Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. htcag ofrainsaeo h nie n aeseictre-oicto ciiy[,] rproduce or [8,9], drugs activity produce target-modification to specific technology have dilution and high antigen overcome specific of the to of under used disease, history state strategies antibodies the natural different conformation of of Thus, change the processing pathogenesis that infections. example, changing the opportunistic For to in and issues. nonselective common therapies these of is biological rates which higher of suppression, progress in immune significant administration resulting to induce the the medications Despite proven with such [4-7]. pathways achieved RA, ( rituximab) been specific anti-IL-6 ( anti-CD20 has (anakinra), targeting and that anti-interleukine-1 agents baricitinib) (tofacitinib, included: biologic inhibitors been novel kinase and factor also emerging necrosis joint minocycline have tumor painful years, sulfasalazine, pathways tocilizumab), drugs recent to hydroxychloroquine, inflammatory anti-rheumatic to methotrexate, In leads disease-modifying contribute therapy that includes line [3]. disease therapy first leflunomide inflammatory RA as Traditional autoimmune such systemic [1,2]. (DMARDs), disability a and is destruction (RA) arthritis Rheumatoid rheumatological-related as with patients INTRODUCTION of subgroup a for anti-inflammatory valuable therapy the IVIG time first propose reduced the We synovium, for RA. proved and experimental diseases. results cartilage Our in the architecture. IVIG into joint of cells preserved immune treatment and inflammatory damage IL-1 joint of of (IFN?, migration extent the cytokines the prevented inflammatory Our treatment mode of ELISA. IVIG Moreover, level that by (P<0.001). revealed circulating tested score plasma reduced was arthritis the significantly clinical plasma in the IVIG profile the (P rreduced Cytokine that in significantly show stained. murine, antibodies H&E in action anti-collagen were IVIG of paws circulating with the treatment of plasma, was that titers for score show technology, clinical bled results The were Luminex mice Murine established. by was The mice. disease analyzed 48. DBA/1j the was day when in study started until arthritis IVIG week current induced with a collagen treatment The twice established The followed in diseases. mice. IVIG DBA/1j autoimmune with in therapy. treatment and induced improved of was disability. sepsis, for arthritis effect subjects, immune-deficiency, and need beneficial healthy with the a destruction 20,000 investigate patients still from to joint in is aim extracted there effect to (IgG) patients, therapeutic immunoglobulin-G leads RA beneficial polyspecific for that showed pooled agents disease a biological autoimmune , of administration (IVIG) inflammatory Intravenous-immunoglobulins in systemic progress significant a a is Despite (RA) arthritis Rheumatoid Abstract 2020 23, August 3 2 1 Amital Petrova Halpert arthritis Gilad rheumatoid in therapy IVIG arthritis- for induced projection collagen in inflammation ameliorate IVIG dt ofo eia Center Medical Wolfson Edith Holding Medica Materia Center Medical Sheba < .0) nii niclae niois(P antibodies anti-collagen inhibit 0.001), 1 2 ieaTocut Milena , 1 tiKatz Itai , 3 lxadrVolkov Alexsander , 1 r Shovman Ora , α (TNF < .0)i h lsao I ie motnl,hsoahlgclexamination histopathological Importantly, mice. CIA of plasma the in 0.001) α lces(niia,eaecp,aaiua nrl,Janus- Enbrel), adalimumab etanercept, (infliximab, blockers ) 1 egyTarasov Sergay , 1 rsBarshack Iris , 1 2 1 snaGanina Ksenia , iiBlank Miri , 1 n Howard and , β, 2 Natalyia , L1,I-,TNF IL-6, IL-17, α ) Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. h aso h iewr bandfo h arfie ieadfie n4 omln(im-lrc St (Sigma-Aldrich formalin 4% in ( microscopy fixed light and by examined mice were Samples sacrificed H&E. the with stained from and obtained cut, decalcified, were USA), mice MO, Herisau, Louis, the (Manostat, of calipers paws The digital with extended score, fully assessment (mm) composite Histopathological legs millimeters in a the measured for was with marked paws added = hind malleoli) erythema were the 3 edema/ (the paws of paw, thickness localized the point four