Asian Pacific Journal of Tropical Disease

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1 Asin Pc J Trop Dis 2016; 6(10): Contents lists vilble t ScienceDirect Asin Pcific Journl of Tropicl Disese journl homepge: Prsitologicl reserch doi: /S (16) by the Asin Pcific Journl of Tropicl Disese. All rights reserved. The current sttus of Toxoplsm gondii infection mong Egyptin rheumtoid rthritis ptients Ngw Mostf El-Syed 1*, Shereen Mgdy Kishik 2, Rsh Mohmed Fwzy 3 1 Medicl Prsitology Deprtment, Reserch Institute of Ophthlmology, Giz, Egypt 2 Prsitology Deprtment, Fculty of Medicine, Benh University, Benh, Egypt 3 Rheumtology nd Rehbilittion Deprtment, Fculty of Medicine, Benh University, Benh, Egypt ARTICLE INFO Article history: Received 25 Aug 2016 Received in revised form 31 Aug 2016 Accepted 2 Sep 2016 Avilble online 4 Sep 2016 Keywords: Toxoplsm gondii Autoimmune diseses Rheumtoid rthritis ELISA ABSTRACT Objective: To scertin reltionship between Toxoplsm gondii (T. gondii) infection nd rheumtoid rthritis (RA) disese mong Egyptin ptients. Methods: One hundred RA ptients nd 50 helthy subjects prticipted in this study. The ptients were clssified into three groups, nmely GI, G2 nd G3. Ptients in G1 were recently dignosed with RA with the disese durtion of less thn one yer (prior tretment); G2 included RA ptients receiving nti-tumor necrosis fctor gents nd RA ptients in G3 received disese modifying nti-rheumtic drugs (methotrexte, ntimlril, corticosteroids). Serum smples of ll prticipnts were exmined for the presence of nti-toxoplsm immunoglobulin G (IgG) ntibodies nd positive smples were further nlyzed for nti- Toxoplsm IgM ntibodies to detect the possibility of rectivtion of ltent toxoplsmosis. Also, the ssocition between Toxoplsm seropositivity nd clinicl, lbortory nd rdiologicl fetures of these ptients were determined. Results: There ws significntly higher percentge of T. gondii IgG positivity in RA ptients (54%) thn in the controls (32%). At the sme time, 20.40% of T. gondii IgG positive ptients hd nti-t. gondii IgM ntibodies with sttisticlly significnt difference s compring to T. gondii IgG positive controls. Out of T. gondii seropositive ptients, 20.37% hd lower IgG level with men titer of (65.3 ± 17.7) IU/mL, 46.29% hd moderte level with men titer of (184.2 ± 60.0) IU/mL nd 33.33% hd higher level with men titer of (404.3 ± 50.0) IU/ ml. A positive correltion ws found between disese ctivity nd Toxoplsm seropositivity. T. gondii seropositive RA ptients hd longer disese durtion, longer time morning stiffness, higher numbers of tender nd swollen joints nd lso increse in disese severity mrkers (erythrocyte sedimenttion rte, C-rective protein, disese ctivity score 28, nti-cyclic citrullinted peptide nti-bodies, rheumtoid fctor) thn T. gondii seronegtive ptients. As regrds rdiologicl findings, Lrsen score ws found significntly higher in T. gondii seropositive RA ptients. Conclusions: The positive correltion between T. gondii infection nd RA disese mong Egyptin ptients indicted the need to improve wreness of this prsitic infection nd its mngement in this risk group. 1. Introduction Toxoplsmosis is prsitic disese cused by Toxoplsm gondii (T. gondii), n intrcellulr protozon prsite. The infection is cquired by orl ingestion of the contminted wter or foods with T. gondii excreted in ct feces or undercooked met contining *Corresponding uthor: Ngw Mostf El-Syed, Medicl Prsitology Deprtment, Reserch Institute of Ophthlmology, Giz, Egypt. Tel: E-mil: ngelsk@hotmil.com, ng.elsk@yhoo.com The study protocol ws performed ccording to the Helsinki declrtion nd pproved by the Reserch Ethics Committee, Fculty of Medicine, Benh University, Egypt. Informed written consent ws obtined from ll prticipnts. The journl implements double-blind peer review prcticed by specilly invited interntionl editoril bord members. tissue cysts. In ddition, this infection cn be trnsmitted through the plcent, orgn trnsplnttion nd blood trnsfusion[1]. T. gondii infection in immunocompetent individuls is mostly symptomtic or cn be mnifested s lymphdenopthy nd is usully followed by lifelong ltent infection tht my be rectivted s result of immune disorders inducing serious complictions[2]. The prevlence of ltent toxoplsmosis rnges from 20% to 80% mong different popultions, which depends on vrious sociologicl nd environmentl fctors including hygienic stndrds, living hbits nd the number of cts in the environment, moisture nd ltitude[3]. Rheumtoid rthritis (RA) is complex utoimmune disese ffecting 1% 2% of the generl worldwide popultion nd more prevlent in femles t lte childbering yers of ge[4]. The

