Aktuelle Rheumatologie 2018; 43(02): 161-168
DOI: 10.1055/s-0043-121139
Übersichtsarbeit
© Georg Thieme Verlag KG Stuttgart · New York

Neue Therapieansätze bei entzündlichen Gelenkerkrankungen

Novel Therapeutic Strategies in Inflammatory Joint Diseases
Karolina Benesova
1   Sektion Rheumatologie, Innere Medizin V, Universität Heidelberg, Heidelberg
,
Niko Kai Bender
1   Sektion Rheumatologie, Innere Medizin V, Universität Heidelberg, Heidelberg
,
Hanns-Martin Lorenz
1   Sektion Rheumatologie, Innere Medizin V, Universität Heidelberg, Heidelberg
› Author Affiliations
Further Information

Publication History

Publication Date:
27 November 2017 (online)

Zusammenfassung

Nachdem in mehreren Phase-III-Studien die Wirksamkeit und Sicherheit gezeigt werden konnte, erhielten Anfang dieses Jahres die ersten beiden JAK-Inhibitoren (Baricitinib und Tofacitinib) auch in Deutschland die Zulassung zur Behandlung der mittelschweren bis schweren aktiven rheumatoiden Arthritis. Apremilast, ein selektiver Phosphodiesterase-4 (PDE4)-Inhibitor, wird seit Anfang 2015 als orale Therapie zur Behandlung der Psoriasis und Psoriasis-Arthritis eingesetzt. Bei Psoriasis-Arthritis führt Apremilast u. a. zu einer Verringerung des Schmerzes sowie einer Verbesserung der druckschmerzhaften und geschwollenen Gelenke, der Daktylitis und der Enthesitis. Secukinumab ist ein rekombinanter humaner monoklonaler Antikörper gegen Interleukin (IL)-17 A, der initial zur Behandlung erwachsener Patienten mit mittelschwerer bis schwerer Plaque-Psoriasis eingesetzt wurde. Im November 2015 hat die EMA die Zulassung von Secukinumab auf die Behandlung von Patienten mit aktiver Psoriasis-Arthritis und ankylosierender Spondylitis erweitert. Ustekinumab ist ein humaner monoklonaler Antikorper gegen IL-12/23 und seit 2009 für die Behandlung der Plaque-Psoriasis eingesetzt. Im September 2013 erhielt Ustekinumab durch die EMA auch die Zulassung für die Behandlung der Psoriasisarthritis.

Abstract

After efficacy and safety were demonstrated in several phase III trials, the first 2 JAK inhibitors (baricitinib and tofacitinib) have recently been approved for the treatment of moderate to severe active rheumatoid arthritis in Germany. Apremilast, a selective phosphodiesterase-4 (PDE4) inhibitor, has been used as an oral treatment for psoriasis and psoriatic arthritis since the beginning of 2015. In psoriatic arthritis, apremilast leads to a reduction in pain and an improvement in tender and swollen joints, dactylitis and enthesitis. Secukinumab is a recombinant, fully human, monoclonal antibody neutralising interleukin (IL)-17 A. It was used initially for the treatment of adult patients with moderate to severe plaque psoriasis. In November 2015, the EMA expanded the approval of Secukinumab to active psoriatic arthritis and ankylosing spondylitis. Ustekinumab is a human monoclonal antibody against the p40 subunit of IL-12/23 and has been used for the treatment of plaque psoriasis since 2009. In September 2013, Ustekinumab was also approved by the EMA for the treatment of psoriatic arthritis.

