Skip to main content
Log in

Comparing the efficacy of low-dose vs high-dose cyclophosphamide regimen as induction therapy in the treatment of proliferative lupus nephritis: a single center study

  • Clinical Trials
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Cyclophosphamide (CYC) has been the backbone immunosuppressive drug to achieve sustained remission in lupus nephritis (LN). The aim was to evaluate the efficacy and compare adverse effects of low and high dose intravenous CYC therapy in Indian patients with proliferative lupus nephritis. An open-label, parallel group, randomized controlled trial involving 75 patients with class III/IV LN was conducted after obtaining informed consent. The low dose group (n = 38) received 6 × 500 mg CYC fortnightly and high dose group (n = 37) received 6 × 750 mg/m2 CYC four-weekly followed by azathioprine. The primary outcome was complete/partial/no response at 52 weeks. The secondary outcomes were renal and non-renal flares and adverse events. Intention-to-treat analyses were performed. At 52 weeks, 27 (73%) in high dose group achieved complete/partial response (CR/PR) vs 19 (50%) in low dose (p = 0.04). CR was higher in the high dose vs low dose [24 (65%) vs 17 (44%)], although not statistically significant. Non-responders (NR) in the high dose group were also significantly lower 10 (27%) vs low dose 19 (50%) (p = 0.04). The change in the SLEDAI (Median, IQR) was also higher in the high dose 16 (7–20) in contrast to the low dose 10 (5.5–14) (p = 0.04). There was significant alopecia and CYC-induced leucopenia in high dose group. Renal relapses were significantly higher in the low dose group vs high dose [9 (24%) vs 1(3%), (p = 0.01)]. At 52 weeks, high dose CYC was more effective in inducing remission with decreased renal relapses in our population.

Trial Registration: The study was registered at http://www.clintrials.gov. NCT02645565.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

ACR:

American College of Rheumatology

ALMS:

The Aspreva Lupus Management Study

CBC:

Complete blood count

CYC:

Cyclophosphamide

CR:

Complete response

C3, C4:

Complement component 3 and 4

dsDNA:

Double-stranded deoxyribonucleic acid

eGFR:

Estimated glomerular filtration rate

ELISA:

Enzyme-linked immunosorbent assay

ELNT:

Euro Lupus Nephritis Trial

HPF:

High power field

IV:

Intravenous

ISN/RPS:

International Society of Nephrology/Renal Pathology Society

ITT:

Intention to treat

IQR:

Interquartile range

LN:

Lupus nephritis

LDL-C:

Low-density lipoprotein cholesterol

MDRD:

Modification of Diet in Renal Disease

MMF:

Mycophenolate mofetil

NR:

No response

NIH:

National Institutes of Health

PR:

Partial response

RBC:

Red Blood cell

SD:

Standard deviation

SLEDAI:

Systemic Lupus Erythematosus Disease Activity Index

WBC:

White blood cell

References

  1. Tunnicliffe DJ, Singh-Grewal D, Kim S, Craig JC, Tong A (2015) Diagnosis, monitoring, and treatment of systemic lupus erythematosus: a systematic review of clinical practice guidelines. Arthritis Care Res 67(10):1440–1452

    Article  Google Scholar 

  2. Chen Y, Sun J, Zou K, Yang Y, Liu G (2017) Treatment for lupus nephritis: an overview of systematic reviews and meta-analyses. Rheumatol Int 37(7):1089–1099

    Article  CAS  PubMed  Google Scholar 

  3. Palmer SC, Tunnicliffe DJ, Singh-Grewal D, Mavridis D, Tonelli M, Johnson DW et al (2017) Induction and maintenance immunosuppression treatment of proliferative lupus nephritis: a network meta-analysis of randomized trials. Am J Kidney Dis 70(3):324–336

    Article  PubMed  Google Scholar 

  4. Houssiau FA (2005). Cyclophosphamide in Lupus Nephritis. Lupus 14(1):53–58

    Article  CAS  PubMed  Google Scholar 

  5. Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG et al (2010) The 10-year follow-up data of the Euro-lupus nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis 69(161–64

    Article  CAS  PubMed  Google Scholar 

  6. Gourley MF, Austin HA 3rd, Scott D, Yarboro CH, Vaughan EM, Muir J et al (1996) Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 125(7):549–557

    Article  CAS  PubMed  Google Scholar 

  7. Boumpas DT, Austin HA 3rd, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH et al (1992) Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 340(8822):741–745

    Article  CAS  PubMed  Google Scholar 

  8. Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG et al (2002) Immunosuppressive therapy in LUPUS NEPHRITIS: the Euro-lupus nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 46(8):2121–2131

    Article  CAS  PubMed  Google Scholar 

  9. Contreras G, Lenz O, Pardo V, Borja E, Cely C, Iqbal K et al (2006) Outcomes in African Americans and Hispanics with lupus nephritis. Kidney Int 69(10):1846–1851

    Article  CAS  PubMed  Google Scholar 

  10. Calvo-Alen J, Reveille JD, Rodriguez-Valverde V, McGwin G Jr, Baethge BA, Friedman AW et al (2003) Clinical, immunogenetic and outcome features of Hispanic systemic lupus erythematosus patients of different ethnic ancestry. Lupus 12(5):377–385

    Article  CAS  PubMed  Google Scholar 

  11. Alarcon GS, Bastian HM, Beasley TM, Roseman JM, Tan FK, Fessler BJ et al (2006) Systemic lupus erythematosus in a multi-ethnic cohort (LUMINA) XXXII: [corrected] contributions of admixture and socioeconomic status to renal involvement. Lupus 15(1):26–31

