News in the biological therapy of rheumatoid arthritis and future prospects

Authors: L. Šenolt;  J. Vencovský
Authors‘ workplace: Revmatologický ústav a 1. LF UK, Praha
Published in: Čes. Revmatol., 17, 2009, No. 1, p. 36-49.
Category: Overview Reports


In recent years, up-to-date knowledge of pathogenetic mechanisms in rheumatoid arthritis contributed to establishment of biological therapy in clinical practice. For patients non-responsive to traditional disease modifying antirheumatic drugs, there are TNF-α inhibitors available. In case of their contraindication, lack of effect or adverse events, the treatment with B-lymphocyte depleting agent (rituximab) or with a drug blocking T-lymphocyte costimulation (abatacept) has been approved in rheumatoid arthritis. The progress in biotechnology manufacturing contributed to the development of several other perspective agents which may form the basis for the immunotherapy of rheumatoid arthritis in the near future. For instance, new or modified TNF-α inhibitors (golimumab, certolizumab pegol), and new monoclonal antibodies against other cytokines (e.g. IL-1, IL-6, IL-12, IL-15, IL-17, IL-23), and agents directed at B-lymphocyte depletion (e.g. ocrelizumab, ofatumumab) are in various stages of development. Many pharmaceutical companies put great expectations in small molecules with possible peroral administration. Nowadays, more than a half of new anti-inflammatory agents in the preclinical and clinical trials are represented by small molecules, which are recognised as potentially very promising drugs in rheumatoid arthritis. In most cases, theese are inhibitors of proteins which mediate the signalling and transcription of proinflammatory genes inside the cells. The increasing numbers of cytokine inhibitors and modulators of immune processes, which are in the current clinical trials, will further expand the spectrum of efficient therapies for patients with rheumatoid arthritis in the future.

Key words:
rheumatoid arthritis, biological therapy, clinical trials, monoclonal antibodies, small molecules


1. Malmstrom V, Trollmo C, Klareskog L. The additive role of innate and adaptive immunity in the development of arthritis. Am J Med Sci 2004; 327: 196–201.

2. Frauwirth KA, Thompson CB. Activation and inhibition of lymphocytes by costimulation. J Clin Invest 2002; 109: 295–9.

3. Lundberg K, Nijenhuis S, Vossenaar ER, et al. Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Res Ther 2005; 7: R458–67.

4. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987; 30: 1205–13.

5. Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol 2003; 171: 538–41.

6. Kaltenhäuser S, Pierer M, Arnold S, et al. Antibodies against cyclic citrullinated peptide are associated with the DRB1 shared epitope and predict joint erosion in rheumatoid arthritis. Rheumatology (Oxford). 2007; 46: 100–4.

7. Vencovský J, Machácek S, Sedová L, Kafková J, Gatterová J, Pesáková V, Růzicková S. Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis. Ann Rheum Dis 2003; 62: 427–30.

8. Gutierrez-Roelens I, Lauwerys BR. Genetic susceptibility to autoimmune disorders: clues from gene association and gene expression studies. Curr Mol Med 2008; 8: 551–61.

9. Andersson AK, Li C, Brennan FM. Recent developments in the immunobiology of rheumatoid arthritis. Arthritis Res Ther 2008; 10: 204.

10. Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006; 54: 38–46.

11. Cope AP, Schulze-Koops H, Aringer M. The central role of T cells in rheumatoid arthritis. Clin Exp Rheumatol 2007; 25: S4–11.

12. Zheng Y, Danilenko DM, Valdez P, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007; 445: 648–51.

13. Šenolt L. Význam synoviálních fibroblastů v patogenezi revmatoidní artritidy. Čes Revmatol 2006; 2: 65–70.

14. Silverman GJ, Carson DA. Roles of B cells in rheumatoid arthritis. Arthritis Res Ther 2003;5 Suppl 4:S1–6.

15. Conti P, Youinou P, Theoharides TC. Modulation of autoimmunity by the latest interleukins (with special emphasis on IL-32). Autoimmun Rev 2007; 6: 131–7.

16. O’ Gradaigh D, Ireland D, Bord S, Compston JE. Joint erosion in rheumatoid arthritis: interactions between tumour necrosis factor alpha, interleukin 1, and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclasts. Ann Rheum Dis 2004; 63: 354–9.

17. Stanczyk J, Ospelt C, Gay S. Is there a future for small molecule drugs in the treatment of rheumatic diseases? Curr Opin Rheumatol 2008; 20: 257–62.

