Januskinase-Inhibitoren

State of the Art im klinischen Einsatz und Zukunftsperspektiven

Janus kinase inhibitors

State of the art in clinical use and future perspectives

Zusammenfassung

Hintergrund

In der Pathogenese von Autoimmunerkrankungen spielen Zytokine und deren intrazelluläre Signalkaskaden eine zentrale Rolle. An dieser intrazellulären Signalübertragung sind auch sog. Januskinasen (JAK) beteiligt. Die zur Gruppe der „targeted synthetic disease-modifying antirheumatic drugs“ (tsDMARDs) zählenden Januskinase-Inhibitoren (JAKi) sind eine relativ junge und vielversprechende Wirkstoffklasse in der Therapie autoimmuner Krankheitsbilder.

Wirksamkeit

Mittlerweile sind für die Behandlung der rheumatoiden Arthritis (RA) drei Wirkstoffe, Tofacitinib, Baricitinib und Upadacitinib, in den USA, der Schweiz und der EU zugelassen. Auch Filgotinib, ein weiterer JAKi, zeigt vielversprechende Ergebnisse in der Therapie der RA. Darüber hinaus wurde Tofacitinib auch für die Therapie der ulzerativen Kolitis und der Psoriasisarthritis zugelassen. Zusätzlich zu den bereits genannten wurden und werden weitere JAKi wie Filgotinib oder Peficitinib in zahlreichen Studien zu Indikationen wie atopische Dermatitis, ankylosierende Spondylitis oder systemischer Lupus erythematodes untersucht.

Sicherheit

Als Immunsuppressiva weisen JAKi eine mit Biologika vergleichbare erhöhte Inzidenz für schwere Infekte auf. Bemerkenswert ist die erhöhte Reaktivierung des Varicella-Zoster-Virus. Auch Zytopenien treten unter JAKi-Therapie überhäufig auf. Klinisch relevant ist hierbei v. a. die beobachtete Lymphopenie, die mit einem erhöhten Auftreten von schweren Infekten assoziiert ist. Ein erhöhtes Risiko besteht weiterhin für thromboembolische Ereignisse, insbesondere Lungenembolien. Die Risiken hinsichtlich metabolischer Veränderungen und des Auftretens maligner Neoplasien sind vergleichbar mit denen unter Biologikatherapie.

Abstract

Background

Cytokines and associated intracellular signal cascades play a major role in the pathogenesis of autoimmune diseases. Janus kinases (JAK) are part of these intracellular signal transduction processes. A relatively new drug group of targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) are JAK inhibitors (JAKi) and are a promising treatment approach for autoimmune diseases.

Efficacy

Hitherto, three JAKis, Tofacitinib, Baricitinib and Upadacitinib, have been approved for treatment of Rheumatoid Arthritis (RA) in the USA, Switzerland and the EU. Filgotinib, another JAKi, also showed promising results in the treatment of RA. Furthermore, tofacitinib received approval for the treatment of ulcerative colitis and psoriatic arthritis. In addition to the JAKis already mentioned, several other JAKis, e.g. filgotinib and peficitinib, are being and were investigated in various studies on indications, such as atopic dermatitis, ankylosing spondylitis and systemic lupus erythematosus.

Safety

Being immunosuppressants, JAKis show an elevated incidence of severe infections, comparable to biologics. The increased reactivation of varicella zoster virus is especially noteworthy. Under JAKi treatment cytopenia is also more frequent. Lymphopenia under JAKi treatment is of particular clinical relevance because of its association with an increase in the number of severe infections. Furthermore, an elevated risk of thromboembolic events, particularly pulmonary embolism has been noted. The risks concerning metabolic alterations and the occurrence of malignant neoplasms are comparable to those under treatment with biologics.

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Literatur

  1. 1.

    Banerjee S et al (2017) JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs 77(5):521–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Rodig SJ et al (1998) Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 93:373–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Neubauer H et al (1998) Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 93:397–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Leonard WJ et al (1994) The molecular basis of X‑linked severe combined Immunodeficiency: the role of the Interleukin‑2 receptor γ chain as a common γ chain, γc. Immunol Rev 138(1):61–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    McIntosh LA et al (2017) Genome-wide association meta-analysis reveals novel juvenile idiopathic arthritis susceptibility loci. Arthritis Rheumatol 69(11):2222–2232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Tao J‑H et al (2011) Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases. Mol Biol Rep 38(7):4663–4672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Nangalia J, Grinfeld J, Green AR (2016) Pathogenesis of myeloproliferative disorders. Annu Rev Pathol 11(1):101–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    O’Shea JJ, Gadina M (2019) Selective Janus kinase inhibitors come of age. Nat Rev Rheumatol 15(2):74–75

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Choy EH (2019) Clinical significance of Janus Kinase inhibitor selectivity. Rheumatology 58(6):953–962

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Fleischmann R et al (2012) Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 367(6):495–507

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Burmester GR et al (2013) 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 381(9865):451–460

    Article  CAS  Google Scholar 

  12. 12.

