Use Of Methotrexate In Rheumatoid Arthritis Research Articles

The use of methotrexate in rheumatoid arthritis. Recommendations of the All-Russian public organization “Association of Rheumatologists of Russia”

Rheumatoid arthritis (RA) is the most frequent immunoinflammatory (autoimmune) rheumatic disease characterized by chronic erosive arthritis and systemic damage to internal organs. The data obtained in the course of basic research on deciphering the mechanisms of action of methotrexate (MT) and the materials of numerous randomized placebocontrolled trials, observational studies and national registries have strengthened the position of MT as the “gold standard” of RA pharmacotherapy and a key component of the “Treatment to Target” strategy. This was the basis for the development of new recommendations of the Association of Rheumatologists of Russia (ARR) concerning the use of MT in RA, according to which MT is considered as the drug of “choice” for induction and maintenance of remission in patients with early and advanced RA, including those who need combination therapy of MT with glucocorticoids, standard Disease-Modifying Antirheumatic Drugs (DMARDs), biologics and targeted synthetic DMARDs. Special attention is paid to the safety of MT therapy and the impact of MT on comorbid pathology associated with cardiovascular complications and interstitial lung disease. Implementation of the ARR recommendations into clinical practice will reduce the risk of disability and improve life prognosis in patients with RA.

Investigating changes in disease activity as a mediator of cardiovascular risk reduction with methotrexate use in rheumatoid arthritis

ObjectiveExamine the association of methotrexate (MTX) use with cardiovascular disease (CVD) in rheumatoid arthritis (RA) using marginal structural models (MSM) and determine if CVD risk is mediated through modification of...

Systematic review of recommendations on the use of methotrexate in rheumatoid arthritis.

Most recommendations for the use of methotrexate (MTX) in rheumatoid arthritis (RA) are issued by developed countries. It is unknown whether they are relevant globally. We reviewed existing recommendations on the use of MTX for the treatment of RA and summarized areas of agreement that could be relevant for least developed countries (LDCs). Electronic databases and registries were searched for recommendations on MTX use in RA, duplicates were eliminated, and the most updated version adopted when there were several versions on the same recommendation. Reviewers used the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument for study quality assessment. Similarities and discrepancies of recommendations are reported. After deduplication, 1693 unique citations were found; 25 full texts were screened and 12 included in the narrative synthesis. Average scores for the AGREE II domains ranged from 33.3 to 83.3%. Recommendations targeted rheumatologists and health care providers involved in RA care. Most covered some but not all of the following areas: baseline "pre-MTX" assessment (7/12;58%), prescription of MTX (10/12;83.3%), management of MTX side effects (6/12;50%), and special considerations (e.g., peri-operative management) (8/12; 66.7%). Recommendations agreed on baseline tests prior to starting MTX, monitoring, and need for folic acid supplementation. These aspects can serve as the foundation for the development of MTX recommendations relevant to LDCs. Recommendations disagreed on the MTX starting dose, optimal route, titration, and intervals to monitor toxicity. Existing recommendations do not uniformly address all aspects related to the use of MTX and disagree in relevant aspects of MTX use. Adaptations to these recommendations are needed to facilitate their implementation in LDCs. Key Points • This paper summarizes current recommendations on the use of methotrexate for the treatment of rheumatoid arthritis. • Areas of agreement between recommendations include the following: pre-methotrexate patient assessment, need for folic acid supplementation, and toxicity monitoring. • Areas of disagreement relate to methotrexate starting and maximal dose, titration, and frequency of assessments.

