1) Early studies showed steroids improved survival for lupus patients compared to no treatment, and high-dose steroids worked better than low-dose. 2) Later trials added cytotoxic drugs to steroids and found fewer unfavorable outcomes for lupus nephritis patients. 3) A randomized trial found low-dose IV cyclophosphamide as effective as high-dose IV cyclophosphamide for lupus nephritis, with fewer infectious side effects from the lower dose.

2. Although survival was poor in both
groups (less than 2 to 5 years in
most cases), this was the first study
showing that patients who received
steroids survived longer.
High dose steroids showed a
survival advantage over low dose.
(1964)

3. NIH Trials

5. • 14 controlled trails previous to 1st NIH study showed that cytotoxic agent
added to steroids give fewer unfavourable outcomes of lupus nephritis.
• Randomized control trial
• 5 arms of the trial. ( Group 2-5 had prednisolone upto 0.5mg/kg/day)
• High dose oral prednisolone alone 1mg/kg for 4-8 weeks f/b tapering as tolerated
• Oral azathioprine upto 4mg/kg/day
• Oral cyclophosphamide upto 4mg/kg/day
• Combined oral azathioprine and cyclophosphamide (upto 1 mg/kg/day each)
• I/V cyclophosphamide 0.5-1 gram/m2 every 3 monthly

6. • Inclusion criteria- diagnosis of SLE and clinical or histological active
lupus nephritis
• Exclusion criteria – CrCl < 20, pregnancy, major infection within 2
week of study, previous cytotoxic therapy within 8 weeks prior,
leukopenia<2000, study drug allergy.
• Total of 107 patients were enrolled
• Cytotoxic therapy given till sustained response for 18 months or total
of 4 years.

13. • More intensive therapy than previous trial
• Enrolled patients with severe lupus nephritis only, defined as
• nephritic urine sediment and impaired renal function
• Creatinine clearance between 25 and 80 ml per min.
• If creatinine clearance > 80 ml per min, the candidate had to have very active
renal histology with crescents or necrosis in more than 25% of glomeruli.
• Research question
• whether pulse methylprednisolone could equal pulse cyclophosphamide in
preserving renal function in patients with lupus nephritis
• whether there was a difference between long and short courses of pulse
cyclophosphamide in preventing exacerbations.

14. • 65 patients (60 female, 5 male; median [range] age 29 [10-48] years) with
severe lupus nephritis
• Exclusion criteria – pregnancy, Received cytotoxic drug therapy for more
than 10 weeks at any time, active infections, insulin-dependent diabetes,
or previous malignancy.
• Three arms in the trial
• Monthly pulse methylprednisolone for 6 months (25 patients),
• Monthly pulse cyclophosphamide for 6 months (20),
• Monthly cyclophosphamide for 6 months followed by quarterly pulse
cyclophosphamide for 2 additional years (20)

15. • All patients received prednisone, starting at 0.5 mg/kg per day and
continuing for 4 weeks
• Tapered at a rate of 5 mg every other day to the minimum dose
required for control of extra-renal disease (but not less than 0.25
mg/kg every other day).
• After the first 6 months of pulse therapy, All patients with evidence of
increased activity of lupus nephritis were treated with prednisone 1.0
mg/kg every other day for 1 month with rapid taper

21. • Pulse methylprednisolone did not match the efficacy of a sustained course of
pulse cyclophosphamide in preserving renal function in severe lupus nephritis.
• The optimal dose, treatment interval, and duration of pulse cyclophosphamide
are not known
• Short courses of pulse cyclophosphamide are associated with higher rates of
exacerbation than courses that include a period of "consolidation" therapy for
several months after disease activity subsides.
• At present, we favour treatment with quarterly pulse cyclophosphamide for at
least 1 year beyond the point where urinary sediment becomes inactive

31. • Combination therapy tended to lead to quicker time to renal response, and
the highest proportion of patients achieving a remission
• However, patients receiving combination therapy are subject to the side
effects caused by both cyclophosphamide and prednisolone
• It might be prudent to reserve such therapy for patients with the most
aggressive cases of lupus nephritis.
• Newer, less toxic, and more specific intervention strategies awaited

32. EURO-LUPUS Trial

34. • Rational of study
• High-dose IV CYC treatment is highly toxic; up to 25% of patients develop
herpes zoster infection, up to 26% experience a severe infection, and up to
52% of women at risk have ovarian failure
• Clinically milder cases of biopsy proven proliferative nephritis—for which less-
aggressive treatment might be justified—are now frequently diagnosed
because of prompt assessment of early renal involvement.

