Methotrexate therapy in rheumatoid arthritis: 15 years experience

doi:10.1016/0002-9343(83)90477-1

The American Journal of Medicine

Volume 75, Issue 6, Part 1, 30 December 1983, Pages 69-73

https://doi.org/10.1016/0002-9343(83)90477-1 Get rights and content

Abstract

An increasing amount of clinical data indicates that low-dose methotrexate therapy for rheumatoid arthritis is both effective and free of serious side effects. Since 1967 we treated 78 patients with definite or classic rheumatoid arthritis who showed inadequate response to conventional therapy. Up to 15 mg of methotrexate was given weekly by the intramuscular route. Morning stiffness, severity of pain at rest and with activity, extent of active synovitis, functional capacity, change in steroid dosage, complete blood count, erythrocyte sedimentation rate, and gamma glutamyl transpeptidase were monitored. Overall assessment indicated that 45 of the 78 (58 percent) patients showed marked improvement or complete remission, usually within four weeks. When maximum improvement was obtained, most patients were switched to oral therapy with a variable degree of success, and dosage was decreased as tolerated. No serious toxicity was noted. In 34 patients a total of 67 liver biopsy specimens were obtained, some after as long as 15 years of therapy. Minor changes observed are the same as in patients with rheumatoid arthritis not treated with methotrexate. Because the risks did not appear justified, routine annual biopsies were discontinued. In contrast to other cytotoxic drugs, no carcinogenesis has been demonstrated with methotrexate. It appears that methotrexate is approximately as effective as intramuscular gold and D-penicillamine but that it has a quicker onset of response and less serious toxicity.

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Cited by (174)

