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Volume 21, Issue 2
  • ISSN: 1573-3971
  • E-ISSN: 1875-6360

Abstract

Rheumatoid arthritis is a crippling autoimmune disease affecting more than 18 million people worldwide and thus becoming one of the important contributors to the global health burden. The majority of the affected are females, especially those above the age of 50, but males and younger adults are equally vulnerable. It is a constellation of genetic and environmental factors that interplay to manifest the joint deformities and disabilities that are the hallmarks of this disease. Painkillers are used alongside disease-modifying anti-rheumatic drugs to minimize the patient’s agony and also to halt the progression of the disease. Worldwide, methotrexate is recommended as the first-line drug, but unexpected resistance is encountered in a significant number of patients. This review summarizes the pathophysiology, clinical findings, and therapeutic strategies for rheumatoid with a focus on research studies performed to establish a genetic basis for response fluctuations of methotrexate across different population groups.

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2024-04-02
2025-05-22

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References

  1. AlmoallimH. Al SalehJ. BadshaH. AhmedH.M. HabjokaS. MenassaJ.A. El-GarfA. A review of the prevalence and unmet needs in the management of Rheumatoid arthritis in Africa and the Middle East.Rheumatol. Ther.20218111610.1007/s40744‑020‑00252‑133226566
     [Google Scholar]
  2. BullockJ. RizviS.A.A. SalehA.M. AhmedS.S. DoD.P. AnsariR.A. AhmedJ. Rheumatoid arthritis: A brief overview of the treatment.Med. Princ. Pract.201827650150710.1159/00049339030173215
     [Google Scholar]
  3. RomãoV.C. FonsecaJ.E. Etiology and risk factors for rheumatoid arthritis: A state-of-the-art review.Front. Med. (Lausanne)2021868969810.3389/fmed.2021.68969834901047
     [Google Scholar]
  4. NemtsovaM.V. ZaletaevD.V. BureI.V. MikhaylenkoD.S. KuznetsovaE.B. AlekseevaE.A. BeloukhovaM.I. DeviatkinA.A. LukashevA.N. ZamyatninA.A.Jr Epigenetic changes in the pathogenesis of Rheumatoid arthritis.Front. Genet.20191057010.3389/fgene.2019.0057031258550
     [Google Scholar]
  5. TanakaY. Rheumatoid arthritis.Inflamm. Regen.20204012010.1186/s41232‑020‑00133‑832944095
     [Google Scholar]
  6. GuoQ. WangY. XuD. NossentJ. PavlosN.J. XuJ. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies.Bone Res.2018611510.1038/s41413‑018‑0016‑929736302
     [Google Scholar]
  7. De StefanoL. D’OnofrioB. ManzoA. MontecuccoC. BugattiS. The Genetic, environmental, and immunopathological complexity of autoantibody-negative Rheumatoid arthritis.Int. J. Mol. Sci.202122221238610.3390/ijms22221238634830268
     [Google Scholar]
  8. MikhaylenkoD.S. NemtsovaM.V. BureI.V. KuznetsovaE.B. AlekseevaE.A. TarasovV.V. LukashevA.N. BeloukhovaM.I. DeviatkinA.A. ZamyatninA.A.Jr Genetic polymorphisms associated with Rheumatoid arthritis development and antirheumatic therapy response.Int. J. Mol. Sci.20202114491110.3390/ijms2114491132664585
     [Google Scholar]
  9. SokolovaM.V. SchettG. SteffenU. Autoantibodies in Rheumatoid arthritis: Historical background and novel findings.Clin. Rev. Allergy Immunol.202163213815110.1007/s12016‑021‑08890‑134495490
     [Google Scholar]
  10. KaduraS. RaghuG. Rheumatoid arthritis-interstitial lung disease: Manifestations and current concepts in pathogenesis and management.Eur. Respir. Rev.20213016021001110.1183/16000617.0011‑202134168062
