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). The sone still was insufficient to meet the of toxicity (15, 16). Therefore, this rationale for this was to obtain a maxi- demand, and its toxic effects were be- drug was not soon evaluated further as mum effect on the accelerated cell cy- ginning to be recognised. Several gold an anti-rheumatic agent. Seven years cle of psoriatic lesions and to diminish compounds that were recognised to act later Edmondson and Guy (Pittsburgh toxicity. It became standard practice.

S-4 Methotrexate: a short history / T.G. Benedek

Methotrexate for rheumatoid cyclophos-phamide therapy of RA af- months, although most improvement arthritis ter experience with 38 patients who occurred during the first three months. When immunosuppressive drugs be- had received the drug for at least half RA flared by three months after cessa- came more widely tried in non-neo- a year (29). It also enabled reduction of tion of this treatment. Subsequently, a plastic diseases they were conceived the dose of other ant-rheumatic drugs, 52-week study was carried out in Mon- of as primary therapy for psoriasis but clinical benefit in most cases was treal in which Leucovorin was added and other proliferative dermatoses, associated with a potentially dangerous double blind to 7.5mg weekly MTX but in rheumatology rather to permit leukopenia. The first controlled study p.o. Side effects were diminished in the lower, less toxic doses of corticoster- of cyclophosphamide, while it demon- Leucovorin cohort without diminished oids. Gross et al. (Zurich) gave this as strated symptomatic benefits, showed MTX efficacy (37). the reason to search for drugs that will that 90% of patients who received Tishler et al. (1988, Tel Aviv) had permit such dosages to be reduced or 150mg per day suffered toxic symp- shown that while Leucovorin success- eliminated (24). They were encouraged toms (30). In 1973 Hurd (Dallas, TX) fully counteracts symptoms of MTX to undertake a trial with RA patients by reviewed experimental data pertaining toxicity, it also blocks its anti-inflam- personal communications with Peter to the anti-inflammatory and immuno- matory action in RA (38). The disparity A. Miescher (then in Lausanne, Swit- suppressive properties of azathioprine, from Tishler’s finding was explained zerland), who had treated SLE patients cyclophosphamide and MTX, and con- in that Leucovorin should be taken in with 6-mercapto-purine, azathioprine, cluded that cyclophosphamide is the a smaller dosage and a day after the or MTX, first published in 1965 (25). most potent immuno-suppressant and MTX. Morgan et al. (1989, Birming- The initial treatment was 50mg IV should be therapeutically superior to ham, AL) concluded that a sub-normal weekly for six weeks. Response fre- the other two drugs, which he consid- serum folate concentration predicts the quently was considered insufficient, ered to be equivalent (31). Evidence of development of MTX toxicity, and they so that some patients received MTX carcinogenic effects, especially on the showed that taking as little as one mg for 20 weeks. The number of the 35 bladder, accumulated in the late 1980s of folic acid per day reduces this risk patients who also received oral 6-MP and led to its abandonment in RA ther- with less cost than Leucovorin (39). or azathioprine is unclear. One leuko- apeutics (32). In 1987 the American College of Physi- penic MTX patient died of systemic Although MTX has usually been pre- cians recommended the dosage scheme candidiasis. This patient had received scribed orally, a trial of intravenous ad- that Weinstein had proposed in 1971: four 50mg injections followed by sev- ministration of up to 50 mg every two to 2.5mg q12h for three doses once per