    Article  CAS  PubMed  Google Scholar 

  12. Mok CC, Ying KY, Tang S, Leung CY, Lee KW, Ng WL et al (2004) Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis. Arthritis Rheum 50(8):2559–2568

    Article  PubMed  Google Scholar 

  13. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40(9):1725

    Article  CAS  PubMed  Google Scholar 

  14. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB et al (2004) The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 15(2):241–250

    Article  PubMed  Google Scholar 

  15. Morel-Maroger L, Mery JP, Droz D, Godin M, Verroust P, Kourilsky O et al (1976) The course of lupus nephritis: contribution of serial renal biopsies. Adv Nephrol Necker Hosp 6:79–118

    CAS  PubMed  Google Scholar 

  16. Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH et al (2012) Joint European league against rheumatism and European Renal Association- European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 71(11):1771–1782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. The American College of (2006) Rheumatology response criteria for proliferative and membranous renal disease in systemic lupus erythematosus clinical trials. Arthritis Rheum. 54(2):421–432

    Article  Google Scholar 

  18. Chan TM, Tse KC, Tang CS, Mok MY, Li FK (2005) Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 16(4):1076–1084

    Article  CAS  PubMed  Google Scholar 

  19. Sabry A, Abo-Zenah H, Medhat T, Sheashaa H, Mahmoud K, El-Huseini A (2009) A comparative study of two intensified pulse cyclophosphamide remission-inducing regimens for diffuse proliferative lupus nephritis: an Egyptian experience. Int Urol Nephrol 41(1):153–161

    Article  CAS  PubMed  Google Scholar 

  20. El-Shafey EM, Abdou SH, Shareef MM (2010) Is mycophenolate mofetil superior to pulse intravenous cyclophosphamide for induction therapy of proliferative lupus nephritis in Egyptian patients? Clin Exp Nephrol 14(3):214–221

    Article  CAS  PubMed  Google Scholar 

  21. Chen W, Tang X, Liu Q, Chen W, Fu P, Liu F et al (2011) Short-term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: a multicenter randomized clinical trial. Am J Kidney Dis  57(2):235–244

    Article  CAS  PubMed  Google Scholar 

  22. Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D et al (2009) Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 20(5):1103–1112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rathi M, Goyal A, Jaryal A, Sharma A, Gupta PK, Ramachandran R et al (2015) Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritiS. Kidney Int 89(1):235–242

    Article  Google Scholar 

  24. Sigdel MR, Kafle MP, Shah DS (2016) Outcome of low dose cyclophosphamide for induction phase treatment of lupus nephritis, a single center study. BMC Nephrol 17(1):145

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT et al (2005) Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 353(21):2219–2228

    Article  CAS  PubMed  Google Scholar 

  26. Ong LM, Hooi LS, Lim TO, Goh BL, Ahmad G, Ghazalli R et al (2005) Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology (Carlton) 10(5):504–510

    Article  CAS  Google Scholar 

  27. Cupps TR, Edgar LC, Fauci AS (1982) Suppression of human B lymphocyte function by cyclophosphamide. J Immunol 128(6):2453–2457

    CAS  PubMed  Google Scholar 

  28. Hurd ER, Giuliano VJ (1975) The effect of cyclophosphamide on B and T lymphocytes in patients with connective tissue diseases. Arthritis Rheum 18(1):67–75

    Article  CAS  PubMed  Google Scholar 

  29. McCune WJ, Golbus J, Zeldes W, Bohlke P, Dunne R, Fox DA (1988) Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. N Engl J Med 318(22):1423–1431

    Article  CAS  PubMed  Google Scholar 

  30. Martin-Suarez I, D’Cruz D, Mansoor M, Fernandes AP, Khamashta MA, Hughes GR (1997) Immunosuppressive treatment in severe connective tissue diseases: effects of low dose intravenous cyclophosphamide. Ann Rheum Dis 56(8):481–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG et al (2004) Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term follow-up of patients in the Euro-lupus nephritis Trial. Arthritis Rheum 50(12):3934–3940

    Article  PubMed  Google Scholar 

  32. Rathi M, Gupta KL, Joshi K, Gupta PK, Sharma A, Kohli HS et al (2015) Histopathological indicators of disease outcome in class IV lupus nephritis: a revisit of various indices. Rheumatol Int 35(9):1511–1517

    Article  PubMed  Google Scholar 

  33. Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O’Nan P et al (2004) Sequential therapies for proliferative lupus nephritis. N Engl J Med 350(10):971–980

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Indian rheumatology association for providing us funding for this project on lupus nephritis.

Funding

This study was funded by the Indian rheumatology association (Research Grant number 2013)

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Vir Singh Negi.

Ethics declarations

Conflict of interest

Sonal Mehra declares that she has no conflict of interest. Jignesh Usdadiya declares that he has no conflict of interest. Vikramraj Jain declares that he has no conflict of interest. Durga Prasanna Misra declares that he has no conflict of interest. Vir Singh Negi declares that he has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Jawaharlal Institute of post graduate medical education and research committee Number : JIP/IEC/SC/2013/5/435 dated 4.3.2014 and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards

Informed consent

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 184 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mehra, S., Usdadiya, J.B., Jain, V.K. et al. Comparing the efficacy of low-dose vs high-dose cyclophosphamide regimen as induction therapy in the treatment of proliferative lupus nephritis: a single center study. Rheumatol Int 38, 557–568 (2018). https://doi.org/10.1007/s00296-018-3995-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-018-3995-3

Keywords

Navigation