Autoimmunity Reviews 10 (2011) 617–623

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Autoimmunity Reviews

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Review

Role of the complement system in rheumatoid arthritis and psoriatic arthritis:Relationship with anti-TNF inhibitors

Eleonora Ballanti a, Carlo Perricone b, Gioia di Muzio a, Barbara Kroegler a, Maria Sole Chimenti a,Dario Graceffa a, Roberto Perricone a,⁎a Rheumatology, Allergology and Clinical Immunology, Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italyb Reumatologia, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy

⁎ Corresponding author at: Department of Internal Mefax: +39 06 20900358.

E-mail address: roberto.perricone@uniroma2.it (R. P

1568-9972/$ – see front matter © 2011 Elsevier B.V. Aldoi:10.1016/j.autrev.2011.04.012

a b s t r a c t

a r t i c l e i n f o

Available online 27 April 2011

Keywords:Complement systemRheumatoid arthritisPsoriatic arthritisAnti-TNF agentsBiomarkers

The complement system is an essential component of innate immunity and also plays an important role inmodulating adaptive immunity. It comprises more than 30 plasma and membrane-bound proteins and can beactivated through three pathways: the classical, the alternative and the lectin pathways. Its activationcontributes to the pathogenesis of several autoimmune and inflammatory conditions. The evidence ofcomplement activation in synovial fluid of Rheumatoid Arthritis (RA) patients is abundant, while few dataexist in Psoriatic Arthritis (PsA) patients. Levels of complement proteins are generally depressed in thesynovial fluid of patients with RA, reflecting consumption of complement. On the other hand, elevated levelsof several complement cleavage products have been observed in synovial fluid. Involvement of complementin the pathogenesis of RA was also confirmed in animal models of arthritis: mice deficient for complementproteins are protected against the development of collagen-induced arthritis and administration of the anti-C5 monoclonal antibody prevents the onset of this arthritis. In the last decade anti-tumor necrosis factoragents have shown to be effective for the treatment of both RA and PsA and some studies suggest that theinteraction between TNFα and complement system may contribute to the pathogenesis of these diseases.Reduction of the complement activation could be one of the mechanism by which TNFα-inhibitors exert theireffectiveness in inflammatory arthritides. Because of these findings, complement could be an attractivetherapeutic target both in RA and in PsA.

dicine, Unit of Rheumatology, University of Rome Tor Ver

erricone).

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© 2011 Elsevier B.V. All rights reserved.

Contents

1. Introduction to the complement system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6181.1. Pathways of complement activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6181.2. Complement and inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6181.3. Complement and autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619

2. Complement and rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6192.1. Where complement components are synthesized in RA? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6192.2. Activation of the complement system in RA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6202.3. Complement and collagen-induced arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620

3. Complement and psoriatic arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6204. Complement and anti-TNFα agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6215. Potential therapies targeting complement cascade in inflammatory arthritides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6216. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622

gata, Via Montpellier 1, 00133 Rome, Italy. Tel.: +39 06 72596287;

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1. Introduction to the complement system

Complement is part of the innate immune system. The term “innateimmunity” was introduced to define the protective mechanismsagainst infection that operate in the absence of specific “adaptive”immunity [1]. Phylogenetically, themajor function of the complementsystem has been thought to be recognition and elimination ofpathogens through direct killing and/or stimulation of phagocytosis[2,3], but, in recent years, also immunoregulatory functions of thecomplement systemhave become clear and it has been discovered thatthe complement proteins play an important role in modulatingadaptive immunity [4]. Given these multiple functions exerted innormal and pathologic conditions, complement provides an uniqueconnection between innate and adaptive immune responses, with itsinvolvement in the pathogenetic mechanisms of various diseasesranging from protective functions to tissue damage [1,4].

