Arthritis und Rheuma 2021; 41(02): 137-147
DOI: 10.1055/a-1400-4468
Kinderrheumatologie
Übersichtsartikel

Januskinase-Inhibitoren in der Kinderrheumatologie

Janus kinase inhibitors in pediatric rheumatology
Alexander Kühn
1   Universitätsklinik und Poliklinik für Pädiatrie I,Halle (Saale)
,
Gerd Horneff
2   Asklepios Kinderklinik Sankt Augustin, St. Augustin
› Author Affiliations

ZUSAMMENFASSUNG

Mit der Entwicklung von Januskinase (JAK)-Inhibitoren, einer neuen Klasse von „targeted synthetic (ts) disease modifying antirheumatic drugs (DMARDs)“, wurden innovative therapeutische Perspektiven geschaffen. Im Gegensatz zu Biologika, die als Antikörper oder Fusionsprotein ein einzelnes Zytokin extrazellulär, einen Zytokinrezeptor oder ein Oberflächenmolekül auf der Zelle blockieren, wirken JAK-Inhibitoren intrazellulär und vor allem breiter. Durch Inhibition von Tyrosinkinasen (JAK 1–3, Tyk 2) können sie den Signalweg von >50 Zytokinen unterbinden. Die JAK-Inhibitoren erweitern damit die Behandlungsoptionen bei rheumatischen Erkrankungen. Studien zu rheumatischen Erkrankungen bei Erwachsenen und erste Daten bei Kindern und Jugendlichen weisen auf eine im Vergleich zu Biologika gleichwertige oder sogar bessere Effektivität hin. In aktuell laufenden und zukünftigen Studien wird sich herausstellen, welche „Jakinibs“ die beste Wirkung-Nebenwirkungs-Relation aufweisen.

SUMMARY

The development of Janus kinase (JAK) inhibitors, a new class of “targeted synthetic (ts) DMARDs”, has opened new perspectives of treatment. Unlike biologics, which are antibodies or fusion proteins that block a single cytokine extracellularly or the corresponding cytokine receptor or a molecule at the cell surface, JAK inhibitors act intracellularly with particularly broader effect. By inhibiting tyrosine kinases (JAK 1–3, Tyk 2), they can stop the signaling pathway of >50 cytokines. JAK inhibitors thus expand treatment options for rheumatic diseases. Studies in rheumatic diseases in adults and initial data in children and adolescents indicate equivalent or even better efficacy compared to biologics. Current and future studies will determine which “Jakinibs” have the best efficacy/side-effect ratio.



Publication History

Article published online:
20 April 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • Literatur

