Research ArticleArticle
Open Access

Canadian Recommendations for Use of Methotrexate in Patients with Rheumatoid Arthritis

WANRUCHADA KATCHAMART, JOSIANE BOURRÉ-TESSIER, TIMEA DONKA, JULIE DROUIN, GINA ROHEKAR, VIVIAN P. BYKERK, BOULOS HARAOUI, SHARON LECLERQ, DIANNE P. MOSHER, JANET E. POPE, KAM SHOJANIA, JOHN THOMSON, J. CARTER THORNE and CLAIRE BOMBARDIER the Canadian 3e Initiative Consensus Group
The Journal of Rheumatology July 2010, 37 (7) 1422-1430; DOI: https://doi.org/10.3899/jrheum.090978

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Abstract

Objective. To develop recommendations for the use of methotrexate (MTX) in patients with rheumatoid arthritis.

Methods. Canadian rheumatologists who participated in the international 3e Initiative in Rheumatology (evidence, expertise, exchange) in 2007–2008 formulated 5 unique Canadian questions. A bibliographic team systematically reviewed the relevant literature on these 5 topics. An expert committee consisting of 26 rheumatologists from across Canada was convened, and a set of recommendations was proposed based on the results of systematic reviews combined with expert opinions using a nominal group consensus process.

Results. The 5 questions addressed drug interactions, predictors of response, strategies to reduce non-serious side effects, variables to assess clinical response, and incorporating patient preference into decision-making. The systematic review retrieved 93 pertinent articles; this evidence was presented to the expert committee during the interactive workshop. After extensive discussion and voting, a total of 9 recommendations were formulated: 2 on drug interactions, 1 on predictors of response, 2 on strategies to reduce non-serious side effects, 3 on variables to assess clinical response, and 1 on incorporating patient preferences into decision-making. The level of evidence and the strength of recommendations are reported. Agreement among panelists ranged from 85% to 100%.

Conclusion. Nine recommendations pertaining to the use of MTX in daily practice were developed using an evidence-based approach followed by expert/physician consensus with high level of agreement.

The need for recommendations

Methotrexate (MTX) is among the most effective and the most commonly prescribed disease modifying antirheumatic drugs (DMARD) in the treatment of rheumatoid arthritis (RA)1–3. Despite the advent of new effective biologic agents, MTX is still used as an anchor drug to enhance or maintain the efficacy of biologic agents4–10. Although MTX has been commonly used in patients with RA over the last 2 decades, clinical practice varies considerably among rheumatologists. It is unclear whether this variation reflects conflicting evidence in the literature or variable application of the evidence in clinical practice.

3e Initiative in Rheumatology

The 3e Initiative in Rheumatology (evidence, expertise, exchange) is a multinational effort aimed at promoting evidence-based medicine by formulating detailed recommendations addressing clinical problems11. The objective of the 3e Initiative 2007–2008 was to develop practical recommendations for the use of MTX in rheumatic disorders, by integrating systematically generated evidence and expert opinion of a broad panel of international rheumatologists. Ten clinical questions on MTX were selected by rheumatologists from 17 countries in Europe and North and South America. The Canadian participants selected 5 additional questions pertaining to drug interaction, monitoring, predictor of response, patient preference, and management of nuisance side effects. The recommendations for the 10 international questions have been published12. This article presents the summary of the evidence and the recommendations for the additional Canadian questions.

MATERIALS AND METHODS

Stakeholders

The Canadian 3e Initiative group consisted of a steering group, a bibliographic team, and an expert committee. The steering group included the principal investigator (CB) and 8 members (VB, BH, SL, DM, JP, KS, JT, and CT). The bibliographic team included 5 rheumatology fellows (WK, JB, JD, TD, and GR) who undertook a systematic review of literature assisted by 3 mentors (CB, BH, and JP). Twenty-six Canadian rheumatologists from across Canada representing academic and community practices formed the expert committee. They reviewed the evidence from the systematic reviews prepared by the bibliographic team and formulated practice recommendations.

Evidence based approach

The methodology for the systematic review and for the practice recommendations is presented in Figure 1. The 5 Canadian questions (Table 1) were selected by the Canadian Steering Committee at the international meeting held April 27–28, 2007. A systematic search of Medline, Embase, and Cochrane Central Register of Controlled Trials to September 2007 was carried out by the bibliographic team assisted by experienced librarians. The sensitive search strategy included MeSH terms, keywords, and text words related to RA and MTX, and other terms specific to each of the 5 questions (Table 1) included: drug toxicity, adverse effects, drug interaction, patient preference, monitor, treatment outcome, and predictor; there were no restrictions on language. To supplement these electronic bibliographic databases, abstracts from annual scientific meetings were also searched (American College of Rheumatology and European League Against Rheumatism 2005–2007). The reference lists of retrieved articles and reviews were also reviewed. To identify eligible articles, prespecified inclusion and exclusion criteria were applied to the citations obtained from the search strategies. These included population (RA), drug (MTX), and for each question specific interventions and outcome measures. Retained studies were systematically reviewed for quality assessment, data extraction, and synthesis. The evidence was summarized. The level of evidence and grade of recommendation were scored using “The Oxford Centre for Evidence-based Medicine Level of Evidence (May 2001)” (URL: www.cebm.net/index.aspx?o=1047) (⇔Table 2). A series of full systematic reviews13–16 underpins the recommendations for the Canadian questions. Four are published in this issue of The Journal14–16.