Using Audiometry to Track Atherosclerosis: Measuring a Beneficial Effect of Methotrexate in Rheumatoid Arthritis

Objectives: To correlate audiometry with atherosclerosis. Presbycusis is associated with age and atherosclerosis; a strong correlation might present opportunities to use audiometry to track atherosclerosis disease. Design: The authors tested 87 elderly patients with rheumatoid arthritis (age range: 80–101 years; median: 86 years) with a history of methotrexate use for over 20 years. After 50 years of age, hearing loss begins slowly and by the age of 90, the majority of the general population require hearing aids. In the 87 elderly participants, however, hearing was remarkably preserved. Results: The observed cohort of 87 individuals showed better hearing than predicted compared to audiometry historically documented in the elderly (p<0.001). The patients tested one to two decades younger than expected on audiometry and 44% of patients qualified for hearing aids instead of the expected 80%, based on age. Conclusion: The known reduction in atherosclerosis with methotrexate use in rheumatoid arthritis may account for this observed preservation of hearing.1,2 As hearing and atherosclerosis are related, the authors further postulated that routine audiometry may provide a cost-effective screening tool for other populations in future atherosclerosis studies.

Molecular mechanism of action and pharmacokinetic properties of methotrexate.

Since its discovery in 1945, methotrexate has become a standard therapy for number of diseases, including oncological, inflammatory and pulmonary ones. Major physiological interactions of methotrexate include folate pathway, adenosine, prostaglandins, leukotrienes and cytokines. Methotrexate is used in treatment of pulmonary sarcoidosis as a second line therapy and is drug of choice in patients who are not candidates for corticosteroid therapy, with recommended starting weekly dose of 5-15mg. Number of studies dealt with methotrexate use in rheumatoid arthritis and oncological patients. Authors are conducting research on oral methotrexate use and pharmacokinetics in chronic sarcoidosis patients and have performed literature research to better understand molecular mechanisms of methotrexate action as well as high level pharmacokinetic considerations. Polyglutamation of methotrexate affects its pharmacokinetic and pharmacodynamic properties and prolongs its effect. Bile excretion plays significant role due to extensive enterohepatic recirculation, although majority of methotrexate is excreted through urine. Better understanding of its pharmacokinetic properties in sarcoidosis patients warrant optimizing therapy when corticosteroids are contraindicated in these patients.

Perceptions of methotrexate use in rheumatoid arthritis by rheumatologists and their patients: an Australian survey study

To improve treatment for rheumatoid arthritis (RA), rheumatologists have embraced patient-reported outcomes; however, limited data are available on patient perceptions of treatment. Our objective was to assess the use and perceptions of methotrexate (MTX) by patients with RA (primary objective) and their rheumatologists, patient-reported adverse events (AEs) related to MTX, and patient-reported use of alcohol, folic acid and biologic agents. Each rheumatologist completed a rheumatologist questionnaire and then asked patients with RA to complete a patient questionnaire. Questionnaires were completed by 46/50 rheumatologists and 1313/1313 patients. Patients (72% female, 38% > 10 years RA) took oral MTX regularly (72% never miss a dose) and at therapeutic doses. Most patients (79%) were currently taking MTX, but 36% of patients were on low doses (≤ 10 mg/week) and 8% intentionally and regularly did not take MTX. Most patients had a positive perception of MTX; 82% of patients considered MTX to be important; 60% preferred to continue taking MTX. Although AEs (generally mild and gastrointestinal) occurred regularly (38%) and in some patients continuously (13%), 41% of patients did not experience an AE. Patients abstained from alcohol (46%) and took folic acid (91%, but with variable dosage regimens and doses). There were 29% of patients taking biologic agent therapy; only 70% of these patients were also taking MTX. MTX was well used, well tolerated and well perceived. However, to ensure that MTX therapy is as effective as possible, rheumatologists should discuss MTX use with their patients and consider alternative strategies for some patients.

Markers of Treatment Response to Methotrexate in Rheumatoid Arthritis: Where Do We Stand?

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, despite its efficacy and affordability, additional DMARDs or biologic agents are often required in order to achieve the recommended goals of low disease activity or remission. Although well tolerated by most, some patients develop important side effects such as cytopenias, gastrointestinal adverse events (stomatitis, nausea), or abnormal liver function tests, which may limit its use and may result in additional health care costs. Given the clinical implications of widespread use of MTX in RA, various studies have evaluated the role of potential biomarkers in predicting treatment effectiveness of MTX. These biomarkers include RBC MTX polyglutamate (PG) levels; genetic variation in genes from relevant biological and metabolic pathways; gene expression profiles; serum proteins. This paper provides an update on the current data regarding biomarkers of treatment response to MTX.