Switzerland). Ankle = of all widest mouse. surface 1 of the per one appearance, 12 scores than at of normal more The score involving = maximum erythema paw. a 0 edema/ waswith whole which = arthritis the in 2 of involving severity paw, scale, the the edema/erythema 3-point and of a daily, surface assessed on one was = over paw arthritis n each of controls, development for as The scored used experiment. were each days. injections mice of injection 48 course Intraperitoneal non-treated after boost and sacrificed later. the (volume) scoring were days after vehicle Arthritis mice 21 2-3 as The of given PBS group. score was each at base. tail, per started weekly the 10 ml/mouse, a 100 of 3mg/0.1 on with base DBA/1J mycobacterium Israel), repeated the tail Rehovot, USA). with and at ltd, the MI, 1:1 PBS, (OMRIX of [32- IVIG in emulsified Detroit, base of collagen us was Laboratories, the II by USA) into (Difco type described WA, injected adjuvant bovine previously ethics Redmond, subcutaneously incomplete as the were (Chondrex, Freund’s performed males of collagen in was protocols animal H37RA II model for the 2.0” (CIA) type tuberculosis guidelines to arthritis Bovine ARRIVE according “The induced fulfill 34]: executed Collagen and individually (no.1221/19) The and in Health kept approved of and research. Ministry were Center Israeli Medical experiments the Sheba of All committee at facility mice The housing Blackthorn,UK). cages. animal (ENVIGO, conventional ventilated mice male a DBA/1J in old maintained week were 7-8 in induced was arthritis Experimental design experimental and several Mice share mice CIA-treated METHODS [32]. AND RA. erosion agents, MATERIALS infiltration, human bone anti-rheumatic cell and inflammatory imitate potential synovial destruction, evaluate which autoantibodies, cartilage to of model hyperplasia, generation studies synovial including (CIA) preclinical RA arthritis with in features induced used pathological collagen model FcRn. the murine of frequent is saturation the and cells of regulatory One T of Fab expansion activity Fc The receptors, of anti-idiotypic [27-31]. activating IVIG regulation cytokines, blocking molecule encompass Whereas of inflammatory scavenging. activities the anaphylatoxin related of action and of Fc (ADCC), neutralization of cytotoxicity the portions to cellular mode dependent Fc related antibody or is The receptors, cellular F(ab)2 IVIG [13-26]. the the more of to and part attributed cytoplasmic mechanisms, such disease anti-neutrophil lupus various diseases Still’s sclerosis, systemic encompass autoimmune chronic vasculitides, disease, systemic Guillain-Barr´e syndrome, diverse rheumatic myopathies, (ANCA)-associated (JCA), of for inflammatory antibody arthritis context expanded idiopathic chronic the juvenile (SLE), been in patients, erythematosis has occurring RA therapy polyneuropathy of demyelinating IVIG subgroups neuropathy inflammatory labeling, specific motor and off multifocal : lymphocytic Food chronic and FDA as the B-cell syndrome in date, Despite therapy To Kawasaki line (ITP). ITP, first purpura [12]. immunodeficiency, a as thrombocytopenic humoral IVIG immune introduced of primary was for use which leukemia, [11], the therapies IVIG approved biological al has first et 1950s. (FDA) the the Administration I of Drug Imbach in one is by diseases and 1981 immunodeficiency profile, primary in another safety in already and of was beneficial proven therapy One good IVIG RA. a of ( has for [10]. use IgG therapy the time predominantly of a first product, triumph as mentioned the blood (IVIG) immunoglobulins a for Intravenous is FDA of IVIG by usage approved the is recently approach nanobodies promising as highly such antibodies domain h lnclsoe n h idpwwdh ftemc eemntrddiyoe the over daily monitored were mice the of widths paw hind the and scores clinical The > 5) sltdfo ,0-000hatydnr.Tefirst The donors. healthy 5,000-20,000 from isolated 95%), γ ,imnmdlto ftefnto fdnrtccells, dendritic of function the of immunomodulation R, 2 μ mlin os neto of injection boost A emulsion. g , lcigof blocking × 200 Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. ssrvae infiatdffrnebtentetetetgop enatrtssoeoe ieF=30.224, time a over score observed arthritis We