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Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs—from bench to bedside

Abstract

The chronic nature of rheumatoid arthritis (RA) means that patients require drug therapy for many years. Many RA patients, however, have to discontinue treatment because of drug-related toxic effects, loss of efficacy, or both. The underlying molecular cause for loss of efficacy of antirheumatic drugs is not fully understood, but it might be mediated, at least in part, by mechanisms shared with resistance to anticancer drugs. This Review outlines molecular mechanisms that could be involved in the onset of resistance to, or the loss of efficacy of, disease-modifying antirheumatic drugs in RA patients, including methotrexate, sulfasalazine, chloroquine, hydroxychloroquine, azathioprine, and leflunomide. The mechanisms suggested are based on findings from experimental laboratory studies of specific drug-uptake and drug-efflux transporters belonging to the superfamily of multidrug-resistance transporters, alterations in intracellular drug metabolism, and genetic polymorphisms of drug transporters and metabolic enzymes. We also discuss strategies to overcome resistance and the current clinical studies aiming to predict response and risk of toxic effects. More in-depth knowledge of the mechanisms behind these features could help facilitate a more efficient use of disease-modifying antirheumatic drugs.

Key Points

  • Disease-modifying antirheumatic drugs (DMARDs) and anticancer drugs share common molecular mechanisms of resistance

  • Resistance to DMARDs can be acquired by upregulation of drug-efflux proteins belonging to the family of multidrug-resistance transporters

  • Multidrug-resistance proteins exert primary physiologic functions in the cellular export of inflammatory mediators

  • The current knowledge of molecular mechanisms of resistance to methotrexate facilitates the prediction of patient response to methotrexate by target-directed genetic and biochemical screening of blood cells

  • Identification of the molecular mechanisms of resistance to various DMARDs opens up new strategies for circumvention of drug resistance

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Figure 1: Mechanisms of pharmacokinetic and cellular resistance to methotrexate.

References

  1. 1

    Smolen JS and Steiner G (2003) Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2: 473–488

    CAS  Article  Google Scholar 

  2. 2

    O'Dell JR (2004) Therapeutic strategies for rheumatoid arthritis. N Engl J Med 350: 2591–2602

    CAS  Article  Google Scholar 

  3. 3

    Goekoop-Ruiterman YP et al. (2005) Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 52: 3381–3390

    CAS  Article  Google Scholar 

  4. 4

    Szakacs G et al. (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5: 219–234

    CAS  Article  Google Scholar 

  5. 5

    Jansen G et al. (2003) Multidrug resistance proteins in rheumatoid arthritis, role in disease-modifying antirheumatic drug efficacy and inflammatory processes: an overview. Scand J Rheumatol 32: 325–336

    CAS  Article  Google Scholar 

  6. 6

    Wollheim FA (2003) Drug resistance in rheumatology: an area in search of investigators. Curr Rheumatol Rep 5: 333–335

    Article  Google Scholar 

  7. 7

    Fleischmann RM (2005) Is there a need for new therapies for rheumatoid arthritis? J Rheumatol 73 (Suppl): S3–S7

    Google Scholar 

  8. 8

    Choy EH et al. (2005) A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology (Oxford) 44: 1414–1421

    CAS  Article  Google Scholar 

  9. 9

    Nurmohamed MT and Dijkmans BA (2005) Efficacy, tolerability and cost effectiveness of disease-modifying antirheumatic drugs and biologic agents in rheumatoid arthritis. Drugs 65: 661–694

    CAS  Article  Google Scholar 

  10. 10

    Aletaha D and Smolen JS (2002) Effectiveness profiles and dose dependent retention of traditional disease modifying antirheumatic drugs for rheumatoid arthritis. An observational study. J Rheumatol 29: 1631–1638

    CAS  PubMed  Google Scholar 

  11. 11

    Bingham S and Emery P (2000) Resistant rheumatoid arthritis clinics—a necessary development? Rheumatology (Oxford) 39: 2–5

    CAS  Article  Google Scholar 

  12. 12

    Wolfe F (1995) The epidemiology of drug treatment failure in rheumatoid arthritis. Baillieres Clin Rheumatol 9: 619–632

    CAS  Article  Google Scholar 

  13. 13

    Morgan C et al. (2003) Contribution of patient related differences to multidrug resistance in rheumatoid arthritis. Ann Rheum Dis 62: 15–19

    CAS  Article  Google Scholar 

  14. 14

    Delano DL et al. (2005) Genetically based resistance to the antiinflammatory effects of methotrexate in the air-pouch model of acute inflammation. Arthritis Rheum 52: 2567–2575

    CAS  Article  Google Scholar 

  15. 15

    Zaher H et al. (2006) Breast cancer resistance protein (Bcrp/abcg2) is a major determinant of sulfasalazine absorption and elimination in mouse. Mol Pharm 3: 55–61