eral injections of 6-MP before thirteen four weeks was reported in 1982 (33), week, to be doubled after six weeks if 25mg injections of MTX. The longest and the first trial with I.M. administra- response was unsatisfactory; intra-mus- MTX treatment lasted 187 days, with tion was reported in 1984 (34). How- cular dosage may be increased from a total dose of 925mg. Anorexia was ever, MTX regimens for RA patients 5mg to 25mg per week. Blood counts more common with MTX, and sto- largely employed Weinstein’s psoriasis and hepatic function tests should be matitis occurred only with MTX. The protocol. Willkens et al. (Seattle) in done monthly (40). trial was considered successful because 1971 began to treat patients whose RA Hoffmeister (Spokane, WA, 1983) re- corticosteroid dosage could be reduced had been unresponsive to other medica- ported that among his 78 patient cohort or discontinued in 27 patients. Azathio- tions with 2.5mg MTX for three doses (41), 35% were withdrawn because prine appeared to be less effective than 12 hours apart once per week. If there of toxic effects, 69% of these occur- MTX in permitting reduction of corti- was no clinical response in four weeks, ring during the first year. None had costeroid dosage. then the dosage was doubled. Twenty received more than 15mg MTX per The chief competitors of MTX were out of 32 patients responded favourably week. Nausea and stomatitis were the azathioprine and cyclophosphamide, within three months (35). Instead of di- most frequent signs of toxicity, but and in Europe, chlorambucil. (26) vided doses, 7.5mg weekly in a single most patients were relieved by a dose These, optimistically, came to be added dose, if necessary increased to 10mg reduction. to gold compounds and penicillamine or 15mg. subsequently also came to be Furst et al. (1989, New Brunswick, NJ) as “disease modifying drugs.” Mason used. But the question of the risk/ben- found no clear dose to toxicity relation- et al. (1969, London) confirmed the efit proportion remained of concern. ship between weekly doses of 7.5–10 better tolerance of MTX over azathio- A trial of 500mg/m2 of MTX IV, fol- mg, 15–22.5 mg and 27.5–35 mg, but prine (27). Urowitz et al. (1973, To- lowed 24 hours later by Leucovorin the findings did suggest better respons- ronto), in a placebo controlled cross- (folinic acid, N-formyl-tetrahydrofolic es with larger doses (42). As was true over investigation found that the in- acid) 50mg/m2 in divided oral doses, of many trials, the cohorts were too cidence of intolerance to azathioprine was begun at the NIH in 1987. Clinical small to arrive at reliable conclusions. was similar to that of MTX, but that it improvement was obtained without tox- In 1990 Scully et al. (Salt Lake City) spares the liver (28). They agreed that ic manifestations after four infusions at published their uniquely designed study it is somewhat less effective. Fosdick two week intervals (36). This was still of 124 RA patients (41% male).(43) All et al. (1968, Tuscon, AZ), introduced well tolerated when extended to six had begun to take MTX no later than

S-5 Methotrexate: a short history / T.G. Benedek

1983 and were followed for up to five comparison of 100mg. azathioprine and woman who received MTX for pso- years from the inception of this medi- 7.5mg MTX gave results more strongly riatic arthropathy. A liver biopsy nine cation, on which 31% remained after in favour of MTX in regard to response months after she had been receiving five years. 