Rheumatoid arthritis therapy: Advances from bench to bedside

Autoimmunity

Volumn 43, Issue 7, 2010, Pages 478-492

  Choi, Soo In ^a   Brahn, Ernest ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

biologic therapy; review; Rheumatoid arthritis; small molecules; treatment

Indexed keywords

ABATACEPT; ADALIMUMAB; ALD 518; ANALGESIC AGENT; ANTIRHEUMATIC AGENT; ARG 098; ART 621; ATACICEPT; BELIMUMAB; CAM 3001; CANAKINUMAB; CERTOLIZUMAB PEGOL; DENOSUMAB; DISEASE MODIFYING ANTIRHEUMATIC DRUG; ETANERCEPT; GLUCOCORTICOID; GOLIMUMAB; HYDROXYCHLOROQUINE; INFLIXIMAB; LEFLUNOMIDE; METHOTREXATE; NONSTEROID ANTIINFLAMMATORY AGENT; OCRELIZUMAB; OFATUMUMAB; RECOMBINANT INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; RITUXIMAB; SALAZOSULFAPYRIDINE; SIMPOM; TOCILIZUMAB; TUMOR NECROSIS FACTOR INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANGIONEUROTIC EDEMA; BRONCHOSPASM; CLINICAL PRACTICE; DISEASE COURSE; DRUG DOSE INCREASE; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; ENVIRONMENTAL FACTOR; FEVER; GENETIC RISK; HUMAN; INCIDENCE; INFECTION; MOLECULARLY TARGETED THERAPY; PATHOGENESIS; PREVALENCE; PRURITUS; REVIEW; RHEUMATOID ARTHRITIS; RIGOR; THROAT DISEASE; UNSPECIFIED SIDE EFFECT;

ANTIRHEUMATIC AGENTS; ARTHRITIS, RHEUMATOID; CLINICAL TRIALS AS TOPIC; DRUG DESIGN; HUMANS;

EID: 77958020350     PISSN: 08916934     EISSN: 1607842X     Source Type: Journal    
DOI: 10.3109/08916931003674717     Document Type: Review

References (143)

1. Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 2005;4(3):130-136.
2. McQueen FM, Stewart N, Crabbe J, Robinson E, Yeoman S, Tan PL, McLean L. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis 1998;57(6):350-356.
3. Firestein GS. Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J Clin Rheumatol 2005;11(Suppl. 3): S39-S44.
4. Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum 1990; 33(10):1449-1461.
5. Pincus T, Marcum SB, Callahan LF. Longterm drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second line drugs and prednisone. J Rheumatol 1992;19(12):1885-1894. (Pubitemid 23018519)
6. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001; 358(9285):903-911.
7. O'Dell JR, Haire CE, Erikson N, Drymalski W, Palmer W, Eckhoff PJ, Garwood V, Maloley P, Klassen LW, Wees S, Klein H, Moore GF. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996; 334(20):1287-1291.
8. O'Dell JR, Leff R, Paulsen G, Haire C, Mallek J, Eckhoff PJ, Fernandez A, Blakely K, Wees S, Stoner J, Hadley S, Felt J, Palmer W, Waytz P, Churchill M, Klassen L, Moore G. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: Results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46(5):1164-1170.
9. Korpela M, Laasonen L, Hannonen P, Kautiainen H, Leirisalo-Repo M, Hakala M, Paimela L, Blafield H, Puolakka K, Mottonen T. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: Five-year experience from the FIN-RACo study. Arthritis Rheum 2004;50(7):2072-2081.
10. Moreland LW, O'Dell JR, Paulus H, Curtis JR, Bridges SL, Jr, Zhang X, Howard G, Cofield SS. TEAR: Treatment of early aggressive RA: A randomized, double-blind, 2-year trial comparing immediate triple DMARD versus MTX plus etanercept to step-up from initial MTX monotherapy. Arthritis Rheum 2009;60(Suppl. 10):S707.
11. Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, Luggen ME, Keystone E, Weisman MH, Bensen WM, Kaine JL, Ruderman EM, Coleman P, Curtis DL, Kopp EJ, Kantor SM, Waltuck J, Lindsley HB, Markenson JA, Strand V, Crawford B, Fernando I, Simpson K, Bathon JM. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Int Med 2002;137(9):726-733.
12. Finckh A, Dehler S, Gabay C. The effectiveness of leflunomide as a co-therapy of tumour necrosis factor inhibitors in rheumatoid arthritis: A population-based study. Ann Rheum Dis 2009;68(1):33-39.
