Vascular involvement in rheumatic diseases: 'vascular rheumatology'

Page 1 o 10 (page numbe no o ci a ion pu poses) A ailable online h p://a h i is- esea ch.com/con en /10/5/224 Abs ac The ascula u e plays a c ucial ole in in lamma ion, angiogenesis, and a he oscle osis associa ed wi h he pa hogenesis o in lam- ma o y heuma ic diseases, hence he e m ‘ ascula heuma ology’. The endo helium lining he blood essels becomes ac i a ed du ing he in lamma o y p ocess, esul ing in he p oduc ion o se e al media o s, he exp ession o endo helial adhesion molecules, and inc eased ascula pe meabili y (leakage). All o his enables he ex a asa ion o in lamma o y cells in o he in e s i ial ma ix. The endo helial adhesion and ansendo helial mig a ion o leukocy es is a well- egula ed sequence o e en s ha in ol es many adhesion molecules and chemokines. P ima ily selec ins, in eg ins, and membe s o he immunoglobulin amily o adhesion ecep o s a e in ol ed in leukocy e ‘ e he ing’, ‘ olling’, ac i a ion, and ans- mig a ion. The e is a pe pe ua ion o angiogenesis, he o ma ion o new capilla ies om p e-exis ing essels, as well as ha o asculogenesis, he gene a ion o new blood essels in a h i is and connec i e issue diseases. Se e al soluble and cell-bound angiogenic media o s p oduced mainly by monocy es/mac o- phages and endo helial cells s imula e neo ascula iza ion. On he o he hand, endogenous angiogenesis inhibi o s and exogenously adminis e ed angios a ic compounds may down egula e he p ocess o capilla y o ma ion. Rheuma oid a h i is as well as sys emic lupus e y hema osus, scle ode ma, he an iphospholipid synd ome, and sys emic asculi ides ha e been associa ed wi h accele a ed a he oscle osis and high ca dio ascula isk leading o inc eased mo ali y. Apa om adi ional isk ac o s such as smoking, obesi y, hype ension, dyslipidemia, and diabe es, in lam- ma o y isk ac o s, including C- eac i e p o ein, homocys eine, ola e de iciency, lipop o ein (a), an i-phospholipid an ibodies, an i- bodies o oxidized low-densi y lipop o ein, and hea shock p o eins, a e all in ol ed in a he oscle osis unde lying in lamma o y heu- ma ic diseases. Ta ge ing o adhesion molecules, chemokines, and angiogenesis by adminis e ing nonspeci ic immunosupp essi e d ugs as well as monoclonal an ibodies o small molecula compounds inhibi ing he ac ion o a single media o may con ol in lamma ion and p e en issue des uc ion. Vasop o ec i e agen s may help o p e en p ema u e a he oscle osis and ca dio ascula disease. In oduc ion Vessels and he ascula endo helium a e in ol ed in he pa hogenesis o in lamma o y heuma ic diseases. Rheuma- oid a h i is (RA) se es as a p o o ype o hese diseases as i is he mos common ype o a h i is and a g ea body o da a is a ailable ega ding leukocy e ec ui men in o he syno ium, angiogenesis, and accele a ed a he oscle osis. The e m ‘ ascula heuma ology’ has been accep ed by many in es iga o s and includes bo h mic o ascula and mac o ascula in ol emen in heuma ic diseases. Apa om RA, sys emic lupus e y hema osus (SLE), sys emic scle osis (SSc), he an iphospholipid synd ome (APS), and sys emic asculi ides ha e been associa ed wi h ascula in lamma ion, al e ed angiogenesis, and inc eased ca dio ascula mo bidi y and mo ali y. In his e iew, we will discuss he mos ele an Re iew Vascula in ol emen in heuma ic diseases: ‘ ascula heuma ology’ Zol án Szekanecz1and Alisa E Koch2,3 1Uni e si y o Deb ecen Medical Cen e , Ins i u e o Medicine, Depa men o Rheuma ology, 22 Mó icz s ee , Deb ecen, H-4032, Hunga y 2Ve e ans’ Adminis a ion Ann A bo Heal hca e Sys em, 2215 Fulle Road, Ann A bo , MI 48105, USA 3Uni e si y o Michigan Heal h Sys em, Di ision o Rheuma ology, Depa men o In e nal Medicine, Uni e si y o Michigan Medical School, 109 Zina Pi che Place, Ann A bo , MI 48109-2200, USA Co esponding au ho : Zol án Szekanecz, [email p o ec ed] Published: 10 Oc obe 2008 A h i is Resea ch & The apy 2008, 10:224 (doi:10.1186/a 2515) This a icle is online a h p://a h i is- esea ch.com/con en /10/5/224 © 2008 BioMed Cen al L d β2GPI = β2 glycop o ein I; AECA = an i-endo helial cell an ibody; Ang = angiopoie in; an i-CCP = an i-cyclic ci ullina ed pep ide; an i-oxLDL = an i-oxidized low-densi y lipop o ein; APA = an iphospholipid an ibody; APS = an iphospholipid synd ome; C = cys eine; CAM = endo helial adhesion molecule; ccIMT = common ca o id in ima-media hickness; CRP = C- eac i e p o ein; CTAP-III = connec i e issue-ac i a ing pep ide-III; CVD = ca dio ascula disease; DMARD = disease-modi ying an i heuma ic d ug; EC = endo helial cell; ECM = ex acellula ma ix; EGF = epide - mal g ow h ac o ; ELR = glu amic acid-leucine-a ginine; ENA-78 = epi helial neu ophil-ac i a ing p o ein-78; EPC = endo helial p ogeni o cell; FGF = ib oblas g ow h ac o ; FMD = low-media ed asodila ion; g oα= g ow h- egula ed oncogene-alpha; HEV = high endo helial enule; HIF = hypoxia-inducible ac o ; ICAM = in e cellula adhesion molecule; IFN = in e e on; IL = in e leukin; IP-10 = in e e on-gamma-inducible 10-kDa p o ein; JAM = junc ional adhesion molecule; LDL = low-densi y lipop o ein; LFA = lymphocy e unc ion-associa ed an igen; MCP-1 = monocy e chemoa ac an p o ein-1; Mig = monokine induced by in e e on-gamma; MIP-1α= mac ophage in lamma o y p o ein-1-alpha; MMP = ma ix me al- lop o einase; MTX = me ho exa e; oxLDL = oxidized low-densi y lipop o ein; PAPS = p ima y an iphospholipid synd ome; PECAM-1 = pla ele - endo helial cell adhesion molecule-1; PF4 = pla ele ac o -4; RA = heuma oid a h i is; SDF-1 = s omal cell-de i ed ac o -1; SLE = sys emic lupus e y hema osus; SSc = sys emic scle osis; TGF-β= ans o ming g ow h ac o -be a; TNF = umo nec osis ac o ; VCAM = ascula cell adhesion molecule; VEGF = ascula endo helial g ow h ac o . Page 2 o 10 (page numbe no o ci a ion pu poses) A h i is Resea ch & The apy Vol 10 No 5 Szekanecz and Koch in o ma ion on a h i is- ela ed ascula in lamma ion, inclu- ding he ole o endo helial cells (ECs), endo helial adhesion molecules (CAMs) and chemokines, as well as he in ol e- men o neo ascula iza ion and some aspec s o accele a ed a he oscle osis in heuma ic diseases. We will discuss RA in mo e de ail, and o he connec i e issue diseases desc ibed abo e will also be men ioned. Finally, some aspec s o ascula a ge ing in heuma ology will also be b ie ly summa ized. Endo helial biology and leukocy e a icking h ough he essel wall Vascula pe meabili y and ascula damage unde lying in lamma ion In a h i is, leukocy e ing ess in o he syno ium occu s by leukocy e adhesion o ECs and hen by ansendo helial mig a ion [1-8]. The chemo axis o hese leukocy es is egu- la ed mainly by a ious chemokines [1,8,9-14]. Se e al CAMs ha e been implica ed in leukocy e-EC in e ac ions [1-4,7,8]. ECs play an ac i e ole in in lamma ion. Syno i is is associa ed wi h asodila ion and inc eased endo helial pe - meabili y (leakage) and ascula inju y ollowed by endo helial egene a ion [4-6]. ECs sec e e se e al asodila o y media o s, including ni ic oxide, p os acyclin (PGI2), pla ele -ac i a ing ac o , his amine, and o he s [4-6]. Inc eased ascula pe meabili y associa ed wi h EC e ac ion and con ac ion may be a physiological p ocess, while in in lamma ion, p o- in lamma o y media o s igge ascula damage [4-6]. Inc eased ascula pe meabili y is induced p ima ily by asoac i e agen s such as his amine, se o onin, b adykinin, and o he s [4-6,15]. Vascula inju y is caused p ima ily by ac i a ed neu ophils, in lamma o y media o s eleased by hese cells, including eac i e oxygen in e media es and ma ix me allop o einases (MMPs). An i-EC an ibodies (AECAs), umo nec osis ac o -alpha (TNF-α), in e leukin-1 (IL-1), o in e e on-gamma (IFN-γ) s imula es EC inju y [4- 6,15]. The abundan p oduc ion o AECAs, ma ke s o ascula damage, has been epo ed in RA, SLE, sys emic asculi is, and o he heuma ic diseases [15] (Table 1). Inju y is ollowed by endo helial egene a ion, which may be associa ed wi h angiogenesis o may occu wi hou he o ma ion o new blood essels [5,6,16]. In e cellula adhesion molecules in a h i is The cascade o leukocy e ansendo helial mig a ion begins wi h he adhesion o leukocy es, including neu ophils, lymphocy es, and monocy es, o pos capilla y enules. Leukocy e ec ui men occu s h ough he wall o hese enules. In some RA pa ien s, specialized ECs esembling high endo helial enules (HEVs) a e ound in he syno ium. These HEVs a e su ounded by lymphoid agg ega es composed o T cells [1,2,8]. In lamma o y leukocy e ec ui - men in o in lamed issue is e y simila o he ‘homing’ associa ed wi h physiological immune su eillance [1-3]. Leukocy e adhesion o ECs o o ex acellula ma ix (ECM) cons i uen s is media ed by endo helial CAMs and hei coun e - ecep o s on in il a ing whi e blood cells. P ima ily selec ins, in eg ins, and some membe s o he immuno- globulin supe amily o adhesion molecules (CAMs) ha e been implica ed in leukocy e ex a asa ion, bu some o he CAMs may also play a ole in his p ocess [2,3,7]. These CAMs a e summa ized in Table 2. Du ing leukocy e ans- endo helial mig a ion, selec ins media e he ini ial ‘ e he ing’ and ‘ olling’ o leukocy es whe eas in eg ins and o he CAMs a e in ol ed in i m adhesion and mig a ion o leukocy es [1,3,8]. All selec ins, mos in eg ins, and membe s o he immunoglobulin supe amily a e abundan ly exp essed in a h i ic syno ial issues [2,3]. O he CAMs in ol ed in leuko- cy e-EC adhesion unde lying in lamma ion include in a- cellula adhesion molecule-3 (ICAM-3), he lymphocy e unc ion-associa ed an igen-3 (LFA-3)-CD2 coun e - ecep o s, a ious al e na i e o ms o CD44, ascula adhesion p o eins (VAP-1 and VAP-2), endoglin (CD105), E-cadhe in, N- cadhe in, cadhe in-11, pla ele -endo helial cell adhesion molecule-1 (PECAM-1) (CD31), junc ional adhesion molecules (JAMs), CD99, and o he s [1-3,7]. All o hese CAMs ha e been de ec ed in a h i ic syno ial issues [1-3]. Chemokines and chemokine ecep o s in syno ial in lamma ion Chemokines a e small p o eins exe ing chemo ac ic ac i i y owa d leukocy es [9-12,14,17,18]. Chemokines ha e been classi ied in o supe gene amilies acco ding o he loca ion o cys eine (C) in hei molecula s uc u e. These amilies a e designa ed as CXC, CC, C, and CX3C chemokines; he pa icula chemokine ligand membe s a e CXCL, CCL, CL, and CX3CL, and he ou chemokine ecep o g oups a e CXCR, CCR, CR, and CX3CR, espec i ely [9,10,12]. To da e, mo e han 50 chemokines and 19 chemokine ecep o s ha e been iden i ied [9,10,12] (Table 3). Mos CXC chemo- kines chemoa ac neu ophils, bu pla ele ac o -4 (PF4)/ CXCL4 and IFN-γ-inducible 10-kDa p o ein (IP-10)/CXCL10 ec ui lymphocy es and monocy es [9]. Among CXC chemokines, IL-8/CXCL8, epi helial neu ophil-ac i a ing Table 1 Some impo an in lamma o y media o s eleased by ascula endo helial cells Cy okines In e leukin-1 In e leukin-6 Chemokines In e leukin-8/CXCL8 Monocy e chemoa ac an p o ein-1/CCL2 G ow h- egula ed oncogene-alpha/CXCL1 G ow h ac o s Endo helial cell-de i ed g ow h ac o T ans o ming g ow h ac o -be a Colony-s imula ing G anulocy e colony-s imula ing ac o ac o s G anulocy e-mac ophage colony-s imula ing ac o O he s Pla ele -ac i a ing ac o Ni ic oxide P os acyclin (PGI2) Page 3 o 10 (page numbe no o ci a ion pu poses) p o ein-78 (ENA-78)/CXCL5, g ow h- egula ed oncogene- alpha (g oα)/CXCL1, connec i e issue-ac i a ing pep ide-III (CTAP-III)/CXCL7, g anulocy e