16% were discontinued of clinical and laboratory parameters 25–50 mg IM per week showed peri- because of lack of response to 7.5mg/ and toxicity (48). portal fibrosis (52). In 1968 three pa- week for 12 weeks, rather than increas- tients (2 psoriasis, 1 psoriatic arthropa- ing the dose. This is similar to the 18% Methotrexate toxicity and its thy) who had been treated with MTX ineffectiveness rate Hoffmeister had evaluation for 11–40 months had developed cir- observed. Since MTX primarily affects rapidly di- rhosis.(53) Weinstein et al. (Miami, viding cells, such as in psoriatic lesions, 1970) found fatty metamorphosis in Clinical comparisons of one characteristic of toxicity pertains to 21 MTX treated psoriatic patients, but anti-rheumatic drugs tissues in which cell division normally they were reluctant to attribute this As the number of potent immunosup- is relatively rapid. Consequently, oral to MTX rather than chronic alcohol pressive drugs increased, so did the ulcerations and dyspepsia typically consumption (22). Dahl et al. (New- clinical comparisons. The first of these are the most frequent early symptoms, castle upon Tyne, 1972) performed pertained to azathioprine, cyclophos- and may occur within weeks of initiat- liver biopsies on 44 patients who did phamide and sodium aurothiomalate ing therapy. Early dermatologic reports not consume significant amounts of al- (Myochrysine®) over 18 months (44). were concerned mainly with possible cohol and were treated with MTX for It appeared in 1974 and found little bone marrow injury and did not test for psoriasis. Seventeen (38%) had hepatic difference in efficacy between any of changes in hepatic function. Kremer cirrhosis or fibrosis (54). They made these drugs, except that both “showed and Phelps (Albany, NY) found in an the important observation that hepatic advantages (over gold) in reducing the RA cohort that had taken MTX for be- injury is more likely when small doses rate of joint deterioration as seen radio- tween 79 and 107 months, adverse reac- of MTX are taken frequently (2.5mg. logically and in steroid sparing” when tions continued to occur at a rather con- several days per week p.o.) than 10–25 they were administered in early RA. stant individually unpredictable rate: mg. p.o. or I.M. q 1–4 weeks. Tolman Williams et al. (Salt Lake City) stated for instance, leukopenia after seven et al. (Salt Lake City, 1985) presumed in 1985 that seven investigations of the years. No adverse occurrence required that the 3%–5% cirrhosis that had been efficacy of MTX in RA had been pub- removal from the cohort, although dos- reported in psoriasis was attributable to lished, but none with a control group age might be reduced. Neither MTX ef- daily dosage of MTX (55). (45). Their placebo-controlled study of ficacy nor toxicity could be correlated Brick et al. (Morgantown, WV) found MTX permitted a stable dose of pred- with HLA haplotypes (49). no case of cirrhosis either in seven re- nisone, or an NSAID to be continued. Fries et al. in a multicentre study col- ports that included liver biopsies of Therapeutic response was favourable lected the most recent determination of 233 RA patients who had not received compared to placebo, but this was only SGOT and SGPT from a large number MTX, or in 13 studies of liver biopsies a 12-week protocol. of RA patients who were taking any of in 694 patients performed after varying A comparative efficacy study of Myo- 12 relevant drugs.(50) Mean SGOT and lengths of MTX therapy (56). How- chrysine and MTX was not undertaken SGPT values were highest and essen- ever, some degree of hepatic fibrosis before 1985. In this Canadian double tially the same in those who were tak- has been found in biopsies of 17% of blind 26-week study of 40 RA patients, ing either aspirin or MTX, but not both. 859 MTX treated RA patients (42). The either 50mg. of Myochrysine or 10mg However, in those patients who were greatest exposure to MTX has been re- MTX was injected at weekly intervals taking both drugs SGOT increased by ported by Aponte and Petrelli (Cleve- (46). Of the 20 MTX patients, five had a 50% and SGOT more than doubled land), who performed liver biopsies on adverse reaction, resulting in withdraw- (15.2%, 16.7% of cases, respectively). 