• 1
    Kinne RW, Stuhlmuller B, Burmester GR. Cells of the synovium in rheumatoid arthritis: macrophages. Arthritis Res Ther 2007; 9: 224.
  • 2
    Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008; 117: 24479.
  • 3
    Franz JK, Burmester GR. The needle and the damage done. Ann Rheum Dis 2005; 64: 798800.
  • 4
    Smeets TJ, Kraan MC, Galjaard S, Youssef PP, Smith MD, Tak PP. Analysis of the cell infiltrate and expression of matrix metalloproteinases and granzyme B in paired synovial biopsy specimens from the cartilage-pannus junction in patients with RA. Ann Rheum Dis 2001; 60: 5615.
  • 5
    Barrera P, Blom A, van Lent PL, van Bloois L, Beijnen JH, van Rooijen N, et al. Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis. Arthritis Rheum 2000; 43: 19519.
  • 6
    Kashiwagi N, Nakano M, Saniabadi AR, Adachi M, Yoshikawa T. Anti-inflammatory effect of granulocyte and monocyte adsorption apheresis in a rabbit model of immune arthritis. Inflammation 2002; 26: 199205.
  • 7
    Mulherin D, FitzGerald O, Bresnihan B. Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum 1996; 39: 11524.
  • 8
    Tak PP, Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis [review]. Arthritis Rheum 2000; 43: 261933.
  • 9
    Tak PP, Smeets TJ, Daha MR, Kluin PM, Meijers KA, Brand R, et al. Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 1997; 40: 21725.
  • 10
    Singh JA, Pando JA, Tomaszewski J, Schumacher HR. Quantitative analysis of immunohistologic features of very early rheumatoid synovitis in disease modifying antirheumatic drug- and corticosteroid-naive patients. J Rheumatol 2004; 31: 12815.
  • 11
    Gerlag DM, Tak PP. Novel approaches for the treatment of rheumatoid arthritis: lessons from the evaluation of synovial biomarkers in clinical trials. Best Pract Res Clin Rheumatol 2008; 22: 31123.
  • 12
    De Groot J, Te Koppele JM, Harris ED Jr, Tak PP. Biological markers. In: HarrisEDJr, BuddRC, FiresteinGS, GenoveseMC, SegentJS, RuddyS, editors. Kelley's textbook of rheumatology. Philadelphia: W.B. Saunders; 2004. p. 72838.
  • 13
    Gerlag DM, Haringman JJ, Smeets TJ, Zwinderman AH, Kraan MC, Laud PJ, et al. Effects of oral prednisolone on biomarkers in synovial tissue and clinical improvement in rheumatoid arthritis. Arthritis Rheum 2004; 50: 378391.
  • 14
    Van der Heijde DM, van't Hof MA, van Riel PL, Theunisse LM, Lubberts EW, van Leeuwen MA, et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis 1990; 49: 91620.
  • 15
    Haringman JJ, Gerlag DM, Zwinderman AH, Smeets TJ, Kraan MC, Baeten D, et al. Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005; 64: 8348.
  • 16
    Wijbrandts CA, Vergunst CE, Haringman JJ, Gerlag DM, Smeets TJ, Tak PP. Absence of changes in the number of synovial sublining macrophages after ineffective treatment for rheumatoid arthritis: implications for use of synovial sublining macrophages as a biomarker. Arthritis Rheum 2007; 56: 386971.
  • 17
    Wijbrandts CA, Dijkgraaf MG, Kraan MC, Vinkenoog M, Smeets TJ, Dinant H, et al. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pre-treatment TNFα expression in the synovium. Ann Rheum Dis 2008; 67: 113944.
  • 18
    Jahangier ZN, Jacobs JW, Kraan MC, Wenting MJ, Smeets TJ, Bijlsma JW, et al. Pretreatment macrophage infiltration of the synovium predicts the clinical effect of both radiation synovectomy and intra-articular glucocorticoids. Ann Rheum Dis 2006; 65: 128692.
  • 19
    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: 54955.
  • 20
    Vergunst CE, van de Sande MG, Lebre MC, Tak PP. The role of chemokines in rheumatoid arthritis and osteoarthritis. Scand J Rheumatol 2005; 34: 41525.