1.1. Pathways of complement activation

The complement system comprises more than 30 plasma andmembrane-bound proteins [5,6]. There are three pathways ofcomplement activation, the classical, the alternative and the lectinpathways. All three pathways are activated according to a cascadesystem, with activation of one factor leading to the activation of thenext (Fig. 1). Activation of the classical pathway is dependent onimmunoglobulins (Ig), IgM or IgG, present in immune complexes,leading to binding of the C1 complex via the C1q subunit [7]. Bindingof C1q to antibody induces conformational changes in the C1 complexand leads to activation of C4 and C2 resulting in the formation of theC4bC2a complex, the classical pathway C3 convertase [8]. In the caseof the alternative pathway, activation of a serine protease, factor D,

Fig. 1. Activation pathways of the complement system. There are three pathways of complemeactivated according to a cascade system, with activation of one factor leading to activation of thactivation of C3. The classical and lectin pathways generate the same C3 convertase (C4b2a), wclassical and lectinpathways generate the sameC5convertase (C4b2a3b),whereas the alternatithe activation of C5 to formC5a (apotent chemoattractant) and themembrane attack complex (complement on self, there aremultiple complement regulators in plasma and on host cells (reppentraxin-3; C1INH, C1-inhibitor;MCP,membrane cofactor protein; DAF, decay-accelerating facMASPs, MBL-associated serine proteases.

cleaves factor B into Ba and Bb when factor B is complexed withspontaneously hydrolyzed iC3b. Bb is a serine protease that generatesthe C3 convertase of the alternative pathway, C3bBb. Properdinincreases the stability of this enzyme [1].

Activation of the lectin pathway occurs in response to recognitionof mannose-binding lectin and ficolins of various carbohydrateligands on the surface of microorganisms [9]. This results in activationof the mannose-binding lectin-associated serine proteases (MASP-1,MASP-2 and MASP-3). MASP-2, which is the key enzyme of the lectinpathway, cleaves C4 and subsequently C2, leading to the formation ofthe same C3 convertase as in the classical pathway, that is C4bC2a [8].Activation of the complement system through any of the threepathways leads to activation of C3. The classical and lectin pathwaysgenerate the same C3 convertase, whereas the alternative pathwaygenerates a different C3 convertase. Likewise, the classical and lectinpathways generate the same C5 convertase (C3bC4bC2a), whereasthe alternative pathway generates a different C5 convertase(C3bBbC3b) [9]. The three pathways converge at the activation ofC5 to form C5a (a potent chemoattractant) and the membrane attackcomplex (MAC) C5b-9, which can lead to cell lysis [9].

To minimize damage induced by over-activation of complementon self, there are multiple complement regulators in plasma and onhost cells that control the complement pathway to maintain theintegrity of the host [10].

1.2. Complement and inflammation

The regulatory mechanisms of complement are finely balanced sothat, on the one hand, the activation of complement is focused on thesurface of invading microorganisms and, on the other hand, thedeposition of complement on normal cells and tissues is limited [5].

nt activation: the classical, the lectin and the alternative pathway. All three pathways aree next. Activation of the complement system through any of the three pathways leads tohereas the alternative pathway generates a different C3 convertase (C3bBb). Likewise, thevepathwaygenerates a different C5convertase (C3bBb3b). The threepathways convergeatMAC)C5b-9,which can lead to cell lysis. Tominimizedamage inducedbyover-activation ofresented in the circles). Ag–Ab, antigen–antibody complex; CRP, C-Reactive Protein; PTX3,tor; CR1, complement receptor 1; C4BP, C4-binding protein;MBL,mannose binding lectin;

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When themechanisms that regulate this delicate balance go awry, thecomplement system may cause injury, by induction and augmenta-tion of inflammation [5]. Several studies demonstrated the involve-ment of complement in inflammatory tissue destruction. The twomeans by which complement is activated in tissues are throughimmune complexes, which activate the classical complement path-way, and through tissue ischemia and reperfusion, which exposephospholipids and mitochondrial proteins [6]. These activate com-plement directly by binding C1q or mannose-binding lectin orindirectly by binding natural antibodies or C-reactive protein (CRP),which can activate the classical pathway by binding C1q. Necrotic cellsand tissues lack the regulatory molecules that in normal tissuesprevent the binding of complement [6]. Undesired complementactivation results in the formation of several proinflammatorymediators, including the anaphylatoxins C3a and C5a. Furthermore,the MAC can contribute to inflammation and tissue injury [11]. C5a isa potent chemoattractant for neutrophils, monocytes and eosinophilsand both C3a and C5a can stimulate the synthesis of pro-inflammatorymediators [11]. Formation of the terminal complement complex C5b-9 can lead to cell activation, proliferation and cell death by necrosis orapoptosis [11]. There is accumulating evidence that complementactivation is an important contributor to the tissue necrosis thatfollows ischemia. For instance, myocardial infarction and stroke areeach associated with the activation of complement in the area oftissue infarction [6,12].