Figure 1.
Figure 1.

The methodology for the systematic review and the practice recommendations.

View this table:
Table 1.

The 5 Canadian questions formulated for the 3e Initiative.

View this table:
Table 2A.

Levels of evidence. From the Oxford Centre for Evidence-based Medicine, available from http://www.cebm.net/index.aspx?o=1047; with permission.

View this table:
Table 2B.

Grades of recommendation.

Expert opinion approach

Summaries of the systematic reviews on the 5 topics were presented to the Canadian expert committee at a national meeting in January 2008. Draft recommendations were formulated by the expert committee based on the results of the systematic review. These recommendations were discussed and reworded using the nominal group approach17. The final statements were established using a touch-pad voting process with prespecified cutoff agreement. Additionally, participants expressed their level of agreement with the final recommendation using a numeric scale from 0 to 100.

RESULTS

For the 5 questions, the literature search identified 9603 citations. After applying the inclusion and exclusion criteria, 93 full-length articles were retained for systematic review. Table 3 presents the final set of 5 recommendations, their level of evidence, the strength of the recommendations, and the agreement among experts based on touch-pad voting.

View this table:
Table 3.

Canadian recommendations on the use of methotrexate (MTX) in patients with rheumatoid arthritis (RA), level of evidence, strength of recommendations, and voting agreement.

Recommendation 1: Drug Interactions

  • The majority of drugs including nonsteroidal antiinflammatory drugs (NSAID) may be used safely in combination with MTX in rheumatic diseases (Grade of recommendation C).

  • Trimethoprim and sulfamethoxazole (TMP-SMX) should be avoided in patients treated with MTX (Grade of recommendation C).

These recommendations are based on the systematic review of 21 pharmacokinetics studies, 5 observational studies, and 78 case reports (Level of evidence 4)16. Cytopenia and elevation of liver enzymes were the main reported toxicities. Most reports of cytopenia were attributed to the use of concomitant NSAID or high-dose aspirin (ASA)18–31. Other medications, e.g., antibiotics, gastroprotective agents, and antihypertensive drugs, have been noted in case reports.

Most NSAID and selective cyclooxygenase-2 inhibitors did not significantly affect the pharmacokinetic profile of MTX32–44. For ibuprofen and naproxen, studies showed conflicting results33–35. Four studies evaluating high-dose ASA (1.3–4.5 g/day) reported an increase of serum concentration of MTX45–48 (Level of evidence 4).

The use of TMP-SMX was mentioned as a risk factor for developing bone marrow suppression in one retrospective case-control study49 and in 17 case reports18,50–62 (Level of evidence 4).

Cytopenia and elevated liver enzymes were reported with several medications other than NSAID and TMP-SMX, but in only one to a few cases each. Experts agreed that the evidence was not strong enough to make a recommendation. Some experts also proposed that drugs that affect renal function should be used cautiously in patients receiving MTX; however, there was no evidence directly supporting this statement, and the expert committees’ agreement for this statement was only 41%. Consequently, it was not included in the final recommendation.

Recommendation 2: Prognostic Factors for Response to MTX

  • In determining treatment strategy of patients treated with MTX, characteristics of poor prognosis should be considered, such as female sex and persistent disease activity (Grade of recommendation B).

This recommendation is based on the systematic review15 consisting of 2 metaanalyses63,64, 3 cohorts of MTX-treated RA65–67, and 4 cohorts using data from randomized controlled trials68–71 (Level of evidence 2b). Both early RA64,65,68–71 and long-standing RA66,67 were included. The dose of MTX used in these studies ranged from 15 to 25 mg/wk. Poor clinical response was defined as a lack of evidence of achieving a low disease activity state, measured by Disease Activity Score (DAS) < 2.465,66, DAS28 < 3.267, or Simplified Disease Activity Index score (SDAI) ≤ 1164 at the end of followup, while poor radiographic outcome was defined as having evidence of significant radiographic progression, measured by Sharp score70,71, Modified Sharp/van der Heijde score69, or Modified Larsen score68 at the end of followup.

Predictors of poor response to MTX include female sex65–67, prior use of DMARD67, high disease activity at baseline measured by DAS65,66 or SDAI64, and high tender joint count67. Other predictors considered in the published literature were not found to be independent predictors of clinical response in both early and established RA.

Predictors of poor radiographic outcome include high baseline erythrocyte sedimentation rate (ESR)68,69, particularly in patients with persistent evidence of inflammation, e.g., high DAS2869, ESR69,71, and C-reactive protein (CRP)69,71.

These studies consistently identify disease activity as a predictor of poor response to MTX. Since different measures of disease activity were used across the studies, the expert panel decided to use the general term “persistent disease activity” instead of specifying the individual parameters of disease activity (e.g., DAS28, tender joint count, etc.).

Recommendation 3: Management of Non-serious Side Effects

  1. To minimize non-serious gastrointestinal side effects of MTX one could try to switch from oral to parenteral (subcutaneous or intramuscular) MTX (Grade of recommendation D).

  2. Other strategies to minimize non-serious side effects could include splitting of the dose of MTX (Grade of recommendation D).

