Rh eumatology intern<'ltionai.(IM)
`v 27, rto. 2. (.!m1 ?.fJ07)
`I r'e n "·r···J I. "oil ·'·l· liMr>
`W 'i RH~:2H
`2007 co-24 ac::;;::;!~
`
`.., .. , L I
`
`-.;J
`
`V
`
`\,
`
`, J
`
`,
`
`t;;
`
`,
`
`PROPERTY OF THE 0/t
`NATIONAL
`d>~
`LIBRARY OF
`MEDICINE
`
`BIOEPIS EX. 1102
`Page 1
`
`

`

`Autho rs arc requcs tcd to crca tt.:: a link to tht.:: !Juhlislt~~!
`st.:: rvice. Th~ link .n~ tt~ 1
`art icll!. Sp ringer"s in ternl!t
`bl! al.:l:Olll pani..:d by the foJJ O\.V illg t.ext: .. fl~~ ongJil<l
`public:ttion is available at spnn ge rllllk.co m ·
`T he author is requcsted_ to use the appt~opriatl.! J?~.l
`fo r tht.:: artick (go to th..: Lmkin g Ol_,ti ons .Ill the: .a rt I~~ :
`..
`then 10 OpcnU RL and usc the lrnk wilh the D
`Art icll!s disscmitwted via. www.springt.::rlin_k.~..:.oJ.~l -~~~~~
`imkxcd. ahstractcd at~d relc_rc t~t..:t.::d hy .man.y .Jb~~~ -~~c..; t l b~­
`and itt iOrmati o n sc:rvH.:es. bthltograplttc n ~,;t wo t k~. ·
`~cripti u n agencies. li brary nt.::tworks. and conso rtia .
`.
`-~~
`The autho r wa tT<ln ts
`that
`this co ntribu tion
`ll1~1 ~.L.
`o ri uina l a nd
`that he/shc has fu ll pow..:r to
`th i: grant. The autho r signs for _a nU accep ts J:csp.o ~ 1~1-
`bility for rd easin g thi s matt.::nal o n heha ll o l •1 Y
`and a ll co-autho rs.
`/\l"ter submission ot" thi s agrt.::..:m~nt signed hy t1_1~
`co rres pondin g aut ho r. chan ges of authorship o r til
`th l.! orde r or thl: ,1uth ors listl:d will n ot he accepted hY
`Sp rin ge r
`1 Vhi!e tlw ruh-in· ({//{/ il!/oi"IIIOiiun in !his jourllt~l / ·':
`hf'lit·l·c•d to /w 1r11c and ttccurale al !he dote t~/ 11
`·'
`puhlic(//hnt. ncitlwr the multors. !lu• editors. /~or t!tt'
`plfhlis!tcr n tll ocn·p! any h·gal I"C'SfUntsihi!ity .for. ~1 11. 1.
`1
`('f/"ors ur oJIIissions !lull 111ay he nwdc. ·nw puh!t.'/11'
`nlllkcs 11o lrmTalltr. c.\}IITS.,. or i111plicd. ll"itlt r cspc•cf 10
`tltc 11/tlfcrio/ co11ft;incd hen• in .
`.'')fJC'( "ial regulot ionsfor t!totoct~pics in(."~' u.~· .. J:_ ~">llll~~
`.
`tocopies may he madl: lor pl! r:-.o n;d 0 1 tn- ~ HHJs~,; _
`hl!yond the: limit ations stip ul a ted under ~ec ~Hlll _10 7 °1
`1 0~ oJ" U.S. Copyrig ht La w. provitkd ;1 !ct.:: IS patd. ;\~I
`fees sho uld IK· paid to the Copyright Ckarancl! Ccnt_L' 1
`Inc.. ~I ConQ rcss Street. Salem. Mi\ 0 I '!70. US I\.
`s tatin~ the ISSN or the journal. the vn lume . and t_he
`first a~d la st pa!.!.l: llltlll b~ rs o !" C<t<.: h a rt_i ck Co pic:d. ') hc
`copy ri ght ow n l.!~r's t..:nnsl!n t docs no t tn clud!..! co py 11 1~
`
`fo r gt.:: ncra l d istribu tio n. promotion. nl!w_ w.o rk~. 0
`rl.!sale. I n these cast.::s. specific writte n pl! rlllJ SS tOil J11l! SI
`firs t he o btaint.::d fro m tilt.:: publi sher
`The: Canada instilll tl: !"or Scit.:: nt i!lc and Tech ni ca l
`Information (C IS"fl) provides a compreh!..!nsive. wo rld (cid:173)
`wide doc ument delivery se rvice lOr al l Spri11gt.::r jo un1a ls.
`Fur mo re informa tio n. or to place an oHkr fo r 11
`t:OI~wct
`copyrigh t-dcart.::d Sprin gt.:: r doc umt.:: nl. plcast.::
`C lient Assistant. Doc ument Dcli v'.!ry. Ca nada lnsututc
`l(lr Scientific and
`lnforma tinn. Ottawa
`·rcchni~..:;i\
`K IA OS2. Canada lTd: 6 IVJ '!3-'12 5 1: j~:ax: (, i VJ
`52-X2 41: t.::-mai l: ~..:ist i .docdd ( u nrc.ca).
`
`_1
`
`•
`
`Electronic edition
`An l! lcc tronic ed iti on o f"
`at sp ringe rlink .com
`
`this jnur nal
`
`is avaibbk
`
`Production
`Produc tion
`.l ou rn;d
`Spri nger. Kari n Q uint C'>.
`Medici ne. Post l<rch I 0 52 KO. D -(> '104~ I kidclber;!.