Side effects of methotrexate therapy for rheumatoid arthritis: A systematic review
2018, European Journal of Medicinal Chemistry
Citation Excerpt :
It has anti-inflammatory and immunomodulating properties [1–4] and used for the treatment of RA and psoriasis in 1951 for the first time [5]. However, until the early 1980s [6,7], MTX therapy started receiving more attention to be used in the treatment of RA. Its high efficacy and marked superiority to placebo in chronic and severe RA patients was then reported a few years later [8,9].
Methotrexate (MTX) is used as an anchor disease-modifying anti-rheumatic drugs (DMARDs) in treating rheumatoid arthritis (RA) because of its potent efficacy and tolerability. MTX benefits a large number of RA patients but partially suffered from side effects. A variety of side effects can be associated with MTX when treating RA patients, from mild to severe or discontinuation of the treatment. In this report, we reviewed the possible side effects that MTX might cause from the most common gastrointestinal toxicity effects to less frequent malignant diseases. In order to achieve regimen with less side effects, the administration of MTX with appropriate dose and a careful pretreatment inspection is necessary. Further investigations are required when combining MTX with other drugs so as to enhance the efficacy and reduce side effects at the same time. The management of MTX treatment is also discussed to provide strategies for occurred side effects. Thus, this review will provide scholars with a comprehensive understanding the side effects of MTX administration by RA patients.
Discoveries of conventional synthetic disease modifying anti-rheumatic drugs - Serendipity or flawless reasoning?
2016, Indian Journal of Rheumatology
Citation Excerpt :
Hoffmeister also showed that the effect of LD-MTX was similar to that of intramuscular gold and d-penicillamine (the commonly used drugs in those days) with less toxicity and rapid action. Around the same time (early 1980s), Willkens also published his initial series of 67 patients who were treated with LD-MTX at a dose varying from 7.5 to 15 mg per week from 3 months to 10 years.64,65 He also reported an overall improvement in more than 75% of RA patients.
Most of the conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) for treating rheumatoid arthritis (RA) were discovered serendipitously. Of course, discoveries do require serendipity, but it is not simply a random process or chance event. It is a process in which an unexpected event is seized upon by a creative mind that chooses to pay attention to the event, and unravels its mystery followed by its careful application for the benefit of mankind. Rheumatology is replete with such brilliant minds helping patients to come out from a hopeless illness and move towards a quality life that is almost as good as normal. In this short review, historical perspective of some of the older and current csDMARDs-related discoveries is described.
Effectiveness, tolerability, and safety of subcutaneous methotrexate in early rheumatoid arthritis: A retrospective analysis of real-world data from the St. Gallen cohort
2015, Seminars in Arthritis and Rheumatism
Citation Excerpt :
Furthermore, gastrointestinal (GI) side effects, such as nausea, abdominal pain, and diarrhea, are a frequent cause of oral MTX therapy discontinuation [3,21]. Guidelines from other European rheumatology societies have also recommended a switch from oral to parenteral MTX as part of the management of RA [22–26]. A retrospective, controlled, population-based, observational study from the United Kingdom assessed the efficacy of SC MTX in patients who had an inadequate response to oral MTX therapy [27].
Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment. Recently updated recommendations by the European League Against Rheumatism (EULAR) show MTX as an important part of the first-line strategy in patients with active RA. The study presented here aimed to assess the clinical effectiveness and tolerability of subcutaneous (SC) MTX among patients with RA.
Patients with RA who were naïve at baseline to both conventional and biologic disease-modifying antirheumatic drugs, fulfilled the American College of Rheumatology/EULAR 2010 criteria, and had one or more follow-up visits were selected through sequential chart review for analysis of retrospective data. Patients received SC MTX at varying doses (10–25 mg per week). The primary end point was a change in the Disease Activity Score including 28 joints (DAS28); secondary end points included time to employment of the first biologic agent and cumulative MTX doses.
Overall, 70 patients were in follow-up for a mean of 1.8 years after initiating SC MTX treatment. During this time, 37 (53%) remained on SC MTX without any biologics (MTX-only) and 33 (47%) required the addition of a biologic therapy (MTX-biol). Biologic therapy was required after a mean ± SD of 387 ± 404 days. Mean weekly MTX doses were 17.4 mg for patients in the MTX-only group and 19.1 mg for patients in the MTX-biol group. Mean baseline DAS28 were similar for patients in the MTX-biol and MTX-only groups (4.9 and 4.7, respectively). Both low disease activity state (LDAS) and remission were achieved by slightly fewer patients in the MTX-biol than MTX-only groups (LDAS, 78.8% vs 81.1%; remission, 69.7% vs 75.7%). Over the full course of the study period, SC MTX was discontinued in 32 patients (46%). Among those who discontinued, the most common reasons were gastrointestinal discomfort (n = 7), lack of efficacy (n = 7), and disease remission (n = 3). Severe infections occurred in 3 patients in the MTX-biol group and 3 patients in the MTX-only group.
SC MTX is a safe and effective treatment option for patients with RA. SC MTX resulted in high rates of remission and LDAS in early disease, over prolonged periods of time, it, therefore, may extend the time before patients require initiation of biologic therapy.
Treatment of rheumatoid arthritis: Unraveling the conundrum
2015, Journal of Autoimmunity
Citation Excerpt :
It was soon shown to be effective in RA (and psoriasis and psoriatic arthritis) by Gubner and co-workers in 1951 [33]. Like SSZ, however, it emerged at the dawning of the short-lived first glucocorticoid era, and its use in RA “suffered” until the early 1980s [34,35]. By the 1990s, MTX had become the first drug of choice of most rheumatologists to treat patients with RA, although early efficacy studies suggested that, at least within the first year of use, other drugs, including SSZ, were equally efficacious [36].
Rheumatoid arthritis (RA) is a heterogeneous disease with a complex and yet not fully understood pathophysiology, where numerous different cell-types contribute to a destructive process of the joints. This complexity results into a considerable interpatient variability in clinical course and severity, which may additionally involve genetics and/or environmental factors. After three decades of focused efforts scientists have now achieved to apply in clinical practice, for patients with RA, the “treat to target” approach with initiation of aggressive therapy soon after diagnosis and escalation of the therapy in pursuit of clinical remission. In addition to the conventional synthetic disease modifying anti-rheumatic drugs, biologics have greatly improved the management of RA, demonstrating efficacy and safety in alleviating symptoms, inhibiting bone erosion, and preventing loss of function. Nonetheless, despite the plethora of therapeutic options and their combinations, unmet therapeutic needs in RA remain, as current therapies sometimes fail or produce only partial responses and/or develop unwanted side-effects. Unfortunately the mechanisms of ‘nonresponse’ remain unknown and most probable lie in the unrevealed heterogeneity of the RA pathophysiology.
In this review, through the effort of unraveling the complex pathophysiological pathways, we will depict drugs used throughout the years for the treatment of RA, the current and future biological therapies and their molecular or cellular targets and finally will suggest therapeutic algorithms for RA management. With multiple biologic options, there is still a need for strong predictive biomarkers to determine which drug is most likely to be effective, safe, and durable in a given individual. The fact that available biologics are not effective in all patients attests to the heterogeneity of RA, yet over the long term, as research and treatment become more aggressive, efficacy, toxicity, and costs must be balanced within the therapeutic equation to enhance the quality of life in patients with RA.
Methotrexate in rheumatoid arthritis: Optimizing therapy among different formulations. Current and emerging paradigms
2014, Clinical Therapeutics
Citation Excerpt :
Therefore, for almost a decade, immunosuppressive drugs were used as rescue therapy, after repeated failure of all other possible therapeutic options. In 1972, Hoffmeister demonstrated both the availability and safety of MTX, at low doses, with a single weekly administration.4 After publication of this article, this strategy became the first choice in the treatment of RA.
Methotrexate (MTX) is currently considered the drug of choice, among the disease-modifying antirheumatic drugs, for the treatment of rheumatoid arthritis (RA) because of its favorable risk/benefit ratio, good safety profile, and low costs. Despite MTX’s widespread use and large experience accumulated over the many years since its introduction into clinical practice, specific guidelines have not been published.
We report here the available research regarding the optimal dosage and route of MTX administration.
MEDLINE and the Cochrane Library were systematically searched for articles published between 1990 and 2013, using terms related to RA and MTX. The search was conducted by using both MeSH terms and free text. The references of the retrieved studies were also screened manually for additional articles.
For the treatment of rheumatic diseases, the antimetabolite drug MTX can be administered weekly by different routes: oral, subcutaneous, or intramuscular. One of the goals of treatment is to minimize acute and chronic toxicity. A starting dose of 15 mg/week orally, escalating to 25 to 30 mg/week or the highest tolerable dose (with a subsequent switch to parenteral administration in cases of insufficient response), seems to be the optimal evidence-based strategy for MTX treatment of RA. Oral MTX is widely preferred because of its low costs and patient preferences; the bioavailability of parenteral MTX is higher, however. This is supported by data from observational studies, in which patients switching from parenteral to oral MTX at an equal dose had disease exacerbations. In several trials, the subcutaneous formulation of MTX was considered, by both physicians and patients, to be more advantageous in terms of discomfort and compliance. In addition, a significant proportion of patients reported that this formulation led to greater independence, with a resulting improvement in quality of life.
Although MTX treatment can be initiated by using the oral administration route, parenteral administration of MTX is indicated in those patients with poor compliance toward the oral form. The subcutaneous route seems to be more effective than the oral route for MTX administration based on the results of several studies, and this route may be preferred because of better usability and absence of pain at the infusion site.
The Methotrexate Story: How did a Cancer Chemotherapeutic Agent Become a Disease-modifying Antirheumatic Drug
2023, Indian Journal of Rheumatology