1.3. Complement and autoimmunity

The complement system participates in the pathogenesis andcontributes to the clinical manifestations of many systemic autoim-mune diseases, such as systemic lupus erythematosus (SLE), vascu-litis, anti-glomerular basement membrane disease, anti-phospholipidantibody syndrome, systemic sclerosis, Sjögren's syndrome, derma-tomyositis and rheumatoid arthritis (RA) [9]. The meticulous study ofpatients with abnormalities of the complement system has illumi-nated our understanding of the immunobiology of complement [5,13].Hereditary homozygous deficiencies of C1q, C1r and C1s, and C4 areeach strongly associated with susceptibility to SLE, with respectivefrequencies of 93%, 57% (since deficiencies of C1r and C1s are usuallyinherited together), and 75% [6]. By contrast, the prevalence of SLEamong subjects with C2 deficiency, which is the most frequenthereditary deficiency in complement classical pathway components,is associated with SLE in 10% of the cases [14]. In the case of C3deficiency, the clinical picture is rather different [6]. It is characterizedby recurrent pyogenic infections, membranoproliferative glomerulo-nephritis and rashes. There are several theories that have beenproposed to explain the association between complement componentdeficiencies and autoimmune disease. Most of this focus on theinability to normally clear immune complexes in the absence ofnormal levels of complements components [15]. Excess immunecomplexes may deposit in tissues, resulting in inflammatory damageand release of autoantigens and initiating an autoimmune response.Alternatively, the presence of apoptotic cells in high concentrationsdue to poor clearance may be sufficient to elicit an autoimmuneresponse [14]. A third hypothesis suggests that the complementsystem plays an important role in the development of toleranceagainst self [16]. Complement is needed for the elimination of self-reactive lymphocytes during maturation of the immune system. Thus,complement deficiency will result in lack of normal B-cell toleranceand production of autoantibodies [17,18].

2. Complement and rheumatoid arthritis

RA is a systemic disease characterized by chronic inflammation ofthe synovium and subsequent destruction of cartilage and bone.

To date, the pathogenesis of RA is not fully understood but there isincreasing evidence for an important role of components of thecomplement cascade in the pathophysiology of RA. In general, thecomplement cascade is involved in the induction and progression ofinflammation reactions and is a major defense system against variouspathogenic agents, including bacteria, viruses, and other antigens[19–21]. Inappropriate activation, however, can lead to tissue damageand manifestation of disease. Although increased complementactivation is potentially related to the occurrence and/or augmenta-tion of inflammation in RA, complement deficiency may induce RA.C1q deficiency and suppression are related to the development of RA[10] as well as C2 deficiency [22]. Association with autoimmunediseases, including RA, has been shown for deficiencies of othercomplement components, including C1r and C1s, C4, C7, C9 and factorI [10]. In the lectin pathway, MBL deficiency while not directlyassociated with the occurrence of RA, is associated with diseaseseverity [23].

2.1. Where complement components are synthesized in RA?

The plasma levels of most complement components are main-tained by hepatic synthesis. Studies on the acute phase response haveshown that complement proteins may act as acute phase proteins,with increased hepatocyte synthesis occurring in response tocytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6), tumornecrosis factor-α (TNF-α) and interferon-γ [24–27]. Complementfactors and receptors have been called to play an important role in RAsince the first report from Brodeur in 1991 [28], and it is evident thatsynthesis and activation of complement take place at distinct siteswithin rheumatoid synovium. Recently, we evaluated plasma levels ofcomplement components in 114 patients with active RA (patientswith an established disease, and suffering from a moderate to severedisease).We demonstrated that the RA patients showmean C3 and C4levels significantly higher than controls and similar CH50. Splitproducts of C3 and factor B were never detected in the patients'plasma (unpublished results). We speculated that the presence ofelevated complement levels may reflect the presence of an under-lining inflammatory process, as previously reported, and complementcomponents can be considered acute phase proteins. Complementactivation probably occurred mainly in the joint space, and these highplasma levels were due to spill over from the joints.

