Targeting Granulocyte-Monocyte Colony-Stimulating Factor Signaling in Rheumatoid Arthritis: Future Prospects

Drugs

Volumn 79, Issue 16, 2019, Pages 1741-1755

  Crotti, Chiara ^a   Agape, Elena ^a,b   Becciolini, Andrea ^a   Biggioggero, Martina ^a   Favalli, Ennio Giulio ^a  

^a ASST G Pini CTO   (Italy)

^b UNIVERSITY OF MILAN   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL MARKER; GIMSILUMAB; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; LENZILUMAB; MAVRILIMUMAB; NAMILUMAB; OTILIMAB;

DRUG EFFICACY; DRUG SAFETY; HUMAN; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; RHEUMATOID ARTHRITIS; RHEUMATOLOGY; SIGNAL TRANSDUCTION; TREATMENT RESPONSE;

ARTHRITIS, RHEUMATOID; GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR; HUMANS;

EID: 85071737639     PISSN: 00126667     EISSN: 11791950     Source Type: Journal    
DOI: 10.1007/s40265-019-01192-z     Document Type: Review

References (107)

1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19.
2. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358(9285):903–11.
3. Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002;4(Suppl 3):S265–72.
4. Lefevre S, Knedla A, Tennie C, Kampmann A, Wunrau C, Dinser R, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med. 2009;15(12):1414–20.
5. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheumatol. 2008;59(12):1690–7.
6. Firestein GS. The disease formerly known as rheumatoid arthritis. Arthritis Res Ther. 2014;16(3):114.
7. Holmqvist M, Ljung L, Askling J. Mortality following new-onset rheumatoid arthritis: has modern rheumatology had an impact? Ann Rheum Dis. 2018;77(1):85–91.
8. Osta B, Benedetti G, Miossec P. Classical and paradoxical effects of TNF-alpha on bone homeostasis. Front Immunol. 2014;5:48.
9. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376(9746):1094–108.
10. Smolen JS, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960–77.
11. Singh JA, Saag KG, Bridges SL, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68(1):1–26.
12. Favalli EG, Biggioggero M, Meroni PL. Methotrexate for the treatment of rheumatoid arthritis in the biologic era: still an “anchor” drug? Autoimmun Rev. 2014;13(11):1102–8.
13. Chighizola CB, Favalli EG, Meroni PL. Novel mechanisms of action of the biologicals in rheumatic diseases. Clin Rev Allergy Immunol. 2014;47(1):6–16.
14. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;17(1):78.
15. Favalli EG, Pregnolato F, Biggioggero M, Becciolini A, Penatti AE, Marchesoni A, et al. Twelve-year retention rate of first-line tumor necrosis factor inhibitors in rheumatoid arthritis: real-life data from a local registry. Arthritis Care Res (Hoboken). 2016;68(4):432–9.
16. Iannone F, Ferraccioli G, Sinigaglia L, Favalli EG, Sarzi-Puttini P, Atzeni F, et al. Real-world experience of tocilizumab in rheumatoid arthritis: sub-analysis of data from the Italian biologics’ register GISEA. Clin Rheumatol. 2018;37(2):315–21.
17. Favalli EG, Biggioggero M, Marchesoni A, Meroni PL. Survival on treatment with second-line biologic therapy: a cohort study comparing cycling and swap strategies. Rheumatology (Oxford). 2014;53(9):1664–8.
18. Iannone F, Sinigaglia L, Favalli EG, Sarzi-Puttini P, Atzeni F, Caporali R, et al. Drug survival of adalimumab in patients with rheumatoid arthritis over 10 years in the real-world settings: high rate remission together with normal function ability. Clin Rheumatol. 2016;35(11):2649–56.
19. Biggioggero M, Favalli EG. Ten-year drug survival of anti-TNF agents in the treatment of inflammatory arthritides. Drug Dev Res. 2014;75(Suppl 1):S38–41.