26 RA patients who had been taking al of one patient, versus 15 adverse re- Consequently, MTX might be discon- weekly MTX for a mean of 12.6 years actions in 11 patients, resulting in seven tinued when it is not the offending drug. and had a mean cumulative dose in ex- withdrawals of Myochrysine patients. Gispen et al. (Birmingham, AL, 1986) cess of 4.6 gm. No cirrhosis was found While several studies that compared the showed that free MTX blood levels are even in these patients, although some effects of azathioprine with other drugs higher with concomitant NSAID ther- fatty infiltration was common (57). followed, the first study that included apy due to displacement of MTX from Pulmonary fibrosis resulting from in- MTX appeared in1987. Hamdy et al. albumin binding sites (51). It has re- terstitial pneumonitis associated with (Ottawa, ONT) compared the efficacy peatedly been shown that the predictive MTX therapy was first reported in dis- of 100mg. azathioprine per day with value of moderately abnormal hepatic eases other than acute lymphatic leu- 10mg. MTX, orally per week for one enzyme tests for the presence of hepatic kaemia in 1971, in a case of psoriasis year (47). The MTX cohort tended to fibrosis is unreliable (22). (58), but in RA not until 1983 (59). more rapid clinical improvement, but The first report of biopsy proven liver Weinblatt (Boston) reviewed nine such overall the response to both agents was injury in a non-leukemic adult was cases in 1985 (60). All had been taking similar. A Dutch 48-week double blind published in 1964 and pertained to a a weekly oral dose of MTX; in seven

S-6 Methotrexate: a short history / T.G. Benedek the cumulative dose at pulmonary di- cept (Enbrel®, Pfizer), another TNF-α Effect of aminopterin in rheumatoid arthritis agnosis was less than 400mg. inhibitor, to MTX therapy was reported and psoriasis. Am J Med Sci 1951; 221: 176- 82. Despite its rapid cellular activity, ef- (68). Subsequently, it has become com- 17. EDMUNDSON WF, GUY WB: Treatment of fects on bone marrow have been rare. mon practice in RA patients who have psoriasis with folic acid antagonists. Arch According to McKinnon et al. (Seat- had an unsatisfactory response to MTX Dermatol 1958; 78: 200-03. tle), as of 1985 only seven instances of to add one of the new synthesised anti- 18. STRAKOSCH EA: A study of folic acid antag- onists in the treatment of psoriasis (Aminop- leukopenia and three of pancytopenia body agents to MTX (69). terin vs. Methotrexate vs. Aminopterin and had been reported, to which they added a corticosteroid). Dermatologica 1963; 126: six cases of pancytopenia, two being References 259-67. fatal.(61) Bone marrow injury appears 1. JOLIVET J, COWAN KH, CURT GA et al.: The 19. SHELLEY WB, HARUN JS, PILLSBURY DM: pharmacology and clinical use of methotex- The treatment of psoriasis and other derma- to be related to renal failure. ate. N Eng J Med 1983; 309: 1094-104. toses with triamcinolone (Aristocort). JAMA 2. JOHNS DG, HOLLINGSWORTH JW, CASH- 1958; 167: 959-63. Methorexate combination therapy MORE AR et al.: Methotrexate displacement 20. O’BRIEN WM, VAN SCOTT EJ, BLACK RL et al.: Clinical trial of amethopterin (Metho- and the introduction of “biologic” in man. J Clin Invest 1964; 43: 621-9. 3. FREEMAN MV: A fluorimetric method for the trexate) in psoriatic and rheumatoid arthritis. agents measurement of 4-amino-10-methyl pter- (Preliminary report). Arthritis Rheum 1962; Could therapeutic efficacy be improved oylglutamic acid (amethopterin) in plasma. 