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Ann Rheum Dis. Aug 2001; 60(8): 729–735.
PMCID: PMC1753808

Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis

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  • GUBNER R, AUGUST S, GINSBERG V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci. 1951 Feb;221(2):176–182. [PubMed]
  • Willkens RF, Watson MA, Paxson CS. Low dose pulse methotrexate therapy in rheumatoid arthritis. J Rheumatol. 1980 Jul-Aug;7(4):501–505. [PubMed]
  • Wilke WS, Calabrese LH, Scherbel AL. Methotrexate in the treatment of rheumatoid arthritis; pilot study. Cleve Clin Q. 1980 Winter;47(4):305–309. [PubMed]
  • Michaels RM, Nashel DJ, Leonard A, Sliwinski AJ, Derbes SJ. Weekly intravenous methotrexate in the treatment of rheumatoid arthritis. Arthritis Rheum. 1982 Mar;25(3):339–341. [PubMed]
  • Steinsson K, Weinstein A, Korn J, Abeles M. Low dose methotrexate in rheumatoid arthritis. J Rheumatol. 1982 Nov-Dec;9(6):860–866. [PubMed]
  • Groff GD, Shenberger KN, Wilke WS, Taylor TH. Low dose oral methotrexate in rheumatoid arthritis: an uncontrolled trial and review of the literature. Semin Arthritis Rheum. 1983 May;12(4):333–347. [PubMed]
  • Hoffmeister RT. Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med. 1983 Dec 30;75(6A):69–73. [PubMed]
  • Thompson RN, Watts C, Edelman J, Esdaile J, Russell AS. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol. 1984 Dec;11(6):760–763. [PubMed]
  • Andersen PA, West SG, O'Dell JR, Via CS, Claypool RG, Kotzin BL. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann Intern Med. 1985 Oct;103(4):489–496. [PubMed]
  • Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, Trentham DE. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med. 1985 Mar 28;312(13):818–822. [PubMed]
  • Williams HJ, Willkens RF, Samuelson CO, Jr, Alarcón GS, Guttadauria M, Yarboro C, Polisson RP, Weiner SR, Luggen ME, Billingsley LM, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum. 1985 Jul;28(7):721–730. [PubMed]
  • Bookbinder SA, Espinoza LR, Fenske NA, Germain BF, Vasey FB. Methotrexate: its use in the rheumatic diseases. Clin Exp Rheumatol. 1984 Apr-Jun;2(2):185–193. [PubMed]
  • Cronstein BN, Naime D, Ostad E. The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest. 1993 Dec;92(6):2675–2682. [PMC free article] [PubMed]
  • Kremer JM. The mechanism of action of methotrexate in rheumatoid arthritis: the search continues. J Rheumatol. 1994 Jan;21(1):1–5. [PubMed]
  • Segal R, Caspi D, Tishler M, Wigler I, Yaron M. Short term effects of low dose methotrexate on the acute phase reaction in patients with rheumatoid arthritis. J Rheumatol. 1989 Jul;16(7):914–917. [PubMed]
  • Cronstein BN. The mechanism of action of methotrexate. Rheum Dis Clin North Am. 1997 Nov;23(4):739–755. [PubMed]
  • Genestier L, Paillot R, Fournel S, Ferraro C, Miossec P, Revillard JP. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest. 1998 Jul 15;102(2):322–328. [PMC free article] [PubMed]
  • Hu SK, Mitcho YL, Oronsky AL, Kerwar SS. Studies on the effect of methotrexate on macrophage function. J Rheumatol. 1988 Feb;15(2):206–209. [PubMed]
  • Johnson WJ, DiMartino MJ, Meunier PC, Muirhead KA, Hanna N. Methotrexate inhibits macrophage activation as well as vascular and cellular inflammatory events in rat adjuvant induced arthritis. J Rheumatol. 1988;15(5):745–749. [PubMed]
  • Cutolo M. Macrophages as effectors of the immunoendocrinologic interactions in autoimmune rheumatic diseases. Ann N Y Acad Sci. 1999 Jun 22;876:32–42. [PubMed]
  • Cronstein BN, Eberle MA, Gruber HE, Levin RI. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2441–2445. [PMC free article] [PubMed]
  • Sonneveld P, Schultz FW, Nooter K, Hählen K. Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in plasma and bone marrow of children receiving low-dose oral methotrexate. Cancer Chemother Pharmacol. 1986;18(2):111–116. [PubMed]