     [Google Scholar]
  11. SchererH.U. HäuplT. BurmesterG.R. The etiology of Rheumatoid arthritis.J. Autoimmun.202011010240010.1016/j.jaut.2019.10240031980337
     [Google Scholar]
  12. NavegantesK.C. de Souza GomesR. PereiraP.A.T. CzaikoskiP.G. AzevedoC.H.M. MonteiroM.C. Immune modulation of some autoimmune diseases: The critical role of macrophages and neutrophils in the innate and adaptive immunity.J. Transl. Med.20171513610.1186/s12967‑017‑1141‑828202039
     [Google Scholar]
  13. MateenS. MoinS. ShahzadS. KhanA.Q. Level of inflammatory cytokines in Rheumatoid arthritis patients: Correlation with 25-hydroxy vitamin D and reactive oxygen species.PLoS One2017126e017887910.1371/journal.pone.017887928594861
     [Google Scholar]
  14. SarkiesP. Evolution beyond DNA: Epigenetic drivers for evolutionary change?BMC Biol.202321127210.1186/s12915‑023‑01770‑438155359
     [Google Scholar]
  15. JosephDB StrandDW VezinaCM DNA methylation in development and disease: An overview for prostate researchers.Am J Clin Exp Urol.201866197218
     [Google Scholar]
  16. LinY.J. AnzagheM. SchülkeS. Update on the pathomechanism, diagnosis, and treatment options for Rheumatoid arthritis.Cells20209488010.3390/cells904088032260219
     [Google Scholar]
  17. TaylorP.C. Update on the diagnosis and management of early Rheumatoid arthritis.Clin. Med. (Lond.)202020656156410.7861/clinmed.2020‑072733199320
     [Google Scholar]
  18. LeinoM. TuominenS. PiriläL. TuominenR. Effects of Rheumatoid arthritis on household chores and leisure-time activities.Rheumatol. Int.201535111881188810.1007/s00296‑015‑3313‑226092613
     [Google Scholar]
  19. NovelliL. LubranoE. VeneritoV. PerrottaF.M. MarandoF. CurradiG. IannoneF. Extra-articular manifestations and comorbidities in psoriatic disease: A journey into the immunologic crosstalk.Front. Med. (Lausanne)2021873707910.3389/fmed.2021.73707934631754
     [Google Scholar]
  20. MitrovićJ. HrkačS. TečerJ. GolobM. Ljilja PosavecA. Kolar MitrovićH. GrgurevićL. Pathogenesis of extraarticular manifestations in Rheumatoid arthritis—A comprehensive review.Biomedicines2023115126210.3390/biomedicines1105126237238933
     [Google Scholar]
  21. KayJ. UpchurchK.S. ACR/EULAR 2010 Rheumatoid arthritis classification criteria.Rheumatology (Oxford)201251Suppl. 6vi5vi910.1093/rheumatology/kes27923221588
     [Google Scholar]
  22. EnginarA.Ü. NurH. GilgilE. KaçarC. Accelerated nodulosis in a patient with Rheumatoid arthritis.Arch. Rheumatol.201934222522810.5606/ArchRheumatol.2019.702031497770
     [Google Scholar]
  23. AletahaD. NeogiT. SilmanA.J. FunovitsJ. FelsonD.T. BinghamC.O.III BirnbaumN.S. BurmesterG.R. BykerkV.P. CohenM.D. CombeB. CostenbaderK.H. DougadosM. EmeryP. FerraccioliG. HazesJ.M.W. HobbsK. HuizingaT.W.J. KavanaughA. KayJ. KvienT.K. LaingT. MeaseP. MénardH.A. MorelandL.W. NadenR.L. PincusT. SmolenJ.S. Stanislawska-BiernatE. SymmonsD. TakP.P. UpchurchK.S. VencovskýJ. WolfeF. HawkerG. 2010 Rheumatoid arthritis classification criteria: An american college of rheumatology/european league against rheumatism collaborative initiative.Arthritis Rheum.20106292569258110.1002/art.2758420872595
     [Google Scholar]
  24. El-GabalawyH.D. LipskyP.E. Why do we not have a cure for Rheumatoid arthritis?Arthritis Res.20024Suppl 3S297S30110.1186/ar56812110149
     [Google Scholar]