`Ge rm a ny. / Jt!dn•ss for cour;cr, c·.rpn·ss all(/ n·gistcn•t!
`moil: Ticrgartcnstrassc 17. L>-()1) 12 1 Heidelberg. Germany,
`Td: (() 62 2 1) 4 X7-R5 25. !:ax: (0 62 21) 4R7K<J I5
`E-mail: kari n.quintcsrfl springer.com
`
`Science communication
`Adve rti sin g: .fens Dcss in . anzeigcn r(/ sp rin gc r .com
`Sp rin ge r. He ide lberger Plat z :l,
`14 197 Berlin . German y
`T e l. : + 4'!-.10-S27X757:l9 . Fa x:
`sp ringc r.com fwikom
`
`i· 49-.10-X27X75~00
`
`Typesetter: SPS. C hcnnai , India
`
`Printer: Stii n z GmbH . Wiirzburg. Ge rm a ny
`
`Publisher
`Springe r is a part or
`Sp rin ge r Sc icncl!-! 13usin c:ss IVkdia
`Print ed o n acid-free papt.::r
`
`SJlringe r.com
`ow nt.::rship a nd copy ri ght
`rr> Sp rin ge r-Verla g Berlin Heidelbe rg :!007
`Print ed in Germa ny
`
`Rheumatology
`International
`
`Clinical and
`Ex peri menta I
`Investigations
`
`Aims and Scope
`RHE UMATO LOGY INTERNAT IONAL is an indc(cid:173)
`p~ntknt jou rn al n.:lkcti ng world-wi~k progr:ss lll t h~
`n:scarc h. diagnosis and trca tm...: nt o l the \~anous ':ht!u(cid:173)
`matic d iseases. It is <.h.:signcd to serve the II.Ih.:rnalton~d
`and intc rdi st..: iplinary gro up o r wo rkers lll ~olvcd Ill
`problems nr rheumatic diseases. Rl l EUMATOLOGY
`INTE RNATI ONAL will cover all nwdcrn trend s 111
`tl~c
`diniL":t l und cxrx: rimcnt;.d rcsc:m..:h as. we ll as 11.1
`ma na!.!CillC!ll o r rheumatic disl..!aSL:S. Spec tal ~ mph <.lSIS wt ll
`he !..!.i \~11 to inll1lllllO-pathogcn...:tic ml!ch<.HliSlllS .. Jnlbn:(cid:173)
`m alo ry reactions. co lla gen n tct:~ho li sn.t.. genetics. ~ p t­
`tkmiology. thc rapcut ic m<~dui;II J Oil o l 11lll1llll10 i oglc; tl
`and in ll amnwto ry nh.::c hanJ sJl lS. and <.kvdopmcnt a~td
`eva luation of diagnostil: proccd un.:s cOJllh.:ctc~l wn_h
`rh~.:umat i~..: d is~as~s. Contribut io ns to t h~o:SI.! topll:S will
`aplx:a r in tht.: ro rm or o rigi nal puh_l ica tions: illl!wmat ive
`case n;po rb. short commun~t.:auons . ..:dllona ls, and
`r'.!V i'.!WS. " Lc\lers to the edi tor·· will he wdcome as an
`t.::nhan<xment to discussion . Every dlUr~ wi l.l ~t.: made. to
`ensure speed of p ublil:ation whll_e mallltaJ ntng a IHgh
`'>ta ndard of content s and produ~..:tJon.
`Manuscri pt submitted !(lr publicat ion nntst contain a
`statement to the dlix:l that all human studies hav\! been
`r~.:viewed by the appro priate cthi<.:s comm i~tcc and h:tvc
`th~ rc l"on: hecn p~rrormed in <H.:cu rdancc wllh the t.::th1cal
`sta ndards laid dOWll ill <Ill itpprnpriatC Vl!!"SiOil of the
`1'!64 Dcclar:rt ion or l ldsink i. It should also he stated
`ck·arly in the tc.\ t tha t all pcrsons gavt.:: thei r in!~) rmcd
`consent prior to thei r inclusion in the study. Det;nls that
`might disclose the i<.kntit y of" the s ubje~..:ts under study
`siH;uld be omi ll..:d.
`Rt.::pons of anima l t.::x pt.::ri mc:nts mus t state that the
`"Prim.:ip\cs o f laborato ry an imal ~.:are" (N IH p ub(cid:173)
`licatio n No. X6-23. rt.::viscd lt.>K5) were fol lowed. as wdl
`asspeci!ic national la ws(c.g. thcc urrcnt ve rsion o l" thc
`German Law on th..: Protection o r Anima ls) where
`app li cable.
`The ed itor rcsc rvl! tht.:: right to rt.::jo.:ct m<tnusc ri pts
`that d o not co tnply with
`tilt.:: above- menti o ned
`requirements . The autho r will he h ~ l d res po nsib le
`!"o r !"a lsi.! SliliC!llelltS Or !"or failure: \ 0 f"u\!i l the ahovt.::(cid:173)
`JllCntioned req uiremen ts.
`
`Manuscripts (in triplicate) may be sent to the
`following:
`Coordinating editor:
`l'ro r. E.-M. Lemmd, Max-G rund ig- Kiin ik
`Schwarzwa ldh ochstr:tsse I
`77~ 15 Biihl. Germa ny
`p rof.km md ru gmx.d e
`
`Subscription Information
`
`ISSN 0172-8172
`
`• Subscription rates
`1:o r inl"ormati o n o n subscription rates pka st.:: co il! act:
`Custo mer Service
`T he Americas (North , South, Centra l A me ri ca
`and the Caribbea n):
`jou rna ls- nyra sprin gc rxo m
`Outside the Amerkas: suhsc riptionsru sprin ger.com
`• Orders and inquiries
`The Americas {North, South, Central America
`and the Caribbean)
`Springer Journa l Fullillmc nt
`1'.0. Box 24X5. Seca ucus. NJ 070'!6- 24X5. US/\
`Tel. : XOO-SI'RI NGER 1777-4643).