Nevertheless, synthesis and activation of complement proteinsalso occurs in extrahepatic sites. To date it has been shown that allnormal tissues are able to synthesize at least one complementcomponent [29]. In addition, synthesis of complement componentsoccurs in chronically inflamed tissues such as the rheumatoid joint[30]. A large number of different cell types have been shown tosynthesize complement components. These include mononuclearphagocytes, fibroblasts, endothelial cells, epithelial cells, alveolar type2 epithelial cells and adipocytes [31–33]. In particular, the cell ofsynovial membrane which are responsible for the synthesis ofcomplement components are the lining cells (type A-mononuclearphagocyte, type B-fibroblast like), fibroblasts, mononuclear phago-cytes and endothelial cells [34]. In 1974 Ruddy and Coltendemonstrated synthesis of complement components C2, C3, C4 andC5 by rheumatoid synovial tissue by three technics: in vivo metabolicstudies with Radio-labeled C3; in vitro biosynthesis of C2, C3, C4 andC5; staining of cell in rheumatoid synovium with fluorescentantiserums to C3 and C4 [29]. More recently, in a very interestingstudy, Neumann et al. demonstrated that complement componentsand receptors are readily produced in situ in the inflamed RAsynovium [35]. Using in situ hybridization, immunohistochemistry,and Western blot techniques, they localized the sites of complementmessenger RNA (mRNA) expression in rheumatoid synovium.Specifically, they found increased expression of mRNA for C3 andFB, as previously reported [36] and for the first time they reported

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increased expression of mRNA for C3a and C5a receptors in synovialtissue [35]. These findings support the idea that they are producedlocally in RA synovium and are not plasma derived.

2.2. Activation of the complement system in RA

Various studies identify complement activation as a main event inthe inflammatory cascade in RA [37–39]. Complement is traditionallyconsidered to be mainly activated by bacteria or immune complexes.RA patients have increased levels of circulating immune complexes[40,41]. Part of these complexes contains rheumatoid factors (RFs),which are autoantibodies against human IgG. RF-containing immunecomplexes are capable of activating complement via the classicalpathway [42–45], with IgM-RF being considerably more effective incomplement activation than IgG-RF [46].

Trouw et al., from in vitro observations, suggested that anti-cycliccitrullinated peptide/protein antibodies (anti-CCP) from RA patientsmay activate complement via both the classical and the alternativepathways [47]. This interesting observation needs to be furtherconfirmed by in vivo analysis.

It is not clear to what extent circulating immune complexescontribute to complement activation in RA. Since there is noconclusive evidence that immune complexes are the main triggerfor complement activation in RA, other potential triggers forcomplement activation in RA should be considered. One of thesetriggers could be C-reactive protein (CRP), since this acute-phaseprotein can activate complement both in vitro and in vivo [48–51]. Inan interesting study Moleenar et al. demonstrated that the plasmalevels of activated complement and CRP–complement complexes areincreased in the majority of patients with RA and that these levels arecorrelated with parameters of disease activity [52]. The observation ofincreased levels of CRP–complement complexes in this study points tothe involvement of CRP in complement activation and to a possiblerole of CRP-mediated complement activation in the pathogenesis ofRA [52].

Furthermore, it appears that molecules present in or released fromcartilage, as fibromodulin (FM), may have a role in activatingcomplement [53]. FM, especially after cartilage degradation producedby metalloproteinases, interacts with the globular head of C1q,activating the classical pathway of complement [53]. Interestingly,other molecules of cartilage, such as decorin and biglycan, are able tobind C1q, but they inhibit the ability of C1 to activate the classicalpathway [54]. Probably the final outcome depends on a balancebetween several local factors.

Both classic and alternative pathways appear to contribute tocomplement activation in RA [55]. If the classical pathway is the maincomplement pathway triggered [55], presumably via binding ofimmune complexes containing rheumatoid factor, the alternativepathway is also activated in RA synovium as demonstrated bydecreased synovial fluid concentration of factor B and properdinand increased levels of Ba [56]. Increased complement activation viathe lectin pathway could also play a role in RA. Changes inglycosylation of IgG in RA cause an increase in binding of mannose-binding lectin resulting in increased complement activation [57].

