E D I T O R I A L Open Access
Methotrexate: who would have predicted
its importance in rheumatoid arthritis?
Michael E. Weinblatt
Forty years ago, the US Food and Drug Administration
approved low dose methotrexate (MTX) for the treat-
ment of active rheumatoid arthritis (RA). MTX was pre-
viously approved for a variety of malignancies at high
doses and at low doses for psoriasis. Little did one an-
ticipate in 1988 that MTX would change the course of
RA. I had the pleasure of being directly involved in the
development of MTX in RA and it has been extremely
gratifying to see the impact of MTX in RA.
For rheumatologists who have recently completed
training, one could not imagine the clinical picture 40
years ago in which many of our patients were disabled,
unable to work, in wheel chairs, and had significant pain
and deformity. That was the landscape of RA in the
1980s. During my fellowship training (1978 to 1980) the
pyramid approach to treatment was used, which in-
cluded high dose aspirin, the newer non-steroidal anti-
inflammatory drug such as ibuprofen, corticosteroids,
and slow-acting anti-rheumatic therapy, i.e., gold salts,
hydroxychloroquine, d-penicillamine, and immuno-
suppressive drugs, including azathioprine and cyclophos-
phamide. Treatment regimens also included joint
injections, short-term hospitalization, physical therapy,
and joint replacement surgery. The therapeutic land-
scape was bleak with failures using total nodal radiation
and plasmapheresis. New drug development for RA was
essentially non-existent with the only drug under devel-
opment being oral gold (auranofin), which proved to
have limited efficacy and gastrointestinal intolerance.
MTX was not specifically developed for RA.
Aminopterin, the parent compound of MTX, was the
first successful anti-metabolite used in the treatment
of childhood leukemia. In 1951, Gubner and col-
leagues reported a positive open study using aminop-
terininRAandpsoriasis. The dermatology
community began using low dose weekly MTX for
the treatment of psoriasis but hepatotoxicity with
long-term treatment was observed. The rheumatology
community was not excited about using cancer drugs
for such a “benign” diseaselikeRA.Therewasalso
greater enthusiasm for using corticosteroids for RA—
the Nobel Prize was awarded in 1950 to Hench and
colleagues for their pioneering work in this area.
Great credit for MTX development in RA needs to go
to a few pioneering community-based rheumatologists, in-
cluding Rex Hoffmeister in Spokane, Washington and
Robert Willkens in Seattle, who initially reported their
personal experience with low dose MTX for RA [2, 3].
Despite their initial observations, however, definitive ran-
domized controlled trials were not performed at that time.
Upon completion of my fellowship in 1980, I became
interested in studying MTX as a treatment for RA. I was
influenced by the reports from Hoffmeister and Willkens
and my own experience with MTX in psoriatic arthritis.
In 1982, I submitted a 35-patient double-blind crossover
study to Lederle Laboratories, the manufacturer of
MTX, for support of this study. Initially they responded
that “we are not interested in supporting studies of
MTX in rheumatoid arthritis but would keep the proto-
col on file.” Approximately 6 months later I was called
by the clinical development team at Lederle to attend a
meeting in Pearl River, New York to discuss MTX in
RA. Attending the meeting were several other rheuma-
tologists who also had submitted protocols, including
Jim Williams and John Ward, Directors of the Coopera-
tive Systematic Studies of Rheumatic Disease program,
who proposed a randomized parallel control trial, and
Joel Kremer from Albany Medical College, who pro-
posed a long-term study to examine the effects of MTX
on the liver. In attendance at that meeting was Harriet
Kiltie, MD, the medical director at Lederle Laboratories.
She was enthusiastic about supporting research on MTX
even though it was now a generic drug. Until recently, I
was unaware that Dr. Kiltie had begun her research car-
eer at Lederle studying folic acid. The history of research
on folic acid and the development of aminopterin and
its subsequent use by Sidney Farber in childhood
leukemia is beyond the scope of this paper but is of
significant historical interest.
Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
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Weinblatt Arthritis Research & Therapy (2018) 20:103