5: 312. more safely by combining MTX with J Pharmacol Exp Ther 1957; 120: 1-8. 21. BLACK RL, O’BRIEN WM, VAN SCOTT EJ: 4. FREEMAN-NARROD M, GERSTLEY BJ, ENG- Methotrexate therapy in psoriatic arthritis. another drug than by increasing its dos- STROM BF et al.: Comparison of serum con- JAMA 1964; 189: 743-7. age? The possibility that combinations centrations of methotrexate after various 22. WEINSTEIN GD, COX JW, DIRK WR et al.: of immunosuppressive drugs, in anal- routes of administration. Cancer 1975; 36: Evaluation of possible chronic hepatotoxici- ogy with oncologic therapeutics, might 1619-24. ty from methotrexate in psoriasis. Arch Derm 5. RASO V, SCHREIBER R: A rapid and specific 1970; 102: 613-8. be effective against recalcitrant RA radio-immunoassay for methotrexate. Can- 23. WEINSTEIN GD, FROST P: Methotrexate for was suggested by McCarty and Carrera cer Res 1975; 35: 407-10. psoriasis. A new therapeutic schedule. Arch (Milwaukee, WI) in 1982 in the first 6. WEINSTEIN GD: Methotrexate. Ann Intern Dermatol 1971; 103: 33-8. 24. GROSS D, ENDERLIN M, FEHR K: Die immu- of several articles. This was based on Med 1977; 86: 199-204. 7. SEGAL R, MOZES E, YARON M: The effects of nosuppressive Behandlung der progredierend their favourable experience, beginning methotrexate on the production and activity chronischen Polyarthritis mit Antimetabolica in 1975, with a combination of cyclo- of interleukin-1. Arthritis Rheum 1989; 32: und Cytostatica. Schweiz Med Wochenschr phosphamide, azathioprine and hy- 370-7. 1967; 97: 1301-10. 25. MIESCHER P, RIETHMÜLLER D: Diagnosis droxy-chloroquine (62). Trials of MTX 8. ALARCÓN GA, SCHROHENLOHER RE, BAR- TOLUCCI AA et al.: Suppression of rheuma- and treatment of systemic lupus erythemato- ® and Auranofin by Williams et al.(63), toid factor production by methotrexate in sus. Semin Hematol 1965; 2: 1-28. or MTX and azathioprine by Willkens patients with rheumatoid arthritis. Arthritis 26. KAHN MF, BESIDEAU M, DE SEZE S: Immu- et al. both reported in 1992 (64), did Rheum 1990; 33: 1156-61. nosupressive drugs in the management of 9. MARKS JS, STEWART IM, HUNTER JA: Intra- malignant and severe rheumatoid arthritis. not substantiate the superiority of sup- articular methotrexate in rheumatoid arthri- Proc Roy Soc Med 1967; 60: 130-33. plementing MTX with these drugs. tis. Lancet 1976; 2: 857-8. 27. MASON M, CURREY HL, BARNES CG et al.: However, the combination of MTX 10. HALL GG, JONES BJ, HEAD AC et al.: Intra- Azathioprine in rheumatoid arthritis. Br Med with cyclosporine has shown therapeu- articular methotrexate: Clinical and laborato- J 1969; 1: 420-21. ry study in rheumatoid and psoriatic arthritis. 28. UROWITZ MB, GORDON DA, SMYTHE HA tic superiority after six months, without Ann Rheum Dis 1978; 37: 351-6. et al.: Azathioprine in rheumatoid arthritis. increased toxicity (65). 11. HENCH PS: The reversibility of certain rheu- A double-blind cross-over study. Arthritis The introduction of several categories matic and nonrheumatic conditions by the Rheum 1973; 16: 411-8. of inhibitors of specific molecular com- use of cortisone or of the pituitary adrenocor- 29. FOSDICK WM, PARSONS JL, HILL DF: Long- ticotropic hormone. Ann Intern Med 1952; term cyclophosphamide therapy in rheuma- ponents of inflammation began about a 36: 1-38. toid arthritis. Arthritis Rheum 1968; 11: 151- decade after MTX became a principal 12. FASSBENDER HG: Rheumatismus, allergisch- 61. anti-rheumatic drug. Their develop- hyperergische Entzündung und Nebennieren- 30. DECKER JL, chair of the COOPERATIVE CLIN- rindenhormone. In: BASEL B (Ed.): Sympo- ICS COMMITTEE: A controlled trial of cyclo- ment will only be alluded to briefly. sium on the Influence of the Hypophysis and