18. Zhou H, Jang H, Fleischmann RM, et al. Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody, in subjects with rheumatoid arthritis. J Clin Pharmacol 2007; 47: 383–96.

19. Keystone E, Heijde DV, Mason D Jr, 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: 3319–29.

20. Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46: 614–24.

21. Ruperto N, Quartier P, Wulffraat N, et al. ACZ885 (canakinumab), A New Il-1 Beta Blocking Monoclonal Antibody Has A Beneficial Effect In Children With Systemic Juvenile Idiopathic Arthritis (sjia). In: Abstracts of the 2008 annual scientific meeting of the American college of Rheumatology; San Francisco, CA.

22. Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis 2007; 66: 1162–7.

23. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008; 58: 2968–80.

24. Carroll HP, Paunovic V, Gadina M. Signalling, inflammation and arthritis: Crossed signals: the role of interleukin-15 and -18 in autoimmunity. Rheumatology (Oxford) 2008; 47: 1269–77.

25. Baslund B, Tvede N, Danneskiold-Samsoe B, et al. Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. Arthritis Rheum 2005; 52: 2686–92.

26. Brok HP, Tekoppele JM, Hakimi J, et al. Prophylactic and therapeutic effects of a humanized monoclonal antibody against the IL-2 receptor (DACLIZUMAB) on collagen-induced arthritis (CIA) in rhesus monkeys. Clin Exp Immunol 2001; 124: 134–41.

27. Young DA, Hegen M, Ma HL, et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum 2007; 56: 1152–63.

28. Churchman SM, Ponchel F. Interleukin-7 in rheumatoid arthritis. Rheumatology (Oxford) 2008; 47: 753–9.

29. Plater-Zyberk C, Joosten LA, Helsen MM, Koenders MI, Baeuerle PA, van den Berg WB. Combined blockade of GM-CSF and IL-17 pathways potently suppresses chronic destructive arthritis in a TNF{alpha}independent mouse model. Ann Rheum Dis 2008 [Epub ahead of print].

30. Leonardi CL, Kimball AB, Papp KA, et al. 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 2008 17; 371: 1665–74.

31. Tan ZY, Bealgey KW, Fang Y, Gong YM, Bao S. Interleukin-23: Immunological roles and clinical implications. Int J Biochem Cell Biol 2008 [Epub ahead of print]

32. Yago T, Nanke Y, Kawamoto M, et al. IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats. Arthritis Res Ther 2007; 9: R96.

33. Malfait AM, Butler DM, Presky DH, Maini RN, Brennan FM, Feldmann M. Blockade of IL-12 during the induction of collagen-induced arthritis (CIA)markedly attenuates the severity of the arthritis. Clin Exp Immunol 1998; 111: 377–83.

34. Brentano F, Ospelt C, Stanczyk J, Gay RE, Gay S, Kyburz D. Abundant expression of the IL-23 subunit p19, but low levels of bioactive IL-23 in the rheumatoid synovium. Ann Rheum Dis 2008 [Epub ahead of print].

35. Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 2008; 118: 3537–45.

36. Braun A, Takemura S, Vallejo AN, Goronzy JJ, Weyand CM. Lymphotoxin beta-mediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum 2004; 50: 2140–50.

37. 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: 4314–21.

38. Tak PP, Thurlings RM, Rossier C, et al. Atacicept in patients with rheumatoid arthritis: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating, single- and repeated-dose study. Arthritis Rheum 2008; 58: 61–72.

39. Ding C. Belimumab, an anti-BLyS human monoclonal antibody for potential treatment of inflammatory autoimmune diseases. Expert Opin Biol Ther 2008; 8: 1805–14.

40. Hamdy NA. Denosumab: RANKL inhibition in the management of bone loss. Drugs Today (Barc) 2008; 44: 7–21.

41. 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: 1299–309.

42. Tak PP. Chemokine inhibition in inflammatory arthritis. Best Pract Res Clin Rheumatol 2006; 20: 929–39.

43. Shahrara S, Proudfoot AE, Park CC, et al. Inhibition of monocyte chemoattractant protein-1 ameliorates rat adjuvant-induced arthritis. J Immunol 2008; 180: 3447–56.

44. Haringman JJ, Gerlag DM, Smeets TJ, et al. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54: 2387–92.

45. Vergunst CE, Gerlag DM, Lopatinskaya L, et al. Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum 2008; 58: 1931–9.

