Landmark trials in lupus-nephritis
Ritasman Baisya
6.11.2020

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

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

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

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
.

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

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

• 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

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.

• 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

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.

Mycophenolate enters in trials …..

• 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

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

• 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

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

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

• 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

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

Trials of maintenance treatments in lupus nephritis

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)

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.

• 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

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

Journey of Rituximab in lupus nephritis

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

• 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

• 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

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

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

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.

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.

Trials in membranous lupus nephritis

• 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

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

• 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

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

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

• 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

• 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

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.

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

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

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