Abstract
Cyclophosphamide treatment of lupus nephritis is associated with ovarian toxicity. Four separate studies have previously demonstrated a lower risk of cyclophosphamide induced premature ovarian failure (POF) in carriers of the CYP2C19*2 null function allele. This hepatic enzyme bioactivates cyclophosphamide. CYP2B6 is also important in the activation of this prodrug however, genetic variants of CYP2B6 have not been associated with POF risk. The aim of this study was to determine the relationship between CYP2C19 and CYP2B6 loss of function variants and prevalence of ovarian toxicity following treatment with monthly pulses of intravenous cyclophosphamide in lupus nephritis patients. In 28 pre-menopausal female patients, there was a 25% incidence of POF. In contrast to previous studies of a similar size we could not detect a significant relationship between the risk of POF and genetic variants of CYP2C19, alone or in combination with variants of CYP2B6. However, 71.4% of the cases with POF had been treated with additional daily oral cyclophosphamide compared with only 4.7% of controls (P < 0.02; OR 14.29 (95% CI, 1.4-144.5). Thus the effect of daily oral cyclophosphamide administration in addition to pulsed intravenous monthly doses may have obscured any protective effect of CYP2C19 loss of function in this cohort.
Highlights
Lupus nephritis occurs commonly in patients with systemic lupus erythematosus and can lead to chronic kidney disease or end stage renal failure [1, 2]
Cyclophosphamide acts through its potent effects on lymphocytes [6], as it can selectively eradicate the autoimmune effectors whilst sparing the bone marrow stem cells due to the differential expression of the detoxifying enzyme ALDH [7,8]
Haemorrhagic cystitis rarely occurs following treatment of lupus nephritis with pulse cyclophosphamide (1000 mg/m2 i.v.) this may be due to the routine use of prophylactic MESNA [10]
Summary
Lupus nephritis occurs commonly in patients with systemic lupus erythematosus and can lead to chronic kidney disease or end stage renal failure [1, 2]. Clinical trials from the 1970s established cyclophosphamide as effective in reducing relapse and preserving renal function for patients with proliferative lupus nephritis [3,4,5]. Haematological toxicities only commonly occur after very high doses (>5000 mg/m2 i.v. 2-4 days) and are relatively rare at low doses. Acute haemorrhagic cystitis, is considered to be due to the accumulation of the breakdown product acrolein in the urine [9]. Haemorrhagic cystitis rarely occurs following treatment of lupus nephritis with pulse cyclophosphamide (1000 mg/m2 i.v.) this may be due to the routine use of prophylactic MESNA [10]
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