The Role of Subcutaneous Administration of
`Methotrexate in Children with ]uvenile Idiopathic
`Arthritis Who Have Failed Oral Methotrexate
`KI,{YRTAH ALSI,JFYANI, OLIVA ORTIZALVAREZ, DAVID A. CABRAL, LORI B. TUCKER, ROSS E. PETTY,
`and PETER N. MALLESON
`ABST?dC?f, Ouecdve. To descib the outcome of patieots with juvenite idiopathic adritis (JIA) Ecated with
`subcutaneous (Sc) methoEente (MTX) after failing oral Mfi (either because of ircfficacy or toxi-
`city) in a clinic population.
`M?rrrodr. The study cohort was identified ftom our clinical databas€, and consisted of 6l chitdren
`with IIA treated with MTX between 1988-2001. All patienB fulfilled Intemational Lcague Against
`Rheumatism (ILAR) criteria for JIA and had discas€ duration of > 6 months alld 3 or morE activc
`joints bcforc institution of MTX. Alt paticnts had a corc set of outcomc vadablcs ass€ssed at base-
`line and at 3 months after achieving both msximum oral and SC MTX. Outcomc variablcs included
`physician global assessment of diseas€ activity, numb€r of active joints, numbcr of joints with
`limitcd range of motion, duration of carly moming stiffncss, and erythrocyte sedimentation ratc
`(ESR). Improvement was defined as at least 30% improvcmcnt fiom baseline in 3 of 5 vadables in
`the core set, with no morc dnn one of the rcmaining variabl€s worscnitrg by morc than 30%.
`Rcsura. A total of 6l patients, 43 females and l8 males with JIA were studied. The disease subtypes
`werc systemic E, polyarticular 25 (12 rhcumatoid factor positive), oligoarticular 14, enthesitis rclaEd
`arthritis 5, and unclassified 4. Thiny-onc patients were switched to SC Mfi, 13 of whom had not
`improved, and 18 who had improved, but had naus€a (lt) or insufficient clinical improvcmcnt (7).
`After 3 months of SC MTX reatment, 76% of paticnts were classificd as improved and 23% as not
`improvcd. Toxicity on SC MTX was lcss than on oral MTX.
`Cor,clasian. Our results suggcst that for patients failing oral MTX either bccause of inefricacy or
`roxiciry, the use of SC MTX has a high likelihood of success with more than 70% of patients
`achicving ctinically significant improvement, without clinically significant toxicity. (I Rheumatol
`2004;3 I : 179-82)
`
`Key lndexiag Teins:
`JUVENILE IDIOPATHIC ARTHRITIS
`
`METHOTREXATE
`
`TREATMENT
`
`Methotrcxate (MTX) is an effective agent in the treatment of
`juvenile idiopathic arthritis (JIA) and has become now the
`most commonly used disease modifying antirheumatic drug
`(DMARD) for this conditionr-ro. Although MTX is widely
`used to ueat childrcn with arthritis, its optimal dose and
`mute of administration remain uncertain. A commonly used
`initial dose is l0 mg/m2 in a single weekly dose6 with doses
`up to 30 mg/m2 being used subsequentlyro. The route of
`administration of MTX in children with arttuitis is not stan-
`dardized and varies according to patient's and treating
`
`Ftom rhe Divbion ol Rhcwnotology Depafim.nt of Pediotics, UniversiD
`of Birish columbio, thncouvcr BC, Canoda.
`N. Alsufiati, MD, Res.arch Fellow; O. Ottiz-Alvanz, MD, Research
`Associa,z: D.A. Cabml, MBBS, FRCPC, Clinical Assistant Profcssor;
`LB- Tucker MD, FMP, Clinkal Associate Prde$or: R.E. Pcuy, MD,
`PhD, FRCPC, Prufessor of Pediatrics; PN. Mallcsoi, MBB9,
`URCP(UK), FRCPC, Ptofcssor of Pcdiatrics.
`Addrcss nprint nquests to Dr. P. Mallcson, Room K4-122, B.C.t
`Chikl,€n\ Hospital, 4480 Oa* StEq Uarcouvet BC V6H 3V4, CaMdo-
`&bnited February 13, 2003: t vision accepted Ju c 27,2003.