chemo ac ic p o ein-2/ CXCL6, IP-10/CXCL10, PF4/CXCL4, monokine induced by IFN-γ(Mig)/CXCL9, s omal cell-de i ed ac o -1 (SDF-1)/ CXCL12, B cell-ac i a ing chemokine-1/CXCL13, and CXCL16 ha e been implica ed in he pa hogenesis o syno ial in lamma ion [14,17,18]. CC chemokines s imula e monocy e chemo axis and some o hem also chemoa ac lymphocy es [10]. Monocy e chemoa ac an p o ein-1 (MCP-1)/CCL2, mac ophage in lamma o y p o ein-1-alpha (MIP-1α)/CCL3, MIP-3α/CCL20, RANTES (Regula ed upon Ac i a ion, No mal T-cell Exp essed and Sec e ed)/CCL5, Eps ein-Ba i us-induced gene-1 ligand chemokine (ELC)/ CCL19, seconda y lymphoid issue chemokine (SLC)/CCL21, and chemokine-like ac o -1 (CKLF1) ha e been implica ed in in lamma o y mechanisms unde lying syno i is [14,17,18]. The C chemokine amily con ains wo membe s: lympho- ac in/XCL1 and single C mo i -1-be a (SCM-1β)/XCL2 [12]. Lympho ac in/XCL1 has been de ec ed on syno ial T cells in RA [14,18]. The CX3C chemokine sub amily con ains ac- alkine/CX3CL1 [12,19]. This chemokine chemoa ac s mononuclea cells and also se es as a CAM [17,19]. F ac alkine/CX3CL1 has also been de ec ed in RA syno ial issues [19]. F ac alkine/CX3CL1 has also been implica ed in he de elopmen o accele a ed a he oscle osis [18], a opic discussed la e . Chemokines bind o hei se en- ansmemb ane domain ecep o s exp essed on he a ge cells [12,18]. Some o hese ecep o s ha e nume ous chemokine ligands whe eas o he s a e speci ic ecep o s o single ligands [14]. Chemokine ecep o s ha e also been associa ed wi h a ious his ological sub ypes o in lamma ion. Fo example, whe eas CXCR3 and CCR5 may be in ol ed p ima ily in Th1 ype diseases (such as RA), CCR3, CCR4, and CCR8 may play a ole in leukocy e mig a ion unde lying Th2 ype in lamma ion (such as as hma) [11]. Mos CXC and CC chemokine ecep o s men ioned abo e as well as XCR1 and CX3CR1 a e exp essed in he a h i ic syno ium [14,17,18]. The p ocess o leukocy e ec ui men in o in lamed issues Leukocy e adhesion o ECs occu s ollowing a cascade o e en s. Whi e blood cells in he bloods eam weakly adhe e o he endo helium lining he inne essel wall ( e he ing) ollowed by olling o leukocy es on he endo helial laye . Te he ing and olling a e media ed p ima ily by selec ins and hei ligands. These e en s a e ollowed by leukocy e ac i a ion, which is dependen upon in e ac ions be ween chemokine ecep o s exp essed on leukocy es and p o eo- glycans on ECs. Ac i a ion-dependen i m adhesion occu s nex , in ol ing α4β1in eg in/VCAM-1 ( ascula cell adhesion molecule-1), β2in eg in/ICAM-1, and JAM/in eg in in e - ac ions. This is associa ed wi h he sec e ion o chemokines. These chemokines may also up egula e in eg in exp ession on he adhe ing cells ia PI3K (phospha idylinosi ol 3-kinase)- A ailable online h p://a h i is- esea ch.com/con en /10/5/224 Table 2 Rele an membe s o he selec in, in eg in, and immunoglobulin adhesion molecule supe amilies Adhesion ecep o s Ligands Selec ins L-selec in (CD62L, LAM-1) Sialyla ed ca bohyd a es, GlyCAM-1 E-selec in (CD62E, ELAM-1) Sialyl-Lewis-X P-selec in (CD62P, PADGEM) Sialyl-Lewis-X, o he ca bohyd a es In eg ins β1in eg ins Laminin, collagen, ib onec in α4β1in eg ins Fib onec in, VCAM-1 β2in eg ins ICAM-1, ICAM-2, ICAM-3, JAM-A β3in eg ins Vi onec in, on Willeb and ac o , o he ma ix molecules Immunoglobulin supe amily ICAM-1, ICAM-3 αLβ2(LFA-1), αMβ2(Mac-1, CR3) VCAM-1 α4β1, α4β7 CD2 LFA-3 PECAM-1 (CD31) PECAM-1, αVβ3in eg in ELAM-1, endo helial-leukocy e adhesion molecule-1; GlyCAM-1, glycosyla ion-dependen cell adhesion molecule-1; ICAM, in acellula adhesion molecule; JAM-A, junc ional adhesion molecule-A; LAM-1, leukocy e adhesion molecule-1; LFA, lymphocy e unc ion-associa ed an igen; Mac-1, mac ophage in eg in; PADGEM, pla ele ac i a ion-dependen g anule-ex e nal memb ane p o ein; PECAM-1, pla ele -endo helial cell adhesion molecule-1; VCAM-1, ascula cell adhesion molecule-1. media ed pa hways. Leukocy e diapedesis h ough he endo helial laye in ol ing in eg ins occu s when chemokines bind o endo helial hepa an sulpha e. Chemokines p e e en- ially chemoa ac EC-adhe en leukocy es. These p ocesses lead o he ansmig a ion o leukocy es in o he in lamed issue [1,8]. Ta ge ing o cell adhesion, chemokines, and leukocy e ec ui men Inhibi ion o cell adhesion, chemokines, and mig a ion using speci ic an ibodies o pu i ied ligands has p o ided an impo an pe spec i e on he molecula pa hogenesis o RA. In addi ion, some o hese s a egies may be included in he u u e he apy o a h i is [20]. Rega ding an i-CAM ials, an an i-human ICAM-1 an ibody (enlimomab) was ied in e ac o y RA wi h li le success [2,20]. O he an iadhesion s a egies ha e been in oduced in o he ea men o o he in lamma o y diseases. Fo example, e alizumab (an i-LFA-1) and ale acep (LFA-3-Ig usion p o ein) ha e been ied in pso iasis, na alizumab (an i-α4in eg in) in mul iple scle osis and C ohn disease, and an an i-α4β7in eg in monoclonal an ibody in ulce a i e coli is [2,3,20]. These and o he an i- CAM s a egies may be ied in a h i is as well [2,3,20]. Chemokines and chemokine ecep o s can be a ge ed in a numbe o ways. Disease-modi ying an i heuma ic d ugs (DMARDs) and an i-TNF biologics, cu en ly used in he ea men o RA, may indi ec ly in luence chemokine p oduc- ion [18]. An ibodies o IL-8/CXCL8, ENA-78/CXCL5, CXCL16, MIP-1α/CCL3, MCP-1/CCL2, and ac alkine/ CX3CL1 ha e been used o con ol a h i is in a ious oden models [18-20]. Se e al o al chemokine ecep o an ago- nis s, including CXCR2, CXCR4, CCR1, CCR2, and CCR5 inhibi o s, ha e been ied in human RA as well as in animal models o a h i is [18,20-22]. Angiogenesis and asculogenesis in heuma ic diseases