The systematic review “Strategies to Reduce “Nuisance” Side-Effects of Methotrexate”13 failed to find direct evidence to support the benefit of modalities to reduce nuisance side effects. Experimental evidence from appropriately designed clinical trials was not available; these recommendations are, therefore, based on extrapolation from studies demonstrating that intramuscular (im) form is more tolerable than oral form in 2 cohorts (Level of evidence 4). In a survey of patients forced to switch to oral MTX when the supply of im MTX ran out72, 69 (48%) patients who tolerated im MTX could not tolerate taking it orally due to nausea (p < 0.001). In a RA cohort of 212 patients73, switching from oral to im MTX was found to decrease gastrointestinal side effects: after 6 months only 9% terminated im MTX due to adverse events.

The recommendation for splitting the dose of MTX was based entirely on expert opinion due to a lack of evidence addressing this issue. The only evidence related to the dose of MTX was from an open-labeled RCT74 showing that starting MTX treatment at a dose of 25 mg/week was associated with a higher rate of minor toxicity (gastrointestinal except liver toxicity) as compared to 15 mg/week (28% vs 17%, p < 0.05, for 25 vs 15 mg/wk, respectively) (Level of evidence 4).

Other strategies or modalities have been studied; however, the expert panel chose not to make recommendations on these modalities due to insufficient evidence75–77.

Recommendation 4: Parameter Used in the Assessment of Clinical Response

  1. Use of validated outcome measures to reach a target of low disease activity or remission is recommended (Grade of recommendation A).

  2. Joint counts should be included in the assessment of disease activity in RA (Grade of recommendation B).

  3. In addition to joint counts, other parameters in the assessment of disease activity in RA could include validated measures of global assessments and acute-phase reactants (Grade of recommendation B).

The systematic review on this topic showed that there was no evidence for which parameters should be used in management of patients with RA to assess a clinically meaningful response in daily practice14. These recommendations were extrapolated from 3 randomized controlled trials of tight control strategy in RA identified by experts (Level of evidence 1a). These studies78–80 demonstrated that targeted care aiming at remission or low disease activity and frequent followup (every month) may lead to more aggressive treatment, resulting in better disease states/clinical outcomes than usual care in RA. These studies used different outcome measures to assess the clinical response. DAS and DAS28 were used in the TICORA study78 and in Fransen, et al79, respectively; whereas in the CAMERA study80, a computer program was used to calculate the 50% improvement response in swollen joint count and the improvement of at least 2 out of 3 of the following variables: number of tender joints, ESR, and patient global assessment of general well-being.

Based on the results of these 3 RCT, all experts but one agreed that in clinical practice validated outcome measures aiming at remission or at least low disease activity should be used to assess clinically meaningful response. Although there is a lack of evidence on which parameter should be used in daily practice, the group reached the following consensus: the use of patient or physician global assessments alone is not sufficient; joint assessment is the most important parameter reflecting disease activity; and other variables including patient global assessment, physician global assessment, and inflammatory marker, e.g., ESR or CRP, should be considered in addition to joint count in the assessment of RA disease activity.

Recommendation 5: Patient preference

  • Patients need to be educated on their disease and treatment options and involved in the decision-making process (Grade of recommendation D).

This recommendation is entirely expert-based. There is no evidence in the literature that incorporating RA patients’ preference in the therapeutic decision improves treatment outcomes, adherence to medications, or patient satisfaction in those taking MTX. Nonetheless, the expert panels agreed that shared decision-making should incorporate patient’s preference, research evidence, and knowledge of the patient’s clinical state. In addition, the expert panel was also aware of the role and impact of patient education on the treatment outcomes based on a Cochrane review, “Patient education for adults with RA”81 (Level of evidence 2b). The results of this review supported a beneficial effect of patient education programs in terms of pain (small benefit, 4% or 0.2 cm in the visual analog scale), functional impairment (moderate benefit, 10% or 0.16 points on the Health Assessment Questionnaire score), tender joint count (moderate benefit, 9% or 1.3 points on the Ritchie index), patient’s overall assessment [moderate benefit, 12% or 0.28 points on the Arthritis Impact Measurement Scales 2 (AIMS2) arthritis subscale], and psychological status (moderate benefit, 5% or 0.15 points on the AIMS2 affect subscale and 12% or 0.14 points on the Hospital Anxiety and Depression Scale). However, no lasting benefits were found at one year after the end of the educational program. These effects were related chiefly to educational programs, as opposed to simple patient information.

DISCUSSION

These recommendations were developed using an evidence-based approach. A methodology team conducted systematic reviews using a comprehensive search in 2 bibliographic databases, Medline and Embase, plus screening of abstracts of scientific meetings. A group of clinical experts considered the quality of the evidence from these systematic reviews as well as the clinical relevance, applicability, and values and preferences of patients and practitioners to ensure that recommendations meet their needs.

We followed an established group decision method, the nominal group process. This included a representative expert panel of academic and community rheumatologists from across Canada, who openly discussed the evidence from the literature followed by a silent voting process. We used the touch-pad methodology with prespecified cutoff levels of agreement to generate the final recommendations. Several rounds of rewording and revoting were sometimes required to reach the agreed cutoff. This process ensured that the final recommendations were evidence-driven as well as clinically relevant.