`Tel.
`I I- 201-34X-4()}3 (outside US and Canada).
`r:ax:
`l 1-20 1-34X-4505
`e-m:t il: jo urnal s- nyr(t sprin gc r.com
`
`Outside the Americas
`via a hooksl! lle r o r
`Sp ringer Distribut ion Ce nt l.!r Gmh l-l
`1-l ahcrstrassc 7. 61J I 26 ll ciddberg. Ge rm any
`
`A 2
`
`Tel. : ·I 4'!-6221-345-4303. Tel. : I· 49-6221-345-4304.
`Fax:
`l 49-622 1-345-4229
`e-ma il : s u bs~..: ri pti o n s fo sp rin gl.!r.co m
`Business hours: Monday to Friday g a. m. to K p. m.
`localtimt.:: a nd o n Germa n public holidays
`Orders or claims can cit her be placed via a bookseller
`or se nt dirl.!ct ly to:
`Springe r
`C ustomt.:r S..: rvicc J ou rn a ls
`1-Ld1erstrassc 7. ()1) 12(1 l lcidcllxrg, Germany
`Tel. : l 49-1>22 1-3454304: hr x: 1- 49-6221-34 522'!
`e- mai l: suhsc ript ion'> (o sp rin ge r.co tn
`
`Cancdlatirms mu st ht.:: received by Septembe r ~() to
`take ellCct at thl.! e nd of thl.! same yl.!ar.
`C/un1~es r~/ (1(/dt<'s.\·: /\ !low six weeks fo r all changt.::s
`to bl.!comc d ll!ct ivc. All co mmun ica ti o n'> shou ld
`indudc bot h o ld a nd nt.::w addresses (wit h postal
`cO<ks) a nd sho uld be accompanied by a mailing \;the!
`from a nxent i..;s uc.
`
`Accord in g to * 4 sc~..:t ion 1 o f the German Post; d
`Snviccs Data Protc~..:tion Regu lat io ns. if a suhscri(cid:173)
`bt.::r"s addrl.!ss chan ges the G~rman Post O!licc can
`inform the publisher of the new ;1tldress even i!" the
`subsc ri bt.:: r ha s not suhmithx.l a rornw l applicati o n !"o r
`mai l to he f"o rwankd. Subscribers not in a gr..::cment
`wit h this proccdurl.! ma y send a writt en co n~1 l aint to
`Sprirt gcr-Ve rla g's Be rl in oll icc wit hin 14 da ys o r
`publica ti o n o f" this iss ue.
`
`Back l'olul!les: Pri<.:t.::s a rc ava ilable on rl.!qucst
`iVIkroform editions an: av ila ble from: ProQul.!s t.
`Fu rtht.::r informations ava ilable at http://www. il. pro(cid:173)
`qucst.com/ umi/
`
`Copyright
`Submission of a maJHiscri pt implil.!s: that th e work
`dcscri hl.!d ha s not bee n publ ished hcf"o r~ kx<.:cp t in tht.::
`form or an <tbstract or as pa rt or a publi sht.::d lecture.
`review. or thesis): that it is nu t un<.kr consitk rati on
`for pub licat io n elsew here: that it s publica ti on ha s ht.::en
`appro ved by all co-authors. if an y. as we ll as by the
`rl.!s ponsible au tho ritit.::s attht.:: institu te whert.:: tht.:: wo rk
`has bee n ca rri ed o ul.
`Th\! aut ho r wa rrant s that his/ her l:Olllri bu tion is
`origi nal and that ht.::/sllc has f"u ll po w~ r to make this
`gra nt. The auth or signs fo r and accepts rt.::spon sihilit y fo r
`relt:asing this mate rial o n behalf of any and a ll co(cid:173)
`aut hors. Transfer of copyright to Spri nge r (respecti v.: to
`owner if o tlh.:r tha n Springer) lxcomcs elli.:cti vc. if and
`when the article is accepted
`l<H publica tion. After
`submi ssio n oftht.:: Copy righ t Tra nsfer S ta tement signcd
`by the co rres-pondi ng aut hor. cha nges o f aut horship or
`in the order or t h ~ authors listed will not ht.:: accepted hy
`Springer. Tht.:: copyri ght cove rs the t.::xdusive ri ght (for
`U.S . gove rnmen t employees: to the exktll tr;mskrahk)
`to reprodu<.:l! a nd distri bute the <l rticle, includ ing rl! print s.
`tran s l t~tions. ph otographic reproducti o ns. micn) IOrm .
`dec\ ronic form (o llline. online) o r ot her reprod ucti o ns of
`si mil t~ r nat ure.
`All art ides publisht.::d in this journal a rc prot ~ct cd by
`copyrigh t. whid1 cov~:rs the cxd usivc rights to reprod uct.::
`and distribute the article (e.g., as olr-pri nts). a ll transla(cid:173)
`tion ri ghts as wdl as th~: ri ghts to publish tilt.:: a rticle in a ny
`electro nic form. No ma teria l published in this jou rna l
`may be reproduced photographicall y o r sto.red on
`micro fi lm. in cb:tronic data hasc:s. video disks. etc..
`without first obtain ing written pc:rmission fro m the:
`publisher (rt.::spective to owner if other tlwn Springer).
`·rhc usc of genera l desc ripti ve ttan11.::s.
`trade names.
`trademarks.
