Table 2 An overview of landmark randomized controlled trials of lupus nephritis treatments published since 2000

Chan et al. [24] (2000)

Randomized, single-center study

42

12

MMF (1 g BID) versus CYC (2.5 mg/kg)

Prednisolone 0.8 mg/kg followed by taper, maintenance dose 10 mg/day

• Complete remission = Upr <0.3 g/day, with normal sediment, normal albumin, and SCr and CrCl ≤15% above baseline

Rate of remission similar between groups

• Partial remission = Upr ≥0.3 and <2.9 g/day, albumin ≥3.0 g/dL, and stable kidney function

• Treatment failure = Upr ≥3.0 g/day, or Upr <3.0 with serum albumin <3.0 g/dL, SCr that has increased >0.6 mg/dL, or CrCl >15% above baseline

Houssiau et al. [48] (2002)

Randomized non-inferiority, multicenter

90

41

High CYC (monthly pulses, dose adjusted based on WBC) versus low-dose CYC (500 mg every 2 weeks)

Methylpred three times followed by prednisolone taper, maintenance dose 5 to 7.5 mg/day

• Treatment failure = one of the following:

Similar treatment failure rates between groups

  ○ Absence of a primary response after 6 months

  ○ Occurrence of glucocorticoid resistant flare

  ○ Doubling of serum creatinine

  ○ Lack of improvement in kidney function if dysfunction present at baseline

Ginzler et al. [27] (2005)

Randomized, open-label, non-inferiority

140

6

Oral MMF daily (up to 3 g/day) versus monthly CYC (up to 1.0 g/m²)

Glucocorticoids 1 mg/kg per day followed by taper at clinician’s discretion

• Complete remission: return to within 10% of normal values for creatinine, proteinuria, and urine sediment

MMF was superior to CYC for induction

Appel et al. [25] (2009)

Randomized controlled, superiority trial

370

6

MMF (3 g/day) versus IV CYC (0.5 to 1.0 g/m²)

Glucocorticoids 60 mg followed by taper

• Response defined as:

Overall response rate the same in MMF and CYC groups

  ○ Decrease in UPCR to <3 from a 24-hour collection in patients with baseline UPCR >3

  ○ Decrease in UPCR of >50% if sub-nephrotic at baseline

  ○ Stabilization (±25%) or improvement in serum creatinine

Rovin et al. [28] (2012)

Randomized, placebo-controlled, multicenter

144

12

Addition of ritxumab versus placebo to MMF and steroids

Methylpred 1 g two times peri-study drug doses

• Complete renal response = normal SCr (if abnormal at baseline), inactive sediment, or UPCR <0.5

Response rates similar among groups

• Partial renal response = SCr ≤115% of baseline, RBCs/hpf ≤50% above baseline, no RBC casts, and at least 50% decrease in UPCR or to <1.0 (if baseline was ≤3.0) or to ≤3.0 (if baseline was >3.0)

• No response = did not meet criteria for complete or partial response, terminated study early, or missing data limited ability to assess

Furie et al. [26] (2014)

Randomized, phase II/III multicenter, double-blind study

298

12

Standard dose abatacept, high-dose abatacept, or placebo

Protocol defined steroid (and MMF) dosing

• Complete response = eGFR ≥90% of screening or pre-flare value, UPCR <0.26, inactive urinary sediment

Time to achievement of complete response was similar in all arms.

ACCESS trial group, 2014 [33]

Randomized double blind, double-blind, placebo-controlled

134

6 and 12 weeks

Euro-Lupus CYC with abatacept versus placebo

Methyl pred x3 followed by taper

Proportion of subjects achieving complete response at 24 weeks defined as:

No difference with abatacept

• Kidney function: stable or improved eGFR

• Proteinuria: UPCR <0.5

• Urine sediment: not included

• Corticosteroid dose: tapered to ≤10 mg daily

Contreras et al. [29] (2004)

Single-center, randomized open-label trial

60

72

IV CYC (0.5 to 1.0 g/m² every 3 months) or AZA 1 to 3 mg/kg per day or MMF (500 to 3,000 mg/day)

Glucocorticoids up to 0.5 mg/kg per day

• Patient survival

Patient survival was significantly better in AZA compared with CYC, and renal survival was similar in all groups.

• Renal survival, defined as sustained increase in SCr to at least two times the lowest level achieved during induction, need for RRT or transplant

Houssiau et al. [49] (2010)

Randomized trial

105

48

AZA (target 2 mg/kg per day) or MMF (target 2 g/day)

Methylpred three times followed by taper

• Time to renal flare = nephrotic syndrome, ≥33% increase in serum creatinine within 1 month, threefold increase in 24-hour proteinuria with hematuria, ≥ 33% reduction in C3 within 3 months

Fewer flares with AZA but failed to show superiority

Dooley et al. [30] (2011)

Randomized double-blind, double-dummy, multicenter

227

36

MMF (1 g BID) versus AZA (2 mg/kg daily)

Glucocorticoids 10 mg/day

• Time to treatment failure = time until the first event (death, ESKD, doubling of SCr, renal flare, or need for rescue therapy)

MMF superior to AZA