mean of groups score 3. treatment the arthritis almost between marginal was P difference to significant score compared a as arthritic revealed ( ysis mice baseline mice IVIG-treated non-treated the or in mice when score mice. and PBS-treated started arthritis CIA mice non-treated marginal treatments CIA lower or in PBS significantly (vehicle) treatment and PBS IVIG with IVIG of which treated effect Both in mice the patients, CIA investigated RA with human We prone efficacy destruction. genetically its joint in compared arthritis the rheumatoid to imitates leads which inflammation model mouse score a clinical is arthritis CIA the abrogates significantly treatment Statistical IVIG for Foundation R computing. statistical RESULTS R for http://www.R-project.org/ using environment multiple URL conducted and for were for Austria. language analysis test Vienna, adjusted A statistical Dunnett’s Computing, R: were and the plots comparisons, (2013). with Both Team followed plotted NY: normal procedure. Core and including Bonferroni Armonk, test Since, the comparisons, H following Kruskal-Wallis 23.0. Post-hoc comparisons distribution. Comparisons the Version for with analysis. comparisons. Windows, statistical assessed began the werepair-wise for concentrations first throughout plotting mean Statistics chosen the were were graph the SPSS as tests concentration and of non-parametric group IBM anti-collagen analysis met, treatment not Statistical and the was 2015. Cytokine distribution 5%. while, Released at effect the Corp. set Bonferroni subject Corp. bias was IBM the within IBM to level using the known significance with comparisons as not The multiple set made is for was effect. assumptions adjusted time Thus, subjects this aggressively models, between assumption. for we sphericity both violation Therefore, For and furthermore, linear (36). adjustment. model the analysis the meet fitted hoc data not for weights did post error the data 1 while score type procedure, arthritis ANOVA increasing assumptions, measures required repeated the the using all made was analysis and Statistical nm 405 (OD) density optical analysis at reader Statistical tempe- ELISA room 405nm. by the at read at by were h OD followed data 2 as USA), The presented PA, for Grove, substrate. incubated West appropriate and Laboratories, of plates ImmunoResearch addition ELISA (Jackson blocked phosphatase the alkaline with to added were ( 1:800 rature of dilution [10 at II immunosorbent plasma type enzyme-linked 4 collagen homemade at with incubation by coated overnight Following were determined plates were ELISA antibodies (ELISA). assay II type anti-collagen Circulating determination manufacturer. Merck antibodies the by (MHSTCMAG-70K); II provided type Panel then protocols Anti-collagen the and Bead to IFN tube Magnetic according measure done Eppendorf to Cell were used containing T quantifications was EDTA Germany) Sensitivity stadt, an High Darm into GmbH, (Mouse samples. collected technology plasma was obtain Luminex to blood min) experiment, 10 the rpm (2000 of centrifuged end the At Luminex with blinded. double Cytokines were of pathologists Quantification by performed evaluations histological All magnification). o57 5 I(.6 .1 o o-rae I ie n .29%L(.5 .7 o B rae I mice CIA treated PBS for comparison 5.77) in (5.45, 4.262), 95%CL (3.995, 5.62 CI and 95% mice, CIA 4.128 non-treated of for mean 6.01) marginal P (5.56, score CI arthritis 95% lowest 5.78 the to had group IVIG The tdy4 Fg1.N infiatcag nmc oywih a ouetdoetm ntetrestudied three the in overtime documented was weight body mice in change significant No groups, (Fig.1). 