`in
`this publication. even
`it" not
`ct~..: ..
`spl.!cifica lly idl! tlli! kd. docs not imply that thcsc names
`arc not pro te<.:ted hy the rckva nt laws and rcgul<11i o ns.
`An aut ho r ma y mak e ;ul art icle published in thi s
`jou rnal avai l:th le o n hi s/ hl.! r perso na l home pa gt.::.
`provided thl! so urce o f the publi shed ar ti cle is cit ed
`and Sp ringe r is 111\! nt io ned as tht.:: co pyri ght ow ner.
`
`This m aterial w as copied
`atth e NLM and m aybe
`Subje<t U!SCopyright Law s
`
`BIOEPIS EX. 1102
`Page 2
`
`

`

`Rheumatology
`International
`
`Clinical and
`Experimental
`Investigations
`
`Editor-in-Chief
`
`Prof. Dr. E-M. Lemmel ,
`Baden-Baden
`
`Advisory Board
`
`L. Bonomo, Rome
`T. D. V. Cooke , Riyadh
`S. D. Deodhar, Chandigarh
`T. E. W. Feltkamp, Amsterdam
`H. Greiling, Aachen
`E. J. Holborow, London
`M. F. Kahn , Paris
`R. N. Maini, London
`D. G. Palmer, Dunedin
`
`P. A. Revell, London
`A. S. Russell , Edmonton, Alberta
`J. D. Stobo, San Francisco, CA
`N. Talal, New York, NY
`R. Timpl, Martinsried
`B. Vernon-Roberts, Adelaide
`M. Zembala, Cracow
`N. J. Zvaifler, San Diego, CA
`
`Honorary Editors
`
`J. B. Natvig, Oslo
`
`eJ Springer
`
`GENERAL INFORMATION
`) springer.com
`
`ELECT RONI C CO NTEN T
`))) springerlink.com
`
`This m ateri al w as co pied
`at th e NLM and m ay t>e
`Subject US Copyr ight Law s
`
`A3
`
`BIOEPIS EX. 1102
`Page 3
`
`

`

`Rheumatology
`I nternationa I
`
`Clinical and
`Experimental
`Investigations
`
`Volume 27 Number 3
`
`January 2007
`
`OR IG INAL ART ICLES
`
`. akamura H . Ma suk o K . Yudoh K. Kat o T . Kanw d a T . K awa h<~ra T : Elfccts of
`J,! lucos:1rninl' :Himinis tratitm on Jla ticnts with rheumatoid arthritis
`2 13
`
`Lee Ell. Lee YJ. S hin DH . C'hoi YM . l'ark M i l. Pandey JP. So ng YW:
`l m m uno~lu hulin GM a nd K!\•1 ~c nol )' pcs in Knn.•an patients wi th S)'Sh.•mi c hiJHIS
`erythematos us
`219
`
`Lee EY . Lee C- K. Lee K-U. l'ar k J Y. C ho K-.1 . C ho YS. Lee HR . Moo n SH .
`M oo n 11-13 . Yoo B: Alpha-liJloic ac id S IIJ)Jlfl'SScs the dc,•clopmcnt nf coll aJ.!C n-induccd
`arthritis and protects a ga inst hnnc destruction in mice
`225
`
`K:tsht..:f S. G l1<1t.:dian fv1M . Rajal.!c /\ . Cihadcri A: Dyslipoprotcinl'lllia durinJ.! the
`actin• course of sysh:mic lupus c rylhl•nw tosus in assnc ia tin n wit h an ti-dnuhlc-slr<Hltlcd
`DNA (anti-dsONA) antibodies
`235
`
`S rikulmont rcc.: T . Massey 1-1 D . Ro bc.: n s W N: Tre<~ tm cnt of skelet a l E rdh cim(cid:173)
`jJrHflOScd mec h:111isrns nf
`(;hes te r disease with zuledrnnic :1cid: case rt.'Jmrt a nd
`303
`aclion
`
`LETTERS TO THE ED ITOR
`
`13ir..;in 6 z..;akar z. Yiik scl S. Ensa ri A. Ekim M. Yah;mka ya J~·: ,\cul e renal failure
`309
`in a p:1 tic nt wit h f:uuili:1l i\'lcdit rrra nca n fC\'e r
`
`Din lcr M . Ka sikciog lu E. Akin A . Sa yli 0 . /\ ksoy C. O ncd A , Bcrkt.:r E: Excrcist~
`;md o xygr n rccm•ery half times o f skeletal muscle
`capacit)'
`in patients with
`311
`lihrnm ya lgi:1
`
`FORTH COM I NG ART IC LES I N PR I NT
`
`h nwuch i M . Shimadzu H. Tamak i C. Yamagata T . Noz: tk i Y. S ugiya ma M .
`l ko ma S. K inos h i1:1 K : S un'i\':.tl stud y by orga n disorders in 306 Jat>:mcsc tJati ('nfs
`with S)'Stcmic lupus c.:ryt hcm:ttosus: n..•sults frurn a single cen ter
`243
`
`pu blished o n li ne.: a nd ci tab le w ith the 0 01 (O ig ita l Ohjcct Jd c ntilic.:r) ~.:a n bc round
`at springc rlink .com
`
`Pc nni .. ;j P. Tro mhelli A. G ios tra E. M e ntha G. Ri zzo li R. Fiore CE: J>:unid ro n:lle
`ami usteo porosis pn..•n·n tion in lh'Cr tr:ms pl:.111t rcl'i JJi cn ts
`251
`
`J'u r Authors arc now a va ilahle onl y o n
`Ins tru ctio n s
`www .springer .comf002Y6
`
`the.:
`
`journal 's webs ite:
`
`l . Pay nt: U. Zlwng X. lwana ga Y. Da vt:y M P. R ose n baum J l '. Inman RD :
`Kim T~ l
`Alh.·rcd host:JJ;.ttho~cn inter:u.· rions confe rred by till' Hlau sy nd rome mutation nf
`257
`N OD2
`
`A rdcn iz 6. Vat ttnst:vc r S. Musahak U. Aks u K . Sin A . Kok uluda i! A : A rthritis :IS~~
`prese nting sy ntJJiom in :1 hypngammaglnhulinl' lllic JJ:Itient with thy~u:ctnm y
`263
`
`\V o h lgt: muth .1 . /\rmhru stc r F~ P. ll c ilig B:
`lkndcr NK. 1-lt.:ilig CE. Drdll B.