 
  • Literatur

  • 1 Alten R. Update zu Kinasehemmern 2016. Z Rheumatol 2016; 75: 611-615
  • 2 Shi JG, Chen X, Lee F. et al. The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. J Clin Pharmacol 2014; 54: 1354-1361
  • 3 Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 2003; 3: 900-911
  • 4 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: 506-517
  • 5 Taylor PC, Keystone EC, van der Heijde D. et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med 2017; 376: 652-662
  • 6 Dougados M, van der Heijde D, Chen YC. et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis 2017; 76: 88-95
  • 7 Genovese MC, Kremer J, Zamani O. et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 2016; 374: 1243-1252
  • 8 van der Heijde D, Tanaka Y, Fleischmann R. et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum 2013; 65: 559-570
  • 9 Kremer J, Li ZG, Hall S. et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med 2013; 159: 253-261
  • 10 van Vollenhoven RF, Fleischmann R, Cohen S. et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012; 367: 508-519
  • 11 Burmester GR, Blanco R, Charles-Schoeman C. et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet 2013; 381: 451-460
  • 12 Fleischmann R, Kremer J, Cush J. et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012; 367: 495-507
  • 13 Lilly Deutschland GmbH. Fachinformation Olumiant®. Stand Februar 2017
  • 14 Pfizer Pharma GmbH. Fachinformation Xelianz®. Stand März 2017
  • 15 Gottlieb AB, Matheson RT, Menter A. et al. Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. J Drugs Dermatol 2013; 12: 888-897
  • 16 Schafer PH, Parton A, Capone L. et al. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal 2014; 26: 2016-2029
  • 17 Schafer PH, Chen P, Fang L. et al. The pharmacodynamic impact of apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in patients with psoriatic arthritis: substudy results from a phase III, randomized, placebo-controlled trial (PALACE 1). J Immunol Res 2015; 2015: 906349
  • 18 Kavanaugh A, Mease PJ, Gomez-Reino JJ. et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis 2014; 73: 1020-1026
  • 19 Cutolo M, Myerson GE, Fleischmann RM. et al. A Phase III, randomized, controlled trial of apremilast in patients with psoriatic arthritis: results of the PALACE 2 trial. J Rheumatol 2016; 43: 1724-1734
  • 20 Edwards CJ, Blanco FJ, Crowley J. et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis 2016; 75: 1065-1073
  • 21 hautnah . Erster oraler PDE4-Inhibitor erhält positive Stellungnahme des CHMP. hautnah 2015; 1: 6-7
  • 22 Celgene Europe Ltd. Fachinformation Otezla®. Stand Dezember 2016
  • 23 DGRh. Therapie-Überwachung, http://dgrh.de/therapieueberwachen. html . Letzter Zugriff 08.06.2017
  • 24 Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 2012; 11: 763-776
  • 25 Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med 2012; 18: 1018-1019
  • 26 Mease PJ. Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis. Curr Opin Rheumatol 2015; 27: 127-133
  • 27 Nickoloff BJ. Cracking the cytokine code in psoriasis. Nat Med 2007; 13: 242-244
  • 28 Bartlett HS, Million RP. Targeting the IL-17- T(H)17 pathway. Nat Rev Drug Discov 2015; 14: 11-12
  • 29 Kemanetzoglou E, Andreadou E. CNS Demyelination with TNF-alpha Blockers. Curr Neurol Neurosci Rep 2017; 17: 36
  • 30 Smith JA. The bench-to-bedside story of IL-17 and the therapeutic efficacy of its targeting in spondyloarthritis. Curr Rheumatol Rep 2016; 18: 33
  • 31 Koenders MI, van den Berg WB. Secukinumab for rheumatology: development and its potential place in therapy. Drug Des Devel Ther 2016; 10: 2069-2080
  • 32 Benson JM, Sachs CW, Treacy G. et al. Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab. Nat Biotechnol 2011; 29: 615-624
  • 33 Kiltz U, Braun J. DGRh-S3-Leitlinie Axiale Spondyloarthritis inklusive Morbus Bechterew und Frühformen. Zeitschrift für Rheumatologie 2014; 2: 20-111
  • 34 Langley RG, Elewski BE, Lebwohl M. et al. Secukinumab in plaque psoriasis – results of two phase 3 trials. N Engl J Med 2014; 371: 326-338
