Vol. 326 No. 16 METHOTREXATE
`
`!N RESIStANT JUVENILE RHEUMATOID ARTHRITIS-GIANN!NI
`
`ET AL
`
`1013
`
`METHOTREXATE IN RESISTANT JUVENILE RHEUMATOID ARTHRITIS
`
`Results of the U.S.A.-U.S.S.R. Double-Bli.nd, Placcbo-Cont,olled
`Tdal
`EDWARD H. GIANNIN.f) M.S.) DR.P.rr., EARL]. BREVttR, M.D.) NrNA KuzMJNAi
`:r·vf.D.~
`AuxANOER SNAtROV, M.D., PH.D., A.LEXEr MAX!Mov, l>vLD., fooR VoRoNTsov. M.D., P>r.D., M.P.H.,
`CH~STER W. FINK, M.D., ART>rtrRJ NEWMAN, MD., JAMES T. CASS!OY, M.O.,
`AND LAWR.E::Nc:F.. S. ZEMEr.., M.D.1 FOR TH.t:: P1::.nxATRrc P,HEUMATOLOOY
`(.ioLLA:eoRA.Trv'.E'.
`STrJoY GRor.rP AND TI-IF. CootE.R.A't:'XVE 01-nr~oREN'.s STUDY GROUP
`
`Background. The antlmetabollte methotrex(cid:173)
`Abstract
`ate has been shown in placebo-controlled trials to be ef·
`fective in adults with rheumatoid arthritis. Methotrexate
`may also be effective in children with resistant juvenile
`rheumatoid arthritis, but the supporting data are from un(cid:173)
`controlled trials.
`Methods. Centers in the United States and the Soviet
`Union participated In this randomized, controlled, double(cid:173)
`bllnd trial designed to evaluate the effectivsness and safe·
`ty of orally administered methotrexate. Patients received
`one of the following treatments each week for six months:
`10 mg ofmethatrexate per square meter of body-surface
`area (low dose), 5 mg of methotrexate per square meter
`(very low dose), or placebo. The use of prednisone ("10
`mg per day) and two nonstemidal antiinflammatory drugs
`was also allowed.
`Results. The 127 children (mean age, 10.1 years) had
`a mean duration of disease of 5.1 years; 114 qualified for
`
`the analysis of efficacy. According to a composite index of
`several response variables, 63 percent of the children who
`received low-dose methotrexate Improved, es compared
`with 32 percent of those in the very-low·dOSli! group and 36
`percent of those in the placebo group (P ~ 0.013). As
`compared with the placebo group, the low-dose group
`also had significantly larger mean reductions from base
`line in the number ofjolnts w'1th pain on motion (-11.0 vs.
`-7.1),
`the pain·severity score (-19.0 vs.
`11.5), the
`number of joints with limited motion (-5.4 vs. -0.7), and
`the erytl1rocyte sedimentation rate (-19 vs. -6 mm per
`hour). In the methotrexate groups only three children had
`the drug discontinued because of mild-to-moderate side
`effects; ncne had severe toxicity.
`Conclusions. Methotrexate given weekly in low doses
`is an effective treatment for children with resistant juvenile
`rheumatoid arthritis, and at least in the short term this
`regimen is safe. (N Engl J Med 1992;326:1043·9.)
`
`J UVENILE
`
`rheumatoid arthritis is the mo. f;t coin·
`mon rheum.atic condition of childhoodi with an
`annual incidence of.about
`J .4 cases per 101000 chil(cid:173)
`dren under the age of 16 years in the United States,
`and a prevalence of roughly I per 1000.' ·' Th.rec types
`of onset of ju.vcnile rheumatoid arthritis are recog(cid:173)
`ni.ied1 each of which has a charact~ri.sdc clinical, epi(cid:173)
`demiologic, and genetic pattern.' The systemic-onset
`form produces a rheumatoid rash and int~.rmittcnt fe(cid:173)
`ver (temperature, >39.4'0, with daily return to nor(cid:173)
`mal); anemia, pcricarditis, and hepatosplcnomegaly
`are common. The arthritis usually involves multiple
`joints. Polyarticular onset is characterized by arthritis
`in five or more joints, a.nd oligouticular onset (also
`referred to as pauciarticular)
`is characterized by ar(cid:173)
`thrltis in fewer than five johns. Rheumatoid rash and
`intermittent fever are absent in the polyarticular and
`oligoarticular forms, although other systemic manifc,.
`tations may occasionally be present.
`
`From the Children's Ho~).'Jil'l.\l Medic.Rl Center, De~rtment of Pedi:1rics, Uni~
`vi:::rsity of Cindrmn!i College of Medieini:t, Cincinnati (e'..li ,G, )·, the Dcpnrtrnent
`(If Pedlatl'ics. B.ayJr.,~ College of Mcdicini:, Houston (E.J,ij,); the ln~dtutl!!i nF
`Rheurm1tology, Academy c;,f Medical Science~, Moscow, l'{uMio (N,K., A.S.,
`A.M.); !hi!i D!!ipnrtmcnt of Chl1d l;)j$;«ses, St. Pl!:tcri;t,1n~ Pcdlatr\c J'li~1it11ti:, St.
