`
`Psoriatic Artl1ri'tis
`
`Double-Elinrl Study on 21 Patients
`R03" L» 3151036» -“'0.
`ll7iNr"mr2 M. O-Bi|'l'i".fl. MD. Etigonc J. Van Scott. MD.
`Robert Arnvrbflrh. ND. .-filrthtrr Z. Erhr-n. MD.
`rm:-I ,;l'o.tc»;_:-J’: I. Hmiinr.
`:lilD.'i' Bethesda, Md
`
`--
`
`A rlouhle-blind stmly comparing the
`response of 21 patients with psoriatir-.
`arthritis to a series of
`three parenteral
`injections of urcthotrexate at .10-rlay inter-
`villa with the response to a similar series
`of three placebo injections has been re-
`ported. Metliotrexatc was
`found to he
`cfi'ect.ive in srrppressing the skin manifes-
`tations, decreasing joint
`tenderness and
`swelling.
`improving joint
`range of mo-
`tiori, and decreasi,n,t_r the erythrocyte sedi-
`mentation
`rate. Side
`cliccts
`included
`anorexia or nausea in Li patients. horn-
`ing sensation in the skin in ten, depres-
`sion of the white blood cell count helow
`-i.0O0,fcr1 mm in seven. oral ulcerations in
`two, and mild hair
`loss
`in one. This
`therapy‘ should he reserved for patients
`with severe disalnlinrr disease who have
`failed to.respond to more conservative _
`urea sltres.
`" "
`
`IN 19.51 Clubncr and co—workers' reported good
`results from oral administration of soditlm am-
`inopterin in six of seven patients with rheumatoid
`arthritis. They also treated six patients with psori-
`atie arthi-itis; skin lesions improved in all and the
`arthritic condition improved in three.
`I-Iowever.
`these workers concluded that "the toxic eliects of
`sodium aminopterin place practical
`limitations on
`its use as a therapeutic agent.”
`The present authors reported preliminary ex-
`perience with another antitolic agent, methotrex-
`ate,
`in the treatment of psoriatic and rheumatoid
`arthritis in 19622.’ The initial observation of favor-
`able response in psoriatic, but not
`rheumatoid,
`arthritis encouraged us to design and conduct a
`double-blind study comparing the edects of meth-
`otrexate and a placebo in the treatment of patients
`Fran-a the National Institute of ArtJu-itig and Mctnbnlig Difleflsrs and
`the Nntiunnl Cancer Insrltute, National
`lnsntiiteg of Hi-nirh,
`l'Drc-nus:-cl.
`-
`
`with psoriatic arthritis. The results nF this stncly
`form the lvrsis of this report.
`
`Design of Study
`
`Patients age 18 years and over were admitted
`to the study, provided that both psoriasis and in-
`llammatory joint disease were present. and that
`either disorder was of at least one year’s duration.
`Excluded from the study were patients who had
`severe renal or liver disease, severe infection.
`(Ir
`a hematological disorder. such as netttropt-tni.-,1. se-
`vere anemia, or thromhocytoponia. Pregnancy was
`alsoicause for exclusion. Participation in the stncly
`required a minimum hospital observation pt-rincl
`of 80 days.
`time for adequatc
`The iirst 20 days providetl
`assessment of skin and joint
`involvement. stabili-
`zation of the clinical state, and complete, pretreat-
`ment
`radiographic
`and
`laboratory
`evaluation.
`Throughout
`the study the patients were treatcrl
`with local applications of a bland ointment (Eu-
`cerin) to the skin. When patients had prev-iousl_i
`received either corticosteroid or salicylate therapy
`or both. dosage was reduced to a level at which -.1
`slight
`increase in skin lesions or joint symptoms
`occurred. This minimum maintenance dosage then
`remained constant throughout the 5t1.1cl_\-'. Although
`their activity was not otherwise limited. patients
`were not permitted to he exposed to sunlight.
`_ During the first 14 days each patient received
`a single 2E—mg parenteral dose of rnethotrexate tn
`test for liypcrsensitivity to this preparation. A pro-
`found reaction to this dose would have ext.-ludcrl
`the patient from further study, but no such reac-
`tion occurred. From the First bottle. either mt.-i‘lir.r-
`trcxate or a placebo according to a randomized
`schedule, each patient then received a series ni-
`three injections (intravenous when possible, other-
`wise intramuscular) at
`intervals of 10 days. Tlw
`schedule included progressively increasing closi.'.~:
`from 1 to 3 mg per kilogram of body weight.
`‘When clinical improvement occurred prior to the
`
`Page 1 of 5
`
`ANTARES Exhibit 1026
`
`
`
`l*_'."[' M,
`
`FIRST PERIOD
`Melhofrexcflo
`
`IJLUA.