2 798 Ngw Mostf El-Syed et l./asin Pc J Trop Dis 2016; 6(10): etiopthogenesis of RA is multifctoril resulting from complex interction between genetic nd environmentl fctors tht cn trigger the immune response[5]. This disese is chrcterized by n inflmmtory synovitis, usully involving peripherl joints in symmetric distribution cusing crtilge dmge, bone erosions nd chnges in joint integrity[6]. The ptients my hve mild oligorticulr illness of brief durtion with miniml joint dmge. However, the most will progress to poly-rthritis with mrked impirment[7]. The ssocition between microbiologicl infections (bcteril, virl nd prsite) nd utoimmune disese hs been shown in severl studies. These infections re believed to ct s triggers inducing or promoting utoimmune disese in geneticlly predisposed individuls by moleculr mimicry, epitope spreding, or bystnder ctivtion[5,8,9]. Toxoplsmosis is considered s mjor helth problem in ptients with systemic lupus erythemtosus, systemic sclerosis, nkylosing spondylitis, utoimmune thyroid diseses nd inflmmtory bowel disese[10-12] nd lso its ssocition with RA hs been studied by severl uthors[7,8,13]. To scertin reltionship between T. gondii infection nd RA, this study ws conducted to determine T. gondii positivity mong Egyptin RA ptients nd its correltion with their clinicl, lbortory nd rdiologicl findings. 2. Mterils nd methods 2.1. RA ptients nd controls One hundred ptients from the outptient nd inptient clinics of the Rheumtology nd Rehbilittion Deprtment of Benh University Hospitls during the period from June 2015 to My 2016 were enrolled in this study. Seventy ptients were femle nd thirty were mle. The ges of the ptients rnged form 30 to 58 yers with men ge of (43.1 ± 4.8) yers. All of them were subjected to full history tking, clinicl exmintion nd they met the clssifiction criteri of the Americn College of Rheumtology/Europen Legue ginst Rheumtism for RA clssifiction[14]. The ptients were divided into three groups, G1, G2 nd G3. G1 included 25 recently dignosed RA ptients with disese durtion of less thn one yer (prior tretment). G2 included 25 RA ptients receiving nti-tumor necrosis fctor (TNF) gents (infliximb, etnercept nd dlimumb) nd G3 ws formed by 50 RA ptients receiving disese modifying nti-rheumtic drugs (DMARDS), methotrexte, ntimlril, corticosteroids. Fifty control subjects from the generl popultion of Benh City, Egypt were lso enrolled in the study. They were 34 femles nd 16 mles with men ge of (40.3 ± 1.9) yers (rnged from yers) nd nd were comptible with both sex nd ge of ptients (P > 0.5) Investigtions Lbortory investigtions All ptients were investigted for erythrocyte sedimenttion rte (ESR) by Westergren method[15], C-rective protein (CRP) nd rheumtoid fctor (RF) by ltex gglutintion tests (Lener Chemicls Co., Spin), nti-cyclic citrullinted peptide ntibodies (nti-ccp) by ELISA (Euro Dignostic, Co., Sweden) Assessment of the disese ctivity score 28 (DAS28) DAS28 is n index clculted fter the exmintion of 28 swollen nd tender joints involving hnds, rms nd knees. The DAS28 rnges from 1 to 9 where low score (< 3.2) indictes low disese ctivity, moderte score ( ) indictes moderte disese ctivity nd high score (> 5.1) indictes high disese ctivity[16] Rdiologicl exmintion Plin X-ry (P A views) on hnds, wrists nd feet were obtined nd scored by Lrsen score[17] tht ws pplied for proximl interphlngel joints (2 5), metcrpophlngel joints (2 5) in ech hnd, four qudrnts in both wrists nd mettrso-phlngel joints (2 5) in ech foot. The grding scle rnged from 0 to 5 where 0 ws intct bony outlines nd norml joint spce, 1 ws erosion (dimeter < 1 mm), 2 referred to one or severl smll erosions (dimeter > 1 mm); 3 indicted mrked