  • 21
    Polzer K, Baeten D, Soleiman A, Distler J, Gerlag DM, Tak PP, et al. TNF blockade increases lymphangiogenesis in murine and human arthritic joints. Ann Rheum Dis 2008; 67: 161061.
  • 22
    Pope RM. Apoptosis as a therapeutic tool in rheumatoid arthritis. Nat Rev Immunol 2002; 2: 52735.
  • 23
    Jutila MA, Banks KL. Locally dividing macrophages in normal and inflamed mammary glands. Clin Exp Immunol 1986; 66: 61524.
  • 24
    Ceponis A, Konttinen YT, Imai S, Tamulaitiene M, Li TF, Xu JW, et al. Synovial lining, endothelial and inflammatory mononuclear cell proliferation in synovial membranes in psoriatic and reactive arthritis: a comparative quantitative morphometric study. Br J Rheumatol 1998; 37: 1708.
  • 25
    Liva SM, Kahn MA, Dopp JM, de Vellis J. Signal transduction pathways induced by GM-CSF in microglia: significance in the control of proliferation. Glia 1999; 26: 34452.
  • 26
    Rekhter MD, Gordon D. Active proliferation of different cell types, including lymphocytes, in human atherosclerotic plaques. Am J Pathol 1995; 147: 66877.
  • 27
    Kerjaschki D. The crucial role of macrophages in lymphangiogenesis. J Clin Invest 2005; 115: 23169.
  • 28
    Tak PP, Firestein GS. Apoptosis in rheumatoid arthritis. In: WinklerJD, editor. Apoptosis and inflammation (Progress in inflammation research). Basel, Switzerland: Birkhauser Publishing Ltd; 1999. p. 14962.
  • 29
    Lalor PA, Mapp PI, Hall PA, Revell PA. Proliferative activity of cells in the synovium as demonstrated by a monoclonal antibody, Ki67. Rheumatol Int 1987; 7: 1836.
  • 30
    Berger I, Weckauf H, Helmchen B, Ehemann V, Penzel R, Fink B, et al. Rheumatoid arthritis and pigmented villonodular synovitis: comparative analysis of cell polyploidy, cell cycle phases and expression of macrophage and fibroblast markers in proliferating synovial cells. Histopathology 2005; 46: 4907.
  • 31
    Schulze-Koops H, Davis LS, Kavanaugh AF, Lipsky PE. Elevated cytokine messenger RNA levels in the peripheral blood of patients with rheumatoid arthritis suggest different degrees of myeloid cell activation. Arthritis Rheum 1997; 40: 63947.
  • 32
    Olsen N, Sokka T, Seehorn CL, Kraft B, Maas K, Moore J, et al. A gene expression signature for recent onset rheumatoid arthritis in peripheral blood mononuclear cells. Ann Rheum Dis 2004; 63: 138792.
  • 33
    Bovin LF, Rieneck K, Workman C, Nielsen H, Sorensen SF, Skjodt H, et al. Blood cell gene expression profiling in rheumatoid arthritis: discriminative genes and effect of rheumatoid factor. Immunol Lett 2004; 93: 21726.
  • 34
    Stuhlmuller B, Ungethum U, Scholze S, Martinez L, Backhaus M, Kraetsch HG, et al. Identification of known and novel genes in activated monocytes from patients with rheumatoid arthritis. Arthritis Rheum 2000; 43: 77590.
  • 35
    Van Furth R, Cohn ZA. The origin and kinetics of mononuclear phagocytes. J Exp Med 1968; 128: 41535.
  • 36
    Vassalli JD, Hamilton J, Reich E. Macrophage plasminogen activator: modulation of enzyme production by anti-inflammatory steroids, mitotic inhibitors, and cyclic nucleotides. Cell 1976; 8: 27181.
  • 37
    Kraan MC, Reece RJ, Smeets TJ, Veale DJ, Emery P, Tak PP. Comparison of synovial tissues from the knee joints and the small joints of rheumatoid arthritis patients: implications for pathogenesis and evaluation of treatment. Arthritis Rheum 2002; 46: 20348.