`Petersburg, R.u$~b1 (l.V .): the Dep1:1r1mi:nt of Pedliicnc~, University of rc~n;
`Southw...,~to'lM'I M('ditnl School, D111ln, (C,W.F.);
`lto.in(lOw Eh•bit:~ und Chl11,1rt:TI'&
`T'lospital, Cleveland (A .. T.N,); the Dep.'lr!mr.mt of Child Ht'mlth, Univenlty ot
`Misso1.tri, Columbia (J.T.C.): and thi: Department or Rhimmatology, NewiTI)itton
`Chil(lron's Ho~plttil, Newingkln, Conti. (L..S.i,), Addres~ reprint n,q\lcatll to Or.
`Giannini at the Children's l.io~pital Mi:dlcal Ceno::r, Pnvilion Bid~ .• lNi PL,
`l;:lls1nd nnd Bethe~da Avi:~ .• Cinclnn111ti, OH. 4.5229-289£1.
`by a grant (:FO·R.·000032) from thi!!i Office of Orph211 Pror;lucts
`S11pp1;1rl1iii;I
`Dcvclapment of the Food and Dru11; Administration. hy thi: Ni:itional lrutllutl!i rl
`
`Arthrlti.t: itn,r Mu~,;mloskelet::1:I ond Skin Oi$<l05c~. by o Clini,;:al Pro:;,jccl~ Orant
`fn:m, the National Arthritiii!, Foundallon, ti,y the Children'~ l'.l(;l~pital Research
`Foundat1o:m, Cincinnati, and by Li:,dcrle Labofaltlrie~. Pearl River, N.Y.
`
`Approximately one third of all patients with juve(cid:173)
`nile rheumatoid
`arthritis
`achleve adequate
`control
`of their disease \l\llth non.steroidal an.tiinflammatory
`drugs; the remainder arc candidates for more aggres(cid:173)
`sive therapy with secon.d-1ine :::i.gents. In large random(cid:173)
`ized trials i.n adults "','ith refractory rheumatoid ar·
`t:htitis1 the anti.metabolite rnethotrexatc has had thcra ..
`peutic advantage over placebo, with an accepta.bk
`safety profile.''·' Long-torm studies have shown that
`the therapeutic effect of methot:r~xatc may persist
`for extended pe.dods.'· 11 Anecdotal reports and the
`results of uncontrolled
`trials of the efficacy and
`safety of low-dose mechotrcxate in juvenile rheuma·
`toid arthritis have been encouraging."·" For these
`.reasons the Pediatric Rheumatology Collabora,tivc
`Study Group
`(P.RCSG), in conjunction with col(cid:173)
`leagues in the then Soviet Union, conducted this dou·
`bk-blind, randomized., placebo-controlled
`trial to as·
`sess the thera.peutic effects of two different doses cf
`methotrexa.te in children wi.th resistant juvenile· rheu-
`mato.id .a.rthritis.
`'
`
`METHODS
`
`The siudy was conductcr.l. i1t1der the C0operat\on in Mlld.ical Sci(cid:173)
`ence and Public Hcattb A~recmcnt (signed on May 23, 197.2, ln
`.Ml'.'l$Cow) and w:i.~ .a t::l')!l~borativc effort between physician, at').d
`sdent.iHs ln the Unit<:d St:>.tes and ch¢ Sovkt lTnion. A tot.i.l of 23
`pediatri¢ rhcumatology eonttr.s ln the cw0 co,1ntrlcs p:a.rtieip;,,.tcd ( 18
`in the United Stiltes and 5 in th('. Soviet Union).
`
`Study Design
`
`The investlgati1;1n w;,.s designed n:i ;:,. pro.speccive, parallel, multi•
`ct::n1cr, placebo-co11ir0lll:'.d, randomized, doublc-bl!nd <::linic:al trial
`of siio: months' duradon. R,uidon1lzation was tn bloel,~ of three
`
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`Vol. 316 No. 16 METflOTREXATE
`
`IN RESISTANT JUVENILE RHEUMATOID ARTHRITIS - GIANNINI ET AL.
`
`I 045
`
`as 40 percent in the rate of response between the active druf:i and
`important
`:.i'~nifi~
`placebo was considered
`to detect as statistically
`cant. \·Ve estimated that approxin1atdy 30 percent of the patients
`given placebo would be clas~,ificd as improved, Accordin,g to the
`tablr::s prr:,J~entcd by Gehan and Schncidcrn1an, 111 and a..-:.suming the
`u.~e cl two~r.ailcd te.~ts, a minimum of .:30 patients were rcgulrcd in
`e.'1.ch ,group.