13. Furst DE. The risk of infections with biologic therapies for rheumatoid arthritis. Semin Arthritis Rheum 2008;PMID: 19117595 (EPub ahead of print).
14. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340(4): 253-259.
15. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Genovese MC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Finck BK. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343(22): 1586-1593.
16. Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, Singh A, Pedersen RD, Koenig AS, Freundlich B. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): A randomised, double-blind, parallel treatment trial. Lancet 2008;372(9636):375-382.
17. Van der HD, Klareskog L, Rodriguez-Valverde V, Codreanu C, Bolosiu H, Melo-Gomes J, Tornero-Molina J, Wajdula J, Pedersen R, Fatenejad S. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: Two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 2006;54(4):1063-1074.
18. Kameda H, Kanbe K, Sato E, Ueki Y, Saito K, Nagaoka S, Hidaka T, Atsumi T, Tsukano M, Kasama T, Shiozawa S, Tanaka Y, Yamanaka H, Takeuchi T. Etanercept (ETN) plus methotrexate (MTX) combination therapy resulted in better clinical and radiographic outcomes than ETN monotherapy even in patients with active rheumatoid arthritis despite MTX treatment: 52-week results from the JESMR study. Arthritis Rheum 2009;60(Suppl. 10):S752-S753.
19. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A randomised phase III trial. ATTRACT study group. Lancet 1999;354(9194):1932-1939.
20. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Furst D, Weisman MH, St Clair EW, Keenan GF, van der HD, Marsters PA, Lipsky PE. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004; 50(4):1051-1065.
21. St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, Keystone E, Schiff M, Kalden JR, Wang B, Dewoody K, Weiss R, Baker D. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial. Arthritis Rheum 2004;50(11):3432- 3443.
22. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial. Arthritis Rheum 2003; 48(1):35-45.
23. Weinblatt ME, Keystone EC, Furst DE, Kavanaugh AF, Chartash EK, Segurado OG. Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Ann Rheum Dis 2006;65(6):753-759.
24. Keystone EC, KavanaughA,van der Heijde DMFM, Sinisi S, Hall J, Guerette B. Long-term impact of adalimumab plus methotrexate on radiographic, clinical, and functional progression of rheumatoid arthritis. Arthritis Rheum 2009; 60(Suppl. 10):S627-S628.
25. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van VR, Sharp J, Perez JL, Spencer-Green GT. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006;54(1):26-37.
26. Navarro-Sarabia F, Riza-Ariza R, Hernandez-Cruz B, Villanueva I. Adalimumab for treating rheumatoid arthritis. Cochrane Database Syst Rev 2005;(3):CD005113.
27. Navarro-Sarabia F, Riza-Ariza R, Hernandez-Cruz B, Villanueva I. Adalimumab for treating rheumatoid arthritis. J Rheumatol 2006;33(6):1075-1081. (Pubitemid 43825455)
28. Emery P, Fleischmann RM, Moreland LW, Hsia EC, Strusberg I, Durez P, Nash P, Amante EJ, Churchill M, Park W, Pons-Estel BA, Doyle MK, Visvanathan S, Xu W, Rahman MU. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: Twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum 2009; 60(8):2272-2283.
29. Emery P, Fleischmann R, van der Heijde DMFM, Keystone EC, Genovese MC, Conaghan PG, Hsia EC, Xu W, Baratelle A, Beutler A, Rahman MU. Golimumab and radiographic progression in rheumatoid arthritis: Results of GO-BEFORE and GO-FORWARD studies. Arthritis Rheum 2009;60(Suppl. 10):S240.
30. Keystone EC, Genovese MC, KlareskogL, Hsia EC, Hall ST, Miranda PC, Pazdur J, Bae SC, Palmer W, Zrubek J, Wiekowski M, Visvanathan S, Wu Z, Rahman MU. Golimumab, a human antibody to TNF-{alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate: The GO-FORWARD study. Ann Rheum Dis 2008;PMID: 19066176 (EPub ahead of print).
31. Smolen J, Kay J, Doyle MK. Golimumab, a human anti-TNFa monoclonal antibody, injected every 4 weeks: Efficacy and safety in RA patients previously treated with anti-TNFa agents (GO-AFTER study). Arthritis Rheum 2008; 58(Suppl.):S523.
