To Compare the Efficacy of Low Dose versus High Dose Cyclophosphamide Regimen as Induction Therapy in the Treatment of Proliferative Lupus

Nephritis

Sonal Mehra, Jignesh Usdadiya, Vikramraj Jain, Bharat Singh, Ankit Jain, Dantis Emmanuel, Chengappa KG ,Mithun CB,

Durga Prasanna Misra, Vir Singh NegiJIPMER, Pondicherry

Aims & Objectives

• To Compare the Efficacy of Low Dose versus High Dose CYC Regimen as Induction Therapy in the Treatment of Proliferative Lupus Nephritis

• To Compare the Adverse Drug Effects and Infection Risks in Low Dose and High Dose CYC Group

 

Clintrials.gov. NCT02645565

Inclusion criteria

• Diagnosis of SLE -ACR• Age >16 yrs• Proteinuria ≥ 500 mg in 24 hrs and/or urine R/M - active cellular

casts/sediments (>5 RBC/hpf & >5 WBC/hpf & cellular casts)• Biopsy-proven class III, IV LN

• Treated previously with IV or oral CYC, MMF, cyclosporine or steroids >15mg/day in last 3M

• Renal thrombotic microangiopathy, preexisting CKD, previous malignancy (except skin & CIN), DM, CAD

• Previously documented severe toxicity to immunosuppressive drugs• Acute & chronic infections• Pregnancy

Exclusion criteria

Primary End pointAssessment of Primary Renal Response at

12 & 24 weeks• Complete Response (CR): Urine protein creatinine ratio

<0.5 gm & Normal (GFR > 90 ml/min) or stable (<10% deterioration from baseline if GFR was previously abnormal) renal function & inactive urinary sediments

• Partial Response (PR): ≥50% reduction in proteinuria to subnephrotic levels, normal or stable GFR & inactive urinary sediments

• No Response (NR): Patients will be classified as non responders if criteria for CR or PR are not met and or if they experience severe flare

Consort Diagram

Baseline Demographic DataVariable Low dose

(n=36)High dose

(n=34)P value OR 95%CI

Female/ Male 32/4 31/3 0.53

Age of SLE onset, Yrs (Mean±SD) 28.86 ± 10.29 24.79±9.82 0.09£ -0.73-8.8

Age of onset of nephritis (Mean±SD) 31.08±10.18 26.38±10.26 0.06£ -0.17-9.57

Disease duration, Months (Median, IQR) 21 (4.50-36) 12 (3-24) 0.19€

Clinical features at the time of nephritis ₴

Fever /systemic 5 (14%) 11 (32%) 0.06 33 0.10-1.1

Mucocutaneous 20(56%) 18(53%) 0.58 40 0.11-1.4Arthritis 13(36%) 8(23%) 0.25 83 0.64-5.2Hemolytic Anemia 8(22%) 9(26%) 0.67 94 0.26-2.3Leucopenia 13(36%) 5(15%) 0.04₴ 3.2 1.02-10.5Thrombocytopenia 9(25%) 8(23%) 0.88 1.08 0.36-3.2

Pericardial Effusion 3(8%) 8(23%) 0.08 0.29 0.07-1.2

Pleural Effusion 6(17%) 5(14%) 0.82 1.16 0.31-4.2

Vasculitis 7(19%) 6(18%) 0.84 1.12 0.33-3.7

Myositis 3(8%) 2(6%) 1.00 1.45 0.22-9.2Myocarditis 0(0%) 2(6%) NA NA NA

Baseline Renal Parameters Before Induction Therapy

Variable Low dose (n=36) High dose (n=34) P value 95%CIRenal Biopsy Class IV no. (%) 21 (58%) 26 (76%) 0.10 0.82-6.5 Class III no. (%) 15 (42%) 8 (24%) 0.10 0.82-6.5Activity Score (Median IQR) 4 (4-8) 6.5(4-9) 0.11

Chronicity Score (Median IQR) 1(0-2) 1(0-2) 0.51

Crescents no. (%) 7 (19%) 13 (38%) 0.08 0.87-7.52 Serum creatinine mg/dL (Median IQR)

0.95 (0.80-1.30) 0.90 (0.78-1.72) 1.00

>1.3mg/dL 10(28%) 12(35%) 0.49eGFR *Mean+SD 68.44 ± 23.5 68.06 ± 32.8 0.95 -13.1-13.95 <30 ml/min 3(8%) 6(18%) 0.06 -12.1-0.44Active urinary sediments no.(%) 27(75%) 32(94%) 0.02 0.03-0.94

uPCR gm/day (Median IQR) 1.4 (0.47-2.1) 1.79 (0.80-2.2) 0.43 >3 no. (%) 7(19%) 6(18%) 0.23Renal SLEDAI (Mean+SD) 7.89 +3.76 11.1+3.38 <0.01¥ -4.99 to -1.57

Low Complements C3/C4 no. (%) 24(67%) 24(70%) 0.72 0.30-2.29

Anti-Dsdna >60 IU/ml no. (%) 27(75%) 28(82%) 0.45 0.48-4.96

SLEDAI Median IQR 16(12-20) 18(15-21) 0.07

Response At 12 Weeks Response Variables no.%

Low Dose (n=36)

High Dose (n=34)

P value₴ OR 95%CI

Complete Response(CR)