35. • European-based multicenter, prospective, randomized study designed
to compare high-dose IV CYC (not a strict NIH protocol) and low-dose
IV CYC as remission-inducing therapy for proliferative lupus nephritis.
• AZA was used in both study arms as a long-term immunosuppressive
agent to maintain remission.

36. • 90 SLE patients were enrolled in the trial at 19 European centers.
• Inclusion criteria:
• Diagnosis of SLE
• Age >14 years
• Biopsy proven proliferative lupus glomerulonephritis (World Health
Organization [WHO] class III, IV, Vc, or Vd)
• Proteinuria 500 mg in 24 hours.

37. • Exclusion criteria
• CYC or AZA during the previous year
• 15 mg/day of prednisolone (or equivalent) during the previous month
• Renal thrombotic microangiopathy
• Preexisting chronic renal failure
• Pregnancy
• Previous malignancy (except skin and cervical intraepithelial neoplasias)
• Diabetes mellitus
• Previously documented severe toxicity to immunosuppressive drugs and
• Anticipated poor compliance with the protocol.

38. • All patients received 3 daily pulses of 750 mg of IV methylprednisolone,
followed by oral glucocorticoid therapy at an initial dosage of 0.5
mg/kg/day of prednisolone (or equivalent) for 4 weeks.
• A dosage of 1 mg/kg/day was allowed in critically ill patients (those with
renal impairment or severe extrarenal disease).
• After 4 weeks, glucocorticoid dosages were tapered by 2.5 mg of
prednisolone (or equivalent) every 2 weeks.
• Low-dose glucocorticoid therapy (5–7.5 mg of prednisolone per day) was
maintained at least until month 30 after inclusion.

39. • All patients received IV CYC therapy beginning on day 1 of study inclusion. They were
randomized by minimization into 2 treatment groups: high-dose or low-dose IV CYC.
• With minimization strategy of randomization, the group allocation does not rely on
chance, but is designed to reduce as much as possible any difference in the distribution
of determinants of outcomes.
• The following determinants were taken into account by the minimization: study center,
age, sex, history of renal disease, history of glucocorticoid treatment, history of
treatment with other immunosuppressive drugs, serum creatinine level, serum albumin
level, 24-hour urinary protein level, diastolic blood pressure, European Consensus Lupus
Activity Measure (ECLAM) score , WHO class, and the presence of crescents, glomerular
necrosis, or fibrosis on kidney biopsy specimens.

40. • Patients assigned to the high-dose group received 8 IV CYC pulses within a year (6
monthly pulses followed by 2 quarterly pulses). The initial CYC dose was 0.5
gm/m2 of body surface area; subsequent doses were increased by 250 mg
according to the TLC measured on day 14, with a maximum of 1,500 mg per
pulse.
• Patients assigned to the low-dose group received 6 fortnightly IV CYC pulses at a
fixed dose of 500 mg.
• In both treatment arms, AZA (2 mg/kg/day) was started 2 weeks after the last
CYC injection and continued at least until month 30 after study inclusion. For
cases of AZA-related toxicity, the dosage was reduced to 1mg/kg/day. Patients
who did not tolerate this AZA dosage were dropped from the trial.

41. • A severe renal flare was defined as 1 of the following 3 features:
• Renal impairment. Renal impairment was defined as an sle-related increase of "33% in the
serum creatinine level within a 1-month period.
• Increase in proteinuria. An increase in proteinuria was defined as the recurrence or
appearance of nephrotic syndrome (albuminemia <3.5 gm/dl and proteinuria >3 gm in a 24-
hour sample). In patients with low-grade proteinuria at baseline (>0.5 gm but <1 gm in 24
hours), a 3-fold increase in 24-hour urinary protein levels within a 3-month period was also
considered a severe flare, provided that it was accompanied by microscopic hematuria and a
"33% reduction of serum C3 levels within a 3-month period.
• Severe systemic disease. Severe systemic disease was defined as any of the following events:
central nervous system disease, thrombocytopenia (100,000 platelets/l), hemolytic anemia,
lupus pneumonitis, lupus myocarditis, extensive skin vasculitis, or serositis not responding to
low-dose glucocorticoid and/or NSAID treatment.
• A severe flare was always treated by an increase in the glucocorticoid dosage (0.5–1.0 mg/kg/day
of prednisolone) for 1 month, and then promptly tapered to the patient’s preflare dosage. Up to 2
IV pulses of methylprednisolone (750 mg) were allowed within a 1-week period.

43. • 3 secondary end points were as follows:
• The kinetics of the response to therapy in the first year, based on serial
measurements of serum creatinine, serum albumin, 24-hour urinary protein,
and serum C3 levels, as well as the ECLAM score
• The rate of renal remission, defined as <10 red blood cells/high-power field
and a 24-hour urinary protein level <1 gm, in the absence of a doubling of the
serum creatinine level
• The number of severe flares.