  25. Del Grossi MouraM. Cruz LopesL. SilvaM.T. Barberato-FilhoS. MottaR.H.L. BergamaschiC.C. Use of steroid and nonsteroidal anti-inflammatories in the treatment of Rheumatoid arthritis.Medicine (Baltimore)20189741e1265810.1097/MD.000000000001265830313057
     [Google Scholar]
  26. RaduA.F. BungauS.G. Management of Rheumatoid arthritis: An overview.Cells20211011285710.3390/cells1011285734831081
     [Google Scholar]
  27. BeckerD.E. Basic and clinical pharmacology of glucocorticosteroids.Anesth. Prog.2013601253210.2344/0003‑3006‑60.1.2523506281
     [Google Scholar]
  28. SpinelliF.R. GarufiC. MancusoS. CeccarelliF. TrugliaS. ContiF. Tapering and discontinuation of glucocorticoids in patients with Rheumatoid arthritis treated with tofacitinib.Sci. Rep.20231311553710.1038/s41598‑023‑42371‑z37730835
     [Google Scholar]
  29. GuilleminF. SarauxA. GuggenbuhlP. RouxC.H. FardelloneP. Le BihanE. CantagrelA. Chary-ValckenaereI. Euller-ZieglerL. FlipoR.M. JuvinR. BehierJ.M. FautrelB. MassonC. CosteJ. Prevalence of Rheumatoid arthritis in France: 2001.Ann. Rheum. Dis.200564101427143010.1136/ard.2004.02919915800010
     [Google Scholar]
  30. SullivanE. KershawJ. BlackburnS. ChoiJ. CurtisJ.R. BoklageS. Biologic disease-modifying antirheumatic drug prescription patterns for Rheumatoid arthritis Among United States Physicians.Rheumatol. Ther.20207238340010.1007/s40744‑020‑00203‑w32318979
     [Google Scholar]
  31. HuaC. ButtgereitF. CombeB. Glucocorticoids in Rheumatoid arthritis: Current status and future studies.RMD Open202061e00053610.1136/rmdopen‑2017‑00053631958273
     [Google Scholar]
  32. Ben MridR. BouchmaaN. AinaniH. El FatimyR. MalkaG. MaziniL. Anti-rheumatoid drugs advancements: New insights into the molecular treatment of Rheumatoid arthritis.Biomed. Pharmacother.202215111312610.1016/j.biopha.2022.11312635643074
     [Google Scholar]
  33. WeinblattM.E. Methotrexate in Rheumatoid arthritis: A quarter century of development.Trans. Am. Clin. Climatol. Assoc.2013124162523874006
     [Google Scholar]
  34. BedouiY. GuillotX. SélambaromJ. GuiraudP. GiryC. Jaffar-BandjeeM.C. RalandisonS. GasqueP. Methotrexate an old drug with new tricks.Int. J. Mol. Sci.20192020502310.3390/ijms2020502331658782
     [Google Scholar]
  35. TanakaY. Subcutaneous injection of methotrexate: Advantages in the treatment of Rheumatoid arthritis.Mod. Rheumatol.202333463363910.1093/mr/roac15636525530
     [Google Scholar]
  36. FraenkelL. BathonJ.M. EnglandB.R. St ClairE.W. ArayssiT. CarandangK. DeaneK.D. GenoveseM. HustonK.K. KerrG. KremerJ. NakamuraM.C. RussellL.A. SinghJ.A. SmithB.J. SparksJ.A. VenkatachalamS. WeinblattM.E. Al-GibbawiM. BakerJ.F. BarbourK.E. BartonJ.L. CappelliL. ChamseddineF. GeorgeM. JohnsonS.R. KahaleL. KaramB.S. KhamisA.M. Navarro-MillánI. MirzaR. SchwabP. SinghN. TurgunbaevM. TurnerA.S. YaacoubS. AklE.A. 2021 American college of rheumatology guideline for the treatment of Rheumatoid arthritis.Arthritis Care Res. (Hoboken)202173792493910.1002/acr.2459634101387
     [Google Scholar]
  37. FriedmanB. CronsteinB. Methotrexate mechanism in treatment of Rheumatoid arthritis.Joint Bone Spine201986330130710.1016/j.jbspin.2018.07.00430081197
     [Google Scholar]
  38. LuS. ZhuX. LiW. ChenH. ZhouD. ZhenZ. SunF. HuangJ. ZhuJ. WangJ. ZhangY. SunX. Influence of methylenetetrahydrofolate reductase C677T and A1298C polymorphism on high-dose methotrexate-related toxicities in pediatric non-hodgkin lymphoma patients.Front. Oncol.20211159822610.3389/fonc.2021.59822633718146
     [Google Scholar]