Evidence of complement activation in synovial fluid is abundant.For example, levels of complement proteins are generally depressedin the synovial fluid of patients with RA, reflecting consumption ofcomplement. Aggarwal et al. recently demonstrated the activation ofthe alternative pathway with formation of the membrane terminalattack complex in patients with juvenile RA [58]. This provided moreconclusive evidence for the pathogenetic significance of complementpathway activation in RA. Moreover, elevated levels of severalcomplement cleavage products, such as C3a, C3c, C5a, sC5b-9, Bb,C1–C1INH complexes have been observed in synovial fluid [59–62].Some studies demonstrated low levels of MAC (membrane attackcomplex) inhibitors in synovial fluid or synovial tissue of patients

with RA, and this might allow lytic or sublytic attacks on local cells[61,63].

One problem with the detection of complement activationproducts is that complement system is susceptible to in vitroactivation, resulting in artificially high levels of activation productsin plasma samples. Wouters et al. recently described novel activationproducts of complement which consists of covalent complexesbetween C1q and activated C4 [64]. This new marker is not onlyspecific for activation of the classical pathway of complement, but alsois remarkably stable in plasma, permitting to avoid artifacts [64].

Several studies failed to demonstrate a correlation between localand systemic activation of complement system in RA and reportedhigher levels of complement cleavage products in synovial fluid thanin plasma [59,65,66], and these findings are consistent with aprevalent local activation of the complement cascade. Associationbetween complement activation and disease activity is another aspectof great interest. Again in the study from Wouters and coworkers, acorrelation between plasma levels of C1q-C4 complexes and diseaseactivity expressed as DAS28 was found [64], likewise Doherty et al.reported raised synovial C3d levels in active compared with inactiveRA joints [59].

2.3. Complement and collagen-induced arthritis

Involvement of complement in the pathogenesis of RA was alsoconfirmed in experimental studies with animal models. In 1977Trentham et al., reported that immunization of rats with type IIcollagen (CII) induce an autoimmune arthritis that in many waysresembled RA [67]. Following immunization with CII, these ratsdeveloped an erosive, polyarticular arthritis mediated by an autoim-mune response to the rat CII. Similarly, this same collagen-inducedarthritis (CIA) model has been reproduced in the mouse [68] and inprimates [69,70]. The significance of this model is that CII is the majorconstituent protein of cartilage in diarthrodial joints, the predominantsite of inflammation in RA. In addition, the pathogenesis of CIA is inmany ways similar to that of RA [71].

In 2002Hietala et al. demonstrated that themice deficient for C3 orFB and immunized with bovine CII displayed reduction or almostcomplete absence of clinically or histologically verifiable arthritis [72].These results showed that the classical pathway and possibly also thealternative pathway are involved in the pathogenesis of CIA [72].

According to these findings, Wang et al. had previously shown thatsystemic administration of the anti-C5 monoclonal antibody (mAb)effectively inhibits terminal complement activation in vivo and thatanti-C5 mAb treatment prevents the onset of arthritis in mice and isalso highly effective in ameliorating established disease [73]. Theseresults demonstrated an important role for activated terminalcomplement components not only in the induction but also in theprogression of disease in this model of immune-mediated jointinflammation.

3. Complement and psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic, inflammatory arthritiscommonly associated with psoriasis. Ten to 30% of the patients withpsoriasis develop PsA. Skin involvement precedes joint symptoms inmost cases, however, articular involvement at disease onset withoutskin lesions occurs in 15% of PsA patients [74]. PsA pathogenesis is stillincompletely understood, but a role for innate immunity has beenrecognized [75].

Data on the role of complement in PsA are poor in the literature.Early studies on psoriatic patients have shown increased plasmaconcentrations of iC3b, C4d, and Bb fragments, especially in patientswith erythrodermic pustular psoriasis and in patients with PsA [76].

Partsch et al. have shown that synovial fluid (SF) from patientswith PsA exhibit a relatively low percentage of the C3c cleavage

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product, in similar amounts than in patients with osteoarthritis (OA)[77]. The same authors showed that the PsA SF displays the highest C3concentration when compared with RA and OA, and it might also behelpful for establishing the differential diagnosis of PSA vs RA on thebasis of the C3 level of the SF in those patients where an elevated levelof C3 is present [77].