    CAS  Article  Google Scholar 

  16. 16

    Borst P and Elferink RO (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71: 537–592

    CAS  Article  Google Scholar 

  17. 17

    Gorlick R et al. (1996) Intrinsic and acquired resistance to methotrexate in acute leukemia. N Engl J Med 335: 1041–1048

    CAS  Article  Google Scholar 

  18. 18

    Rots MG et al. (2000) Classification of ex vivo methotrexate resistance in acute lymphoblastic and myeloid leukaemia. Br J Haematol 110: 791–800

    CAS  Article  Google Scholar 

  19. 19

    Matherly LH and Goldman ID (2003) Membrane transport of folates. Vitam Horm 66: 403–456

    CAS  Article  Google Scholar 

  20. 20

    Nakashima-Matsushita N et al. (1999) Selective expression of folate receptor beta and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis Rheum 42: 1609–1616

    CAS  Article  Google Scholar 

  21. 21

    Hooijberg JH et al. (1999) Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res 59: 2532–2535

    CAS  PubMed  Google Scholar 

  22. 22

    Shafran A et al. (2005) ABCG2 harboring the Gly482 mutation confers high-level resistance to various hydrophilic antifolates. Cancer Res 65: 8414–8422

    CAS  Article  Google Scholar 

  23. 23

    Van der Heijden J et al. (2004) Acquired resistance of human T cells to sulphasalazine: stability of the resistant phenotype and sensitivity to non-related DMARDs. Ann Rheum Dis 63: 131–137

    CAS  Article  Google Scholar 

  24. 24

    Van der Heijden J et al. (2004) Development of sulphasalazine resistance in human T cells induces expression of the multidrug resistance transporter ABCG2 (BCRP) and augmented production of TNFalpha. Ann Rheum Dis 63: 138–143

    CAS  Article  Google Scholar 

  25. 25

    Oerlemans R et al. (2006) Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance-associated protein 1 and provokes high levels of cross-resistance to glucocorticoids. Arthritis Rheum 54: 557–568

    CAS  Article  Google Scholar 

  26. 26

    Glennas A and Rugstad HE (1986) Cultured human cells with high levels of gold-binding cytosolic metallothionein are not resistant to the growth inhibitory effect of sodium aurothiomalate. Ann Rheum Dis 45: 101–109

    CAS  Article  Google Scholar 

  27. 27

    Clunie GP and Lennard L (2004) Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology (Oxford) 43: 13–18

    CAS  Article  Google Scholar 

  28. 28

    Wielinga PR et al. (2002) Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells. Mol Pharmacol 62: 1321–1331

    CAS  Article  Google Scholar 

  29. 29

    Loffler M et al. (2004) Dihydroorotate dehydrogenase mRNA and protein expression analysis in normal and drug-resistant cells. Nucleosides Nucleotides Nucleic Acids 23: 1281–1285

    CAS  Article  Google Scholar 

  30. 30

    Chikanza IC and Kozaci DL (2004) Corticosteroid resistance in rheumatoid arthritis: molecular and cellular perspectives. Rheumatology 43: 1337–1345

    CAS  Article  Google Scholar 

  31. 31

    Buttgereit F et al. (2004) Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum 50: 3408–3417

    CAS  Article  Google Scholar 

  32. 32

    Maetzel A et al. (2000) Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs. Rheumatology (Oxford) 39: 975–981

    CAS  Article  Google Scholar 

  33. 33

    Galindo-Rodriguez G et al. (1999) Disappointing longterm results with disease modifying antirheumatic drugs. A practice based study. J Rheumatol 26: 2337–2343

    CAS  PubMed  Google Scholar 

  34. 34

    Salmon SE and Dalton WS (1996) Relevance of multidrug resistance to rheumatoid arthritis: development of a new therapeutic hypothesis. J Rheumatol 44 (Suppl): S97–S101

    Google Scholar 

  35. 35

    Maillefert JF et al. (1996) Expression of the multidrug resistance glycoprotein 170 in the peripheral blood lymphocytes of rheumatoid arthritis patients. The percentage of lymphocytes expressing glycoprotein 170 is increased in patients treated with prednisolone. Br J Rheumatol 35: 430–435

    CAS  Article  Google Scholar 

  36. 36

    Llorente L et al. (2000) Multidrug resistance-1 (MDR-1) in rheumatic autoimmune disorders. Part I: increased P-glycoprotein activity in lymphocytes from rheumatoid arthritis patients might influence disease outcome. Joint Bone Spine 67: 30–39