View all citing articles on Scopus

^☆: This study was supported in part by the Rockwood Clinic Medical Foundation.

¹: From the Section of Rheumatology, Department of Medicine, Rockwood Clinic, Spokane, Washington.

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Methotrexate therapy in rheumatoid arthritis: 15 years experience☆

Abstract

Comparison of azathioprine, cyclophosphamide and gold in treatment of rheumatoid arthritis

Br Med J

Long-term effects of azathioprine in rheumatoid arthritis

Ann Rheum Dis

Methotrexate in rheumatoid arthritis (abstr)

Arthritis Rheum

Long term therapy of psioriatic and rheumatoid arthritis with oral methotrexate monitored by serial liver biopsies (abstr)

Arthritis Rheum

Low-dose pulse therapy in rheumatoid arthritis

J Rheumatol

Low dose methotrexate therapy in rheumatoid arthritis

Arthritis Rheum

Methotrexate in the treatment of rheumatoid arthritis: pilot study

Clev Clin Q

Methotrexate therapy in psoriatic arthritis

JAMA

Reiter's syndrome. Treatment with methotrexate

JAMA

Pulmonary disease complicating intermittent therapy with methotrexate

JAMA

Treatment of rheumatoid arthritis with nitrogen mustard. Preliminary report

JAMA