Title:Low-Dose Methotrexate (LD-MTX) in Rheumatology Practice - A Most Widely Misunderstood Drug
Volume: 12
Issue: 3
Author(s): Anand N. Malaviya
Affiliation:
Keywords:
Methotrexate, low-dose methotrexate, high-dose methotrexate, rheumatoid arthritis, India, developing countries,
rheumatology practice.
Abstract: Methotrexate (MTX) was synthesised as a folate antagonist for use in
treating childhood leukaemia in 1940s. Gubner and colleagues in 1953 used several
log-order lower doses of MTX that mimicked the anti-inflammatory properties of
cortisone. They used it successfully in treating rheumatoid arthritis (RA). Their work
was however overlooked because the Nobel Prize winning drug cortisone held sway
in those days. With increasing awareness of the adverse effects of cortisone, interest
was rekindled in discovering ‘steroid-sparing’ drugs. Hoffmeister and Willkens used
low-dose MTX (LD-MTX) in treating RA patients in 1960s with impressive results.
Pivotal trials in 1984-5 established the efficacy and safety of LD-MTX in treating
RA that gained FDA approval in 1988. LD-MTX at doses <25-30 mg weekly as
mini-pulses, is presently the standard-of-care for the treatment of RA. Its toxicities and adverse effects
are rarely if ever life-threatening. This is in contrast to the high-dose methotrexate (HD-MTX) for treating
malignancies at doses that are several log-orders higher and usually cause serious toxicities. While
LD-MTX acts mainly as an anti-inflammatory drug by increasing tissue adenosine levels besides other
mechanisms, HD-MTX has anti-proliferative cytotoxic action with different toxicity profile and adverse
effects. In practical terms LD-MTX and HD-MTX are 2 different therapeutic agents. However, in
developing countries like India the stigma attached to MTX as a cytotoxic ‘cancer drug’ still persists
and most non-rheumatologists fear its use in RA. This review aims to allay such anxiety attached to
LD-MTX so that they start using it in appropriate doses for treating RA.