`'\-Ve tested proportionfil d~ta for signi5cal'!c~ u:lf.it'.'tg the chi~sq\1:1re
`
`test or, where appropriate, Fisher's exact test. SttiliHieal $itniG·
`cance by the chi~gguarc teat was rcguired for tables with more than
`(lf freedom before partitioning. For continuous vari<1bles,
`I
`rnean vainer. were compared by one-way analysis of variance. When
`rn,)lr.iple-r~nge 1.¢.~t$ bc:camo::: appropriate, Dunnett's method for
`making multiple c;omparir.onr. with a placebo:::!> wa~ used. Two-way
`:i,ri,i'lJy$i$ r)f v11ri::U'ICt wa$ Ll!.cd to tc:!lt for the effect~ of drug and
`cou.t'ltry ori the c'hapge in ~rt,icular indexes. The Bonfcrronl correc(cid:173)
`lo <'ldji.1!,t (or the tc~ting or 1nultlplc hypothef,C:.!I
`tion wl\$ used
`(n ~ 12) among :5eCond<rry v:1ri,,blts and ln the analy!.ir. of rer.ponr.c
`in subgroup3 of vatienta. Both un<'!.dju~tr,d 11.nd :idju~i:ed value~ .arc
`sho\vn, howo:::ver, if a P value w.i:; significant
`(~0.05) berore correc(cid:173)
`t.ion, ;and the: l'C~ultr. a.re referred to as statistically significant.
`\112.$ placed. on the intention-to-treat
`analysis r.ither
`Emphasis
`th.ID th~ :'1.l"l:J.ly~is of those \vho completed tbe entire six-month
`trial.
`The inttT'ltiOl'.Jnto-irc:.i !.C('.hniquc u::ed the value3 of response vari(cid:173)
`tit thi:: ·fin.i.l vi~i~, whether or not the patient completed
`the
`abl~s
`entire
`trial. Thi~
`.i.ppl"O(l,Ch offered r.cveral advantages: more pa(cid:173)
`tients were available for the :1.n.1.ly!;ir. or ~fficac.y, data on those who
`dropped out before completion could be iticl1,1di:;:d, and it more do9c(cid:173)
`ly reflected how physicians evalu11.1:e ~. r.],el";i.peutic a~c.nt in the clini(cid:173)
`cal ~ctting; outside an i::Xperimerit;;i.l protoc:ol.
`
`RE!i:.ULTS
`A total of 127 patients (96 girls and 31 boys) were
`enrolled in the trial (66 in the United States and 61 in
`the Soviet Union). Age and duration of disease •t
`entry averaged 10.1 and 5.1 years, respectively. The
`disease course was system.ic in 32 patients (25 per(cid:173)
`cent), all of whom also had polyarthritis. Forty-six
`children received low-dose mcthotrexate, 40 received
`very-low-dose methotrcxate, and 41 were given pla·
`cebo. Randomization worked well; there were 110 sig(cid:173)
`in
`nificant differe~.ces among the treatment groups
`any of the demographic or disease chara.cteristics
`shown i.n Table 1. Patients from the two countries
`were di.stributed about equally among the three treat(cid:173)
`ment groups. Those from. the United States had a
`higher mean (±SE) number of joints with active ar·
`thritis (27±2 vs. 20±2, P<0.046), but the mean ar·
`ticular·severity score (112) was the same for the two
`countries.
`Indomcthacin. was the most frequently used concur·
`rent nonsteroidal drug (26 percent), followed by na·
`proxen ( l 8 percent),
`tolmetin sodi.um ( 17 percent).
`diclofenac sodium (16 percent), a.spirin (16 percent),
`and other agents (6 percent).
`
`lalfi¢11oy
`in the a.na.ly.sis of efficacy if
`Patients wer~ included
`they met all eligibility crir.eria, received the study drug
`in blinded fa.shion for a minimum·of one mon(h, were
`100 percent compliant with the prescribed regimen
`during at least 80 percent of the follow-up period, and
`co:rn.plitd with the othCr specifications· of the protocol
`regarding
`re~trictions on. other ·medications and return
`visits to ·the clinic.
`
`Tab[@ 1. Demographic and Clinical Cl1aract0rtstics of the Patients
`at Entry. According to Study Group.
`
`CM11n11C1'11.k?ST1C~
`
`Agt. (yr)
`Average
`Range
`Dl~ea..'le duration (yr)
`Average
`R~ng(',
`No. (%) female
`Nr.i, (\Ii:,) fakio~ low.dti.~e
`prednisone
`No, (%) 111kil'IJ; 1w~
`NSAIO~t
`No. {%) with aye.tcmic-
`onse1· di.~en~e
`!Vkan (::tSE) no. of joints
`with active t1rthritist
`
`LOW·DO~~
`r.lSTl.!OTP.f,X,~TI;
`iN "'•li:i)
`
`Vltl\Y•U:.W•D<:!tr.
`Mi;Tl{m111;:11;i.n;
`(N .. ~O)
`
`p1,~r,1;:n<:.>
`{N - 41)
`
`10.1
`2.5-17.5
`
`4.i
`0.6-13.5
`33 (72)
`IS (ll)
`s (l 1)
`
`9 (20)
`
`9.6
`3.3-17.4
`
`4.8
`o.s-n.s
`29 (73)
`15 (3"7)
`
`10.6
`3,2.-17,8
`
`5,8
`O.S-14.4
`34 (83)
`1' (34)
`
`3 (7.!i)
`
`l 1,.l)
`
`1 l (28)
`
`12 (29)
`
`27 (2)
`
`21 (2)
`
`24 (2)
`
`•'Mier"' wu~ nr., .1lgniflcnnt dlf~~n~1 11.mong the t~ntment graupr. in Dny of the achnrnrt~r·
`i~li~~.
