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MTX Suppl. 61 Methotrexate: from its introduction to non-oncologic therapeutics to anti-TNF-α T.G. Benedek Division of Rheumatology, University of ABSTRACT therapeutics. Although MTX has come Pittsburgh School of Medicine, Pittsburgh, The history of the rheumatologic use of to be used in the treatment of many of PA, USA. methotrexate until the 1990s will be re- these diseases, this review is limited to Please address correspondence to: viewed, beginning with its pharmacol- rheumatoid arthritis (RA): How did it Prof. Thomas G. Benedek, MD, MS, ogy, with the focus on rheumatoid ar- become favoured over other agents in Division of Rheumatology, thritis (RA). The insufficient availability the treatment of progressive RA, how University of Pittsburgh School of Medicine, 1130 Wightman Street, of cortisone in the 1950s as well as the has the risk-benefit ratio of MTX been Pittsburgh, PA, USA. early recognition of its potential toxic- evaluated, and how did the enthusiasm E-mail: [email protected] ity stimulated searches for alternative for the use of MTX as the principal Received and accepted on September 1, anti-inflammatory drugs. Two related drug in the treatment of progressive RA 2010. derivatives of folic acid, aminopterin wane in favour of its combination with Clin Exp Rheumatol 2010; 28 (Suppl. 61): and amethopterin (MTX,) were found other categories of powerful immuno- S3-S8. to give rapid symptomatic relief in cas- suppressive drugs. © Copyright CLINICAL AND es of psoriasis vulgaris and psoriatic EXPERIMENTAL RHEUMATOLOGY 2010. arthritis. For several years MTX was Pharmacology of methotrexate used primarily to treat psoriasis, and Pteroyl-glutamic acid was isolated in Key words: Methotrexate, psoriasis, the dermatologic treatment protocols 1941 from leafy vegetables and named rheumatoid arthritis, hepatotoxicity. came to be used by rheumatologists. folic (foliage) acid. It has different co- Giving MTX weekly rather than daily enzymatic functions depending on the was found to diminish the risk of toxic position on the pteroyl ring at which a effects. MTX became favoured over particular radical is attached. The phar- cyclophosphamide because of its lack maceutical pteroyl-glutamic acid is not of carcinogenicity, and although aza- an active co-enzyme. To become meta- thioprine lacked the hepatotoxicity of bolically active, folic acid is reduced to MTX, its anti-rheumatic effects were tetra-hydro folic acid by dihydrofolate considered to be somewhat weaker. Al- reductase. Methotrexate (MTX) differs though trials of MTX for the treatment structurally from folic acid at two sites: of severe RA began in the 1960s, the an amino is replaced by a hydroxyl at first placebo-controlled study of MTX one site and a methyl group replaces an in RA was reported in 1985 and a com- amino at another. Its effects result from parison with Myochrysine in 1987. inhibition of the reductase. At higher MTX has replaced gold compounds oncologic dosages, MTX also inhibits because it has been found to be more thymidylate synthetase, and this indi- rapidly effective and better tolerated. rectly interferes with DNA synthesis. The mechanisms of its anti-rheumatic MTX is oxidised to 7-hydroxy-MTX effects remain incompletely explained, by aldehyde reductase and primarily as are explanations of instances of its has renal excretion. Thus, the action of failure. Its recent use in combination MTX is prolonged by renal failure (1). with anti-TNFα agents appears to be About 40% of tritium-labelled MTX is another therapeutic advance. excreted unchanged in the urine within 48 hours after intravenous administra- Introduction tion. Thereafter, one to two percent per Methotrexate® (Lederle, MTX) entered day is excreted for several weeks, large- clinical medicine as an innovative ly as cleavage products of MTX (2). A anti-neoplastic drug in 1948. This ar- fluorimetric method to determine MTX ticle traces its adaptation first to non- concentrations in blood was published neoplastic proliferative dermatoses, in 1958 (3). Two hours after administra- mainly psoriasis, and to its competi- tion, the MTX concentration in blood is Competing interests: none declared. tive introduction into rheumatologic the same whether it has been taken oral- S-3 Methotrexate: a short history / T.G. Benedek ly or by intra-muscular injection and is slowly and have a substantial potential dermatologists) treated 32 psoriatic usually immeasurable after 24 hours.