Table 3.

Summary of pediatric lupus nephritis treatment studies from 2012 including biologics, disease modifying anti-rheumatic drugs and mesenchymal stem cell therapy.

Study	Patients	treatment	Outcome measures	Main result(s)	Safety outcomes	Level of evidence
Efficacy and safety of rituximab in comparison with common induction therapies in pediatric active lupus nephritis. Basu et al. (47) Study type: Retrospective cohort study Type of LN: active LN - class IIIA or IIIA/C (±V); class IVA or IVA/C (±V) LN, and pure class V nephritis with nephrotic- range proteinuria (ISN/RPS classification)	Total: 32 Pediatric study Rituximab 17 MMF 12 CYC 15 Age (year); mean (SD) Rituximab: 8.4 (4.6) MMF: 8.1 (3.2) CYC: 8.7 (4.1)	Induction therapy: Methylprednisolone pulses (15 mg/kg daily for 3 days) followed by either two rituximab pulses (375 mg/m2 weekly) or MMF (1,200 mg/mt2 daily) or six pulses of CYC (500 mg/m2 once very fortnight) with prednisolone 2 mg/kg daily for 1 month and then weaned at the discretion of the clinicians. MMF was added as maintenance (800 mg/m2 daily) in all children from the third month onwards	Primary outcome: flare-free survival LN flare defined if there was reappearance or deterioration of clinical manifestations of LN and renal biochemical parameters (≥25% decrease in baseline eGFR or proteinuria ≥1g/24h) along with rising titres of immunological parameters after initial postinduction stabilization or improvement. Secondary outcomes: Overall patient survival, renal survival, time to first flare after induction, number of flares, drug-related adverse reactions	Flare-free survival was significantly higher at 36 months with rituximab compared with MMF and CYC (100% for rituximab vs. 83% for MMF and 53% for CYC, p = 0.006). 13/17 (76.5%) achieved complete remission with rituximab compared with 5/12 (41.7%) and 7/15 (46.7%) with MMF and CYC, respectively, at last follow-up. Mean daily prednisone dosage was significantly lower in rituximab treated patients [rituximab vs. MMF, p = 0.005, Rituximab vs. CYC, p = 0.0001] at 36 months.	Adverse events were reported in 5/17 (29.4%) in the rituximab group compared with 7/12 (58.3%) in MMF and 15/15 (100%) in CYC group (no p values stated) No serious adverse events occurred after rituximab or MMF therapy.	3
Efficacy and Safety of Rituximab in Patients With Active Proliferative Lupus Nephritis. The Lupus Nephritis Assessment With Rituximab Study Rovin et al. (49) Study type: randomized, double-blind, placebo controlled phase III trial Type of LN: class III or IV LN	Adult study including some JSLE patients Total: 144 F 130 M 14 Age, mean +/- SD Placebo: 29.4 +/- 9.3 Rituximab: 31.8 +/- 9.6	Induction Placebo or rituximab 1,000mg administered intravenously on days 1, 15, 168, and 182. MMF was initiated at 1.5 gm/day in 3 divided doses and the dosage increased to 3 gm/day by week 4 as tolerated. This was continued to at least week 52. Methylprednisolone 1,000 mg was administered IV 30–60 min prior to study drug on day 1 and again within 3 days as therapy for active LN. To prevent infusion reactions, methylprednisolone 100 mg was given intravenously 30–60 min prior to the administration of study drug on day 15, 168, 182.	Primary end point: Complete renal response Partial renal response No renal response Secondary end points: Clinical:Number of patients with a baseline urinary PCR of >3 who achieved a UPC ratio of <1 at week 52 Median number of months to first complete response ratio Time adjusted AUCMB of BILAG index global score Change from baseline to week 52 in the SF-36 physical function score Achievement of a complete renal response from week 24 to week 52 Achievement of complete renal response at week 52 Serological Relative change from baseline in anti-dsDNA Change in baseline C3 and C4	Primary end point: Renal response rates (complete, partial and no response rate) at week 52 showed no statically significant difference between rituximab and placebo groups (p = 0.55) The overall (complete and partial) renal response rate was 45.8% for placebo and 56.9% for rituximab treated patients (P = 0.18). Partial renal responses accounted for most of the difference. Secondary end points: Clinical: No statistically significant difference between rituximab and placebo group Serological: Statistically significant improvements in C3, C4 and ds-DNA levels were observed amongst patients treated with rituximab. Eight placebo-treated patients and no rituximab-treated patients required cyclophosphamide rescue therapy.	The rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leukopenia, and hypotension occurred more frequently in the rituximab group.	1b
		Oral prednisolone 0.75 mg/kg/day (maximum 60mg) was administered until day 16 and tapered to ≤ 10 mg/day by week 16. Other immunosuppressants in addition to steroids and MMF were not permitted and discontinued during the screening period. If a new immunosuppressant agent and/or high dose steroids for >2 weeks were used, the study subject was classed as a non-responder. ACE/ARBs had to initiated at least 10 days before randomization. Antimalarials had to be maintained at a constant dose if used. NSAIDs were prohibited.
