Neue Entwicklungen in der Biologikatherapie

Zusammenfassung

Der Erkenntniszugewinn im Verständnis für die Pathophysiologie vieler entzündlich-rheumatischer Erkrankungen hat auch die Entwicklung neuer Pharmaka nach sich gezogen. Besonders die Fortschritte auf dem Gebiet der Biologika haben dazu beigetragen, den Lei-densdruck betroffener Patienten zu verringern und die Lebensqualität zu verbessern. Aller-dings weisen selbst diese effektiven Substanzen ein in der Nutzen-Risiko-Abwägung zwar akzeptables, dennoch aber in der klinischen Anwendung bedeutsames Nebenwirkungsprofil auf – und sie helfen nicht in jedem Fall. Es bleibt daher das Bestreben, anhand von neuen oder spezifischeren Angriffspunkten Medikamente mit geringeren Nebenwirkungsprofilen und vereinfachten Applikationsmodalitäten in größeren Intervallen mit dem Ziel einer schnelleren Remissionsindukti-on und -erhaltung zu finden und zu etablieren. Im Zuge dieser Bemühungen haben sich mehrere Agenzien herauskristallisiert, die auf die Ausweitung des medikamentösen Arsenals hoffen lassen. Einige dieser Substanzen werden auf der Grundlage aktueller Studienveröffentlichungen kurz vorgestellt. Sie sind sowohl Teil bestehender Strategien wie der TNF-Blockade, betreffen aber auch die Neutralisation neuer Zytokine und die B- und T-Zell-Biologie.

Summary

The increasing knowledge in the understanding of pathophysiological characteristics in different inflammatory conditions paved the way for the development of new pharmacological agents. Particularly, the advances in the field of biological therapy facilitated to reduce the burden of disease for the affected individuals and to ameliorate their quality of life. Considering the risk-benefit analysis, however, even these effective substances show an indeed acceptable but still not negligible profile of side effects, and they do not help in any case. Therefore, the ambition remains to further optimise the modalities of medication by means of reduced side effects and simplified application with expanded intervals to aim at an accelerated induction and sustainment of remission. Concomitantly with these efforts several agents turned out to be expected to broaden the pharmacological armamentarium. Based on recently published clinical trials some of these agents will be presented in their review. They form not only part of established strategies such as TNF inhibition but are as well related to neutralisation of novel cytokines and to the biology of B- and T-cells.

Schlüsselwörter

Pharmaka - Pathophysiologie - Zytokine - Lymphozyten

Keywords

Pharmacological - pathophysiologic - cytokines - lymphocytes

• Literatur

• 1 Cha HS, Boyle DL, Inoue T. et al. A novel spleen tyrosine kinase inhibitor blocks c-Jun N-terminal kinase-mediated gene expression in synoviocytes.. J Pharmacol Exp Ther 2006; 317 (02) 571-578.
• 2 Cheema GS, Roschke V, Hilbert DM, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases.. Arthritis Rheum 2001; 44 (06) 1313-1319.
• 3 Cohen SB, Dore RK, Lane NE. et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial.. Arthritis Rheum 2008; 58 (05) 1299-1309.
• 4 Dall'Era M, Chakravarty E, Wallace D. et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial.. Arthritis Rheum 2007; 56 (12) 4142-4150.
• 5 Emery P, Keystone E, Tony HP. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial.. Ann Rheum Dis 2008; 67 (11) 1516-1523.
• 6 Furie R, Stohl W, Ginzler EM. et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus.. Arthritis Res Ther 2008; 10 (05) R109
• 7 Genovese MC, Kaine JL, Lowenstein MB. et al. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I/II randomized, blinded, placebo-controlled, dose-ranging study.. Arthritis Rheum 2008; 58 (09) 2652-2661.
• 8 Gottlieb A, Menter A, Mendelsohn A. et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial.. Lancet 2009; 373 9664 633-640.
• 9 Gross JA, Johnston J, Mudri S. et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease.. Nature 2000; 404 6781 995-999.
• 10 Inman RD, Davis Jr. JC., Heijde D. et al. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial.. Arthritis Rheum 2008; 58 (11) 3402-3412.
• 11 Kay J, Matteson EL, Dasgupta B. et al. Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study.. Arthritis Rheum 2008; 58 (04) 964-975.
• 12 Keystone E, Heijde D, Mason Jr. D.. et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.. Arthritis Rheum 2008; 58 (11) 3319-3329.
• 13 Mease PJ, Gladman DD, Keystone EC. Alefacept in combination with methotrexate for the treatment of psoriatic arthritis: results of a randomized, double-blind, placebo-controlled study.. Arthritis Rheum 2006; 54 (05) 1638-1645.
• 14 Mease PJ, Reich K. Alefacept with methotrexate for treatment of psoriatic arthritis: open-label extension of a randomized, double-blind, placebo-controlled study.. J Am Acad Dermatol 2009; 60 (03) 402-411.
• 15 Moore PA, Belvedere O, Orr A. et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator.. Science 1999; 285 5425 260-263.
• 16 Nesbitt A, Fossati G, Bergin M. et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents.. Inflamm Bowel Dis 2007; 13 (11) 1323-1332.
• 17 Papp KA, Caro I, Leung HM. et al. Efalizumab for the treatment of psoriatic arthritis.. J Cutan Med Surg 2007; 11 (02) 57-66.
• 18 Papp KA, Langley RG, Lebwohl M. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).. Lancet 2008; 371 9625 1675-1684.
• 19 Petri M, Stohl W, Chatham W. et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus.. Arthritis Rheum 2008; 58 (08) 2453-2459.
• 20 Ramanujam M, Wang X, Huang W. et al. Similarities and differences between selective and nonselective BAFF blockade in murine SLE.. J Clin Invest 2006; 116 (03) 724-734.
• 21 Roschke V, Sosnovtseva S, Ward CD. et al. BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases.. J Immunol 2002; 169 (08) 4314-4321.
• 22 Scapini P, Nardelli B, Nadali G. et al. G-CSF-stimulated neutrophils are a prominent source of functional BLyS.. J Exp Med 2003; 197 (03) 297-302.
• 23 Smolen JS, Beaulieu A, Rubbert-Roth A. et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.. Lancet 2008; 371 9617 987-997.
• 24 Thompson JS, Bixler SA, Qian F. et al. BAFF-R, a newly identified TNF receptor that specifically in-teracts with BAFF.. Science 2001; 293 5537 2108-2111.
• 25 Vanags D, Williams B, Johnson B. et al. Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a double-blind randomised trial.. Lancet 2006; 368 9538 855-863.
• 26 Weinblatt ME, Kavanaugh A, Burgos-Vargas R. et al. Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial.. Arthritis Rheum 2008; 58 (11) 3309-3318.
• 27 Yan M, Marsters SA, Grewal IS. et al. Identification of a receptor for BLyS demonstrates a crucial role in humoral immunity.. Nat Immunol 2000; 1 (01) 37-41.
• 28 Yokota S, Imagawa T, Mori M. et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial.. Lancet 2008; 371 9617 998-1006.