Dysfunctional immune-mediated inflammation in rheumatoid arthritis dictates that development of anti-rheumatic disease drugs target multiple intracellular signaling pathways

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry

Volumn 10, Issue 2, 2011, Pages 78-84

  Malemud, Charles J ^a  

^a CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Autoimmunity; Drug development; Inflammation; Jak stat; Pi3k akt; Rheumatoid arthritis; Sap mapk

Indexed keywords

ANTIRHEUMATIC AGENT; CYCLOOXYGENASE 2; GAMMA INTERFERON; INTERLEUKIN 1; INTERLEUKIN 12; INTERLEUKIN 15; INTERLEUKIN 17; INTERLEUKIN 18; INTERLEUKIN 21; INTERLEUKIN 23; INTERLEUKIN 32; INTERLEUKIN 6; INTERLEUKIN 7; INTERLEUKIN 8; JANUS KINASE; JANUS KINASE INHIBITOR; MATRIX METALLOPROTEINASE; METHOTREXATE; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 10; MITOGEN ACTIVATED PROTEIN KINASE P38; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; PAMAMIPOD; PHOSPHATIDYLINOSITOL 3 KINASE; RUXOLITINIB; STAT3 PROTEIN; TASOCITINIB; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; VX 702;

ARTHRITIS; ARTICLE; B LYMPHOCYTE; CARTILAGE CELL; CD4+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL SUBPOPULATION; CELL SURVIVAL; CLINICAL TRIAL (TOPIC); DISEASE COURSE; DISEASE SEVERITY; DRUG EFFICACY; DRUG TARGETING; DRUG TOLERABILITY; HUMAN; IMMUNOLOGICAL TOLERANCE; INFLAMMATION; MOLECULAR INTERACTION; NONHUMAN; OSTEOCLASTOGENESIS; PATHOPHYSIOLOGY; PATIENT SAFETY; PROTEIN EXPRESSION; PROTEIN INDUCTION; PROTEIN PROTEIN INTERACTION; REGULATORY T LYMPHOCYTE; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; SYNOVIAL FLUID; SYNOVIOCYTE; T LYMPHOCYTE; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT; UPREGULATION;

EID: 79959975619     PISSN: 18715230     EISSN: 1875614X     Source Type: Journal    
DOI: 10.2174/187152111795508315     Document Type: Article

References (91)

1. Feldmann, M.; Brennan, F. M; Maini, R. N. Rheumatoid arthritis. Cell, 1996, 85(3), 307-310.
2. G. C. Tsokos, Ed. Principles of Molecular Rheumatology, Humana Press: Totowa, 2000.
3. Firestein, G. S.; Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J. Clin. Rheumatol., 2005, 11, 3 Suppl, S39-S44.
4. Toh, M. L.; Moissec, P. The role of T cells in rheumatoid arthritis: new subsets and new targets. Curr. Opin. Rheumatol., 2007, 19(3), 284-288.
5. Malemud, C. J.; Reddy,S. K. Targeting cytokines, chemokines and adhesion molecules in rheumatoid arthritis. Curr. Rheumatol. Rev., 2008, 4(4), 219-234.
6. Asquith, D. L.; McInnes, I. B. Emerging cytokine targets in rheumatoid arthritis. Curr. Opin. Rheumatol., 2007, 19(3), 246-251.
7. Hartgring, S. A.; Bijlsma, J. W.; Lafeber, F. P.; van Roon, J. A. Interleukin-7-induced immunopathology in arthritis. Ann. Rheum. Dis.,2006, 65(Suppl. 3), iii69-iii73.
8. Petrovic-Rackov, P.; Pejnovic, N. Clinical significance of IL-18,IL-15, IL-12 and TNF-α measurement in rheumatoid arthritis. Clin. Rheumatol., 2006, 25(4), 448-452.
9. Lubberts, E. The role of IL-17 and family members in the pathogenesisof arthritis. Curr. Opin. Investig. Drugs, 2003, 4(5), 572-577.