Of the 15 questions initially proposed by the Canadian steering committee at the international meeting of the 3e Initiative, 10 were also rated highly by the 17 participating countries. Recommendations for these 10 top-rated international questions have been published12. This article addressed the 5 remaining Canadian questions. Although these 5 questions are clinically important, the 10 international questions addressing MTX initiation, monitoring, and safety were considered of higher priority by the international experts. In their selection of the top 10 questions, experts may also have taken into account whether there would be sufficient evidence in the literature to generate robust recommendations. Indeed, we found that many of the 5 questions lacked high-quality studies, or studies were not specifically related to MTX treatment; for instance, no study directly addressed which of the objective parameters should be used to assess the clinical response to MTX, or should patient preference be taken into account in MTX treatment decisions. Our recommendations were, therefore, based on expert opinion, resulting in the lowest “grade of recommendation” on the Oxford scale. Nevertheless, our recommendations emphasize the need for future research in these clinically important areas.

Of several recent guidelines available to assist in the management of patients with RA82–86, none addressed our question on drug interactions. Most guidelines addressed none or just a few of our 5 questions, but where our questions were addressed, the result was generally congruent with our recommendations.

In conclusion, using a nominal group process and scientific evidence, we provide recommendations for the use of MTX in patients with RA to assist specialists in everyday practice. These 9 Canadian recommendations complement the 10 recommendations from the international 3e Initiative expert panel. These recommendations are intended to benefit all patients with RA who receive MTX therapy.

Acknowledgments

Canadian 3e Initiative Consensus Group: Kenneth Blocka, Cathy Elizabeth Flanagan, Paul Davis, Wojciech Olszynski, Vandana Ahluwalia, Michel Zummer, Gilles Boire, Jamie Henderson, Barry Koehler, Philip Baer, Zareen Ahmad, Anne St-Pierre, Martin Cohen, Maysan Abu-Hakima, Majed Khraishi, Elaine Soucy, and Jacob Karsh.

Footnotes

  • Full Release Article. For details see Reprints/Permissions at jrheum.org

  • Supported by an unrestricted educational grant from Abbott. Dr. Bombardier holds a Canada Research Chair in Knowledge Transfer for Musculoskeletal Care.

  • Accepted for publication December 13, 2009.

