Table 1.
Characteristics of the studies included in this meta-analysis
| Author, year | Study design | Treatment strategies | Detailed scheme | Patient characteristics | Main outcome measures | Adverse events |
|---|---|---|---|---|---|---|
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| Zhang et al, 200625 | Randomized clinical trial | TAC + GC vs CYC + GC | Patients in both groups received oral prednisone (0.6 mg/kg per day, maximal dose was 40 mg/d) divided into three times for 4 weeks. The daily dose of prednisone was tapered by 5 mg/d every 2 weeks to 20 mg/d and then by 2.5 mg/d every 2 weeks to maintenance dose of 10 mg/d. Some patients with renal active lesion received intravenous methylprednisolone pulse therapy (0.5 g/d for 3 d). The TAC + GC group received TAC (0.1 mg/kg per day, twice daily) and blood concentration of TAC maintained within 5–15 ng/mL. The initial dose is treated for at least 3 months. If the patient achieves complete remission, the TAC is reduced to 0.08 mg/kg per day, twice daily, and blood concentration of TAC is maintained within 5–10 ng/mL. For patients in the CYC + GC group, IVCY was initiated at a dose of 0.75 g/m2 body surface area and then adjusted to a dose of 0.5–1.0 g/m2 body surface area every 4 weeks for six doses. | The average age of 34 female patients was 27.1±9.9 years, and the patients had a diagnosis of class IV LN according to the ISN/RPS 2003 classification of LN. | CR, TR, proteinuria levels, urine erythrocyte number, albumin, negative rate of ds-DNA, SLE-DAI | Gastrointestinal syndrome, leucopenia, hyperglycemia, infection, pneumonia, herpes zoster or varicella, alopecia, irregular menstruation, blood creatinine increase, liver function disorder |
| Zhang et al, 200624 | Randomized clinical trial | TAC + GC vs CYC + GC | Patients in both groups received oral prednisone (0.6 mg/kg per day, maximal dose was 40 mg/d) divided into three times for 4 weeks. The daily dose of prednisone was tapered by 5 mg/d every 2 weeks to 20 mg/d and then by 2.5 mg/d every 2 weeks to a maintenance dose of 10 mg/d. Some patients with renal active lesion received intravenous methylprednisolone pulse therapy (0.5 g/d for 3 d). The TAC + GC group received TAC (0.1 mg/kg per day, twice daily) and blood concentration of TAC maintained within 5–15 ng/mL. The initial dose is treated for at least 3 months. If the patient achieves complete remission, the TAC is reduced to 0.08 mg/kg per day, twice daily, and blood concentration of TAC is maintained within 5–10 ng/mL. For patients in the CYC + GC group, IVCY was initiated at a dose of 0.75 g/m2 body surface area and then adjusted to a dose of 0.5–1.0 g/m2 body surface area every 4 weeks for six doses. | The average age of 37 female patients was 30.0±9.8 years, and the patients had a diagnosis of class V + IV LN according to the ISN/RPS 2003 classification of LN. | CR, TR, proteinuria levels, urine erythrocyte number, albumin, C3 levels, C4 levels, negative rate of ds-DNA, SLE-DAI | Gastrointestinal syndrome, leucopenia, hypertension, hyperglycemia, infection, upper respiratory infection, herpes zoster or varicella, urinary tract infection, alopecia, irregular menstruation, blood creatinine increase, liver function disorder |
| Xu et al, 200722 | Randomized clinical trial | TAC + GC vs CYC + GC | Patients in both groups received oral prednisone (1 mg/kg/d) for 8 weeks. The daily dose of prednisone was tapered by 5 mg/d every 1–2 weeks to 30 mg/d and then by 2.5 mg/d every 1–2 weeks to a maintenance dose of 10 mg/d. The TAC + GC group received TAC (0.1 mg/kg per day, twice daily) and blood concentration of TAC maintained within 5–15 ng/mL. The initial dose is treated for at least 6 months. For patients in the CYC + GC group, IVCY was initiated at a dose of 1 g per month for six times, and then adjusted to once every 3 months. The total treatment was for 2 years. | 40 patients had a diagnosis of class III, IV, V LN according to the ISN/RPS 2003 classification of LN. | CR, TR, proteinuria levels, albumin, C3 levels, C4 levels, negative rate of ds-DNA, SLE-DAI | Leucopenia, hypertension, hyperglycemia, infection, blood creatinine increase |