phosphamide in rheumatoid arthritis. N Eng The first trial of such an agent was the Adrenal Cortex on Biological Reaction. J Med 1970; 283: 883-9. reported from Switzerland in 1987: a Schwabe & Co, 1952, pp. 169-73 31. HURD ER: Immunosuppressive and anti-in- monoclonal antibody against CD4 cells 13. JIMÉNEZ DIAZ C, LOPEZ GARCIA E, MERCH- flammatory properties of cyclophosphamide, ENTE A et al.: Treatment of rheumatoid ar- azathioprine and methotrexate. Arthritis (66). The first of a series of monoclonal thritis with nitrogen mustard. Preliminary Rheum 1973; 16: 84-8. antibodies against tumour necrosis fac- report. JAMA 1951; 147: 1418-9. 32. BAKER GL, KAHL LE, STOLZER BL et al.: tor alpha (TNF-α) was reported from 14. SCHERBEL AL: Intravenous administration Malignancy following treatment with cyclo- London in 1993 (67). In an eight week of nitrogen mustard alone and with cortico- phosphamide: a controlled retrospective fol- ® trophin for rheumatoid arthritis. Cleveland low-up study. Am J Med 1987; 83: 1-9. trial of infliximab (Remicade , Cento- Clin Quart 1957; 24: 71-7. 33. MICHAELS RM, NASHEL DJ, LEONARD A et cor) 10 RA patients received two in- 15. GUBNER R: Therapeutic suppression of tis- al.: Weekly inravenous methotrexate in the fusions and another 10 received four sue reactivity. I. Comparison of the effects treatment of rheumatoid arthritis. Arthritis infusions, with identical, favourable of cortisone and aminopterin. Am J Med Sci Rheum 1982; 25: 339-41. 1951; 221: 169-75. 34. THOMPSON RN, WATTS C, EDELMAN J et al.: immunological and symptomatic re- 16. GUBNER R, AUGUST S, GINSBERG V: Thera- A controlled two-centre trial of parenteral sults. In 1999 the addition of etaner- peutic suppression of tissue reactivity. II. methotrexate therapy for refractory rheuma-

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toid arthritis. J Rheum 1984; 11: 760-3. treatment of rheumatoid arthritis. J Rheuma- JJ: Methotrexate pneumonitis after low dose 35. WILLKENS RF, WATSON MA, PAXSON CS: tol 1988; 15: 753-6. therapy for rheumatoid arthritis. Arthritis Low dose pulse methotrexate therapy in rheu- 47. HAMDY H, MCKENDRY RJ, MIERINS E et Rheum 1983; 26: 1275-8. matoid arthritis. J Rheumatol 1980; 7: 501-5. al.: Low-dose methotrexate compared with 60. WEINBLATT ME: Toxicity of low dose metho- 36. SHIROKY J, ALLEGRA C, INGHIRAMI G et azathioprine in the treatment of rheumatoid trexate in rheumatoid arthritis. J Rheum al: High dose intravenous methotrexate with arthritis. Arthritis Rheum 1987; 30: 361-8. 1985; (Suppl. 12): 35-9. leucovorin rescue in rheumatoid arthritis. J 48. JEURISSEN ME, BOERBOOMS AM, VAN DEN 61. MACKINNON SK, STARKEBAUM G, Rheumatol 1988; 15: 251-5. PUTTE LB: Methotrexate versus azathio- WILLKENS RF: Pancytopenia associated with 37. SHIROKY JB, NEVILLE C, ESDAILE JM et al.: prine in the treatment of rheumatoid arthritis. low dose pulse methotrexate in the treat- Low-dose methotrexate with leucovorin (fo- Arthritis Rheum 1991; 34: 961-72. ment of rheumatoid arthritis. Semin Arthritis linic acid) in the management of rheumatoid 49. KREMER JL, PHELPS CT: Long-term prospec- Rheum 1985; 15: 119-26. arthritis. Arthritis Rheum 1993, 36: 795-803. tive study of the use of methotrexate in the 62. MCCARTY DJ, CARRERA GF: Intractable 38. TISHLER M, CASPI D, FISHEL B et al.: The treatment of rheumatoid arthritis. Arthritis rheumatoid arthritis. Treatment with com- effects of leucovorin (folinic acid) on metho- Rheum 1992; 35: 138-45. bined cyclophosphamide, azathioprine, and trexate therapy in rheumatoid arthritis. 50. FRIES JF, SINGH G, LENERT L et al.: Aspirin, hydroxychloroquine. JAMA 1982; 2488: Arthritis Rheum 1988; 31: 906-08. hydroxychloroquin, and hepatic enzyme ab- 1718-23. 