Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Cytokine networks in rheumatic diseases: Implications for therapy

Iain B McInnes, FRCP, PhD
Section Editor
Daniel E Furst, MD
Deputy Editor
Paul L Romain, MD


Understanding the contribution of cytokines to the pathogenesis of rheumatic diseases offers novel and creative therapeutic options that were not previously available. This is especially true in rheumatoid arthritis (RA), in which the cytokine milieu of the joint is reasonably well-understood and in which data on human clinical trials are already available. Therapies designed to block the effects of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 receptor (IL-6R) action in this illness are effective in many patients with RA, as are TNF inhibitors and IL-17A inhibitors in psoriatic arthritis. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases".)

Although biologic agents that regulate cytokines have met with success in the treatment of RA and other inflammatory arthropathies, small molecules that block cytokine production and/or signaling may have a competitive advantage in the coming years. An important note of caution, however, is that there is the possibility that suppressing even physiologic concentrations of some cytokines could have serious adverse effects on immune surveillance.

This topic will review the issues relating to the manipulation of cytokine networks in patients with rheumatic disease, with an emphasis on RA. The pathogenesis of RA is discussed separately. (See "Pathogenesis of rheumatoid arthritis".)


A host of biologic and small molecules with anticytokine properties are being developed or are already in clinical use.