10. Young, D. A.; Hegen, M.; Ma, H. L.; Whitters, M. J.; Albert, L. M.; Lowe, L.; Senices, M.; Wu, P. W.; Sibley, B.; Leathurby, Y.; Brown, T. P.; Nickerson-Nutter, C.; Keith Jr, J. C.; Collins, M. Blockade of the interleukin-21/interleukin-21 receptor pathwayameliorates disease in animal models of rheumatoid arthritis. ArthritisRheum., 2007, 56(4), 1152-1163.
11. Joosten, L. A.; Netea, M. G.; Kim, S. H.; Yoon, D. Y. Oppers-Walgreen, B.; Radstake, T. R.; Barrera, P.; van de Loo, F. A.; Dinarello, C. A.; van den Berg, W. B. IL-32, a proinflammatory cytokinein rheumatoid arthritis. Proc. Natl. Acad. Sci. USA, 2006, 103(9), 3298-3303.
12. DiPlacido, L. D.; Craft, J. Emerging from the shadows: Follicularhelper T cells in autoimmunity. Arthritis Rheum., 2010, 62(1), 6-8.
13. Collison, L. W.; Vignali, D. A. Interleukin-35: odd one out or part ofthe family? Immunol. Rev., 2008, 226, 248-262.
14. Collison, L. W.; Workman, C. J.; Kuo, T. T.; Boyd, K.; Wang, Y.; Vignali, K. M.; Cross, R.; Sehy, D.; Blumberg, R. S.; Vignali, D. A. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature, 2007, 450(7169), 566-569.
15. Furuzawa-Carballeda, J.; Vargas-Rojas, M. I.; Cabral, A. R.; Autoimmuneinflammation from the Th17 perspective. Autoimmun. Rev., 2007, 6(3), 169-175.
16. Pacholczyk, R.; Kern, J. The T-cell receptor repertoire of regulatoryT cells. Immunology, 2008, 125(4), 450-458.
17. McGleachy, M. J.; Bak-Jensen, K. S.; Chen, Y; Tato, C. M.; Blumenshein, W.; McClanahan, T.; Cua, D. J. TGF-β and IL-6 drivethe production of IL-17 and IL-10 by T cells and restrain T(H)-17cell-mediated pathology. Nat. Immunol., 2007, 8(12), 1390-1397.
18. Zhou, L.; Lopes, J. E.; Chong, M. M.; Ivanov, I. I.; Min, R.; Victora, G. D.; Shen, Y.; Du, J.; Rubtsov, Y. P.; Rudensky, A. Y.; Ziegler, S. F.; Littman, D. R. TGF-β-induced FoxP3 inhibits T(H)17 cell differentiationby antagonizing RORγt function. Nature, 2008,453(7192), 236-240.
19. Boniface, K.; Blom, B.; Liu, Y. J.; de Waal Malefyt, R. From interleukin-23 to T-helper 17 cells: human T-helper cell differentiationrevisited. Immunol. Rev. 2008, 226, 132-146.
20. McGleachy, M. J.; Chen, Y.; Tato, C. M.; Laurence, A.; Joyce-Shaikh, B.; Blumenschein, W. M.; McClanahan, T. K.; O'Shea, J. J.; Cua, D.J. The interleukin-23 receptor is essential for the terminaldifferentiation of interleukin 17-producing effect T helper cells invivo. Nat. Immunol., 2009, 10(3), 314-324.
21. Cornelissen, F.; Mus, A. M. C.; Asmawidjaja, P. S.; van Hamburg, J. P.; Tocker, J.; Lubberts, E. Interleukin-23 is critical for fullblownexpression of non-autoimmune destructive arthritis andregulates interleukin-17A and RORγδ T-cells. Arthritis Res. Ther.,2009, 11(6), R194.
22. Esensten, J. H.; Wofsy, D.; Bluestone, J. A. Regulatory T cells astherapeutic targets in rheumatoid arthritis. Nat. Rev. Rheumatol.,2009, 5(10), 560-565.