32. Keystone EC, Genovese MC, Klareskog L, Hsia EC, Hall S, Miranda PC, Pazdur J, Bae SC, Palmer W, Xu S, Rahman MU. Golimumab in rheumatoid arthritis: GO-FORWARD week 52 results. Arthritis Rheum 2009; 60(Suppl. 10):S622-S623.
33. Smolen JS, Kay J, Doyle MK, Landewe R, Matteson EL, Wollenhaupt J, Gaylis NB, Murphy FT, Neal J, Zhou Y, Visvanathan S, Hsia EC, Rahman MU. Golimumab in rheumatoid arthritis patients previously treated with anti-TNFa agents (GO-AFTER study): Week 52 results. Arthritis Rheum 2009;60(Suppl. 10):S623-S624.
34. Keystone E, Heijde D, Mason D, Jr, Landewe R, Vollenhoven RV, Combe B, Emery P, Strand V, Mease P, Desai C, Pavelka K. 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(11):3319-3329.
35. Smolen JS, Landewe RB, Mease PJ, Brzezicki J, Mason D, Luijtens K, van Vollenhoven RF, Kavanaugh A, Schiff MH, Burmester GR, Strand V, Vencovsky J, van der Heijde DM. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: The RAPID 2 study. Ann Rheum Dis 2009;68(6):797-804.
36. Fleischmann R, Vencovsky J, van VR, Borenstein D, Box J, Coteur G, Goel N, Brezinschek HP, Innes A, Strand V. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: The FAST4-WARD study. Ann Rheum Dis 2009;68(6):805-811.
37. Keystone EC, Fleischmann R, Smolen JS, Strand V, Landewe R, Combe B, Mease PJ, Ansari Z, Goel N, van der Heijde DMFM. The efficacy of certolizumab pegol added to methotrexate is sustained over 2 years in the treatment of rheumatoid arthritis. Arthritis Rheum 2009 2009;60(Suppl. 10):S622.
38. Combe B, Schwartzman S, Massarotti E, Keystone EC, Luijtens K, van der Heijde DMFM. Incremental benefit of open-label certolizumab pegol \+ MTX in rheumatoid arthritis (RA) patients following double-blind placebo \+ MTX treatment out to 2 years. Arthritis Rheum 2009;60(Suppl. 10):S623.
39. Van Vollenhoven RF, Smolen JS, Schiff M, Fleischmann R, Combe B, Goel N, Desai C, Curtis JR, Keystone EC. Safety update on certolizumab pegol (CZP) in patients with active rheumatoid arthritis (RA). Arthritis Rheum 2009; 60(Suppl. 10):S636-S637.
40. Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, Kremer J, Bear MB, Rich WJ, McCabe D. Treatment of rheumatoid arthritis with anakinra, a recombi-nant 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(3):614-624.
41. Cohen SB, Moreland LW, Cush JJ, Greenwald MW, Block S, Shergy WJ, Hanrahan PS, Kraishi MM, Patel A, Sun G, Bear MB. A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis 2004;63(9):1062-1068.
42. Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with metho-trexate. Arthritis Rheum 2004;50(5):1412-1419.
43. Nash P, Nayiager S, Genovese M, Kivitz A, Oelke K, Ludivico C, Palmer W, Rodriguez C, Dalaet I, Overfield S, Elegbe A, Corbo M. Immunogenicity is not increased with subcutaneous administration of abatacept with and without methotrexate in patients with rheumatoid arthritis: Results from a phase III study. Arthritis Rheum 2009;60(Suppl. 10): S633-S634.
44. Kremer JM, Genant HK, MorelandLW, Russell AS, Emery P, bud-Mendoza C, Szechinski J, Li T, Ge Z, Becker JC, Westhovens R. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: A randomized trial. Ann Int Med 2006;144(12):865-876.
45. Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, Li T, Aranda R, Hagerty DT, Dougados M. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005;353(11):1114-1123.
46. Schiff M, Pritchard C. The safety of abatacept in patients with active RA and inadequate response to anti-TNF therapy: Results from the ARRIVE trial. Ann Rheum Dis 2007; 66(Suppl.):OP0212.
47. Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, Saldate C, Li T, Aranda R, Becker JC, Lin C, Cornet PL, Dougados M. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: A phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and aninadequate response to methotrexate. Ann Rheum Dis 2008;67(8):1096-1103.
48. 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 antirheu-matic drugs: A one-year randomized, placebo-controlled study. Arthritis Rheum 2006;54(9):2807-2816.