  • 35 Mease PJ, McInnes IB, Kirkham B. et al. Secukinumab Inhibition of Interleukin-17 A in Patients with Psoriatic Arthritis. N Engl J Med 2015; 373: 1329-1339
  • 36 McInnes IB, Mease PJ, Kirkham B. et al. Secukinumab, a human anti-interleukin-17 A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2015; 386: 1137-1146
  • 37 Arends S, Brouwer E, van der Veer E. et al. Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther 2011; 13: R94
  • 38 Baeten D, Sieper J, Braun J. et al. Secukinumab, an Interleukin-17 A Inhibitor, in Ankylosing Spondylitis. N Engl J Med 2015; 373: 2534-2548
  • 39 Deodhar AA, Dougados M, Baeten DL. et al. Effect of secukinumab on patient-reported outcomes in patients with active ankylosing spondylitis: a phase iii randomized trial (MEASURE 1). Arthritis Rheumatol 2016; 68: 2901-2910
  • 40 Sieper J, Deodhar A, Marzo-Ortega H. et al. Secukinumab efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 Study. Ann Rheum Dis 2017; 76: 571-592
  • 41 Baraliakos X, Borah B, Braun J. et al. Long-term effects of secukinumab on MRI findings in relation to clinical efficacy in subjects with active ankylosing spondylitis: an observational study. Ann Rheum Dis 2016; 75: 408-412
  • 42 McInnes IB, Kavanaugh A, Gottlieb AB. et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 2013; 382: 780-789
  • 43 Ritchlin C, Rahman P, Kavanaugh A. et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis 2014; 73: 990-999
  • 44 McKeage K. Ustekinumab: a review of its use in psoriatic arthritis. Drugs 2014; 74: 1029-1039
  • 45 Kavanaugh A, Ritchlin C, Rahman P. et al. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann Rheum Dis 2014; 73: 1000-1006
  • 46 Müller-Ladner U, Lange U. Neue Medikamente in der Rheumatologie. Internist 2014; 377-381
  • 47 Poddubnyy D, Hermann KG, Callhoff J. et al. Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann Rheum Dis 2014; 73: 817-823
  • 48 Yeremenko N, Paramarta JE, Baeten D. The interleukin-23/interleukin-17 immune axis as a promising new target in the treatment of spondyloarthritis. Curr Opin Rheumatol 2014; 26: 361-370
  • 49 Blauvelt A, Reich K, Tsai TF. et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: Results from the CLEAR study. J Am Acad Dermatol 2017; 76: 60-69 e69
  • 50 Feagan BG, Sandborn WJ, Gasink C. et al. Ustekinumab as induction and maintenance therapy for Crohn's Disease. N Engl J Med 2016; 375: 1946-1960
  • 51 Nash P, Kirkham B, Okada M. et al. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet 2017; 389: 2317-2327
  • 52 Dong J, Goldenberg G. New biologics in psoriasis: an update on IL-23 and IL-17 inhibitors. Cutis 2017; 99: 123-127
  • 53 Khatri A, Klunder B, Minocha M et al. Exposure-response analyses of efficacy of ABT-122, a Dual-Variable Domain Immunoglobulin (DVD-Ig™) Targeting TNF-α and IL-17 A. Compared with adalimumab in subjects with rheumatoid arthritis and background MTX [abstract number 643] Arthritis Rheumatol 2016
  • 54 Genovese MC, Weinblatt M, Aelion JA et al. ABT-122, a Tnf– and IL-17–Targeted Dual Variable Domain (DVD)–Ig™ in rheumatoid arthritis patients with inadequate response to methotrexate: Results from a phase 2 trial [abstract number 650]. Arthritis Rheumatol 2016
  • 55 Mease PJ, Genovese MC, Weinblatt M et al. Safety and efficacy of ABT-122, a TNF and IL-17–Targeted Dual Variable Domain (DVD)–Ig™, in psoriatic arthritis patients with inadequate response to methotrexate: Results from a phase 2 trial [abstract number 958]. Arthritis Rheumatol 2016
  • 56 Torres T, Romanelli M, Chiricozzi A. A revolutionary therapeutic approach for psoriasis: bispecific biological agents. Expert Opin Investig Drugs 2016; 25: 751-754
  • 57 Tanaka Y, Martin Mola E. IL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab. Ann Rheum Dis 2014; 73: 1595-1597
  • 58 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: 1009-1019
  • 59 Westhovens R, Taylor PC, Alten R. et al. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis 2017; 76: 998-1008
  • 60 Burmester GR, McInnes IB, Kremer J. et al. A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis 2017; 76: 1020-1030