16(44%) 7 (21%) 0.04 3.08 1.06-8.90

Complete /Partial Response(CR/PR)

20(56%) 9 (26%) 0.01 3.47 1.26-9.49

No response(NR) 16 (44%) 25 (73%) 0.01 0.28 0.10-0.78

Response At 24 Weeks Response Parameters

Low Dose (n=36)

High Dose (n=34)

P value ₴ OR 95% CI

Complete Response(CR)

19 (53%) 18 (53%) 0.98 0.99 0.38-2.54

Complete/Partial Response(CR/PR)

21(58%) 21 (62%) 0.77 0.86 0.33-2.25

No response(NR) 15 (42%) 13 (38%) 0.77 1.15 0.44-3.00

Response At 12 And 24 Weeks

0

10

20

30

40

50

60

70

80

44

21

53 53

56

26

5862

44

73

4238

Primary Response outcome

CR CR/PR NR

Perc

enta

ge o

f Pa

tient

s

LOW DOSE HIGH DOSE LOW DOSE HIGH DOSE12 WEEKS 24 WEEKS

The Kinetics of Serum Albumin With Therapy

2.883.39 3.44

2.66

3.42 3.57

Baseline 12 weeks 24 weeks

Ser

um A

lbum

in

(Mea

n)

Kinetics of Serum AlbuminLow Dose High Dose

The Kinetics of Urine-PCR With Therapy

1.4

0.3 0.25

1.79

0.7

0.20

Baseline 12 weeks 24 weeks

Urin

e P

rote

in C

reat

inin

e R

atio

(M

edia

n)

Kinetics of Urine PCR Low Dose High Dose

The Kinetics of Glomerular Filtration Rate With Therapy

68.4

7273.2

68

7272.8

Baseline 12 weeks 24 weeks

eGFR

(M

ean)

Kinetics of eGFR Low Dose High Dose

Kinetics of SLEDAI with therapy

Baseline 12 weeks 24 weeks0

2

4

6

8

10

12

14

16

18

20

16

4

4

18

6

3

Kinetics of SLEDAILow Dose High Dose

SLE

DA

I (M

edia

n)

The Kinetics of Renal SLEDAI With Therapy

8

2 2

12

4

2

Baseline 12 weeks 24 weeks

Ren

al S

LED

AI

(Med

ian)

Kinetics of Renal SLEDAILow Dose High Dose

Kinetic of Low Complements (C3/C4) With Therapy

Baseline 12 weeks 24 weeks0%

10%

20%

30%

40%

50%

60%

70%

80%

67%

47%

33%

70%

38%

20%

Kinetics of Low C3/C4Low Dose High Dose

SLED

AI

(Med

ian)

Kinetics of Anti-dsDna Positivity With Therapy

Baseline 12 weeks 24 weeks0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

75%

58%

82%

50%

50%

Kinetics of anti-dsDNA positivity Low Dose High Dose

SLE

DA

I (M

edia

n)

Adverse Events During The Induction TherapyAdverse Events Low Dose (n=36) High Dose(n=34) No. of Deaths 2(5%) 2(6%)Benign Non Renal flare 6(17%) 3(9%)Severe Non Renal Flare* 1(3%) 0(0%)Atleast one adverse event 30(83%) 29(85%)Alopecia₴ 1(3%) 7(21%)Gastrointestinal (nausea/Vomiting/Diarrhea) 2(5%) 5(9%)InfectionsTotal No. Of Episodes 20(55%) 16(47%)Severe infections Sepsis 2(5%) 2(6%) Pneumonia 4(11%) 1(3%) Osteomyelitis 1(3%) 0(0%)URTI/ Nasopharyngitis 4(11%) 4(12%)Herpes Zoster 1(3%) 0(0%)Varicella Zoster 0(0%) 1(3%)Urinary tract Infection 1(3%) 0(0%)Strongyloides infection 0(0%) 2(6%)Oral candidiasis 4(11%) 2(6%)Skin tissue infections 3(8%)

3(8%)

Toxic anemia 2(5%) 6(18%)New onset CYC induced Leukopenia$ (<4000/cumm)

0(0%) 6(18%)

Thrombocytopenia 0(0%) 1(3%)Transaminitis 1(3%) 5(15%)Menstrual Irregularity 7(19%) 8(23%)

Conclusion• We observed an earlier response in the low dose therapy (12

weeks) arm in contrast to the high dose arm (24 weeks)• At the end of 24 weeks, both low dose and high dose CYC

were able to produce a similar rate of complete response without significantly increasing the infection risk

• High dose had lower non-renal flares• High dose monthly CYC therapy was more effective in

reducing the prevalence of hypocomplimentemia and anti-dsDNA percentage positivity

• May be beneficial for higher and sustained renal remission and decrease renal relapses and disease flares

Limitations

• Small sample size that may be inadequate to detect the difference

• Single center study with single ethnicity • Not blinded (more actual clinical scenario than blinded

controlled trials)• Short duration of follow up, sustainability of the response

over the long term can not be predicted• In spite of randomization, the baseline mean renal SLEDAI

was higher in the high dose group vs low dose group, may be one confounding factor that resulted in early renal response in the low dose group

Future Perspectives

• Further studies investigating the kinetics of response to two weekly CYC administration vs monthly

• We may suggest another RCT that compared two weekly administration of 500 mg each for six months compared to monthly dose of 750 mg/m2 of CYC for 6 months

Thank you