = 12);

Placebo group (n = 11)

100 mg/day for 3 months followed by 200 mg/day for 21 months

Lung function, exercise capacity, QOL, shuttle walk distance, MMP levels, VEGF-D.

Goldberg [36] (2015) USA

Eur Respir J

Multicenter, open-label, nonrandomized, phase 2 trial

LAM (n = 19),

TSC-LAM

(n = 5),

Treatment for 26 weeks

Everolimus (n = 24)

2.5 mg/day for 4 weeks, 5 mg/day for 4 weeks, 10 mg/day for 18 weeks

Lung function, VEGF-D, 6MWD, everolimus pharmacokinetics, AEs.

Takada [37] (2016) Japan

Ann Am Thorac Soc

Multicenter, single-arm, open-label trial

LAM and TSC-LAM (n = 63)

2 years of treatment

Sirolimus (n = 63)

2 mg/day

Lung function, QOL scores, AEs

EI-Chemaly [38] (2017) USA

Chest

Two-center phase 1 trial

LAM (n = 13)

24 weeks of treatment,

24 weeks of observation

Hydroxychloroquine and sirolimus (n = 13)

Hydroxychloroquine (200 mg or 400 mg)

Sirolimus (2 mg/day)

Lung function, 6MWD, QOL, AMLs, VEGF-D, AEs.

Author, Publication Year, Country

Journal

Study design

Diagnosis,

No of patients

Study duration

Intervention and sample size

Treatment regimen

Study outcomes

Bee [9] (2018)

UK

Thorax

A prospective national cohort, single-arm study,

LAM (n = 38),

TSC-LAM

(n = 9)

35.8 ± 18 months of treatment

Sirolimus (n = 47)

1–2 mg/day

Lung function, VEGF-D, AEs.

Cai [39] (2018) China

Orphanet J Rare Dis

Single-center, nonrandomized, open-label phase 2 trial

TSC-LAM (n = 6),

TSC (n = 12)

1 year of treatment

1 year of observation

Everolimus (n = 18)

10 mg/day

AMLs, skin lesions, lung function, AEs.

Aghaeimeybodi [40] (2019) Iran

Caspian J Intern Med

A prospective phase 1 trial

LAM (n = 2),

TSC-LAM (n = 4)

1 year of treatment

Sirolimus (n = 6)

2 mg/day

Lung function, 6MWD, AEs.