23. Tran, C. N.; Thacker, S. G.; Louie, D. M.; Oliver, J.; White, P. T.; Endres, J. L.; Urquhart, A. G.; Chung, K. C.; Fox, D. A. Interactionsof T cells with fibroblast-like synoviocytes; role of the BH7 familyof costimulatory ligand B7-H3. J. Immunol., 2008, 180(5), 2989-2998.
24. + T cells. Immunity,2008, 28(3), 425-435.
25. Burrage, P. S. Mix, K. S.; Brinckerhoff, C. E. Matrix metalloproteinases:Role in arthritis. Front. Biosci., 2006, 11, 529-543.
26. Roccaro, A. M.; Russo, F.; Cirulli, T.; Di Petro, G.; Vacca, A. Dammaco, F. Antiangiogenesis for rheumatoid arthritis. Curr. Drug Targets Inflamm. Allergy, 2005, 4(1), 27-30.
27. Malemud, C. J. Growth hormone, VEGF and FGF: Involvement inrheumatoid arthritis. Clin. Chim. Acta, 2006, 375(1-2), 10-19.
28. Mimori, T. Clinical significance of anti-CCP antibodies in rheumatoidarthritis. Intern. Med. 2005, 44(11), 1122-1126.
29. Snir, O; Widhe, M.; Hermansson, M; von Spee, C.; Lindberg, J.; Hensen, S.; Lundberg, K.; Engström, Å; Venables, P. J. W.; Toes, R. E. M.; Holmdahl, R.; Klareskog, L.V. Malmström, V. Antibodiesto several citrullinated antigens are enriched in the joints of rheumatoidarthritis patients. Arthritis Rheum. 2010, 62(1), 44-52.
30. + B cells: memory Bcells or "memory" B cells. J. Immunol., 2007, 179(1), 13-19.
31. Bugatti, S.; Codullo, V.; Caporali, C.; Montecucco, C. B cells inrheumatoid arthritis. Autoimmun. Rev., 2007, 6(7), 482-487.
32. Gabay, C.; Krenn, V.; Bosshard, C.; Seemayer, C. A.; Chizzolini,C.; Huard, B. Synovial tissues concentrate secreted APRIL. ArthritisRes. Ther., 2009, 11(5), R144.
33. Liu, H.; Pope, R. M. Apoptosis in rheumatoid arthritis: Friend orfoe. Rheum. Dis. Clin. No. Am., 2004, 30(3), 603-625.
34. Malemud, C. J.; Gillespie H. J. The role of apoptosis in arthritis. Curr. Rheumatol. Rev., 2005, 1(1), 131-142.
35. Hutcheson, J.; Perlman, H. E. Apoptotic regulators and RA. Curr. Rheumatol. Rev., 2008, 4(4), 254-58.
36. Leibbrandt, A.; Penninger, J. M. RANKL/RANK as key factors forosteoclast differentiation and bone loss in arthopathies. Adv. Exp. Med. Biol., 2009, 649, 100-113.
37. Anandarajah, A. P. Role of RANKL in bone diseases. TrendsEndocrinol. Metab., 2009, 20(2), 88-94.
38. Stolina, M.; Schett, G.; Dwyer, D.; Vonderfecht, S.; Middleton, S.; Duryea, D.; Pacheco, E.; Van, G.; Bolon, B.; Feige, U.; Zack, D.; Kostenuik, P. RANKL inhibition by osteoprotegerin prevents boneloss without affecting local or systemic inflammation parameters intwo rat arthritis models: comparison with anti-TNFα or anti-IL-1therapies. Arthritis Res. Ther., 2009, 11, R187.
39. Leibbrandt, A.; Penninger, J. M. RANK/RANKL: regulators ofimmune responses and bone physiology. Ann. N. Y. Acad. Sci.,2008, 1143, 123-150.
40. Spelling, P.; Bonfá, E.; Caparbo, V. F.; Pereira, R. M. Osteoprotegerin/RANKL system imbalance in active polyarticular juvenileidiopathic arthritis: a bone damage biomarker? Scand. J. Rheumatol.,2008, 37(6), 439-444.