Glucocorticoids — Glucocorticoids (eg, prednisone, prednisolone, or triamcinolone), which are potent transcriptional inhibitors of production of a variety of cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF), have been available for many years and have clear utility in rheumatic disorders. It is not certain whether this activity accounts for their therapeutic benefit or, more likely, whether it represents only one of many effects of glucocorticoids. Other activities that might be therapeutically important include the inhibition of adhesion molecule expression, arachidonic acid metabolism, and metalloproteinase production. These and other effects of glucocorticoids on the immune system are discussed in more detail elsewhere. (See "Glucocorticoid effects on the immune system".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Mar 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Moreira AL, Sampaio EP, Zmuidzinas A, et al. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 1993; 177:1675.
  2. Sajjadi FG, Takabayashi K, Foster AC, et al. Inhibition of TNF-alpha expression by adenosine: role of A3 adenosine receptors. J Immunol 1996; 156:3435.
  3. Huizinga TW, Dijkmans BA, van der Velde EA, et al. An open study of pentoxyfylline and thalidomide as adjuvant therapy in the treatment of rheumatoid arthritis. Ann Rheum Dis 1996; 55:833.
  4. Baharav E, Bar-Yehuda S, Madi L, et al. Antiinflammatory effect of A3 adenosine receptor agonists in murine autoimmune arthritis models. J Rheumatol 2005; 32:469.
  5. Knight R. IMiDs: a novel class of immunomodulators. Semin Oncol 2005; 32:S24.
  6. Kiely PD, Gillespie KM, Oliveira DB. Oxpentifylline inhibits tumor necrosis factor-alpha mRNA transcription and protects against arthritis in mercuric chloride-treated brown Norway rats. Eur J Immunol 1995; 25:2899.
  7. Kiely PD, Johnson D, Bourke BE. An open study of oxpentifylline in early rheumatoid arthritis. Br J Rheumatol 1998; 37:1033.
  8. Dubost JJ, Soubrier M, Ristori JM, et al. An open study of the anti-TNF alpha agent pentoxifylline in the treatment of rheumatoid arthritis. Rev Rhum Engl Ed 1997; 64:789.
  9. Maksymowych WP, Avina-Zubieta A, Luong MH, Russell AS. An open study of pentoxifylline in the treatment of severe refractory rheumatoid arthritis. J Rheumatol 1995; 22:625.
  10. van Troostenburg AR, Clark EV, Carey WD, et al. Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men. Int J Clin Pharmacol Ther 2004; 42:534.
  11. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood 1996; 87:2095.
  12. Pavelka K, Kuba V, Moeller J, et al. Clinical effects of pralnacasan (PRAL), an orally-active interleukin -1beta converting enzyme (ICE) inhibitor, in a 285 patient PhII trial in rheumatoid arthritis (abstract). Arthritis Rheum 2002; 46:3415.
  13. Zhang Y, Xu J, Levin J, et al. Identification and characterization of 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1), a novel dual tumor necrosis factor-alpha-converting enzyme/matrix metalloprotease inhibitor for the treatment of rheumatoid arthritis. J Pharmacol Exp Ther 2004; 309:348.
  14. Bonilla-Hernán MG, Miranda-Carús ME, Martin-Mola E. New drugs beyond biologics in rheumatoid arthritis: the kinase inhibitors. Rheumatology (Oxford) 2011; 50:1542.
  15. Firestein GS, Manning AM. Signal transduction and transcription factors in rheumatic disease. Arthritis Rheum 1999; 42:609.
  16. Badger AM, Griswold DE, Kapadia R, et al. Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum 2000; 43:175.
  17. Cohen SB, Cheng TT, Chindalore V, et al. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthritis Rheum 2009; 60:335.
  18. Damjanov N, Kauffman RS, Spencer-Green GT. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. Arthritis Rheum 2009; 60:1232.
  19. Genovese MC. Inhibition of p38: has the fat lady sung? Arthritis Rheum 2009; 60:317.
  20. Alten RE, Zerbini C, Jeka S, et al. Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy. Ann Rheum Dis 2010; 69:364.
  21. Miagkov AV, Kovalenko DV, Brown CE, et al. NF-kappaB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc Natl Acad Sci U S A 1998; 95:13859.
  22. Okazaki Y, Sawada T, Nagatani K, et al. Effect of nuclear factor-kappaB inhibition on rheumatoid fibroblast-like synoviocytes and collagen induced arthritis. J Rheumatol 2005; 32:1440.
  23. Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum 1993; 36:1681.
  24. Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 344:1105.
  25. Elliott MJ, Maini RN, Feldmann M, et al. Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 1994; 344:1125.
  26. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41:1552.
  27. Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Gastroenterology 2005; 129:807.
  28. Tak PP, Taylor PC, Breedveld FC, et al. Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 1996; 39:1077.
  29. Taylor PC, Peters AM, Paleolog E, et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum 2000; 43:38.
  30. Baeten D, Kruithof E, Van den Bosch F, et al. Immunomodulatory effects of anti-tumor necrosis factor alpha therapy on synovium in spondylarthropathy: histologic findings in eight patients from an open-label pilot study. Arthritis Rheum 2001; 44:186.
  31. van de Loo FA, Joosten LA, van Lent PL, et al. Role of interleukin-1, tumor necrosis factor alpha, and interleukin-6 in cartilage proteoglycan metabolism and destruction. Effect of in situ blocking in murine antigen- and zymosan-induced arthritis. Arthritis Rheum 1995; 38:164.
  32. Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 2004; 50:372.
  33. Nikas SN, Drosos AA. Onercept. Serono. Curr Opin Investig Drugs 2003; 4:1369.
  34. Steed PM, Tansey MG, Zalevsky J, et al. Inactivation of TNF signaling by rationally designed dominant-negative TNF variants. Science 2003; 301:1895.
  35. Arend WP. Interleukin 1 receptor antagonist. A new member of the interleukin 1 family. J Clin Invest 1991; 88:1445.
  36. Dinarello CA. Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation. Curr Opin Pharmacol 2004; 4:378.
  37. Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study. Arthritis Rheumatol 2015; 67:1424.
  38. Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis 2017; 76:840.
  39. Fleischmann R, van Adelsberg J, Lin Y, et al. Sarilumab and Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol 2017; 69:277.
  40. Smolen JS, Weinblatt ME, Sheng S, et al. Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis 2014; 73:1616.
  41. Aletaha D, Bingham CO 3rd, Tanaka Y, et al. Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study. Lancet 2017; 389:1206.
  42. Weinblatt ME, Mease P, Mysler E, et al. The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate: results from a multinational, phase IIb, randomized, double-blind, placebo/active-controlled, dose-ranging study. Arthritis Rheumatol 2015; 67:2591.