`l'J{'IMltrol<iRI fintllnn~mmMory dn11;,
`tNSAID dtnOIM
`:l:Soo !ht Mt.!lli:'.ldS ~e~11~n ((It~
`t1~ri11i!lrm nf n~riv~ nrthrltl~.
`
`Of the 127 enrolled patients, 114 (90 percent) guali"
`lied for the analysis of efficacy, including 38 (83 per(cid:173)
`cent) of the 46 in the low-dose group, 3 7 (92 percent)
`of the 40 in the very-low-dose group, and 39 (95 per·
`cent) of the 41 who took placebo. Among the 13 pa·
`tient$ excluded. from the efficacy analysis, 8 violated
`the specified doses for concurrent nonsteroidal agents,
`3 violated
`l was noneom·
`the prednison.e regimen,
`pliant in taking the study medication, and 1 was dis(cid:173)
`covered to have had fewer than three joints that met
`the criteria. for active arthritis
`.tJ.t the ba.se ... Jb,e vi$it.
`Only 11 of the 114 children in the efficacy subgroup
`took two concu.rrent nonsteroidal agents during the
`trial. These patients were equally divided among the
`treatment groups, and thdr data were not considered
`separately. A total of 40 patieu.ts in the efficacy sub(cid:173)
`group received low·dose prednisonc during the trial,
`including 14 who were given low-close mcthotre"ate
`and 13 in each of the other rwo groups. Since the
`numbers were sm.all and the do:se low and constant,
`data for those who received prcdnisone were not ~.:na ...
`ly1..ed separately.
`Among the 127 randomi?.ed pat.ients, 108 completed
`the entire six-month trial, including 97 (85 percent) of
`the 114 in the efficacy subgroup.
`
`Gfabal Assessmeint
`Figure I shows the percentages of patients at each
`rCtl.l.r:r'l visit who had clinical
`improvement
`from
`their b.ase-l,in<; conditioni
`according
`to the physi(cid:173)
`cian's global assessment. Both methotrexate groups
`had consistently higher proportions of patients with
`improvement
`than
`the placebo group. According
`to the physician 1s final global a.ssessment 1 a sig(cid:173)
`improved
`nlficantly higher proportion of patients
`in the Iov,.rrdose group
`in the placebo group
`than
`(x' with 2 df - 7.53, P"" 0.023). Those in the very-
`
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`104-8
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`THE N,EW ENGLAND JOURNAL OF MEDlO!NE
`
`April J 6i l 992
`
`tion of the oral mucosa accompanied by headach<:: and
`problems. Five of the 4-1 pa.ticnts
`gastrointestinal
`who took placebo (12 percent) had side effects, all
`of ,,vhich ·v1erc gastrointestinal.
`·AU sl.de effects we~·e
`graded as e)ther mild or nioderatc in severity, except
`for t1,,vo episodes of ston1ach pain graded as severe
`iu a patient receiving placebo. No patient had evi(cid:173)
`dence of mcthotrexate-induced
`pulmonary disease
`during the trial.
`
`La.bor~tory Evidence of Toxicity
`had more abM
`Patients who recehred mcthotrexate
`normal results on laboratory tests that were judged to
`be clinically important and possibly, probably, or defi(cid:173)
`nitely related to the study medication than those given
`pla,ccbo, Fifteen patients who received low-dose meth·
`otrexate, 15 who were givert vr.:ry~low .. dose methotrex~
`ate, and 5 who were given placebo had such results,
`the most fre(cid:173)
`Among the patients given methotrexatc,
`quent abnormal results were alterations
`in the differ·
`ential white-cell count, hematuria, pyuria, a,nd the de·
`levels, Elevations
`vation of setum aminotransferase
`of aminotransferase
`levels and anemia were the most
`frequent abnormal
`results among the patients given
`placebo, Other clinical-chemistry
`data were unre"
`markable.
`
`Dropouts
`A total of 19 patients ( 10 in the United StMes and
`9 in the Soviet· Union) discontinued
`therapy before
`trial (Table 3), Two pa(cid:173)
`completing
`the six-month
`tients in the low .. dose group dropped out because of
`a.dversc effects: persistent elevations of serum aspar(cid:173)
`tate and aJanine aminotr-ansfcrase (leve:ls up to 120 IU
`per liter) fr:,. one and persistent b.cmaturia
`in tbe other.
`Beth problems resolved quickly after the discontinua(cid:173)
`tio.n of the: study medication. One patient given very(cid:173)
`low-dose methotrexate had a persistent skin rash and
`was dropped from the study on.e month after entry.
`The total numbers of dropouts were not significantly
`different among the group,,
`
`DISCUSSION
`The resu.lts of this trial confirm anecdotal reports
`and evidence from uncontrolled
`trials that low~dosc
`methotre:x:ate has antiinflarnmatory activity and clini~
`
`Table 3. Reasons Patients Left the Study, Acoording to Study
`Group.
`
`~E ... $01'1
`
`LOW·Dt'I!!