  • 1 S2k-Leitlinie:. „Therapie der Juvenilen idiopathischen Arthritis“. Gesellschaft für Kinder- und Jugendrheumatologie (GKJR) und Deutsche Gesellschaft für Kinder- und Jugendmedizin (DGKJ). 2019
  • 2 Rodig SJ, Meraz MA, White JM. et al Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 1998; 93 (03) 373-383
  • 3 Neubauer H, Cumano A, Müller M. et al Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998; 93 (03) 397-409
  • 4 Leonard WJ, Noguchi M, Russell SM, McBride OW. The molecular basis of X-linked severe combined immunodeficiency: the role of the interleukin-2 receptor gamma chain as a common gamma chain, gamma c. Immunol Rev 1994; 138: 61-86
  • 5 Caporali R, Zavaglia D. Real-world experience with tofacitinib for the treatment of rheumatoid arthritis. Clin Exp Rheumatol 2019; 37 (03) 485-495
  • 6 Fleischmann R, Mysler E, Hall S. et al Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet 2017; 390 10093 457-468
  • 7 BfArM. Empfehlung zur Dosisbegrenzung von Tofacitinib: Rote-Hand-Brief zu Xeljanz® (Tofacitinib): „Erhöhtes Risiko für venöse thromboembolische Ereignisse und erhöhtes Risiko für schwerwiegende und tödlich verlaufende Infektionen“. 2020
  • 8 Safety Study Of Tofacitinib Versus Tumor Necrosis Factor (TNF) Inhibitor In Subjects With Rheumatoid Arthritis. https://ClinicalTrials.gov/show/NCT02092467
  • 9 Kremer JM, Bingham 3rd CO, Cappelli LC. et al Postapproval Comparative Safety Study of Tofacitinib and Biological Disease-Modifying Antirheumatic Drugs: 5-Year Results from a United States-Based Rheumatoid Arthritis Registry. ACR Open Rheumatol 2021
  • 10 Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet 2011; 377 9783 2138-2149
  • 11 Thierry S, Fautrel B, Lemelle I, Guillemin F. Prevalence and incidence of juvenile idiopathic arthritis: a systematic review. Joint Bone Spine 2014; 81 (02) 112-117
  • 12 Harrold LR, Salman C, Shoor S. et al Incidence and prevalence of juvenile idiopathic arthritis among children in a managed care population, 1996–2009. J Rheumatol 2013; 40 (07) 1218-1225
  • 13 Peterson LS, Mason T, Nelson AM. et al Juvenile rheumatoid arthritis in Rochester, Minnesota 1960–1993 Is the epidemiology changing?. Arthritis Rheum 1996; 39 (08) 1385-1390
  • 14 Guzman J, Oen K, Tucker LB. et al The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort. Ann Rheum Dis 2015; 74 (10) 1854-1860
  • 15 Hissink Muller P, Brinkman DMC, Schonenberg-Meinema D. et al Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial. Ann Rheum Dis 2019; 78 (01) 51-59
  • 16 Ruperto N, Brunner HI, Zuber Z. et al Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study. Pediatr Rheumatol Online J 2017; 15 (01) 86
  • 17 Brunner HI.. Tofacitinib for the Treatment of Polyarticular Course Juvenile Idiopathic Arthritis: Results of a Phase 3 Randomized, Double-blind, Placebo-controlled Withdrawal Study. 2019 ACR/ARP Annual Meeting; 23.10.2019; Atlanta 2019
  • 18 Ruperto N, Synoverska O, Ting T. et al on behalf of PRINTO/PRCSG. Tofacitinib for the treatment of polyarticular course juvenile idiopathic arthritis: results of a phase 3, randomised, double-blind, placebo-controlled withdrawal study. Ann Rheum Dis 2020; 79: 180
  • 19 Wollenhaupt J, Lee EB, Curtis JR. et al Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study. Arthritis Res Ther 2019; 21 (01) 89
  • 20 Taylor PC, Keystone EC, van der Heijde D. et al Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med 2017; 376 (07) 652-662
  • 21 Fleischmann R, Schiff M, van der Heijde D. et al Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment. Arthritis Rheumatol 2017; 69 (03) 506-517
  • 22 A Study of Baricitinib in Participants From 1 Year to Less Than 18 Years Old With Juvenile Idiopathic Arthritis. https://ClinicalTrials.gov/show/NCT03773965
  • 23 Fleischmann RM, Genovese MC, Enejosa JV. et al Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response. Ann Rheum Dis 2019; 78 (11) 1454-1462
  • 24 Rubbert-Roth A, Enejosa J, Pangan AL. et al Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis. N Engl J Med 2020; 383 (16) 1511-1521
  • 25 A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Upadacitinib in Pediatric Subjects With Polyarticular Course Juvenile Idiopathic Arthritis. https://ClinicalTrials.gov/show/NCT03725007