`lnununc,gcnicit y, dlicacy nnd :ul\'(:rst• C\'Cnts nf adalimum:1 h in I~ A 1•at ients
`269
`
`Ala ~c hirli B. Oc mi ryii rc k ~- Anca E. Gn rsoy S. D c m iryl"1rr.:k !\ T : No C\'ide ncc fu r an
`:1ssnciation hc twecn the Glu29HAsp poi)'IHOrphism of the t•ndoth eli:ll nitric oxide
`275
`synth:tst gene :.1nd l ihrcun y:1l~ia sy ndrome
`
`CASE REPORTS
`
`In dexed in/abstracted by Currl'lll Cou/ell/.1' and tude.\' Jl!hdicu.v
`
`296-27 (3) 2 13- 3 14 (2007)
`
`Bas kin E. i\g ras P l. M c nc k )c N. Ozdr.:mir II. Cc ng iz N: Full~hu usc ncJ•hrnp at hy in :1
`281
`(l:tlit·nt with nc~:lti \'C se rolnJ.!)' fur hiJUIS
`
`G<~rth wa i t t.: EA . Borde r 0.1 . .l o nt.:s C ll. \Vorth JJP: /Uunlocot·t·u.\· equi infrc tion
`durin!.! rrc;.~ tm('nt nf a (.'~ ANCA JIIISi ti n· ' ':IStulitis: a co1sc repo rt
`285
`
`fl Springer
`
`Klumb EM . d~: Andrad~ MC .. k:s t'ts NR. C amp:tni C. Campos C l< Lcvy RA .
`1\ lbuqu r.: rquc.: E. C\: r va nt c.:s V: Primar)' antiphnsphulipid ll('phrnJl:lth y ht.•J,!inning
`289
`durin J.! J•rcJ.! n:mcy
`
`llc r M ~Y. Kim T -11. C han g 1·1- K . Lcc W~S . Yoo D - 11 : S uccl•ssful treatme nt of
`:1ccruired ~llll l'J.!:Ik:tryucyti c thrumhncy tufJCni a wi th cyclos pnrinc in ;ulult o nse t S till 's
`295
`diseose
`
`K oz OC i . l\t c.:~ /\ . Nu man /\lp M . Gult;ul E. Kara as lan Y. Kur;li (i : Bilatcrnl ucu l:1r
`isd 1cm ic syrulruml' :1s an initiollmanift•st:ll iu n uf T akayo1su's artt•ritis associ :~ ted with
`299
`.
`c :~rutid stea l syndrumt
`
`Online First
`Immediately Online
`springerlink.com
`fio
`
`A4
`
`Thi,; m at erial w a,;copie·d
`at the NLM an.d may ~e
`Su~ject US Copyright Law s.
`
`BIOEPIS EX. 1102
`Page 4
`
`

`

`Rh e um a to llnt (2007) 27:269-274
`DO l 10.1007 ls00296-006-0 L83-7
`
`ORIGINAL ARTICLE
`
`lmmunogenicity, efficacy and adverse events of adalimumab
`in RA patients
`
`Niko K. Bender · Christoph E. Heilig· Benjamin Droll .
`Jessica Wohlgemuth· Franz-Paul Armbruster·
`Bernhard Heilig
`
`Received : I .Jul y 2006 I Acce pted: 23 Jul y 2006 I Pu blished o nline : 28 Septe m be r 2006
`© Sprin ge r-Ve rl ag 2006
`
`Abstract To assess
`immunoge nicity of ada(cid:173)
`th e
`limum ab, a hum a n anti-TN F-cr mAb, we evaluated th e
`fo rm a ti o n of antibodies to ad alimumab, efficacy and
`adverse eve nts amo ng 15 pati e nts with highl y active
`rh e um a to id a rthritis. Four patie nts we re trea ted with
`ada limumab as mo no the ra py, and t I pa ti ents with con(cid:173)
`co mita nt DMARDs. Disease activity was measured by
`DAS28. The a ntibodi es we re de tected by E LISA.
`Thirtee n (87 % ) pati e nts withdrew fro m th e rapy within
`45 wee ks and ove rall 13
`(87 % ) pati ents showed
`a ntibodi es to ada limuma b including 11 pati ents who
`withdrew fro m
`th erapy.
`In fo ur pa ti ents without
`co ncomita nt DMA RD s and in nin e patie nts with con(cid:173)
`comi ta nt DM A RDs, we de tected a nti -adalimumab
`a ntibodi es. Ove rall , fi ve o f seve n pa ti e nts with adve rse
`drug reactio ns and all nin e pa ti e nts with lack of e fficacy
`we re assoc iated with the fo rm a ti o n o f antibodies. Two
`a ntibod y-positive patie nts deve lo ped an exanth e me.
`Th e res ults indicate that ada limumab is, in spite of its
`full y hum an seque nces, immun ogenic and induces anti(cid:173)
`bodies in a hi gh rate of ada limuma b-treated pa ti ents.
