Extremely high titer of anti-human chimeric antibody following re-treatment with rituximab in a patient with active systemic lupus erythematosus.

and Femodene [1] standard strength combined oral contraceptive (gestodene 75 g þ ethinylestradiol 30 g) (combined oral contraceptive). Her arthritis improved with the methotrexate but she developed intermenstrual bleeding of bright red blood for 3 h after every methotrexate dose. She stopped the methotrexate for 2 weeks and bled again after rechallenge. Her normal withdrawal periods became heavy whilst taking methotrexate and were associated with right iliac fossa pain. She stopped taking methotrexate after 3 months and her intermenstrual bleeding also stopped. Menstrual irregularities have been reported in association with methotrexate [2–4] but they are uncommon and not often considered in routine clinical practice. To our knowledge, this is the first case report on methotrexate associated with breakthrough uterine bleeding in a patient taking the combined contraceptive pill. As effective contraception is vital to the management of young female patients taking methotrexate [2–4], we feel this case warrants further discussion. Methotrexate may interact with the oestrogen and progesterone components of the combined oral contraceptive pill at a number of sites. Methotrexate is extensively protein-bound [2] and is renally excreted unchanged, with a half-life of approximately 7 h in low-dose treatment [5]. Circulating oestrogens and progestogens are largely protein-bound [6, 8]. In addition, oestrogen causes an increase in proteins, particularly globulins, that bind hydrocorti-sone, thyroxine and iron. As a result the total plasma concentration of bound substances is increased, though the concentration of free and active substance remains normal [6]. Since oestrogens are partially metabolized by cytochrome P450 3A4 (CYP3A4), inducers or inhibitors of CYP3A4 may affect oestrogen metabolism [8]. Well-known CYP3A4 inducers include St John's wort preparations, phenobarbitone, carbam-azepine and rifampicin. These may reduce the plasma concentration of oestrogens, resulting in a decrease in therapeutic affect and a change in the uterine bleeding profile. CYP3A4 inhibitors include erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice and they may increase oestrogen plasma concentrations and its side effects [7, 8]. There is no evidence that methotrexate causes (i) enzyme induction or (ii) impairment of the efficacy of or (iii) interference with the metabolism of oral contraceptive steroids. In our patient, it is difficult to postulate the cause of breakthrough bleeding. The timing in relation to her methotrexate suggests a rapid effect, either a direct effect of methotrexate on the uterus or possibly by displacement of oestrogen or proges-terone from protein binding sites. The fact that this patient was 4 months post-partum may …