`M!!'!'HO'l'l!t,:,1.rt
`(N • 4$)
`
`Vl!RY•Law.J)o~r,
`M;THOT1\EXll1'E
`(N,.. 40)
`
`PL..1.Cl!hO
`CN = 4j)
`
`1'1'1, of patl,mts (%/
`
`tni!frl!!Cl.iven~s.s of drug
`
`Advi:r.se e:1'1'¢cts
`Intercum:mt Ulness
`
`Admin!strotiVt: rc:.isons .
`Noncomplhmcc with pr01ocol
`Total
`
`0 (0)
`;, (4)
`2 (4)
`2 (4)
`I (2)
`7 (15)
`
`l, (5)
`l (21
`2 (SI
`0 (0)
`0 (0)
`S (12)
`
`5 (l2)
`0 (0)
`I (2)
`I (l)
`0 (0)
`7 (17)
`
`cal cffectivene.5s in resistant juvcnilt.:: rheumatoid ar~
`thr.itis. We also found a trend toward a dose-response
`relation in the low-dose and verv-Jo\1;·-dose n1ethotrex(cid:173)
`atc groups, si.milar to that repOrtcd by Furst ct al.~0
`in adult rheum.atojd arthritis. The favorable findings
`from the present study
`.!ihould be encouraging nev,rs
`for clinicians faced with m.a.naging a child)s disease
`to nonsteroidaI
`that has failed to respond adequately
`drugs.
`!\1:ethotrexa.tc has distjn.ct advantages over
`other sccond~line agcnts 1 includihg
`its oral
`route
`of admirdstra.tion) once .. a~,,vcck dosage, htck of kno,vn.
`oncogcnicity, and lack of long-term effects on fcrtil·
`ity, The choice of which second-line agent
`to t1Sc
`initially has becorne more difficult
`in recent yea.rsi
`after controlled trials a,nd long-term prospective stud(cid:173)
`among the agents in com·
`ies showed a lack of
`mon u.sc.19' 21•31 Parenteral gold remains a therapeutic
`toxicity 12 .a,nd inconven-(cid:173)
`option, but its considerable
`icnce must be considered, Furthermore,
`injectable
`gold salts have never been assessed in a controlled trial
`in children with arthritis, Thus, the tendency among
`to consider the ose of meth(cid:173)
`pediatr.ic rhcumatologists
`otrcxate earlier in the disease, and before other sec·
`ond-line agents, is likely to continue,
`There was a consistent trend in t;his study toward
`in the low-dose group across all
`greater improvement
`indexes of ardc1.1Jar disease; some of the mean changes
`,..,,.ere not statisdcaJly significant, bO'Vl.··eve:r. The vari(cid:173)
`ability of the changes within the treatment groups, the
`limited s,:3.mplc .size, t.he corrections
`[or testing of
`multiple hypotheses, and the high rate of response to
`placebo in all previous PRCSG studies undoubtedly
`affected our ability to detect some changes as statisti~
`cally significant. The recen.t dcvclopn1ent of a child(cid:173)
`hood health~assessmcnt guestionnairc and functional(cid:173)
`abiHty tool may provide more sensiti\,•e measures of
`the results
`response in future trials. ~3.:.14 N~vcrtheless,
`obtained here represent by far the rnost encouraging
`data from a trial of a second-line agent undertaken by
`the PRCSG,
`The equality of response a.cro~s treatment groups in
`the subgroup of patients with severe disease ls unex(cid:173)
`im(cid:173)
`plained. Since all three groups showed dramatic
`score 1 it i.s possible
`in the ardcular-sevcrity
`provement
`that there was a greater rcgre$sion toward the mean in
`tbe.sc children with severe disease
`tha.t effectively
`blurred any difference in response produced by mcth(cid:173)
`otrexate.
`The c:o.ncurrc:nt administration of ~spirin is known
`to slow systemic a.:nd renal clearance and increase the
`u.nbound fraction of methotrcxate, perhaps resulting
`in grea.ter toxicity," We did not observe such an asso(cid:173)
`ciation among the 20 children (16 percent) who took
`aspidn, Among the 14 children who had clinically im(cid:173)
`portant physical adverse effects while receiving meth·
`atre,:a,te, 2 (14 percent) were taking aspirin, Among
`the 30 children
`treated with methotrexatc who had
`sub~t:.i.nti::i.1 a.1,norm~.litles i.:t:".I laboratory
`in.dexes of tox(cid:173)
`icity, 4: (13 percent) were receiving aspirin.
`Although mild elevations of serum aminatrans·
`
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`Vol. 326 No. 16 METHOTREXAT,E !N RESISTANT JUVENILE RHEUMATOID ARTHRITIS - GIANNINI ET AL
`
`1049
`
`ferase levels were common in all the study group.Si
`only four children
`in the l.o"V\-·-dose group, one in the
`very-low·dose group, and one in the placebo group
`had markedly eleva.ted (more than. two times the up(cid:173)
`per limit of normal) enzyme levels (range, 85 to
`134- IU per liter). Possible explanations for the lack
`of hepatotoxic effects i.ncludc the duration of the
`trial; the administration
`schedule of a .slngle dose
`per weeki and the lOv\' cumulative doses to which the
`chi.ldren had been exposed.