Free online via JRheum Full Release option

REFERENCES

  1. 1.↵
    1. Tugwell P,
    2. Bennett K,
    3. Gent M
    . Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. Ann Intern Med 1987;107:358–66.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Felson DT,
    2. Anderson JJ,
    3. Meenan RF
    . The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: results of two metaanalyses. Arthritis Rheum 1990;33:1449–61.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Felson DT,
    2. Anderson JJ,
    3. Meenan RF
    . Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum 1992;35:1117–25.
    OpenUrlPubMed
  4. 4.↵
    1. van der Heijde D,
    2. Burmester G,
    3. Melo-Gomes J,
    4. Codreanu C,
    5. Mola EM,
    6. Pedersen R,
    7. et al.
    The safety and efficacy of adding etanercept to methotrexate or methotrexate to etanercept in moderately active rheumatoid arthritis patients previously treated with monotherapy. Ann Rheum Dis 2008;67:182–8.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Lipsky PE,
    2. van der Heijde D,
    3. St. Clair EW,
    4. Furst DE,
    5. Breedveld FC,
    6. Kalden JR,
    7. et al.
    Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594–602.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. St. Clair W,
    2. van der Heijde D,
    3. Smolen J,
    4. Maini R,
    5. Bathon J,
    6. Emery P,
    7. et al.
    Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial. Arthritis Rheum 2004;50:3432–43.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Breedveld FC,
    2. Weisman MH,
    3. Kavanaugh AF,
    4. Cohen SB,
    5. Pavelka K,
    6. van Vollenhoven R,
    7. et al.
    The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006;54:26–37.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Heiberg MS,
    2. Rodevand E,
    3. Mikkelsen K,
    4. Kaufmann C,
    5. Didriksen A,
    6. Mowinckel P,
    7. et al.
    Adalimumab and methotrexate is more effective than adalimumab alone in patients with established rheumatoid arthritis: results from a 6-month longitudinal, observational, multicentre study. Ann Rheum Dis 2006;65:1379–83.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Cohen SB,
    2. Emery P,
    3. Greenwald MW,
    4. Dougados M,
    5. Furie RA,
    6. Genovese MC,
    7. et al.
    Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793–806.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Emery P,
    2. Fleischmann R,
    3. Filipowicz-Sosnowska A,
    4. Schechtman J,
    5. Szczepanski L,
    6. Kavanaugh A,
    7. et al.
    The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390–400.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Sidiropoulos PI,
    2. Hatemi G,
    3. Song IH,
    4. Avouac J,
    5. Collantes E,
    6. Hamuryudan V,
    7. et al.
    Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practising rheumatologists. Rheumatology 2008;47:355–61.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Visser K,
    2. Katchamart W,
    3. Loza E,
    4. Martinez-Lopez JA,
    5. Salliot C,
    6. Trudeau J,
    7. et al.
    Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3e Initiative. Ann Rheum Dis 2009;68:1086–93.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Rohekar G,
    2. Pope J
    . Strategies to reduce “nuisance” side-effects of methotrexate: A systematic review. (Manuscript in preparation)
  14. 14.↵
    1. Katchamart W,
    2. Bombardier C
    . Systematic monitoring of disease activity using an outcome measure improves outcomes in rheumatoid arthritis. J Rheumatol 2010 May 1. Epub ahead of print.
  15. 15.↵
    1. Drouin J,
    2. Haraoui B
    . Predictors of clinical response and radiographic progression in rheumatoid patients treated with methotrexate monotherapy. J Rheumatol 2009;37:1405–10.
    OpenUrl
  16. 16.↵
    1. Bourre-Tessier J,
    2. Haraoui B
    . Methotrexate drug interactions: a systematic review of the literature. J Rheumatol 2009;37:1416–21.
    OpenUrl
  17. 17.↵
    1. Fink A,
    2. Kosecoff J,
    3. Chassin M,
    4. Brook RH
    . Consensus methods: characteristics and guidelines for use. Am J Public Health 1984;74:979–83.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Franck H,
    2. Rau R,
    3. Herborn G
    . Thrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dose methotrexate. Clin Rheumatol 1996;15:266–70.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Singh RR,
    2. Malaviya AN,
    3. Pandey JN,
    4. Guleria JS
    . Fatal interaction between methotrexate and naproxen [letter]. Lancet 1986;i:1390.
    OpenUrlPubMed
  20. 20.↵
    1. Kraus A,
    2. Alarcon-Segovia D
    . Low dose MTX and NSAID induced “mild” renal insufficiency and severe neutropenia [letter]. J Rheumatol 1991;18:1274.
    OpenUrlPubMed
  21. 21.↵
    1. Ohosone Y,
    2. Okano Y,
    3. Kameda H,
    4. Hama N,
    5. Mimori T,
    6. Akizuki M,
    7. et al.
    Clinical characteristics related to methotrexate-induced pancytopenia [letter]. Clin Rheumatol 1997;16:321–3.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Calvo-Romero JM
    . Severe pancytopenia associated with low-dose methotrexate therapy for rheumatoid arthritis. Ann Pharmacother 2001;35:1575–7.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Basin KS,
    2. Escalante A,
    3. Beardmore TD
    . Severe pancytopenia in a patient taking low dose methotrexate and probenecid. J Rheumatol 1991;18:609–10.