  • Baugh CM, Krumdieck CL, Nair MG. Polygammaglutamyl metabolites of methotrexate. Biochem Biophys Res Commun. 1973 May 1;52(1):27–34. [PubMed]
  • Zimmerman CL, Franz TJ, Slattery JT. Pharmacokinetics of the poly-gamma-glutamyl metabolites of methotrexate in skin and other tissues of rats and hairless mice. J Pharmacol Exp Ther. 1984 Nov;231(2):242–247. [PubMed]
  • Gruber HE, Hoffer ME, McAllister DR, Laikind PK, Lane TA, Schmid-Schoenbein GW, Engler RL. Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes, and injury. Circulation. 1989 Nov;80(5):1400–1411. [PubMed]
  • Bouma MG, Stad RK, van den Wildenberg FA, Buurman WA. Differential regulatory effects of adenosine on cytokine release by activated human monocytes. J Immunol. 1994 Nov 1;153(9):4159–4168. [PubMed]
  • Allegra CJ, Drake JC, Jolivet J, Chabner BA. Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates. Proc Natl Acad Sci U S A. 1985 Aug;82(15):4881–4885. [PMC free article] [PubMed]
  • Lazdins J, Karnovsky ML. Effect of phosphate esters, nucleotides and nucleosides on 5'-nucleotidase of cultured mouse macrophages. J Cell Physiol. 1978 Jul;96(1):115–122. [PubMed]
  • Edwards NL, Magilavy DB, Cassidy JT, Fox IH. Lymphocyte ecto-5'-nucleotidase deficiency in agammaglobulinemia. Science. 1978 Aug 18;201(4356):628–630. [PubMed]
  • Christensen LD, Andersen V, Nygaard P, Bendtzen K. Effects of immunomodulators on ecto-5'-nucleotidase activity on blood mononuclear cells in vitro. Scand J Immunol. 1992 Apr;35(4):407–413. [PubMed]
  • Armstrong MA, Shah S, Hawkins SA, Bell AL, Roberts SD. Reduction of monocyte 5'nucleotidase activity by gamma-interferon in multiple sclerosis and autoimmune diseases. Ann Neurol. 1988 Jul;24(1):12–16. [PubMed]
  • Savic V, Stefanovic V, Ardaillou N, Ardaillou R. Induction of ecto-5'-nucleotidase of rat cultured mesangial cells by interleukin-1 beta and tumour necrosis factor-alpha. Immunology. 1990 Jul;70(3):321–326. [PMC free article] [PubMed]
  • Mazzoni MR, Martini C, Lucacchini A. Regulation of agonist binding to A2A adenosine receptors: effects of guanine nucleotides (GDP[S] and GTP[S]) and Mg2+ ion. Biochim Biophys Acta. 1993 Dec 16;1220(1):76–84. [PubMed]
  • Morabito L, Montesinos MC, Schreibman DM, Balter L, Thompson LF, Resta R, Carlin G, Huie MA, Cronstein BN. Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5'-nucleotidase-mediated conversion of adenine nucleotides. J Clin Invest. 1998 Jan 15;101(2):295–300. [PMC free article] [PubMed]
  • Straub RH, Männel DN. How the immune system puts the brain to sleep. Nat Med. 1999 Aug;5(8):877–879. [PubMed]
  • Xaus J, Mirabet M, Lloberas J, Soler C, Lluis C, Franco R, Celada A. IFN-gamma up-regulates the A2B adenosine receptor expression in macrophages: a mechanism of macrophage deactivation. J Immunol. 1999 Mar 15;162(6):3607–3614. [PubMed]
  • Figueíredo F, Uhing RJ, Okonogi K, Gettys TW, Johnson SP, Adams DO, Prpic V. Activation of the cAMP cascade inhibits an early event involved in murine macrophage Ia expression. J Biol Chem. 1990 Jul 25;265(21):12317–12323. [PubMed]
  • Renz H, Gong JH, Schmidt A, Nain M, Gemsa D. Release of tumor necrosis factor-alpha from macrophages. Enhancement and suppression are dose-dependently regulated by prostaglandin E2 and cyclic nucleotides. J Immunol. 1988 Oct 1;141(7):2388–2393. [PubMed]
  • Snijdewint FG, Kaliński P, Wierenga EA, Bos JD, Kapsenberg ML. Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J Immunol. 1993 Jun 15;150(12):5321–5329. [PubMed]
  • Novogrodsky A, Patya M, Rubin AL, Stenzel KH. Agents that increase cellular cAMP inhibit production of interleukin-2, but not its activity. Biochem Biophys Res Commun. 1983 Jul 18;114(1):93–98. [PubMed]
  • van der Pouw Kraan TC, Boeije LC, Smeenk RJ, Wijdenes J, Aarden LA. Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production. J Exp Med. 1995 Feb 1;181(2):775–779. [PMC free article] [PubMed]