`i\h:;01 previous conce.ri;:i
`about
`t.he hepatic
`toxicity of mcthotrexate may have
`been exaggerated." A prospective study of the chil(cid:173)
`dren who received mcthotrexate during this study is
`now under way to evaluate: longaterm outcorn.e and
`safety.
`In con.clusion, methotre:it.atc at a dose of l O mg per
`square meter per week appears to have greater clinjcal
`than placebo in children with juvenile
`effectiveness
`rheumatoid
`arthritis. The short-term
`sa.fety profile is
`acceptable. Given the results of previous trials by the
`PRCSG, the use of rncthotrexate
`as the initial second(cid:173)
`line agent in resistant juvenile rheumatoid arthritis
`appears to be justified.
`
`Wr:. arc indcbtr.d
`to Ac;;idcmician Valcntin:i. A, Naaaonova, M.D.,
`of the Academy ot Medic.:1.l Sciences, Mo~cow;John
`Klippel, M.O.,
`and LaWTcnce E:. Sbulman;
`:rv!.D., Ph.0.,
`i:ifthi:: National
`Jn~tir.ute~
`of Health, Bethesda; Md.; Marlene B);ffner., M.D.,
`John H~.rr.er,
`M.O.,
`and Ki::nt Johnson, M.O., of th~ Food and Drug Ad.minisM
`t,...atiot"I., W:ashin~ton, D.C.; and Diek Ryan, Harriet. Kiltie, M.D,;
`l'e;i . .-l Rivi:=:r1
`:l.t'ld M:argaret Gandt, M.D.,
`i,j" Ledo::r[i:=: Laboratarie~,
`N.Y.,
`for
`their
`assistance
`in organizing
`and
`coriductin~
`this
`study.
`in the United States wcrc
`clil')icaJ. inveatigator~
`The participating
`:Harry t.
`orde.r) Bram H. Bcrr1.~tei.n.1 M.D,;
`(in alphabetical
`I\.1.0., Jerry C. Jacobs, M.D., Deborah V•l. Kred.ich.,
`Gcwantcr,
`M.D., Rabet·t N. L:ipnick 1 M.D., Dani~l.J. Lovell) M.D., M.P.H
`..
`Lauren M. P;,,,chman; M.D., Murr-ay H. Passo,
`!vLD., 0(1ri~ld A.
`Pct'san, M . .O., Jane G. Schatler, M.O., Charles I·I. Speno:;et\ M.D.!
`Ilona S'lc:r, M.D.,
`and Carolyn L, Yanci=y; M.D.
`In
`t.he Soviet
`Uniol'l
`the p:,,r6i;:;ipating clinical
`irive.<;t:igators were Danutr.: A$tr:i.us•
`kel')I:\ M.D.) Ludmila
`Isacva., M.D.
`(dctc:asc:d), Nin;lil Let~nkova,
`M.:O,, .Elic1na Puogicnc:nc:, M.:O,, Inessa
`Shakhba:trati,
`M.D.,
`M:;i.rll:'I:\ Stch-=:rbakova, M.O., Alexandra
`Yakovleva, M.D.,
`and
`Ser.i.phim.a Yandashcvskaya., M.D. The senior scic,ntist, it'l. the Soviet
`UTiiOli waa Boris Shokh, M.0.
`
`REFER£N"C£S
`
`J, Towner SR, MichetCJ Jr, O':Fallon WM, Nelaon AM. Th!'! t'!tiidi:m.iology of
`juvt'!ni)e l'lrihriiis io Rochcst~r. Minn~~c,~ 1960-1979. Arthr:iti~ Rheum
`L983;:26:)10S·I~.
`2. Pett~,' RE. M.llli!!~Cm P. Epi(l~miology ofjuvenill! rhi!!umntl;lii;l nrthritis. World
`:Pi:.dlatrics Child Cart 1987;3:20!i· IO.
`3. c~~~idy JT. Pi:-tty RE. Textbook or J'lt'!di~tric r.h~t1rnntology. 2od ed. New
`York! Clmrc:hill f..ivingstone, 1990:1 [4.
`4. William~ HJ, Willkt'!n.~ R.F, Snrnueloon CO Jr, et 31. C¢rnp1rrison of
`
`k)'w•i,-11;),S,: oral pulse mcthotre'.(1!111!! n11d placebo io the treatment eif rhi!!u·
`\98S:2A:
`m3!Qid nn:hrifis: a controlled elixtk~I !rinl. Arthritis Rheum
`721-30.
`5. Weil'lkl~tt MP., Coblrn JS, Foii: DA, et o.l. E:fl'le11ey <'If l<;>.,.,·,;l=o m1:1thotrei1L(cid:173)
`nte in rheumatoid arth.r:iti~. N fTJ$1 .T Med 1985dl2:818-22.
`6. K~ml!r 1M, Lc:.i: JK. The safety snd eflk:l!lty of ihc 11se of rnethotrcxatc irt
`long-term thol'3py t'or rheumntoid arthrltie. Arth.ritit. Rheum 1986;29;822-
`3 ! .
`7. Weinblart ME, Trrmtham DE, Frasc.r PA. et al. LOl'IS-lt'!tm prospective trial
`of low-do~e methotrexate iri rht'!um.itQ1d nnhritis, Arthritis Rhtul'I'! 198.8;
`!il.;]67-75.