46. Mohan K, Issekutz TB. Blockade of chemokine receptor CXCR3 inhibits T cell recruitment to inflamed joints and decreases the severity of adjuvant arthritis. J Immunol 2007; 179: 8463–9.

47. Hirota K, Yoshitomi H, Hashimoto M, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med 2007; 204: 2803–12.

48. Shahrara S, Proudfoot AE, Woods JM, et al. Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum 2005; 52: 1907–19.

49. Lainer-Carr D, Brahn E. Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis. Nat Clin Pract Rheumatol 2007; 3: 434–42.

50. Grothey A, Ellis LM. Targeting angiogenesis driven by vascular endothelial growth factors using antibody-based therapies. Cancer J 2008;14:170–7.

51. Mould AW, Scotney P, Greco SA, Hayward NK, Nash A, Kay GF. Prophylactic but not therapeutic activity of a monoclonal antibody that neutralizes the binding of VEGF-B to VEGFR-1 in a murine collagen-induced arthritis model. Rheumatology (Oxford) 2008; 47: 263–6.

52. Baier A, Meineckel I, Gay S, Pap T. Apoptosis in rheumatoid arthritis. Curr Opin Rheumatol 2003; 15: 274–9.

53. Pope RM. Apoptosis as a therapeutic tool in rheumatoid arthritis. Nat Rev Immunol 2002; 2: 527–35.

54. Pap T, Franz JK, Hummel KM, Jeisy E, Gay R, Gay S. Activation of synovial fibroblasts in rheumatoid arthritis: lack of Expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res 2000; 2: 59–64.

55. Wang CR, Shiau AL, Chen SY, et al. Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer. Arthritis Rheum 2008; 58: 1650-6.

56. Sakai K, Matsuno H, Morita I, et al. Potential withdrawal of rheumatoid synovium by the induction of apoptosis using a novel in vivo model of rheumatoid arthritis. Arthritis Rheum 1998; 41: 1251–7.

57. Schnitzer TJ, Yocum DE, Michalska M, et al. Subcutaneous administration of CAMPATH-1H: clinical and biological outcomes. J Rheumatol 1997; 24: 1031–6.

58. Mason U, Aldrich J, Breedveld F, et al. CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized monoclonal anti-CD4 treatment of active rheumatoid arthritis. J Rheumatol 2002; 29: 220–9.

59. Hepburn TW, Totoritis MC, Davis CB. Antibody-mediated stripping of CD4 from lymphocyte cell surface in patients with rheumatoid arthritis. Rheumatology (Oxford) 2003; 42: 54–61.

60. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab versus placebo in ATTEST: a phase III, multicenter, randomized, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 2008; 67: 1096–103.

61. Genant HK, Peterfy CG, Westhovens R, et al. Abatacept inhibits structural damage progression in rheumatoid arthritis: results from the long-term extension of the AIM trial. Ann Rheum Dis 2008; 67: 1084–9.

62. Genovese MC, Schiff M, Luggen M, et al. Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. Ann Rheum Dis 2008; 67: 547–54.

63. Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E. Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. Arthritis Rheum 2006; 54: 2807–16.

64. Johnson PW, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer 2001; 85: 1619–23.

65. Smolen JS, Keystone EC, Emery P, et al. Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66: 143–50.

66. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006; 54: 2793–806.

67. 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: 2652–61.

68. Robak T. Ofatumumab, a human monoclonal antibody for lymphoid malignancies and autoimmune disorders. Curr Opin Mol Ther 2008; 10: 294–309.

69. Jacobi AM, Goldenberg DM, Hiepe F, Radbruch A, Burmester GR, Dörner T. Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls. Ann Rheum Dis. 2008; 67: 450–7.

70. Thabet MM, Huizinga TW. Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis. Curr Opin Investig Drugs 2006; 7: 1014–9.

71. Stoch SA, Wagner JA. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther 2008; 83: 172–6.

72. Asagiri M, Hirai T, Kunigami T, et al. Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science 2008; 319: 624–7.

73. Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298: 1911–2.

74. Sweeney SE, Firestein GS. Primer: signal transduction in rheumatic disease-a clinician’s guide. Nat Clin Pract Rheumatol 2007; 3: 651–60.

75. Šenolt L, Vencovský J, Pavelka K. Transdukční signální dráhy – cíl terapie revmatoidní artritidy budoucnosti? Čes Revmatol 2005; 2: 58–66.

76. Schett G, Zwerina J, Firestein G. The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann Rheum Dis 2008; 67: 909–16.