`
`physician's preference. In most of the rcported studies in
`children with JIA, MTX has becn given orally; however,
`some investigators have chosen the parenteral routerr. The
`oral route is generally preferable because of its ease of
`administrationi however the parenteral route (intramuscular
`or subcutaneous, SC) has the potential advantages of geater
`absorption and high drug bioavailabilityr2-Is. In our clinic
`practice we start oral MTX at a dose of about l0 mg/m2
`weekly in combination with oral folic acid I mg daily, and
`increase the dose as nerded on clinical grounds until either
`beneflrt is obtained or side effects occur. Evidence suggests
`that bioavailability with oral dosing often does not increase
`significantly beyond 20 mg/m2 per weekl3; thereforc if there
`is no benefit at about this dose, we switch to sc MTX.
`There is however little or no pubtshed data to show that
`switching to SC administration is clinically effective in chil-
`dren with JIA who have failed oral Mfi. Our objective was
`to examinc reEospectively what proportion of children with
`JIA who had failed or were intolerant of oral MTX
`improved after changing to SC dosing.
`
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`Alsufy@i, et al: Subcutan ous MTXfot IIA
`
`179
`
`Page 1 of 4
`
`Frontier Therapeutics Exhibit 1006
`
`

`
`MATERIAI,S AND METHODS
`Pariufis. Wc idenrified rll children with JIA who wcrc Ecated with MIX
`ftorn 1988-2001. A chan rcvicw of all 6l parienls who md inclusion
`critcria was unddtaken. The dala collected includcd the following vari-
`ablcs: agc, sax, age rt diagnosis. dis.{se subtype, diseasc duration, initial
`and marimum MTX dosc, time to rEsponsa to MTX, and obs€rvcd advffsc
`€ffccts of Mfi such as livcr toxicity (enzymopathy), lymphopenia, muco-
`cutaocous manifcsratioas, and gastointcstinal sidc efrccta.
`Vadablcs collcctad to asscss oulcome aod clinical improvemcnt wcrc
`(l) physician Slobal assessmcot of discasc activiry (PGDA) scorcd on a 4
`point scalc (l = inactivc,2 = mild activity,3 = mod.ratc activity,4 = scverc
`activity): (2) number of join6 with acrirc anhdris; (3) numbcr of joints
`with limited tangc of morion (defined for cach joint as a lo6s of ar lcast 50
`in any articular movcmcno; (4) duration of aarty moming stiffnass in
`minutes: and (5) crythrocytc s€dimentation
`rarc (ESR).
`Rcsponse to oral MTX uEatm.nt wss evaluatcd in all paticnts by
`comparing thc valucs of thcsc 5 variablcs aftcr 3 months on maximal dosas
`of oral MTX 1{ilh thc v.lucs at the time of instirurion of oral MTX. Wc did
`not includc s mcasurc of furctional out@mc such as the Child Hcahh
`Asscssmcnt QuestiooMire (CHAQ) or. parcmal asscssment of wcll bcing
`in our outcome maasurcs, as suggcstad by Giannini, ?l alr6 as ihese
`mcasures hed not be€n routinely pcrfomed in our clinic.
`For padants who swirched to SC MTX, rcsponse to MTX was asscsscd
`by clmpadng lhcs€ vadabl€s afler 3 months of maximum doscs of SC
`MTX with the valucs obtained efter 3 months of maximum oral MTX. This
`for thc SC MTX group as most childrcn werc switched
`basclinc was chos€n
`from oral to SC at aboul this time poiot.
`lmprovcment was considercd to havc occurrcd whcn palients had at
`la{st 30% improvemcnt from bas€lin.
`in 3 of thc 5 variabtcs assesscd, with
`no tnorc than onc of the rcmai[ing variablcs u/orscning by morc than 3096.
`Inclusioi criteio. All paticnts fulfillcd ILAR crircria for rhc diaSnosis of
`JIAr7. All paricnrs had dis..se duration of.t lclsr 6 monrhs, and al least 3
`activejoints (defincd as the p.esance of swclling or limitation of movcmcnt
`with cithcr pain on movemcnt o( tandcmcss) beforc insdtution of MTX. All
`paticnts had to havc bccn trcatad for ai lcast 3 montlN with at lcast tO
`mg/m2 pcr weEk oral MTX (if tolcrat d). All paticnts reccivcd oral folic
`acid at thc dosc of I to 2 mg oratly dailr,.
`Exclusion c rcia. Paticnts werc cxcludcd if MTX was uscd primarily to
`trc& othcr discasc manifcstation such as uvcitis, if they had poor clmpli-
`aocc with MTX bas€d on the physicirn's assessmcnt, or if they wcrc lost to
`followup.
