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

Mehra, Sonal; Usdadiya, Jignesh; Jain, Vikramraj K; Misra, Durga Prasanna; Negi, Vir Singh

doi:10.1007/s00296-018-3995-3

Cited by 26 publications

(22 citation statements)

References 32 publications

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“…80 Importantly, the low-dose CY regimen (ELNT) was tested also in non-exclusively Caucasian populations, with similar results. 10 13 14 65 Regarding the use of CNI or ‘multitarget’ therapy (combination of CNI with MMF), it is important to point out that the majority of studies (both randomised and observational) testing this class of drugs have used TAC, hence the respective clarification in the manuscript of the updated EULAR/ERA-EDTA recommendations. 55 The scepticism raised by the fact that initial studies using the multitarget regimen were performed in Asian populations has been partly addressed by the multi-ethnic phase II study of voclosporin/MMF combination 20 ; the results of the phase III study, which recently announced positive results, are expected to provide more data regarding a possible future universal recommendation of multitarget regimens for LN.…”

Section: Discussionmentioning

confidence: 99%

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations

et al. 2020

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ObjectivesTo analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations.MethodsAccording to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012.ResultsWe identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (<500–700 mg/day) at 12 months (LoE 2a-2b). High-quality evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) as initial treatment of active class III/IV LN (LoE 1a). Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a). There is low-quality level evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease, all methods of kidney replacement treatment can be used, with transplantation having the most favourable outcomes (LoE 2b).ConclusionsThere is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression.

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Section: Discussionmentioning

confidence: 99%

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations

et al. 2020

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“…34 The 10-year Euro-Lupus Nephritis Trial data showed equal efficacy of low-dose versus high-dose CY, 24 and the low-dose regimen has been used in non-European populations. [35][36][37][38] Consequently, both MMF/MPA and low-dose CY are recommended as firstline options for initial (induction) treatment. The recommended target dose of MMF is now changed to 2-3 g/day (MPA 1.44-2.16 g/day), based on evidence that therapeutic drug dosage may range between 1 and 3 g/day.…”

Section: Initial Treatmentmentioning

confidence: 99%

2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis

et al. 2020

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ObjectiveTo update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN).MethodsFollowing the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements.ResultsThe changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5–0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2–3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3–0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease.ConclusionsWe have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

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“…There is a paucity of data on the ovarian toxicity of modified NIH regimens of CYC. A 6-month randomised controlled trial from the Indian subcontinent compared modified NIH and Euro-Lupus regimens in lupus nephritis and found the rates of sustained amenorrhoea to be 5% and 2% in the two arms, respectively [ 14 ]. In our study, the rate of sustained (> 12 months) amenorrhoea with CYC was 4% but no premature ovarian failure was observed at a mean cumulative dose of 4.6 ± 1.8 g.…”

Section: Discussionmentioning

confidence: 99%

“…With the use of CYC through intravenous route at lower doses for a shorter duration, and development of better markers of ovarian reserve, the incidence of ovarian toxicity with CYC needs reassessment. There is limited data on gonadal toxicity with CYC use in the current era where modified National Institute of Health (NIH) regimens (employing azathioprine or MMF instead of quarterly CYC pulses for maintenance after the initial 6 monthly pulses) or low-dose Euro-Lupus regimen are used [ 13 , 14 ]. Additionally, the possible negative impact of underlying SLE on ovarian function is an important confounding factor that needs to be taken into consideration [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Ovarian dysfunction with moderate-dose intravenous cyclophosphamide (modified NIH regimen) and mycophenolate mofetil in young adults with severe lupus: a prospective cohort study

et al. 2020

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Background Ovarian toxicity is a dreaded complication of cyclophosphamide (CYC). With the use of lower cumulative doses of intravenous CYC (modified NIH regimens) and availability of better markers of ovarian toxicity, the incidence of ovarian dysfunction needs reassessment. Lupus disease activity, by itself, is also believed to affect ovarian function negatively. Methods This single-centre prospective cohort study recruited 50 female patients of severe lupus aged 18–40 years. Twenty-five patients each received induction with either monthly intravenous CYC (0.5–0.75 g/m 2 ) for 6–9 months or daily oral mycophenolate mofetil (MMF). Details of menstrual irregularities; serum levels of FSH, LH, estradiol, AMH, and inhibin B; and sonographic assessment of ovarian volume and antral follicular count were done at baseline and 6 months after treatment. Amenorrhoeic patients were re-evaluated at 1 year. Results Mean (SD) age of subjects in the CYC and MMF groups was 31.4 (6.3) and 28.4 (4.4) years, respectively. Mean (SD) SLEDAI at the initiation of therapy was 7.2 (2.5) in the CYC group and 5.8 (3.4) in the MMF group. The mean cumulative dose of CYC used was 4.6 (1.8) g. Three patients in the CYC group (versus none in MMF) had amenorrhoea at 6 months—two of these regained menses within 6 months, while only one (4%) developed sustained amenorrhoea (lasting more than 12 months) at 41 years of age, likely menopause. Serum FSH levels increased ( p = 0.03), while AMH ( p = 0.002) and inhibin B ( p < 0.001) levels decreased significantly with 6 months of CYC therapy. Ovarian volume also reduced significantly ( p = 0.005) with 6 months of CYC therapy, while antral follicular count reduced numerically ( p = 0.32). Levels of AMH, inhibin-B, estradiol, ovarian volume, and antral follicular count after 6 months therapy were significantly lesser in the CYC group compared to the MMF group, despite being similar before the start of therapy. Conclusions Ovarian dysfunction with monthly intravenous CYC (modified NIH regimen) was predominantly subclinical, with a negative effect on ovarian reserve. No premature ovarian failure was noted at 1 year. No ovarian dysfunction occurred in the MMF group, despite having patients with severe background lupus. Use of intravenous CYC for induction may thus not be restricted in young lupus females with incomplete families for fear of gonadotoxicity, especially in life- or organ-threatening situations, where the benefits outweigh this subclinical risk.

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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

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

Cited by 26 publications

References 32 publications

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations

2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis

Ovarian dysfunction with moderate-dose intravenous cyclophosphamide (modified NIH regimen) and mycophenolate mofetil in young adults with severe lupus: a prospective cohort study

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