    OpenUrlPubMed
  24. 24.↵
    1. Frenia ML,
    2. Long KS
    . Methotrexate and nonsteroidal antiinflammatory drug interactions. Ann Pharmacother 1992;26:234–7.
    OpenUrlPubMed
  25. 25.↵
    1. Thonofer R,
    2. Kriessmayr M,
    3. Thonofer U,
    4. Wipfler E,
    5. Uitz E,
    6. Bahadori B,
    7. et al.
    Rheumatoid arthritis patients with therapy-induced myelodysplastic syndrome present with long-term remission after recovery. Scand J Rheumatol 2007;36:149–50.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Berthelot JM,
    2. Maugars Y,
    3. Hamidou M,
    4. Chiffoleau A,
    5. Barrier J,
    6. Grolleau JY,
    7. et al.
    Pancytopenia and severe cytopenia induced by low-dose methotrexate. Eight case-reports and a review of one hundred cases from the literature (with twenty-four deaths). Rev Rhum (Engl Ed) 1995;62:477–86.
    OpenUrlPubMed
  27. 27.↵
    1. Tanaka Y,
    2. Shiozawa K,
    3. Nishibayashi Y,
    4. Imura S
    . Methotrexate induced early onset pancytopenia in rheumatoid arthritis: Drug allergy? Idiosyncrasy? [letter]. J Rheumatol 1992;19:1320–1.
    OpenUrlPubMed
  28. 28.↵
    1. Laroche F,
    2. Perrot S,
    3. Menkes CJ
    . Pancytopenia in rheumatoid arthritis patients receiving methotrexate [French]. Presse Med 1996;25:1144–6.
    OpenUrlPubMed
  29. 29.↵
    1. Serraj K,
    2. Federici L,
    3. Maloisel F,
    4. Alt M,
    5. Andres E
    . Pancytopenia related to low-dose methotrexate: study of five cases and review of the literature. Rev Med Interne 2007;28:584–8.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Maier WP,
    2. Leon-Perez R,
    3. Miller SB
    . Pneumonitis during low-dose methotrexate therapy. Arch Intern Med 1986;146:602–3.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Doolittle GC,
    2. Simpson KM,
    3. Lindsley HB
    . Methotrexate-associated, early-onset pancytopenia in rheumatoid arthritis. Arch Intern Med 1989;149:1430–1.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Karim A,
    2. Tolbert DS,
    3. Hunt TL,
    4. Hubbard RC,
    5. Harper KM,
    6. Geis GS
    . Celecoxib, a specific cox-2 inhibitor, has no significant effect on methotrexate pharmacokinetics in patients with rheumatoid arthritis. J Rheumatol 1999;26:2539–43.
    OpenUrlPubMed
  33. 33.↵
    1. Tracy TS,
    2. Worster T,
    3. Bradley JD,
    4. Greene PK,
    5. Brater DC
    . Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis. Br J Clin Pharmacol 1994;37:453–6.
    OpenUrlPubMed
  34. 34.↵
    1. Stewart CF,
    2. Fleming RA,
    3. Arkin CR,
    4. Evans WE
    . Coadministration of naproxen and low-dose methotrexate in patients with rheumatoid arthritis. Clin Pharmacol Ther 1990;47:540–6.
    OpenUrlPubMed
  35. 35.↵
    1. Skeith KJ,
    2. Russell AS,
    3. Jamali F,
    4. Coates J,
    5. Friedman H
    . Lack of significant interaction between low dose methotrexate and ibuprofen or flurbiprofen in patients with arthritis. J Rheumatol 1990;17:1008–10.
    OpenUrlPubMed
  36. 36.↵
    1. Vakily M,
    2. Amer F,
    3. Kukulka MJ,
    4. Andhivarothai N
    . Coadministration of lansoprazole and naproxen does not affect the pharmacokinetic profile of methotrexate in adult patients with rheumatoid arthritis. J Clin Pharmacol 2005;45:1179–86.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Hartmann SN,
    2. Rordorf CM,
    3. Milosavljev S,
    4. Branson JM,
    5. Chales GH,
    6. Juvin RR,
    7. et al.
    Lumiracoxib does not affect methotrexate pharmacokinetics in rheumatoid arthritis patients. Ann Pharmacother 2004;38:1582–7.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Hamilton SF,
    2. Campbell NR,
    3. Kara M,
    4. Watson J,
    5. Connors M
    . The effect of ingestion of ferrous sulfate on the absorption of oral methotrexate in patients with rheumatoid arthritis. J Rheumatol 2003;30:1948–50.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Schwartz JI,
    2. Agrawal NG,
    3. Wong PH,
    4. Bachmann KA,
    5. Porras AG,
    6. Miller JL,
    7. et al.
    Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients. J Clin Pharmacol 2001;41:1120–30.
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Iqbal MP,
    2. Baig JA,
    3. Ali AA,
    4. Niazi SK,
    5. Mehboobali N,
    6. Hussain MA
    . The effects of non-steroidal anti-inflammatory drugs on the disposition of methotrexate in patients with rheumatoid arthritis. Biopharm Drug Dispos 1998;19:163–7.
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Hubner G,
    2. Sander O,
    3. Degner FL,
    4. Türck D,
    5. Rau R
    . Lack of pharmacokinetic interaction of meloxicam with methotrexate in patients with rheumatoid arthritis. J Rheumatol 1997;24:845–51.
    OpenUrlPubMed
  42. 42.↵
    1. Gumbhir-Shah K,
    2. Cevallos WH,
    3. DeCleene SA,
    4. Korth-Bradley JM
    . Lack of interaction between bromfenac and methotrexate in patients with rheumatoid arthritis J Rheumatol 1996;23:984–9.
    OpenUrlPubMed
  43. 43.↵
    1. Ahern M,
    2. Booth J,
    3. Loxton A,
    4. McCarthy P,
    5. Meffin P,
    6. Kevat S
    . Methotrexate kinetics in rheumatoid arthritis: Is there an interaction with nonsteroidal antiinflammatory drugs? J Rheumatol 1988;15:1356–60.
    OpenUrlPubMed
  44. 44.↵
    1. Svendsen KB,
    2. Bech JN,
    3. Pfeiffer-Jensen M,