`
`Keywords
`lmmunogenicity · Anti-adalimumab
`a ntibodies· Adve rse eve nts · C linical response
`
`Introduction
`
`T he tumor necrosis factor cr-blocking mo noclonal anti(cid:173)
`body adalimumab is described as safe and we ll tole rated
`and shows clinical efficacy with o r witho ut the concomi(cid:173)
`tant use of methotrexa te in co ntrolled clinical trials
`amo ng patients with RA . A dalimumab is gene ticall y
`e ngineered by phage-display technique and beca use o f
`its full y hum an sequences it is supposed to be less immu(cid:173)
`nogeni c than murine or chimeric monoclo nal antibodies.
`However, th e form atio n of human anti-hum an antibod(cid:173)
`ies (H AH A) has been repo rted by several autho rs (1-3].
`It still remains unclea r which part of adalimumab
`induces H A HA response. Lmmunogenicity of ada(cid:173)
`limumab and its clinical significa nce in dail y clinical
`practice is poorly investiga ted compa red to the immuno(cid:173)
`genicity of in fli ximab and may dille r from th at shown in
`previo us controlled studi es [ L -3]. The aim o f this tria l
`was to assess the immunogenicity of ad alimumab and
`the correlati on o f effica cy and adverse eve nts amo ng a
`sma ll number of patie nts in regul ar clinical settings.
`
`Patients and methods
`
`Pa ti e nts
`
`N . K. Be nde r (l8J ) · C. E . H e ili g· B. H e ilig
`Rh e um a praxis H e id elbe rg, Wie la nclstr. 20,
`69 120 H e idelbe rg, Ge rm a ny
`e-ma il : n. bencler@rh e um a praxis- he iclelbe rg.d e
`
`B. D ro ll · J . W o hlge muth · F. -P. A rm b ruste r
`lmmundi agnosti k AG , Stu benwa lcl -A llee Sa,
`64625 Benshe im , Ge rm a ny
`e-m ail : inl'o@immuncl iagnostik .com
`
`Fifteen eligible pati e nts had rhe um ato id a rthritis (RA)
`di agnosed according to th e 1987 revised criti e ria of th e
`Ame rica n College of Rh e um a tology (4] with a di sease
`activity score (DAS 28) of mo re than 4.0 who were tak(cid:173)
`ing adalimumab with o r witho ut concomitant meth o(cid:173)
`trexa te o r le flun o mide. All participants we re trea ted
`with co rti coste roids a nd had previo usly received mo re
`th an o ne DMARD witho ut clinica l e fficacy.
`
`This mat eri al w as copie d
`at the NLM and may De
`SuDject US Copyright Law s
`
`~Springer
`
`BIOEPIS EX. 1102
`Page 5
`
`

`

`270
`
`Rh e um ato l lnl (2007) 27:269- 274
`
`Exclusion criteria consisted of the British Society for
`Rheumatology guidelines for prescribing TN Fa blockers
`in ad ults with RA [5].
`
`Study protocol
`
`We assessed 15 patients between November 2003 and
`January 2006 at a single center in Ge rmany. Eleve n
`patients were tak ing adalimumab with concomitant
`methotrexate or leflunomid e and four patients were
`taking adalimumab as monotherapy. Informed consent
`was obtained fro m all patients enrolled. After screen(cid:173)
`ing for tuberculosis, which included chest radiographs
`and tuberculin skin testing, base line assessment which
`included measurement of DAS28 and medical history
`were perfo rmed. Study visits were conducted every
`month to every 3 months in most cases. Every patient
`received ada limumab at a dosage of 40 mg subcutane(cid:173)
`ously every oth er week . Patients were instructed about
`self- injection techniques.
`
`Assessment
`
`OAS28 and morning stiffness were measured at base(cid:173)
`line, after 3, 6, 12 and 18 months th ereafter. A change
`in the OAS 28 of >1.2 (twice the meas urement error) is
`a clinically significant change [6].
`Safety was assessed on the basis of adverse events
`reported by patients and findings on physical examina(cid:173)
`ti on and laboratory evaluations.
`
`lmmunogenicity assessment
`
`Serum levels of anti-adalimum ab antibodi es were mon(cid:173)
`itored at base line and every other time on follow-up
`(i.e. , in most cases between 4 weeks and 3 months
`thereafter) . According to the optical density (OD) of the
`HAHA serum level, we divided the antibody-positive
`patients into three groups: patients with low serum lev(cid:173)
`els (0.02 ::: 00 < 0.2), intermediate levels (0.2 S 00 <
`1.0), and high levels of antibodies against adalimumab
`(OD =:: 1.0). Serum levels of anti-adalimum ab antibod(cid:173)
`ies were measured by sandwich enzyme linked immu(cid:173)
`nosorbent assay
`(EUSA;
`Immundiagnostik AG ,
`Bensheim, Germany). Ninety-six-well microtiter plates
`were coated with 100 f.ll/well of solution containing
`3 ~tg/ml F(ab') 2 fragments of adalimumab (Abbott,
`Wiesbaden, Ge rmany) buffered with 50 mM of sodium
`carbonate (pH 9.6). After incubati on overnight at 4°C,
`the plates were blocked with 2% BSA in PBS for l h at
`room temperature. Patient serum and control sa mples
`diluted 1:200 in 2% BSA in PBS , pH 7.2, were added to
`in duplicate and
`incubated
`the appropriate well
`
`~Springer
`
`overnight at 4°C. After washing, horseradish peroxy(cid:173)
`dase-conjuga ted adalimumab was added and the prep(cid:173)
`arations were incubated for l h at room temperature.