An update on methotrexate

Methotrexate (MTX) has been used for the treatment of rheumatoid arthritis (RA) for about three decades now. MTX is one of the most effective and commonly used medicines to treat various forms of arthritis and other rheumatic conditions. MTX was shown to improve signs and symptoms of RA, disease activity and function, to a similar degree as the tumor necrosis factor blockers, and it inhibits radiographic progression to a smaller degree than the antitumor necrosis factor agents. MTX is considered as the anchor drug among the disease-modifying antirheumatic agents, and it is internationally accepted as the first choice in the management of RA. This review was performed on the basis of a PubMed literature search looking at all publications on MTX and arthritis in 2008. MTX seems to even prolong the life span of patients who tolerate the drug and have clinical benefit from this therapy; this may partly be explained by beneficial effects on cardiovascular mortality. The reason for this may well be the suppression of inflammation, but direct atheroprotective effects of MTX may also play a role. MTX is used as monotherapy and in combination with other disease-modifying antirheumatic agents or biologic agents such as the antitumor necrosis factor agents. The 'early' use of MTX within 5 years after disease onset is clearly associated with improved outcomes. The management of RA should include an early strong suppression of inflammation and continuously a tight control strategy. The pharmacodynamics and kinetics of MTX are still incompletely understood. In this review, we especially cover the following themes: new clinical studies on the use of MTX in RA, the use of MTX in other rheumatic conditions, prediction of response to MTX, optimal dosage, MTX use in the elderly, the mechanism of action, the pharmacokinetics and the pharmacogenetics of MTX, the prevention of side effects, and the overall long-term safety.

Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review.

The folate antagonist methotrexate (MTX) has become established as the most commonly used disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA) but is commonly discontinued due to adverse effects. Adverse effects are thought to be mediated via folate antagonism. In this paper we summarize the current data on the use of folates as a supplement to MTX use in RA for the prevention of adverse effects and as a potential modulator of cardiovascular risk, and propose guidelines for standard practice. A Medline search was performed using the search terms "methotrexate", "folic acid", "folinic acid", "folate" and "homocysteine". Literature relevant to the use of folates as a supplement to MTX in the treatment of RA was reviewed and other papers referred to as references were explored. The use of supplemental folates, including folic and folinic acid, in RA patients treated with MTX has been shown to improve continuation rates by reducing the incidence of liver function test abnormalities and gastrointestinal intolerance. Folate supplements do not appear to significantly reduce the effectiveness of MTX in the treatment of RA. Furthermore, supplemental folic acid offsets the elevation in plasma homocysteine associated with the use of MTX. This may in turn reduce the risk of cardiovascular disease, which is over-represented amongst patients with RA, and for which hyperhomocysteinaemia is now recognized as an independent risk factor. We propose that folic acid supplements be prescribed routinely to all patients receiving MTX for the treatment of RA. We recommend a pragmatic dosing schedule of 5 mg of oral folic acid given on the morning following the day of MTX administration.