`
`,SL~p|_ T.
`
`[Qf-H
`
`SECOND PERIOD
`Plucebu
`
`Methotrexote
`
`FINALSKININVOLVEMENT,5'
`
`MIETI-l(l'l‘ltl:2l{.rlt'l‘l-2-|il..M‘_)!\;
`744
`third injection. the thirtl dose was kept at i‘ mg/kg,
`If at any time the white hlood ccll‘{‘W'.l3C) Cl:)l_1I'lt
`fell below 4.000/"cu mm or the platelet count fell
`liclow 10fl.i.lOU,»'cr_i mm.
`the next scheduled dose
`was withheld. On completion of the first series of
`lTllCC’ll0l.1S.
`tllree successive injections of the alter-
`nate preparation were administered at
`the same
`closzige schedule. again at
`intervals of 10 days.
`During the entire study the status of skin and
`sinint ilwolvement was evaluated twice weekly by
`the same observer. The area of skin involved was
`estimated and expressed as a percentage of total
`body surface. Joints were evaluated and scored
`on a O to 3 scale For pain on- motion,
`tenderness.
`and swelling;
`the total score for all joints for all
`three variables comprised the "joint
`index." The
`range of motion (I-'l0M) of hips, knees, ankles,
`shoulders, elbows, and wrists was measured week-
`ly, and the score expressed as a percentage deficit
`of the normal. Westergren erythrocyte sedimenta-
`tion rate (ESE) was determined and WBC and
`platelet counts were performed twice weekly.
`Blood urea nitrogen (BUN) and serum glutarnic
`osalacetic
`transarninase
`(SCOT) determinations
`were made weekly. Sulfobromophthalein excretion
`(ESP), and alkaline phosphatase, cholesterol, and
`serum protein levels were cletermined monthly.
`Composition of Series
`
`Twcnty—one patients participated in this double-
`hlind study, 11 females and ten males (Table 1).
`The ages ranged from 29 to 69 years. One woman.-
`who participated in the methotrexate phase only
`and showed dramatic improvement
`in skin and
`joint manifestations, was clrclpped from the series
`when after three injections she cleveloped severe
`thromhophlehitis, and it was considered unwise
`to continue the double-blind regimen.
`Diiration of psoriasis ranged from 2 to 49 years;
`the mean duration was 16 years. The extent of
`skin surface affected was 6% in one patient, be-
`tween ll"/in and 25% in five, between 26% and
`-30% in another five, between 50% and 75% in four.
`and over 7395.» in six; five of the latter six had be-
`tween 9D”?c: and 100% skin surface involvement. In
`every case. scalp and nail lesions of psoriasis were
`uiiservecl. Eleven of the patients exhibited appear-
`ance of a psoriatic lesion at
`the site of trauma
`(Koeliner phcnornenon).
`All patients had had arthritis ranging in dura-
`
`Table 1.—-Composition of Series
`Duration of Pnrlult. ‘l'r
`......j.._.._...:.,
`15-20
`21~25
`_‘_.':-26
`
`D 20 40 60 HQ H30
`Cl 20 40 60 SD IDD
`INITIAL SKIN lNVDLVEME.'NT,'%
`
`average values
`Bars indicate initial - and final
`Fig 1.—Chungn In purcentug-i oi skin irlvpluqmanl during
`double-blink] study. Begun of
`lmprov-mun!
`reflnctrcl by
`distance at which piflllid point falls bolow-«diagonal
`ling.
`
`tion from six months to 30 years (three for only six
`months). The mean duration of arthritis was eight
`years. All 21 patients had clinical signs of involve-
`ment of the small
`joints of the hands and.
`in all
`hut one patient. distal interphalangeal joints were
`affected. Symptoms of spinal
`involvement. most
`frequently in the cervical region. were present in
`12 patients. The knees were aifected in 15.
`Fourteen of the patients reported a synchronous
`relationship between exacerhations of skin involve-
`ment and increasing severity of
`joint disease:
`abatement of arthritis followed recession of skin
`lesions. either spontaneously or
`in response to
`treatment. All 2], patients had morning stillness:
`none had subcutaneous nodules. The hentonitr
`Hocculation test for rheumatoid factor yielded re-
`peatedly negative results in :20 of the 21 patients.
`In the one patient with a positive result.
`the titer
`was 1:64;
`this patient had extensive psoriasis and
`distal
`interphalangeal
`joint
`involvement. Lupus
`orytliemattlstis cell _prr-.'.paratinns gave negat.ive re-
`sults in all Cases.