    CAS  PubMed  Google Scholar 

  37. 37

    Yudoh K et al. (1999) Increased expression of multidrug resistance of glycoprotein on Th1 cells correlates with drug resistance in rheumatoid arthritis. Arthritis Rheum 42: 2014–2015

    CAS  Article  Google Scholar 

  38. 38

    Rahman P et al. (2000) Increased MDR1 P-glycoprotein expression in methotrexate resistance: comment on the article by Yudoh et al. Arthritis Rheum 43: 1661–1662

    CAS  Article  Google Scholar 

  39. 39

    Norris MD et al. (1996) Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate. Int J Cancer 65: 613–619

    CAS  Article  Google Scholar 

  40. 40

    Oerlemans R et al. (2005) Differential expression of multidrug resistance-related proteins on monocyte-derived macrophages from rheumatoid arthritis patients. Arthritis Res Ther 7 (Suppl 1): P83

    Article  Google Scholar 

  41. 41

    Van der Heijden JW et al. (2005) Expression of the multidrug resistance protein BCRP in synovial tissue of RA patients—a marker for inflammation or resistance to MTX? Arthritis Rheum 52 (Suppl): S540

    Google Scholar 

  42. 42

    Scotto KW (2003) Transcriptional regulation of ABC drug transporters. Oncogene 22: 7496–7511

    CAS  Article  Google Scholar 

  43. 43

    Hider SL et al. (2006) Down-regulation of MRP1 expression in early RA patients exposed to methotrexate as a first DMARD. Ann Rheum Dis 65: 1449–1455

    CAS  Article  Google Scholar 

  44. 44

    Stranzl T et al. (2003) Expression of folylpolyglutamyl synthetase predicts poor response to methotrexate therapy in patients with rheumatoid arthritis. Clin Exp Rheumatol 21: 27–32

    CAS  PubMed  Google Scholar 

  45. 45

    Wolf J et al. (2005) Expression of resistance markers to methotrexate predicts clinical improvement in patients with rheumatoid arthritis. Ann Rheum Dis 64: 564–568

    CAS  Article  Google Scholar 

  46. 46

    Ranganathan P et al. (2003) Will pharmacogenetics allow better prediction of methotrexate toxicity and efficacy in patients with rheumatoid arthritis? Ann Rheum Dis 62: 4–9

    CAS  Article  Google Scholar 

  47. 47

    Dervieux T et al. (2004) Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 50: 2766–2774

    CAS  Article  Google Scholar 

  48. 48

    Dervieux T et al. (2004) Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics 14: 733–739

    CAS  Article  Google Scholar 

  49. 49

    Weisman MH et al. (2006) Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum 54: 607–612

    CAS  Article  Google Scholar 

  50. 50

    Wessels JA et al. (2006) Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum 54: 1087–1095

    CAS  Article  Google Scholar 

  51. 51

    Kremer JM (2004) Toward a better understanding of methotrexate. Arthritis Rheum 50: 1370–1382

    CAS  Article  Google Scholar 

  52. 52

    Smolen JS et al. (2005) Superior efficacy of combination therapy for rheumatoid arthritis: fact or fiction? Arthritis Rheum 52: 2975–2983

    CAS  Article  Google Scholar 

  53. 53

    Jansen G et al. (2004) Sulfasalazine is a potent inhibitor of the reduced folate carrier: implications for combination therapies with methotrexate in rheumatoid arthritis. Arthritis Rheum 50: 2130–2139

    CAS  Article  Google Scholar 

  54. 54

    O'Dell JR et al. (2002) Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications. Arthritis Rheum 46: 1164–1170

    CAS  Article  Google Scholar 

  55. 55

    Goekoop-Ruiterman YP et al. (2005) Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 52: 3381–3390

    CAS  Article  Google Scholar 

  56. 56

    Rots MG et al. (1999) Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates. Blood 94: 3121–3128

    CAS  PubMed  Google Scholar 

  57. 57

    Wolbink GJ et al. (2006) Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 54: 711–715

    Article  Google Scholar 

  58. 58

    Cronstein BN (1996) Molecular therapeutics. Methotrexate and its mechanism of action. Arthritis Rheum 39: 1951–1960

    CAS  Article  Google Scholar 

  59. 59

    Cutolo M et al. (2001) Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 60: 729–735

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Work described in this Review was supported by grants from the Dutch Arthritis Association and The Netherlands Organization for Scientific Research. JW van der Heijden is a recipient of the 2006 Rheumatology Grant from the Dutch Association for Rheumatology. We apologize to authors whose work could not be cited for space reasons.

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Correspondence to Gerrit Jansen.

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van der Heijden, J., Dijkmans, B., Scheper, R. et al. Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs—from bench to bedside. Nat Rev Rheumatol 3, 26–34 (2007). https://doi.org/10.1038/ncprheum0380

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