  • Rossi AG, McCutcheon JC, Roy N, Chilvers ER, Haslett C, Dransfield I. Regulation of macrophage phagocytosis of apoptotic cells by cAMP. J Immunol. 1998 Apr 1;160(7):3562–3568. [PubMed]
  • Koshiba M, Kojima H, Huang S, Apasov S, Sitkovsky MV. Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. J Biol Chem. 1997 Oct 10;272(41):25881–25889. [PubMed]
  • Link AA, Kino T, Worth JA, McGuire JL, Crane ML, Chrousos GP, Wilder RL, Elenkov IJ. Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. J Immunol. 2000 Jan 1;164(1):436–442. [PubMed]
  • Ritchie PK, Spangelo BL, Krzymowski DK, Rossiter TB, Kurth E, Judd AM. Adenosine increases interleukin 6 release and decreases tumour necrosis factor release from rat adrenal zona glomerulosa cells, ovarian cells, anterior pituitary cells, and peritoneal macrophages. Cytokine. 1997 Mar;9(3):187–198. [PubMed]
  • Haskó G, Szabó C, Németh ZH, Kvetan V, Pastores SM, Vizi ES. Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. J Immunol. 1996 Nov 15;157(10):4634–4640. [PubMed]
  • Sajjadi FG, Takabayashi K, Foster AC, Domingo RC, Firestein GS. Inhibition of TNF-alpha expression by adenosine: role of A3 adenosine receptors. J Immunol. 1996 May 1;156(9):3435–3442. [PubMed]
  • Haskó G, Németh ZH, Vizi ES, Salzman AL, Szabó C. An agonist of adenosine A3 receptors decreases interleukin-12 and interferon-gamma production and prevents lethality in endotoxemic mice. Eur J Pharmacol. 1998 Oct 9;358(3):261–268. [PubMed]
  • Huschtscha LI, Bartier WA, Ross CE, Tattersall MH. Characteristics of cancer cell death after exposure to cytotoxic drugs in vitro. Br J Cancer. 1996 Jan;73(1):54–60. [PMC free article] [PubMed]
  • Friesen C, Herr I, Krammer PH, Debatin KM. Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat Med. 1996 May;2(5):574–577. [PubMed]
  • Seitz M, Zwicker M, Loetscher P. Effects of methotrexate on differentiation of monocytes and production of cytokine inhibitors by monocytes. Arthritis Rheum. 1998 Nov;41(11):2032–2038. [PubMed]
  • Cutolo M, Bisso A, Sulli A, Felli L, Briata M, Pizzorni C, Villaggio B. Antiproliferative and antiinflammatory effects of methotrexate on cultured differentiating myeloid monocytic cells (THP-1) but not on synovial macrophages from patients with rheumatoid arthritis. J Rheumatol. 2000 Nov;27(11):2551–2557. [PubMed]
  • Seitz M, Loetscher P, Dewald B, Towbin H, Baggiolini M. In vitro modulation of cytokine, cytokine inhibitor, and prostaglandin E release from blood mononuclear cells and synovial fibroblasts by antirheumatic drugs. J Rheumatol. 1997 Aug;24(8):1471–1476. [PubMed]
  • Cutolo M, Barone A, Accardo S, Setti M, Villaggio B. Effect of cyclosporin on apoptosis in human cultured monocytic THP-1 cells and synovial macrophages. Clin Exp Rheumatol. 1998 Jul-Aug;16(4):417–422. [PubMed]
  • Smoleńska Z, Kaznowska Z, Zarówny D, Simmonds HA, Smoleński RT. Effect of methotrexate on blood purine and pyrimidine levels in patients with rheumatoid arthritis. Rheumatology (Oxford) 1999 Oct;38(10):997–1002. [PubMed]
  • Hornung N, Stengaard-Pedersen K, Ehrnrooth E, Ellingsen T, Poulsen JH. The effects of low-dose methotrexate on thymidylate synthetase activity in human peripheral blood mononuclear cells. Clin Exp Rheumatol. 2000 Nov-Dec;18(6):691–698. [PubMed]
  • Allegra CJ, Chabner BA, Drake JC, Lutz R, Rodbard D, Jolivet J. Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates. J Biol Chem. 1985 Aug 15;260(17):9720–9726. [PubMed]
  • Connolly KM, Stecher VJ, Danis E, Pruden DJ, LaBrie T. Alteration of interleukin-1 production and the acute phase response following medication of adjuvant arthritic rats with cyclosporin-A or methotrexate. Int J Immunopharmacol. 1988;10(6):717–728. [PubMed]
  • Brody M, Böhm I, Bauer R. Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells. Eur J Clin Chem Clin Biochem. 1993 Oct;31(10):667–674. [PubMed]
