Rheumatoid arthritis and the complement system

Figures & data

Figure 1. Scheme of the complement system and its inhibitors. Three pathways by which the human complement system can be activated and their physiological effects: 1) clearance of apoptotic cells, 2) opsonization of pathogens and immune complexes for phagocytosis, 3) release of anaphylatoxins and lysis. Furthermore, sites of action of soluble (italics) and membrane‐bound (regular font) complement inhibitors are indicated.

Figure 2. Schematic diagram of possible contributions of the complement system to development of rheumatoid arthritis(RA) in a joint. Complement can be activated in several ways in the RA joint. Examples are deposited autoantibodies and immune complexes (IC), apoptotic and necrotic cells, certain cartilage molecules such as fibromodulin (FM) exposed upon initial cartilage damage. Activation of complement leads to a release of proinflammatory anaphylatoxin C5a that attracts and activates neutrophils and macrophages. These cells in turn release proteases and cytokines attracting T and B lymphocytes and other inflammatory cells, further fuelling the process of inflammation. As a result of complement activation membrane attack complex (MAC) is formed and has a plethora of effects on cells even at sublytic concentrations.

Table I. Evidence for involvement of complement in rheumatoid arthritis (RA) observed in animal models.

Animal	Type of intervention	RA model	Observed effect	References
mouse	Natural deficiency of C5	CIA	Resistance to disease.	78,81,127
mouse	Crossing C5‐deficient and sufficient strains	CIA	No arthritis in C5−/− population, lower incidence of arthritis in C5+/− than in C5 +/+ mouse.	76
mouse	Anti‐C5 antibody	CIA	Prevention of disease onset after immunization, amelioration of established disease.	86
mouse	C1q, C3, C4, factor B, C5, C6, and C5aR knockout or natural deficiency	K/B×N	No arthritis upon passive transfer of serum in C3‐ or C5‐deficient mouse, little manifestation of disease in factor B knockout, normal clinical onset in C1q, C4, and C6 knockout.	77,87,128
mouse	CR1 and CR2 knockout	K/B×N	Normal clinical onset of disease.	128
mouse	C3 knockout	CIA	Resistance to CIA and decreased collagen II‐specific IgG Ab compared to control mouse after first immunization. Second immunization resulted in lower clinical score.	82
mouse	C3 knockout	CAIA	Clinical score of disease markedly decreased. Delayed onset of disease and lower clinical score.	83
				84
mouse	Factor B knockout	CIA	Partial resistance to CIA and decreased collagen II‐specific IgG Ab compared to control mouse after the first immunization. Second immunization resulted in intermediate clinical score.	82
mouse	Factor B knockout	CAIA	Clinical score of arthritis decreased. Decreased clinical score but not as much as in C3 knockout mouse.	83,84
mouse	Injection of sCR1‐expressing arthritogenic splenocytes or fibroblasts	CIA	Inhibition of clinical symptoms, anti‐collagen II antibody production and T cell response to collagen II in vitro.	129
mouse	Cobra venom factor (CVF)‐mediated decomplementation	Bacterial cell‐wall induced arthritis	Diminished incidence and severity of disease	130
mouse	CVF‐mediated decomplementation	AA	Silenced clinical manifestation of arthritis	131
rat	C5aR antagonist or sCR1 i.a. administration	AIA	sCR1 but not C5aR antagonist caused suppressed synovium thickening, joint swelling, and inflammation.	132
rat	CVF‐mediated decomplementation or i.v. application of sCR1	CIA	Delayed disease onset.	133
rat	Systemic or local decomplementation by CVF or i.a. application of sCR1	AA	Reduced joint swelling after local but not systemic decomplementation before disease onset.	134

CIA = collagen induced arthritis; CAIA = collagen antibody‐induced arthritis; AA = antigen arthritis; AIA = antibody‐induced arthritis; i.a. = intraarticular; i.v. = intravenous.

Table II. Therapeutic approaches to complement inhibition in rheumatoid arthritis.