    4. Stengaard-Pederson K,
    5. Pederson EB
    . Urinary excretion of alpha-GST and albumin in rheumatoid arthritis patients treated with methotrexate or other DMARDs alone or in combination with NSAIDs. Scand J Rheumatol 2005;34:34–9.
    OpenUrlCrossRefPubMed
  45. 45.↵
    1. Stewart CF,
    2. Fleming RA,
    3. Germain BF,
    4. Seleznick MJ,
    5. Evans WE
    . Aspirin alters methotrexate disposition in rheumatoid arthritis patients. Arthritis Rheum 1991;34:1514–20.
    OpenUrlPubMed
  46. 46.↵
    1. Seideman P,
    2. Muller-Suur R
    . Renal effects of aspirin and low dose methotrexate in rheumatoid arthritis. Ann Rheum Dis 1993;52:613–5.
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. Tracy TS,
    2. Krohn K,
    3. Jones DR,
    4. Bradley JD,
    5. Hall SD,
    6. Brater DC
    . The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis. Eur J Clin Pharmacol 1992;42:121–5.
    OpenUrlCrossRefPubMed
  48. 48.↵
    1. Furst DE,
    2. Herman RA,
    3. Koehnke R,
    4. Ericksen N,
    5. Hash L,
    6. Riggs CE,
    7. et al.
    Effect of aspirin and sulindac on methotrexate clearance. J Pharm Sci 1990;79:782–6.
    OpenUrlPubMed
  49. 49.↵
    1. Al-Awadhi A,
    2. Dale P,
    3. McKendry R
    . Pancytopenia associated with low dose methotrexate therapy. A regional survey. J Rheumatol 1993;20:1121–5.
    OpenUrlPubMed
  50. 50.↵
    1. Kaneko Y,
    2. Suwa A,
    3. Ikeda Y,
    4. Hirakata M
    . Pneumocystis jiroveci pneumonia associated with low-dose methotrexate treatment for rheumatoid arthritis: report of two cases and review of the literature. Mod Rheumatol 2006;16:36–8.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. Sosin M,
    2. Handa S
    . Low dose methotrexate and bone marrow suppression. BMJ 2003;326:266–7.
    OpenUrlFREE Full Text
  52. 52.↵
    1. Saravana S,
    2. Lalukotta K
    . Myelotoxicity due to methotrexate — an iatrogenic cause [letter]. Eur J Haematol 2003;71:315–6.
    OpenUrlCrossRefPubMed
  53. 53.↵
    1. Chevrel G,
    2. Brantus JF,
    3. Sainte-Laudy J,
    4. Miossec P
    . Allergic pancytopenia to trimethoprim-sulphamethoxazole for pneumocystis carinii pneumonia following methotrexate treatment for rheumatoid arthritis [letter]. Rheumatology 1999;38:475–6.
    OpenUrlFREE Full Text
  54. 54.↵
    1. Steuer A,
    2. Gumpel JM
    . Methotrexate and trimethoprim: a fatal interaction [letter]. Br J Rheumatol 1998;37:105–6.
    OpenUrlFREE Full Text
  55. 55.↵
    1. Nygaard H
    . Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis: comment on the article by Gutierrez-Urena, et al [letter]. Arthritis Rheum 1997;40:194–5.
    OpenUrlCrossRefPubMed
  56. 56.↵
    1. Govert J,
    2. Patton S,
    3. Fine R
    . Pancytopenia from using trimethoprim and methotrexate [letter]. Ann Intern Med 1992;117:877–8.
    OpenUrlPubMed
  57. 57.↵
    1. Groenendal H,
    2. Rampen FH
    . Methotrexate and trimethoprim-sulphamethoxazole — a potentially hazardous combination. Clin Exp Dermatol 1990;15:358–60.
    OpenUrlCrossRefPubMed
  58. 58.↵
    1. Jeurissen M,
    2. Boerbooms A,
    3. van de Putte L
    . Pancytopenia and methotrexate with trimethoprim-sulfamethoxazole [letter]. Ann Intern Med 1989;111:261.
    OpenUrlPubMed
  59. 59.↵
    1. Buchbinder R,
    2. Hall S,
    3. Ryan PFJ,
    4. Littlejohn GO,
    5. Harkness AJL
    . Severe bone marrow failure due to low dose oral methotrexate [letter]. J Rheumatol 1988;15:1586–8.
    OpenUrlPubMed
  60. 60.↵
    1. Thevenet JP,
    2. Ristori JM,
    3. Cure H,
    4. Mizony MH,
    5. Bussiere JL
    . Pancytopenia during treatment of rheumatoid arthritis with methotrexate after administration of trimethoprim-sulfamethoxazole [French]. Presse Med 1987;16:1487.
    OpenUrlPubMed
  61. 61.↵
    1. Thomas MH,
    2. Gutterman LA
    . Methotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole. J Rheumatol 1986;13:440–1.
    OpenUrlPubMed
  62. 62.↵
    1. Maricic M,
    2. Davis M,
    3. Gall E
    . Megaloblastic pancytopenia in a patient receiving concurrent methotrexate and trimethoprim-sulfamethoxazole treatment. Arthritis Rheum 1986;29:133–5.
    OpenUrlPubMed
  63. 63.↵
    The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis. Rheumatoid Arthritis Clinical Trial Archive Group. J Rheumatol 1995;22:218–23.
    OpenUrlPubMed
  64. 64.↵
    1. Aletaha D,
    2. Funovits J,
    3. Keystone E,
    4. Smolen J
    . Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients. Arthritis Rheum 2007;56:3226–35.
    OpenUrlCrossRefPubMed
  65. 65.↵
    1. Wessels J,
    2. van der Kooij SM,
    3. le Cessie S,
    4. Kievit W,
    5. Barerra P,
    6. Allaart CF,
    7. et al.
    A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum 2007;56:1765–75.
    OpenUrlCrossRefPubMed
  66. 66.↵
    1. Hoekstra M,
    2. van Ede AE,
    3. Haagsma CJ,
    4. van de Laar MAFJ,
    5. Huizinga TWJ,
    6. Kruijsen MWM,
    7. et al.
    Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis 2003;62:423–6.
    OpenUrlAbstract/FREE Full Text
  67. 67.↵
    1. Lie E,
    2. Heiberg MS,
    3. Nordvag BY,
    4. Rodevand E,
    5. Kaufmann C,
    6. Mikkelsen K,
    7. et al.
    Predictors of response to methotrexate treatment: Results from a longitudinal observational study of 876 patients with RA. Ann Rheum Dis 2006;65 Suppl II:342.
    OpenUrlAbstract/FREE Full Text
  68. 68.↵
    1. Rau R,
    2. Herborn G,