Efficacy and safety of rituximab in Japanese patients with systemic lupus erythematosus and lupus nephritis who are refractory to conventional therapy Tanaka et al. (50) Study type: multicentre, open label, phase II clinical trial Type of LN: any	Adult study including some JSLE patients Total: 34 No details on gender No details regarding age – inclusion criteria: patients aged 16-75 years	Rituximab - 1,000 mg given 2 weeks apart (days 1 and 15), repeated after 6 months (days 169 and 183) Before each rituximab infusion: acetaminophen, chlorpheniramine maleate and methylprednisolone Other drugs: Corticosteroid and any concomitant immunosuppressant at a stable dose before study entry.	Renal responses: complete, partial or no renal response based on LUNAR (Lupus nephritis assessment with rituximab) [1] and ACR (American College of Rheumatology) guidelines. [2] Overall renal response = complete and partial Change in BILAG scores Disease remission: change in BILAG A or B score to a BILAG C or D score in every organ system. Partial remission: change in BILAG A or B score to a C or D score in least one organ system but with presence of one BILAG A or B score in another organ system. No improvement: BILAG A or B score that remained unchanged at week 53.	Renal responses:In 17 patients with LN, overall renal response rates of 58.8% (95% CI 32.9–81.6) and 52.9% (95% CI 27.8 −77) by ACR and LUNAR criteria respectively were seen. The median value of urinary PCR/urinary creatinine ratio decreased from 2.2 (IQR 1.4-3.8) at baseline to 0.4 (IQR 0.10-2.44) at week 53 p = 0.0068). eGFR remained stable with a median value of 71.3mL/min/1.73m2 (IQR 41.2 – 101.5) at baseline vs. 72.3 mL/min/1.73m2 (IQR 56.8-93.0) at week 53 p = 0.1928).	Rituximab was well tolerated, and most adverse drug reactions were grade 1 – 2 in severity.	2B
			For patients with involvement of one study organ, remission was a change from a BILAG A or B score to C or D score and partial remission was a change from a BILAG A score to B score.	BILAG scores: 24/34 (76.5%) responded to rituximab therapy at week 53; 16/34 (47.1%) achieved remission and 10/34 (29.4%) achieved partial remission. BILAG global score in 34 patients decreased significantly from a median of 12.5 (interquartile range (IQR) 10-14) at baseline to 3.5 (IQR 1-6) at week 53 (p <0.0001). A significant reduction in concomitant prednisolone was achieved – 45mg/kg/day (IQR 35-55) at baseline to 6mg/kg/day (IQR 5 – 8.9) at week 53 (p <0.0001). Serological improvements were seen: C3 levels (69mg/dL (IQR: 48.8 – 82.0) at baseline vs. 88.5mg/dL (IQR 81.5 – 103.8) at week 53 p <0.0001) C4 levels (16.5mg/dL (IQR 8 – 332) at baseline vs. 22mg/dL (IQR 18-28) at week 53 p < 0.0001, data not shown) CH50 (31.2/mL (IQR 14.7-39.4) at baseline vs. 39.0/mL (IQR 34 – 46.7) at week 53 p = 0.0027, data not shown) Anti-dsDNA–(20.5 IU/mL (IQR 10 – 67.8) at baseline vs. 10 IU/ml (IQR 10-12.8) at week 53 p < 0.0001)
Efficacy and Safety of Ocrelizumab in Active Proliferative Lupus Nephritis Mysler et al. (51)	Adult study including some JSLE patients Total 381 M 49 F 332	In patients with active proliferative LN, placebo or 400mg ocrelizumab or 1,000mg ocrelizumab given as an infusion on days 1 and 15, followed by an infusion at week 16 and every 16 weeks thereafter.	At week 48: Complete renal response Partial renal response Nonresponse	Overall renal response: 54.7% - placebo-treated 66.7%−400 mg ocrelizumab-treated 67.1%−1,000 mg ocrelizumab-treated 66.9%–combined ocrelizumab- treated groups.	Serious adverse events: 27.2% placebo-treated patients 35.7% 400 mg ocrelizumab–treated patients, 22.0% 1,000 mg ocrelizumab–treated patients.	1b
Study type: Randomized, double-blind phase III study Type of LN: active proliferative	Age mean (range) years 31.3 (16–69) <30 years, % 50	Patients also received ELNT regimen induction treatment (i.e., CYC 500mg IV every 2 weeks for 6 months) or MMF as induction therapy	There was trend (p = 0.065) toward greater overall renal response rates at 48 weeks with ocrelizumab treatment and the ELNT regimen vs. placebo treatment and the ELNT regimen. Add ocrelizumab to background MMF had little effect on the overall renal response with adjusted treatment differences (vs. MMF alone) of −0.3% (95% CI −20.0, 19.7) and 13.3% (95% CI −6.0, 32.6) for the 400 mg ocrelizumab-treated and 1,000 mg ocrelizumab-treated groups respectively.	Serious infection rates (events/100 patient-years): 18.7 (95% CI 12.2, 28.7) placebo-treated patients 28.8 (95% CI 20.6, 40.3) 400 mg ocrelizumab-treated patients 25.1 (95% CI 17.4, 36.1) 1,000 mg ocrelizumab-treated patients. Patients receiving background MMF who received ocrelizumab had high serious infection rates per 100 patient-years (34.5 [95% CI 23.5, 50.7] and 28.6 [95% CI 18.6, 43.8] for 400 mg ocrelizumab and 1,000 mg ocrelizumab respectively) than those who received placebo (19.4 [95% CI 11.5, 32.7). Study terminated early due to higher rate of serious infections.

LN, lupus nephritis; M, Male; F, female; MMF, mycophenolate mofetil; PCR, protein creatinine ratio; ESRD, End stage renal disease; BILAG, British Isle Lupus Assessment; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CYC, cyclophosphamide; ELNT, Euro Lupus Nephritis treatment regimen; BILAG, British Isle Lupus Assessment; NSAID, nonsteroidal anti-inflammatory drugs; TAC, tacrolimus; AZA, azathioprine; ECLAM, European Consensus Lupus Activity Measurement; SLEDAI score, Systemic Lupus Erythematosus Disease Activity Index scores; UPC ratio, urine protein creatinine ratio.