Approach/agent	Company	Stage of development	Ref/homepage
Clinical and pre‐clinical phase:
sCR1‐related compound APT070	Inflazyme Pharmaceuticals	Clinical phase I/II	http://www.inflazyme.com/files/April%207%202004.pdf
Anti‐C5 eculizumab	Alexion Pharmaceuticals	Clinical phase IIb	124,125
C5a antagonist PMX‐53	Peptech	Clinical phase II	3
Vaccination against C5a	Resistentia Pharmaceuticals	Pre‐clinical development	http://www.resistentia.se/se/researchdevelopement/c5a/
Anti‐CD59 CD59‐Prodaptin^TM	Inflazyme Pharmaceuticals	Pre‐clinical development	http://www.inflazyme.com/files/July%2027%202004.pdf
Animal trials:
Serine protease inhibitor. FUT‐175	Torii Pharmaceutical Company	Tested in rat adjuvant arthritis model	135
C3aR antagonist SB290157	–	Tested in rat adjuvant arthritis model	136
C5aR antagonist AcF‐[OPdChaWR]	–	Tested in rat antigen arthritis model	137
Hybrid Ig‐CD55 molecule	–	Tested in rat antigen arthritis model	138
Hybrid of CD59 and membrane‐address tag	–	Tested in rat antigen arthritis model	139

McIndoe R. A., Bohlman B., Chi E., Schuster E., Lindhardt M., Hood L. Localization of non‐Mhc collagen‐induced arthritis susceptibility loci in DBA/1j mice. Proc Natl Acad Sci U S A 1999; 96: 2210–4

 PubMed Web of Science ®Google Scholar

Wang Y., Kristan J., Hao L., Lenkoski C. S., Shen Y., Matis L. A. A role for complement in antibody‐mediated inflammation: C5‐deficient DBA/1 mice are resistant to collagen‐induced arthritis. J Immunol 2000; 164: 4340–7

 PubMed Web of Science ®Google Scholar

Johansson A. C., Sundler M., Kjellen P., Johannesson M., Cook A., Lindqvist A. K., et al. Genetic control of collagen‐induced arthritis in a cross with NOD and C57BL/10 mice is dependent on gene regions encoding complement factor 5 and FcgammaRIIb and is not associated with loci controlling diabetes. Eur J Immunol 2001; 31: 1847–56

 Google Scholar

Spinella D. G., Jeffers J. R., Reife R. A., Stuart J. M. The role of C5 and T‐cell receptor Vb genes in susceptibility to collagen‐induced arthritis. Immunogenetics 1991; 34: 23–7

 PubMedGoogle Scholar

Wang Y., Rollins S. A., Madri J. A., Matis L. A. Anti‐C5 monoclonal antibody therapy prevents collagen‐induced arthritis and ameliorates established disease. Proc Natl Acad Sci U S A 1995; 92: 8955–9

 PubMed Web of Science ®Google Scholar

Ji H., Gauguier D., Ohmura K., Gonzalez A., Duchatelle V., Danoy P., et al. Genetic influences on the end‐stage effector phase of arthritis. J Exp Med 2001; 194: 321–30

 Google Scholar

Ji H., Ohmura K., Mahmood U., Lee D. M., Hofhuis F. M., Boackle S. A., et al. Arthritis critically dependent on innate immune system players. Immunity 2002; 16: 157–68

 PubMed Web of Science ®Google Scholar

Solomon S., Kolb C., Mohanty S., Jeisy‐Walder E., Preyer R., Schollhorn V., et al. Transmission of antibody‐induced arthritis is independent of complement component 4 (C4) and the complement receptors 1 and 2 (CD21/35). Eur J Immunol 2002; 32: 644–51

 Google Scholar

Hietala M. A., Jonsson I. M., Tarkowski A., Kleinau S., Pekna M. Complement deficiency ameliorates collagen‐induced arthritis in mice. J Immunol 2002; 169: 454–9