erosion, 4 ws severe erosion (usully no joint spce left nd the originl bony outlines were only prtly preserved) nd 5 ws mutilting chnges (the originl bony outlines hve been destroyed). Then, the score ws summed up giving mximum score of 160 when ll joints were fully destroyed Determintion of the nti-t. gondii ntibodies positivity Serum smples of ll prticipnts were nlyzed for nti- Toxoplsm IgG ntibodies using commercilly enzyme immunossy, Toxoplsm IgG kit, (DRG Interntionl Inc., USA). Anti-T. gondii IgG ntibody levels were expressed s IU/mL, nd result equl or greter thn 32 IU/mL ws considered positive. Low IgG ntibody level ws less thn 100 IU/mL, moderte level ws IU/mL while the high level ws more thn 300 IU/ ml. Additionlly, positive smples for nti-t. gondii IgG ntibodies were further nlyzed for nti-t.gondii immunoglobulin M (IgM) ntibodies by the commercilly enzyme immunossy, Toxoplsm IgM kit, (DRG Interntionl Inc., USA). The tests were performed following the mnufcturer s instructions Sttisticl nlysis Sttisticl nlysis ws crried out by SPSS softwre (sttisticl pckge for socil science) (version 16, SPSS, Inc., USA). Qulittive dt were expressed in numbers nd percents nd quntittive dt were expressed s men nd stndrd devition. The collected dt were nlyzed using Chi-squre test, nd student s t-test for significnce differences. P < 0.05 ws considered sttisticlly significnt Ethicl considertions The study ws pproved by the Reserch Ethics Committee,

3 Ngw Mostf El-Syed et l./asin Pc J Trop Dis 2016; 6(10): Fculty of Medicine, Benh University, Egypt. The im of the study ws explined to ll prticipnts, nd n informed consent ws obtined from ll of them. 3. Results The results reveled higher T. gondii infection rte in RA ptients (54%) s compred with the controls (32%), with sttisticlly significnt difference (P = 0.01). It ws observed tht 40% of the recently dignosed RA ptients (G1), 64% of ptients treted with nti-tnf gents (G2) nd 56% of ptients treted with DMARDS (G3) hd ltent toxoplsmosis (Tble 1). Tble 1 Toxoplsm IgG positivity in RA ptients versus helthy controls. Groups Anti-Toxoplsm IgG IgG positive [n (%)] IgG negtive [n (%)] Totl G1 10 b (40%) 15 (60%) 25 RA ptients G2 16 (64%) 9 (36%) 25 G3 28 (56%) 22 (44%) 50 Totl 54 (54%) 46 (46%) 100 Controls 16 (32%) 34 (68%) 50 : Significnt difference compred with the controls; b : No significnt difference compred with the controls. Additionlly, T. gondii IgG positive ser of the prticipnts were further nlyzed for the presence of nti-t. gondii IgM ntibodies to detect the possibility of rectivtion of ltent toxoplsmosis (Tble 2). It ws found tht 20.40% of T. gondii IgG positive ptients hd nti-t. gondii IgM ntibodies with sttisticlly significnt difference (P = 0.049) s compring to T. gondii IgG positive controls. Out of them, 31.25% of ptients treted with nti-tnf gents (G2) nd 21.40% of ptients treted with DMARDS (G3) hd significnt rectivtion of ltent toxoplsmosis (P = 0.014, P = 0.046, respectively). Tble 2 Toxoplsm IgM positivity mong Toxoplsm IgG positive RA ptients. Group Anti-Toxoplsm IgM IgM positive [n (%)] IgM negtive [n (%)] Totl G1 0 b (0.00%) 10 (100.00%) 10 RA ptients G2 5 (31.25%) 11 (68.75%) 16 G3 6 (21.40%) 22 (78.60%) 28 Totl 11 (20.40%) 43 (79.60%) 54 Controls 0 b (0.00%) 10 ( %) 16 : Significnt difference compred with the controls; b : No significnt difference compred with the controls. Another interesting finding ws the significntly higher levels of nti-t. gondii IgG in RA ptients thn in controls (P = ). Out of 54 T. gondii IgG positive ptients, 20.37% hd lower IgG level with men titer of (65.3 ± 17.7) IU/mL, 46.29% hd moderte level with men titer of (184.2 ± 60.0) IU/mL nd 33.33% hd higher level with men titer of (404.3 ± 50.0) IU/mL. However, the most of T. gondii IgG positive controls hd lower level with men titer of (55.2 ± 16.0) IU/mL nd only 25.00% of them with moderte level (121.0 ± 20.6) nd none of them hd higher level (Tble 3). T. gondii seropositive RA ptients hd longer disese durtion thn T. gondii seronegtive ptients in spite of this difference did not rech to ny significnt vlue. Additionlly, T. gondii seropositive RA ptients hd longer time