50. • The results of the trial indicate that
1) there was no significantly greater cumulative probability of treatment failure in patients
taking a low-dose IV CYC regimen than in those taking a high-dose regimen
2) the kinetics of the initial response did not differ between the two groups
3) the cumulative probability of achieving renal remission was similar in both groups
4) the number of renal flares did not differ between the two groups.
5) severe infectious side effects were less common in the low-dose group, although the
difference was not statistically significant.

51. • Most patients included in the ELNT did not have clinically severe kidney disease.
Although all patients had proliferative glomerulonephritis, only 22% presented with renal
impairment and 28% presented with nephrosis, compared with 64% and 62%
respectively, in the study by boumpas et al (NIH trial).
• It should be stressed, however, that the patients randomized into the elnt are
representative of those currently treated there. Milder cases of proliferative lupus
nephritis, for which less-aggressive treatment is certainly justified, are now frequently
diagnosed due to the prompt assessment of kidney involvement

52. • few black or African Caribbean patients were included in the ELNT (9% of the cohort);
this is in contrast to the high percentage of black patients randomized into the NIH
studies reported by Boumpas et al (43%) and Gourley et al (34%).
• Since the outcome of lupus nephritis is poorer in black patients compared with the
outcome in white patients , the underrepresentation of this ethnic group in our
European populations might explain, at least in part, why a low-dose IV CYC regimen was
effective.

53. • High-dose IV CYC regimen prescribed in the ELNT is shorter than that of the studies
conducted in north america, and as a consequence, the cumulative dose of IV CYC is
lower, and may have affected the results.

58. • Induction with maximum of seven monthly boluses of intravenous
cyclophosphamide (0.5 to 1.0 g per square meter of body-surface area) and
corticosteroids.
• After induction, the patients were randomly assigned, in order of
enrollment by means of sealed envelopes (stratified in two groups: blacks
and other patients), to one of three regimens of maintenance therapy:
• 0.5 to 1.0 g of intravenous cyclophosphamide per square meter every three months
• 1 to 3 mg of oral azathioprine per kilogram of body weight per day
• 500 to 3000 mg of oral mycophenolate mofetil per day

59. • All three groups received maintenance immunosuppressive therapy with
oral prednisone (up to 0.5 mg per kilogram per day) or an equivalent
corticosteroid for one to three years
• primary end points of the study were patient and renal survival
• The secondary end points of the study were renal relapse, amenorrhea for
> 12 months, hospitalization, infection, and other adverse events
• median duration of treatment was 25 months in the cyclophosphamide
group, 29 months in the mycophenolate mofetil group, and 30 months in
the azathioprine group

63. ALMS Trial
Induction → Maintenance

65. • MMF was at least as effective as IVC in induction treatment in previous
trials in Hong Kong, Malaysia, China, and the United States.
• Meta-analyses of these and smaller trials suggested that MMF may offer
advantages over IVC.
• Comparison of MMF with IVC, both with corticosteroids, for the induction
treatment of active classes III, IV, and V LN. (class III or V LN must have had
proteinuria (at least 2 g/d)
• The hypothesis was that more patients with LN would respond to MMF
than to IVC during 24 wk.

66. • Patients (n370) were enrolled at 88 centers in 20 countries
• Inclusion criteria
• 12 to 75 years of age
• Diagnosis of systemic lupus erythematosus according to the ACR
• Kidney biopsy within the 6 months prior to first randomization classes III, IV-S or IV-
G, (A) or (A/C); or class V, alone or in combination with class III or IV
• Laboratory evidence of active nephritis at screening
• Exclusion criterias
• On dialysis for 2 weeks before randomization ( but only 32 patients had eGFR <30)
• Randomisation (1:1, stratified by race and biopsy class)

67. • primary end point, proportion of patients responding to treatment
• Response was defined as a decrease in urine protein/creatinine ratio (P/Cr),
calculated from a 24-h urine collection, to < 3 in patients with baseline
nephrotic range P/Cr (>3), or by >50% in patients with subnephrotic
baseline P/Cr (<3), and stabilization (+25%) or improvement in serum
creatinine at 24 wk.
• secondary end points included the proportion of patients who achieved
complete remission (return to normal serum creatinine, urine protein 0.5
g/d, and inactive urinary sediment), combined renal and extrarenal
remission

73. • MMF did not show superiority over IVC for the induction therapy of
LN, as measured by renal response rate after 24 wk of treatment
• more patients in the high-risk, non white, non-Asian group
responding to MMF than to IVC (black or Latin American mixed race)
• The low remission rates across all of the racial/ethnic groups studied
in the Aspreva Lupus Management Study (ALMS) highlight the need
to investigate the ideal regimen and its duration in patients with LN

75. • Those who had a clinical response to either oral mycophenolate mofetil or
intravenous cyclophosphamide during the induction study were randomly
assigned (in a 1:1 ratio) to one of these two agents in the maintenance
study.
• The definition of a response was based on investigator judgment (not
necessarily trial end-points)
• Patients were followed for 36 months, regardless of events
• Mycophenolate mofetil (1 g, twice daily) or oral azathioprine (2 mg per
kilogram of body weight per day).