 PubMedGoogle Scholar

Banda N. K., Thurman J. M., Kraus D., Wood A., Carroll M. C., Arend W. P., et al. Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen‐induced arthritis. J Immunol 2006; 177: 1904–12

 PubMedGoogle Scholar

Hietala M. A., Nandakumar K. S., Persson L., Fahlen S., Holmdahl R., Pekna M. Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis. Eur J Immunol 2004; 34: 1208–16

 PubMed Web of Science ®Google Scholar

Dreja H., Annenkov A., Chernajovsky Y. Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen‐induced arthritis. Arthritis Rheum 2000; 43: 1698–709

 PubMed Web of Science ®Google Scholar

Koga T., Kakimoto K., Hirofuji T., Kotani S., Ohkuni H., Watanabe K., et al. Acute joint inflammation in mice after systemic injection of the cell wall, its peptidoglycan, and chemically defined peptidoglycan subunits from various bacteria. Infect Immun 1985; 50: 27–34

 PubMed Web of Science ®Google Scholar

van Lent P. L., van den Bersselaar L. A., van den Hoek A. E., van de Loo A. A., van den Berg W. B. Cationic immune complex arthritis in mice—a new model. Synergistic effect of complement and interleukin‐1. Am J Pathol 1992; 140: 1451–61

 PubMed Web of Science ®Google Scholar

Mizuno M., Nishikawa K., Morgan B. P., Matsuo S. Comparison of the suppressive effects of soluble CR1 and C5a receptor antagonist in acute arthritis induced in rats by blocking of CD59. Clin Exp Immunol 2000; 119: 368–75

 PubMed Web of Science ®Google Scholar

Goodfellow R. M., Williams A. S., Levin J. L., Williams B. D., Morgan B. P. Soluble complement receptor one (sCR1) inhibits the development and progression of rat collagen‐induced arthritis. Clin Exp Immunol 2000; 119: 210–6

 PubMed Web of Science ®Google Scholar

Goodfellow R. M., Williams A. S., Levin J. L., Williams B. D., Morgan B. P. Local therapy with soluble complement receptor 1 (sCR1) suppresses inflammation in rat mono‐articular arthritis. Clin Exp Immunol 1997; 110: 45–52

 PubMed Web of Science ®Google Scholar

Kohl J. Drug evaluation: the C5a receptor antagonist PMX‐53. Curr Opin Mol Ther 2006; 8: 529–38

 PubMedGoogle Scholar

Ino Y., Sato T., Koshiyama Y., Suzuki K., Oda M., Iwaki M. Effects of FUT‐175, a novel synthetic protease inhibitor, on the development of adjuvant arthritis in rats and some biological reactions dependent on complement activation. Gen Pharmacol 1987; 18: 513–6

 Google Scholar

Ames R. S., Lee D., Foley J. J., Jurewicz A. J., Tornetta M. A., Bautsch W., et al. Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models. J Immunol 2001; 166: 6341–8

 PubMed Web of Science ®Google Scholar

Woodruff T. M., Strachan A. J., Dryburgh N., Shiels I. A., Reid R. C., Fairlie D. P., et al. Antiarthritic activity of an orally active C5a receptor antagonist against antigen‐induced monarticular arthritis in the rat. Arthritis Rheum 2002; 46: 2476–85

 PubMed Web of Science ®Google Scholar

Harris C. L., Williams A. S., Linton S. M., Morgan B. P. Coupling complement regulators to immunoglobulin domains generates effective anti‐complement reagents with extended half‐life in vivo. Clin Exp Immunol 2002; 129: 198–207

 PubMed Web of Science ®Google Scholar

Fraser D. A., Harris C. L., Williams A. S., Mizuno M., Gallagher S., Smith R. A., et al. Generation of a recombinant, membrane‐targeted form of the complement regulator CD59: activity in vitro and in vivo. J Biol Chem 2003; 278: 48921–7

 Google Scholar