morning stiffness, higher numbers of tender nd swollen joint nd lso increse in disese severity mrkers, ESR, CRP, DAS28 score, nti-ccp nd RF, thn those of T. gondii seronegtive ptients. The difference between both groups ws sttisticlly significnt. As regrds rdiologicl findings, Lrsen score ws found significntly higher in T. gondii seropositive RA ptients (Tble 4). Tble 3 Sero-intensity of Toxoplsm IgG ntibodies mong Toxoplsm positive RA ptients nd the controls. Anti-Toxoplsm IgG level (IU/ ml) Low (< 100) Moderte ( ) High (> 300) RA ptients (n = 54) Controls (n = G1 (n = 10) G2 (n = 16) G3 (n = 28) 16) Number (75%) Totl [n (%)] 11 (20.37%) Men titer (IU/mL) 65.3 ± ± 16.0 Number (25%) Totl [n (%)] 25 (46.29%) Men titer (IU/mL) ± ± 20.6 Number (0%) Totl [n (%)] 18 (33.33%) Men titer (IU/mL) ± : Significnt difference compred with the controls. Tble 4 Correltion between Toxoplsm seropositivity nd clinicl, lbortory nd rdiologicl findings of RA ptients. Clinicl, lbortory nd rdiologicl findings RA ptients (n = 100) T. gondii seropositive (n = 54) T. gondii seronegtive (n = 46) Disese durtion (yers) ± ± Morning stiffness (min) ± ± Swollen joint count 8.21 ± ± Tender joint count 6.51 ± ± DAS ± ± 0.60 < Lbortory prmeters RF (IU/mL) Positivity 83% 78% Men titer ± ± 6.60 < Anti-CCP (IU/mL) Positivity 72% 64% Men titer ± ± ESR (mm/h) ± ± < CRP (mg/l) ± ± 1.20 < Rdiologicl findings Lrsen score ± ± 6.30 < : Significnt correltion between Toxoplsm seropositive nd clinicl, lbortory nd rdiologiclfindings of RA ptients s compred with seronegtive ptients. 4. Discussion Humn toxoplsmosis is considered s mjor helth problem mong vrious Egyptin ptients with prevlence of 59.10% mong oculr ptients[18], 56.70% mong schizophreni ptients, 40.00% mong ptients with depressive disorder[19] nd 33.67% mong blood donors[1]. Thus, this study determined the reltionship between Toxoplsm infection nd Egyptin RA ptients by detecting IgG nd IgM ntibodies in blood smples of the ptients compred with the controls. The dignosis of toxoplsmosis might be highly desirble in those ptients s they my be t risk for rectivtion of ltent infection s well s increse the risk of cute P

4 800 Ngw Mostf El-Syed et l./asin Pc J Trop Dis 2016; 6(10): toxoplsmosis. Egyptin RA ptients were found to hve significnt ltent toxoplsmosis (54%) with elevted levels of IgG to T. gondii compred to norml controls (32%) nd lso the presence of Toxoplsm IgM ntibodies in 20.4% of T. gondii IgG positive ptients indicted the rectivtion of T. gondii infection in them, especilly whose receiving nti-tnf nd DMARDS tretments. These results re comptible with Kub et l.[7] who found tht the seroprevlence of T. gondii IgM nd IgG were 20.40% nd 33.33% in RA ptients receiving methotrexte, 8.00%, nd 36.00% in RA ptients without tretment, while it ws 24.00% nd 12.00% in helthy controls. In Kirkuk, city in Irq, the overll seroprevlence of toxoplsmosis ws observed in 54.09% RA ptients, nd 47.54% nd 6.55% of them hd Toxoplsm IgG nd IgM ntibodies, respectively[13]. Furthermore, Toxoplsm positivity ws found in 63% of Europen RA ptients[8]. Shpir et l.[11] showed tht nti-t. gondii IgG were positive in 42% of ptients with vrious utoimmune diseses versus 29% of controls. Conversely, Sert et l.[20] found no significnt difference between the frequency of IgG ntibodies positivity nd IgG levels in the ptients with rective rthritis nd those in the helthy symptomtic controls (52.0% vs. 47.5%) nd they suggested tht T. gondii does not seem to be triggering gent for rective rthritis nd pst infection my be coincidentl finding. Infection with T. gondii results in strong nd persistent T-helper-1 (Th1) response chrcterized by the production of proinflmmtory cytokines, including interleukin-12, interferon-γ nd TNF-α. The combined ction of these cytokines nd other immunologicl mechnisms protect the host ginst rpid repliction of Toxoplsm tchyzoites nd subsequent pthologicl chnges. In chronic toxoplsmosis, depletion of these cells in the ptients receiving immunosuppressive drugs cn cuse rectivtion of this ltent infection nd my result in severe complictions[21-23]. Despite the effect of DMARDS, especilly methotrexte, to reverse the symptoms of RA disese, reduce the progression of joint dmge nd improve the qulity of life of ptients[24], they re lso used for long-time decresing immune response nd promoting the microbil infections[25]. In this study, it ws found tht 56.0% of RA ptients receiving methotrexte hd chronic toxoplsmosis nd 21.4% of them hd rectivtion of this ltent infection. This finding ws in greement with vn der Veen et l.