49. Westhovens R, Robles M, Nayiager S, Wollenhaupt J, Durez P, Gomez-Reino J, Grassi W, Haraoui B, Shergy W, Park SH, Genant H, Peterfy C, Becker J-C, Covucci A, Helfrick R, Bathon J. Disease remission is achieved within two years in over half of methotrexate naive patients with early erosive rheumatoid arthritis (RA) treated with abatacept plus MTX: Results from the AGREE trial. Arthritis Rheum 2009; 60(Suppl.):S239.
50. Westhovens R, Dougados M, Hall S, Reed DM, Becker JC, Teng J, Kremer JM. Disease remission, radiographic non-progression and normalization of function achieved at year 1 are sustained long-term in a majority of patients: 5-year outcomes with abatacept in biologic-naive patients. Arthritis Rheum 2009;60(Suppl. 10):S618.
51. Genovese MC, Schiff M, Luggen ME, Le BarsM, Becker JC, Aranda R, Elegbe A, Cohen R, Dougados M. Abatacept demonstrates consistent safety and sustained improvements in efficacy through 4 years of open-label treatment in patients with an inadequate response to anti-TNF therapy. Arthritis Rheum 2009;60(Suppl. 10):S632.
52. Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, Racewicz AJ, van Vollenhoven RF, Li NF, Agarwal S, Hessey EW, Shaw TM. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54(5):1390-1400.
53. Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, Keystone EC, Loveless JE, Burmester GR, Cravets MW, Hessey EW, Shaw T, Totoritis MC. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multi-center, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54(9):2793-2806.
54. Keystone E, Emery P, Peterfy CG, Tak PP, Cohen S, Genovese MC, Dougados M, Burmester GR, Greenwald M, Kvien TK, Williams S, Hagerty D, Cravets MW, Shaw T. Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies. Ann Rheum Dis 2009; 68(2):216-221.
55. Tak PP, Rigby WFC, Rubbert-Roth A, Peterfy CG, van Vollenhoven RF, Stohl W, Hessey E, Chen AC, Tyrrell H, Shaw TM. Rituximab in combination with methotrexate (MTX) significantly inhibits joint damage and improves clinical outcomes in patients with early active RA who are naive to MTX: A randomized active comparator placebo-controlled trial (IMAGE). Arthritis Rheum 2009;60(Suppl. 10):S238.
56. Rigby W, Ferraccioli G, Greenwald M, Zazueta-Montiel B, Fleischmann R, Wassenberg S, Jahreis A, Burke L, Mela C, Chen A. Rituximab improved physical function and quality of life in patients with early rheumatoid arthritis who were naive to methotrexate (IMAGE study). Arthritis Rheum 2009; 60(Suppl. 10):S621-S622.
57. Van Vollenhoven RF, EmeryP,Bingham III CO, Keystone EC, Fleischmann RM, Furst DE, Macey K, Sweetser MT, LehanePB,FarmerP,LongSG.Long- termsafetyofrituximab: Long-term follow-up of the RA clinical trials and retreatment population. Arthritis Rheum 2009;60(Suppl. 10):S730.
58. Tekstra J, Teng OYK, Welsing PMJ, van Laar JM, Lafeber FPJG, Bijlsma JWJ. Comparison of clinical outcome in rheumatoid arthritis patients treated with a fixed or on-demand regime of rituximab: Two year followup. Arthritis Rheum 2009;60(Suppl. 10):S254-S255.
59. Vander Cruyssen B, Westhovens R, Durez P, De Keyser F. The Belgian MIRA (MabThera in rheumatoid arthritis) registry: Clues for the optimization of rituximab treatment strategies. Arthritis Rheum 2009;60(Suppl. 10):S374.
60. Emery P, Mease PJ, Rubbert-Roth A, Curtis JR, Muller-Ladner U, Gaylis NB, Armstrong GK, McLean L, Reynard M, Tyrrell H. Retreatment with rituximab (RTX) based on a treatment to target (TT) approach provides better disease control than treatment as needed (PRN) in patients (pts) with rheumatoid arthritis (RA). Arthritis Rheum 2009; 60(Suppl. 10):S753-S754.
61. Emery P, Keystone E, Tony HP, Cantagrel A, van VR, Sanchez A, Alecock E, Lee J, Kremer J. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: Results from a 24-week multi-centre randomised placebo-controlled trial. Ann Rheum Dis 2008;67(11):1516-1523.
62. Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): A double-blind, placebo-controlled, randomised trial. Lancet 2008; 371(9617):987-997.
63. Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, Woodworth T, Gomez-Reino JJ. 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(10):2968-2980.
64. Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, Siri DA, Tomsic M, Alecock E, Woodworth T, Genovese MC. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study. Ann Rheum Dis 2009; PMID: 19297346 (EPub ahead of print).
65. Smolen JS, Gomez-Reino JJ, Davies C, Alecock E, Rubbert-Roth A, EmeryP. Long-term efficacy of tocilizumab in rheumatoid arthritis for up to 3.5 years. Arthritis Rheum 2009;60(Suppl. 10):S152-S153.
66. Van Vollenhoven RF, Siri D, Furie R, Krasnow J, Alecock E, Alten R. Long-term safety and tolerability of tocilizumab treatment in patients with rheumatoid arthritis and a mean treatment duration of 2.4 years. Arthritis Rheum 2009; 60(Suppl. 10):S731.
67. Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: A critical review. Arthritis Res Ther 2009; 11(Suppl. 1):S1.
68. Ang HT, Helfgott S. Do the clinical responses and complications following etanercept or infliximab therapy predict similar outcomes with the other tumor necrosis factor-alpha antagonists in patients with rheumatoid arthritis? J Rheumatol 2003;30(11):2315-2318.
69. Nalysnyk L, Xu Y, Williams K. Treatment of rheumatoid arthritis after failure of TNF antagonists: A systematic review and meta-analysis. Ann Rheum Dis 2008;67(Suppl. II):326.
70. Finckh A, Ciurea A, Brulhart L, Kyburz D, Moller B, Dehler S, Revaz S, Dudler J, Gabay C. B-cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum 2007;56(5):1417-1423.
71. ClinicalTrials.gov. http://clinicaltrials.gov 2009.
72. Genovese MC, Kaine JL, Lowenstein MB, Giudice JD, Baldassare A, Schechtman J, Fudman E, Kohen M, Gujrathi S, Trapp RG, Sweiss NJ, Spaniolo G, Dummer W. 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(9):2652-2661.
73. Genentech Pipeline as of October 2009. http://www.gene. com/gene/pipeline/status/ 2009.
74. Ostergaard M, Baslund B, Rigby W. Ofatumumab, a human CD20 monoclonal antibody, in the treatment of rheumatoid arthritis: Early results from an ongoing, double-blind, randomized, placebo controlled clinical trial. Arthritis Rheum 2007;56(Suppl. 9):S793.
75. Ostergaard M, Baslund B. Ofatumumab, a human CD20 monoclonal antibody, in the treatment of rheumatoid arthritis (RA): Subgroup analysis at week 24 from a Phase I/II clinical trial. Arthritis Rheum 2008;58(Suppl.):S305.
76. Genmab Products in Development: Ofatumumab. http:// www.genmab.com/ ScienceAndResearch/ProductsinDevelop ment/Ofatumumab.aspx 2009.
77. Stromatt S, Chopiak V, Dvoretskiy L, Koshukova G, Nasonov E, Povoroznyuk V, Stanislavchuk M, Leith P. Sustained safety and efficacy of TRU-015 with continued retreatment of rheumatoid arthritis subjects following a phase 2B study. Arthritis Rheum 2009;60(Suppl. 10):S148-S149.
78. Trubion Pharmaceuticals: Product Candidates: TRU-015. http://www.trubion.com/products/product-candidates/ tru-015/ 2009.
79. Medarex Pipeline. http://www.medarex.com/Development/ Pipeline.htm 2009.
80. Dillon SR, Harder B, Lewis KB, Moore M, Burkowski TR, Hamacher NB, Lantry MM, Maurer M, Ellsworth JL, Pederson S, Krejsa C, Elkon KB, Wener MH, Gross JA. BLYS/APRIL heterotrimers activate human B cells are neutralized by atacicept and are elevated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Ann Rheum Dis 2009;68(Suppl. 3):368.
81. Merck Serono Pipeline as of October 2009. http://www. merckserono.com/corp.merckserono/en/images/Pipeline- tcm112-44406.pdf 2009.
82. Human Genome Sciences: Products: BENLYSTA. http:// www.hgsi.com/BENLYSTA. html 2009.
83. Genovese MC, Mociran E, Biagini M, Bojin S, Sloan-Lancaster J. Phase 2 study of safety and efficacy of a novel anti-BAFF monoclonal antibody, in patients with RA treated with methotrexate (MTX). Arthritis Rheum 2009; 60(Suppl. 10):S717-S718.
84. Eli Lilly and Company: Research Pipeline as of October 1, 2009. http://www.lilly.com/pdf/Pipeline-Slide.pdf 2009.
85. Church LD, McDermott MF. Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammatory disorders. Curr Opin Mol Ther 2009;11(1):81-89.