  • Seitz M, Loetscher P, Dewald B, Towbin H, Rordorf C, Gallati H, Baggiolini M, Gerber NJ. Methotrexate action in rheumatoid arthritis: stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. Br J Rheumatol. 1995 Jul;34(7):602–609. [PubMed]
  • Seitz M, Loetscher P, Dewald B, Towbin H, Rordorf C, Gallati H, Gerber NJ. Interleukin 1 (IL-1) receptor antagonist, soluble tumor necrosis factor receptors, IL-1 beta, and IL-8--markers of remission in rheumatoid arthritis during treatment with methotrexate. J Rheumatol. 1996 Sep;23(9):1512–1516. [PubMed]
  • Janson RW, Hance KR, Arend WP. Production of IL-1 receptor antagonist by human in vitro-derived macrophages. Effects of lipopolysaccharide and granulocyte-macrophage colony-stimulating factor. J Immunol. 1991 Dec 15;147(12):4218–4223. [PubMed]
  • Cauli A, Yanni G, Panayi GS. Interleukin-1, interleukin-1 receptor antagonist and macrophage populations in rheumatoid arthritis synovial membrane. Br J Rheumatol. 1997 Sep;36(9):935–940. [PubMed]
  • Roux-Lombard P, Modoux C, Dayer JM. Production of interleukin-1 (IL-1) and a specific IL-1 inhibitor during human monocyte-macrophage differentiation: influence of GM-CSF. Cytokine. 1989 Nov;1(1):45–51. [PubMed]
  • Towbin H, Schmitz A, van Oostrum J, Seitz M, Dewald B, Zingel O, Motz J, Vosbeck K, Rordorf C. Monoclonal antibody based enzyme-linked and chemiluminescent assays for the human interleukin-1 receptor antagonist. Application to measure hIL-1ra levels in monocyte cultures and synovial fluids. J Immunol Methods. 1994 Mar 29;170(1):125–135. [PubMed]
  • Merrill JT, Shen C, Schreibman D, Coffey D, Zakharenko O, Fisher R, Lahita RG, Salmon J, Cronstein BN. Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. Arthritis Rheum. 1997 Jul;40(7):1308–1315. [PubMed]
  • Crilly A, McInness IB, McDonald AG, Watson J, Capell HA, Madhok R. Interleukin 6 (IL-6) and soluble IL-2 receptor levels in patients with rheumatoid arthritis treated with low dose oral methotrexate. J Rheumatol. 1995 Feb;22(2):224–226. [PubMed]
  • Straub RH, Müller-Ladner U, Lichtinger T, Schölmerich J, Menninger H, Lang B. Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying anti-rheumatic drugs. Br J Rheumatol. 1997 Dec;36(12):1298–1303. [PubMed]
  • Miossec P, Briolay J, Dechanet J, Wijdenes J, Martinez-Valdez H, Banchereau J. Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin-4 in an ex vivo model of rheumatoid synovitis. Arthritis Rheum. 1992 Aug;35(8):874–883. [PubMed]
  • Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. [PubMed]
  • Vergne P, Liagre B, Bertin P, Cook-Moreau J, Treves R, Beneytout JL, Rigaud M. Methotrexate and cyclooxygenase metabolism in cultured human rheumatoid synoviocytes. J Rheumatol. 1998 Mar;25(3):433–440. [PubMed]
  • Mello SB, Barros DM, Silva AS, Laurindo IM, Novaes GS. Methotrexate as a preferential cyclooxygenase 2 inhibitor in whole blood of patients with rheumatoid arthritis. Rheumatology (Oxford) 2000 May;39(5):533–536. [PubMed]
  • Kraan MC, de Koster BM, Elferink JG, Post WJ, Breedveld FC, Tak PP. Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis: findings in a prospective, randomized, double-blind clinical trial in fifteen patients. Arthritis Rheum. 2000 Jul;43(7):1488–1495. [PubMed]
  • Leroux JL, Damon M, Chavis C, Crastes De Paulet A, Blotman F. Effets du méthotrexate sur la synthèse de leucotriénes et de dérivés de la lipoxygénase par les polynucléaires au cours de la polyarthrite rhumatoïde. Rev Rhum Mal Osteoartic. 1992 Oct;59(9):587–591. [PubMed]
  • Frenia ML, Long KS. Methotrexate and nonsteroidal antiinflammatory drug interactions. Ann Pharmacother. 1992 Feb;26(2):234–237. [PubMed]
  • Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg. J Rheumatol. 1995 Nov;22(11):2072–2077. [PubMed]
