`
`Vol. 325 No. 16 METHDTREXATE IN RESISTANTJUVENILE RHEUMATOID ARTHRITIES —- GIANNINI ET AL.
`
`l.[l'i-3
`
`METHDTREXATE IN RESISTANT JUVENILE RHEUMATOID ARTHRITIS
`
`Results of the U.S.A.-—U.S.S.R. Double-Blind, Placebo-Controlled Trial
`EDWARD H. GIANNINI, M.S., Ds.P.H., EARL]. Bnewsn, M.D., NINA Kuzmrrva, I‘-/[.D.,
`ALEXANDER St-mu-:ov, M..D., PH.D., Ausxsr NIAXIMGV, M.D., loos. Voaoursov-, M.D., Pt-:.D., M.P.H.,
`Cr-n-:sTE1=r. W. FINK, M.D., ARTI-ITJR J. Newman, M..D., j.-sues T. Classrnv, M.D.,
`sun LAWRENCE S. ZEMEL, M.D., roe TI-IE PEDIATRIC RHEUMATOLDGY CloLLaeoam:wa
`Sruov Gnotrr AND rt-ts Coorsnmzrva Gt-trr.os.aN’s Sruov Gnour
`
`Abstract Background. The antlmetahoilte methotrex-
`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-
`controlled trials.
`
`Methods. Centers in the United States and the Soviet
`Union participated in this randomized. controlled, double-
`bllnd trial designed to evaluate the effectiveness and safe-
`ty of orally administered methotrexate. Patients received
`one of the following treatments each weeit for six months:
`10 mg of methotreirate per square meter of body—sur1ace
`area (low dose). 5 mg of methotrexate per square meter
`(very low dose), or placebo. The useful prednlsone (-5210
`mg per day) and two nonsteroidal antiinfiammatory drugs
`was also allowed.
`.
`Flesuits. 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 Iow—dose methotre;-rate improved, as compared
`with 32 percent of those in the very-low-dose 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 of joints with pain on motion (-11.0 vs.
`-11),
`the pain-severity score (-19.0 vs. -11.5], the
`number of joints with limited motion (-5.4 vs. -0.7), and
`the erythrocyte sedimentation rate (-19 vs. -5 mm per
`hour). in the methotrexate groups only three children had
`the drug discontinued because of mild-to—moderate side
`i effects; none had severe toxicity.
`Conclusions. Methotrexate given weeitly 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-Q.)
`
`UVENILE rheumatoid arthri.t.is is the most com-
`mon rheumatic condition of childhood, with an
`annual. incidence of about l.4- cases per 10,000 chi].-
`dren under the age oi" 16 years in the United States,
`and a prevalence of roughly 1 per 1000.“? Three types
`of onset of juvenile rheumatoid arthritis are recog-
`nized, each of which has a characteristic cli11ical, epi-
`dcrniologic, and genetic pattern? The systemic-onset
`form produces a rheumatoid rash. and interrnittent fe-
`ver (temperature, 3=39.¢i-“C, with daily return to nor-
`mal); anemia, pericarditis, and l1epatosplcnornega].y
`are common. The arthritis usually involves multiple
`joints. Polyarticular onset is characterized by arthritis
`in five or more joints, and oligoarticuiar onset {also
`referred to as pauciartieular) is characterized by at-
`thritis in fewer than fivejoints. Rheumatoid rash and
`intermittent fever are absent in the polyarticular and
`oligoarticular forms, although other systemic manifes-
`tations may occasionally be present,
`
`From the Children‘: Hospital Medical Center. Department of Pediaii-ios, Uni-
`versity of Cincinnati College of Medicine. Cincinnati (E.l-LG‘): the Department
`of Pediatrics. Baylor College of Medicine. Houston (E.J,H,); the Institute of
`Rheumntology. Academy of Medical Sciences, Moscow, Russin (N.}C_, A_S_,
`A-M-it iii! i3=tT'"|'tI1'|l-‘-Hi Of Child Diseases. St. Fetnrsblirg Pediatric littttihrte, St_
`Pebersbutg. Russia r'I.V.).- the Deptsrtnient of Pediatrics, University of Tang
`Southwckinrn Medical School, Dn|1na(C.W.F.): Rainbow Babies and Children's
`Hospital, Cleveland (A..T.N.); the Department of Child Health, University of
`Missouri. Columbia (J.T.C.); and the Department or Rherrmatology, Newington
`Children's Hospital. Ncwirlgton. Conn. [L.S.Z..). Address reprinrrequests to Dr.