48 day at < < .01(ofroiajse) h infiatylwratrtssoelse ni h iewr sacrificed were mice the until lasted score arthritis lower significantly The adjusted). (Bonferroni 0.0001 .01(oe-on dutd.Mria rhii cr ftedffrn tde ruswsa follow: as was groups studied different the of score arthritis Marginal adjusted). (lower-bound 0.0001 n P > 0frec ramn ru) h idn a rbdwt otat-os g conjugated IgG anti-mouse goat with probed was binding The group). treatment each for 10 = .5(aantshown). not (data 0.05 ° ,tepae eebokdwt %bvn eu lui BA.Mouse (BSA). albumin serum bovine 3% with blocked were plates the C, P < .0)a lutae nFg .Rpae esrsAOAanal- ANOVA measures Repeated 1. Fig. in illustrated as 0.001) 3 γ, IL-1 β, L6 L1,adTNF and IL-17, IL-6, μ /lpopaebffrdsln (PBS)]. saline phosphate-buffered g/ml α ntepam.All plasma. the in Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. n oesgicnl irliae-etdsseicII a on ob 0 ie oeeceti the in efficient more times production 200 cytokines be inflammatory to the IVIG) inhibiting found disease (ACPA-specific activity, was peptides inflammation of IVIG curillin CIA severity on of specific the purified reduction citrullinated-peptides affinity inhibited IVIG significantly IVIG study, more that with and In treatment CIA. prophylactic murine that in inflammation observation accompanied was previous score our clinical lower strength ( The (IFN antibodies mice. cytokines CIA anti-collagen flammatory destruc- subjected of the joints PBS levels inhibited inhibit or reduced IVIG untreated examination the by CIA. histopathological with by inflammatory murine compared circulating cells established of immune as in levels tion, of treatment the infiltration reduced the prevent by in IVIG exemplified cytokines. IVIG condition, of inflammatory score, effect clinical beneficial arthritis a vasculitides, herein ANCA-associated show as and We [13-24]. disease, sclerosis, ) rheumatic systemic more of myopathies, and context inflammatory disease idiopathic the Guillain-Barr´eStill’s syndrome SLE, in disease, IVIG (e.g in occurring then, Still’s autoimmunity as Since (JCA), polyneuropathy sepsis, well . arthritis demyelinating deficiency, [11] chronic immune inflammatory (ITP) juvenile as chronic purpura patients, such and RA introdu- thrombocytopenic conditions was immune of of which for subgroups range therapies al, wide specific biological et first in I the successfully Imbach [11]. of employed disability by one was and is 1981 destruction profile, in joint safety already painful and to ced beneficial leads proven that good disease with inflammatory IVIG autoimmune systemic a is RA DISCUSSION < 13,969 and pg/ml 1,173 10,318 were were mice levels TNF CIA the The treated mice IVIG CIA of treated 896 PBS plasma be or the to in , found levels cytokines were IL-17 tested IVIG The the with of treated 13,481 mice all and CIA pg/ml for comparison of mice in plasma non-treated lower the significantly or in were of PBS mice recruitment control CIA beside IVIG-treated the in mechanism to (IFN level another cytokines cytokines or inflammatory inflammatory joint The circulating Fig,5A-E. the the evaluated of We destruction [1,2,37]. the 1 shown on been has cytokines cells the mice inflammatory mice, of CIA CIA effect untreated in direct or levels A PBS cytokines in OD circulating OD showed regulated +-0.7 group treatment, 1.76 IVIG-CIA IVIG and in OD collagen 1.56+-0.31 to against compared antibodies as respectively, of 405nm, (Fig.4). examination +-treatment at IVIG ELISA mice 1.15+-0.28 of of CIA Fig.4, effect of in the a plasma illustrated analyzed autoantibodies, the As we pathogenic in Therefore, of antibodies anti-collagen portion activities. Fab of anti-idiotypic the amelioration an targeting in mice as antibodies CIA described neutralizing in previously consist antibodies a phenomenon to anti-collagen (Fig.3D), known destruction. of mice joint is CIA production and IVIG non-treated bone the as in reduced injected well and significantly non as treatment (Fig.3C) healthy observed PBS in IVIG be as with can tissue, treated neutrophils fat mice of uninflamed infiltration CIA cartilage demonstrates and massive in normal Fig.3A, organization Whereas infiltration, in bone neutrophil (Fig.3B). described typical or mice as structure, process mice muscle inflammatory IVIG-treated no and the layer hyperplasia, from synovial sections less tissue significantly (Fig.2). joints a respectively the observed, induction of was diseases staining mice of IVIG, H&E 0 CIA with day non-treated treated from or mice 48 PBS (day CIA administration for in boost 4.48+-0.98 7.51+-1.05 the of after score 27 showed day ), at score clinical the Analyzing β, 0.001. L1,I-,TNF IL-6, IL-17, α eesi h I ietetdwt VGwr 2,164.28 were IVIG with treated mice CIA the in levels P < 0.001. ± ± 6 gm,frnntetdCAmc n B rae I ie respectively, mice, CIA treated PBS and mice CIA non-treated for pg/ml, 869 ,4 gm ntenntetdCAmc rPStetdCAmc,respectively, mice, CIA treated PBS or mice CIA non-treated the in pg/ml 3,044 α eesi h I iepam pntetetwt VG eil rnon-treatment, or vehicle IVIG, with treatment upon plasma mice CIA the in levels ) γ, IL-1 β, L6 L1,TNF IL-17, IL-6, P ± ,2 gm n 11,487 and pg/ml 1,521 < .0) ieie h iiihdlvl fcruaigin- circulating of levels diminished the Likewise, 0.001). 