(4) toxicity had been standard therapy for patients with aminopterin, and sev- A more sensitive radio-immunoassay progressive rheumatoid arthritis (RA) eral subsequently with MTX (17). Re- became available in 1975 (5). since the 1930s. Thus, there were stim- sponse to both drugs was favourable It is likely that the early research on uli to search for potential alternative and similar. the mechanism of the MTX effect, fo- anti-inflammatory medications. The largest early (1963) comparative cused on epidermal cell metabolism in Jimenez Diaz et al. (1951, Madrid) trial included 91 psoriasis patients psoriasis, has little relevance to the ex- suspected that nitrogen mustard “might treated with aminopterin and 36 with planation of its anti-rheumatic effects well be useful” in the treatment of RA MTX. Aminopterin was more effec- (6). In addition to retarding the rate of based on the tenuous analogy that cor- tive, but elicited more frequent, mainly epidermal cell division, MTX inhib- ticotrophin, cortisone and nitrogen gastro-intestinal, signs of toxicity. No its granulocyte activity, depresses B- mustard all cause lymphopenia. It was hepatic function tests were reported lymphocytes, but not T-lymphocytes; administered in four 6mg doses to nine (18). it does not inhibit the synthesis or se- patients, of whom five “improved ex- Corticosteroid research was continuing cretion of the pro-inflammatory inter- traordinarily” (13). This admittedly simultaneously. Triamcinolone, orally leukin-1 (IL-1), although it may inhibit preliminary report stimulated a flurry of or topically, was shown in 1958 to be some parameters of IL-1 activity (7). interest. Whether the varied short-term superior to previous non-fluorinated Alarcón et al. (1990, Birmingham, AL) results should be attributed to different steroids in affecting psoriatic lesions reported the interesting observation that treatment courses is unclear. By far the (19). However, also in 1958, the pos- MTX reduces the concentration of both largest experience with nitrogen mus- sibility of using an anti-metabolite was IgA and IgM rheumatoid factor, while tard therapy of RA was that of Arthur revived at the National Institutes of clinical improvement correlates only L. Scherbel at the Cleveland Clinic Health (NIH) with a clinical study of with reduction of IgM RF (8). The pre- (14). He employed it as IV solo therapy MTX in cases of psoriatic arthropathy cise mechanisms of its anti-rheumatic in 1951 for 17 patients, but then used and RA. Patients with psoriatic arthrop- effects remain uncertain. Intra-articular it in combination with ACTH in the athy had a more favourable response of injection of MTX is relatively inef- next five years. “In 88 per cent of 263 their arthritis than those with RA (20). fective compared to corticosteroids in patients there was rapid and complete This investigation then was modified acutely counteracting synovitis (9, 10). or almost complete relief of joint mani- into a double-blind study of 21 cases festations, toxicity and fever.” Despite of psoriatic arthropathy (20 rheumatoid Circumstances of the introduction Scherbel’s enthusiasm, this therapeutic factors negative). Cutaneous and artic- of methotrexate in non-oncologic approach had vanished by 1960. ular improvement persisted throughout therapeutics However, in the hope of more durable treatment, regardless of its duration, In December 1950, Philip S. Hench effects, derivatives of nitrogen mustard but relapses occurred within weeks of (1894-1965) in his Nobel Prize lecture came to be employed in connective tis- discontinuance (21). The 1964 report of stated referring to corticosteroids: “But sue disease therapy. Even before the in- this investigation appears to have been how these hormones accomplish, for troduction of these “alkylating agents” particularly influential in stimulating in- example, their anti-rheumatic effect is into oncologic therapy, aminopterin, terest in MTX for the treatment of pso- still quite unknown…. Current opinion an anti-metabolic analogue of the vi- riatic arthropathy, and equivocally of is that the hormones act at the tissue, tamin, folic acid, began in 1948 to be RA. However, interest in MTX therapy or cell, level. But this tentative conclu- used experimentally in the treatment of developed much more rapidly among sion must be the subject of much fur- childhood leukaemia. One of its effects dermatologists than rheumatologists, ther study” (11). A Swiss symposium is to interfere with the proliferation of perhaps because its dermatologic ac- “On the Influence of the Hypophysis connective tissue. Therein, although by tion could be better defined. and the Adrenal Cortex on Biological a different mechanism, it resembles the In the 1960s MTX was administered Reactions” in 1951 contained 31 pa- action of corticosteroid drugs. Based to treat psoriasis either with 2.5mg or pers, of which only one pertained to on this consideration, Richard Gubner, 5.0mg per day, usually for 5 consecu- “rheumatism,” and this not to cortisone a New York cardiologist, in 1951 ad- tive days per week, or a weekly oral (12). Thus the immediate demand for ministered aminopterin to several pa- or I.M. dose of 25mg. or 50mg (22). synthetic cortisone to treat a plethora tients with psoriasis, psoriatic arthritis, In 1971 Weinstein (Miami, FL) intro- of conditions that had in common only and RA. Improvement in both cutane- duced a weekly oral schedule of three inflammation and/or pain had no basis ous and articular symptoms occurred, doses in 24 hours once per week, begin- in patho-physiologic understanding. usually by the second week of therapy, ning with 2.5mg per dose and gradually In the early 1950s the supply of corti- although complicated by various signs increasing to 5mg per dose (23).
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