20. Sarzi-Puttini P, Antivalle M, Marchesoni A, Favalli EG, Gorla R, Filippini M, et al. Efficacy and safety of anti-TNF agents in the Lombardy rheumatoid arthritis network (LORHEN). Reumatismo. 2008;60(4):290–5.
21. de Hair MJH, Jacobs JWG, Schoneveld JLM, van Laar JM. Difficult-to-treat rheumatoid arthritis: an area of unmet clinical need. Rheumatology (Oxford). 2017. 10.1093/rheumatology/kex349.
22. Conigliaro P, Triggianese P, De Martino E, Fonti GL, Chimenti MS, Sunzini F, et al. Challenges in the treatment of rheumatoid arthritis. Autoimmun Rev. 2019;18(7):706–13.
23. Cantini F, Niccoli L, Nannini C, Cassarà E, Kaloudi O, Giulio Favalli E, et al. Tailored first-line biologic therapy in patients with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis. Semin Arthritis Rheum. 2016;45(5):519–32.
24. Favalli EG, Raimondo MG, Becciolini A, Crotti C, Biggioggero M, Caporali R. The management of first-line biologic therapy failures in rheumatoid arthritis: Current practice and future perspectives. Autoimmun Rev. 2017;16(12):1185–95.
25. Todoerti M, Favalli EG, Iannone F, Olivieri I, Benucci M, Cauli A, et al. Switch or swap strategy in rheumatoid arthritis patients failing TNF inhibitors? Results of a modified Italian Expert Consensus. Rheumatology (Oxford). 2018;57(57 Suppl 7):vii42–53.
26. Cantini F, Niccoli L, Nannini C, Cassarà E, Kaloudi O, Giulio Favalli E, et al. Second-line biologic therapy optimization in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Semin Arthritis Rheum. 2017;47(2):183–92.
27. Selmi C, Kon E, De Santis M, Favalli EG, Cimaz R, Generali E, et al. How advances in personalized medicine will change rheumatology. Per Med. 2018;15(2):75–8.
28. Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. 2008;8(7):533–44.
29. 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):554–9.
30. Dougan M, Dranoff G, Dougan SK. GM-CSF, IL-3, and IL-5 family of cytokines: regulators of inflammation. Immunity. 2019;50(4):796–811.
31. Shiomi A, Usui T. Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediat Inflamm. 2015;2015:568543.
32. Wicks IP, Roberts AW. Targeting GM-CSF in inflammatory diseases. Nat Rev Rheumatol. 2016;12(1):37–48.
33. Crotti C, Raimondo MG, Becciolini A, Biggioggero M, Favalli EG. Spotlight on mavrilimumab for the treatment of rheumatoid arthritis: evidence to date. Drug Des Dev Ther. 2017;11:211–23.
34. Metcalf D. The colony-stimulating factors and cancer. Cancer Immunol Res. 2013;1(6):351–6.
35. Hamilton JA, Achuthan A. Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol. 2013;34(2):81–9.
36. Shibata Y, Berclaz PY, Chroneos ZC, Yoshida M, Whitsett JA, Trapnell BC. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity. 2001;15(4):557–67.
37. Berclaz PY, Shibata Y, Whitsett JA, Trapnell BC. GM-CSF, via PU.1, regulates alveolar macrophage Fcgamma R-mediated phagocytosis and the IL-18/IFN-gamma -mediated molecular connection between innate and adaptive immunity in the lung. Blood. 2002;100(12):4193–200.
38. Bezbradica JS, Gordy LE, Stanic AK, Dragovic S, Hill T, Hawiger J, et al. Granulocyte-macrophage colony-stimulating factor regulates effector differentiation of invariant natural killer T cells during thymic ontogeny. Immunity. 2006;25(3):487–97.
39. Williamson DJ, Begley CG, Vadas MA, Metcalf D. The detection and initial characterization of colony-stimulating factors in synovial fluid. Clin Exp Immunol. 1988;72(1):67–73.