4 α eerecorded, were ) P < .0,weesasoeo .9+21 and +-2.13 8.09 of score a whereas 0.001, ± ± ± 6p/li oprsnt 13,999 to comparison in 168pg/ml 9 gm,weesi h non-treated the in whereas pg/ml, 497 5 gm oprdt 11,099 to compared pg/ml 652 P ± P 7 gm respectively, pg/ml 371 < < .0.Freape L6levels IL-6 example: For 0.001. .0.Ordt upr and support data Our 0.001. ex-vivo P P yspleen by < < ± 0.001. 0.001. γ, ± 4176 917 IL- P Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. apr,Kt,Somn ou,Vlo,Brhc,Bak n mtl elr htte aen oflc of conflict no have they that declare Amital, and Blank, Barshack, the Volkov, interest. Tocut, writing: of Shovman, Manuscript Katz, version Halpert, current Katz. the Blank, analysis: Halpert, approved Statistical Disclosure Amital. experiments: authors Tocut, Barshack; the all Halpert, Volkov, Performing Blank, and Tarasov, ; Petrova, analysis: Aital article Ganina, Petrova, Pathology Tarasov, the Shovman; Blank, drafting Katz, design: in Study involved manuscript. were authors All Russia. Moscow, HOLDING”, safe MEDICA a “MATERIA contribution as “NPF Author IVIG, OOO by of funded use was the study reconsider arthritis. The to rheumatoid reducing clinicians with of by patients for concentrations presented of way the was subgroup the declining Acknowledgment a pave and in effect may with antibodies treatment study beneficial II mice optional .The type in beneficial anti-collagen Our mice and CIA of in of . titers cytokine amelioration CIA the circulating an in reducing time score, pathogenesis first clinical the the the attenuating in for IVIG demonstrate of we study current arthritis established the in summary, of In burden financial the might biological change IVIG diseases. current might the Moreover, inflammatory/autoimmune it Conclusion to in long-term. other therefore compared the assumptions and agents, in RA as common biological efficacy in expansive effects some of interaction treatment Fc current side loss biological to the than , and less and opposed cheaper effect cells have even antibodies side as regulatory to severe be the and cause T found of might note, of was portion which Of treatments expansion IVIG Fc community, the the [50,51]. scientific of to receptors medical content contributing Fc acid thus ITAM-bearing sialic portion with the production Fc including the the blocking limiting through receptor activation , STAT5 function GM-CSF-driven activin can inhibiting as and by IVIG RS-Cov-2 activation differentiation on ; JNK macrophage protein inflammatory data) inducing spike of by (personal the that macrophages protein severe specifically shown syndrome, anti-inflammatory bind binding was antiphospholipid IVIG derived receptor it catastrophic [43-48]. of the activities, activities: cases COVID-19 as cytokine following in in well anti-inflammatory storm the currently has cytokine also on the IVIG and in based that influenza, therapy is fact efficient an IVIG the is to of IVIG Due activity F(ab) anti-inflammatory [41-45]. the The inhibitors to part a activities. in in related Fc given a) functions IVIG the biological to numerous [39]. encompass and/or arthritis action transfer of of Passive mode model [40]. IVIG murine group).. mice additional of K/BXN already artherogenic an have (name (Fc- the is mice of hexamer in mice the treatment Fc score IgG1 when prophylactic K/BxN recombinant started the to or treatment patients to protocol the prophylactic RA compared when from as even sera of 2-3, disease, of expansion of IL-10 of spleen, score up-regulated course the arthritis IVIG the Similarly, in an abrogate cells . to Th17 [38] inhibited found joints of IVIG was the number that showed in the mice, cytokines reduce Fc CIA inflammatory mice, and in and CIA treatment cells IVIG in T-regulatory the score spleen for disease protocol of prophylactic development a the using