Methotrexate - an old trusted friend who deserves better Save
Methotrexate (MTX) has been used as the anchor drug for the treatment of RA and PsA for many years. It has been co-prescribed with biologics (e.g., TNFi) and JAKi in clinical trials and as well as in clinical practice. Despite our long experience with the use of MTX, one area that has remained uncertain is its effect on male fertility. Due to the concern about possible effects on the sperm and subsequent harm to the fetus, MTX would often be stopped in men before any attempts to try for a baby. This may cause a flare of the underlying condition, e.g., RA and PsA.
There is now increasing evidence that cessation of MTX in males prior to trying conceive is not necessary. Current guidance such as from the British Society of Rheumatology (BSR) on the use of DMARDs in pregnancy 1 has been recently updated. The 2023 version states that paternal exposure to MTX up to 25mg/week is compatible with pregnancy (evidence GRADE 1B, strong recommendation and moderate quality of evidence).
At EULAR 2023, the oral presentation by Perez-Garcia LF et al in Abst#OP0224 showed a mechanism which supports the new guidance. In this study, the aim was to show if MTX and
its bioactive forms, the MTX-polyglutamates (MTX-PGs) can be found in spermatozoa. The intracellular conversion of MTX to MTX-PGs is dependent on a process that is catalysed by the enzyme folylpolyglutamate synthetase (FPGS).
The set up of the study was that blood and semen samples were obtained from 10 adult men diagnosed with an immune-mediated disease (RA, SpA, psoriasis) after 13 weeks of exposure
to MTX (cases) and from 4 adult healthy men (controls). The results showed that MTX-PG1 was the predominant form of MTX-PGs detected in spermatozoa. In comparisons with other cell types, MTX-PGs accumulation in spermatozoa was markedly lower than in RBCs and PBMCs. The lack of MTX-PGs formation was associated with a lower FPGS catalytic activity in spermatozoa.
This study measured the concentration of MTX-PGs and concomitant FPGS activity in spermatozoa. Hardly any bioactive forms of MTX (MTX-PG) could be detected in spermatozoa. This is related to the fact that spermatozoa have very low FPGS activity and hence lack the capacity to form MTX-PGs. These results support the findings that treatment with MTX does not affect sperm quality parameters and provides further evidence that MTX can be safely used in men with a wish to have a baby. This is in keeping with the current BSR guidelines.
While MTX may not affect sperm quality, does it cause sexual dysfunction in male patients? A study by Natalucci F et al, Abst#POS0314, looked at the impact of MTX on sexual dysfunction in male patients with RA and PsA utilising the IIEF5 questionnaire. In this study, each patient underwent blood collection for a complete serum sexual hormone evaluation. IIEF5 questionnaire which consists of 5 items with a maximum score of 25 was administered to the patients. The study showed the total IIEF5 score was lower in patients treated with MTX compared to the control group. When broken down further, the total IIEF5 score of patients treated with MTX ≥ 5 years was statistically significantly lower when compared to those non
MTX- exposed patients and compared to those treated for < 5 years. A negative correlation between the total IIEF5 score and MTX exposure (years) was identified. Thus, long-term MTX exposure was associated with sexual dysfunction reported by a lower IIEF5 score in male patients adjusted for age.
These two studies highlight that paternal use of MTX in RA and PsA was compatible with trying for a baby.On the flip side, there is a small hint that MTX is associated with sexual dysfunction. This is a preliminary result and it needs to be confirmed in larger prospective studies.For now, we need to treat our old friend MTX better and not stop its use in male patients who are trying for a baby. This will help ensure good disease (RA, PsA etc) and reduce the risk of flares.
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