DENVER – Chronic methotrexate therapy may harm the future fertility of girls and young women being treated for rheumatoid arthritis or juvenile idiopathic arthritis, based on preliminary findings from an observational study.
“The biggest issue is that rheumatologists have become much more aggressive in their therapy for these young girls with juvenile idiopathic arthritis in the last 5-10 years. As early as 1 year of age, these girls are placed on methotrexate weekly for years and years and years,” Dr. Amber R. Cooper said at the meeting.
The study findings suggest a need to alter how physicians counsel patients and their families on this score in light of emerging evidence that long-term cytotoxic therapy with methotrexate may threaten the oocyte pool, she said.
Thus far, 168 females aged 4-49 years have been recruited for the ongoing study from pediatric and adult rheumatology clinics. Every 3-4 months they undergo measurement of serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), inhibin B, and other indicators of ovarian reserve. In addition, transabdominal ultrasound is performed annually by sonographers blinded as to the patients' treatment regimen in order to assess ovarian volume and antral follicle count, explained Dr. Cooper of Washington University in St. Louis.
Among the study participants, 55% have juvenile idiopathic arthritis, formerly called juvenile rheumatoid arthritis, and 43% have rheumatoid arthritis. The rest have psoriatic arthritis or undifferentiated spondyloarthropathies. The subjects' mean age at diagnosis was 18.6 years, while at enrollment in the fertility study they averaged 25.4 years of age. Forty-three percent were on methotrexate or the related drug leflunomide, 12% were on a tumor necrosis factor (TNF) antagonist, 30% were on both, and 15% were on other agents, mainly corticosteroids, hydroxychloroquine, or sulfasalazine.
The primary study end point was change over time in AMH level, widely considered to be the best indicator of ovarian reserve. At enrollment, the median AMH level was 2.25 ng/mL in patients on methotrexate or leflunomide, 1.65 ng/mL in those on a TNF antagonist, 2.42 ng/mL in patients on both, and 2.54 ng/mL in patients on other agents.
A multifactorial analysis showed that patients on methotrexate/leflunomide were the only ones who showed a progressive decline in AMH with increasing time on therapy. In addition, patients on methotrexate or methotrexate plus an anti-TNF biologic had significantly lower antral follicle counts than did other patients.
A key question is whether patients on chronic therapy take an irreversible hit to the primordial oocyte pool, or if their oocyte count will eventually recover after they come off methotrexate, Dr. Cooper said.
Dr. Cooper's study is funded by a grant from the Society for Reproductive Endocrinology and Infertility. She had no other relevant financial disclosures.
'As early as 1 year of age, these girls are placed on methotrexate weekly for years and years and years.'
Source DR. COOPER