al, et activity SY anti-idiotypic contribution Lee Fc its the to exclude attributed More- can’t was we [35]. study although number. treatment this molecules, IVIG cells the in regular of IVIG to portion compared of Fab as makeup the cells immunomodulatory regulatory the T , spleen over of expansion enhanced and cells etaiaino namtr yoie ic VGtresa es 3dffrn yoie rcytokine- or cytokines different 13 least at targets IVIG since cytokines inflammatory of Neutralization γ eetrIBepeso ysle el 3) ti ot etoigta norcretsuy IVIG study, current our in that mentioning worth is It (38). cells spleen by expression IIB receptor sn ramn rtcl eso eenapwru niiflmaoypotential anti-inflammatory powerful a herein show We protocol. treatment a using 5 b) Vgipistegnrto fhmnmonocyte- human of generation the impairs IVIg μ PL0C,rsle natnaino arthritis of attenuation in resulted TP-L309C), via lvto fTregulatory T of elevation 2 ftemolecule the of in-vitro [49]. via c) Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. O NF”AEI EIAHLIG osntmnfcueII rhv n te commercial other any the have experiment of or References the IVIG design of manufacture the results not the in does in part HOLDING” interest MEDICA took ”MATERIA and ”NPF study OOO the writing. manuscript sponsored the HOLDING” HOLDING”. and MEDICA MEDICA experiments “MATERIA “MATERIA “NPF “NPF OOO of OOO employees are Petrova and Ganina, Tarasov. Lv ,Aia ,LneizPe l nrvnu muolblnmdltsctnosinvolvement cutaneous modulates immunoglobulin Intravenous al. et P Langevitz Exp H, immunoglobulin Clin Intravenous Amital Y. Y, vasculitis. Shoenfeld Levy P, livedo Langevitz 22. in H, Chwalinska with immunoglobulin Y. treated Levy intravenous Y, patients of Sherere sclerosis M, Use Meissner systemic Y. in 21. Shoenfeld decrease Y, score Levy Skin H, al. Amital Rheumatology Pet diseases. 20. Langevitz rheumatic Y, in IVIG Sherer for Y, Indications the Levy in al. 19. et immunoglobulins B, intravenous IN.Mulhearn of Bruce role Nat B, The Mulhearn diseases. G. rheumatic 18. Zandman-Goddard in S, therapy immunoglobulin Khattri Intravenous N, diseases al. Katz-Agranov inflammatory et 17. and SV autoimmune Kaveri of VS, Immunomodulation Negi J, al. Bayry et 16. G mecha- Hassan (IVIg) N, immunoglobulins Misra intravenous im- A, on intravenous Ephrem Update G. with 15. Zandman-Goddard therapy Y, Long-term Shoenfeld U, Katz al. 14. et Y, Levy A, Krauthammer G, Zandman-Goddard 13. intravenous High-dose al. https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/immune-globulin- et V 12. d’Apuzzo 2020; BioDrugs S, Barandun Nanobodies. P, Imbach of Potential 11. Therapeutic The Muyldermans. Serge Jovˇcevska , Ivana 10. SotD,WleF uznaT.Remti rhii.TeLne 2010; Lancet 2016; The Lancet The arthritis. Rheumatoid arthritis. TW. Rheumatoid Huizinga al. F, et Wolfe IB. DL, McInnes Scott D, 2. Aletaha JS, Smolen 1. Dgn L ervV,Bbyv Re l admzd pnlbl oprtv,6mnhtilof trial 6-month comparative, open-label, randomized, A al. 103. et 2018;10: AR – Babayeva Symmetry. VI, Janus // Petrov oral hypothesis an JL, - homeostasis Dugina tofacitinib spatial of 9. The action O. of mechanism Epstein The activity 8. al. Anti-inflammatory et jv. S ravetch Krishnaswami TT, authors: Kawabata JA, Among Hodge al. 7. et JV Immunol Ravetch Rev F, Nat Nimmerjahn responses immune Y, of Kaneko regulators 6. as receptors Fcgamma JV. Ravetch tuberculosis F, latent Nimmerjahn with patients 5. of management the for Guidance the al. in et arthritis L rheumatoid Niccoli C, of Nannini treatment F, the Cantini for 4. Methotrexate PL. Meroni M, Biggioggero EG, Favalli 3. hrp naptetwt uu eoii n ehii.RemtlIt2000; Int Rheumatol nephritis. and serositis lupus with patient a in therapy 2000; 2000; Rheumatol Rheumatol Clin report. preliminary a - immunoglobulin intravenous 2015; (Oxford) 2015 Rev Autoimmun arthritis. rheumatoid of treatment 2011; Rheumatol Rev 2011; 2005 Des Med Pharm Exp Curr Clin intravenousimmunoglobulin. diseases. with autoimmune in use off-label and 2012; action Immunol of Allergy nisms Rev Clin diseases. autoimmune with patients :247–55. in beneficial is munoglobulin intravenous-igiv-indications 1981; Lancet childhood. in purpura cytopenic :11-26. 