    Kremer J et al (2013) Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med 159(4):253–261

    Article  PubMed  Google Scholar 

  13. 13.

    van Vollenhoven RF et al (2012) Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 367(6):508–519

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Lee EB et al (2014) Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 370(25):2377–2386

    Article  CAS  Google Scholar 

  15. 15.

    Fleischmann R et al (2017) 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 390(10093):457–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    van der Heijde D et al (2013) 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 65(3):559–570

    Article  CAS  Google Scholar 

  17. 17.

    FDA Approves Xeljanz Drugs.com. https://www.drugs.com/newdrugs/fda-approves-xeljanz-rheumatoid-arthritis-3558.html. Zugegriffen: 30. Aug. 2019

  18. 18.

    Xeljanz. European Medicines Agency https://www.ema.europa.eu/en/medicines/human/EPAR/xeljanz#authorisation-details-section. Zugegriffen: 30. Aug. 2019

  19. 19.

    Wollenhaupt J et al (2019) 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 21(1):89

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Fleischmann R et al (2017) Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol 69(3):506–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Dougados M et al (2017) Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis 76(1):88–95

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Taylor PC et al (2017) Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 376(7):652–662

    Article  CAS  Google Scholar 

  23. 23.

    Genovese MC et al (2016) Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 374(13):1243–1252

    CAS  Article  Google Scholar 

  24. 24.

    Emery P et al (2017) Patient-reported outcomes from a phase III study of baricitinib in patients with conventional synthetic DMARD-refractory rheumatoid arthritis. RMD Open 3(1):e410

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Smolen JS et al (2017) Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). Ann Rheum Dis 76(4):694–700

    Article  PubMed  Google Scholar 

  26. 26.

    Schiff M et al (2017) Patient-reported outcomes of baricitinib in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Res Ther 19(1):208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Keystone EC et al (2017) Patient-reported outcomes from a phase 3 study of baricitinib versus placebo or adalimumab in rheumatoid arthritis: secondary analyses from the RA-BEAM study. Ann Rheum Dis 76(11):1853–1861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Takeuchi T et al (2019) Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study. Ann Rheum Dis 78(2):171–178

    Article  CAS  Google Scholar 

  29. 29.

    Drugs.com (2019) FDA approves olumiant. https://www.drugs.com/newdrugs/fda-approves-olumiant-baricitinib-2-mg-adults-moderately-severely-active-rheumatoid-arthritis-4760.html. Zugegriffen: 30. Aug. 2019

  30. 30.

    Olumiant. European Medicines Agency (2019) https://www.ema.europa.eu/en/medicines/human/EPAR/olumiant. Zugegriffen: 30. Aug. 2019

  31. 31.

    Markham A, Keam Peficitinib SJ (2019) Peficitinib: first global approval. Drugs 79(8):887–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Takeuchi T et al (2019) Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III randomised, double-blind, placebo-controlled trial (RAJ4) in Japan. Ann Rheum Dis 78(10):1305–1319

  33. 33.

    Tanaka Y et al (2019) Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to conventional DMARDs: a randomised, double-blind, placebo-controlled phase III trial (RAJ3). Ann Rheum Dis 78(10):1320–1332

  34. 34.

    Genovese MC et al (2019) 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 322(4):315–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Genovese M et al (2018) Effect of filgotinib, a selective JAK 1 inhibitor, with and without methotrexate in patients with rheumatoid arthritis: patient-reported outcomes. Arthritis Res Ther 20(1):57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Burmester GR et al (2018) Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 391(10139):2503–2512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Smolen JS et al (2019) Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet 393(10188):2303–2311

    Article  Google Scholar 

  38. 38.

    Genovese MC et al (2018) Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet 391(10139):2513–2524

    Article  CAS  Google Scholar 

  39. 39.

    Fleischmann RM et al (2019) Upadacitinib versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and an inadequate response to methotrexate: results of a phase III, double-blind, randomized controlled trial. Arthritis Rheumatol 71:1788– 1800

  40. 40.