86. Amgen Pipeline. as of September 3, 2009. http://www.amgen. com/science/pipe.jsp 2009.
87. Alder Biopharmaceuticals Pipeline. http://www.alderbio. com/11/PIPELINE/ 2009.
88. Tak PP, Durez P, Gomez-Reino J, Wittmer B, Chindalore V, Padova FD, Wright A, Bruin G, Hueber W. AIN457 shows a good safety profile and clinical benefit in patients with active rheumatoid arthritis (RA) despite methotrexate therapy: 16-weeks results from a randomized proof-of-concept trial. Arthritis Rheum 2009;60(Suppl. 10):S717.
89. Genovese MC, van den Bosch F, Roberson SA, Bojin S, Biagini M, Ryan P, Sloan-Lancaster J. LY2439821, A novel anti-IL-17 Mab: Safety, tolerability, and efficacy in patients with RA on background DMARDs. Arthritis Rheum 2009; 60(Suppl. 10):S153-S154.
90. Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, van der HD, Zhou L, Tsuji W, Newmark R. 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 IIclinical trial.Arthritis Rheum 2008;58(5):1299-1309.
91. KaloBios Pipeline: KB002/003. http://www.kalobios.com/ kb-pipeline-002.php 2009.
92. Burmester G, Wagner F, Feist E, Sleeman M, Magrini F, White B. Cam-3001: A novel human monoclonal antibody against GM-CSFR-a, in subjects with rheumatoid arthritis (RA)-results of a phi study. Arthritis Rheum 2009;60(Suppl. 10):S719-S720.
93. Sadis S, Mukherjee A, Olson S, Dokmanovich M, Maher R, Cai CH, Le V, Crawford M, Fedechko R, Whitfield L, Stock T, Hellio le Graverand Gastineau MP, Zeiher B. Safety, pharmacokinetics, and pharmacodynamics of PD-0360324, a human monoclonal antibody to monocyte/macrophage colony stimulating factor, in healthy volunteers. Arthritis Rheum 2009;60(Suppl. 10):S150-S151.
94. Pfizer Pipeline as of March 31, 2009. http://www.pfizer.com/ files/research/pipeline/2009-0331/pipeline-2009-0331.pdf 2009.
95. Arana Therapeutics Pipeline: ART621. http://www.arana. com/inflammation-franchise-art621.htm 2009.
96. Yellin M, Paliienko I, Balaneuscu A, Vizir V, Ter-Vartanian S, Tian J, Zhu X, Ignatenko G, Chirieac R. A Phase II, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of MDX-1100, A fully human ANti-CXCL10 monoclonal antibody, in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA). Arthritis Rheum 2009;60(Suppl. 10):S153.
97. GlaxoSmithKline Product Pipeline as of February 2009. http://www.gsk.com/investors/product-pipeline/docs/gsk-pipeline-feb09.pdf 2009.
98. Baker MB, Bendit M, Campanile AM, Feeney M, Hodsman P, Toso JF. A randomized, single-blind, placebo-controlled dose escalation study to investigate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of GSK315234 in healthy volunteers. Arthritis Rheum 2009;60(Suppl. 10):S158.
99. Appelboom T, Mann H, Senolt L, Suchy D, Nemec P, Rolova J, Cerinic MM. Preliminary results of a phase I clinical trial of intra-articular administration of ARG098, a novel anti-Fas IgM Mab, in RA. Arthritis Rheum 2009; 60(Suppl. 10):S156.
100. Biotest AG Pipeline. http://www.biotest.de/ww/en/pub/ biotherapeutics/product-pipeline.cfm 2009.
101. Biocon Pipeline. http://www.biocon.com/biocon-research- pipeline.asp 2009.
102. Runnels HA, Weber GL, Min J, Kudlacz E, Zobel J, Donovan C, Thiede M, Zhang J, Alpert R, Salafia M, Burdette D, Bell R, Beebe J, Xu X. Characterization of a potent and neutralizing fully human anti CD44 antibody PF 03475952. Arthritis Rheum 2009;60(Suppl. 10):S149.
103. Genovese MC, Greenwald MW, Alloway JA, Baldassare AR, Chase W, Newman C, Weaver ML, Browning J, Goyal J, O'Gorman J, Cravets M, Beckman EM, Nirula A. Efficacy and safety of baminercept in the treatment of rheumatoid arthritis (RA)-results of the phase 2B study in the TNF-IR population. Arthritis Rheum 2009;60(Suppl. 10):S154.