Methotrexate use in rheumatoid arthritis. A clinician's perspective

Aminopterine, a precursor of methotrexate (MTX), was first used for the treatment of rheumatoid arthritis (RA) in 1951 [Gubner, R., 1951. Therapeutic suppression of tissue reactivity: I. Comparison of the effects of cortisone and aminopterin. Am. J. Med. Sci. 221, 169–175; Gubner, R., August, S., Ginsberg, V., 1951. Therapeutic suppression of tissue reactivity: II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am. J. Med. Sci. 221, 176–182.]. Corticosteroids, and to some extent cyclophosphamide, took MTX out of the rheumatologist's armamentarium until the late 1970s–early 1980s when the toxic profile of these compounds became apparent. By the mid 1980s, four randomized clinical trials (RCTs) had proven beyond doubt the beneficial effects of MTX when administered to patients with established disease who had failed to respond to other compounds such as gold salts and d-penicillamine [Thompson, R.N., Watts, C., Edelman, J., Esdaile, J., and Russell, A.S., 1984. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J. Rheumatol. 11, 760–763; Andersen, P.A., West, S.G., O'Dell, J.R., Via, C.S., Claypool, R.G., and Kotzin, B.L., 1985. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann. Intern. Med. 103, 489–496; Weinblatt, M.E., Coblyn, J.S., Fox, D.A., Fraser, P.A., Holdsworth, D.E., Glass, D.N., and Trentham, D.E., 1985. Efficacy of low-dose methotrexate in rheumatoid arthritis. N. Engl. J. Med. 312, 818–822; Williams, H.J., Willkens, R.F., Samuelson, C.O.J., Alarcón, G.S., Guttadauria, M., Yarboro, C., Polisson, R.P., Weiner, S.R., Luggen, M.E., Billingsley, L.M., Dahl, S.L., Egger, M.J., Reading, J.C., and Ward, J.R., 1985. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum. 28, 721–730.]. Subsequently, these four trials were included in a meta-analysis and the drug was approved by the Food and Drug Administration for use in RA [Health and Public Policy Committee, H.P.P.C. and American College Physicians, A.C.P., 1987. Methotrexate in rheumatoid arthritis. Ann. Intern. Med. 107, 418–419; Paulus, H.E., 1986. FDA Arthritis Advisory Committee meeting: Methotrexate; guidelines for the clinical evaluation of antiinflammatory drugs; DMSO in scleroderma. Arthritis Rheum. 29, 1289–1290; Tugwell, P., Bennett, K., and Gent, M., 1987. Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. Ann. Intern. Med. 107, 358–366.]. Since then, rheumatologists have become aware of what Pincus et al. have called “the side effects” of RA comparing the morbidity and mortality caused by RA with that potentially caused by medications used to treat this disease [Pincus, T. and Callahan, L.F., 1993. The “side effects” of rheumatoid arthritis: joint destruction, disability and early mortality. Br. J. Rheumatol. 32, 28–37.]. Thus, during the 1990s the use of MTX for the treatment of RA became generalized [O'Dell, J.R., 1997. Methotrexate use in rheumatoid arthritis. Rheum. Dis. Clin. N Am. 23, 779–796 (a); Bannwarth, B., Vernhes, J., Schaeverbeke, T., and Dehais, J., 1995. The facts about methotrexate in rheumatoid arthritis. Rev. Rhum. 62, 471–473 (b); Bologna, C., Jorgensen, C., and Sany, J., 1997a. Methotrexate as the initial second-line disease modifying agent in the treatment of rheumatoid arthritis patients. Clin. Exp. Rheumatol. 15, 597–601; Bologna, C., Viu, P., Picot, M.C., Jorgensen, C., and Sany, J., 1997b. Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate an open, retrospective, observational study. Br. J. Rheumatol. 36, 535–540.]. By now, basic and clinical investigators have gathered a wealth of information covering many aspects related to this compound, ranging from its mechanism of action to how it can be administered in a much safer way to patients.This article highlights the way in which MTX is currently used by rheumatologists for the treatment of RA primarily, and to a lesser extent for the treatment of other rheumatic disorders. Other aspects of this compound have been covered elsewhere and will not be emphasized in this review.

Proposition: Methotrexate should not be the first second-line agent to be used in rheumatoid arthritis if NSAIDs fail

Although methotrexate (MTX) is an effective antirheumatic drug, it cannot clearly be defined as a disease modifying antirheumatic drug (DMARO), when this term is characterized by its effect on radiographs or laboratory data. Current data, in the form of small studies or case reports, show that MTX's hepatic toxicity is not yet fully defined, that its acute pulmonary toxicity is significant, that systemic fungal infections may be associated with MTX use in rheumatoid arthritis (RA), that unexplained significant weight loss can be a problem, and that the consequence of drug interactions with MTX are not yet fully known. Thus, although clearly an effective antiinflammatory drug in RA, the place of MTX in the RA armamentarium is not fully defined. For this reason, MTX should not at present be used as the first second-line agent in RA after nonsteroidal antiinflammatory drugs (NSAIDs) fail.