Skip to main content

Advertisement

SpringerLink
Log in

MTX-Intoleranz bei Kindern und Jugendlichen mit juveniler idiopathischer Arthritis

MTX intolerance in children and adolescents with juvenile idiopathic arthritis

  • Leitthema
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Zusammenfassung

Methotrexat (MTX) ist das in der antirheumatischen Therapie der juvenilen idiopathischen Arthritis am häufigsten eingesetzte Medikament mit insgesamt guter Wirksamkeit und Verträglichkeit sowie einem hervorragenden Sicherheitsprofil. Nicht selten kommt es jedoch zu einer Intoleranzsymptomatik, die sich als Übelkeit, Ekelgefühle oder abdominelle Beschwerden bereits vor oder kurz nach der Medikamentengabe ausdrückt. Eine direkte unerwünschte Wirkung kann hier meist ausgeschlossen werden, trotzdem tritt die Symptomatik eng begrenzt nur bei Behandlung mit MTX auf. Diese MTX-Intoleranz verursacht bei den betroffenen Patienten eine deutliche Einschränkung der Lebensqualität, bringt den behandelnden Arzt häufig in eine schwierige Situation und führt nicht selten zum Abbruch der Therapie. Konventionelle Gegenmaßnahmen wie Antiemetika, Wechsel der Gabe von subkutan auf oral bzw. umgekehrt oder z. B. Geschmacksüberdeckung sind meist nur begrenzt wirksam. Neuere verhaltenstherapeutische Ansätze lassen hier auf eine wirksamere Bekämpfung der Symptome hoffen.

Abstract

Methotrexate (MTX) is the medication most commonly used for antirheumatic treatment in juvenile idiopathic arthritis. It has high efficacy, is usually well tolerated and has an excellent safety profile. However, intolerance symptoms frequently develop, which manifest as nausea, feelings of disgust, or abdominal complaints prior to or directly after application of the medication. A direct side effect can usually be easily excluded; however, the symptoms are limited to treatment with MTX. This MTX intolerance causes a significant reduction in the quality of life of affected patients, frequently puts the treating physician in an uncomfortable situation, and not uncommonly results in discontinuation of treatment. Conventional countermeasures such as antiemetics, change of route from subcutaneous to oral or vice versa, or, for example, taste masking, usually have only limited effect. Newer behavioral treatment strategies raise hopes of more effective symptom control.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Literatur

  1. Hashkes PJ, Laxer RM (2005) Medical treatment of juvenile idiopathic arthritis. JAMA 294(13):1671–1684

    Article  CAS  Google Scholar 

  2. Ortiz-Alvarez O, Morishita K, Avery G, Green J, Petty RE, Tucker LB, Malleson PN, Cabral DA (2004) Guidelines for blood test monitoring of methotrexate toxicity in juvenile idiopathic arthritis. J Rheumatol 31(12):2501–2506

    PubMed  CAS  Google Scholar 

  3. Malaviya AN, Sharma A, Agarwal D, Kapoor S, Garg S, Sawhney S (2010) Low-dose and high-dose methotrexate are two different drugs in practical terms. Int J Rheum Dis 13(4):288–293

    Article  Google Scholar 

  4. Kremer JM (2004) Toward a better understanding of methotrexate. Arthritis Rheum 50(5):1370–1382

    Article  CAS  Google Scholar 

  5. Cronstein BN, Naime D, Ostad E (1993) The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest 92(6):2675–2682

    Article  CAS  Google Scholar 

  6. Niehues T, Lankisch P (2006) Recommendations for the use of methotrexate in juvenile idiopathic arthritis. Paediatr Drugs 8(6):347–356

    Article  Google Scholar 

  7. Singsen BH, Goldbach-Mansky R (1997) Methotrexate in the treatment of juvenile rheumatoid arthritis and other pediatric rheumatoid and nonrheumatic disorders. Rheum Dis Clin North Am 23(4):811–840