2005; factor- Reactions necrosis Tissue tumor of to Journal antibodies International of doses ultra-low 2016; oral Rheumatol. Exp Clin arthritis. rheumatoid of treatment the for 2006; inhibitor Science kinase sialylation. Fc from resulting G immunoglobulin of Autoimmun 2008; practice. . clinical dermatology and rheumatology in 2015; therapy Rev biologic 2014; requiring Rev infection Autoimmun drug? ‘anchor’ an still era: biologic 8 :34-47. 14 :503-9. 54 18 :383-91. 404-6. : 7 :349-59. 1 6 XXVII (8232):1228-31 5 1:15-21. (1): :135-40. 14 α 13 n ilfnci huaodatrts// arthritis rheumatoid in diclofenac and :651–8. :1102-8. 313 γ goui o doahcthrombo- idiopathic for -globulin :670-3. 19 376 19 207-11. : :199-201. :1094-108. 17 388 :3166-75. 34 :2023-38. :318-28. 42 34 Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. MysiM i .ioh ,e l olgnIdcdAtrtsMdl.MtosMlBo.2018; Biol. Mol Methods Models. Arthritis Collagen-Induced candidate al. drug et a M, the in S.Miyoshi results modulate Liu IVIg of M, IgG sialylation Miyoshi tetra-Fc does Controlled 32. how al. et D therapy: Ortiz I, immunoglobulin Schwab Intravenous N, Washburn 31. Nimmerjahn. F and system immune I, cellular the Schwab of J.Modulation 30. Kwekkeboom SV, Kaveri HJ, Metselaar J, Bayry T, Tha-In 29. CreaR orıuzPn´ ,Epns .evr ,e l h igoi n lnclmngmn of management clinical and diagnosis 1995; The cytokines al. to et autoantibodies R, and Rodr´ıguez-Pint´o G.Cervera Cytokines R, Espinosa Cells. Cervera prepa- I, Stem (IVIg) 44. al. immunoglobulin et intravenous C various Ross in MB, levels Hansen Cytokine K, Bendtzen al. immunoglobulin 43. et Itravenous I JO. Krause Pers R, Wu Y, Y, chronic, Shoenfeld Sherer P, endogenous, 42. Youinou of B, model Bendaoud mouse T, K/BxN Sapir the L, Using Pottier Le for al. 41. model et a M, as Blacquiere arthritis serum-transfer J, K/BxN Ville JA. BJB, Hamilton Lewis AD, 40. Cook C, autoimmune Haase experimental AD, attenuates Christensen immunoglobulin Intravenous 39. al. peptide et multiepitope JG Ryu with Med YO, induction Lab Jung tolerance J SY, Immune Lee Korean H. 38. variance. Amital of Y, analysis Shoenfeld measures G, repeated Serre of mice. use S, in Correct Gertel arthritis CS. 37. collagen-induced Ki attenuates M, immunoglobulin Cho E, al. Park et Q 36. Odeh S, Kivity tuftsin-phosphorylcholine molecule, N, bi-functional Svetlicky Helminths-based 35. atten- al. et tuftsin-phosphorylcholine J compound Lachnish T, therapeutic Bashi Novel M, Blank al. et 34. M Fridkin O, Shovman T, Bashi 33. resulting G immunoglobulin of activity Anti-inflammatory al. et JV with Ravetch F, diseases Nimmerjahn inflammatory Y, and Kaneko autoimmune 28. of immunomod- Immunomodulation an Kaveri. as SV therapy and immunoglobulin MD, High-dose Kazatchkine G. 27. Rinaldi doses M, high Veneziani with P, arthritis Casoli rheumatoid B, of Tumiati treatment 26. term Long al. et idiopathic R with Ercolani patients A, adult Bertotto in C, modification Muscat level 25. Autoantibody al. et with A experience Ahmed our Y, conditions: Sherer malignant Y, and Levy fibrosis, autoimmune, 24. for IVIG I. Krause Y, Shoenfeld 23. ihcnitn nacdat-namtr ciiy rcNt cdSiUSA 2015; A. S U Sci Acad Natl Proc activity. anti-inflammatory enhanced consistent with 2013; Immunol Rev Nat system? immune 2008; Immunol Trends immunoglobulin. intravenous by :206-22. Sci 2001;10:51-3. Acad Antibodies NY Hum Ann APRIL. rations. and BAFF members family factor necrosis tumor 2007; on Focus cytokines. and including agents, Fc- therapeutic immunoglobulin-based and potential IVIg of evaluation the for arthritis rheumatoid 2016; Immunol Front arthritis. man- inflammatory interleukin-10-dependent human an in cells Treg 2014; and Rheumatol Th17 Arthritis of regulation ner. reciprocal inducing by J arthritis rats. arthritis adjuvant 5674-80. in manifestations 194: arthritis 2015; attenuates Immunol. autoantigens citrullinated from derive 2009; 2015; Immunol. 2018; Exp One. Clin PLoS arthritis. murine established an ameliorates (TPC), 2016; Immunol Exp Clin arthritis. collagen-induced uates :3-7 2006; Science. sialylation. Fc from 2001; Med J Engl N globulin. immune 1992; intravenous Dis Rheumatol Arthritis Rheum arthritis. Ann rheumatoid of cytokines. treatment serum ulatory and activity disease on effects 1995; immunoglobulins: intravenous of 1998; Immun Nat treatment. immunoglobulin intravenous 207-24. following purpura thrombocytopenic 2004; Immunol 2004; Clin J Rheumatology Arthritis patients. 