39. MORGAN SL, BAGGOTT JE, VAUGH WH et normalities with methotrexate in rheumatoid 63. WILLIAMS HJ, WARD JR, READING JC et al.: al.: The effect of folic acid supplementation arthritis. Arthritis Rheum 1990; 33: 1611-9. Comparison of Auranofin, methotrexate, and on the toxicity of low-dose methotrexate in 51. GISPEN JG, ALARCÓN GS, JOHNSON JJ et the combination of both in the treatment of patients with rheumatoid arthritis. Arthritis al.: Toxicity to methotrexate in rheumatoid rheumatoid arthritis. Arthritis Rheum 1992; Rheum 1990; 33: 9-18. arthritis. J Rheumatol 1987; 14: 74-9. 35: 259-69. 40. TUGWELL P, BENNETT K, GENT M: Meth- 52. O’ROURKE RA, ECKERT GE: Methotrex- 64. WILLKENS RF, UROWITZ MB, STABLEIN DM otrexate in rheumatoid arthritis. Ann Intern ate-induced hepatic injury in an adult. Arch et al.: Comparison of azathioprine, metho- Med 1987; 107: 418-9. Intern Med 1964; 113: 191-4. trexate, and the combination of both in the 41. HOFFMEISTER RT: Methotrexate therapy in 53. MULLER SA, FARROW GM, MARTALOCK treatment of rheumatoid arthritis: a control- rheumatoid arthritis: 15 year experience. Am DL: Cirrhosis caused by methotrexate in the led clinical trial. Arthritis Rheum 1992; 35: J Med 1983; 75 (Suppl. 6A): 69-73. treatment of psoriasis. Arch Derm 1969; 100: 849-56. 42. FURST DE, KOEHNKE R, BURMEISTER LF 523-30. 65. TUGWELL P, PINCUS T, YOCUM D et al.: et al.: Increasing methotexate effect with 54. DAHL MG, GREGORY MM, SCHEUER PJ: Combination therapy with cyclosporine and increasing dose in the treatment of resistant Methotrexate hepatotoxicity in psoriasis methotrexate in severe rheumatoid arthritis. rheumatoid arthritis. J Rheumatol 1989; 16: – comparison of different dosage regimens. N Eng J Med 1995; 333: 137-41. 313-20. Br Med J 1972; 1: 654-6. 66. HERZOG CH, WALKER CH, PICHLER W et al.: 43. SCULLY CJ, ANDERSON CJ, CANNON GW: 55. TOLMAN KG, CLEGG DO, LEE RG: Metho- Monoclonal anti-CD4 in arthritis. Lancet, Long-term methotrexate therapy for rheuma- trexate and the liver. J Rheum 1985; 12 (Sup- 1987; 2: 1461-2. toid arthritis. Sem Arthritis Rheum 1991; 20: pl. 12): 29-34. 67. ELLIOTT MJ, MAINI RN, FELDMANN M et 317-31. 56. BRICK JE, MORELAND LW, AL-KAWAS F et al.: Treatment of rheumatoid arthritis with 44. CURREY HL, HARRIS J, MASON RM et al.: al.: Prospective analysis of liver biopsies chimeric monoclonal antibodies to tumor Comparison of azathioprine, cyclophospha- before and after methotrexate therapy in necrosis factor α. Arthritis Rheum 1993; 36: mide, and gold in treatment of rheumatoid rheumatoid arthritis. Semin Arthritis Rheum 1681-90. arthritis. Br Med J 1974; 1: 763-6. 1989; 19: 31-44. 68. MORELAND LW, SCHIFF MH, BAUM- 45. WILLIAMS HJ, WIILLKENS RF, SAMUELSON 57. APONTE J, PETRELLI M: Histopathologic GARTNER SW et al.: Etanercept therapy in CO et al.: Comparison of low-dose oral pulse findings in the liver of rheumatoid arthritis rheumatoid arthritis. Ann Intern Med 1999, methotrexate and placebo in the treatment of patients treated with long-term bolus metho- 130: 478-86. rheumatoid arthritis. Arthritis Rheum 1985; trexate. Arthritis Rheum 1988; 31: 1457-64. 69. WEINBLATT ME, KREMER JM, BANKHURST 28: 721-30. 58. FILIP DJ, LOGUE GL, HARLE TS et al.: Pul- AD et al.: A trial of Etanercept, a recombinant 46. SUAREZ-ALMAZOR ME, FITZGERALD A, monary and hepatic complications of meth- tumor necrosis factor receptor: Fc fusion GRACE M et al.: A randomized controlled tri- otrexate therapy of psoriasis. JAMA 1971; protein, in patients with rheumatoid arthritis al of parenteral methotrexate compared with 216: 881-2. receiving methotrexate. N Eng J Med 1999; sodium aurothiomalate (myochrysine) in the 59. ENGELBRECHT JA, CALHOON SL, SCHERER 340: 253-9.

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