40. Lukens JR, Barr MJ, Chaplin DD, Chi H, Kanneganti TD. Inflammasome-derived IL-1beta regulates the production of GM-CSF by CD4(+) T cells and gammadelta T cells. J Immunol. 2012;188(7):3107–15.
41. El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, et al. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol. 2011;12(6):568–75.
42. Gasson JC. Molecular physiology of granulocyte-macrophage colony-stimulating factor. Blood. 1991;77(6):1131–45.
43. Jansen JH, Wientjens GJ, Fibbe WE, Willemze R, Kluin-Nelemans HC. Inhibition of human macrophage colony formation by interleukin 4. J Exp Med. 1989;170(2):577–82.
44. Ozawa H, Aiba S, Nakagawa S, Tagami H. Interferon-gamma and interleukin-10 inhibit antigen presentation by Langerhans cells for T helper type 1 cells by suppressing their CD80 (B7-1) expression. Eur J Immunol. 1996;26(3):648–52.
45. Sagawa K, Mochizuki M, Sugita S, Nagai K, Sudo T, Itoh K. Suppression by IL-10 and IL-4 of cytokine production induced by two-way autologous mixed lymphocyte reaction. Cytokine. 1996;8(6):501–6.
46. Fleetwood AJ, Lawrence T, Hamilton JA, Cook AD. Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J Immunol. 2007;178(8):5245–52.
47. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–55.
48. Parajuli B, Sonobe Y, Kawanokuchi J, Doi Y, Noda M, Takeuchi H, et al. GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia. J Neuroinflammation. 2012;9:268.
49. Zhan Y, Vega-Ramos J, Carrington EM, Villadangos JA, Lew AM, Xu Y. The inflammatory cytokine, GM-CSF, alters the developmental outcome of murine dendritic cells. Eur J Immunol. 2012;42(11):2889–900.
50. Lari R, Fleetwood AJ, Kitchener PD, Cook AD, Pavasovic D, Hertzog PJ, et al. Macrophage lineage phenotypes and osteoclastogenesis—complexity in the control by GM-CSF and TGF-beta. Bone. 2007;40(2):323–36.
51. Avci AB, Feist E, Burmester GR. Targeting GM-CSF in rheumatoid arthritis. Clin Exp Rheumatol. 2016;34(4 Suppl 98):39–44.
52. Ryan PC, Sleeman MA, Rebelatto M, Wang B, Lu H, Chen X, et al. Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: relevance for human safety. Toxicol Appl Pharmacol. 2014;279(2):230–9.
53. Trapnell BC, Carey BC, Uchida K, Suzuki T. Pulmonary alveolar proteinosis, a primary immunodeficiency of impaired GM-CSF stimulation of macrophages. Curr Opin Immunol. 2009;21(5):514–21.
54. Stanley E, Lieschke GJ, Grail D, Metcalf D, Hodgson G, Gall JA, et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci USA. 1994;91(12):5592–6.
55. Fleetwood AJ, Cook AD, Hamilton JA. Functions of granulocyte–macrophage colony-stimulating factor. Crit Rev Immunol. 2005;25(5):405–28.
56. Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M, Powell J, et al. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell. 2008;134(3):496–507.
57. Jenkins BJ, Blake TJ, Gonda TJ. Saturation mutagenesis of the beta subunit of the human granulocyte-macrophage colony-stimulating factor receptor shows clustering of constitutive mutations, activation of ERK MAP kinase and STAT pathways, and differential beta subunit tyrosine phosphorylation. Blood. 1998;92(6):1989–2002.
58. Sato N, Sakamaki K, Terada N, Arai K, Miyajima A. Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling. EMBO J. 1993;12(11):4181–9.
59. Broughton SE, Nero TL, Dhagat U, Kan WL, Hercus TR, Tvorogov D, et al. The betac receptor family—structural insights and their functional implications. Cytokine. 2015;74(2):247–58.
60. Hercus TR, Dhagat U, Kan WL, Broughton SE, Nero TL, Perugini M, et al. Signalling by the betac family of cytokines. Cytokine Growth Factor Rev. 2013;24(3):189–201.