200 study. open-label an sclerosis: systemic in :1005-7. fibrosis skin reduces and 1110 29 54 :1-9.. :382–5. 426-32. : μ PL0C eobnn g1F eae.BCImnl2019;20:44-54. Immunol BMC hexamer. Fc IgG1 recombinant a TP-L309C, 182 :241-50. 66 313 :1768-7. 24 :107-14. :670-3. 13 :176–89. 7 345 7 :213-7. :747–55. 29 184 :608–15. :19-28. 13 35 :e0200615. :1126–33. 112 :E1297-306. 1868 16 13 50 : Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. h aaaepeetda rhii cr vrtm nDAjCAmc,uo ramn ihII,PSor PBS IVIG, with treatment upon mice, mice, of CIA group DBA/j studied in each time per over N=10 score arthritis mice. mice as non-treated CIA presented in are data score The arthritis on effect IVIG Fig.1: FIGURES TO LEGEND hsatrtssoewseautda a 8(7dy ic h einn ftetetwt VG.Kruskal- IVIG). with treatment of beginning the since experiment days the (27 of 48 day point at last evaluated Wallis, the was at score arthritis score This arthritis on effect IVIG Fig.2: Cmbl K ishrS rnhD ta.Teaetceeto VGo namtr rhii in arthritis inflammatory on IVIG of effect Therapeutic al. inhibitors into et IgG DR arthritogenic Branch converts S, Sialylation Miescher al. IK, et Campbell D Takakura 51. A, Harazono W, Ise Y, Ohmi 50. Dom´ınguez-Soto49. immuno- and Atag syndromes G, storm cytokine Keser consider M, COVID-19: Soy al. 48. et M im- Brown intravenous DF, hyperimmune McAuley Anti-influenza P, Mehta al. 47. immuno- et of development N and Markowitz influenza E, severe Fernbndez-Cruz of storm Jr, cytokine RT The Davey al. 46. et ZQ Yang YH, Zhou Q, Liu 45. iei eedn nteF oto n needn fsayaino aohl.JImnl2014; Immunol J basophils. or sialylation of independent and portion Fc the :5031-8. on dependent is mice 2016; Commun Nat 2018; arthritis. Immunol collagen-induced J of Vivo. In and Vitro In 2020; Stimuli Rheumatol Inflammatory Clin against treatment. in used agents anti-inflammatory of :2085-94. overview and pathogenesis randomised, double-blind, (FLU-IVIG):a 2020; Lancet infection suppression. B or 2019; Med A Respir influenza Lancet trial. with placebo-controlled adults for munoglobulin 2016; Immunol Mol Cell 2018; therapy. Autoimmun modulatory J review. comprehensive A syndrome: antiphospholipid catastrophic the χ 2 2 38.65, = (2) P ,Smo-une ,d a aa-ne ta.II rmt Cross-Tolerance Promote IVIg al. et M Casas-Engel Las de Sim´on-Fuentes M, A, ´ < 0.001. und ¨ 395 zP aa ,Atag F, Tabak P, uz ¨ :1033-4. 13 8 :3-10. und 7 ¨ 7 :11025-37. P 951–63. : zI ahnS yoiesomi COVID-19: in storm Cytokine S. Kayhan I, uz ¨ < 0.001. 201 :41-52. 92 :1-11. 192 39 Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. os niclae yeI icltn niois eetse ntepam ftetregop fmc at mice of Kruskal-Wallis, groups three 405nm. the at of OD plasma at the presented in are tested Data were 1:800. antibodies, of circulating dilution II type anti-collagen Mouse antibodies anti-collagen Circulating Fig.4: presented Magnification mice. mouse. CIA CIA of non-treated group D) study each from paws, × arthritic representative of staining H&E analysis Histological Fig.3: 0.)CAmuetetdwt VG )hatymuewtotCA )CAmuetetdwt PBS; with treated mouse CIA C) CIA; without mouse healthy B) IVIG; with treated mouse CIA 200.A) 9 χ 2 2=07 p (2)=30.7, < 0.001. Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. h aaaepeetda ocnrto np/l 0prgop )IFN A) group. per 10 = n pg/ml. in χ concentration IL-1 as B) presented 42.76; are data The IVIG with IFN mice treatment cytokines CIA inflammatory upon of the mice of concentrations CIA the in analyzed We cytokines circulating of Levels Fig.5: 2 2=24 )TNF E) ; (2)=42.42 ± β ramn ihII,PSo on-treated. or PBS IVIG, with treatment Kruskal-Wallis, α Kruskal-Wallis, χ 2 2=27;C L6Kruskal-Wallis, IL-6 C) (2)=42.77; χ 2 2=86 p (2)=38.6. 10 < .0 o l tde ruso mice. of groups studied all for 0.001 γ, IL-1 χ 2 2=32;D L1 Kruskal-Wallis, IL-17 D) (2)=43.22; β, L1,I-,TNF IL-6, IL-17, γ Kruskal-Wallis, α, nteplasma the in χ 2 2 = (2) Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. 11 Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818918.88340956 — This a preprint and has not been peer reviewed. Data may be preliminary. 12