  • 26 Vanhoutte F, Mazur M, Voloshyn O. et al Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials. Arthritis Rheumatol 2017; 69 (10) 1949-1959
  • 27 Kavanaugh A, Kremer J, Ponce L. et al Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis 2017; 76 (06) 1009-1019
  • 28 Genovese MC, Kalunian K, Gottenberg JE. et al Effect of Filgotinib vs Placebo on Clinical Response in Patients With Moderate to Severe Rheumatoid Arthritis Refractory to Disease-Modifying Antirheumatic Drug Therapy: The FINCH 2 Randomized Clinical Trial. JAMA 2019; 322 (04) 315-325
  • 29 Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006; 6 (11) 823-835
  • 30 Sanchez GAM, Reinhardt A, Ramsey S. et al JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest 2018; 128 (07) 3041-3052
  • 31 Kim H, Brooks KM, Tang CC. et al Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients. Clin Pharmacol Ther 2018; 104 (02) 364-373
  • 32 Ruperto N, Pistorio A, Oliveira S. et al Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial. Lancet 2016; 387 10019 671-678
  • 33 Oddis CV, Reed AM, Aggarwal R. et al Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum 2013; 65 (02) 314-324
  • 34 Aggarwal R, Bandos A, Reed AM. et al Predictors of clinical improvement in rituximab-treated refractory adult and juvenile dermatomyositis and adult polymyositis. Arthritis Rheumatol 2014; 66 (03) 740-749
  • 35 Ladislau L, Suárez-Calvet X, Toquet S. et al JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis. Brain 2018; 141 (06) 1609-1621
  • 36 Aeschlimann FA, Frémond ML, Duffy D. et al A child with severe juvenile dermatomyositis treated with ruxolitinib. Brain 2018; 141 (11) e80
  • 37 Papadopoulou C, Hong Y, Omoyinmi E. et al Janus kinase 1/2 inhibition with baricitinib in the treatment of juvenile dermatomyositis. Brain 2019; 142 (03) e8
  • 38 Dörner T, Furie R. Novel paradigms in systemic lupus erythematosus. Lancet 2019; 393 10188 2344-2358
  • 39 Mease P, Coates LC, Helliwell PS. et al Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled, phase 2 trial. Lancet 2018; 392 10162 2367-2377
  • 40 Gadina M, Le MT, Schwartz DM. et al Janus kinases to jakinibs: from basic insights to clinical practice. Rheumatology (Oxford) 2019; 58 (Suppl. 01) i4-i16
  • 41 Aringer M, Leuchten N, Dörner T. [Biologicals and small molecules for systemic lupus erythematosus]. Z Rheumatol 2020; 79 (03) 232-240
  • 42 Wallace DJ, Furie RA, Tanaka Y. et al Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2018; 392 10143 222-231
  • 43 Xing L, Dai Z, Jabbari A. et al Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 2014; 20 (09) 1043-1049
  • 44 Olamiju B, Friedmann A, King B. Treatment of severe alopecia areata with baricitinib. JAAD Case Rep 2019; 5 (10) 892-894
  • 45 Jabbari A, Dai Z, Xing L. et al Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib. EBioMedicine 2015; 2 (04) 351-355
  • 46 Craiglow BG, King BA. Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. J Invest Dermatol 2014; 134 (12) 2988-2990
  • 47 Pieri L, Guglielmelli P, Vannucchi AM. Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia. Am J Hematol 2015; 90 (01) 82-83
  • 48 Miserocchi E, Giuffrè C, Cornalba M. et al JAK inhibitors in refractory juvenile idiopathic arthritis-associated uveitis. Clin Rheumatol 2020; 39 (03) 847-851
  • 49 Strand V, Ahadieh S, French J. et al Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther 2015; 17: 362
  • 50 Curtis JR, Xie F, Yun H. et al Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis. Ann Rheum Dis 2016; 75 (10) 1843-1847
  • 51 Hamaguchi H, Amano Y, Moritomo A. et al Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor. Bioorg Med Chem 2018; 26: 4971-4983
  • 52 Nakayamada S, Kubo S, Iwata S, Tanaka Y. Recent progress in JAK inhibitors for the treatment of rheumatoid arthritis. BioDrugs 2016; 30: 407-419
  • 53 Virtanen AT, Haikarainen T, Raivola J, Silvennoinennen O. Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases. Biodrugs 2019; 33: 15-32
  • 54 Choy EH. Clinical significance of Janus Kinase inhibitor selectivity. Rheumatology 2019; 58 (06) 953-962