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Stellenwert von interleukingerichteten Therapien bei Autoimmunkrankheiten

Importance of interleukin-directed treatment for autoimmune diseases

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Zusammenfassung

Das Verständnis der Pathophysiologie von Autoimmunerkrankungen ermöglicht die Identifikation neuer Angriffspunkte für präzisere Pharmakotherapien. Diese sollen idealerweise neben einer hohen Effektivität auch ein besseres Sicherheitsprofil aufweisen. Interleukine (IL) sind eine Gruppe von Entzündungsmediatoren, die ganz unterschiedliche Autoimmun- und Autoinflammationserkrankungen in ihrem Verlauf beeinflussen können. Obwohl viele Biologika für die rheumatoide Arthritis entwickelt wurden, weitet sich ihr Einsatzgebiet mitunter auf andere Indikationen aus, wo sie teilweise sogar einen höheren Stellenwert haben, wie z. B. die IL-1-Antagonisten bei den Autoinflammationssyndromen. Mittlerweile therapieren wir mit Antikörpern gegen IL oder ihre Rezeptoren ein wachsendes Spektrum an Erkrankungen. Auch synthetische DMARD („disease modifying antirheumatic drugs“) sind im weitesten Sinne IL-gerichtete Therapien. Aus Gründen der Übersichtlichkeit soll es in diesem Artikel jedoch in erster Linie um Biologika, die unmittelbar IL hemmen, bzw. im Fall von IL‑2 um ein therapeutisch eingesetztes IL selbst gehen.

Abstract

Understanding the pathophysiology of autoimmune diseases enables the identification of new targets for more precise pharmacotherapies. Ideally, these should not only be highly effective but also have a better safety profile. Interleukins (IL) are a group of inflammatory mediators that can influence the course of very different autoimmune and autoinflammatory diseases. Although many biologicals have been developed for rheumatoid arthritis, their application has extended to other indications where they are even more important, e.g. IL‑1 antagonists in autoinflammatory syndromes. In the meantime, a growing spectrum of diseases are being treated with antibodies against IL or their receptors. Synthetic disease-modifying antirheumatic drugs (DMARD) are also IL-directed therapies in the broadest sense. For reasons of clarity, however, this article primarily addresses biologicals that directly inhibit IL or in the case of IL‑2 an IL which is itself used for treatment.

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Literatur

  1. 1.

    Araujo EG, Englbrecht M, Hoepken S et al (2019) Effects of ustekinumab versus tumor necrosis factor inhibition on enthesitis: results from the enthesial clearance in psoriatic arthritis (ECLIPSA) study. Semin Arthritis Rheum 48:632–637

  2. 2.

    Baeten D, Sieper J, Braun J et al (2015) Secukinumab, an Interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med 373:2534–2548

  3. 3.

    Baeten D, Østergaard M, Wei JC et al (2018) Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study. Ann Rheum Dis 77:1295–1302

  4. 4.

    Beringer A, Miossec P (2019) Systemic effects of IL-17 in inflammatory arthritis. Nat Rev Rheumatol 15:491–501

  5. 5.

    Billiard F, Litvinova E, Saadoun D et al (2006) Regulatory and effector T cell activation levels are prime determinants of in vivo immune regulation. J Immunol 177:2167–2174

  6. 6.

    Blauvelt A, Papp KA, Griffiths CE et al (2017) Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol 76:405–417

  7. 7.

    Burkett PR, Meyer zu Horste G, Kuchroo VK (2015) Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity. J Clin Invest 125:2211–2219

  8. 8.

    Cavalli G, Dinarello CA (2015) Treating rheumatological diseases and co-morbidities with interleukin‑1 blocking therapies. Rheumatology 54:2134–2144

  9. 9.

    De Benedetti F, Gattorno M, Anton J et al (2018) Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 378:1908–1919

  10. 10.

    Deodhar A, Gensler LS, Sieper J et al (2019) Three multicenter, randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of ustekinumab in axial spondyloarthritis. Arthritis Rheumatol 71:258–270

  11. 11.