41. Kitami, S.; Tanaka, H.; Kawato, T.; Tanabe, N.; Katono-Tani, T.; Zhang, F.; Suzuki, N.; Yonehara, Y.; Maeno, M. IL-17A suppressedthe expression of bone resorption-related proteinases andosteoclast differentiation via IL-17RA or IL-17RC receptors inRAW264. 7 cells. Biochimie, 2010, 92(4), 398-404.
42. Kalliolias, G. D.; Zhao, B.; Triantafyllopoulou, A.; Park-Min, H. -K.; Ivashkiv, L. B. Interleukin-27 inhibits osteoclastogenesis by abrogatingRANKL-mediated induction of nuclear factor of activatedT cells c1 and suppressing proximal RANK signaling. ArthritisRheum., 2010, 62(2), 402-413.
43. + monocytes. Arthritis Rheum., 2010, 62(2), 515-523.
44. Tunyogi-Csapo, M.; Kis-Toth, K.; Radacs, M.; Farkas, B.; Jacobs, J. J.; Finnegan, A.; Mikecz, K.; Glant, T. T. Cytokine-controlledRANKL and osteoprotegerin expression by human and mousesynovial fibroblasts: fibroblast-mediated pathologic bone resorption. Arthritis Rheum., 2008, 58(8), 2397-2408.
45. Xiong, W. C.; Feng, X. PYK2 and FAK in osteoclasts. Front. Biosci.,2003, 8, D1219-D1226.
46. Malemud, C. J.; Schulte, M. E. Is there a final common pathway forarthritis? Fut. Rheumatol., 2008, 3(3), 253-268.
47. Korb, A.; Tohidast-Akrad, M.; Cetin, E.; Axmann, R.; Smolen, J.; Schett, G. Differential tissue expression and activation of p38MAPK, α, β, γ, δ isoforms in rheumatoid arthritis. ArthritisRheum., 2006, 54(9), 2745-2756.
48. Malemud, C. J. Miller, A. H. Pro-inflammatory cytokine-inducedSAPK/MAPK and JAK/STAT in rheumatoid arthritis and the newanti-depression drugs. Expert Opin. Ther. Targets, 2008, 12(2),171-183.
49. Malemud, C. J. Recent advances in neutralizing the IL-6 pathwayin arthritis. Open Access Rheumatol. Res. Rev., 2009, 1, 133-150.
50. Wu, T.; Mohan, C. The AKT axis as a therapeutic target in autoimmunediseases. Endocr. Metab. Immune Disord. Drug Targets,2009, 9(2), 145-150.
51. Zhang, H. G.; Hyde, K.; Page, G. P.; Brand, J. P.; Zhou, J.; Yu, S.;Allison, D. B.; Hsu, H. C.; Mountz, J. D. Novel tumor necrosis factor-α-regulated genes in rheumatoid arthritis. Arthritis Rheum.,2004, 50(2), 420-431.
52. Tang, M.; Wei, X.; Guo, Y.; Breslin, P.; Zhang, S.; Zhang, S.; Wei, W.; Xia, Z.; Diaz, M.; Akira, S.; Zhang, J. TAK1 is requiredfor the survival of hematopoietic cells and hepatocytes in mice. J. Exp. Med., 2008, 205(7), 1611-1619.
53. Kajino-Sakamoto, R.; Inagaki, M.; Lippert, E.; Akira, S.; Robine, S.; Matsumoto, K.; Jobin, C.; Ninomiya-Tsuji, J. Entrocyte-derivedTAK1 signaling prevents epithelium apoptosis and the developmentof ileitis and colitis. J. Immunol., 2008, 181(2), 1143-1152.
54. Fong, C. H.; Bebien, M.; Didierlaurent, A.; Nebauer, R.; Hussell, T.; Broide, D.; Karin, M.; Lawrence, T. An anti-inflammatory rolefor IKKβ through the inhibition of "classical" macrophage activation. J. Exp. Med., 2008, 205(6), 1269-1276.