61. Mulherin D, Fitzgerald O, Bresnihan B. Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheumatol. 1996;39(1):115–24.
62. Farahat MN, Yanni G, Poston R, Panayi GS. Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis. Ann Rheum Dis. 1993;52(12):870–5.
63. Bell AL, Magill MK, McKane WR, Kirk F, Irvine AE. Measurement of colony-stimulating factors in synovial fluid: potential clinical value. Rheumatol Int. 1995;14(5):177–82.
64. Berenbaum F, Rajzbaum G, Amor B, Toubert A. Evidence for GM-CSF receptor expression in synovial tissue. An analysis by semi-quantitative polymerase chain reaction on rheumatoid arthritis and osteoarthritis synovial biopsies. Eur Cytokine Netw. 1994;5(1):43–6.
65. Wright HL, Bucknall RC, Moots RJ, Edwards SW. Analysis of SF and plasma cytokines provides insights into the mechanisms of inflammatory arthritis and may predict response to therapy. Rheumatology (Oxford). 2012;51(3):451–9.
66. Greven DE, Cohen ES, Gerlag DM, Campbell J, Woods J, Davis N, et al. Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis. Ann Rheum Dis. 2015;74(10):1924–30.
67. Leizer T, Cebon J, Layton JE, Hamilton JA. Cytokine regulation of colony-stimulating factor production in cultured human synovial fibroblasts: I. Induction of GM-CSF and G-CSF production by interleukin-1 and tumor necrosis factor. Blood. 1990;76(10):1989–96.
68. Campbell IK, Novak U, Cebon J, Layton JE, Hamilton JA. Human articular cartilage and chondrocytes produce hemopoietic colony-stimulating factors in culture in response to IL-1. J Immunol. 1991;147(4):1238–46.
69. Hirota K, Hashimoto M, Ito Y, Matsuura M, Ito H, Tanaka M, et al. Autoimmune Th17 cells induced synovial stromal and innate lymphoid cell secretion of the cytokine GM-CSF to initiate and augment autoimmune arthritis. Immunity. 2018;48(6):1220–32.e5.
70. Makris A, Adamidi S, Koutsianas C, Tsalapaki C, Hadziyannis E, Vassilopoulos D. Increased frequency of peripheral B and T cells expressing granulocyte monocyte colony-stimulating factor in rheumatoid arthritis patients. Front Immunol. 2017;8:1967.
71. Campbell IK, Bendele A, Smith DA, Hamilton JA. Granulocyte-macrophage colony stimulating factor exacerbates collagen induced arthritis in mice. Ann Rheum Dis. 1997;56(6):364–8.
72. de Vries EG, Willemse PH, Biesma B, Stern AC, Limburg PC, Vellenga E. Flare-up of rheumatoid arthritis during GM-CSF treatment after chemotherapy. Lancet. 1991;338(8765):517–8.
73. Hazenberg BP, Van Leeuwen MA, Van Rijswijk MH, Stern AC, Vellenga E. Correction of granulocytopenia in Felty’s syndrome by granulocyte-macrophage colony-stimulating factor. Simultaneous induction of interleukin-6 release and flare-up of the arthritis. Blood. 1989;74(8):2769–70.
74. Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, et al. RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011;12(6):560–7.
75. Donatien P, Anand U, Yiangou Y, Sinisi M, Fox M, MacQuillan A, et al. Granulocyte-macrophage colony-stimulating factor receptor expression in clinical pain disorder tissues and role in neuronal sensitization. Pain Rep. 2018;3(5):e676.
76. Bali KK, Venkataramani V, Satagopam VP, Gupta P, Schneider R, Kuner R. Transcriptional mechanisms underlying sensitization of peripheral sensory neurons by granulocyte-/granulocyte-macrophage colony stimulating factors. Mol Pain. 2013;9:48.
77. Stösser S, Schweizerhof M, Kuner R. Hematopoietic colony-stimulating factors: new players in tumor–nerve interactions. J Mol Med (Berl). 2011;89(4):321–9.