  • 38
    Henderson B, Revell PA, Edwards JC. Synovial lining cell hyperplasia in rheumatoid arthritis: dogma and fact. Ann Rheum Dis 1988; 47: 3489.
  • 39
    Nasir K, Guallar E, Navas-Acien A, Criqui MH, Lima JA. Relationship of monocyte count and peripheral arterial disease: results from the National Health and Nutrition Examination Survey 1999-2002. Arterioscler Thromb Vasc Biol 2005; 25: 196671.
  • 40
    BaumJ, ZiffM, editors. Arthritis and allied conditions: a textbook of rheumatology. Philadelphia: Lea & Febringer; 1985.
  • 41
    Seitz M, Deimann W, Gram N, Hunstein W, Gemsa D. Characterization of blood mononuclear cells of rheumatoid arthritis patients. I. Depressed lymphocyte proliferation and enhanced prostanoid release from monocytes. Clin Immunol Immunopathol 1982; 25: 40516.
  • 42
    Buchan GS, Palmer DG, Gibbins BL. The response of human peripheral blood mononuclear phagocytes to rheumatoid arthritis. J Leukoc Biol 1985; 37: 22130.
  • 43
    Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003; 19: 7182.
  • 44
    Ziegler-Heitbrock L. The CD14+ CD16+ blood monocytes: their role in infection and inflammation. J Leukoc Biol 2007; 81: 19.
  • 45
    Geissmann F, Auffray C, Palframan R, Wirrig C, Ciocca A, Campisi L, et al. Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses. Immunol Cell Biol 2008; 86: 398408.
  • 46
    Kawanaka N, Yamamura M, Aita T, Morita Y, Okamoto A, Kawashima M, et al. CD14+,CD16+ blood monocytes and joint inflammation in rheumatoid arthritis. Arthritis Rheum 2002; 46: 257886.
  • 47
    Cairns AP, Crockard AD, Bell AL. The CD14+ CD16+ monocyte subset in rheumatoid arthritis and systemic lupus erythematosus. Rheumatol Int 2002; 21: 18992.
  • 48
    Ochi T, Hakomori S, Adachi M, Owaki H, Okamura M, Ono Y, et al. The presence of a myeloid cell population showing strong reactivity with monoclonal antibody directed to difucosyl type 2 chain in epiphyseal bone marrow adjacent to joints affected with rheumatoid arthritis (RA) and its absence in the corresponding normal and non-RA bone marrow. J Rheumatol 1988; 15: 160915.
  • 49
    Tomita T, Kashiwagi N, Shimaoka Y, Ikawa T, Tanabe M, Nakagawa S, et al. Phenotypic characteristics of bone marrow cells in patients with rheumatoid arthritis. J Rheumatol 1994; 21: 160814.
  • 50
    Hirohata S, Miura Y, Tomita T, Yoshikawa H, Ochi T, Chiorazzi N. Enhanced expression of mRNA for nuclear factor κB1 (p50) in CD34+ cells of the bone marrow in rheumatoid arthritis. Arthritis Res Ther 2006; 8: R54.
  • 51
    Dreher R, Robe-Oltmanns B, Fink K, Seidel H. Pathogenesis and therapy of rheumatoid inflammation. Immun Infekt 1986; 14: 1008. In German.
  • 52
    Seitz M, Zwicker M, Pichler W, Gerber N. Activation and differentiation of myelomonocytic cells in rheumatoid arthritis and healthy individuals: evidence for antagonistic in vitro regulation by interferon-γ and tumor necrosis factor α, granulocyte monocyte colony stimulating factor and interleukin 1. J Rheumatol 1992; 19: 103844.
  • 53
    Owaki H, Ochi T, Yamasaki K, Yukawa K, Wakitani S, Okamura M, et al. Elevated activity of myeloid growth factor in bone marrow adjacent to joints affected by rheumatoid arthritis. J Rheumatol 1989; 16: 5727.
  • 54
    Kotake S, Higaki M, Sato K, Himeno S, Morita H, Kim KJ, et al. Detection of myeloid precursors (granulocyte/macrophage colony forming units) in the bone marrow adjacent to rheumatoid arthritis joints. J Rheumatol 1992; 19: 15116.