`Color reaction was induced by incub ation with th e
`substrate solution (TMB) for 30 min . The reaction was
`stop ped by addition of 0.4 M sulfuric acid and a micro(cid:173)
`plate reader was used to measure the OD at a wave(cid:173)
`length o f 450 nm. The res ults were determined by
`cuto ff.
`
`Results
`
`Antibodies to adalimumab
`
`The baseline characteristics of the patients are shown
`in Table 1. Overall, 13 (87%) patients had low serum
`levels up to high serum levels of antibodies against ada(cid:173)
`limumab (Fig. 1 ). All four patients with adalimumab
`monotherapy and nine patients with additiona l
`DMARDs had elevated serum levels (Fig. 1). Three
`patients had high levels of antibodi es (00 2': 1.0), two
`patients had intermedi ate levels, and eight patients had
`low levels (0.02 ::: 00 < 0.2). One patient with high
`levels of anti-adalimumab antibodi es was taking ada(cid:173)
`limumab without concomitant DMARD and withdrew
`from th era py owing to the development of a drug(cid:173)
`related exantheme. The other two patients dropped
`out owing to lack of etficacy- one ta kin g concomitant
`le flun omide, one concomitant methotrexate.
`The two patients with inte rm edi ate serum levels of
`anti-adalimumab antibodies had to discontinue owing
`to adverse events, including one with exantheme and
`one with herpes zoster. Among the eight patients with
`low levels, six had to discontinue treatment, four owing
`to lack of e f1icacy , two owing to adverse drug reactions,
`and two patients are still taking adalimumab without
`lack of etficacy or adverse events.
`
`Dropouts and antibody formation
`
`In 13 (86%) patients adalimumab treatment failed and
`led to withdrawal from therapy (Ta ble 2). Six patients
`discontinued treatment owing to lack o f efiicacy, six
`owing to adve rse drug react ions, one beca use of bon e
`surgery (Table 2). Of those patients with side effects,
`three discontinued treatment owing to hypersensitivity
`reactions (two with monotherapy) , one owing to th e
`developme nt of herpes zoste r, and one owing to short(cid:173)
`ness breath , both were takin g adalimumab with con(cid:173)
`comitant methotrexate (Ta ble 3). Of three RA patients
`who did not reach the third month of therapy we had
`no further DAS28 a fter base line. On ly one patient
`
`BIOEPIS EX. 1102
`Page 6
`
`

`

`Rheumatol lnt (2007) 27:269- 274
`
`27 1
`
`Table 1 Base lin e characteristics o f I 5 patie nts with R A trea ted
`with adalimumab
`
`Table 2 Dropouts, treatment duration a nd disease activity in the
`course o f trea tme nt
`
`Variables
`
`Mea n ± SEM
`(ra nge)/n (%)
`
`Dropout patients
`(week 2-45)
`
`A ll
`Owing to lack o f e iTicacy
`Owing to AEs
`Exantheme
`Other AEs
`Needed surgery
`
`Treatment duration
`
`Numbe r of inj ections until
`drop out
`Number o f weeks until
`d rop out
`
`Mea n disease ac ti vity
`
`DAS28 at baseline
`DAS28 three months la te r
`
`R esults
`II(%)
`
`13 (87)
`6 (40)
`6 (40)
`3 (20)
`3 (20)
`I (7)
`
`Mea n ± SEM (ra nge)
`
`7.8 ± 4.2 (2-23)
`
`13.2 ± 7.8 (2-45)
`
`Mean± SEM (ra nge)
`
`6.5 ± 1.2 (4.0-8.5)
`6. 1 ± 0.6 (4.5-7.2)
`
`Age , yea rs
`Female sex
`Disease duration , yea rs
`Numbe r of previous DMARDs
`DAS 28 at baselin e
`M o rnin g stiffness, minutes
`Se ropositivity
`
`Indi ca tion fo r ada limum a b
`
`High disease ac ti vity
`AEs to othe r biologicals
`R e fractory to other biologica ls
`
`Concomitant medication
`
`Corti costeroids
`M e th otrexa te
`Le nuno mide 20 mg/day
`
`Dosage (mg)
`
`Pre dnisone, mg/clay
`M e thotrexate, mg/week
`
`55.9 ± 8.1 (34- 73)
`10 (67)
`12.2 ± 8.2 (2.5-40)
`3.1 ± l.l (1- 5)
`6.5 ± 1.2 (4.0- 8.5)
`132 ± 121 (0-480)
`9 (60)
`
`11 (%)
`
`14 (93)
`1 (7)
`6 (40)
`
`n (%)
`
`15 ( 100)
`10 (67)
`J (7)
`
`Mean ± SEM (range
`
`7.7 ± 2.7 (2.5-15)
`13. 1 ± 2.3 (7.5-20)
`
`SEM standa rd e rror of the me an , n number o f patients
`
`I
`
`I
`
`Overal I
`
`2
`
`Drop out
`
`2
`
`.,
`
`1"':1.'-
`
`Adverse events
`
`2
`
`Exantheme
`
`~
`
`~1~'
`
`•
`
`lloHAHA neg.
`aHAHA pos.
`
`Concomitant DMARDs
`
`2
`
`Without concomitant
`DMARDs
`
`Lack of efficacy
`
`I
`
`Fig. 1 Numbe r o f patients with/without HAHA response in rela(cid:173)
`to clinica l pa ra meters among J 5 acla limumab-treate d
`tion
`pa tients
`
`reached 45 weeks of treatment and one reached
`28 weeks of treatment before dropout. The other l1
`patients discontinued adalimumab treatment within
`15 weeks including three patients with adverse events
`who had to drop out after 3 weeks.