78. Malipiero UV, Frei K, Fontana A. Production of hemopoietic colony-stimulating factors by astrocytes. J Immunol. 1990;144(10):3816–21.
79. McLay RN, Kimura M, Banks WA, Kastin AJ. Granulocyte-macrophage colony-stimulating factor crosses the blood–brain and blood–spinal cord barriers. Brain. 1997;120(Pt 11):2083–91.
80. Cook AD, Louis C, Robinson MJ, Saleh R, Sleeman MA, Hamilton JA. Granulocyte macrophage colony-stimulating factor receptor alpha expression and its targeting in antigen-induced arthritis and inflammation. Arthritis Res Ther. 2016;18(1):287.
81. Nair JR, Edwards SW, Moots RJ. Mavrilimumab, a human monoclonal GM-CSF receptor-α antibody for the management of rheumatoid arthritis: a novel approach to therapy. Expert Opin Biol Ther. 2012;12(12):1661–8.
82. Burmester GR, Feist E, Sleeman MA, Wang B, White B, Magrini F. 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(9):1542–9.
83. Burmester GR, Weinblatt ME, McInnes IB, Porter D, Barbarash O, Vatutin M, et al. Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis. Ann Rheum Dis. 2013;72(9):1445–52.
84. Takeuchi T, Tanaka Y, Close D, Godwood A, Wu CY, Saurigny D. Efficacy and safety of mavrilimumab in Japanese subjects with rheumatoid arthritis: findings from a Phase IIa study. Mod Rheumatol. 2015;25(1):21–30.
85. Burmester GR, McInnes IB, Kremer J, Miranda P, Korkosz M, Vencovsky J, et al. A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2017;76(6):1020–30.
86. Weinblatt ME, McInnes IB, Kremer JM, Miranda P, Vencovsky J, Guo X, et al. A randomized phase IIb study of mavrilimumab and golimumab in rheumatoid arthritis. Arthritis Rheumatol. 2018;70(1):49–59.
87. Burmester GR, McInnes IB, Kremer JM, Miranda P, Vencovský J, Godwood A, et al. Mavrilimumab, a fully human granulocyte-macrophage colony-stimulating factor receptor α monoclonal antibody: long-term safety and efficacy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2018;70(5):679–89.
88. Strand V, Ahadieh S, French J, Geier J, Krishnaswami S, Menon S, et al. Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther. 2015;17:362.
89. Lacaille D, Guh DP, Abrahamowicz M, Anis AH, Esdaile JM. Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis. Arthritis Rheumatol. 2008;59(8):1074–81.
90. Favalli EG, Bugatti S, Biggioggero M, Caporali R. Treatment comparison in rheumatoid arthritis: head-to-head trials and innovative study designs. Biomed Res Int. 2014;2014:831603.
91. Ingegnoli F, Favalli EG, Meroni PL. Does polymorphysm of genes coding for pro-inflammatory mediators predict the clinical response to tnf alpha blocking agents? A review analysis of the literature. Autoimmun Rev. 2011;10(8):460–3.
92. Monti S, Klersy C, Gorla R, Sarzi-Puttini P, Atzeni F, Pellerito R, et al. Factors influencing the choice of first- and second-line biologic therapy for the treatment of rheumatoid arthritis: real-life data from the Italian LORHEN Registry. Clin Rheumatol. 2017;36(4):753–61.
93. Atzeni F, Bongiovanni S, Marchesoni A, Filippini M, Caporali R, Gorla R, et al. Predictors of response to anti-TNF therapy in RA patients with moderate or high DAS28 scores. Joint Bone Spine. 2014;81(1):37–40.
94. Guo X, Higgs BW, Bay-Jensen AC, Wu Y, Karsdal MA, Kuziora M, et al. Blockade of GM-CSF pathway induced sustained suppression of myeloid and T cell activities in rheumatoid arthritis. Rheumatology (Oxford). 2018;57(1):175–84.