`Statistical onaltsis. Descaiptive statistics werc used io summsIize thc
`dcmoFaphic data. Th€ Wilcoxon test or paircd Mst wcrc used to.sscss thc
`outcome vadablcs bcforc and aftcr trcatmcnt.
`
`RESIJLTS
`There werc 6l patients, 18 males and 43 females. The
`disease subtypes were systemic 8; polyarticular 25 (12
`rheumatoid factor positive); oligoarticular 14; enrhesitis
`related arthritis 5; and unclassified 4. Mean age at onset of
`JIA was ll.4 years (standard deviation, SD, r 2, range 1.6-
`16), and mean disease duration was 10.9 months (t 18.4,
`range 2-99). Mean age at time of treatment with oral MTX
`was ll.9 years (i 4.3, range 3-20).
`Forty of these 6l patients (66%) fulfilled the crireria for
`improvement after oral Mfi (mean maximum oral dose
`was 13.8 mg/m2 per week, range 5-20). Thirty-one patients
`were subsequently switched to SC MTX (mean maximum
`dose: 15.4 mg/m2 per week, range 5-20). These included 13
`patients whose arthritis had fail€d
`to improve by the defined
`criteria. The other 18 children had fulfilled criteria for
`
`improvement, but were switched to SC MTX because of
`persistent nausea (n = ll) or insufficient clinical improve-
`ment as judged by the pediatric rheumatologists (n = 7)
`(Figure l).
`Thirty of these 3l patients had adequate data to assess
`outcome. Twenty-three of the 30 patients (779o) who were
`switched to SC MTX fulfilled the defined criteria for
`improvement when compared to the values obtained after 3
`months of maximum dose oral MTX. Seven patients failed
`to improve.
`Improvement ) 30% was calculated separately for each
`outcome variable: PGDA 25131 (80.6%); activejoints 24131
`(77.4%); number ofjoints with limited range of movement
`16130 (53.3%): early morning stiffness l4l29 (48.3%); and
`ESR 23127 (85.2%). There was a statistically significant
`difference in each of these variables before and after SC
`MTX (p < 0.05 for each variable).
`A total of I 5 patients had toxicity related to oral MTX ( I I
`with nausea and 4 with raised serum liver enzyme levels).
`Nine of the I I patients with nausea had complete resolution
`of their symptoms after switching to SC MTX; the other 2
`patients continued to have nausea, but this was less severe,
`and they were able to continue with SC MTX. All4 children
`with raised liver enzymes were able to remain on oral MTX
`as the abnormalities resolved after temporary discontinua-
`tion of oral MTX.
`Four children had rransient toxicity related to SC MTX
`(liver enzyme abnormalities, or mild lymphopenia),
`rc4uiring temporary discontinuation of SC MTX in 2
`patients, which did not recur when it was reinstituted.
`
`DISCUSSION
`Our study shows that in children with JIA who have an inad-
`equate response to oral MTX, or who develop toxicity to oral
`MTX, approximately 15% will get substantial benefit fiom
`swirching to SC MTX. One probable explanation for thc
`increased efricacy of SC MTX may be inadequate absorption
`of MTX via the oral route. Oral absorption of MTX is knowr
`to vary widely betwecn individualsr2.r8-22. Wallace, €, a, havc
`shown a 2o-fold variance in I h serum MTX levels at oral
`dosages between 0.ll-0.6.mg/kg per week in children with
`juvenile rheumatoid arthritis (JRA)re. Dupus, e, at showed
`that oral bioavailability of MTX is geater in the fasting sane
`in children with JRA2r. It is knownr3 that in some individ-
`uals, saturation of oral absorption may occur at doses as low
`as 12 mg/m2. Jundt, ?t a, found that the rclativc bioavail-
`ability of low dose MTX is less with oral than with par€ntenl
`administration in adults with RAm.
`The apparent beneficial effect of swirching from oral io
`SC MTX in our patients who failed to respond to oral MTX
`may be best explained by the increased bioavailability of SC
`MTX. It is also possible that there is improved adhercnce to
`MTX therapy when it is given by SC injection than when
`taken orally.
`
`It is
`nrusea)
`SC MT
`apparcnt
`Our r
`dcsign.