The p ocesses o angiogenesis and asculogenesis Angiogenesis is he o ma ion o new capilla ies om p e- exis ing essels, whe eas asculogenesis in ol es ci cula ing endo helial p ogeni o cells (EPCs) [14,16,23-27]. Angio- genesis in ol es cell su ace-bound and soluble angiogenic media o s, which ac i a e ascula ECs (Table 4). In esponse, ECs elease MMPs, which diges he unde lying basal memb ane and he ECM enabling he emig a ion o ECs. Single ECs will hen ga he o o m capilla y sp ou s. Lumen o ma ion wi hin he sp ou s leads o capilla y loops. Finally, he syn hesis o new basemen memb ane leads o he o ma ion o new capilla ies [23]. Rega ding asculo- genesis, a subpopula ion o ci cula ing CD34+cells exp es- sing he ascula endo helial g ow h ac o -2 (VEGF-2) ecep o has been iden i ied and cha ac e ized as unc ional EPCs. Dec eased numbe s o EPCs as well as impai ed asculogenesis ha e been associa ed wi h a h i is [27,28]. A h i is Resea ch & The apy Vol 10 No 5 Szekanecz and Koch Page 4 o 10 (page numbe no o ci a ion pu poses) Table 3 Chemokine ecep o s wi h ligands ele an o a h i is and angiogenesis Chemokine ecep o Chemokine ligand CXC chemokine ecep o s CXCR1 IL-8/CXCL8 CXCR2 IL-8/CXCL8, ENA-78/CXCL5, g oα/CXCL1, CTAP-III/CXCL7 CXCR3 IP-10/CXCL10, PF4/CXCL4, Mig/CXCL9, ITAC/CXCL11 CXCR4 SDF-1/CXCL12 C-C chemokine ecep o s CCR1 MIP-1α/CCL3, RANTES/CCL5, MCP-3/CCL7, MPIF-1/CCL23 CCR2 MCP-1/CCL2, MCP-3/CCL7 CCR6 MIP-3α/CCL20 CCR7 MIP-3β/CCL19, SLC/CCL21 C chemokine ecep o s XCR1 Lympho ac in/XCL1 C-X3-C chemokine ecep o s CX3CR1 F ac alkine/CX3CL1 CTAP-III, connec i e issue-ac i a ing pep ide-III; ENA-78, epi helial neu ophil-ac i a ing p o ein-78; g oα, g ow h- egula ed oncogene-alpha; IL-8, in e leukin-8; IP-10, in e e on-gamma-inducible 10-kDa p o ein; ITAC, in e e on-inducible T-cell alpha chemoa ac an ; MCP, monocy e chemoa ac an p o ein; Mig, monokine induced by in e e on-gamma; MIP, mac ophage in lamma o y p o ein; MPIF-1, myeloid p ogeni o inhibi o y ac o -1; PF4, pla ele ac o -4; RANTES, Regula ed upon Ac i a ion, No mal T-cell Exp essed and Sec e ed; SDF-1, s omal cell-de i ed ac o -1; SLC, seconda y lymphoid issue chemokine. The majo chemoa ac an ha d i es EPCs is he SDF- 1/CXCL12 chemokine and i s ecep o , CXCR4 [29]. In a h i is, p oin lamma o y cy okines s imula e he p oduc ion o SDF-1/CXCL12 and hus issue asculogenesis by ec ui ing CXCR4+EPCs [14,17,29]. Angiogenic media o s and inhibi o s in heuma oid a h i is The hypoxia-VEGF-angiopoie in pa hway is an essen ial angiogenic ne wo k in syno i is [16,23-25,30]. VEGF, a g ow h ac o ha binds o hepa in in he syno ial ECM, plays a cen al ole in he egula ion o neo ascula iza ion [23,30]. The e is hypoxia p esen wi hin he join ca i y, and hypoxia as well as TNF-αand IL-1 s imula e VEGF elease [16]. Hypoxia ac s h ough he hypoxia-inducible ac o he e odime , HIF-1α/ HIF-1β[16]. Se e al o he angiogenic media o s also ac indi ec ly ia VEGF [23]. Angiopoie in-1 (Ang1) and Ang2 egula e EC unc ions upon s imula ion by VEGF. Bo h Ang1 and Ang2 in e ac wi h he Tie2 endo helial y osine kinase ecep o [16,24]. Ang1-Tie2 in e ac ions esul in essel s abiliza ion. On he o he hand, Ang2, an an agonis o Ang1, inhibi s essel ma u a ion [24]. Ano he impo an playe in his ne wo k is su i in, an apop osis inhibi o , which is also in ol ed in VEGF-induced angiogenesis and EC su i al [16]. VEGF, HIF-1, Ang1, Tie2, and su i in a e all exp essed in he a h i ic syno ium [16,25]. G ow h ac o s o he han VEGF bu implica ed in angiogenesis include ib oblas (FGF-1 and FGF-2), hepa ocy e, pla ele -de i ed, epide mal (EGF), insulin- like, and ans o ming (TGF-β) g ow h ac o s [16,24,25]. Among chemokines desc ibed abo e, CXC chemokines ha con ain he ELR (glu amic acid-leucine-a ginine) amino acid mo i p omo e angiogenesis [13]. ELR+CXC chemokines ha s imula e angiogenesis and also syno ial in lamma ion include IL-8/CXCL8, ENA-78/CXCL5, g oα/CXCL1, and CTAP-III/CXCL7. SDF-1/CXCL12 is a unique CXC chemo- kine as i exe s mainly a homeos a ic unc ion, ye i has been implica ed in in lamma ion such as in RA [13,14,17,29]. Mo eo e , his chemokine lacks he ELR mo i bu is s ill angiogenic [14,29]. The c ucial ole o SDF-1/CXCL12 in asculogenesis is discussed abo e [29]. In con as o angiogenic CXC chemokines, he ELR–PF4/CXCL4, IP-10/ CXCL10, and Mig/CXCL9 supp ess neo ascula iza ion [13,14,17]. Rega ding CC chemokines, MCP-1/CCL2 p omo es neo ascula iza ion induced by g ow h ac o s [14,17]. The sole CX3C chemokine, ac alkine/CX3CL1, also p omo es syno ial angiogenesis [14,17,19]. Rega ding chemokine ecep o s, CXCR2, which binds mos ELR+CXC chemokines desc ibed abo e, is a c ucial chemokine ecep o in angiogenesis [13,14,17]. CXCR4 has been implica ed in SDF-1/CXCL12-induced neo ascula iza ion in a h i is [14,17,29]. In con as , CXCR3, a ecep o o he angios a ic IP-10/CXCL10 and Mig/CXCL9, may be in ol ed in chemokine-media ed angios asis [14,17]. Nume ous p oin lamma o y cy okines, such as TNF-α, IL-1, IL-6, IL-15, IL-17, IL-18, g anulocy e and g anulocy e-mac ophage colony-s imula ing ac o s, oncos a in M, and mac ophage mig a ion inhibi o y ac o , also induce syno ial angiogenesis [16,31]. In con as , o he cy okines, such as IFN-α, IFN-γ, IL-4, IL-12, IL-13, and leukemia inhibi o y ac o , supp ess he p oduc ion o angiogenic media o s and hus inhibi neo- ascula iza ion [16,31,32]. ECM componen s, ma ix-deg a- ding p o eases, and cellula adhesion molecules desc ibed abo e may be in ol ed in EC emig a ion, sp ou ing, and hus angiogenesis. Among ECM componen s, a ious ypes o collagen, ib onec in, laminin, i onec in, enascin, and p o eoglycans p omo e neo ascula iza ion [16]. P o eoly