  • 55
    Colmegna I, Diaz-Borjon A, Fujii H, Schaefer L, Goronzy JJ, Weyand CM. Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis. Arthritis Rheum 2008; 58: 9901000.
  • 56
    Muller M, Emmendorffer A, Lohmann-Matthes ML. Expansion and high proliferative potential of the macrophage system throughout life time of lupus-prone NZB/W and MRL lpr/lpr mice: lack of down-regulation of extramedullar macrophage proliferation in the postnatal period. Eur J Immunol 1991; 21: 22117.
  • 57
    Vieten G, Hadam MR, De Boer H, Olp A, Fricke M, Hartung K. Expanded macrophage precursor populations in BXSB mice: possible reason for the increasing monocytosis in male mice. Clin Immunol Immunopathol 1992; 65: 2128.
  • 58
    Hayashida K, Ochi T, Fujimoto M, Owaki H, Shimaoka Y, Ono K, et al. Bone marrow changes in adjuvant-induced and collagen-induced arthritis: interleukin-1 and interleukin-6 activity and abnormal myelopoiesis. Arthritis Rheum 1992; 35: 2415.
  • 59
    Kikuchi S, Santiago-Raber ML, Amano H, Amano E, Fossati-Jimack L, Moll T, et al. Contribution of NZB autoimmunity 2 to Y-linked autoimmune acceleration-induced monocytosis in association with murine systemic lupus. J Immunol 2006; 176: 32407.
  • 60
    Ikehara S, Kawamura M, Takao F, Inaba M, Yasumizu R, Than S, et al. Organ-specific and systemic autoimmune diseases originate from defects in hematopoietic stem cells. Proc Natl Acad Sci U S A 1990; 87: 83414.
  • 61
    Brooks PM, Atkinson K, Hamilton JA. Stem cell transplantation in autoimmune disease. J Rheumatol 1995; 22: 180911.
  • 62
    Davis TA, Lennon G. Mice with a regenerative wound healing capacity and an SLE autoimmune phenotype contain elevated numbers of circulating and marrow-derived macrophage progenitor cells. Blood Cells Mol Dis 2005; 34: 1725.
  • 63
    Papadaki HA, Marsh JC, Eliopoulos GD. Bone marrow stem cells and stromal cells in autoimmune cytopenias. Leuk Lymphoma 2002; 43: 75360.
  • 64
    Weyand CM, Goronzy JJ. Stem cell aging and autoimmunity in rheumatoid arthritis. Trends Mol Med 2004; 10: 42633.
  • 65
    Van Laar JM, Tyndall A. Adult stem cells in the treatment of autoimmune diseases. Rheumatology (Oxford) 2006; 45: 118793.
  • 66
    McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007; 7: 42942.
  • 67
    Bresnihan B, Gerlag DM, Rooney T, Smeets TJ, Wijbrandts CA, Boyle D, et al. Synovial macrophages as a biomarker of response to therapeutic intervention in rheumatoid arthritis: standardization and consistency across centers. J Rheumatol 2007; 34: 6202.
  • 68
    Tak PP, Taylor PC, Breedveld FC, Smeets TJ, Daha MR, Kluin PM, et al. Decrease in cellularity and expression of adhesion molecules by anti–tumor necrosis factor α monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 1996; 39: 107781.
  • 69
    Paleolog EM, Hunt M, Elliott MJ, Feldmann M, Maini RN, Woody JN. Deactivation of vascular endothelium by monoclonal anti–tumor necrosis factor α antibody in rheumatoid arthritis. Arthritis Rheum 1996; 39: 108291.
  • 70
    Taylor PC, Peters AM, Paleolog E, Chapman PT, Elliott MJ, McCloskey R, et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor α blockade in patients with rheumatoid arthritis. Arthritis Rheum 2000; 43: 3847.
  • 71
    Mangan DF, Welch GR, Wahl SM. Lipopolysaccharide, tumor necrosis factor-α, and IL-1 β prevent programmed cell death (apoptosis) in human peripheral blood monocytes. J Immunol 1991; 146: 15416.