  • Karim A, Tolbert DS, Hunt TL, Hubbard RC, Harper KM, Geis GS. Celecoxib, a specific COX-2 inhibitor, has no significant effect on methotrexate pharmacokinetics in patients with rheumatoid arthritis. J Rheumatol. 1999 Dec;26(12):2539–2543. [PubMed]
  • Martel-Pelletier J, Cloutier JM, Pelletier JP. In vivo effects of antirheumatic drugs on neutral collagenolytic proteases in human rheumatoid arthritis cartilage and synovium. J Rheumatol. 1988 Aug;15(8):1198–1204. [PubMed]
  • Haraoui B, Pelletier JP, Cloutier JM, Faure MP, Martel-Pelletier J. Synovial membrane histology and immunopathology in rheumatoid arthritis and osteoarthritis. In vivo effects of antirheumatic drugs. Arthritis Rheum. 1991 Feb;34(2):153–163. [PubMed]
  • Firestein GS, Paine MM, Boyle DL. Mechanisms of methotrexate action in rheumatoid arthritis. Selective decrease in synovial collagenase gene expression. Arthritis Rheum. 1994 Feb;37(2):193–200. [PubMed]
  • MacNaul KL, Chartrain N, Lark M, Tocci MJ, Hutchinson NI. Discoordinate expression of stromelysin, collagenase, and tissue inhibitor of metalloproteinases-1 in rheumatoid human synovial fibroblasts. Synergistic effects of interleukin-1 and tumor necrosis factor-alpha on stromelysin expression. J Biol Chem. 1990 Oct 5;265(28):17238–17245. [PubMed]
  • Seitz M, Dayer JM. Enhanced production of tissue inhibitor of metalloproteinases by peripheral blood mononuclear cells of rheumatoid arthritis patients responding to methotrexate treatment. Rheumatology (Oxford) 2000 Jun;39(6):637–645. [PubMed]
  • Nakashima-Matsushita N, Homma T, Yu S, Matsuda T, Sunahara N, Nakamura T, Tsukano M, Ratnam M, Matsuyama T. Selective expression of folate receptor beta and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis Rheum. 1999 Aug;42(8):1609–1616. [PubMed]
  • Bressolle F, Kinowski JM, Morel J, Pouly B, Sany J, Combe B. Folic acid alters methotrexate availability in patients with rheumatoid arthritis. J Rheumatol. 2000 Sep;27(9):2110–2114. [PubMed]
  • Griffith SM, Fisher J, Clarke S, Montgomery B, Jones PW, Saklatvala J, Dawes PT, Shadforth MF, Hothersall TE, Hassell AB, et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology (Oxford) 2000 Oct;39(10):1102–1109. [PubMed]
  • Shiroky JB. The use of folates concomitantly with low-dose pulse methotrexate. Rheum Dis Clin North Am. 1997 Nov;23(4):969–980. [PubMed]
  • Jobanputra P, Hunter M, Clark D, Lambert CM, Hurst NP. An audit of methotrexate and folic acid for rheumatoid arthritis. Experience from a teaching centre. Br J Rheumatol. 1995 Oct;34(10):971–975. [PubMed]
  • Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, Krumdieck CL, Alarcón GS. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med. 1994 Dec 1;121(11):833–841. [PubMed]
  • van Ede AE, Laan RF, Blom HJ, De Abreu RA, van de Putte LB. Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity. Semin Arthritis Rheum. 1998 Apr;27(5):277–292. [PubMed]
  • Montesinos MC, Yap JS, Desai A, Posadas I, McCrary CT, Cronstein BN. Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonists theophylline and caffeine: evidence that the antiinflammatory effects of methotrexate are mediated via multiple adenosine receptors in rat adjuvant arthritis. Arthritis Rheum. 2000 Mar;43(3):656–663. [PubMed]
  • Straub RH, Cutolo M. Involvement of the hypothalamic--pituitary--adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role. Arthritis Rheum. 2001 Mar;44(3):493–507. [PubMed]

Figures and Tables

Figure 1
Adenosine increase by MTX and subsequent immunosuppression through adenosine receptors. (A) MTX inhibits both, conversion of GAR → FGAR and AICAR → FAICAR. However, inhibition of the second step is stronger, which results ...
Figure 2
Anti-inflammatory effects exerted by low dose MTX at the level of the synovial tissue in RA. (A) MTX reduces monocytic cell growth and increases their apoptosis. (B) MTX decreases the IL1 and IL6 secretion and increases IL1ra production. At the same ...

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