ic enzymes, such as MMPs and plasminogen ac i a o s, play a ole in ma ix deg ada ion unde lying syno ial angiogenesis [16,25]. On he o he hand, issue inhibi o s o me allo- p o einases and plasminogen ac i a o inhibi o s an agonize he angiogenic e ec s o p o eases desc ibed abo e [16,32]. Among CAMs, β1and β3in eg ins, E-selec in, glycoconju- ga es (including Lewisy/H), melanoma cell adhesion molecule (MUC18), VCAM-1, PECAM-1, and endoglin ha e been implica ed in neo ascula iza ion [2,16,25,33,34]. The αVβ3 in eg in is o ou s anding impo ance as his CAM media es bo h syno ial angiogenesis and os eoclas -media ed bone eso p ion and he de elopmen o e osions in RA [34]. O he impo an angiogenic ac o s no men ioned abo e include endo helin-1, angiogenin, angio opin, and many o he s [16,25] (Table 4). Angios a ic media o s and compounds also include angios a in (a agmen o plasminogen), endos a in (a agmen o ype XIII collagen), h ombospondin-1, 2-me hoxyes adiol, pacli axel, os eonec in, chond omodulin-1, and o he s [16,30,32,35] (Table 4). These molecules supp ess he ac ion o angiogenic media o s, such as VEGF, HIFs, o he αVβ3in eg in [16,30,32,35]. Angiogenesis in o he ypes o a h i is and connec i e issue diseases Di e en ial ascula mo phology may exis in he syno ia o RA e sus pso ia ic a h i is (PsA) pa ien s [16,25]. Fu he - mo e, VEGF p oduc ion may be associa ed wi h inc eased disease ac i i y and accele a ed angiogenesis in PsA and ankylosing spondyli is [16]. In SLE, angiogenic EGF, FGF, and IL-18 as well as angios a ic endos a in ha e been de ec ed in he se a o pa ien s. Se um VEGF le els we e co ela ed wi h he SLAM (sys emic lupus ac i i y measu e) ac i i y sco e [16,25]. Angiogenesis in SSc is somewha con o e sial. On one hand, he e is signi ican loss o essels in scle ode ma despi e se e e issue hypoxia associa ed wi h inc eased concen a ions o he angios a ic endos a in [16,28]. On he o he hand, SSc skin biopsy explan s s imu- la ed neo ascula iza ion and he e is inc eased p oduc ion o VEGF in he se a and skin o scle ode ma pa ien s [16,28]. Thus, hypoxia may induce angiogenesis in SSc bu his is ansien and he newly o med essels a e a he uns able in his disease [28]. Fu he mo e, sus ained p oduc ion o VEGF esul s in he o ma ion o gian capilla ies seen using capil- la oscopy in SSc [16,28]. Simila ly o SSc, in in lamma o y myopa hies, exp ession o hypoxia-associa ed inc eased HIF-1, αVβ3in eg in, and VEGF ecep o in muscle biopsies A ailable online h p://a h i is- esea ch.com/con en /10/5/224 Page 5 o 10 (page numbe no o ci a ion pu poses) was no su icien o compensa e he loss o blood essels [16,25]. Rega ding sys emic asculi ides, abundan p oduc- ion o angiogenic VEGF and TGF-βhas been associa ed wi h Kawasaki synd ome [16]. Inc eased se um le els o TGF-βwe e ound in ANCA (an ineu ophil cy oplasmic an ibody)-associa ed aculi ides, including Wegene g anuloma osis, Chu g-S auss synd ome, and mic oscopic polyangii is [16,25]. Ta ge ing o angiogenesis in in lamma o y heuma ic diseases The e may be wo majo s a egies o con ol angiogenesis in a h i is as well as in malignancies [16,32,35]. Endogenous inhibi o s o neo ascula iza ion desc ibed abo e, including cy okines, chemokines, p o ease inhibi o s, and o he s, a e na u ally p oduced in he a h i ic syno ium. Howe e , angio- genic media o s a e abundan wi hin he in lamed issue; he e o e, hese endogenous angios a ic molecules need o be adminis e ed in excess in o de o a enua e neo- ascula iza ion. In addi ion, nume ous syn he ic compounds cu en ly used o con ol in lamma ion and o ea a h i is may, among o he e ec s, inhibi capilla y o ma ion as well. These exogenous angios a ic compounds include co ico- s e oids, adi ional disease-modi ying agen s (DMARDs) and biologics, an ibio ic de i a i es, halidomide, and o he s [16,32,35] (Table 5). Among endogenous angiogenesis inhibi o s, angios a in and endos a in block αVβ3in eg in- dependen angiogenesis and bo h molecules inhibi ed he de elopmen o a h i is in a ious animal models [16,35]. Th ombospondin-1 and -2 a e angios a ic ECM componen s p oduced by RA syno ial mac ophages and ib oblas s [16,32]. IL-4 and IL-13 gene ans e a enua ed syno ial in lamma ion and angiogenesis in a s [16]. The PF4/CXCL4 chemokine has also been ied in oden models [16]. Fumagillin analogs, such as TNP-470 and PPI2458, also exe angios a ic and an ia h i ic p ope ies [16,32,35]. T adi ional DMARDs and biologics exe a ious an i- in lamma o y e ec s. In addi ion, hese compounds may inhibi syno ial essel o ma ion by nonspeci ically blocking he ac ion o angiogenic media o s [16,17]. Thalidomide, ecen ly in oduced in o he ea men o RA and lupus, is a po en TNF-αan agonis and angiogenesis inhibi o [16,35]. CC1069, a halidomide analog, e en mo e po en ly inhibi ed a h i is in a s [35]. The hypoxia-HIF pa hway may also be a ge ed using nonspeci ic inhibi o compounds, including YC-1 [16,35]. 