  • 72
    Lombardo E, Alvarez-Barrientos A, Maroto B, Bosca L, Knaus UG. TLR4-mediated survival of macrophages is MyD88 dependent and requires TNF-α autocrine signalling. J Immunol 2007; 178: 37319.
  • 73
    Smeets TJ, Kraan MC, van Loon ME, Tak PP. Tumor necrosis factor α blockade reduces the synovial cell infiltrate early after initiation of treatment, but apparently not by induction of apoptosis in synovial tissue. Arthritis Rheum 2003; 48: 215562.
  • 74
    Catrina AI, Trollmo C, af Klint E, Engstrom M, Lampa J, Hermansson Y, et al. Evidence that anti-tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: extended report. Arthritis Rheum 2005; 52: 6172.
  • 75
    Wijbrandts CA, Remans PH, Klarenbeek PL, Wouters D, van den Bergh Weerman MA, Smeets TJ, et al. Analysis of apoptosis in peripheral blood and synovial tissue very early after initiation of infliximab treatment in rheumatoid arthritis patients. Arthritis Rheum 2008; 58: 33309.
  • 76
    Jaworowski A, Wilson NJ, Christy E, Byrne R, Hamilton JA. Roles of the mitogen-activated protein kinase family in macrophage responses to colony stimulating factor-1 addition and withdrawal. J Biol Chem 1999; 274: 1512733.
  • 77
    Henson PM, Hume DA. Apoptotic cell removal in development and tissue homeostasis. Trends Immunol 2006; 27: 24450.
  • 78
    Ritchlin CT, Haas-Smith SA, Li P, Hicks DG, Schwarz EM. Mechanisms of TNF-α- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 2003; 111: 82131.
  • 79
    Gengenbacher M, Sebald HJ, Villiger PM, Hofstetter W, Seitz M. Infliximab inhibits bone resorption by circulating osteoclast precursor cells in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 2008; 67: 6204.
  • 80
    Lorenz HM, Antoni C, Valerius T, Repp R, Grunke M, Schwerdtner N, et al. In vivo blockade of TNF-α by intravenous infusion of a chimeric monoclonal TNF-α antibody in patients with rheumatoid arthritis: short term cellular and molecular effects. J Immunol 1996; 156: 164653.
  • 81
    Lugering A, Schmidt M, Lugering N, Pauels HG, Domschke W, Kucharzik T. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway. Gastroenterology 2001; 121: 114557.
  • 82
    Urbaschek R, Mannel DN, Urbaschek B. Tumor necrosis factor induced stimulation of granulopoiesis and radioprotection. Lymphokine Res 1987; 6: 17986.
  • 83
    Yao Z, Li P, Zhang Q, Schwarz EM, Keng P, Arbini A, et al. Tumor necrosis factor α increases circulating osteoclast precursor numbers by promoting their proliferation and differentiation in the bone marrow through up-regulation of c-Fms expression. J Biol Chem 2006; 281: 1184655.
  • 84
    Metcalf D, Nicola NA. The hemopoietic colony-stimulating factors: from biology to clinical applications. Cambridge: University Press; 1995.
  • 85
    Hamilton JA, Stanley ER, Burgess AW, Shadduck RK. Stimulation of macrophage plasminogen activator activity by colony-stimulating factors. J Cell Physiol 1980; 103: 43545.
  • 86
    Hamilton JA. Rheumatoid arthritis: opposing actions of haemopoietic growth factors and slow-acting anti-rheumatic drugs. Lancet 1993; 342: 5369.
  • 87
    Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 2008; 8: 53344.
  • 88
    Hamilton JA. GM-CSF in inflammation and autoimmunity. Trends Immunol 2002; 23: 4038.
  • 89
    Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol 2006; 18: 3948.
  • 90
    Roberts AW. G-CSF: a key regulator of neutrophil production, but that's not all! Growth Factors 2005; 23: 3341.
  • 91
    Xu WD, Firestein GS, Taetle R, Kaushansky K, Zvaifler NJ. Cytokines in chronic inflammatory arthritis. II. Granulocyte-macrophage colony-stimulating factor in rheumatoid synovial effusions. J Clin Invest 1989; 83: 87682.