`
`SSSeSSm,
`patients
`Americz
`validater
`afiected
`virh M'
`child acl
`frirly ro
`arc ina(
`siffic:
`SC lvfl)
`
`REFER
`l. Tru,
`rhel
`198
`2. Spe
`syst
`
`198
`3. Ros
`
`180
`
`Thz Jounal ofRhzu atolo|f 2N4: 3l:l
`
`, tl'{fiya,ri,
`
`Page 2 of 4
`
`

`
`use
`rpmve-
`n-?)
`
`aSSeSS ,
`o wele
`ria for
`after 3
`r failcd
`
`,r each .
`;2481
`/emenl
`i); and
`,ificant
`ter SC
`
`rx (11
`evels).
`rlution
`rther 2
`ieverq
`rildrcn
`IMTX
`rtinua-
`
`M'TX
`rcnia), .
`.in2
`
`r inad- ,
`to oral
`t fron
`br thc
`lrption
`known
`rl havc
`at oml
`n with
`howed
`I stale
`divid-
`as low
`ravail- l
`:nteral
`
`cral m
`Mlx
`of sc i;
`Ince to
`whcr ,l
`
`Totd suqi.cts iiclud.d in dlc s0dy
`"ndl
`
`lrnprcv€d on oral MTX
`D-{0
`
`Not improrcd or or.l MTX
`D-21
`
`Switched to SC MfX
`n=13
`
`Improvcd or SC MTX
`!-23
`
`Not imEovcd on SC MTX
`
`Unablc to assast
`
`Fi8!r, ,. Flow diagram showing the ouicomc of patients trcat€d with methotrexate. * I 5 patients had toxicily
`on oral MTX: l[ with nausea and 4 with elevated liver cnzymes. .*Patients werc switchcd to SC MTX
`bccausc of pcBistcnt nausea (n = I [) or insufficient clinical improvemcnt (n = 7). ]4 patienrs had elcvatcd
`liver enzymes or lymphopcnia.
`
`It is perhaps surprising that MTX toxicity (pa icularly
`nausea) was less marked in some patients once switched to
`SC MTX. The explanation for this is not immediately
`rpparent.
`Our study has the timitations of being rerospective in
`dcsign. As we had not mutinely obtained parental global
`assessment of well being or CHAQ assessments in all
`patients included in this study, we werc unable to use the
`American College of Rheumatology pediatric core setr6, a
`validated definition of improvement, and this might have
`affected our evaluation of how many children improved
`with MTX therapy. Nevertheless we believe that as each
`child acts as his/her own gontrol, the results of this study arc
`fairly robust and that rhe majority of children with JIA who
`inadequately responsive to oral MTX will improve
`ar€
`siSnificantly without increased toxicity after switching to
`sc MTX.
`
`REFERENCES
`l. Truckenbrcdt H, Hafner R. Melhotrexate thcrapy injuvcoilc
`.heum4loid anlEitis: a rcEosp€ctive study. Arthritis Rhcum
`1986;29:80t-6.
`2. Sp€ckmaicr M, Findeis€n J, Woo R et al. t ow-dose merhoEexaE in
`systcmic onsct juvenile chrcnic anMtis. Clin Exp Rhcumatol
`1989;7:647-50.
`3. Rose CD, Singscn BH, Eichcnfield AH, ColdsmiIh De Athrcy.
`
`BH. Safcty and cfficacy of methoEexaia thcmpy forjuvenilc
`rhcumatoid anhids. J Pediarr 1990:ll7:653-9.
`Halle F, Pricur AM. Evaluation of mcthotrcxate in thc treatmcnt of
`juvcnilc chonic lnhritis acco.ding ro thc subtype. CIin Exp
`Rheumatol 199 I ;9:297-302.
`Ravclli A, Ncirorri G, Viola S, Giaccad MC, cuidi T, Martini A.
`Low dos€ mathotrcxate therapy for seroncgativc juvenilc
`rheumatoid .rthriris. Riv ltal Pediatr l99l;17:315-9.
`Ciannini EH, Brewer El, Kuzmina N, .! al. Mclhotr€xatc
`in
`rcsista juveflile rhcumaroid arthritis. Results ofthe USA-USSR
`double-blird, placcbo-controll.d trial. N Engl J Med
`1992.326:lM3-7 .
`Wallace CA, Sherry DD. Preliminory report of highcr dose
`mcthoEaxatc Eratmant in juvcnilc rhcumaioid anhritis.J Rheumaol
`1992:19:1fi47.