2-Me hoxyes adiol, men ioned abo e, and pacli axel ( axol), a d ug al eady used in human cance , des abilize he in acellula cy oskele on and also block HIF- 1α[35]. Soluble Fas ligand (CD178) inhibi ed syno ial VEGF p oduc ion and angiogenesis [16]. Piogli azone, an an i- diabe ic PPAR-γ(pe oxisome p oli e a o -ac i a ed ecep o - gamma) agonis , is also angios a ic. Piogli azone e ec i ely con olled pso ia ic a h i is in 10 pa ien s [16,35]. Rega ding speci ic exogenous s a egies, VEGF is he key a ge [30,35]. Nume ous syn he ic VEGF and VEGF ecep o inhibi o s (including a alanib, suni inib, so a enib, and ande anib), an i-VEGF an ibodies (including be acizumab), and inhibi o s o VEGF and VEGF ecep o signaling inhibi neo ascula iza ion and a e unde de elopmen o cance he apy [30,35]. To da e, a alanib has been ied and A h i is Resea ch & The apy Vol 10 No 5 Szekanecz and Koch Page 6 o 10 (page numbe no o ci a ion pu poses) Table 4 Some angiogenic and angios a ic ac o s in a h i is Media o s Inhibi o s Chemokines IL-8/CXCL8, ENA-78/CXCL5, g oα/CXCL1, CTAP-III/CXCL7, PF4/CXCL4, IP-10/CXCL10, Mig/CXCL9, SDF-1/CXCL12, MCP-1/CCL2, SLC/CCL21, MPIF/CCL23, SLC/CCL21 ac alkine/CX3CL1 Ma ix molecules Type I collagen, ib onec in, laminin, hepa in, hepa an sulpha e Th ombospondin, RGD sequence Cell adhesion molecules β1and β3in eg ins, E-selec in, P-selec in, CD34, VCAM-1, RGD sequence (in eg in ligand) endoglin, PECAM-1, ascula endo helial-cadhe in, Lewisy/H, MUC18 G ow h ac o s VEGF, bFGF, aFGF, PDGF, EGF, IGF-I, HIF-1, TGF-βaTGF-βa Cy okines TNF-α, IL-6a, IL-15, IL-18 IL-4, IL-6a, IFN-α, IFN-γ P o eases MMPs, plasminogen ac i a o s TIMPs, plasminogen ac i a o inhibi o s O he s Angiogenin, subs ance P, p olac in DMARDs, in liximab, e ane cep , angios a in, endos a in aMedia o s wi h bo h p oangiogenic and an iangiogenic e ec s. aFGF, acidic ib oblas g ow h ac o ; bFGF, basic ib oblas g ow h ac o ; CTAP- III, connec i e issue-ac i a ing pep ide-III; DMARD, disease-modi ying an i heuma ic d ug; EGF, epide mal g ow h ac o ; ENA-78, epi helial neu ophil-ac i a ing p o ein-78; g oα, g ow h- egula ed oncogene-alpha; HIF-1, hypoxia-inducible ac o -1; IFN, in e e on; IGF-I, insulin-like g ow h ac o -I; IL, in e leukin; IP-10, in e e on-gamma-inducible 10-kDa p o ein; MCP-1, monocy e chemoa ac an p o ein-1; Mig, monokine induced by in e e on-gamma; MMP, ma ix me allop o einase; MPIF, myeloid p ogeni o inhibi o y ac o ; MUC18, melanoma cell adhesion molecule; PDGF, pla ele -de i ed g ow h ac o ; PECAM-1, pla ele -endo helial cell adhesion molecule-1; PF4, pla ele ac o -4; RGD, a ginine-glycine-aspa ic acid; SDF-1, s omal cell-de i ed ac o -1; SLC, seconda y lymphoid issue chemokine; TGF-β, ans o ming g ow h ac o -be a; TIMP, issue inhibi o s o me allop o einase; TNF-α, umo nec osis ac o -alpha; VCAM-1, ascula cell adhesion molecule-1; VEGF, ascula endo helial g ow h ac o . a enua ed knee a h i is in abbi s [35]. The Ang-Tie sys em may also be a ge ed. A soluble Tie2 ecep o ansc ip was deli e ed ia an adeno i al ec o o mice. The inhibi ion o Tie2 delayed he onse and a enua ed he se e i y o a h i is [16,35]. Vi axin, a humanized an ibody o he αVβ3in eg in, inhibi ed syno ial angiogenesis [16,34] bu , in a phase II human RA ial, showed only limi ed e icacy [35]. Nume ous speci ic MMP inhibi o s ha e been ied in angiogenesis models [16,35]. Endo helin-1 an agonis s cu en ly used in he he apy o p ima y and SSc-associa ed seconda y pulmona y hype ension may also exe angios a ic e ec s [16,28]. Accele a ed a he oscle osis in heuma ic diseases The basis o a he oscle osis and inc eased ascula isk Accele a ed a he oscle osis and inc eased ca dio ascula mo bidi y and mo ali y ha e been associa ed wi h RA, SLE, APS, and SSc [36-41]. Ca dio ascula disease (CVD) causes educed li e expec ancy and became a majo mo ali y ac o in hese diseases [36-41]. A he oscle osis is also conside ed an in lamma o y disease; hus, i may sha e common pa hogenic mechanisms wi h heuma ic diseases [36,42,43] (Table 6). Nume ous s udies ha e demons a ed he ole o adi ional, F amingham, and in lamma ion-asso- cia ed isk ac o s in a he oscle osis associa ed wi h a h i is [36-38,44]. Among adi ional isk ac o s, ciga e e smoking no only is a majo isk ac o o CVD bu has ecen ly been implica ed in issue ci ullina ion, he p oduc ion o an i-cyclic ci ullina ed pep ide (an i-CCP) an ibodies, and hus suscep ibili y o RA [36,38]. In addi ion o smoking, physical inac i i y, obesi y, hype ension, dyslipidemia, and diabe es melli us may be implica ed in accele a ed a he oscle osis [36-38,44]. Ye excess CVD mo ali y occu s p edominan ly in RA pa ien s wi h a highe deg ee o sys emic in lamma ion [36]; he e o e, accele a ed a he oscle osis canno be ully explained on he basis o adi ional isk ac o s [42,43]. Indeed, se e al in lamma o y and a he ogenic media o s, including homocys eine, lipop o ein (a), C- eac i e p o ein (CRP), hype homocys einemia, and ola e, and i amin B12 de iciency and dec eased pa aoxonase-1 ac i i y a e s ongly associa ed wi h a he oscle osis and CVD [36,42,43]. A he o- scle o ic plaques, simila ly o he RA join , a e cha ac e ized by enhanced accumula ion o in lamma o y monocy es/ mac ophages and T cells. These in lamma o y leukocy es abundan ly p oduce p oin lamma o y cy okines, chemokines, and MMPs [42,43]. CD4+T cells, especially he CD4+/ CD28–T-cell subse , ha e been associa ed wi h bo h a h i is and in lamma ion- ela ed ascula damage [37,38,43]. Rega ding p oin lamma o y cy okines, TNF-αand IL-6 play an impo an ole in a he oscle osis as well as in RA [31,36,43]. Inc eased p oduc ion o TNF-αand IL-6 has been associa ed wi h hea ailu e as well as wi h insulin esis ance, dys- lipidemia, and obesi y [36,43]. In con as , IL-4 and IL-10 may exe an an i-in lamma o y ole du ing he de elopmen o a he oscle osis by d i ing Th2 esponses [31,43] (Table 6). Vascula in ol emen in a ious heuma ic diseases In RA, age, gende , e hnici y, adi ional isk ac o s desc ibed abo e as well as (among RA- ela ed isk ac o s) disease du a ion, ac i i y, and se e i y, unc ional impai men , heuma- oid ac o and an i-CCP s a us, CRP, adiog aphic indica- o s, p esence o he sha ed epi ope, and ea men modali ies ha e been implica ed in he de elopmen o accele a ed a he oscle osis [36-38,44]. We ha e ecen ly assessed common ca o id in ima-media hickness (ccIMT) indica ing a he oscle osis and low-media ed