`Giannini at the Children's Hctspital Medical Center. Pnvilion Bidg_,
`ls! FL.
`Ell:-ind nnd Bethesda Aves.. Cincinnati. CJI-T, 45229-2899.
`Supporter! by a grant (FD-R-000032) from the other of Orphan Products
`Development of lhe Food and Drug Administration, by the National institute of
`Arthritis anti Musculoskelatol and Skin Diseases. by in Clinical Projects Grant
`Front
`the National Arthritis Foundation. by the Children‘; I-lnspitnl Research
`Foundation. Cincinnati. anti by Letlerlc L.al.ior:nnries. Pearl River, N.‘r'.
`
`Approximately one third of all patients with juve-
`rrilc rlteumatoiel arthritis achieve adequate control
`of their disease with nonsteroidal antiinfiarnmatory
`drugs; the remainder are candidates for more aggres-
`sive therapy with secon,d—line agents. In large random-
`ized trials in adults with refractory rheumatoid ar-
`thritis, the an t1',metabol.it.e mcthotrexatc has had thera-
`peutic advantage over placebo, with an acceptable
`safety profile.“ Lon.g—tcrm studies have shown that
`the therapeutic effect of methot:re;»cate may persist
`for extended periods.“'” Anecdotal reports and the
`results of uncontrolled trials of the efficacy and
`safety of low—dose methotrexate in juveni.le rheuma-
`told arthritis have been encourag.i.t'.rg.”'” For these
`reasons the Pediatric Rheumatology Collaborative
`Study Group (PRCSG),
`in conjunction with col-
`leagues in the then Soviet Union, conducted this dou-
`ble-biind, randomized. placebo-controlled trial to as-
`sess the therapeutic effects of two cii.lTl.'.rcnt doses of
`methotrcxate in children with tesistant_1"r.rvcnile-rheu-
`matoid arthritis.
`
`METHODS
`
`The stutiy was conducted under the Cooperation in Medical Sci-
`ence and Public Health Agreement (signed on May 23, ]972,
`in
`Moscow) and was a collaborative etTort between physicians and
`Sflichtists in the United States and the Sotrict l_l'nj¢:.n_ A tcttal of 23
`pediatric rheumatology centers in the two countries part.'iciprrted (13
`in tl1l: Uhitctl States and 5 in ti-re. Soviet Union).
`
`Study Design
`
`The investigation was clesigneei as a prospective, parallel, multi-
`ccntcr. placebo-cortrrolleei, randomized. double-blind clinical trial
`of six months‘ duration. Randontization was in blocks of three
`
`
`
`Page 1 of 4
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`ANTARES Exhibit 1029
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`
`
`Vol. 326 No. 15
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`METHCITREXATE IN RESISTANT _]T_l‘-/ENILE RHEUMATOID ARTHRITIS — GIANNINI ET AL.
`
`1041-5
`
`as 40 percent in the rate of response between the active drug and
`placebo was considered important to detect as statistically signifi-
`cant. We estimated that approximately 30 percent of t|1e patients
`given plaeeho would be classified as improved. According to tl1e
`tables presented hy Gehan and Sclineidermanfil and assuming the
`use of two-tailed tests, a minimum of 30 patients were required in
`each group.
`We tested proportional data for significance using the ciii-sonar:
`test or, where appropriate, Fisher's exact test. Statistical signif-
`eance by the chi-square test was required For tables with more than.
`1 degree of freedom before partitioning. For continuous variables,
`mean values were compared by one-way analysis of variance. When
`rnulriple-range I‘.ests
`loeearne appropriate, Dunnett's method for
`making multiple comparisons with a placebo” was used. Two-way
`analysis of variance was used to test For the effects of drug and
`country on the change in articular indexes. The Bonferrotri correc-
`tion was used to adjust For the testing o‘|' multiple hypotheses
`(n 9- 12) among secondary variables and in the analysis of response
`in subgroups of patients. Both unadjusted and adjusmd values are
`shown, however, if a P value was significant (‘$0.05) htiorc correc-
`tion, and the results are referred to as statistically significant.