A possible implication of complement activation in the pathogen-esis of PsA is supported by the finding of impaired expression ofcomplement regulators in these patients. Triolo et al. demonstrated alow expression of erythrocyte membrane-anchored CD59, which is animportant membrane inhibitor of MAC [78]. Consistently with thisobservation, increased SC5b-9 was seen in the plasma of patients withactive disease and an inverse correlation was also found betweenplasma SC5b-9 and the CD59 expression levels [78]. Consideringerythrocyte CD59 levels as representative of the CD59 tissuedistribution, the authors supposed that reduced CD59 expressioncould facilitate the activation of complement pathway and exacerbatesynovial cell injury [78].

In another interesting study published in 1994, the complementreceptor type 1 (CRl) levels on erythrocyte membranes from 23patients with PsAwas determined using ELISA [79]. The authors founda statistically significant decrease of CR1 density in PsA patients withpoliarthritis compared with controls. Moreover, the CRl concentrationhad an inverse correlation with the articular index of patients (but nocorrelation was found with CRP and ESR levels), which indicated thatthe decreased concentration of CRl in these patients could be relatedto the severity of disease [79].

Our group has recently conducted a study evaluating thecomplement system in PsA treated with anti-TNF, in which wedemonstrated that PsA patientswithmoderate to severe disease showhigher plasma levels of C3 and C4, compared with healthy subjects(unpublished results). In addition, we evaluated the release of splitproducts of C3 and B, to verify complement activation. These cleavagefragments were not detected suggesting that complement proteinsmay contribute to the acute phase response. In this view, in our studyit is not surprising to find elevated baseline C3 and C4 levels inpatients with a moderate to severe disease activity (unpublishedresults).

4. Complement and anti-TNFα agents

TNFα is a potent proinflammatory cytokine with pleiotropiceffects and represents one of the major players in the inflammatorycascade [80]. In the last decade anti-TNF agents have shown to beeffective for treatment of both RA [81–84] and PsA [85–88]. Thesefindings support the involvement of TNF in the pathogenesis of theserheumatic diseases. Thus, there is a strong evidence for an importantrole of both complement system and TNFα in the pathophysiology ofRA and PsA. However, whether there is any interaction between thesepathogenetic elements still is a controversial issue. In previous studiesTNFα has been reported to interact with complement system, byincreasing the synthesis of factor B and C3 in human hepatoma celllines [89].

Moreover Brodeur et al. reported that the mean levels of TNF in RAsynovial fluids were over 2-fold higher than those in degenerativejoint diseases and that TNF levels correlate positively with comple-ment activation markers C3a, SCSb-9, and Bb [28].

Effect of TNF-inhibitors on the complement profile could behelpful to clarify these aspects.

Recently, Mitoma et al. performed an in vitro study concerning thecytotoxic effects of several anti-TNF agents. They reported that bothadalimumab and infliximab showed a potent complement-dependentcytotoxicity (CDC), while etanercept did not. This could explain whyetanercept (in contrast with adalimumab and infliximab) is notclinically effective for granulomatous diseases, such as Crohn's diseaseand Wegener's granulomatosis [90]. This finding was not confirmed

by Kaymakcalan et al. who suggested that the different clinicalefficacy profiles of these biologic agents are not explained bydifferences in complement-dependent lysis, because none of thethree drugs was able to induce CDC in activated human mononuclearcells [91].

Few studies in vivo have evaluated complement activation so far.Familian et al. investigated the effect of treatment with the anti-TNFmonoclonal antibody infliximab on overall complement activation, aswell as on CRP levels and CRP mediated complement activation, inpatients with RA [92]. Plasma levels of C3b/c and C4b/c, reflectingactivation of C3 and C4, respectively, before the start of infliximabtreatment were significantly higher than levels in healthy volunteers.Two weeks after the start of infliximab treatment all patients wereresponders according to change of the DAS28 and showed signifi-cantly lower levels of C3b/c and C4b/c than before treatment.Furthermore, plasma levels of CRP and CRP–complement complexessignificantly decreased in the patients during treatment and thedecrease of CRP and C3b/c levels wasmore pronounced in the patientswith a good response [92]. Considering these data together, theauthors supposed that cytokines released during inflammation triggercomplement activation, presumably through mechanisms involvingCRP and that reduction of this activation contributes to the anti-inflammatory effects of anti-TNF agents [92].

Wouters et al. reported a decrease (although not statisticallysignificant) of C1q–C4 complexes in ten RA patients treated withinfliximab after 22 weeks of therapy, in parallel with DAS28improvement [64].