| Hong et al, 200717 | Randomized clinical trial | TAC + GC vs CYC + GC | Patients were randomly assigned to either oral TAC (initial dose 0.1 mg/kg/d) in addition to corticosteroids (initial dose 0.8 mg/kg/d) or intravenous cyclophosphamide (0.5–0.75 g/m2 monthly) in addition to corticosteroids (initial dose 0.8 mg/kg/d). | Twenty-five patients (23 females, 2 males; 30.7±5.1 years old) with diffuse proliferative LN proven by renal biopsy were included. | CR, TR | NA |
| Chen et al 201116 | Multicenter noninferiority randomized controlled trial | TAC + GC vs CYC + GC | Patients in both groups received oral prednisone (1 mg/kg/d). The daily dose of prednisone was tapered by 10 mg/d every 2 weeks to 40 mg/d and then by 5 mg/d every 2 weeks to a maintenance dose of 10 mg/d. The TAC + GC group received TAC (0.05 mg/kg/d, twice daily) and blood concentration of TAC was maintained within 5–10 ng/mL. For patients in the CYC + GC group, IVCY was initiated at a dose of 750 mg/m2 of body surface area for 6 months. | Eligibility criteria for this trial included age 14–65 years, and the patients had a diagnosis of class III, IV, V, III + V, IV + V LN according to the ISN/RPS 2003 classification of LN. | CR, TR, GFR | Gastrointestinal syndrome, leucopenia, hyperglycemia, infection, upper respiratory infection, pneumonia, herpes zoster or varicella, urinary tract infection, alopecia, irregular menstruation, blood creatinine increase, liver function disorder |
| Wang et al, 201221 | A non-randomized prospective cohort study | TAC + GC vs CYC + GC | Patients in both groups received oral prednisone (0.8 mg/kg/d, maximum dose 50 mg/d) for 4 weeks, and this dose was gradually decreased to 0.5 mg/kg/d at 1 month and maintained for 2 weeks after PR. The prednisone dose was then tapered over 4 weeks by 5 mg per week, until CR, and then maintained at 10–15 mg/d during the maintenance period. No patients in the two groups were given intravenous pulse methylprednisolone. For the TAC + GC group, the initial dosage of TAC was 0.08/mg/kg/d for patients with GFR more than 40 mL/min/1.73 m2 and 0.04 mg/kg/d for patients with GFR less than 40 mL/min/1.73 m2. The dosage was adjusted to achieve a whole blood TAC concentration of 6–8 ng/mL when induction therapy was required, 4–6 ng/mL when maintenance therapy was required, and 4.0 ng/mL when serum creatinine was more than 133 mmol/L and GFR was less than 40 mL/min/1.73 m2. For the CYC group, the protocol was pulse CYC at a dose of 750 mg/m2 every month for 6 months followed by AZA (100 mg/d) for 6 months. | 40 patients (32 female, eight male; median age at study entry, 33.88±9.72 (range 16–64) years) with SLE entered this open, prospective study of LN, and had a diagnosis of class IV, V, III + V, IV + V LN according to the ISN/RPS 2003 classification of LN. | CR, TR, GFR, C3 levels, C4 levels, negative rate of ds-DNA, SLE-DAI | Gastrointestinal syndrome, hypertension, hyperglycemia, pneumonia, herpes zoster or varicella, urinary tract infection, irregular menstruation, liver function disorder |
| Li et al, 201218 | Randomized, open-label, clinical trial | TAC + GC vs CYC + GC vs MMF + GC | The patients were randomly assigned to one of the three treatment groups (MMF + GC group, TAC + GC group, or CYC + GC group) in an open-label manner. The daily doses of prednisolone were started at 0.8–1.0 mg/kg/d orally in a maximum dose of 60 mg/d, reduced by 10 mg every 2 weeks until the dose was 40 mg/d, after which it was reduced by 5 mg every 2 weeks, until a maintenance dose of 10 mg/d had been reached, at ~4 months. Pulse intravenous corticosteroids were prohibited throughout the study. The initial dose of TAC was 0.08–0.1 mg/kg/d administered orally in two divided doses and was titrated to maintain 12-hour trough levels at 6–8 ng/mL. Oral MMF was given twice daily, at a dose of 1.5 g/d in patients weighing 55 kg and 2.0 g/d in whose body weight >55 kg. IVC was given in monthly pulses of 0.5–0.75 g/m2 of body surface. Immunosuppressive agents (MMF, TAC, and CYC) were prescribed during 6 months. | Patients aged from 18 to 65 years, and had a diagnosis of class III, IV, V, III + V, IV + V LN according to the ISN/RPS 2003 classification of LN. | CR, TR, proteinuria levels, negative rate of ds-DNA | Leucopenia, hyperglycemia, infection, irregular menstruation, blood creatinine increase, liver function disorder |