    Fleischmann RM et al (2019) Safety and effectiveness of upadacitinib or adalimumab plus methotexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response. Ann Rheum Dis

  41. 41.

    v. Vollenhoven R et al (2019) THU0197 monotherapy with upadacitinib in MTX-Naïve patients with rheumatoid arthritis: results at 48 weeks from the select-early study. Ann Rheum Dis 78(Suppl 2):376–377

    Google Scholar 

  42. 42.

    FDA Approves Rinvoq (2019) Drug.com, https://www.drugs.com/history/rinvoq.html. Zugegriffen: 30. Aug. 2019

  43. 43.

    Rinvoq (2019) European Medicines Agency, https://www.ema.europa.eu/en/medicines/human/EPAR/rinvoq#authorisation-details-section. Zugegriffen: 21. März 2020

  44. 44.

    Asahina A et al (2016) Oral tofacitinib efficacy, safety and tolerability in Japanese patients with moderate to severe plaque psoriasis and psoriatic arthritis: A randomized, double-blind, phase 3 study. J Dermatol 43(8):869–880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Mease P et al (2017) Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med 377(16):1537–1550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Gladman D et al (2017) Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med 377(16):1525–1536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Drugs.com (2019) Pfizer announces FDA approval of Xeljanz (tofacitinib) and Xeljanz XR for the treatment of active psoriatic arthritis. https://www.drugs.com/newdrugs/pfizer-announces-fda-approval-xeljanz-tofacitinib-xeljanz-xr-active-psoriatic-arthritis-4677.html. Zugegriffen: 30. Aug. 2019

  48. 48.

    Mease P et al (2018) 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 392(10162):2367–2377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    ClinicalTrials.gov (2019) janus kinase inhibitor | Spondyloarthritis—List Results. https://clinicaltrials.gov/ct2/results?cond=Spondyloarthritis&term=janus+kinase+inhibitor&cntry=&state=&city=&dist. Zugegriffen: 30. Aug. 2019

  50. 50.

    van der Heijde D et al (2017) Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis 76(8):1340–1347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    van der Heijde D et al (2018) Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial. Lancet 392(10162):2378–2387

    Article  PubMed  Google Scholar 

  52. 52.

    A Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects With Active Ankylosing Spondylitis ( SELECT Axis 1 ) (SELECT Axis 1). ClinicalTrials.gov, Z.a. Zugegriffen: 30. Aug. 2019

  53. 53.

    Sandborn WJ et al (2017) Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 376(18):1723–1736

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    Panes J et al (2018) Tofacitinib in patients with ulcerative colitis: health-related quality of life in phase 3 randomised controlled induction and maintenance studies. J Crohns Colitis 12(2):145–156

    Article  PubMed  Google Scholar 

  55. 55.

    Drugs.com (2019) Pfizer Announces U.S. FDA Approves Xeljanz (tofacitinib) for the Treatment of Moderately to Severely Active Ulcerative Colitis. https://www.drugs.com/newdrugs/pfizer-announces-u-s-fda-approves-xeljanz-tofacitinib-moderately-severely-active-ulcerative-colitis-4756.html. Zugegriffen: 30. Aug. 2019

  56. 56.

    Bundesinstitut für Arzneimittel und Medizinprodukte Roter Hand Brief XELJANZ (Tofacitinib). https://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RHB/2019/rhb-xeljanz2.pdf?__blob=publicationFile&v=4. Zugegriffen: Zugriff: 30. Aug. 2019

  57. 57.

    Sands BE et al (2018) Peficitinib, an oral Janus Kinase inhibitor, in moderate-to-severe ulcerative colitis: results from a randomised, phase 2 study. J Crohns Colitis 12(10):1158–1169

    Article  PubMed  Google Scholar 

  58. 58.

    ClinicalsTrials.gov (2019) janus kinase inhibitor | Ulcerative Colitis—List Results. https://clinicaltrials.gov/ct2/results?cond=Ulcerative+Colitis&term=janus+kinase+inhibitor&cntry=&state=&city=&dist. Zugegriffen: 30. Aug. 2019

  59. 59.

    Levy LL, Urban J, King BA (2015) Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol 73(3):395–399

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Bissonnette R et al (2016) Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol 175(5):902–911

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Guttman-Yassky E et al (2019) Baricitinib in adult patients with moderate-to-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J Am Acad Dermatol 80(4):913–921e9

    Article  CAS  PubMed  Google Scholar 

  62. 62.

    Lilly’s BREEZE-AD1 & BREEZE-AD2 phase 3 studies of baricitinib in patients with moderate to severe AD meets primary endpoint. Indianapolis: Pharmabiz.com, Z.a. Zugegriffen: 30. Aug. 2019

  63. 63.