`Ernpliasis was placetl_ on the intention-to-treat analysis rather
`than the analysis of those who completed the entire six-month trial.
`The intention-to-treat technique used the values of response vari-
`ables or the Final visit, whether or not the patient completed the
`entite ttial. This approach o'FFcrcr:l several advantages: more pa-
`tients were nunilnl-_i]e for the analysis of efficacy, data on those who
`dropped out before completion could be included, and it more close-
`ly reflected how physicians evaluate a. tl_iers.pe1itic agent in the clini-
`cal setting, outside an experimental protocol.
`
`Rm-r.ULTs
`
`A total of 12? 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 01" disease at
`entry averaged 10.1 and 5.1 years, respectively. The
`-disease course was systernic in 32 patients (25 per-
`cent), all of whom also had polyarthritis. Forty-sir;
`children received low—dosc methotrexatc, '4-O received
`very-low-dose methotrcxatc, and <.1.»l were given pla-
`echo. Randomization worked. well; there were no sig-
`nificant clifi"eren,ces among the treatment groups in
`any of the demographic or disease characteristics
`shown in Table 1. Patients from the two countries
`were di.stribut.=.-d about equally among the three treat-
`ment groups. Those from,
`the United States had a
`higher mean ($513) number of joints with active at‘-
`thritis (2732 vs. 20:2, P-110.046), but the mean ar-
`ticular-severity score (112) was the same for the two
`countries.
`Indotncthacin was the most frequently used concur-
`rent nonsteroitlal drug (25 percent}, J."ollowed by Da-
`proxen (18 percent),
`t|2|l1TlC1LlI'1 sodiu.r.n (17 percent),
`di¢1oi;"on-no sodium [16 percent), aspirin (15 percent),
`and other agents (6 percent).
`
`Efficacy
`
`Patients were included in the a.11a.lysis of ciiicaoy if
`they met all eligibility criteria, received the study drug
`in blinded fashion for a minimum of one motitii, Write
`100 percent compliant with the prescribed regimen
`during at least 80 percent of the follow-up period, and
`nnmpligti with the other specifieati.ons‘ of the protocol
`regarding restrictions on other ‘medications and return
`visits to the clinic.
`
`Table 1. Demographic and Clinical Characteristics of tho Patients
`at Entry. According to Study Group.
`Low-DOSE
`vzrtwr-i..ow»1:>oxr:
`Msrsorssmrs
`Msrsmnsrirs
`(N - 45)
`(N - -10)
`
`CI-l.iI.llACTEl'l.l!lTlC"'
`
`PLACEHO
`{N rt 4|)
`
`one (it)
`Average
`Rsngc
`Disease duration (yr)
`Average
`Range
`No.
`(9%) Female
`No. {on taking low-close
`prednisone
`No. {Em taking two
`Nsftlbsi
`No. {deal with systcnric-
`onset disease
`
`Mean (:t:SE] no. ofjcinis
`with active ttrthritist
`
`10.1
`2.5—l'a'.5
`
`4.8
`l.'|.fi-13-.5
`33 ('72)
`15 (33)
`
`5 [1 1}
`
`9 (20)
`
`9.6
`3-.El—|7.4
`
`4.3
`|.'|.5—~l 1.5
`29 ('73)
`15 (31)
`
`3 (7.5)
`
`ll [23]
`
`10.6
`3.2—l7.S
`
`5.8
`U.5—l4.4
`34 (33)
`14 (34)
`
`'
`
`3- (7.3)
`
`12 [29]
`
`27 (2)
`
`2! (2)
`
`24 (2.)
`
`""l'liere were no slgniflcnnt differences among the trentrnent groups in my of the character-
`iltli¢3.
`TNSAID denotes nnnsteroitiitl Itntlinnarrtmnrory tints.
`ism: the Mctltods section for A definition of native nnltrlrls.