104. Issacs JD, Genovese MC, Emery P, Scheinberg MA, Spindler A, Newman C, Weaver ML, Browning J, O'Gorman J, Cravets M, Hagerty D, Beckman EM, Nirula A. Efficacy and safety of baminercept in the treatment of rheumatoid arthritis (RA)-preliminary results of the phase 2B study in the DMARD-IR population. Arthritis Rheum 2009;60(Suppl. 10):S154.
105. McInnes IB, Battersby C, Shirt L, Wang M, Parmar H. Functional outcomes from a phase II study of a novel P2X7 receptor antagonist, AZD9045, in patients with active rheumatoid arthritis (CREATE study). Ann Rheum Dis 2009;68(Suppl. 3):132.
106. AstraZeneca Pipeline as of July 30, 2009. http://www. astrazeneca.com/-mshost3690701/content/resources/media/ investors/AZN-Q2-2009/ AZN-Q2-2009-Pipeline.pdf 2009.
107. Van den Berg WB, Miossec P. IL-17 as a future therapeutic target for rheumatoid arthritis. Nat Rev Rheumatol, 2009, 5, 10, 549-553
108. Schett G, Hayer S, Zwerina J, Redlich K, Smolen JS. Mechanisms of disease: The link between RANKL and arthritic bone disease. Nat Clin Pract Rheumatol 2005;1(1): 47-54.
109. Cornish AL, Campbell IK, McKenzie BS, Chatfield S, Wicks IP. G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nat Rev Rheumatol 2009;5(10): 554-559.
110. Sweeney SE, Firestein GS. Primer: Signal transduction in rheumatic disease\-a clinician's guide. Nat Clin Pract Rheumatol 2007;3(11):651-660.
111. D'Aura SC, Paniagua RT, Lindstrom TM, Robinson WH. Tyrosine kinases as targets for the treatment of rheumatoid arthritis. Nat Rev Rheumatol 2009;5(6):317-324.
112. KremerJ,Cohen S, Wilkinson B, Gruben D, Wallenstein GV, Kanik KS, Zwillich SH. Safety and efficacy after 24 week (WK) dosing of the oral JAK inhibitor CP-690,550 (CP) in combination with methotrexate (MTX) in patient (PTS) with active rheumatoid arthritis (RA). Arthritis Rheum 2009; 60(Suppl. 10):S719.
113. Fleischmann RM, Genovese MC, Gruben D, Kanik KS, Wallenstein GV, Wilkinson B, Zwillich SH. Safety and efficacy after 24 week (wk) dosing of the oral JAK inhibitor CP-690,550 (CP) as monotherapy in patients (pts) with active rheumatoid arthritis (RA). Arthritis Rheum 2009; 60(Suppl. 10):S718.
114. Wallenstein GV, Cohen S, Cutolo M, Gruben D, Kanik KS, Kremer JM, Lee EB, Wilkinson B, Zwillich SH. Effects of the oral JAK inhibitor CP-690,550 (CP) on pain, physical functioning (PF), fatigue, and health-related quality of life (HRQoL) in patient (pts) with active rheumatoid arthritis (RA). Arthritis Rheum 2009;60(Suppl. 10):S154-S155.
115. Incyte Product Pipeline. http://www.incyte.com/drugs- product-pipeline.html 2009.
116. Fridman J, Scherle P. Preclinical characterization of INCB028050, JAK1/JAK2 selective clinical candidate. Arthritis Rheum 2008;58(Suppl. 9):S296.
117. Weinblatt ME, Kavanaugh A, Burgos-Vargas R, Dikranian AH, Medrano-Ramirez G, Morales-Torres JL, Murphy FT, Musser TK, Straniero N, Vicente-Gonzales AV, Grossbard E. Treatment of rheumatoid arthritis with a Syk kinase inhibitor: A twelve-week, randomized, placebo-controlled trial. Arthritis Rheum 2008;58(11):3309-3318.
118. Rigel Pharmaceuticals TASKi2 & TASKi3 Results Presentation. http://www.rigel.com/pdf/R788TASKI2-3RA Results.pdf 2009.
119. Bristol-Myers Squibb Pipeline. http://www.bms.com/ research/pipeline/ Pages/default.aspx 2009.
120. Schreiber S, Feagan B, D'Haens G, Colombel JF, Geboes K, Yurcov M, Isakov V, Golovenko O, Bernstein CN, Ludwig D, Winter T, Meier U, Yong C, Steffgen J. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: A randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006;4(3): 325-334.
