Pharmakogenetik bei juveniler idiopathischer Arthritis

Zusammenfassung

Die juvenile idiopathische Arthritis (JIA) ist die häufigste chronische rheumatische Erkrankung im Kindesalter. Viele Kinder benötigen nach Diagnosestellung über viele Jahre immunmodulierende Therapien. Ein beträchtlicher Anteil von Kindern zeigt schwere therapierefraktäre Verläufe und einige entwickeln schwerwiegende Medikamentennebenwirkungen. Zahlreiche Genpolymorphismen wurden als potenzielle prädiktive Biomarker in klinischen Studien zur Pharmako genetik von Methotrexat und Etanercept bei der JIA analysiert, ohne jedoch eindeutige Ergebnisse erbracht zu haben. Dies ist möglicherweise auf kleine und klinisch heterogene Studienpopulationen, Unterschiede in der Bewertung der Krankheitsaktivität und der Analyse von nur wenigen Kandidatengenvarianten zurückzuführen. Die erste pharmakogenetische genomweite Untersuchung bei der JIA hat Genregionen von besonderem biologischen Interesse identifiziert. Eine Validierung ist jedoch erforderlich. Die Entdeckung neuer pharmakogenetischer Biomarker und deren Netzwerke können zur Entwicklung neuer Medikamente führen und eine „individuelle“ Therapie ermöglichen, die das Nutzen-Risiko-Verhältnis einer Therapie für den einzelnen JIA-Patienten verbessert.

Summary

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. Many children require immunomodulatory therapies for many years following diagnosis. A considerable proportion of children experience therapeutic inefficacy or substantial adverse effects. The identification of valid candidate gene variants in many clinical pharmacogenetic studies of Methotrexate and Etanercept in JIA has seen little success to date. This is possibly due to heterogenic small study populations, differences in disease activity outcome parameters that have been used and the small number of candidate gene variants analysed. The first genome-wide pharmacogenetic study in JIA has identified gene regions of particular biological interest, but these findings require validation. The discovery of new pharmacogenomic biomarkers and systems pathways can provide new drug targets and will enable individualized drug therapy with improving the risk-benefit ratios of immunomodulatory therapies in JIA.