77. Genovese MC, Cohen SB, Wofsy D, et al. A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of an Oral p38@ MAPK Inhibitor, SCIO-469, in Patients with Active Rheumatoid Arthritis. In: Abstracts of the 2008 annual scientific meeting of the American college of Rheumatology; San Francisco, CA.

78. Zer C, Sachs G, Shin JM. Identification of genomic targets downstream of p38 mitogen-activated protein kinase pathway mediating tumor necrosis factor-alpha signaling. Physiol Genomics 2007; 31: 343–51.

79. Walker JG, Smith MD. The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 2005; 32: 1650-3.

80. Walker JG, Ahern MJ, Coleman M, et al. Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66: 992–9.

81. Changelian PS, Flanagan ME, Ball DJ, et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 2003; 302: 75–8.

82. Kremer J, Cohen S, Wilkinson B, et al. The Oral Jak Inhibitor CP-690,550 (CP) in Combination with Methotrexate (MTX) is Efficacious, Safe and Well Tolerated in Patients with Active Rheumatoid Arthiritis (RA) with an Inadequate Response to Methotrexate Alone. In: Abstracts of the 2008 annual scientific meeting of the American college of Rheumatology; San Francisco, CA.

83. Williams W, Scherle P, Shi J, et al. A Randomized Placebo-Controlled Study of INCB018424, a Selective Janus Kinase1& 2 (JAK1&2) Inhibitor in Rheumatoid Arthritis (RA) In: Abstracts of the 2008 annual scientific meeting of the American college of Rheumatology; San Francisco, CA. Presentation 1189.

84. 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: 571-8.

85. 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: 3309–18.

86. Friday BB, Adjei AA. Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein dinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res 2008; 14: 342–6.

87. Carter L, Brown S, Klopfenstein N, et al. ARRY-162, A Novel MEK Inhibitor: Results of a 14-Day Phase 1a Study in Healthy Subjects and a 28-Day Phase 1b Study in Rheumatoid Arthritis patiens. In: Abstracts of the 2008 annual scientific meeting of the American college of Rheumatology; San Francisco, CA. Presentation: 358.

88. Thiel MJ, Schaefer CJ, Lesch ME, et al. Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms. Arthritis Rheum 2007; 56: 3347–57.

89. Distler JH, Distler O. Intracellular tyrosine kinases as novel targets for anti-fibrotic therapy in systemic sclerosis. Rheumatology (Oxford). 2008 Oct;47 Suppl 5:v10-1.

90. Paniagua RT, Robinson WH. Imatinib for the treatment of rheumatic diseases. Nat Clin Pract Rheumatol 2007; 3: 190–1.

91. Okamoto H, Cujec TP, Yamanaka H, Kamatani N. Molecular aspects of rheumatoid arthritis: role of transcription factors. FEBS J 2008; 275: 4463–70.

92. Zenz R, Eferl R, Scheinecker C, et al. Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease. Arthritis Res Ther 2008; 10: 201.

93. Aikawa Y, Morimoto K, Yamamoto T, et al. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat Biotechnol 2008; 26: 817–23.

94. Tas SW, Vervoordeldonk MJ, Hajji N, May MJ, Ghosh S, Tak PP. Local treatment with the selective IkappaB kinase beta inhibitor NEMO-binding domain peptide ameliorates synovial inflammation. Arthritis Res Ther 2006; 8: R86.

95. Pessler F, Dai L, Cron RQ, Schumacher HR. NFAT transcription factors-new players in the pathogenesis of inflammatory arthropathies? Autoimun Rev 2006; 5: 106–10.

96. Wada Y, Lu R, Zhou D, et al. Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor Blood. 2007; 109: 1156–64.

97. Meanwell NA, Kadow JF. Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS. Curr Opin Investig Drugs 2007; 8: 669–81.

98. Barsante MM, Cunha TM, Allegretti M, et al. Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats. Br J Pharmacol 2008; 153: 992–1002.

99. Verstappen SM, Jacobs JW, van der Veen MJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis 2007; 66: 1443–9.

1 00. Stanczyk J, Pedrioli DM, Brentano F, et al. Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 2008; 58: 1001–9.

101. Huber LC, Stanczyk J, Jüngel A, Gay S. Epigenetics in inflammatory rheumatic diseases. Arthritis Rheum 2007; 56: 3523–31.

Dermatology & STDs Paediatric rheumatology Rheumatology
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account