asodila ion (FMD), a ma ke o endo helial dys unc ion in RA. Inc eased ccIMT and impai ed FMD ha e been associa ed wi h age, disease du a ion, and an i-CCP, CRP, and IL-6 p oduc ion [44]. In SLE, p ima y APS (PAPS) and seconda y APS associa ed wi h SLE, adi ional, and au oimmune-in lam- ma o y ac o s a e in ol ed [40]. Among hese ac o s, longe disease du a ion and cumula i e co icos e oid dose seem o A ailable online h p://a h i is- esea ch.com/con en /10/5/224 Page 7 o 10 (page numbe no o ci a ion pu poses) Table 5 An iangiogenic a ge s Endogenous inhibi o s Angios a in Endos a in Th ombospondin-2 In e leukin-4, in e leukin-13 Pla ele ac o -4/CXCL4 chemokine Exogenous inhibi o s Classical disease-modi ying an i heuma ic d ugs An i- umo nec osis ac o biologics Thalidomide Fumagillin analogs Vascula endo helial g ow h ac o inhibi o s Hypoxia-inducible ac o he e odime inhibi o s Angiopoie in-1/Tie2 inhibi o s αVβ3in eg in inhibi o s Mic o ubule des abilize s ( o example, pacli axel) O he s ( o example, gli azones) be he majo p edic o s o clinical a he oscle osis [37,38,40,41]. Addi ional in lamma o y isk ac o s include CRP, ib inogen, IL-6, cos imula o y molecules (CD40/CD40L), CAMs, an i-phospholipid an ibodies (APAs), including an i- ca diolipin and an i-β2 glycop o ein I (an i-β2GPI), an i- oxidized low-densi y lipop o ein (an i-oxLDL), an i-oxidized palmi oyl a achidonoyl phosphocholine (an i-oxPAPC), an i- HDL and an i-hsp an ibodies, homocys eine, and lipop o ein (a) [37,40,41]. APAs a e o impo ance in bo h SLE and APS. APAs may bind o neoepi opes o oxLDL as well as o oxLDL- β2GPI complexes, and bo h APA and an i-oxLDL an ibodies ha e been implica ed in he pa hogenesis o a he oscle osis associa ed wi h SLE and APS [37,38,40,41]. Au oan ibodies agains oxLDL-β2GPI complexes ha e been de ec ed in SLE and PAPS pa ien s [40,41]. Bo h APA and an i-oxLDL may accoun o inc eased mo ali y in CVD [41]. The β2GPI phospholipid co ac o has been de ec ed in he wall o la ge a e ies in he icini y o CD4+T-cell in il a es. Mac ophages and ECs bind o β2GPI du ing he a he oscle o ic p ocess [37,38,41]. A he oscle osis is he mos p onounced in lupus- associa ed seconda y APS, in which adi ional and non adi ional isk ac o s a e mul iplied and a he oscle osis occu s mo e p ema u ely [40,41]. SSc is associa ed wi h bo h mac o ascula disease (including CVD, pulmona y hype ension, and pe iphe al a e ial occlusion) and mic o- ascula disease (including Raynaud phenomenon) [37-39, 45,46]. Pa hogenic ac o s in ol ed in SSc-associa ed ascula damage include inc eased LDL, homocys eine, and CRP p oduc ion [37,39,46]. We ecen ly desc ibed he associa ion o 5,10-me hylene- e ahyd o ola e educ ase (MTHFR) C677T polymo phism wi h homocys eine, i amin B12 p oduc ion, and mac o ascula abno mali ies in SSc [46]. Inc eased a e ial s i ness and ccIMT as well as impai ed FMD ha e been de ec ed by us [39,45] and o he s [37] in scle ode ma. The apeu ic conside a ions An i-in lamma o y ea men used in in lamma o y heuma ic diseases may be ei he p oa he ogenic o an ia he ogenic [37,47]. Co icos e oids a e a he ogenic by augmen ing dys- lipidemia, hype ension, and diabe es melli us [36,47]. In au opsy s udies, long exposu e o co icos e oid he apy was associa ed wi h he de elopmen o a he oscle osis. Howe e , o he clinical s udies could no con i m his associa ion [36,47]. Glucoco icoids may exe a bimodal ac ion as hey a e a he ogenic bu , on he o he hand, also an i-in lamma o y. The e is e idence ha he abo e-desc ibed in lamma o y ac o s associa ed wi h mo e ac i e disease may exe highe isk o a he oscle osis han an i-in lamma o y ea men [37,47]. In con as o co icos e oids, an imala ial d ugs such as chlo oquine and hyd oxychlo oquine may exe e iden an ia he ogenic p ope ies. An imala ials may educe LDL choles e ol, e y LDL choles e ol, and (in co icos e oid- ea ed pa ien s) iglyce ide p oduc ion [36,37,47]. Me ho exa e (MTX) exe s bipola e ec s on a he oscle osis in RA: on one hand, MTX ea men inc eases plasma le els o homocys eine, bu , on he o he hand, MTX con ols se e al o he media o s o in lamma ion and hus may bene icially in luence he ne ou come o CVD in RA [36,47]. Concomi an ola e supplemen a ion p e en ed he inc ease o homocys eine p oduc ion and educed CVD mo ali y in MTX- ea ed pa ien s [36]. Among biologic agen s, TNF-α A h i is Resea ch & The apy Vol 10 No 5 Szekanecz and Koch Page 8 o 10 (page numbe no o ci a ion pu poses) Table 6 Common isk ac o s in he pa hogenesis o a he oscle osis unde lying heuma ic diseases 1. T adi ional Age Smoking Dyslipidemia Hype ension Diabe es melli us Immobiliza ion Seden a y li es yle 2. In lamma o y Acu e-phase p o eins (C- eac i e p o ein, ib inogen) Lipop o ein (a) Fola e and i amin B12 de iciency Dec eased pa aoxonase ac i i y CD4+/CD28–T cells Au oan ibodies (an i-CCP, heuma oid ac o , an i-oxLDL, an i-phospholipid an ibody, an i-hsp) P oa he ogenic cy okines ( umo nec osis ac o -alpha, in e leukin-6) Chemokines Angiogenic g ow h ac o s Ma ix-deg ading me allop o einases Inc eased cell adhesion molecule exp ession Hype homocys einemia De ec i e apop osis 3. Ia ogenic Me ho exa e - bimodal? Co icos e oids - bimodal? an i-CCP, an i-cyclic ci ullina ed pep ide; an i-oxLDL, an i-oxidized low-densi y lipop o ein. blocke s may ha e signi ican e ec s on he ascula u e [48]. In RA, in liximab ea men educed endo helial dys unc ion and ccIMT [48]. We ecen ly p oposed ha i uximab may also exe a o able e ec s on FMD, ccIMT, and dyslipidemia [49]. A he oscle osis ea men s a egies in heuma ic diseases should include an agg essi e con ol o all adi ional isk ac o s, including hype lipidemia, hype