`ll. KTemer ,TM, Lee JK. A long-tt!:'n'I prti~pl!ctivl! ~t;udy of the use of methlltrt.~(cid:173)
`atc ln rht'!umatoi(I Ort:hritis; 1.1pdatc after a rneari of fifty.ch~!!! mr:mths. Arthri(cid:173)
`ti~ Rhe11m 1988;31:577-81,.
`
`9. Alnrcon GS. Tracy lC, 13:lackbum WD Jr. M:t'!thot~;,;ate io rhoumntoid ar(cid:173)
`thriii.~: to11:ic effects as th~ major factor io llmltirtg h:mg-ti::nn trcatmt.l'll.
`Arthritis ~he.um [989;32!671-6.
`JO. WolfoF, Hawley l")J, Cathey MA. Termination of slow acting antirhi:.11m.atic
`tht'!r.11.py in rheumatoid arthriti~; ft 14-year prospl'.!e1:ivi:. evaluation cf 1017
`cott~l!!tutlve starts. J Rhournl!lt¢1 1990;17:994-1002.
`l l. Mid.'!.!11~ H, Veys EM, van der Str.i.l!ti:.n C, Ackerman C, 0(1i:.rn.aerc S, The
`efficacy and to~icity of a conatant low d(lSe of rnethotrexato af. .i. tri:.11tmcnt
`for intractable rhcur'!latnii;l nrthritis: no oi,en J'l:'O.'';pe.ctive study. J Rht'!umntol
`199 J ;) 8;978-83.
`12. TrucktsnbMdt ~l, HRfncr R. Mi!!th!'.!trl!!x11ti:
`therapy in juvl!ni!e. rheumatoid
`nrthritis; a retrospoetiv~ .~tudy, Arthrltls ~hi!!Llm 1986;2:9;801-7.
`l3. Sp~ck.maii::r M, Flndeiseri J, Woo P, et al. Lew-dose me.lhotrexate Jn sy~(cid:173)
`tcmlc t.'lli~l!! juvc:.nilc chronic arthrhl~. Clin Exp Rheumatol 1189;7;647-50.
`14, Wallace CA, B!o!y.!r WA, Sherry DD, SalmQl)~Oll KL, Wedgw¢¢d RT,
`T'oxlcity Rild ~rum ll!lvel~ of rnethotrexate In children with juvenllc rh!um.i•
`.irtlir.itis. Arthritis Rht.:u!'l'I J 989;32;677-81.
`[()id
`15. Rosi!! CD, $hig~cn BH, Eichcnflcld.AH'. Goldsmith DP, Athrey~ .BH. Safety
`and efficacy of rni:.lhotrcxatc ther:1i,y for juvenile rheum3toid nrthritls.
`1 Pi;diatr 1990:177:6.5:3.9,
`16. Mnrtfni A, Ravclli A, V!ola S. BurgioRG. Mcthotrc:,:.a11!: hep11totoxic effects
`io childten with ,iuvcnilc rheumatoid arthritis. J Pedintr t 99 t: 11. 9;333-4.
`I 7. Hslle F, Prleur AM. ~vn)nR.tion of metho!tt!xati: in thi:. treatment of juvl!nili:
`chri;mic nrthritis 11i::cording to 1hc ~uhtypi;. Clio Exp R.h!!:t.im.i.11;!1
`1991 ;9:297-
`302.
`18. Bsum J, Aleksl!!cv r..S, Brewer EJ Jr, DolgCJp¢1¢vfl AV. Mudholkar 0$.
`Patt'!;] K. J1Jvenilc rheumatoid l!rthii.!is; 11 compS!lson of pnt:ii:ntll from the
`USSR ."Ind t.JSA. Arthritis Rheut't'l 19$0;43;977-84.
`19. Brcwi:=:r EJ, Oimmini EH, Kuzmina N, A1ck~i!!i:.v L. Pcnicillaminc am;l hy(cid:173)
`in 1he treatment of severt juv~ilc:. rheum11toid arthrlci~!
`droxychloroqulnc
`re.~11lts of the U.S.A.-U.$.$.R.
`double-blind
`rlact'!l:JQ•i;:ontrolled trial.
`N E:ngl J Mi:d 1986;314!1269-76.
`20. Giannini EH, Bl'cwer E,T, Kuzmins N, Ak!k~i!!!v [.., Shokh BP. Char3clcri~·
`tics of res,Poodel"!l and neinre.:,ponder:i to slow-acting ~ntirhcumatic drugs in
`juvenjli:. rheumatoid arthrlti!:. Arthritis Rh~tlm 1988:3l: 1S-20.
`2 l. Giannini EH, Bl'L'.!~r):.] Jr, Kuzmina N. Shai'k.av A, V.'allin B. Aurano!'in in
`the treatment Df juvt!nilt'! ,hi:µmntoid arthritis: rc~ulI~ ()f the:. USA-USSR
`dOl.lbli:.-blind, pJacebo-cDn[rc,1lod trin!. Arthritis Rheum 1990;3);466-76.