  • 92
    Alvaro-Gracia JM, Zvaifler NJ, Firestein GS. Cytokines in chronic inflammatory arthritis. IV. Granulocyte/macrophage colony-stimulating factor-mediated induction of class II MHC antigen on human monocytes: a possible role in rheumatoid arthritis. J Exp Med 1989; 170: 86575.
  • 93
    Rioja I, Hughes FJ, Sharp CH, Warnock LC, Montgomery DS, Akil M, et al. Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23, transforming growth factor α, tumor necrosis factor receptor superfamily member 9, and macrophage colony-stimulating factor. Arthritis Rheum 2008; 58: 225767.
  • 94
    Cecchini MG, Dominguez MG, Mocci S, Wetterwald A, Felix R, Fleisch H, et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development 1994; 120: 135772.
  • 95
    Vogel SN, Douches SD, Kaufman EN, Neta R. Induction of colony stimulating factor in vivo by recombinant interleukin 1 α and recombinant tumor necrosis factor α 1. J Immunol 1987; 138: 21438.
  • 96
    Branch DR, Turner AR, Guilbert LJ. Synergistic stimulation of macrophage proliferation by the monokines tumor necrosis factor-α and colony-stimulating factor 1. Blood 1989; 73: 30711.
  • 97
    Stehle B, Weiss C, Ho AD, Hunstein W. Serum levels of tumor necrosis factor α in patients treated with granulocyte-macrophage colony-stimulating factor. Blood 1990; 75: 18956.
  • 98
    Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis? [editorial]. Arthritis Rheum 1990; 33: 76873.
  • 99
    Haworth C, Brennan FM, Chantry D, Turner M, Maini RN, Feldmann M. Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-α. Eur J Immunol 1991; 21: 25759.
  • 100
    Yang YH, Hamilton JA. Dependence of interleukin-1–induced arthritis on granulocyte–macrophage colony-stimulating factor. Arthritis Rheum 2001; 44: 1119.
  • 101
    Kitaura H, Zhou P, Kim HJ, Novack DV, Ross FP, Teitelbaum SL. M-CSF mediates TNF-induced inflammatory osteolysis. J Clin Invest 2005; 115: 341827.
  • 102
    Hamilton JA. A colony-stimulating factor network involving mononuclear phagocytes and other cells. In: FurthVR, editor. Haematopoietic growth factors and mononuclear phagocytes. Basel: S. Karger AG; 1993. p. 2935.
  • 103
    Campbell IK, Bendele A, Smith DA, Hamilton JA. Granulocyte-macrophage colony stimulating factor exacerbates collagen induced arthritis in mice. Ann Rheum Dis 1997; 56: 3648.
  • 104
    Bischof RJ, Zafiropoulos D, Hamilton JA, Campbell IK. Exacerbation of acute inflammatory arthritis by the colony-stimulating factors CSF-1 and granulocyte macrophage (GM)-CSF: evidence of macrophage infiltration and local proliferation. Clin Exp Immunol 2000; 119: 3617.
  • 105
    Abd AH, Savage NW, Halliday WJ, Hume DA. The role of macrophages in experimental arthritis induced by Streptococcus agalactiae sonicate: actions of macrophage colony-stimulating factor (CSF-1) and other macrophage-modulating agents. Lymphokine Cytokine Res 1991; 10: 4350.
  • 106
    Campbell IK, Rich MJ, Bischof RJ, Hamilton JA. The colony-stimulating factors and collagen-induced arthritis: exacerbation of disease by M-CSF and G-CSF and requirement for endogenous M-CSF. J Leukoc Biol 2000; 68: 14450.
  • 107
    Campbell IK, Rich MJ, Bischof RJ, Dunn AR, Grail D, Hamilton JA. Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice. J Immunol 1998; 161: 363944.
  • 108
    Cook AD, Braine EL, Campbell IK, Rich MJ, Hamilton JA. Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res 2001; 3: 2938.
  • 109
    Lawlor KE, Campbell IK, Metcalf D, O'Donnell K, van Nieuwenhuijze A, Roberts AW, et al. Critical role for granulocyte colony-stimulating factor in inflammatory arthritis. Proc Natl Acad Sci U S A 2004; 101: 11398403.