`
`Of‘ the 127 enrolled patients, 1 I4 {SID percent) quali-
`fied For the analysis of eilicacy, including 33 (33 per-
`cent) of the 46 in the low—dosc group, 37 (92 percent)
`of the 4|} in the vcry—low—-close group, and 39 (95 per-
`cent) of the 41 who took placebo. Among the IS pa-
`tients e5tcl,udct,l, from the efficacy analysis, 8 violated
`the specified doses for concurrent nonstcroidal agents,
`3 violated the prednisonc regimen,
`1 was noncom-
`plinnt in taking the study medication, and I was dis-
`covered to have had fewer than. three joints that met
`the criteria for active arthritis at the base-line visit.
`
`Clnly ll of the ll.-‘-lr children in the cilicacy subgroup
`tool; two concurrent nonsteroidal agents during the
`trial, These patients were equally divided among the
`treatment groups, and their data were not considered
`separately. A total of 40 patients in the efficaey sub-
`group received low-dose prcdnisone during the trial,
`including I4 who were given lc«w—dosc mcthotrcxate
`and 13 in each of the other two groups. Since the
`numbers were small, and the close low and constant,
`data for those who received prcdnisonc were not sna-
`lyzcd separately.
`Among the 127 randomized patients, .108 completed
`the entire six-month trial, including 97 (85 percent) of‘
`the I14 in the efficacy subgroup.
`Global Assessment
`
`Figure I shows the percentages of patients at each
`tcturn visit. who had clinical
`improvement from
`their base-l,iric condition, according to the physi-
`eian‘s global assessment. Both methotrexatc groups
`had consistently higher proportions of patients with
`improvement than the placebo group. According
`to the physician's final global assessment, a sig-
`nificantly l-tighct proportion of patients improved.
`in tlio 1ow—elose group than in the placebo group
`[X3 with 2 df = 7.53, P i 0.023). These in the very-
`
`
`
`Page 2 of 4
`
`
`
`lD-4-El
`
`THE N.E1W ENGLAND _]Cl'URN.AI_. OF MEDICINE
`
`April is, 1992
`
`tion of the oral mucosa accompanied by headache and
`gastrointestinal problems. Five of the "-1-l patients
`who took placebo (12 percent} bad side effects, all
`of which were gastrointestinal. -All side effects were
`graded as either mild or moderate in severity, except
`for two episodes of stomach pain graded as severe
`in a patient receiving placebo. No patient had evi-
`dence of mcthotrexate—induced pulmonary disease
`during the trial.
`
`Laboratory Evidenco of Toxicity
`
`Patients who received mcthotrexate had more ab-
`normal results on laboratory tests that werejudged to
`be clinically important and possibly, probably, or defi-
`nitely related to the study medication than those given
`placebo. Fifteen patients who received l.ow—dose meth-
`otrexate, l5 who were given very-low-dose rnethotrex-
`ate, and 5 who were given placebo had such results.
`Among the patients given methotrexate, the most Fre-
`quent abnormal results were alterations in the differ-
`ential whitc—cc1l count, hematuria, pyuria, and the ele-
`vation of serum aminotransferasc levels. Elevations
`of aminotransferase levels and anemia were the most
`frequent abnormal results among the patients given
`placebo. Other clinical-chemistry data were unre-
`marl-table.
`
`Dropouts
`
`A total of 19 patients (10 in the United States and
`9 in the Soviet Union) discontinued therapy before
`completing the six-month trial. (Table
`Two pa-
`tients in the low-dose group dropped out because of
`adverse effects: persistent elevations of serum aspar-
`tame and alanine arninotransfcrase (levels up to 120 IU
`per .liter) in one and persistent b.ematuria in the other.
`Both problems resolved quickly after the discontinua-
`tion of the study medication. One patient given very-
`low-dose rnethotrexate had a persistent skin rash and
`was dropped from the study one month after entry.
`The total numbers of dropouts were not significantly
`different among the groups.
`DISCUSSICIN
`
`The results of this trial confirm anecdotal reports
`and evidence from uncontrolled trials that low-dose
`methotrexate has antiinflammatory activity and clini-
`
`Tablo 3. Fleasons Patients Left the Study. According to Study
` Group.