    3. Menninger H,
    4. Sangha O
    . Progression in early erosive rheumatoid arthritis: 12 month results from a randomized controlled trial comparing methotrexate and gold sodium thiomalate. Br J Rheumatol 1998;37:1220–6.
    OpenUrlAbstract/FREE Full Text
  69. 69.↵
    1. Smolen JS,
    2. van der Heijde D,
    3. St. Clair W,
    4. Emery P,
    5. Bathon JM,
    6. Keystone E,
    7. et al.
    Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: Results from the ASPIRE trial. Arthritis Rheum 2006;54:702–10.
    OpenUrlCrossRefPubMed
  70. 70.↵
    1. Van der Heijde D,
    2. Landewe R,
    3. Sharp JT,
    4. Bathon J,
    5. Patra K,
    6. Spencer-Green G
    . Baseline CRP concentrations predict radiographic progression in MTX-naive patients with early RA: Subanalysis of the PREMIER study. Ann Rheum Dis 2005;64 Suppl III:436.
    OpenUrl
  71. 71.↵
    1. Weinblatt M,
    2. Keystone EC,
    3. Cohen MD,
    4. Freundlich B,
    5. Li J,
    6. Chon Y,
    7. et al.
    Predictors of poor radiographic response in rheumatoid arthritis subjects treated with methotrexate: preliminary analysis from ERA and TEMPO studies [abstract]. Arthritis Rheum 2006;54 Suppl:S181.
    OpenUrl
  72. 72.↵
    1. Wegrzyn J,
    2. Adeleine P,
    3. Miossec P
    . Better efficacy of methotrexate given by intramuscular injection than orally in patients with rheumatoid arthritis. Ann Rheum Dis 2004;63:1232–4.
    OpenUrlAbstract/FREE Full Text
  73. 73.↵
    1. Linde L,
    2. Hetland ML,
    3. Ostergaard M
    . Drug survival and reasons for discontinuation of intramuscular methotrexate: a study of 212 consecutive patients switching from oral methotrexate. Scand J Rheumatol 2006;35:102–6.
    OpenUrlCrossRefPubMed
  74. 74.↵
    1. Schnabel A,
    2. Reinhold-Keller E,
    3. Willmann V,
    4. Gross W
    . Tolerability of methotrexate starting with 15 or 25 mg/week for rheumatoid arthritis. Rheumatol Int 1994;14:33–8.
    OpenUrlCrossRefPubMed
  75. 75.↵
    1. Luis M,
    2. Pacheco-Tena C,
    3. Cazarín-Barrientos J,
    4. Lino-Pérez L,
    5. Goycochea MV,
    6. Vázquez-Mellado J,
    7. et al.
    Comparison of two schedules for administering oral low-dose methotrexate (weekly versus every-other-week) in patients with rheumatoid arthritis in remission: A twenty-four-week, single-blind, randomized study. Arthritis Rheum 1999;42:2160–5.
    OpenUrlCrossRefPubMed
  76. 76.↵
    1. Wu Y,
    2. Lao Z,
    3. Zhang Z
    . Clinical observation on small doses Tripterygium wilfordii polyglycoside combined with methotrexate in treating rheumatoid arthritis. Zhongguo Zhong Xi Yi Jie He Za Zhi 2001;21:895–6.
    OpenUrlPubMed
  77. 77.↵
    1. Yoshida T,
    2. Hirakata M
    . Therapeutic benefits of irsogladine maleate on aphthous stomatitis induced by methotrexate in rheumatoid arthritis. J Rheumatol 2003;30:2082–3.
    OpenUrlFREE Full Text
  78. 78.↵
    1. Grigor C,
    2. Capell H,
    3. Stirling A,
    4. McMahon AD,
    5. Lock P,
    6. Vallance R,
    7. et al.
    Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004;364:263–9.
    OpenUrlCrossRefPubMed
  79. 79.↵
    1. Fransen J,
    2. Moens H,
    3. Speyer I,
    4. van Riel P
    . Effectiveness of systematic monitoring of rheumatoid arthritis disease activity in daily practice: a multicentre, cluster randomised controlled trial. Ann Rheum Dis 2005;64:1294–8.
    OpenUrlAbstract/FREE Full Text
  80. 80.↵
    1. Verstappen SMM,
    2. Jacobs JWG,
    3. van der Veen MJ,
    4. Heurkens AHM,
    5. Schenk Y,
    6. ter Borg EJ,
    7. et al.
    Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis 2007;66:1443–9.
    OpenUrlAbstract/FREE Full Text
  81. 81.↵
    1. Riemsma R,
    2. Kirwan JR,
    3. Taal E,
    4. Rasker JJ
    . Patient education for adults with rheumatoid arthritis. Cochrane Database Syst Rev 2003: CD003688.
  82. 82.↵
    1. Saag KG,
    2. Gim GT,
    3. Patkar NM,
    4. Anuntiyo J,
    5. Finney C,
    6. Curtis JR,
    7. et al.
    American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Care Res 2008;59:762–84.
    OpenUrlCrossRef
  83. 83.↵
    1. Deighton C,
    2. O’Mahony R,
    3. Tosh J,
    4. Turner C,
    5. Rudolf M,
    6. Guideline Development Group
    . Management of rheumatoid arthritis: summary of NICE guidance. BMJ 2009;338:b702.
    OpenUrlFREE Full Text
  84. 84.↵
    1. Luqmani R,
    2. Hennell S,
    3. Estrach C,
    4. Birrell F,
    5. Bosworth A,
    6. Davenport G,
    7. et al.
    British Society for Rheumatology and British Health Professionals in Rheumatology: Guideline for the Management of Rheumatoid Arthritis (the first two years). Rheumatology 2006;45:1167–9.
    OpenUrlFREE Full Text
  85. 85.↵
    1. Fautrel B,
    2. Pham T,
    3. Gossec L,
    4. Combe B,
    5. Flipo RM,
    6. Goupille P,
    7. et al.
    Role and modalities of information and education in the management of patients with rheumatoid arthritis: development of recommendations for clinical practice based on published evidence and expert opinion. Joint Bone Spine 2005;72:163–70.
    OpenUrlCrossRefPubMed
  86. 86.↵
    1. Scott DL,
    2. Steer S
    . NICE guidelines on anti-tumor necrosis factor therapy for RA. Nat Clin Pract Rheumatol 2009;5:16–7.
    OpenUrlCrossRefPubMed
View Abstract
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools

 Request Permissions

Save to my folders

Jump to section