55. Ronkina, N.; Kotlyarov, A.; Dittrich-Breiholz, O.; Kracht, M.; Hitti, E.; Milarski, K.; Askew, R.; Marusic, S.; Lin, L. L.; Gaestel, M.; Telliez, J. B. The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulationof tumor necrosis factor biosynthesis and stabilization of p38MAPK. Mol. Cell Biol., 2007, 27(1), 170-181.
56. Ananieva, O.; Darragh, J.; Johansen, C.; Carr, J. M.; McIlrath, J.; Park, J. M.; Wingate, A.; Monk, C. E.; Toth, R.; Santos, S. G.; Iversen, L.; Arthur, J. S. C. The kinases MSK1 and MSK2 act asnegative regulators of Toll-like receptor signaling. Nat. Immunol.,2008, 9(8), 1028-1036.
57. Malemud, C. J. Small molecular weight inhibitors of stressactivatedand mitogen-activated protein kinases. Mini Rev. Med. Chem., 2006, 6 (6), 689-698.
58. Malemud, C. J. Inhibitors of stress-activated protein/mitogenactivatedprotein kinase pathways. Curr. Opin. Pharmacol., 2007, 7(3), 339-343.
59. Pfeifer, A. C.; Timmer, J.; Klingmüller, U. Systems biology ofJAK/STAT signaling. Essays Biochem., 2008, 45, 109-20.
60. Watling, D.; Carmo, C. R.; Kerr, I. M.; Costa-Pereira, A. P. Multiplekinases in the interferon-γ response. Proc. Natl. Acad. Sci. USA,2008, 105(16), 6051-6056.
61. Ivanenkov, I.; Balakin, K. V.; Tkachenko, S. E. New approaches tothe treatment of inflammatory disease: focus on small molecule inhibitorsof signal transduction pathways. Drugs R D, 2008, 9(6),397-434.
62. Kim, B. H.; Oh, S. R.; Yin, C. H. Lee, S.; Kim, E. A.; Sandoval, C.; Jayabose, S.; Bach, E. A.; Lee, H. K.; Baeg, G. H. MS-1020 is anovel small molecules that selectively inhibits JAK3 activity. Br. J. Haematol., 2010, 148(1), 132-143.
63. Milici, A. J.; Kudlacz, E. M.; Audoly, L.; Zwillich, S.; Changelian, P. Cartilage preservation by inhibition of Janus kinase 3 in two rodentmodels of rheumatoid arthritis. Arthritis Res. Ther., 2008, 10(1),R14.
64. Kremer, J. M.; Bloom, B. J.; Breedveld, F. C.; Coombs, J. H.; Fletcher, P.; Gruben, M. D.; Krishnaswami, S.; Burgos-Vargas, R.; Wilkinson, B.; Zebrini, C. A.; Zwillich, S. H. The safety and efficacyof a JAK inhibitor in patients with active rheumatoid arthritis:Results of a double-blind, placebo-controlled phase IIa trial of 3dosage levels of CP-690,550 versus placebo. Arthritis Rheum.,2009, 60(7), 1895-1905.
65. Malemud, C. J.; Pearlman, E. Targeting JAK/STAT signaling pathwayin inflammatory diseases. Curr. Signal Transduct. Ther., 2009,4, 201-221.
66. Deon, D.; Ahmed, S.; Tai, K.; Scaletta, N.; Herrero, C.; Lee, I. H.; Krause, A.; Ivashkiv, L. B. Cross-talk between IL-1 and IL-6 signalingpathways in rheumatoid arthritis synovial fibroblasts. J. Immunol.,2001, 167(9), 5395-5403.
67. Kumar, S.; Votta, B. J.; Reiman, D. J.; Badger, A. M.; Gowen, M.;Lee, J. C. IL-1 and TNF-α-induced bone resorption is mediated byp38 mitogen activated protein kinase. J. Cellular Physiol., 2001,187(3), 294-303.
68. Sweeny, S. E.; Firestein, G. S. Signal transduction in rheumatoidarthritis. Curr. Opin. Rheumatol., 2004, 16(3), 231-237.