    Article  CAS  Google Scholar 

  8. Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, Bombardier C, Wells GA, Tugwell P (2013) Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 5:CD951

    Google Scholar 

  9. van der Meer A, Wulffraat NM, Prakken BJ, Gijsbers B, Rademaker CM, Sinnema G (2007) Psychological side effects of MTX treatment in juvenile idiopathic arthritis: A pilot study. Clin Exp Rheumatol 25(3):480–485

    PubMed  Google Scholar 

  10. Bulatović M, Heijstek MW, Verkaaik M, van Dijkhuizen EH, Armbrust W, Hoppenreijs EP, Kamphuis S, Kuis W, Egberts TC, Sinnema G et al (2011) High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: Development and validation of a methotrexate intolerance severity score. Arthritis Rheum 63(7):2007–2013

    Article  CAS  Google Scholar 

  11. Ćalasan MB, van den Bosch OF, Creemers MC, Custers M, Heurkens AH, van Woerkom JM, Wulffraat NM (2013) Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis. Arthritis Res Ther 15(6):R217

    Article  CAS  Google Scholar 

  12. Kamen C, Tejani MA, Chandwani K, Janelsins M, Peoples AR, Roscoe JA, Morrow GR (2014) Anticipatory nausea and vomiting due to chemotherapy. Eur J Pharmacol 722:172–179

    Article  CAS  Google Scholar 

  13. Fráňová J, Fingerhutová S, Kobrová K, Srp R, Němcová D, Hoza J, Uher M, Saifridová M, Linková L, Doležalová P (2016) Methotrexate efficacy, but not its intolerance, is associated with the dose and route of administration. Pediatr Rheumatol Online J 14(1):36

    Article  Google Scholar 

  14. Scheuern A, Tyrrell PN, Haas J‑P, Hügle B (2017) Countermeasures against methotrexate intolerance in juvenile idiopathic arthritis instituted by parents show no effect. Rheumatology (Oxford) 56(6):901–906

    Google Scholar 

  15. Patil P, Parker RA, Rawcliffe C, Olaleye A, Moore S, Daly N, Sen D, Ioannou Y (2014) Methotrexate-induced nausea and vomiting in adolescent and young adult patients. Clin Rheumatol 33(3):403–407

    Article  Google Scholar 

  16. van Dijkhuizen EH, Pouw JN, Scheuern A, Hügle B, Hardt S, Ganser G, Kümmerle-Deschner JB, Horneff G, Holzinger D, Bulatović Ćalasan M et al (2016) Methotrexate intolerance in oral and subcutaneous administration in patients with juvenile idiopathic arthritis: A cross-sectional, observational study. Clin Exp Rheumatol 34(1):148–154

    PubMed  Google Scholar 

  17. Stockhorst U, Steingrueber HJ, Enck P, Klosterhalfen S (2006) Pavlovian conditioning of nausea and vomiting. Auton Neurosci 129(1/2):50–57

    Article  Google Scholar 

  18. Ramanan AV, Whitworth P, Baildam EM (2003) Use of methotrexate in juvenile idiopathic arthritis. Arch Dis Child 88(3):197–200

    Article  CAS  Google Scholar 

  19. Maetzel A, Wong A, Strand V, Tugwell P, Wells G, Bombardier C (2000) Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs. Rheumatology 39(9):975–981

    Article  CAS  Google Scholar 

  20. Spyridopoulou KP, Dimou NL, Hamodrakas SJ, Bagos PG (2012) Methylene tetrahydrofolate reductase gene polymorphisms and their association with methotrexate toxicity: A meta-analysis. Pharmacogenet Genomics 22(2):117–133

    Article  CAS  Google Scholar 

  21. Scheuern A, Fischer N, McDonald J, Brunner HI, Haas JP, Hügle B (2016) Mutations in the MTHFR gene are not associated with methotrexate intolerance in patients with juvenile idiopathic arthritis. Pediatr Rheumatol Online J 14(1):11