`22. Ca.~i:idy J'J, l..cvioson JE. Bsss JC. l!!t al. A ~tudy of i.:Iassiflc,ation tritcria fQr
`a dingnosi~ Df juv~nile ~hc:.umntoid arthrltiS;. Ar'fhritb Rheum 1986;29:274,
`81.
`23. 0('.)lf.c;ipolova AV, Blsiarina VP. A!ek.~c,:v 1S, Lepskaia ES. Drtiiln;iv11 NA.
`Elaborat!on <Yf thi!! criti:-ria for the early diagitof.i:1; qf jlivcnile rheumatoid
`m"th.ritis (JRA). Vopr Rcvm (Rvssian) 1979:4:3-7.
`14. Brewer EJ .Tr, Bass J, Baum l, ct aJ. Current propo~cd revision of JRA
`tl11:i:r).i, Arthritis Rheum 1977::20:SuppJ;l95-9.
`2,. Brc,vl!!r e.r .Tr, Giaonini EH. Standsrd Mi!!chadology for Segment I. II. and HI
`Pcdiatrk R.ht'!Llni."ltoloff;Y Collaborative Study Oraup ~tµi;lics. ]. Design.
`1 Rhi:.umntol ]982;9:109-l.:I.
`26. Paulu.~ M.C, Eggi:.r M.T, Ward JR, WillfamS; rt.r, Cooperative SyRt~m3tk
`Studici; of Rhi!!Utn3tic Di$e.nsi:.s Group. Analysls or irt'lpraveme.llt in individ(cid:173)
`ii11l rheumatoid arthriti~ p.i.ticnt~ treai~d with dlsea.ac-l'l'!odifying antirheu-
`
`111.i.tii;: ,;ln;cgs, based on the findings in p:itil!nl:O ~nti;d wlth placebo. Arthrili$
`Rhi!:um 1990:.;!,:477·84.
`'J.7. Giaoninl EH. Bttwer Ei Jr, Stn.nclnrd methodology fi!lr ,jfolil:mcnt I. JI, and Ill
`P~diatric Rhcumatobgy Colltthc;im\ivi:: Study Group siudii!!~. II. AnaJysis
`ll.tid pre.s~11t11tio11 of data. J Rhl'.!uma!t:il 198l;9;l l4-22.
`28. Gehat'I EA, $chne.iQermnn MA. Expcriinental dt'!~)jll of clinical t.ria1S;. ln;
`Hol!aod JF, Frd E. Ill, .!d$. Omci::r medicine. Philadelphia; ~i:11 & Febiger,
`J.973;5[4,
`29. Zor JH, :F.l)C1st~tistical aoalysis. :2nd 00. l';;ngl~wood Cliffs, N.1.! Pre.ntice(cid:173)
`Hall, 1984,.
`JO. Furst DE. Koehnkt! P-., 13urmei;tc:.r LF, Kohler J. Catgi!1 (. lnc~8ing mcth(cid:173)
`otre~n.~ ~ffuct with lncrea.~ing do~e in ~he t~tment of resistant rh~umnioid
`arthritis . .I R,hi!!:tJrnll.fol 1989:16;3!3-20.
`3L. Giannlnf EH, Batl'on :K.:., Spencer CH, ct nL Auranofirt tht'!rnl'Y for jtivi::nile
`tht'!12m11toid arthritis: results of the fiv~-yenr open label cx.tet'!S;icm l:nn.l.
`J Rh!!!Ur'nttlOI 199);!8;1240-2.
`32. Brewer EJ Jr, Oi~t1rtinj EH, Bnrklcy EL Gold therapy in (he management of
`jllvenile rheumntald arthrl1!f.. Arihriti~ Rheum 1980:2:3!404.J I.
`::13. $ingh G, Athreya B, Fries. J, Oo1tL~miih J), O~trov B. Mea!.Ul'l!!tl'll!nC of
`1'\JnctiOrtlll ~IIJLu~ in juvenile rhcum11t,;il(I artnrlc!s. AnllritiJ Rheum 1990;
`33:Supi,I.Sl.5. ah~trnct,
`34. Howe 5, Levins en J, Shi'.!M r-:. l!t n.1, D~velopmcnt of a disabiliiy mc:.11~1,1ri.:(cid:173)
`tlit71l !Ciel t'ar ju~nili:. rheumatoid ari:hriti~: thl'.! Ju,·enile. Arthritis Functional
`Assessment Report for C.:hildn:11 nnd their Parents. Arthl"iti~ Rhe11m 1991;
`14:87.1.1,(),
`35. Stewart CF, F1cmin_g RA, Cie.rmain BF, Sclcznick MJ, Bvan.~ \\'E, Aspirin
`11lte!'!I mctho!:rt'...>:att di!pt>~llicn in rhi;:umfltoicl :nrthrlti3 )'.laticnL~. Arthriti.~
`.R.he11m 1991;34:1~14-20.
`36. Kaplan MM. Methotr:ex~te h~patotoxkiiy and thi!! p~mnturc reporting of
`IVTn.r"-: Tw~.in's death: both gt~ttlly l!X.IF.J;Cr(ltci.-1. Hcpntology l99o: 12:184-6.
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