`LUW-Doll
`Wtwr-Low-Dose
`Meritorttitsrit
`Msruonsxvrs
`(N " 45)
`[N " 40}
`no. qfpotienrs |"ill£-,I
`
`Ptxceno
`EN = 41)
`
`Reason
`
`5 (12)
`3'. (5]
`0 (0)
`.l11Isf|'Eel.i\re11es5 of drug
`0 ml
`1 (33
`1 (4)
`Adverse effects
`1
`('2)
`2 i5}
`2 I14]
`Intercurrent illness
`l (2)
`G (El)
`2 (4)
`Adminisbative reasons _
`U (0)
`III
`(0.1
`1 (2)
`Noncompllance with protocol
`
`
`
`7' {I5} 5 (1.2)Total 7 ('7)
`
`cal effectiveness in resistant juvenile rheumatoid ar-
`thritis. We also found a trend. 1'.owar_d a dose—response
`relation in the low-dose and very-low—dose methotrex-
`atc groups, similar to that reported by Furst ct a1.-‘°
`in adult rheumatoid arthritis. The favorable :lin.dings
`from the present study should be encouraging news
`for clinicians faced with managing a ehild’s disease
`that has failed to respond. adequately to nor.tsteroida.l
`drugs. Methotre:>ta.te has distinct advantages over
`other second-line agents,
`including its oral
`route
`of administration, once-a-week dosage, lack of known
`oncogenieity, and lack of long—term effects on fertil-
`ity. The choice of which second—linc agent
`to use
`i1'1itia..l.ly has become more difficult in recent years,
`after controlled trials and long—term. prospective stud-
`ies showed a lack of efficacy among the agents in com-
`mon u.sc.‘-M‘-5" Parenteral gold remains a therapeutic
`option, but its considerable toxicity” and inconven-
`ience must be considered. Furthermore,
`injcctable
`gold salts have never been assessed in a controlled trial
`in children with arthritis. Thus, the tendency among
`pediatric rheumatologists to consider the use of meth-
`otrcxate earlier in the disease, and before other see-
`ond-line agents, is likely to cotitiriuc.
`There was a consistent trend in this study toward
`greater improvement in the low-dose group across all
`indexes of articular disease; some of the mean changes
`were not statistically significant, however. The vari-
`ability of the changes within the treatment groups, the
`limited sample size,
`the corrections for
`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 recent development of a child-
`hood health-assessment questionnaire and functional-
`ability tool may provide more sensitive measures of
`response in future trials.”'i” Nevertheless, the results
`obtained here represent by far the most encouraging
`data from a trial of a second-line agent undertaken by
`the PRCSG.
`.
`The equality of response across treatment groups in
`the subgroup of patients with severe disease is unex-
`plained. Since all three groups showed dramatic im-
`provement in the articulanseverity score, it is possible
`that there was a greater regression toward the mean in
`th ese children with severe disease that‘ effectively
`blurred any difference in response produced by meth-
`otrexafe,
`
`The concurrent administration of aspirin is known
`to slow systemi.c and renal clearance and increase the
`unbound fraction of rnethotrcxate, perhaps resulting
`in greater toxicity.” We did not observe such an asso-
`ciation among the 2O children (16 percent} who tool»:
`aspirin. Among the 14- children who had clinically im-
`portant physical adverse effects while receiving meth-
`otrexate, 2 (14 percent) were taking aspirin. Among
`the 30 e.hil.dren treated with methotrexate who had
`substant1'a.l abnorr.nal.ities in la.bI:ir.atary inelestes of tox-
`icity, tl: (13 percent) were receiving aspirin.
`Although mild elevations of serum arninotrans-
`
`
`
`Page 3 of 4
`
`
`
`Vol. 326 No. I6 METHDTREXAT.E'. IN RESISTANTJUVENILE RI-IEUMATOID ART!-IRITIS — GIANNINI ET AL.
`
`104-9
`
`the study groups,
`ferase levels were common in a.ll
`only four children in the low-dose group, nnu in the
`ve'ry—low-dose group, and one in the placebo group
`hacl markedly elevated (more than two times the up-
`per limit of normal) enzyme levels (range, 85 to
`l3-4 IU perliter). Possible explanations for the lack
`of hepatotoxie effects include the duration of tl'l.e
`trial,
`the administration schedule of a single dose
`per week, and the low euntulative doses to which the
`children had been exposed. Also, previous concern
`about the hepatic toxicity of methotrexate may have
`been exagge.ra.ted.35 A prospective study of the chil-
`dren who received mcthotreotate during this study is
`now under way to evaluate long-terrn outcome and
`safety.