  • 110
    Kremer JM. Methotrexate and leflunomide: biochemical basis for combination therapy in the treatment of rheumatoid arthritis. Semin Arthritis Rheum 1999; 29: 1426.
  • 111
    Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 2001; 60: 72935.
  • 112
    Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007; 65: 16873.
  • 113
    Dolhain RJ, Tak PP, Dijkmans BA, De Kuiper P, Breedveld FC, Miltenburg AM. Methotrexate reduces inflammatory cell numbers, expression of monokines and of adhesion molecules in synovial tissue of patients with rheumatoid arthritis. Br J Rheumatol 1998; 37: 5028.
  • 114
    Kraan MC, Reece RJ, Barg EC, Smeets TJ, Farnell J, Rosenburg R, et al. Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis: findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers. Arthritis Rheum 2000; 43: 182030.
  • 115
    Cutolo M, Bisso A, Sulli A, Felli L, Briata M, Pizzorni C, et al. Antiproliferative and antiinflammatory effects of methotrexate on cultured differentiating myeloid monocytic cells (THP-1) but not on synovial macrophages from patients with rheumatoid arthritis. J Rheumatol 2000; 27: 25517.
  • 116
    MacKinnon SK, Starkebaum G, Willkens RF. Pancytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid arthritis. Semin Arthritis Rheum 1985; 15: 11926.
  • 117
    Chan J, Sanders DC, Du L, Pillans PI. Leflunomide-associated pancytopenia with or without methotrexate. Ann Pharmacother 2004; 38: 120611.
  • 118
    Hirshberg B, Muszkat M, Schlesinger O, Rubinow A. Safety of low dose methotrexate in elderly patients with rheumatoid arthritis. Postgrad Med J 2000; 76: 7879.
  • 119
    Lester SE, Proudman SM, Lee A, Hall CA, McWilliams L, James MJ, et al. Treatment-induced stable, moderate reduction in blood cell counts correlate with disease control in early rheumatoid arthritis. Intern Med J. In press.
  • 120
    Vernon-Roberts B, Dore JL, Jessop JD, Henderson WJ. Selective concentration and localization of gold in macrophages of synovial and other tissues during and after chrysotherapy in rheumatoid patients. Ann Rheum Dis 1976; 35: 47786.
  • 121
    Kay AG. Myelotoxicity of D-penicillamine. Ann Rheum Dis 1979; 38: 2326.
  • 122
    Hamilton JA, Williams N. Effects of auranofin and other antirheumatic drugs on human myelopoiesis in vitro. J Rheumatol 1987; 14: 21620.
  • 123
    Farr M, Tunn EJ, Symmons DP, Scott DG, Bacon PA. Sulphasalazine in rheumatoid arthritis: haematological problems and changes in haematological indices associated with therapy. Br J Rheumatol 1989; 28: 1348.
  • 124
    Howell A, Gumpel JM, Watts RW. Depression of bone marrow colony formation in gold-induced neutropenia. Br Med J 1975; 1: 43234.
  • 125
    Hamilton JA, Williams N. In vitro inhibition of myelopoiesis by gold salts and D-penicillamine. J Rheumatol 1985; 12: 8926.
  • 126
    Vernon-Roberts B. Action of gold salts on the inflammatory response and inflammatory cell function. J Rheumatol Suppl 1979; 5: 1209.
  • 127
    Thomas D, Gallus AS, Brooks PM, Tampi R, Geddes R, Hill W. Thrombokinetics in patients with rheumatoid arthritis treated with D-penicillamine. Ann Rheum Dis 1984; 43: 4026.
  • 128
    Fauci AS, Dale DC, Balow JE. Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann Intern Med 1976; 84: 30415.
  • 129
    Metcalf D. Cortisone action on serum colony-stimulating factor and bone marrow in vitro colony-forming cells. Proc Soc Exp Biol Med 1969; 132: 3914.