    Dhorepatil A, Ball S, Ghosh RK et al (2019) Canakinumab: promises and future in cardiometabolic diseases and malignancy. Am J Med 132:312–324

  12. 12.

    Dick AD, Tugal-Tutkun I, Foster S et al (2013) Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials. Ophthalmology 120:777–787

  13. 13.

    Dinarello CA (2011) Interleukin‑1 in the pathogenesis and treatment of inflammatory diseases. Blood 117:3720–3732

  14. 14.

    Evans DM, Spencer CC, Pointon JJ et al (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43:761–767

  15. 15.

    Eyerich S, Eyerich K, Pennino D et al (2009) Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 119:3573–3585

  16. 16.

    Fragoulis GE, Siebert S, McInnes IB (2016) Therapeutic targeting of IL-17 and IL-23 cytokines in immune-mediated diseases. Annu Rev Med 67:337–353

  17. 17.

    Gabay C, Emery P, van Vollenhoven R et al (2013) Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 381:1541–1550

  18. 18.

    Genovese MC, Durez P, Richards HB et al (2013) Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 72:863–869

  19. 19.

    Gregory SG, Schmidt S, Seth P et al (2007) Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 39:1083–1091

  20. 20.

    He J, Zhang R, Shao M et al (2020) Efficacy and safety of low-dose IL‑2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 79(1):141–149

  21. 21.

    He J, Zhang X, Wei Y et al (2016) Low-dose interleukin‑2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med 22:991–993

  22. 22.

    Hellmich B, Csernok E, Gross WL (2005) Proinflammatory cytokines and autoimmunity in Churg-Strauss syndrome. Ann N Y Acad Sci 1051:121–131

  23. 23.

    Hueber W, Sands BE, Lewitzky S et al (2012) Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61:1693–1700

  24. 24.

    Jones G, Sebba A, Gu J et al (2010) Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 69:88–96

  25. 25.

    Jones SA, Scheller J, Rose-John S (2011) Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 121:3375–3383

  26. 26.

    Kang KY, Kim HO, Kwok SK et al (2011) Impact of interleukin-21 in the pathogenesis of primary Sjögren’s syndrome: increased serum levels of interleukin-21 and its expression in the labial salivary glands. Arthritis Res Ther 13:R179

  27. 27.

    Klatzmann D, Abbas AK (2015) The promise of low-dose interleukin‑2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 15:283–294

  28. 28.

    Kobayashi T, Okamoto S, Hisamatsu T et al (2008) IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut 57:1682–1689

  29. 29.

    Lebwohl MG, Papp KA, Marangell LB et al (2018) Psychiatric adverse events during treatment with brodalumab: analysis of psoriasis clinical trials. J Am Acad Dermatol 78(5):81–89.e8

  30. 30.

    Leipe J, Schramm MA, Grunke M et al (2011) Interleukin 22 serum levels are associated with radiographic progression in rheumatoid arthritis. Ann Rheum Dis 70:1453–1457

  31. 31.

    Leonard WJ, Lin JX, O’Shea JJ (2019) The γ. Immunity 50:832–850

  32. 32.

    Leonardi CL, Kimball AB, Papp KA et al (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371:1665–1674

  33. 33.

    Long D, Chen Y, Wu H et al (2019) Clinical significance and immunobiology of IL-21 in autoimmunity. J Autoimmun 99:1–14

  34. 34.

    Lyons PA, Peters JE, Alberici F et al (2019) Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nat Commun 10:5120

  35. 35.

    Mazzoni A, Maggi L, Liotta F et al (2019) Biological and clinical significance of T helper 17 cell plasticity. Immunology 158:287–295

  36. 36.

    McInnes IB, Kavanaugh A, Gottlieb AB et al (2013) 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 382:780–789

  37. 37.

    Nakou M, Papadimitraki ED, Fanouriakis A et al (2013) Interleukin-21 is increased in active systemic lupus erythematosus patients and contributes to the generation of plasma B cells. Clin Exp Rheumatol 31:172–179

  38. 38.