[26] who reported tht RA ptients receiving methotrexte re more lible to hve infections of the respirtory trct nd skin nd to receive prescriptions for ntibiotics thn RA ptients receiving no DMARDS other thn methotrexte. In ddition, the use of nti-tnf gents such s infliximb, etnercept nd dlimumb hve number of contrindictions nd side effects, including rectivtion of opportunistic infections such s toxoplsmosis[27,28]. In the present study, it ws observed the incresed risk of toxoplsmosis in RA ptients treted with nti-tnf-α therpy (64.00%) nd hlf of them (31.25%) hd rectivtion of this disese. This observtion ws in greement with Lssoued et l.[21] who reported two cses of oculr toxoplsmosis in ptients with rheumtoid rthritis receiving nti-tnf-α gent. One of the two cses ws becuse of the rectivtion of previous toxoplsmosis infection, wheres the other hd primry cquired oculr toxoplsmosis. Also, cerebrl toxoplsmosis hs been reported in RA ptients receiving methotrexte, dlimumb nd infliximb[22,23].experimentlly, El-Syed et l.[28] concluded tht etnercept, TNF-α ntgonist, plyed role in rectivtion of ltent toxoplsmosis by incresing the number nd size of tissue cysts in brin of T. gondii infected mice. Tretment with immunosuppressive drugs stimulted the relese of brdyzoites from tissue cysts which convert into tchyzoites nd proliferte in host tissue without restriction, leding to the dissemintion of Toxoplsm orgnisms to other cells. Trimethoprim-sulphmethoxzole prophylxis ws recommended to be given to ptients who needed high doses of immunosuppressive to prevent toxoplsmosis, especilly if there is serologic evidence of ltent infection[29]. It is importnt to point out tht significnt correltion ws found between RA disese severity nd Toxoplsm positivity. Toxoplsm seropositive RA ptients presented with severe clinicl mnifesttions such s morning stiffness, higher numbers of tender nd swollen joints nd higher DAS28 scores thn Toxoplsm seronegtive ptients. The disturbnces in the immunologicl response interfere with prsite control nd thereby hve n impct on the clinicl course. RA ptients typiclly hve circulting uto-ntibodies, rheumtoid fctor nd nti-cyclic citrullinted peptide[30,31]. These ntibodies were significntly linked to Toxoplsm positivity, prticulrly when presenting in high titres. The obtined results were supported by severl clinicl nd experimentl studies which found tht microbil infections cn induce nd/or exggerte the symptoms of rthritis[5]. There might be cusl reltionship between Toxoplsm infection nd RA. Either, RA-susceptible genetic nd environmentl fctors, such s predisposed genes nd living hbits, my cuse incresed risk of infection even before or in the erly stge of RA or RAssocited bnorml immune response nd immunosuppressive medicine my contribute to decresed host defense to infection[32]. On the other hnds, Toxoplsm infection my be risk fctor for the development of RA. It ws reported tht Toxoplsm my cuse symmetricl polyrthritis of the smll joints of hnds, wrists nd knees in rheumtoid pttern[33,34]. Different prsites cn cuse joint diseses by severl mechnisms including invsion from neighboring bones or muscles vi the blood or lymphtic with the presence of the prsitic stges in the joint cvity nd lso by triggering rective inflmmtory rection to the presence of the prsite in the surrounding tissue without n ctul joint invsion[35]. Bsed on the results obtined, the positive correltion between T. gondii infection nd RA disese mong Egyptin ptients indicted the need to improve the wreness of this prsitic infection nd its mngement in this risk group to void ny resulting serious complictions from rectivtion of ltent infection. Conflict of interest sttement We declre tht we hve no conflict of interest.