`In conclusion, II1€tl'lDtl“t;'.3t.:a.tC at a dose of 10 mg per:
`square meter per week appears to have greater clinical
`effectiveness than placebo in children with juvenile
`rheumatoid arthritis. The short-term safety profile is
`acceptable. Given the results of previous trials by the
`PRCSG, the use of methotrexate as the initial second-
`line agent in resistant juvenile rheurnatoid arthritis
`appears to lziejustifiecl.
`
`We are indebted to Academician Valentin.1.A. Nassnnova, M..D.,
`ofthe Academy oi.‘ Medical Sciences, Moscnw;_]ohn Klippel, M.lD.,
`and Lawrence E. Shtllman, M.D.. l’h.l3.. of the National Institiltes
`oi" Health, Bethesda, Mel.; Marlene I-l:i,-i'l'ner__ M_D_,Jol1n Hnrter,
`M.D., and Kent Johnson, M.D., of the Food and Drug Adminis-
`traticn. Washington, D.C.; and Dick Ryan, Harriet Kiltie, M.D.,
`and Margaret Gandt, M.D.. of Lcclcrle Laboratories, Pearl River,
`N.Y.,
`for their assistance in organizing and conducting this
`study.
`The participating clinical. investigators in the United States were
`(in alpliahetical order} Bram H. Bernstein, M.D., Harry L.
`Gewantcr, M.l.'.3.. Jerry C. Jaeolaa, M..U.. Deborah W. Kret:l_ieh,
`M.D., Robert N. Lipnielc, M.D., Daniel__], Lovell, M_D_, M'..I-‘J-I.,
`Lauren M. P-‘tchman, M.D., Murray H. Passn, M_D., Donald A.
`Person, M.D.,_]anc G. Schaller, M.D., Charles H. Spencer, M.D.,
`llona Seer. M.D., and Carolyn L. Yancey,‘ M_D. In the Sov-is.-1;
`Ufllflfl l-l'l¢ P-‘l.1'ti|.‘.ipa.t:ll1g clinical investigators wcrt: Dan-i_it¢ Age‘-,1,u5.
`kcne, M.D‘., Ludrnila Isaeva, M.D. (deceased), Nina Letenltova,
`M..D.. E-lltina Puogienetle.
`lV.l..lll.. Inessa Sltakhbazyan, M.D.,
`lV.la.rina Stehcrhakova, M.D., Alexandra Yaltovleva, M.D.. and
`Sernphima Yandashevskaya, M.D. The senior scientist in_t]1u Soviet
`‘ Union was Boris Shokh, l'vl.D,
`
`Re:-anewces
`
`l. Towtlct SR. Mi<thl.'-tC.l .l1'.. D‘l"'allo11 WM. Nelson AM. The epidemiology of
`juvenile nrthriiis in Rochester. Minnesota 1950-1-sis. Affllritis Rheum
`l9.B3;25:I103-l3.
`2. Potty RE. Malleson P. Epidemiology oi’_|uvcn:'|e rheumntnid nt'tl1ritis. world
`Pediatrics Child Care l987-,3:2l)5- lo.
`3. Cassidy JT. Petty RE. Textbook cl‘ pediatric rheumntology. 2nd ed. New
`York.‘ Cllurehill Livingstone. 199011 M.
`4-. Willlamc H3. Wlllltens RF. Samuelson C0 Jr. et a1. C¢11'|pnI,'i5Dll of
`lowwtlose oral pulse methotreitale and placebo in the treatrnent of rheu-
`rnatoicl nrthritis: a controlled clinical
`trial. Arthritis Rheum 193593:
`721-30.
`5. Weiflhlalt ME. Cololyn 35, Fort DA, is: nl. Efficaey est‘ Inw-nlnsp n-uutl-intrn;t-
`tile in rheumatoid arthritis. N Eng] J Med l9B5:312:8lB-12.
`lCt¢T|'|E1'lM. l-cc lK- Tho Salt‘-ti’ and cllionty of the use of metliotrcxnte in
`long-tenn therapy for rheumatoid arthritis. Arthritis Rheum 1936;29:322-
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