121. Cohen SB, Cheng TT, Chindalore V, Damjanov N, Burgos-Vargas R, Delora P, Zimany K, Travers H, Caulfield JP. 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(2):335-344.
122. Genovese MC, Cohen SB. A randomized, double-blind, placebo-controlled phase 2 study of an oral p38 MAPK inhibitor, SCIO-469, in patients with active rheumatoid arthritis. Arthritis Rheum 2008;58(Suppl. 9):S431.
123. 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(5):1232-1241.
124. Phytomedics: Portfolio: Botanical Drugs. http://www. phytomedics.com/ portfolio/products-botanical.html 2009.
125. Goldbach-Mansky R, Wilson M, Fleischmann R, Olsen N, Silverfield J, Kempf P, Kivitz A, Sherrer Y, Pucino F, Csako G, Costello R, Pham TH, Snyder C, van der HD, Tao X, Wesley R, Lipsky PE. Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: A randomized trial. Ann Intern Med 2009;151(4):229-251.
126. Kowa Pharmaceuticals Pipeline. http://www.kowa.co.jp/eng/ g/rd/pipeline.htm 2009.
127. Synta Pharmaceuticals Pipeline: Apilimod. http://www. syntapharma.com/PrdOralIL12Inhibitor.aspx 2009.
128. Chelsea Therapeutics Pipeline: Antifolates. http://chelsea therapeutics.com/pipeline/antifolates/antifolates.html 2009.
129. Keystone EC, Hewitt LA, Simon LS, Shirinsky V, Pedder S. CH-1504: A metabolically inert antifolate, is an effective and well-tolerated treatment for patietns with moderate to severe rheumatoid arthritis. Arthritis Rheum 2009; 60(Suppl. 10):S720.
130. Veenendaal A, Boland J, Hewitt LA, Phase I. Single and multiple ascending dose studies to investigate the safety, tolerance and Pharmacokinetics of CH-4051 in healthy male subjects. Arthritis Rheum 2009;60(Suppl. 10):S159-S160.
131. 4SC AG: Products: 4SC-101. http://www.4sc.de/en/ 2009.
132. CanFite Biopharma Pipeline. http://www.canfite.com/ pipeline.html 2009.
133. Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P. Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: Data from a phase II clinical trial. J Rheumatol 2008;35(1):41-48.
134. OxyPharma R&D Activities. http://www.oxypharma.com/ RDActivities/ 2009.
135. Lexicon Pharmaceuticals Pipeline. http://www.lexicon-gen etics.com/pipeline/lx2931.html 2009.
136. Fleischmann R, Frazier KS, Freiman J, Brooks B, Oravecz T, Augeri D, Kelly M, Brown P. Co-administration of the oral S1P-lyase inhibitor LX2931 with methotrexate was well tolerated over 14 days in patients with stable rheumatoid arthritis. Arthritis Rheum 2009;60(Suppl. 10):S157-S158.
137. Hollis-Eden Pharmaceuticals Pipeline. http://dev.holliseden. com/content/?page-id/438 2009.
138. Stock T, Fleishaker D, Mukherjee A, Le V, Xu J, Zeiher B. Evaluation of safety, pharmacokinetics, and phamacodynamics of a selective glucocorticoid receptor modulator (SGRM) in healthy volunteers. Arthritis Rheum 2009;60(Suppl. 10): S155-S156.
139. Kelly J. RA Drug Array ARRY-162 Fails in Phase 2. MusculoSkeletal Report. www.mskreport.com/articles.cfm? articleID/3421 2009.
140. Fleishaker D, Wang X, Menon S, Zeiher BG, Stock TC. A phase 2 study to assess the efficacy and safety of maraviroc, a CCR-5 antagonist in the treatment of rheumatoid arthritis. Arthritis Rheum 2009;60(Suppl. 10):S146.
141. Walker JG, Smith MD. The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 2005;32(9):1650-1653.
142. Cha HS, Boyle DL, Inoue T, Schoot R, Tak PP, Pine P, Firestein GS. A novel spleen tyrosine kinase inhibitor blocks c-jun N-terminal kinase-mediated gene expression in synoviocytes. J Pharmacol Exp Ther 2006;317(2):571-578.
143. Sweeney SE, Firestein GS. Mitogen activated protein kinase inhibitors: Where are we now and where are we going? Ann Rheum Dis 2006;65(Suppl. 3):iii83-iii88.