  39. ShaH.X. VeerapenK. ChowS.K. GunS.C. LauI.S. LimR.L.H. ZulkifliZ. YowY.Y. PehS.C. HwangJ.S. Genetic variations in methotrexate metabolic pathway genes influence methotrexate responses in Rheumatoid arthritis patients in Malaysia.Sci. Rep.20221211184410.1038/s41598‑022‑15991‑035831345
     [Google Scholar]
  40. InoueK. YuasaH. Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in Rheumatoid arthritis therapy.Drug Metab. Pharmacokinet.2014291121910.2133/dmpk.DMPK‑13‑RV‑11924284432
     [Google Scholar]
  41. MoffattB.A. AshiharaH. Purine and pyrimidine nucleotide synthesis and metabolism.Arabidopsis Book20021e001810.1199/tab.001822303196
     [Google Scholar]
  42. ChanE.S.L. CronsteinB.N. Molecular action of methotrexate in inflammatory diseases.Arthritis Res.20024426627310.1186/ar41912106498
     [Google Scholar]
  43. KinderA.J. HassellA.B. BrandJ. BrownfieldA. GroveM. ShadforthM.F. The treatment of inflammatory arthritis with methotrexate in clinical practice: Treatment duration and incidence of adverse drug reactions.Br. J. Rheumatol.2005441616610.1093/rheumatology/keh51215611303
     [Google Scholar]
  44. AletahaD. SmolenJ.S. The Rheumatoid arthritis patient in the clinic: Comparing more than 1300 consecutive DMARD courses.Br. J. Rheumatol.200241121367137410.1093/rheumatology/41.12.136712468815
     [Google Scholar]
  45. MaetzelA. WongA. StrandV. TugwellP. WellsG. BombardierC. Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs.Rheumatology (Oxford)200039997598110.1093/rheumatology/39.9.97510986302
     [Google Scholar]
  46. GosseltH.R. MullerI.B. JansenG. van WeeghelM. VazF.M. HazesJ.M.W. HeilS.G. de JongeR. Identification of metabolic biomarkers in relation to methotrexate response in early Rheumatoid arthritis.J. Pers. Med.202010427110.3390/jpm1004027133321888
     [Google Scholar]
  47. MaciejewskiM. SandsC. NairN. LingS. VerstappenS. HyrichK. BartonA. ZiemekD. LewisM.R. PlantD. Prediction of response of methotrexate in patients with Rheumatoid arthritis using serum lipidomics.Sci. Rep.2021111726610.1038/s41598‑021‑86729‑733790392
     [Google Scholar]
  48. TianH. CronsteinB.N. Understanding the mechanisms of action of methotrexate: Implications for the treatment of Rheumatoid arthritis.Bull. NYU Hosp. Jt. Dis.200765316817317922664
     [Google Scholar]
  49. WesselsJ.A.M. HuizingaT.W.J. GuchelaarH.J. Recent insights in the pharmacological actions of methotrexate in the treatment of Rheumatoid arthritis.Rheumatology (Oxford)200747324925510.1093/rheumatology/kem27918045808
     [Google Scholar]
  50. KremerJ.M. Toward a better understanding of methotrexate.Arthritis Rheum.20045051370138210.1002/art.2027815146406
     [Google Scholar]
  51. HashiguchiM. ShimizuM. HakamataJ. TsuruT. TanakaT. SuzakiM. MiyawakiK. ChiyodaT. TakeuchiO. HiratsukaJ. IrieS. MaruyamaJ. MochizukiM. Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population.J. Pharm. Health Care Sci.2016213510.1186/s40780‑016‑0069‑027980801
     [Google Scholar]
  52. RestrepoL.F. GiraldoR. LondoñoJ. PinzónC. CortesA. BallesterosG. SantosA.M. Farmacogenética del metotrexato en artritis reumatoide. Revisión sistemática.Revista Colombiana de Reumatología201623210211410.1016/j.rcreu.2016.02.002
     [Google Scholar]
  53. KolanS.S. LiG. GrimolizziF. SextonJ. GollG. KvienT.K. SundlisæterN.P. ZucknickM. LillegravenS. HaavardsholmE.A. SkålheggB.S. Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis.Front. Pharmacol.202213107560310.3389/fphar.2022.107560336467057
     [Google Scholar]