Schlüsselwörter

Juvenile idiopathische Arthritis - Pharmakogenetik - Methotrexat - Etanercept

Keywords

Juvenile idiopathic arthritis - pharmakogenetics - methotrexate - etanercept

• Literatur

• 1 Petty RE, Southwood TR, Manners P. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004; 31: 390-392.
• 2 Andersson Gare B. Juvenile arthritis - who gets it, where and when? A review of current data on incidence and prevalence. Clin Exp Rheumatol 1999; 17: 367-374.
• 3 Adib N, Silman A, Thomson W. Outcome following onset of juvenile idiopathic inflammatory arthritis: I. frequency of different outcomes. Rheumatology (Oxford) 2005; 44: 995-1001.
• 4 McErlane F, Beresford MW, Baildam EM. et al. Recent developments in disease activity indices and outcome measures for juvenile idiopathic arthritis. Rheumatology (Oxford) 2013; 52: 1941-1951.
• 5 Ringold S, Wallace CA. Measuring clinical response and remission in juvenile idiopathic arthritis. Curr Opin Rheumatol 2007; 19: 471-476.
• 6 Dueckers G, Guellac N, Arbogast M. et al. Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis. Clin Immunol 2012; 142: 176-193.
• 7 Beukelman T, Patkar NM, Saag KG. et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken) 2011; 63: 465-482.
• 8 Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants: part II. Clin Pharmacokinet 2002; 41: 1077-1094.
• 9 Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants: part I. Clin Pharmacokinet 2002; 41: 959-998.
• 10 Husain A, Loehle JA, Hein DW. Clinical pharmacogenetics in pediatric patients. Pharmacogenomics 2007; 8: 1403-1411.
• 11 Giannini EH, Brewer EJ, Kuzmina N. et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children’s Study Group. N Engl J Med 1992; 326: 1043-1049.
• 12 Bulatovic M, Heijstek MW, Verkaaik M. et al. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score. Arthritis Rheum 2011; 63: 2007-2013.
• 13 Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007; 65: 168-173.
• 14 Mikkelsen TS, Thorn CF, Yang JJ. et al. PharmGKB summary: methotrexate pathway. Pharmacogenet Genomics 2011; 21: 679-686.
• 15 Rozen R. Molecular genetics of methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis 1996; 19: 589-594.
• 16 Weisberg I, Tran P, Christensen B. et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998; 64: 169-172.
• 17 Schmeling H, Biber D, Heins S, Horneff G. Influence of methylenetetrahydrofolate reductase polymorphisms on efficacy and toxicity of methotrexate in patients with juvenile idiopathic arthritis. J Rheumatol 2005; 32: 1832-1836.
• 18 Tukova J, Chladek J, Hroch M. et al. 677TT genotype is associated with elevated risk of methotrexate (MTX) toxicity in juvenile idiopathic arthritis: treatment outcome, erythrocyte concentrations of MTX and folates, and MTHFR polymorphisms. J Rheumatol 2010; 37: 2180-2186.
• 19 Albers HM, Wessels JA, van der Straaten RJ. et al. Time to treatment as an important factor for the response to methotrexate in juvenile idiopathic arthritis. Arthritis Rheum 2009; 61: 46-51.
• 20 Bulatovic M, Heijstek MW, Van Dijkhuizen EH. et al. Prediction of clinical non-response to methotrexate treatment in juvenile idiopathic arthritis. Ann Rheum Dis 2012; 71: 1484-1489.
• 21 Yanagimachi M, Naruto T, Hara T. et al. Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis. Br J Clin Pharmacol 2011; 71: 237-243.
• 22 Hinks A, Moncrieffe H, Martin P. et al. Association of the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene with response to methotrexate in juvenile idiopathic arthritis. Ann Rheum Dis 2011; 70: 1395-1400.
• 23 de Rotte MC, Bulatovic M, Heijstek MW. et al. ABCB1 and ABCC3 gene polymorphisms are associated with first-year response to methotrexate in juvenile idiopathic arthritis. J Rheumatol 2012; 39: 2032-2040.
• 24 Becker ML, Gaedigk R, van Haandel L. et al. The effect of genotype on methotrexate polyglutamate variability in juvenile idiopathic arthritis and association with drug response. Arthritis Rheum 2011; 63: 276-285.
• 25 Moncrieffe H, Hinks A, Ursu S. et al. Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype. Pharmacogenet Genomics 2010; 20: 665-676.
• 26 Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol 2001; 169: 453-459.
• 27 Cobb J, Cule E, Moncrieffe H. et al. Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases. Pharmacogenomics J 2014; 14: 356-364
• 28 Franke A, McGovern DP, Barrett JC. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 2010; 42: 1118-1125.
• 29 Patsopoulos NA, Esposito F, Reischl J. et al. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol 2011; 70: 897-912.
• 30 Horneff G. Update on biologicals for treatment of juvenile idiopathic arthritis. Expert Opin Biol Ther 2013; 13: 361-376.
• 31 Tracey D, Klareskog L, Sasso EH. et al. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008; 117: 244-279.
• 32 Horneff G, Schmeling H, Biedermann T. et al. The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann Rheum Dis 2004; 63: 1638-1644.
• 33 Giannini EH, Ilowite NT, Lovell DJ. et al. Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis. Arthritis Rheum 2009; 60: 2794-2804.
• 34 Schmeling H, Horneff G. Tumour necrosis factor alpha promoter polymorphisms and etanercept therapy in juvenile idiopathic arthritis. Rheumatol Int 2007; 27: 383-386.
• 35 Basic J, Pavlovic D, Jevtovic-Stoimenov T. et al. Etanercept reduces matrix metalloproteinase-9 level in children with polyarticular juvenile idiopathic arthritis and TNF-alpha-308GG genotype. J Physiol Biochem 2010; 66: 173-180.
• 36 Cimaz R, Cazalis MA, Reynaud C. et al. IL1 and TNF gene polymorphisms in patients with juvenile idiopathic arthritis treated with TNF inhibitors. Ann Rheum Dis 2007; 66: 900-904.