This document summarizes landmark trials in the treatment of lupus nephritis over 50 years. Early trials in the 1960s established the benefit of high-dose steroids over low-dose. The 1986 NIH trial showed intravenous cyclophosphamide reduced end-stage renal failure compared to oral steroids alone. Subsequent trials tested maintenance therapies like mycophenolate mofetil versus azathioprine, and induction therapies like belimumab and voclosporin. Recent trials explored rituximab and found benefits without oral steroids. While treatment has improved over decades of research, heterogeneity remains a challenge in lupus nephritis clinical trials.

1. Landmark trials in lupus-nephritis
Ritasman Baisya
6.11.2020

2. Points of discussion
• Introduction
• Induction treatment trials
• Maintenance treatment trials
• Trials for lupus membranous nephropathy
• Recent trials
• Limitation

3. Introduction
• Lupus nephritis ( LN ) occurs in up to 80% of SLE patients
• Risk of death > 2 times in LN than without LN
• LN with chronic kidney disease have > 3 times the risk of death
• First studies to describe LN written approximately 50 years ago
• It is fascinating to look back on the history of the treatment of lupus nephritis

5. 1964- Journey begins ( Pollak et al study )
• First kidney biopsy was utilized to classify
LN
• High dose steroid had a survival advantage
of low dose
• Overall survival was poor

6. 1986 – NIH trial
• Renal function in 107 patients with active LN were evaluated (median follow-up- 7
years)
• 5 treatment groups – oral steroid alone ( 30) , AZA ( 20) , oral CYC (18), combined
AZA & oral CYC (23) , iv CYC (20)
• Patient on oral prednisone alone, probability of renal failure increased after 5 years
.

7. Results
Austin HA 3rd, Klippel JH, Balow JE, le Riche NG, Steinberg AD, Plotz PH, Decker JL. Therapy of lupus
nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med. 1986 Mar 6;314(10):614-9.
• Renal function difference was
statistically significant for ( IV
CYC + LDS ) as compared with
HDS alone (p = 0.027)
• Treatment of LN with IV CYC
reduces the risk of end-stage renal
failure with few serious
complications

8. NIH regimen
Monthly intravenous CYC for 6 months followed by quarterly infusions for 24
additional months as an accepted treatment for severe LN

9. • 65 patients severe LN .
• Monthly pulse MPS (6m ) vs CYC ( 6 m) vs CYC (6 m ) and then quarterly for 2 years
• pulse MPS had a higher probability of doubling serum creatinine than those treated with
long-course CYC (p<0·04).
• Risk of doubling creatinine was not significantly different between short and long course
CYC
• Patients treated with short-course CYC had a higher probability of exacerbations than
long-course CYC (p<0·01).
1992- Boumpas et al

10. Results
Cumulative probability of not doubling serum creatinine
after treatment
Cumulative probabilities of no exacerbation on completion
of monthly cycles in groups receiving short (CY-S) or long
(CY-L) courses of pulse cyclophosphamide.

11. • 82 LN patients , >10 RBC/HPF , cellular casts, proteinuria (> 1 g / day), renal biopsy showing
proliferative nephritis.
• MPS(1 g/m2 BSA) monthly for 1 year vs CYC (0.5 to 1.0 g/m2 BSA ) for 6 m & then quarterly vs
bolus therapy with both MPS and CYC .
• Renal remission - 17 / 20 in the combination group (85%), 13 / 21 in CYC group (62%), and 7 / 24
in MPS group (29%) (p< 0.001).
• Likelihood of remission was greater in the combination therapy group than in the MPS group (p =
0.028)
• Combination therapy and CYC therapy were not statistically different.
Annals of Internal
Medicine
October , 1996

12. Results
• The combination therapy group (MP
+ CY) differs from MPS group (MP)
(P = 0.028);
• CYC did not differ from the
combination therapy group (P> 0.2)
or the methylprednisolone group (P =
0.16
Probability of remission during the study period by treatment
group.

13. Mycophenolate enters in trials …..

14. • 42 patients with diffuse proliferative LN taken
• Efficacy & side effects of prednisolone & MMF regimen ( group 1 ) for 12 months vs
prednisolone & CYC given for 6 months, followed by prednisolone and azathioprine for
6 months ( group 2 ) compared
• 81% ( n= 21 ) in group 1 had a complete remission, and 14 % a partial remission
• 76 % ( n=21 ) in group 2 had complete remission and 14% partial remission
October 19, 2000

15. Results- non-inferiority
Serum Cr , C3 , 24 hr UP changes in group 1 vs group 2

16. • Multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT])
• 90 SLE patients with proliferative glomerulonephritis
• High-dose IV CYC regimen (6 monthly pulses & 2 quarterly pulses ) vs a low-dose
IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was
followed by AZA.
• Intent-to-treat analyses were performed.
ELNT - 2002

17. Hazard ratio for treatment failure in
the low-dose group compared with
the high-dose group was 0.79 (95%
CI - 0.30–2.14; p- 0.64).
It was not statistically significant by
Kaplan-Meier analysis
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, et al .
Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose
versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002 Aug;46(8):2121-31