  54. ZhangQ. FuP. CaoZ. HuangH. WenQ. WangK. KongT. WuX. ZhengJ. MTHFR and MTRR genetic polymorphism of methotrexate therapy outcomes in early Rheumatoid arthritis.Pharm. Genomics Pers. Med.20231640742310.2147/PGPM.S40494937159804
     [Google Scholar]
  55. WesselsJ.A.M. de Vries-BouwstraJ.K. HeijmansB.T. SlagboomP.E. Goekoop-RuitermanY.P.M. AllaartC.F. KerstensP.J.S.M. van ZebenD. BreedveldF.C. DijkmansB.A.C. HuizingaT.W.J. GuchelaarH.J. Efficacy and toxicity of methotrexate in early Rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes.Arthritis Rheum.20065441087109510.1002/art.2172616572443
     [Google Scholar]
  56. LeeY.C. CuiJ. CostenbaderK.H. ShadickN.A. WeinblattM.E. KarlsonE.W. Investigation of candidate polymorphisms and disease activity in Rheumatoid arthritis patients on methotrexate.Rheumatology (Oxford)200948661361710.1093/rheumatology/ken51319193698
     [Google Scholar]
  57. OwenS.A. HiderS.L. MartinP. BruceI.N. BartonA. ThomsonW. Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in Rheumatoid arthritis patients.Pharmacogenomics J.201313322723410.1038/tpj.2012.722450926
     [Google Scholar]
  58. LimaA. MonteiroJ. BernardesM. SousaH. AzevedoR. SeabraV. MedeirosR. Prediction of methotrexate clinical response in Portuguese Rheumatoid arthritis patients: Implication of MTHFR rs1801133 and ATIC rs4673993 polymorphisms.BioMed Res. Int.2014201411110.1155/2014/36868124967362
     [Google Scholar]
  59. IqbalM.P. AliA.A. MehboobaliN. IqbalK. Short Communication: Lack of association between MTHFR gene polymorphisms and response to methotrexate treatment in Pakistani patients with Rheumatoid arthritis.Pak. J. Pharm. Sci.20152851789179226408898
     [Google Scholar]
  60. TazoeY. HayashiH. TsuboiS. ShiouraT. MatsuyamaT. YamadaH. HiraiK. TsujiD. InoueK. SugiyamaT. ItohK. Reduced folate carrier 1 gene expression levels are correlated with methotrexate efficacy in Japanese patients with Rheumatoid arthritis.Drug Metab. Pharmacokinet.201530322723010.1016/j.dmpk.2015.02.00126003891
     [Google Scholar]
  61. CenH. WenQ.W. ZhangH.Q. YuH. ZengZ. JinT. WangT.H. QinW. HuangH. WuX.D. Associations Between genetic polymorphisms within transporter genes and clinical response to methotrexate in chinese Rheumatoid arthritis patients: A pilot study.Pharm. Genomics Pers. Med.20221532733910.2147/PGPM.S35041735437350
     [Google Scholar]
  62. MelikogluM.A. BalkanE. Can we predict unresponsiveness to methotrexate in Rheumatoid arthritis? A pharmacogenetic study.Inflammopharmacology202230119319710.1007/s10787‑021‑00921‑935043269
     [Google Scholar]
  63. CeballosF.C. Chamizo-CarmonaE. Mata-MartínC. Carrasco-CuberoC. Aznar-SánchezJ.J. Veroz-GonzálezR. Rojas-HerreraS. DoradoP. LLerenaA. Pharmacogenetic sex-specific effects of methotrexate response in patients with Rheumatoid arthritis.Pharmaceutics2023156166110.3390/pharmaceutics1506166137376109
     [Google Scholar]
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Pharmacogenetic Basis of Response Fluctuations to Methotrexate in Rheumatoid Arthritis: A Narrative Review
Curr. Rheumatol. Rev. 21, 160 (2025); https://doi.org/10.2174/0115733971285147240327051637
/content/journals/crr/10.2174/0115733971285147240327051637
/content/journals/crr/10.2174/0115733971285147240327051637
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  • Article Type:     Review Article
Keyword(s): anti-rheumatic drugs; autoimmune disease; Methotrexate; pharmacogenetics; response fluctuations; rheumatoid arthritis

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