`Eleven dropout patients had elevated serum levels
`of anti-adalimumab antibodies; two patients were neg(cid:173)
`a tive (Fig. 1).
`
`Table 3 Adve rse events amon g 15 adalimumab-trea ted pati ents
`
`Variable
`
`Patie nts with adverse events
`Adverse events leading to withdrawa l
`Exantheme
`Herpes zoster
`Edema
`Nausea
`Headac he
`Dyspnea
`Abnormal menses
`Diarrhea
`
`Results
`11 (%)
`
`7 (47)
`6 (40)
`3 (20)
`I (7)
`1 (7)
`1 (7)
`1 (7)
`2 ( 13)
`1 (7)
`1 (7)
`
`Efficacy and antibody formation
`
`At baseline we measured a mea n DAS28 of 6.5 and
`3 months thereafter a mean OAS28 of 6.1 (Table 2).
`No clinically significant change in the DAS28 was
`observed in nine (60%) patients. These nine patie nts
`showed elevated levels of anti-adalimumab antibodies.
`The duration of morning stilli1ess afte r 3 months could
`not be evaluated in five patients because they dropped
`out before the 3-month follow-up .
`The two antibody-negative patients showed clinical
`response to adalimumab.
`
`Adverse events and antibody formation
`
`Seven ( 47 %) patients showed adverse drug reactions
`(Ta ble 3). Five patients with adverse events were anti(cid:173)
`body positive (Fig. 1). Three patients developed an
`
`Ttt i.s m at erial w a:s. copie-d
`
`~Springer
`
`BIOEPIS EX. 1102
`Page 7
`
`

`

`272
`
`ada limuma b-re lated exa nthe me, including two patients
`wit h antibodies to ada limumab in the ir se rum (Fig. 1).
`Two patie nts without a nti-adalimumab a ntibodies in
`their se rum showed adve rse events, including one case
`with exa nth eme and one with local inflammation at th e
`inj ectio n site.
`
`Methotrexate and a ntibody formation
`
`A ll four pati ents without concomitant DMARDs had
`to disco ntinue adalimumab trea tm e nt a nd all were
`tested positive o n antibodi es aga inst
`the TNF-cx(cid:173)
`blocke r (Fig. 1). One patie nt dropped out owing to
`lack o f ellicacy, o ne owing to lack of effic acy and drug(cid:173)
`related exa ntheme, one owing to drug-re lated exa n(cid:173)
`the me, a nd one owing to herpes zoster. Of the 11
`pa ti e nts with concomitant DMARDs, nine were tested
`positive for antibodies aga inst aclalimumab (Fig. 1). In
`this gro up nine patients had to discontinue the anti(cid:173)
`TNFcx therapy, including seven patients with antibod(cid:173)
`ies against aclalimumab. A ll seven antibody-positive
`patients were associa ted with an inadequate response
`to adalimumab and two patients showed adverse drug
`reacti o ns.
`
`Antibody titers in the course of treatment
`
`Seven patients with a nega tive base line titer of anti(cid:173)
`adalimumab a ntibodi es showed a n increasing OD of
`th e a ntibody titer after the fir st ada limum a b inj ec(cid:173)
`tions. After withdrawal from aclalimumab treatment
`we obse rved a decrease of th e OD to base line anti(cid:173)
`bod y se rum levels in mos t cases. The o th e r six
`patients showed antibodies to ada lim uma b in the
`further course of therapy. Examples are shown in
`F igs. 2 a nd 3.
`
`0 ,06
`
`0,07
`
`0,06
`
`0,05
`
`0,04
`
`0 ,03
`
`0,02
`
`0,01
`
`c
`0
`
`I
`I
`I
`
`I
`
`Rhe umatol t nt (2007) 27:269-274
`
`~075
`
`I ~
`~
`~7
`
`/
`I
`
`" " ' 0,034
`
`-
`
`-
`
`\
`\
`\
`6~.oos
`
`6
`
`0
`
`, -0,004
`
`1
`
`-om
`
`2
`
`3
`
`4
`
`5
`
`Time (months)
`
`Fig. 2 Optica l de nsity (OD) o r the antibody se rum leve l (!lli~1
`lin e) in th e co urse or trea tme nt with adalimumab (!luck llll e) of"
`54- year-o ld fe mal e pati ent who had to stop ada limum ab-mo no(cid:173)
`the rapy within 2 months owin g to lack of e !Ticacy
`
`c
`0
`
`0,1
`
`0,06
`
`0,06
`
`0,04
`
`0 ,02
`
`-o,02
`
`-0,04
`
`-o,06
`
`I
`I
`
`0
`
`I
`1-0,051
`
`~ 0,075
`
`/0,037
`
`=---------=--=
`
`1
`
`2
`
`3
`
`4
`
`Time (months)
`
`Fig. 3 Op tica l density (00) o f th e a ntibody serum level (1 /Iin
`lin e) in the course o f treatme nt with acla limumab (1/Iick OITOII' ) o f
`a 56-yea r-old m ale pati ent. H e sta rted acla limum ab treatme nt
`with conco mita nt metho trexate a fte r discontinuing inniximab be(cid:173)
`ca use o r lack o f c lllcacy. T he th erapy with adal imumab is still
`ongoing; no adve rse drug reacti ons we re o bserved un til prese nt
`
`Discussion
`
`In this regular clinical se tting, o ur investiga tion indi(cid:173)
`cates that in spite of its full y hum an sequ ences ada(cid:173)
`limumab induces HAHA responses in a hi gh rate of
`aclalimumab-trea ted patients with or without th e con(cid:173)
`comitant use of DMARDs. Pre