18. Other results from ELNT
• Serum creatinine, albumin, C3, 24-h UP , disease activity scores significantly
improved in both groups during the first year of follow up.
• Renal remission was achieved in 71% of the low-dose group & 54% of the high-
dose group (not statistically significant).
• Renal flares were noted in 27% of the low-dose group & 29% of the high-dose
group.
• Although episodes of severe infection were more than twice as frequent in the
high dose ,it was not statistically significant

19. • Multinational, two-phase (induction and maintenance) study
• 370 patients - 185 in each group
• Classes III - V LN - open-label MMF (target 3 g/d) or IVC (0.5 to 1.0 g/m2 in
monthly) in a 24-wk induction study
• Primary end point - prespecified decrease in urine protein/creatinine ratio &
stabilization or improvement in serum creatinine
J Am Soc Nephrol 20: 1103–1112, 2009
ALMS induction trial - 2009

20. Result of ALMS trial
• Primary efficacy end point achieved
in 104 (56.2%) on MMF & 98
(53.0%) on IVC (OR- 1.2; 95% CI-
0.8 to 1.8; P 0.58 )
• Statistical significance between
treatment group & race (P 0.047)
• Between treatment group and region
(P 0.069).
• high-risk, nonwhite, non-Asian group
responding more to MMF than to
IVC

22. Trials of maintenance treatments in lupus nephritis

23. Maintenance phase of ALMS trial
• Maintenance treatment compared in a follow-on ALMS study in patients with acceptable clinical responses
to either MMF or IV CYC
• Re-randomized patients to treatment with either MMF ( 2g/d) or azathioprine( 2 mg/kg/d ) for 36 months
• MMF was superior to AZR with respect to the primary end point, time to treatment failure (hazard ratio, 0.44;
95% CI - 0.25 to 0.77; P=0.003),
• MMF superior to respect to time to renal flare and time to rescue therapy (hazard ratio, <0.05)

24. Mycophenolate mofetil was superior to azathioprine in
maintaining a renal response to treatment and in
preventing relapse in patients with lupus nephritis who
had a response to induction therapy.

25. • Tested maintenance treatment with either AZR or MMF in patients with proliferative
LN after induction with iv CYC using the Euro-Lupus protocol
• The primary endpoint was renal flare- development of nephrotic syndrome/ increase
in serum creatinine/ increase in proteinuria accompanied by hematuria and depression
of C3 levels.
MAINTAIN Trial – 2011

26. Results • Time to renal flare, severe systemic flare,
benign flare and to renal remission did not
statistically differ between groups
• Over 3-year period, 24 h proteinuria, Cr ,
Alb , serum C3, Hb & global disease activity
scores improved similarly in both groups.
• Doubling of serum creatinine occurred in 4 -
AZA-treated and 3 - MMF treated patients.
• Adverse events did not differ between the
groups
Ann Rheum Dis 2010;69:2083–2089. doi:10.1136/ard.2010.131995

27. Journey of Rituximab in lupus nephritis

28. Landmark Nephrology: Use of Rituximab in Lupus
Nephritis
August 26, 2020

29. • Single center, open label, prospective, observational study ( n-18 ) with class III, IV
or V lupus nephritis, on steroids for SLE.
• RTX given - 1 g on days 1 and 15 with or without MPS
• 78% achieved complete or partial remission with a sustained response in twelve
patients (67%) at 1 year.
• Following treatment with rituximab, 6 patients stopped prednisolone, 6 patients
reduced their maintenance dose and 6 patients remained on the same dose (maximum
10 mg)
RITUXRESCUE - 2009

30. • Lupus Nephritis Assessment with Rituximab (LUNAR) study ( 2012)
• To test whether rituximab boost complete renal responses in active LN with other IS
• All patients ( 144 ) on induction with MMF 3 g/d & pulse MPS
• Blinded treatment with rituximab (1 g) or placebo was given on days 1, 15, 168 and
182 of treatment ( n - 72 each )
LUNAR 2012

31. Results
• Renal response rates
(CRR/PRR/NR) at week 52 - not
statistically different (P = 0.55)
• Statistically significant
improvements in C3, C4, anti-
dsDNA levels were observed
among patients treated with RTX

32. Ann Rheum Dis 2013;72:1280–1286.
doi:10.1136/annrheumdis-2012-202844
• 50 class III, IV or V patients were enrolled in a prospective observational study to
receive 1 g rituximab and methylprednisolone 500 mg on days 1 and 15.
• All patients received MMF,
• oral steroids were not used.
Rituxilup – 2013

33. Results
• 90% achieved CR or PR by a median
time of 37 weeks
• At 52 weeks, CR and PR had been
achieved in 52% & 34%
respectively.
• 12 relapses occurred in 11 patients,
at a median time of 65.1 weeks
• Rituxilup cohort demonstrates that
oral steroids can be safely avoided in
the treatment of LN.