76. • Primary efficacy end point was the time to treatment failure,
measured as the time until the first event and defined as
• Death
• End-stage renal disease
• Sustained doubling of the serum creatinine level
• Renal flare (proteinuric or nephritic)
• Need for rescue therapy (glucocorticoids, plasmapheresis, intravenous
immune globulin, or immunosuppressive drugs not specified in the protocol)

81. • Rates of complete remission at the end of induction therapy were low (8.6% with
mycophenolate mofetil and 8.1% with cyclophosphamide)
• complete remission eventually achieved in 62.1% of patients in the
mycophenolate mofetil group (72 of 116) and in 59.5% of those in the
azathioprine group (66 of 111) (catch - only responders included)
• This finding suggests that the distinction between induction therapy and
maintenance therapy in patients with lupus nephritis may be an artificial one.
• many black patients did not meet the clinical response criteria, few were included
in the maintenance trial

82. MAINTAIN Trial

84. • Randomised superiority trial comparing AZA and MMF as longterm
immunosuppressive treatment of LN, after a short course of low-dose
intravenous CYC, in order to test the hypothesis that MMF would reduce
renal relapses.
• 27 european centres
• Primary end point of the trial was time to renal flare
• Renal remission was not a prerequisite to receive maintenance treatment
with aza or mmf and could therefore be reached at any time during follow-
up

87. • MMF was not significantly superior to AZA in preventing renal fl ares in patients with
proliferative LN, with a renal relapse rate of 19 and 25% in the MMF and AZA group
• Drug-related toxicities were similar except for cytopenia, which were more common in
the aza group but were readily controlled
• Relatively small size study
• Mainly caucasian patients
• Open label and not a double-blinded trial
• Serum measures of the active metabolites of AZA or of MMF were not routinely
performed
• No external funding

88. V
V
V

95. • most prevalent recent change in this subset of patients has been a
shift in treatment away from high-dose cyclophosphamide, raising the
question of whether these new treatment approaches result in
different long-term outcomes.

96. Multi-Target Therapy

100. • Current induction therapy regimens for lupus nephritis (LN) have low
rates of complete remission. A drug regimen that targets different
components of the immune response might be more effective and
have fewer adverse effects than a single drug regimen.
• Patients with LN were randomly assigned to a multitarget regimen
consisting of tacrolimus and mycophenolate mofetil or intravenous
cyclophosphamide for 24 weeks. Both groups also received
corticosteroid therapy.

107. • Multitarget regimen as a superior induction regimen for LN compared
with IVCY.
• More multitarget recipients than IVCY recipients dropped out of the
study because of adverse events
• 6 months may be too short to differentiate between study treatments
because the disease may continue to improve

114. Outcomes
• The primary endpoint for the AURA-LV trial was the
proportion of CRR at 24 weeks.
• CRR was defined as-
➢ A decrease in UPCR to ≤0.5 mg/mg in 2 consecutive
specimens + eGFR >60 ml/min /1.73 m2

115. Treatment failures
• Subjects who either died,
• Received a rescue medication for SLE during the study, or
• Given >10 mg prednisone for >3 consecutive days or
• For > 7 total days from weeks 16 to 26.

117. • Interestingly, patients with a Class V component did not show a benefit with VCS
treatment.
• Durability of remission was generally good, with all low-dose VCS subjects who
were in remission at 24 weeks remaining so at 48 weeks.

118. Safety/adverse events
• The majority of AEs and serious AEs occurred within the first 24 weeks of the
study.
• The incidence of AEs and treatment-related AEs increased with high-dose VCS
subjects
• But serious AEs were observed in more low-dose VCS subjects (28.1%)
compared with the high-dose VCS (25.0%) and placebo (15.9%) groups.

119. B-Cell targeting Therapy

120. LUNAR TRIAL

121. • Aimed to show adding Rituximab on MMF + steroids will improve the
remission rates

122. BELONG TRIAL

123. ACCESS TRIAL

128. THANK YOU