ension, smoking, obesi y, and diabe es melli us. Bo h pha macological ea men and changes in li es yle should be in oduced in hese pa ien s [47]. The e is e y li le solid e idence om andomized con olled ials indica ing he p e en a i e ac ion o any d ugs in a h i is-associa ed CVD [47]. D ug he apy may include he use o an ipla ele agen s, s a ins, olic acid, B i amins, and (as desc ibed abo e) possibly an imala ials [36,47]. A ecommenda ion om he Eu opean League Agains Rheuma ism o he p e en ion and managemen o CVD in a h i is is abou o be published [50]. Summa y In his e iew, we discussed he pu a i e ole o leukocy e-EC adhesion, chemokines, and angiogenesis in leukocy e ec ui - men unde lying he pa hogenesis o in lamma o y syno i is. A numbe o CAMs a e in ol ed in his p ocess. These CAMs in e ac wi h soluble in lamma o y media o s such as cy okines and chemokines. The p esence o a ious CAM pai s and he exis ence o dis inc s eps o olling, ac i a ion, adhesion, and mig a ion accoun o he di e si y and speci ici y o leukocy e-EC in e ac ions. Chemokines and hei ecep o s d i e in lamma o y leukocy es in o he syno ium. A numbe o soluble and cell-bound ac o s may s imula e o inhibi angiogenesis. The ou come o in lam- ma o y and o he ‘angiogenic diseases’ such as a ious o ms o a h i is depends on he imbalance be ween angiogenic and angios a ic media o s. The e ha e been se e al a emp s o he apeu ically in e e e wi h he cellula and molecula mechanisms desc ibed abo e. Speci ic a ge ing o leukocy e adhesion, CAMs, chemokines, chemokine ecep o s, and/o angiogenesis, p ima ily by using agen s wi h mul iple ac ions, may be use ul o he u u e managemen o in lamma o y heuma ic diseases. Compe ing in e es s The au ho s decla e ha hey ha e no compe ing in e es s. Acknowledgmen s This wo k was suppo ed by Na ional Ins i u es o Heal h (Be hesda, MD, USA) g an s AR-048267 and AI-40987 (AEK), he William D Robinson, MD, and F ede ick GL Hue well Endowed P o esso ship (AEK), unds om he Ve e ans’ Adminis a ion (AEK), and g an T048541 om he Na ional Scien i ic Resea ch Fund (OTKA) (ZS). Re e ences 1. Imho BA, Au and-Lions M: Adhesion mechanisms egula ing he mig a ion o monocy es. Na Re Immunol 2004, 4:432- 444. 2. Szekanecz Z, Szegedi G, Koch AE: Cellula adhesion mole- cules in heuma oid a h i is. Regula ion by cy okines and possible clinical impo ance. J In es ig Med 1996, 44:124-135. 3. Aga wal SK, B enne MB: Role o adhesion molecules in syn- o ial in lamma ion. Cu Opin Rheuma ol 2006, 18:268-276. 4. Szekanecz Z, Koch AE: Endo helial cells in in lamma ion and angiogenesis. Cu D ug Ta g 2005, 4:319-323. 5. Szekanecz Z, Koch AE: Vascula endo helium and immune esponses: implica ions o in lamma ion and angiogenesis. Rheum Dis Clin N Am 2004, 30:97-114. 6. Co an RS, Pobe JS: Cy okine-endo helial in e ac ions in in lamma ion, immuni y and ascula inju y. J Am Soc Neph ol 1990, 1:225-235. 7. Sp inge TA: Adhesion ecep o s o he immune sys em. Na u e 1990, 346:425-433. 8. Bu che EC: Leukocy e-endo helial cell ecogni ion: h ee (o mo e) s eps o speci ici y and di e si y. Cell 1991, 67: 1033-1036. 9. Walz A, Kunkel SL, S ie e RM: C-X-C chemokines – an o e iew. In Chemokines in Disease. Edi ed by Koch AE, S ie e RM. Aus in, TX: RG Landes Company; 1996:1-25. 10. Taub DD: C-C chemokines – an o e iew. In Chemokines in Disease. Edi ed by Koch AE, S ie e RM. Aus in, TX: RG Landes Company; 1996:27-54. 11. Mose B, Loe sche P: Lymphocy e a ic con ol by chemo- kines. Na Immunol 2001, 2:123-128. 12. Zlo nik A, Yoshie O: Chemokines: a new classi ica ion sys em and hei ole in immuni y. Immuni y 2000, 12:121-127. 13. S ie e RM, Pol e ini PJ, Kunkel SL, A enbe g DA, Bu dick MD, Kaspe J, Dzuiba J, Van Damme J, Walz A, Ma io D, Chan S-Y, Roczniak S, Shana el AB: The unc ional ole o he ELR mo i in CXC chemokine-media ed angiogenesis. J Biol Chem 1995, 270:27348-27357. 14. Szekanecz Z, Gáspá L, Koch AE: Angiogenesis in heuma oid a h i is. F on Biosci 2005, 10:1739-1753. 15. Wes phal JR, Boe booms AMT, Schalkwijk CJM Kwas H, De Weije M, Jacobs C, Vie winden G, Rui e DJ, Van de Pu e LB, De Waal RM: An i-endo helial cell an ibodies in se a o pa ien s wi h au oimmune diseases: compa ison be ween ELISA and FACS analysis. Clin Exp Immunol 1994, 96:444-449. 16. Szekanecz Z, Koch AE: Mechanism o disease: angiogenesis in in lamma o y diseases. Na Clin P ac Rheuma ol 2007, 3:635- 643. 17. Szekanecz Z, Koch AE: Chemokines and angiogenesis. Cu Opin Rheuma ol 2001, 13:202-208. 18. Szekanecz Z, Szücs G, Szán ó S, Koch AE: Chemokines in heuma ic diseases. Cu D ug Ta g 2006, 7:91-102. 19. Ru h JH, Volin MV, Haines III GK, Koch AE: F ac alkine, a no el chemokine in heuma oid a h i is and a adju an -induced a h i is. A h i is Rheum 2001, 44:1568-1581. 20. Szekanecz Z, Koch AE: The apeu ic inhibi ion o leukocy e ec ui men in in lamma o y diseases. Cu Opin Pha macol 2004, 4:423-428. 21. Pease JR, Ho uk R: CCR1 an agonis s in clinical de elopmen . Expe Opin In es ig D ugs 2005, 14:785-796. 22. Ha ingman JJ, K aan MC, Smee s TJM, Zwinde man KH, Tak PP: Chemokine blockade and ch onic in lamma o y disease: p oo o concep in pa ien s wi h heuma oid a h i is. Ann Rheum Dis 2003, 62:715-721. 23. Folkman J, Klagsb un M: Angiogenic ac o s. Science 1987, 235: 442-448. A ailable online h p://a h i is- esea ch.com/con en /10/5/224 Page 9 o 10 (page numbe no o ci a ion pu poses) This a icle is pa o a special collec ion o e iews, The Scien i ic Basis o Rheuma ology: A Decade o P og ess, published o ma k A h i is Resea ch & The apy’s 10 h anni e sa y. O he a icles in his se ies can be ound a : h p://a h i is- esea ch.com/sb The Scien i ic Basis o Rheuma ology: A Decade o P og ess