34. RTX in severe /refractory lupus nephritis
• Melander et al - achieved a complete remission rate (CRR) of 60% in 20 patients
(retrospective study) with severe LN.
• Catapano et al - achieved a CRR of 91% in 11 cases (retrospective study) of
refractory/relapsing lupus nephritis.
• Pooled cohorts - achieved CRRs between 30 -90% with RTX in refractory
Lupus Nephritis.

35. Trials in membranous lupus nephritis

36. • Open-label randomized trial
• Cyclosporine 200 mg/m2 /d and high-dose alternate-day prednisone vs iv CYC 0.5
– 1.0 g/m2 every other month for 6 infusions and high-dose alternate-day
prednisone vs high-dose alternate day prednisone alone
• 42 patients with membranous LN with proteinuria of at least 2 g daily (median 5.4
g daily)
J Am Soc Nephrol. 2009 Apr; 20(4): 901–911

37. Results
• Primary outcome, time to remission of
proteinuria during the 12-m protocol
• At 1 yr, the cumulative probability of
remission was 27% with prednisone, 60%
with IVCY, and 83% with CsA
• relapse of nephrotic syndrome occurred
significantly more often after completion of
CsA than after IVCYC

38. • To assess the efficacy and safety of a 24-week course of abatacept in treatment of
active LN
• To assess the potential of abatacept to induce “clinical tolerance’’
• 134 were enrolled in a randomized, double-blind phase II add-on trial in which they
received either abatacept or placebo
• All treated with ELNT regimen of low-dose CYC followed by AZA

39. Results
• Primary efficacy outcome was the frequency of
complete response at week 24
• A complete response was achieved in 33% in
treatment group & 31% in control group at week 24
• Addition of abatacept to a regimen of CYC
followed by AZA did not improve the outcome of
LN at either 24 or 52 weeks

40. SYNTHESIS OF THE EVIDENCE
• Cochrane review
• In a review of 50 randomized
controlled trials, Henderson and
colleagues concluded –
MMF was as effective as intravenous
cyclophosphamide for induction
treatment while having lower risks of
ovarian failure

42. • Phase 3, multinational, multicenter, randomized, double-blind 104-week trial at
107 sites in 21 countries
• Primary end point - primary efficacy renal response ( PERR ) at 104 week
• Major secondary end point was a complete renal response (CRR )
• 448 patients underwent randomization (224 to the belimumab & placebo group
each )
Sep , 2020

44. • The AURA-LV study tested voclosporin for efficacy and safety in active LN
• Phase 2, multi-center, randomized, double-blind, of two doses of voclosporin
(23.7 mg or 39.5 mg, each twice daily) vs placebo in combination with MMF (2 g/d)
• Rapidly tapered low-dose oral corticosteroids for induction of remission
• The primary endpoint was CRR at 24 weeks

45. Results
• The CRR rate was significantly higher with low-
dose VCS (23.7 mg twice a day) than with placebo
at week 24
• Both low-dose and high-dose VCS were superior to
placebo with respect to CRR at week 48
• CRRs were achieved more rapidly (P < 0.001) in
both VCS groups compared with placebo
• Patients with a Class V component did not show an
improvement in CRR upon treatment with VCS.

46. Limitation in SLE trial
• Heterogeneity of disease
• Inadequate trial size or duration
• Choice of primary endpoints
• Non-standardized use of background therapy
• No consensus on the best way to conduct these trials

47. Take home messages
• Trials of lupus nephritis - long journey for more than 50 years
• NIH trial (1986) - first to show efficacy of iv CYC in induction
• ELNT trial (2002)showed low fixed dose CYC had similar effect as NIH regimen
• ALMS trial(2009) - MMF was non inferior to CYC in induction treatment
• ALMS-maintain(2011) trial – MMF superior , MAINTAIN trial (2011)–AZA & MMF
similar
• Rituximab – LUNAR trial(2012) failed primary end point
• RITUXILUP trial (2013)– achieved renal remission without oral steroids
• Voclosporin ( 2020), Belimumab(2020) are upcoming drugs for LN

48. References
• Ward MM. Recent clinical trials in lupus nephritis. Rheum Dis Clin North Am. 2014;40(3):519-ix.
doi:10.1016/j.rdc.2014.05.001
• Henderson L, Masson P, Craig JC, Flanc RS, Roberts MA, Strippoli GF, Webster AC. Treatment for lupus
nephritis. Cochrane Database Syst Rev. 2012 Dec 12;12:CD002922
• Mahieu MA, Strand V, Simon LS, Lipsky PE, Ramsey-Goldman R. A critical review of clinical trials in
systemic lupus erythematosus. Lupus. 2016;25(10):1122-1140.
• Pakozdi A, Rajakariar R, Pyne D, Cove-Smith A, Yaqoob MM. Systematic Review and the External
Validity of Randomized Controlled Trials in Lupus Nephritis. Kidney Int Rep. 2017;3(2):403-411.
• Fanouriakis A, Bertsias G. Changing paradigms in the treatment of systemic lupus erythematosus. Lupus
Sci Med. 2019 Feb 8;6(1):e000310