69. Miyashita, T.; Kawakami, A.; Tamai, M.; Izumi, Y.; Mingguo, H.; Tanaka, F.; Abiru, S.; Nakashima, K.; Iwanaga, N.; Aratake, K.; Kamachi, M.; Arima, K.; Ida, H.; Migita, K.; Origuchi, T.; Tagashira, S.; Nishikaku, F.; Eguchi, K. Akt is an endogenous inhibitortoward tumor necrosis factor-related apoptosis inducing ligandmediatedapoptosis in rheumatoid synovial cells. Biochem. Biophys. Res. Commun., 2003, 312(2), 397-404.
70. Tamai, M.; Kawakami, A.; Tanaka, F.; Miyashita, T.; Nakamura, H.; Iwanaga, N.; Izumi, Y.; Arima, K.; Aratake, K.; Huang, M.; Kamachi, M.; Ida, H.; Origuchi, T.; Eguchi, K. Significant inhibitionof TRAIL-mediated fibroblast-like synovial cell apoptosis byIFN-γ through JAK/STAT pathway by translational regulation. J. Lab. Clin. Med., 2006, 147(4), 182-190.
71. Zwerina, J. Hayer, S.; Redlich, K.; Bobacz, K.; Kollias, G.; Smolen, J. S.; Schett, G. Activation of p38 MAPK is a key step intumor necrosis factor-mediated inflammatory bone destruction. ArthritisRheum., 2006, 54(2), 463-172.
72. Stanczyk, J.; Ospelt, C.; Gay, S. Is there a future for small moleculedrugs for the treatment of rheumatic diseases? Curr. Opin. Rheumatol.,2008, 20(3), 257-262.
73. Böhm, C; Hayer, S.; Kilian, A.; Zaiss, M. M.; Finger, S.; Hess, A.; Engelke, K.; Kollias, G.; Krönke, G.; Zwerina, J.; Schett, G.; David, J. P. The α-isoform of p38 MAPK specifically regulates arthriticbone loss. J. Immunol., 2009, 183(9), 5938-5947.
74. Luo, S. F. Fang, R. Y.; Hsieh, H. L.; Chi, P. L.; Lin, C. C.; Hsiao, L. D.; Wu, C. C.; Wang, J. S.; Yang, C. M. Involvement of MAPKsand NF-κB in tumor necrosis factor α-induced vascular cell adhesionmolecule 1 expression in human rheumatoid arthritis synovialfibroblasts. Arthritis Rheum., 2010, 62(1), 105-116.
75. El Kasmi, K. C.; Holst, J.; Coffre, M.; Mielke, L.; de Pauw, A.; Lhocine, N.; Smith, A. M.; Rutschman, R.; Kaushal, D.; Shen, Y.; Suda, T.; Donnelly, R. P.; Myers M. G. Jr, Alexander, W.; Vignali, D. A.; Watowich, S. S.; Ernst, M.; Hilton, D. J.; Murray, P. J. Generalnature of the STAT-3-activated anti-inflammatory response. J. Immunol., 2006, 177(11), 7880-7888.
76. Greenhalgh, C. J.; Hilton, D. J. Negative regulation of cytokinesignaling. J. Leukoc. Biol., 2001, 70(3), 348-356.
77. Shuai, K. Regulation of cytokine signaling pathways by PIASproteins. Cell Res., 2006, 16(2), 196-202.
78. Pettus, L. H.; Wurz, R. P. Small molecule p38 MAP kinase inhibitorsfor the treatment of inflammatory diseases: novel structuresand developments during 2006-2008. Curr. Top. Med. Chem.,2008, 8(16), 1452-1467.
79. Cohen, S. B.; Cheng, T. T.; Chindalore, V.; Damjanov, N.; Burgos-Vargas, R.; Delora, P.; Zimany, K.; Travers, H.; Caulfield, J. P. Evaluation of the efficacy and safety of pamapimod, a p38 kinaseinhibitor, in a double-blind, methotrexate-controlled study of patientswith active rheumatoid arthritis. Arthritis Rheum., 2009,60(2), 335-344.