`Lepo.c L, Pennesi M. Trcatment with low-dos€ methotrcxate in
`intrlcrablc juvenilc chronic anhritis. Pediar Mcd Chi!
`l992il4tsm-12.
`Corooa R Bardarc M, Cimaz R, Rognoni MC. M.thotrcxat in
`juvcnilc chonic anhritis, Clin Exp Rh.umatol l993illt346-7.
`ReitrA, Shaham B, Wood BR Bemstcin BH, Sranley B Szcr IS.
`High dose mcthoEcxate in lhc trcatment of rcfractory juvenile
`d€umatoid anhritis. Clin Exp Rhcumarot 1995: t 3: I l3-8.
`Ravclli A, Gerloni V Corona F, et al. Oral versus inEamuscular
`mcftotExab in juvcnilc chronic anhdtis. Italian pediatric
`RheumaioloSy Shdy Croup. Clin Exp Rheumatol 1998;16: t8l-3.
`Ter€si ME, Crcm WR. Choi KE, Mirro J. Evans WE. Mcthorcrate
`bioavailability aftcr oral and intnmuscular administation in
`childrcn. J Pediatr t98?; I t0:788-92.
`Balis FM, Mino JU, Reamafl cH, et al. Pharmacokinerics of
`
`4.
`
`7.
`
`9.
`
`r0.
`
`ll.
`
`12.
`
`r3.
`
`t4:31:l
`
`Ah4yani, a a!: Stu@eous tfiTX lor ltA
`
`Page 3 of 4
`
`

`
`subcutaDcous mcthotscxate. J Clin Oncol 1988;6:18826.
`Brooks PJ, Spruill WJ, Psdsh Rc, Birchmorc DA.
`Pharmacokinctics of mcthorcxatc sdministcrEd by intramuscular
`and subcutaoeous injectioff in paticnts with rhcumstoid arthritis.
`Arthritis Rheum 1990i33:91-4.
`Halnilton RA, Krcmcr JM. Why intramuscular methotrExatc may
`be morc cfiicacious than olal dosing in patients wilh fteumatoid
`arthdtis. Br J Rheumatol 199?:36:86'90.
`Giannini EH, RuFrto N, R.velli A, lnvclt DJ, Felson m, Maflini
`A. Prcliminary dcfinition of improvcment in juvcnitc orthritis.
`Anhritis Rheum 1997;40: I 202-9.
`Petty RE, Southwood TR, Baum J, et al. Revisioo of $e prcposed
`cl.ssification crit ris forjuvcnil. idiopalhic atthritis: Durba& 1997.
`, Rhcumatol 198i25: l99t-4.
`
`16.
`
`t1.
`
`Keamey PJ, Light PA, Prce.c A, Motr MC. Unpr.dictable se[um
`kvels aftcr oral mcthotrcxatc in childrcn with acutc tymphoblasdq
`leukemia. Cancer Chemother Pharmacol 1979;3:l17-20.
`Wallace CA, Bteyer WA, Sh.rry DD, Sa.lmonson KL, Wedgeood
`R . Toxicity arld scrum l.velE of methoEexate in childrcn with
`juvenilc rhcumatoid a(hdtis. Aahritis Rheum 1989,12t671 -81.
`Jundt fW, Brownc BA, Fiocco GB ct al. A comparison of low
`methoEcxatc bioavailabilily: oral solutiotr, oral tablet, sutrcutane6ql
`and int$muscular dosing. J Rheumatol 1993;20:1845-9.
`Dupuis LL, Korcn C, Silvcman ED, Laxcr RM. lnflucnce of food
`on the bioavailability of oral methoEexate in children. J Rleumatol
`1995l'22:1570-3.
`Waltaca CA, Shcrry DD. A practical approach to avoidance of
`mcthotrcxat toxicity. J Rheumatol 1995;22:1009-12.
`
`m.
`
`21.
`
`Autt
`Con
`Bloc
`
`TBIKKI
`r tBS
`
`Fto,l, the
`Uniyctsit
`L bomtot
`Chidren
`Firlatld: .
`llv Scip
`$ppone,
`h. Sigri.
`Unive'I,it
`E,.lulht
`P.ijas Ht
`MD, ctih
`lobomo
`adW
`MD, ped
`Hclsid<i
`Address i
`U..licin
`Finland.
`Subzl.i r,,
`
`182
`
`Thc Jounal of Rheuaatology 2004; 3 I : I
`
`- ttlkra,ncr
`
`Page 4 of 4