| Yap et al, 201223 | A prospective, randomized, open-label study | TAC + GC vs MMF + GC | In both groups, prednisolone was commenced at 0.8 mg/kg/d (maximum 50 mg/d), then tapered by 5 mg/d every fortnight until reaching a dose of 10 mg/d after about 4 months. Prednisolone dosage was further reduced to 7.5 mg/d after 4 weeks and then maintained at this dose until the end of 12 months. Prednisolone dose in the second year was 7.5 mg/d in patients with a body weight of 50 kg or higher and 5 mg/d in other subjects. TAC was commenced at 0.1–0.15 mg/kg per day in two divided doses, followed by titration to achieve the target 12-hour trough blood level of 6–8 mg/L for the first 6 months, 5.0–5.9 mg/L for the subsequent 6 months, and 3.0–4.9 mg/L during the second year. MMF dose was 0.75–1 g bid for the first 6 months, then 0.75 g bid until the end of 12 months, and 0.5 g bid during the second year. | 16 male or female patients 18–65 years of age, biopsy-proven class V membranous LN without significant endocapillary proliferation within 6 months, according to the ISN/RPS 2003 classification of LN. | CR, TR, proteinuria levels, albumin | Leucopenia, hyperglycemia, infection, herpes zoster or varicella |
| Mok et al 201620 | An open randomized controlled parallel group study | TAC + GC vs MMF + GC | All patients were given oral prednisone (0.6 mg/kg/d for 6 weeks, then tapered by 5 mg/d every week to <10 mg/d), which was continued indefinitely as maintenance therapy. Participants were randomized by computer-generated blocks of four in a 1:1 ratio to one of the following treatment arms: (1) TAC for 6 months (Initial dosage 0.1 mg/kg/d in two divided doses, reduced to 0.06 mg/kg/d if clinical response was satisfactory at month 3) or (2) MMF (2 g/d initially, augmented to up to 3 g/d if clinical response was suboptimal at month 3), in two divided doses for 6 months. | 150 male or female patients (92% women; aged 35.5±12.8 years) were divided into two groups, and biopsy-proven class V, III + V, IV + V according to the ISN/RPS 2003 classification of LN. | CR, TR, proteinuria levels, albumin | Hyperglycemia, serious infection, herpes zoster or varicella, blood creatinine increase |
| Bao et al 200815 | Multicenter, randomized, open-label, clinical trial | TAC + MMF + GC vs CYC + GC | All patients in the two groups received intravenous methylprednisolone pulse therapy (0.5 g/d for 3 days) at the beginning, following by oral prednisone (0.6–0.8 mg/kg/d for 4 weeks and then reduced by 5 mg/d every 2 weeks to 20 mg/d; after that point, it was reduced by 2.5 mg/d every 2 weeks until a maintenance dosage of 10 mg/d). In TAC + MMF + GC group, a triple therapy of MMF, TAC, and corticosteroid was adopted. The TAC dosage was initiated at 4 mg/d (3 mg/d for ≤50 kg) twice daily, and blood concentration of TAC was maintained within 5–7 ng/mL. The dosage of MMF was initiated at 1.0 g/d (0.75 g/d for ≤50 kg) twice daily. Mycophenolic acid concentrations were measured and the dosage was titrated to maintain an area under the time concentration curve from 0 to 12 hours of mycophenolic acid at 20–45 mg⋅h/L. In the CYC + GC group, CYC pulse therapy was applied monthly. Dosing was initiated at 0.75 g/m2 of body surface area for the first month and then adjusted between 0.5 and 1.0 g/m2 body surface area monthly according to the white cell count after the infusion. | Eligible patients were of either gender and between 12 and 60 years of age, and had a diagnosis of class V + IV LN according to the ISN/RPS 2003 classification of LN. | CR, TR, urinary protein decline, rise of serum albumin, negative rate of ds-DNA | Gastrointestinal syndrome, leucopenia, hypertension, hyperglycemia, upper respiratory infection, pneumonia, herpes zoster or varicella, urinary tract infection, alopecia, irregular menstruation |