  • 130
    Young L, Katrib A, Cuello C, Vollmer-Conna U, Bertouch JV, Roberts-Thomson PJ, et al. Effects of intraarticular glucocorticoids on macrophage infiltration and mediators of joint damage in osteoarthritis synovial membranes: findings in a double-blind, placebo-controlled study. Arthritis Rheum 2001; 44: 34350.
  • 131
    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5: 95364.
  • 132
    Hume DA. Macrophages as APC and the dendritic cell myth. J Immunol 2008; 181: 582935.
  • 133
    Sunderkotter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets DA, et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol 2004; 172: 44107.
  • 134
    Belge KU, Dayyani F, Horelt A, Siedlar M, Frankenberger M, Frankenberger B, et al. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol 2002; 168: 353642.
  • 135
    Baeten D, Boots AM, Steenbakkers PG, Elewaut D, Bos E, Verheijden GF, et al. Human cartilage gp-39+,CD16+ monocytes in peripheral blood and synovium: correlation with joint destruction in rheumatoid arthritis. Arthritis Rheum 2000; 43: 123343.
  • 136
    Chan J, Leenen PJ, Bertoncello I, Nishikawa SI, Hamilton JA. Macrophage lineage cells in inflammation: characterization by colony-stimulating factor-1 (CSF-1) receptor (c-Fms), ER-MP58, and ER-MP20 (Ly-6C) expression. Blood 1998; 92: 142331.
  • 137
    Drevets DA, Dillon MJ, Schawang JS, Van Rooijen N, Ehrchen J, Sunderkotter C, et al. The Ly-6Chigh monocyte subpopulation transports Listeria monocytogenes into the brain during systemic infection of mice. J Immunol 2004; 172: 441824.
  • 138
    Ginhoux F, Tacke F, Angeli V, Bogunovic M, Loubeau M, Dai XM, et al. Langerhans cells arise from monocytes in vivo. Nat Immunol 2006; 7: 26573.
  • 139
    Tacke F, Ginhoux F, Jakubzick C, van Rooijen N, Merad M, Randolph GJ. Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery. J Exp Med 2006; 203: 58397.
  • 140
    Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007; 117: 195205.
  • 141
    Cheung DL, Hamilton JA. Regulation of human monocyte DNA synthesis by colony-stimulating factors, cytokines, and cyclic adenosine monophosphate. Blood 1992; 79: 197281.
  • 142
    Moss ST, Hamilton JA. Proliferation of a subpopulation of human peripheral blood monocytes in the presence of colony stimulating factors may contribute to the inflammatory process in diseases such as rheumatoid arthritis. Immunobiology 2000; 202: 1825.
  • 143
    Clanchy FI, Holloway AC, Lari R, Cameron PU, Hamilton JA. Detection and properties of the human proliferative monocyte subpopulation. J Leukoc Biol 2006; 79: 75766.
  • 144
    De Rycke L, Baeten D, Foell D, Kruithof E, Veys EM, Roth J, et al. Differential expression and response to anti-TNFα treatment of infiltrating versus resident tissue macrophage subsets in autoimmune arthritis. J Pathol 2005; 206: 1727.
  • 145
    Smith MD, Kraan MC, Slavotinek J, Au V, Weedon H, Parker A, et al. Treatment-induced remission in rheumatoid arthritis patients is characterized by a reduction in macrophage content of synovial biopsies. Rheumatology (Oxford) 2001; 40: 36774.
  • 146
    Broker BM, Edwards JC, Fanger MW, Lydyard PM. The prevalence and distribution of macrophages bearing Fc γ R I, Fc γ R II, and Fc γ R III in synovium. Scand J Rheumatol 1990; 19: 12335.
  • 147
    Athanasou NA. Synovial macrophages. Ann Rheum Dis 1995; 54: 3924.
  • 148
    Balsa A, Dixey J, Sansom DM, Maddison PJ, Hall ND. Differential expression of the costimulatory molecules B7.1 (CD80) and B7.2 (CD86) in rheumatoid synovial tissue. Br J Rheumatol 1996; 35: 337.
  • 149
    Hamann J, Wishaupt JO, van Lier RA, Smeets TJ, Breedveld FC, Tak PP. Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue. Arthritis Rheum 1999; 42: 6508.