  43. Murphy CA, Langrish CL, Chen Y, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003; 198:1951.
  44. 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.
  45. 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; 373:633.
  46. Genovese MC, Durez P, Richards HB, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 2013; 72:863.
  47. Hueber W, Patel DD, Dryja T, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2010; 2:52ra72.
  48. Genovese MC, Van den Bosch F, Roberson SA, et al. LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum 2010; 62:929.
  49. Genovese MC, Durez P, Richards HB, et al. One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: phase II, dose-finding, double-blind, randomized, placebo-controlled study. J Rheumatol 2014; 41:414.
  50. Baeten D, Baraliakos X, Braun J, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382:1705.
  51. Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012; 366:1190.
  52. McInnes I, Sieper J, Braun J. Anti-interleukin 17A monoclonal antibody secukinumab reduces signs and symptoms of psoriatic arthritis in a 24-week multicenter, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2011; 63:S306.
  53. Kuestner RE, Taft DW, Haran A, et al. Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J Immunol 2007; 179:5462.
  54. Gracie JA, Forsey RJ, Chan WL, et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest 1999; 104:1393.
  55. Dinarello CA. Interleukin-18 and the treatment of rheumatoid arthritis. Rheum Dis Clin North Am 2004; 30:417.
  56. Burmester GR, Feist E, Sleeman MA, et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study. Ann Rheum Dis 2011; 70:1542.
  57. Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum 2009; 60:1895.
  58. Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken) 2011; 63:1150.
  59. Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012; 64:617.
  60. Fleischmann R. Novel small-molecular therapeutics for rheumatoid arthritis. Curr Opin Rheumatol 2012; 24:335.
  61. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012; 367:495.
  62. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012; 367:508.
  63. 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.
  64. Keystone EC, Taylor PC, Drescher E, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis 2015; 74:333.
  65. Tanaka Y, Emoto K, Cai Z, et al. Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study. J Rheumatol 2016; 43:504.
  66. 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.
  67. 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.
  68. Genovese MC, Kremer J, Zamani O, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med 2016; 374:1243.
  69. 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; 58:3309.
  70. Weinblatt ME, Kavanaugh A, Genovese MC, et al. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med 2010; 363:1303.
  71. Genovese MC, Kavanaugh A, Weinblatt ME, et al. An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents. Arthritis Rheum 2011; 63:337.
  72. Weinblatt ME, Genovese MC, Ho M, et al. Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheumatol 2014; 66:3255.
  73. Brandes ME, Allen JB, Ogawa Y, Wahl SM. Transforming growth factor beta 1 suppresses acute and chronic arthritis in experimental animals. J Clin Invest 1991; 87:1108.
  74. Miossec P, Naviliat M, Dupuy d'Angeac A, et al. Low levels of interleukin-4 and high levels of transforming growth factor beta in rheumatoid synovitis. Arthritis Rheum 1990; 33:1180.
  75. Miossec P, Briolay J, Dechanet J, et al. Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin-4 in an ex vivo model of rheumatoid synovitis. Arthritis Rheum 1992; 35:874.
  76. Alvaro-Gracia JM, Zvaifler NJ, Firestein GS. Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes. J Clin Invest 1990; 86:1790.
  77. Cannon GW, Emkey RD, Denes A, et al. Prospective two-year followup of recombinant interferon-gamma in rheumatoid arthritis. J Rheumatol 1990; 17:304.
  78. Panitch HS, Hirsch RL, Haley AS, Johnson KP. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1987; 1:893.
  79. Sigidin YA, Loukina GV, Skurkovich B, Skurkovich S. Randomized, double-blind trial of anti-interferon-gamma antibodies in rheumatoid arthritis. Scand J Rheumatol 2001; 30:203.
  80. Moore KW, O'Garra A, de Waal Malefyt R, et al. Interleukin-10. Annu Rev Immunol 1993; 11:165.
  81. Cush JJ, Splawski JB, Thomas R, et al. Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum 1995; 38:96.
  82. Maini RN, Paulus H, Breedveld FC, et al. rhuIL-10 in subjects with active rheumatoid arthritis (RA): a Phase I and cytokine response study (abstract). Arthritis Rheum 1997; 40:S224.
  83. McInnes IB, Illei GG, Danning CL, et al. IL-10 improves skin disease and modulates endothelial activation and leukocyte effector function in patients with psoriatic arthritis. J Immunol 2001; 167:4075.
  84. Fedorak RN, Gangl A, Elson CO, et al. Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. Gastroenterology 2000; 119:1473.
  85. Walmsley M, Butler DM, Marinova-Mutafchieva L, Feldmann M. An anti-inflammatory role for interleukin-11 in established murine collagen-induced arthritis. Immunology 1998; 95:31.
  86. Moreland LW, Chase W, Fife R, et al. Phase I/II study evaluating the safety and potential efficacy of recombinant interleukin-11 in patients with refractory rheumatoid arthritis (abstract). Arthritis Rheum 1999; 42:S171.
  87. Firestein GS. Mechanisms of tissue destruction and cellular activation in rheumatoid arthritis. Curr Opin Rheumatol 1992; 4:348.
  88. Woessner JF Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 1991; 5:2145.
  89. Firestein GS, Paine MM. Stromelysin and tissue inhibitor of metalloproteinases gene expression in rheumatoid arthritis synovium. Am J Pathol 1992; 140:1309.
  90. Conway JG, Wakefield JA, Brown RH, et al. Inhibition of cartilage and bone destruction in adjuvant arthritis in the rat by a matrix metalloproteinase inhibitor. J Exp Med 1995; 182:449.
  91. van Marle S, van Vliet A, Sollie F, et al. Safety, tolerability and pharmacokinetics of oral S-3304, a novel matrix metalloproteinase inhibitor, in single and multiple dose escalation studies in healthy volunteers. Int J Clin Pharmacol Ther 2005; 43:282.
  92. Cronstein BN, Weissmann G. The adhesion molecules of inflammation. Arthritis Rheum 1993; 36:147.
  93. Kavanaugh AF, Davis LS, Nichols LA, et al. Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1. Arthritis Rheum 1994; 37:992.
  94. Dayer JM, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 1985; 162:2163.
  95. Moreland LW, Sewell KL, Trentham DE, et al. Interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis. A double-blind, placebo-controlled trial with open-label extension. Arthritis Rheum 1995; 38:1177.