    ClinicalsTrials.gov janus kinase inhibitor | Atopic Dermatitis—List Results. https://clinicaltrials.gov/ct2/results?term=janus+kinase+inhibitor&cond=Atopic+Dermatitis&rank=3&view=results#rowId2. Zugegriffen: 30. Aug. 2019

  64. 64.

    Wallace DJ et al (2018) Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 392(10143):222–231

    Article  CAS  Google Scholar 

  65. 65.

    ClinicalTrials.gov (2019) Safety of Tofacitinib, a.O.J.K.I., in Systemic Lupus Erythematosus. https://clinicaltrials.gov/ct2/show/NCT02535689?term=janus+kinase+inhibitor&cond=Systemic+Lupus+Erythematosus&rank=1. Zugegriffen: 28. Aug. 2019

  66. 66.

    A Study to Investigate the Safety and Efficacy of ABBV-105 and Upadacitinib Given Alone or in Combination in Participants With Moderately to Severely Active Systemic Lupus Erythematosus. ClinicalTrials.gov. Zugegriffen: 30. Aug. 2019

  67. 67.

    ClinicalTrials.gov (2019) baricitinib | systemic lupus erythematodes—list results. https://clinicaltrials.gov/ct2/results?cond=Systemic+Lupus+Erythematosus&term=baricitinib&cntry=&state=&city=&dist=&Search=Search. Zugegriffen: 30. Aug. 2019

  68. 68.

    Cohen S et al (2018) Worldwide, 3‑year, post-marketing surveillance experience with tofacitinib in rheumatoid arthritis. Rheumatol Ther 5(1):283–291

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Cohen SB et al (2017) Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann Rheum Dis 76(7):1253–1262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Strand V et al (2015) 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 17:362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Curtis JR et al (2016) Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis. Ann Rheum Dis 75(10):1843–1847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Winthrop KL et al (2017) Herpes zoster and tofacitinib: clinical outcomes and the risk of concomitant therapy. Arthritis Rheumatol 69(10):1960–1968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Winthrop KL et al (2017) The safety and immunogenicity of live zoster vaccination in patients with rheumatoid arthritis before starting tofacitinib: a randomized phase II trial. Arthritis Rheumatol 69(10):1969–1977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Smolen JS et al (2019) Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol 46(1):7–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Schulze-Koops H et al (2016) Analysis of haematological changes in tofacitinib-treated patients with rheumatoid arthritis across phase 3 and long-term extension studies. Baillieres Clin Rheumatol 56(1):46–57

    Google Scholar 

  76. 76.

    Skoda RC (2014) Less 〈em〉Jak2〈/em〉 makes more platelets. Blood 124(14):2168–2169

    Article  CAS  Google Scholar 

  77. 77.

    Ogdie A et al (2018) Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population-based cohort study. Eur Heart J 39(39):3608–3614

    Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Hoppe B, Dörner T (2012) Coagulation and the fibrin network in rheumatic disease: a role beyond haemostasis. Nat Rev Rheumatol 8:738

    Article  CAS  Google Scholar 

  79. 79.

    McInnes IB et al (2015) Effect of interleukin‑6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann Rheum Dis 74(4):694–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Strangfeld A et al (2017) Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Ann Rheum Dis 76(3):504–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Mariette X et al (2018) Lymphoma in the tofacitinib rheumatoid arthritis clinical development program. Arthritis Care Res 70(5):685–694

    Article  CAS  Google Scholar 

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Correspondence to Prof. Dr. med. R. Alten.

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Interessenkonflikt

R. Alten gibt an, von AbbVie Vortragshonorare, von Gilead Sciences, Eli Lilly und Pfizer Vortrags- und Beraterhonorare erhalten zu haben. Weiterhin erhielt sie Forschungsunterstützung von Gilead Sciences, Eli Lilly und Pfizer. T. Dörner gibt an, von Gilead Sciences Beraterhonorare und von AbbVie und Eli Lilly Vortrags- und Beraterhonorare erhalten zu haben. Weiterhin erhielt er Forschungsunterstützung von AbbVie und Eli Lilly. M. Mischkewitz und A.‑L. Stefanski 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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Alten, R., Mischkewitz, M., Stefanski, AL. et al. Januskinase-Inhibitoren. Z Rheumatol 79, 241–254 (2020). https://doi.org/10.1007/s00393-020-00768-5

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Schlüsselwörter

  • Zytokine
  • Rheumatoide Arthritis
  • Psoriasisarthritis
  • Immunsuppressiva
  • Infekt

Keywords

  • Cytokines
  • Rheumatoid arthritis
  • Psoriatic arthritis
  • Immunosuppressants
  • Infection