5 Ngw Mostf El-Syed et l./asin Pc J Trop Dis 2016; 6(10): References [1] El-Syed NM, Abdel-Whb MM, Kishik SM, Alhusseini NF. Do we need to screen Egyptin voluntry blood donors for toxoplsmosis? Asin Pc J Trop Dis 2016; 6(4): [2] Meers S, Lgrou K, Theunissen K, Dierickx D, Delforge M, Devos T, et l. Myelobltive conditioning predisposes ptients for Toxoplsm gondii rectivtion fter llogeneic stem cell trnsplnttion. Clin Infect Dis 2010; 50(8): [3] Tenter AM, Heckeroth AR, Weiss LM. Toxoplsm gondii: from nimls to humns. Int J Prsitol 2000; 30: [4] Scott DL, Wolfe F, Huizing TW. Rheumtoid rthritis. Lncet 2010; 376(9746): [5] Li S, Yu Y, Yue Y, Zhng Z, Su K. Microbil infection nd rheumtoid rthritis. J Clin Cell Immunol 2013; 4(6): 174. [6] Bruns A, Nicise-Rolnd P, Hyem G, Plzzo E, Dieudé P, Grootenboer-Mignot S, et l. Prospective cohort study effects of infliximb on rheumtoid fctor, nti-cyclic citrullinted peptide ntibodies nd ntinucler ntibodies in ptients with long-stnding rheumtoid rthritis. Joint Bone Spine 2009; 76: [7] Kub RH, Zghir KH, Alosmi MH. Detection of Toxoplsm ntibodies nd TNF-α in rheumtoid rthritis ptients treted with methotrexte. Irqi J Sci 2014; 55: [8] Fischer S, Agmon-Levin N, Shpir Y, Port Ktz BS, Grell E, Cerver R, et l. Toxoplsm gondii: bystnder or cofctor in rheumtoid rthritis. Immunol Res 2013; 56: [9] El-Syed NM, Rmdn ME. Schistosomisis: n ssocition with utoimmunity. Autoimmune Dis Ther Approches 2015; doi: / [10] Azevedo VF, Pietrovski CF, de Almeid Sntos M Jr. [Acute toxoplsmosis infection in ptient with nkylosing spondylitis treted with dlimumb: cse report]. Reumtismo 2010; 62(4): Itlin. [11] Shpir Y, Agmon-Levin N, Selmi C, Petríková J, Brzili O, Rm M, et l. Prevlence of nti-toxoplsm ntibodies in ptients with utoimmune diseses. J Autoimmun 2012; 39(1-2): [12] Hung YK, Lieu AS, Chen YT. A rre presenttion of Toxoplsm encephlitis in systemic lupus erythemtous ptient: cse report nd review of literture. Int J Adv Med 2015; 2(4): [13] Slmn YJ, Mohmmed KA. Reltionship between Toxoplsm gondii nd rthritis mong ptients in Kirkuk city. Int J Curr Res Ac Rev 2015; 3(8): [14] Aleth D, Neogi T, Silmn AJ, Funovits J, Felson DT, Binghm CO 3rd, et l. Rheumtoid rthritis clssifiction criteri: n Americn College of Rheumtology/Europen Legue Aginst Rheumtism collbortive inititive. Arthritis Rheumtol 2010; 62: [15] Westergren A. Studies of suspension stbility of the blood in pulmonry tuberculosis. J Int Med 1921; 54: [16] Frnsen J, vn Riel PL. The disese ctivity score nd the EULAR response criteri. Rheum Dis Clin North Am 2009; 35(4): [17] Lrsen A. How to pply Lrsen score in evluting rdiogrphs of rheumtoid rthritis in long-term