| Liu et al, 201519 | Multicenter, randomized, open-label, clinical trial | TAC + MMF + GC vs CYC + GC | Patients in both groups received intravenous methylprednisolone pulse therapy (0.5 g/d) for 3 days, followed by oral prednisone (0.6 mg/kg/day) every morning for 4 weeks. The daily dose of prednisone was tapered by 5 mg/d every 2 weeks to 20 mg/d and then by 2.5 mg/d every 2 weeks to a maintenance dose of 10 mg/d. After methylprednisolone pulse therapy, the multitarget group received MMF (0.5 g twice daily) and TAC (2 mg twice daily). For patients in the IVCY group, after completion of methylprednisolone pulse therapy, IVCY was initiated at a dose of 0.75 g/m2 body surface area and then adjusted to a dose of 0.5–1.0 g/m2 body surface area every 4 weeks for six doses. | Patients aged 18–65 years with biopsy-proven LN diagnosed within 6 months before enrollment, and had a diagnosis of class III, IV, V, III + V, and IV + V LN according to the ISN/RPS 2003 classification of LN. | CR, TR, urinary protein decline, rise of serum albumin, negative rate of ds-DNA | Gastrointestinal syndrome, leucopenia, hypertension, hyperglycemia, upper respiratory infection, pneumonia, herpes zoster or varicella, urinary tract infection, alopecia, irregular menstruation |
| Sakai et al, 201827 | A prospective, single-arm, single-center, open-label pilot study | TAC + CYC + GC vs CYC + GC | Oral prednisolone was started at a dose of 0.6–1.0 mg/kg/d. CYC was administered intravenously at a dose of 500 mg every 2 weeks for a total of six times as per the Euro-Lupus protocol. TAC was administered orally at a dose of up to 3.0 mg/d as per national health insurance guidelines in Japan. After 2 weeks, prednisolone was tapered by 5 mg/d every 2 weeks to 20 mg/d, after which it was usually reduced by 2.5 mg/d every 2–4 weeks to a maintenance dosage of 510 mg/d, at the discretion of an attending physician. TAC was continued as maintenance therapy after induction therapy achieved remission. | 15 patients aged 18–64 years with active LN were included, and had a diagnosis of class IV, III + V, and IV + V LN according to the ISN/RPS 2003 classification of LN. | CR, albumin, C3 levels, C4 levels, negative rate of ds-DNA, SLE-DAI, etc | Death due to thrombotic microangiopathy, cellulitis, pneumocystis pneumonia, anterior thoracic abscess, myelosuppression, deepvein thrombosis |
| Miyasaka et al, 200926 | A randomized, multicenter, placebo-controlled, double-blind study | TAC + GC vs GC | Eligible patients had been on GC therapy at a daily dose of more than 10 mg for at least 8 weeks prior to administration of the study drug, and the attending physician had judged that it was difficult to reduce the dose to below 10 mg/d because of the possibility of recurrence. Sixty-three patients were assigned randomly to the TAC group or the placebo group and were treated with oral TAC (3 mg/d) or placebo once daily after dinner for 28 weeks. After starting the trial, the GC dose could not be increased, although tapering was allowed. | 63 patients were included, and had a diagnosis of class II, III, IV, V, VI, II + III LN according to the ISN/RPS 2003 classification of LN. | Daily urinary protein excretion, urinary red blood cell count, ds-DNA, C3 levels, maintenance of normal serum creatinine, etc | Gastrointestinal syndrome, hypertension, hyperglycemia, etc |
Abbreviations: TAC, tacrolimus; GC, glucocorticoids; CYC, cyclophosphamide; IVC, intravenous cyclophosphamide; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; AZA, azathioprine; CR, complete remission; TR, total remission (complete plus partial remission [PR]); GFR, glomerular filtration rate; SLE-DAI, systemic lupus erythematosus disease activity index; LN, lupus nephritis; NA, not available; ISN, International Society of Nephrology; RPS, Renal Pathology Society; bid, twice a day.