    Article  Google Scholar 

  22. Kyvsgaard N, Mikkelsen T, Estmann A, Als T, Hvarregaard Christensen J, Corydon T, Herlin T (2018) Are single nucleotide polymorphisms in methotrexate transporter proteins associated with methotrexate intolerance in juvenile idiopathic arthritis? [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/are-single-nucleotide-polymorphisms-in-methotrexate-transporter-proteins-associated-with-methotrexate-intolerance-in-juvenile-idiopathic-arthritis/. Zugegriffen: 29. Apr. 2019

    Google Scholar 

  23. Becker ML, van Haandel L, Funk R, Gaedigk R, Leeder JS (2015) Disruptions in folate homeostasis may lead to increased risk for methotrexate intolerance in juvenile idiopathic arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/disruptions-in-folate-homeostasis-may-lead-to-increased-risk-for-methotrexate-intolerance-in-juvenile-idiopathic-arthritis/. Zugegriffen: 30. Apr. 2019

    Google Scholar 

  24. Wendt L, Albring A, Benson S, Engler H, Engler A, Hinney A, Rief W, Witzke O, Schedlowski M (2014) Catechol-O-methyltransferase Val158Met polymorphism is associated with somatosensory amplification and nocebo responses. PLoS ONE 9(9):e107665

    Article  CAS  Google Scholar 

  25. Hügle B, Scheuern A, Dollinger S, Fischer N, Haas J‑P (2017) Cathechol-O-methyltransferase Val158Met polymorphism is associated with nocebo effects, but not with methotrexate intolerance in patients with juvenile idiopathic arthritis. Scand J Rheumatol 46(6):502–503

    Article  CAS  Google Scholar 

  26. Kempinska A, Benchimol EI, Mack A, Barkey J, Boland M, Mack DR (2011) Short-course ondansetron for the prevention of methotrexate-induced nausea in children with Crohn disease. J Pediatr Gastroenterol Nutr 53(4):389–393

    PubMed  CAS  Google Scholar 

  27. Malaviya AN (2017) Methotrexate intolerance in the treatment of rheumatoid arthritis (RA): Effect of adding caffeine to the management regimen. Clin Rheumatol 36(2):279–285

    Article  Google Scholar 

  28. Dupuis LL, Robinson PD, Boodhan S, Holdsworth M, Portwine C, Gibson P, Phillips R, Maan C, Stefin N, Sung L et al (2014) Guideline for the prevention and treatment of anticipatory nausea and vomiting due to chemotherapy in pediatric cancer patients. Pediatr Blood Cancer 61(8):1506–1512

    Article  Google Scholar 

  29. Ostermeier E, Koetter H, Tony H, Pfister R (2013) iSyMind significantly reduces MTX-induced nausea in a pilot trial. Arthritis Rheum 65(Suppl. 10):1362

    Google Scholar 

  30. Höfel L, Eppler B, Storf M, Schnöbel-Müller E, Haas JP, Hügle B (2018) Successful treatment of methotrexate intolerance in juvenile idiopathic arthritis using eye movement desensitization and reprocessing—Treatment protocol and preliminary results. Pediatr Rheumatol Online J 16(1):11

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Zentrum für Schmerztherapie junger Menschen, Deutsches Zentrum für Kinder- und Jugendrheumatologie, Gehfeldstraße 24, 82467, Garmisch-Partenkirchen, Deutschland

    B. Hügle MSc

Authors
  1. B. Hügle MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Hügle MSc.

Ethics declarations

Interessenkonflikt

B. Hügle gibt an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Redaktion

H.-I. Huppertz, Bremen

K. Minden, Berlin

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hügle, B. MTX-Intoleranz bei Kindern und Jugendlichen mit juveniler idiopathischer Arthritis. Z Rheumatol 78, 620–626 (2019). https://doi.org/10.1007/s00393-019-0644-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00393-019-0644-5

Schlüsselwörter

Keywords

Search

Navigation