studies? J Rheumtol 1995; 22: [18] El-Syed NM, Ismil KA. Role of intrcellulr dhesion molecules-1 (ICAM-1) in the pthogenesis of toxoplsmic retinochoroiditis. J Mol Pthophysiol 2012; 1(1): [19] El-Syed NM, Ismil KA, Ahmed SA, Ezz-El-Din HM, Azzm HM. Possible ssocition between Toxoplsm gondii infection nd schizophreni: Egyptin study. Infect Dis Clin Prct 2012; 20(6): [20] Sert M, Ozbek S, Pyds S, Ymn A. Is there ny reltionship between Toxoplsm infection nd rective rthritis? J Postgrd Med 2007; 53: [21] Lssoued S, Zbrniecki L, Mrin F, Billey T. Toxoplsmic choriore tinitis nd ntitumor necrosis fctor tretment in rheumtoid rthritis. Semin Arthritis Rheum 2007; 36(4): [22] Nrdone R, Zuccoli G, Brigo F, Trink E, Golszewski S. Cerebrl toxoplsmosis following dlimumb tretment in rheumtoid rthritis. Rheumtology (Oxford) 2014; 53: 284. [23] Pulivrthi S, Reshi RA, McGry CT, Gurrm MK. Cerebrl toxoplsmosis in ptient on methotrexte nd infliximb for rheumtoid rthritis. Intern Med 2015; 54: [24] Smolen JS, Aleth D, Koeller M, Weismn MH, Emery P. New therpies for tretment of rheumtoid rthritis. Lncet 2007; 370(9602): [25] Deeming GM, Collingwood J, Pemberton MN. Methotrexte nd orl ulcertion. Br Dent J 2005; 198(2): [26] vn der Veen MJ, vn der Heide A, Kruize AA, Bijlsm JW. Infection rte nd use of ntibiotics in ptients with rheumtoid rthritis treted with methotrexte. Ann Rheum Dis 1994; 53: [27] Sfikkis PP. The first decde of biologic TNF ntgonists in clinicl prctice: lessons lerned, unresolved issues nd future directions. Curr Dir Autoimmun 2010; 11: [28] El-Syed NM, Ismil KA, Bdwy AF, Elhsnein KF. In vivo effect of nti-tnf gent (etnercept) in rectivtion of ltent toxoplsmosis. J Prsit Dis 2015; doi: /s y. [29] Pglvn L, Kn FK. Cerebrl toxoplsmosis in systemic lupus erythemtosus following intrvenous methylprednisolone. Med J Mlysi 2011; 66(1): [30] Avouc J, Gossec L, Dougdos M. Dignostic nd predictive vlue of nti-cyclic citrullinted protein ntibodies in rheumtoid rthritis: systemtic literture review. Ann Rheum Dis 2006; 65: [31] Nielen MM, vn Schrdenburg D, Reesink HW, vn de Stdt RJ, vn der Horst-Bruinsm IE, de Koning MH, et l. Specific utontibodies precede the symptoms of rheumtoid rthritis: study of seril mesurements in blood donors. Arthritis Rheum 2004; 50: [32] Dorn MF, Gbriel SE. Infections in rheumtoid rthritis new phenomenon? J Rheumtol 2001; 28: [33] Antezn E. Polytenosynovitis cused by Toxoplsm gondii. S Afr Med J 1979; 56: 746. [34] Gemou V, Messritkis J, Krpthios T, Kingo A. Chronic polyrthritis of toxoplsmic etiology. Helv Peditr Act 1983; 38: [35] Richi Alberti P. [Review, rheumtologic pthology imported]. Seminn Fund Esp Reumtol 2010; 11: Ctlà.