Cyclophosphamide (CyP) is perhaps the most venerable of immunosuppressants used to treat lupus nephritis (LN). Its use was established in the so-called NIH regimen in the 1980s and high-dose monthly injections for at least 6 months along with high-dose steroids became standard of care, globally. The issue became, not that it isn’t an effective treatment, but the ‘cost’ to the patients was too high.

It was recognised that the main issues were using a drug in doses associated with premature ovarian failure and teratogenicity to treat a disease that mostly affects women of childbearing age. There was also the very real risk of neutropenic sepsis associated with the high doses and infection has always been a major cause of death in patients with LN. Most clinicians were therefore relieved when an alternative immunosuppressant, mycophenolate mofetil (MMF) – albeit one which is teratogenic but has no impact on fertility-was shown to be effective in treating LN. Although the original study by Chan et al was small and only in Chinese population,¹ many clinicians rapidly switched to using MMF instead of CyP.

The next challenge came from a paper by Contreras et al² showing that prolonged courses were less effective than switching to maintenance with mycophenolate (MMF) or azathioprine. However, CyP has been rehabilitated by the Eurolupus trial (ELNT) – a small, underpowered study but which has shown benefit in long term outcomes and in multiple ethnic groups.³ The ELNT regimen, whilst still steroid heavy, uses very low doses of CyP and has been shown, as a one-off course, unlikely to reduce fertility and have low rates of infectious complications. Most recent trials, however, have not included CyP as standard of care (SOC) – the exception being the BLISS-LN study,⁴ where 1/3 of the patients received CyP as SOC induction therapy and there was no apparent benefit when belimumab added, despite the overall positive outcome of the trial.

Does this mean CyP has no role in the modern management of LN? Almost certainly not. From a very practical perspective, it is a very cheap drug and therefore highly suitable to use low-dose regimens in resource poor countries. Importantly, it is effective, it has the advantage of being given intravenously, which overcomes issues with adherence and is still favoured by many for more severe disease.

References

1. Chan TM, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000 Oct 19;343(16):1156–1162.

2. Contreras G, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004 Mar 4;350(10):971–980.

3. Houssiau FA, et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis 2010 Jan;69(1):61–64.

4. Furie R, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med 2020 Sep 17;383(12):1117–1128.

5. Rathi M, et al. Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis. Kidney Int 2016 Jan;89(1):235–242.

Learning Objectives

• Describe the evidence base for current cyclophosphamide-based regimens

• Discuss the advantages and disadvantages of using cyclophosphamide-based regimens

• Explain how cyclophosphamide might be used in combination with newer therapies