80. Genovese, M. C. Inhibition of p38: has the fat lady sung? ArthritisRheum., 2009, 60(2), 317-320.
81. Damjanov, N.; Kauffman, R. S.; Spencer-Green, G. T. Efficacy,pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor,in rheumatoid arthritis: results of two randomized, doubleblind,placebo-controlled clinical studies. Arthritis Rheum., 2009,60(5), 1232-1241.
82. Sweeney, S. E. Therapy: the as-yet unfulfilled promise of p38kinase inhibitors. Nat. Rev. Rheumatol., 2009, 5(9), 475-77.
83. Hampton, T. Arthritis clinical trials revealed. JAMA, 2007, 297(1),28-29.
84. Coombs, J. H.; Bloom, B. J.; Breedveld, F. C.; Fletcher, M. P.; Gruben, D.; Kremer, J. M.; Burgos-Vargas, R.; Wilkinson, B.; Zerbini, C. A.; Zwillich, S. H. Improved pain, physical functioning, andhealth status in rheumatoid arthritis patients treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor. Resultsfrom a randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis., 2010, 69(2), 413-416.
85. West, K. CP-690550, a JAK3 inhibitor, as an immunosuppressantfor the treatment of rheumatoid arthritis, transplant rejection, psoriasisand other immune mediated disorders. Curr. Opin. Investig. Drugs, 2009, 10(5), 491-504.
86. Williams, W.; Scherle, P.; Shi, P.; Newton, R.; McKeeve, E.; Fridman, J.; Burn, T.; Vaddi, K.; Levy, R.; Moreland, L. A randomizedplacebo-controlled study of INCB018424, a selectivejanus kinase 1&2 (JAK1&2) inhibitor in rheumatoid arthritis (RA). Arthritis Rheum., 2008, 58 Suppl, S431 [Abstract].
87. Tarner, I. H.; Müller-Ladner, U.; Gay, S. Emerging targets of biologictherapies for rheumatoid arthritis. Nat. Clin. Pract. Rheumatol.,2007, 3(6), 336-345.
88. Yount, S.; Sorensen, M. V.; Cella, D.; Sengupta, N.; Grober, J.; Chartash, E. K. Adalimumab plus methotrexate or standard therapyis more effective than methotrexate or standard therapies alone inthe treatment of fatigue in patients with active, inadequately treatedrheumatoid arthritis. Clin. Exp. Rheumatol., 2007, 25(6), 838-846.
89. Lovell, D. J.; Ruperto, N.; Goodman, S.; Reiff, A.; Jung, L.; Jarosova, K.; Nemcova, D.; Mouy, R.; Sandborg, C.; Bohnsack, J.; Elewaut, D.; Foeldvari, I.; Gerloni, V.; Rovensky, J.; Minden, K.; Vehe, R. K.; Weiner, L. W.; Horneff, G.; Huppertz, H. I.; Olsen, N. Y.; Medich, J. R.; Carcereri-De-Prati, R.; McIlraith, M. J.; Giannini, E. H.; Martini A. A Pediatric Rheumatology CollaborativeStudy Group; Pediatric Rheumatology International Trials Organisation,Adalimumab with or without methotrexate in juvenilerheumatoid arthritis. N. Engl. J. Med., 2008, 359(8), 810-820.
90. Lee, Y. H.; Woo, J. H.; Rho, Y. H.; Choi, S. J.; Ji, J. D.; Song, C. G. Meta-analysis of the combination of TNF inhibitors plus MTXcompared to MTX monotherapy, and the adjusted indirect comparisonof TNF inhibitors in patients suffering from active rheumatoidarthritis. Rheumatol. Int., 2008, 28(6), 553-559.
91. Genovese, M. C.; McKay, J. D.; Nasonov, E. L.; Mysler, E. F.; deSilva, N. A.; Alecock, E.; Woodworth, T.; Gomez-Reino, J. J. Interleukin-6 receptor inhibition with tocilizumab reduces disease activityin rheumatoid arthritis with inadequate response to diseasemodifyingantirheumatic drugs. The tocilizumab in combinationwith traditional disease-modifying antirheumatic drug therapystudy. Arthritis Rheum., 2008, 58(10), 2968-2980.