To the best of our knowledge, no data on the modifications of thecomplement system in PsA patients treated with anti-TNF have beenreported.

As above mentioned, we performed the evaluation of complementsystem in patients with RA and PsA treated with the anti-TNF agentsadalimumab or etanercept (unpublished results). We observed astatistically significant decrease in C3 and C4 levels, independentlyfrom the anti-TNF used, both in RA and in PsA. A higher reduction incomplement C3 levels was observed in patients with good response aswell as patients with baseline lower C3 levels had a better response.Taking these findings together, we may consider reduction ofcomplement native components as an improvement of a pre-existingpro-inflammatory status reverted by anti-TNF drugs (unpublishedresults). It could be suppose that persistently elevated C3 levels mayrepresent as negative predictive factor influencing the outcome ofanti-TNF therapy in RA and PsA. As a consequence, C3 dosage mayprovide an additional tool in monitoring disease activity duringtreatment with anti-TNF (unpublished results). Our preliminary dataneed to be further confirmed.

5. Potential therapies targeting complement cascade ininflammatory arthritides

The complement system is increasingly recognized to be causallyinvolved in tissue injury during ischemic, inflammatory, and autoim-mune diseases. Because of this, complement is an attractivetherapeutic target for a wide range of diseases, such as connectivetissue diseases, glomerulonephritis, myocarditis, multiple sclerosis,type I diabetes mellitus, asthma, myocardial infarction, paroxysmalnocturnal hemoglobinuria, vasculitis and many others [9,12,93–95].

Up to date, several compounds interfering with complementcascade were studied in experimental models of arthritis, such assoluble CR1 [96] (which suppress complement activation at the maingathering point C3), C3a [97] and C5a [98] receptor antagonists (thatcan used to control the anaphylatoxins C3a and C5a), recombinantCD59 [99] (that inhibits the formation ofMAC). An important problemwith the modulation of complement activity is that a long-termsystemic suppression may cause side-effects due to diminished

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complement activity, such as increased susceptibility to bacterialinfections [10].

Interesting results have been obtained in vivo with PMX53, a C5amimetic compound that binds the C5a receptor, without causingagonist effects. Rats treated with PMX53 showed a significantimprovement of arthritis [98]. Unfortunately, the results of itsapplication in human disease were not so promising. Vergunst et al.performed a double-blind, placebo controlled trial in 21 patients withactive RA [100]. They reported that RA patients didn't show a clinicalimprovement when compared with patients who received placebo[100]. Other studies are needed to clarify the potential use ofcomplement as a therapeutic target in inflammatory arthritides.

6. Conclusions

Extensive scientific evidence is now available supporting a role ofcomplement system in the pathogenesis of RA and, to a less extent,the contribution of the complement cascade has been demonstratedin PsA too. TNFα could interact with complement system byincreasing the synthesis of complement proteins in hepatic cells,during acute phase response [89], and this explain the finding ofincreased complement levels in sera of patients with inflammatoryarthritides, reverted by anti-TNF administration. On the other hand,TNFα seems to activate complement system, as demonstrated by areduction of complement cleavage products in sera of patients treatedwith anti-TNF agents [92]. A mechanism proposed is that anti-TNFαdecrease plasma levels of CRP, which can activate complementcascade through classical pathway. Therefore, the reduction ofcomplement activation could contribute to the anti-inflammatoryeffects of anti-TNFα agents [92].

To conclude, specific modulation and inhibition of local comple-ment production could be an attractive target for RA and PsA.Potential compounds interfering with the complement cascade havebeen tested, but further studies are needed to find complement-modulating agents able to act on the pathogenetic mechanisms ofthese diseases without interfering with essential, beneficial comple-ment functions.

Take-home messages

• Activation of the complement system can have opposing effects: onthe one hand complement proteins have many protective functions,contributing to host defense against invading pathogens, on theother hand can contribute to inflammation and tissue injury.

• There is evidence of a role of the complement system in thepathogenesis of RA and, to a less extent, in PsA and this support apossible effectiveness of anti-complement agents for the treatmentof both these diseases.

• Reduction of the complement activation is, probably, one of themechanism by which TNFα-inhibitors exert their effectiveness ininflammatory arthritides.

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