    Pascart T, Norberciak L, Ea HK et al (2019) Difficult-to-treat gout flares: eligibility for interleukin‑1 inhibition in private practice is uncommon according to current EMA approval. Rheumatology 58(12):2181–2187

  39. 39.

    Ridker PM, Everett BM, Thuren T et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131

  40. 40.

    Robb RJ (1984) Interleukin 2: the molecule and its function. Immunol Today 5:203–209

  41. 41.

    Rosenberg SA, Yang JC, Topalian SL et al (1994) Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271:907–913

  42. 42.

    Rosenzwajg M, Lorenzon R, Cacoub P et al (2019) Immunological and clinical effects of low-dose interleukin‑2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis 78:209–217

  43. 43.

    Saadoun D, Rosenzwajg M, Joly F et al (2011) Regulatory T‑cell responses to low-dose interleukin‑2 in HCV-induced vasculitis. N Engl J Med 365:2067–2077

  44. 44.

    Sakaguchi S, Sakaguchi N, Asano M et al (1995) Immunologic self-tolerance maintained by activated T cells expressing IL‑2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164

  45. 45.

    Shen H, Goodall JC, Hill GJS (2009) Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum 60:1647–1656

  46. 46.

    Sivera F, Wechalekar MD, Andrés M et al (2014) Interleukin‑1 inhibitors for acute gout. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD009993.pub2

  47. 47.

    Smolen JS, Agarwal SK, Ilivanova E et al (2017) A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann Rheum Dis 76:831–839

  48. 48.

    Smolen JS, Landewé R, Bijlsma J et al (2017) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 76:960–977

  49. 49.

    Stone JH, Tuckwell K, Dimonaco S et al (2017) Trial of tocilizumab in giant-cell arteritis. N Engl J Med 377:317–328

  50. 50.

    Stone JH, Tuckwell K, Dimonaco S et al (2019) Glucocorticoid dosages and acute-phase reactant levels at giant cell arteritis flare in a randomized trial of tocilizumab. Arthritis Rheumatol 71:1329–1338

  51. 51.

    Tzellos T, Kyrgidis A, Zouboulis CC (2013) Re-evaluation of the risk for major adverse cardiovascular events in patients treated with anti-IL-12/23 biological agents for chronic plaque psoriasis: a meta-analysis of randomized controlled trials. J Eur Acad Dermatol Venereol 27:622–627

  52. 52.

    van de Kerkhof PC, Griffiths CE, Reich K et al (2016) Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol 75(4):83–98.e8

  53. 53.

    Veldhoen M, Hocking RJ, Atkins CJ et al (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189

  54. 54.

    Wechsler ME, Akuthota P, Jayne D et al (2017) Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med 376:1921–1932

  55. 55.

    Yamaguchi T, Wing JB, Sakaguchi S (2011) Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions. Semin Immunol 23:424–430

  56. 56.

    Yu A, Zhu L, Altman NH et al (2009) A low interleukin‑2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 30:204–217

  57. 57.

    Zheng ZH, Zeng X, Nie XY et al (2019) Interleukin‑1 blockade treatment decreasing cardiovascular risk. Clin Cardiol 42:942–951

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Correspondence to Dr. med. P. Moog.

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A. Hammitzsch, U. Heemann und P. Moog geben 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.

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U. Heemann, München

U. Kunzendorf, Kiel

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Hammitzsch, A., Heemann, U. & Moog, P. Stellenwert von interleukingerichteten Therapien bei Autoimmunkrankheiten. Nephrologe (2020). https://doi.org/10.1007/s11560-020-00413-x

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Schlüsselwörter

  • Immunsystem
  • Autoinflammationssyndrome
  • Antikörper
  • Biologika
  • DMARD

Keywords

  • Immune system
  • Autoinflammatory syndromes
  • Antibodies
  • Biologicals
  • Antirheumatic agents