95. Guo X, Wang S, Godwood A, Close D, Ryan PC, Roskos LK, et al. Pharmacodynamic biomarkers and differential effects of TNF- and GM-CSF-targeting biologics in rheumatoid arthritis. Int J Rheum Dis. 2019;22(4):646–53.
96. Grant E, Schwickart M, Godwood A, Moate R, Song E, Chavez C, et al. Lack of autoantibodies to peptidyl arginine deiminase 4 predict increased efficacy of mavrilimumab in rheumatoid arthritis. Arthritis Rheumatol. 2016;68(Suppl 10):1–2.
97. Mortensen JH, Guo X, De Los Reyes M, Dziegiel MH, Karsdal MA, Bay-Jensen AC, et al. The VICM biomarker is released from activated macrophages and inhibited by anti-GM-CSFRα-mAb treatment in rheumatoid arthritis patients. Clin Exp Rheumatol. 2019;37(1):73–80.
98. Kivitz A, Hazan L, Hoffman K, Wallin BA. MORAb-022, an anti-granulocyte macrophage-colony stimulating factor (GM-CSF) monoclonal antibody (MAB): results of the first study in patients with mild-to-moderate rheumatoid arthritis (RA). Ann Rheum Dis. 2016;75(Suppl 2):507.
99. Behrens F, Tak PP, Ostergaard M, Stoilov R, Wiland P, Huizinga TW, et al. MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial. Ann Rheum Dis. 2015;74(6):1058–64.
100. Genovese MC, Berkowitz M, Conaghan PG, Davy K, Inman D, Fisheleva E, et al. A Phase IIa mechanistic study of anti-GM-CSF (GSK3196165) with methotrexate treatment in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate [abstract]. Arthritis Rheumatol. 2018;70(Suppl):10.
101. Buckley C, Simon Campos JA, Yakushin S, Zhdan V, Davy K, Inman D, et al. A phase IIb dose-ranging study of anti-GM-CSF with methotrexate treatment in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate [abstract]. Arthritis Rheumatol. 2018;70(Suppl):10.
102. Chris B, Simon CJ, Vyacheslav Z, Brandon B, Deven C, Katherine D, et al. GSK3196165 an investigational anti-GM-CSF monoclonal antibody, improves patient reported outcomes in a phase IIb study of patients with rheumatoid arthritis (RA). Ann Rheum Dis. 2019;78(Suppl 2):A191.
103. Huizinga TW, Batalov A, Stoilov R, Lloyd E, Wagner T, Saurigny D, et al. Phase 1b randomized, double-blind study of namilumab, an anti-granulocyte macrophage colony-stimulating factor monoclonal antibody, in mild-to-moderate rheumatoid arthritis. Arthritis Res Ther. 2017;19(1):53.
104. Taylor PC, Saurigny D, Vencovsky J, Takeuchi T, Nakamura T, Matsievskaia G, et al. Efficacy and safety of namilumab, a human monoclonal antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) ligand in patients with rheumatoid arthritis (RA) with either an inadequate response to background methotrexate therapy or an inadequate response or intolerance to an anti-TNF (tumour necrosis factor) biologic therapy: a randomized, controlled trial. Arthritis Res Ther. 2019;21(1):101.
105. Cook AD, Pobjoy J, Steidl S, Durr M, Braine EL, Turner AL, et al. Granulocyte-macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development. Arthritis Res Ther. 2012;14(5):R199.
106. Schett G, Bainbridge C, Berkowitz M, Davy K, Fernandes S, Griep E, et al. A phase IIa study of anti-GM-CSF antibody GSK3196165 in subjects with inflammatory hand osteoarthritis [abstract]. Arthritis Rheumatol. 2018;70(Suppl):10.
107. Higashioka K, Ota Y, Nakayama T, Mishima K, Ayano M, Kimoto Y, et al. GM-CSF-producing B cells: a novel B cell subset involved in the pathogenesis of systemic sclerosis [abstract]. Arthritis Rheumatol. 2017;69(Suppl):10.