`
`t0[JlC“=ll
`All 21 patients had prtrvimrsly reccit-'t.‘I:l
`rneclieation (usually tar ointment) for the psoI'iasiS-
`All but one had received systemic corticosteroid
`therapy with inaclequate or unsatisfacto.ry 1'1Tl‘
`provernent in the skin or joint disorder. F0111." pa-
`tients had previously received chloroquine plies-
`phate for treatment of their arthritis: three of thesis
`four had experienced a.
`rn-arlted exacerbation 1'11
`slti.n disease t'ollowir'I,i._:'administration of this drug;
`in one.
`the exacerbation DCC!'t.lt"l‘Et‘.i after only nine‘
`days of therapy.
`
`Page 2 of 5
`
`
`
`Vol
`
`I39, No Ill
`
`FIRE T PE FHOLV
`Méfhfitfenqfe
`
`
`
`
`
`FINALJOINTiN|:IE}(.'I.
`
`ED
`
`1'1!-.4
`
`-
`
`Ml-lhctroxtatc
`
`O
`0
`ED
`40
`INJTML. -JOINT INDEX..%
`
`40
`
`745
`.\u:'ri|(rrlu9x_-n+:_ar__:.c:x er AL
`EECDND PERIOD
`Placebo
`=.I.L*.'r area of skin involved prior to administration
`of rnctliotrcxatc in this first group was more than
`-16"/T-. whereas the final involvement avcragetl
`]t:FE_
`Very little change was OlJ.'iCh.rEd during gm p]m.,_._
`ho period. the average changing from 18% to .I_5*.':-,
`[77 21'0"]? EA there was no change in the area of
`sltin involved during the plnoelm plmw; ]mM.w_s,i‘
`when t'he,drug was given the average flxtc-Inf Hf
`skin involvernent fell from 56% to 22%,
`[11 hath groups the most pronounced improve-
`ment occurred after the second injection of metho-
`trcxate (between .10 and 20 (lays after the first in-
`jection). It is of interest that some changes in the
`skin often followed the lirst injection;
`first, there
`was a decrease in the arnount of scale iiormmjun,
`followed hv a softening in the texture of the skin.
`hut a persistence of erythema. A decrease in the
`area of sltin involvement was not recorded until the
`learing. Four patients in
`the entire series failed to show improvement
`in
`their skin condition during the administration of
`the antifolic compound. One of these was in group
`AB, receiving methotrexate first and the placebo
`later. This patient was treated at a later date with
`methotrexate and showed complete clearing of
`skin manifestations. The other three patients were
`in group BA, receiving the placebo first. One of
`these patients, described later. died. One other
`was treated at :1
`later date and responded with
`complete clearing of tl1e skin. The remaining pa-
`tient was not retreated.
`Figure :2 illustrates the changes that took plEl<.'i-‘
`in the severity of joint
`involvement
`in these pa-
`tients. The joint
`index prior to the start of
`the
`study is plotted along the horizontal axis and the
`final score along the vertical axis. It will he noted
`in Fig 2 that in both groups AB and BA there was
`a decidedly greater decrease in the average joint
`index during methotrexate administration than
`during the placebo periods. In general,
`the joint
`improvement occurred somewhat less rapidly than
`did the favorable change in the skin.
`
`Bars indicate initial - and final
`
`Fly 1.—CIInngu in severity to!
`da|lHe—BliIId study.
`
`laint
`
`Results
`
`qt.-emgg vglug-5
`
`lnvnlvarnunl during
`
`By random selection, ten patients. six men and
`Four women.
`received a course of methotrexate
`prior to the placebo (group AB). The remaining
`four men and seven women received a placebo
`before methotrexate (‘group BA). An attempt was
`withdraw the corticosteroid
`medication in all patients receiving these com-
`pounds prior to the study. In eight patients, it was
`nccessary to continue corticosteroid administration
`during the trial in doses varying from a minimum
`of 6 mg of triamoinolone daily to a maximum of
`20 mg of prednisdne daily. Three of these eight
`patients were in group AB and Eve were in group
`BA. Four of these patients also received aspirin
`daily. Two patients in group AB and three in
`group BA received maintenance dosage of aspirin
`without a corticosteroid during the period of ob-
`servation.
`
`The response to methotrexate was favorable in
`most instances. Figure lshows the changes in skin
`involvement during the double-blind study. The
`upper two diagrams illustrate the response of the
`ten patients who received the antifolic compound
`prior to a placebo (group AB). The percentage of
`skin surface involved. prior to drug administration
`is plotted along the horizontal axis, and that at the
`end of the study is plotted on the vertical. If. hy-
`pothetically, no improvement would occu.r
`in a
`given patient, then the point plotted for that pa-
`tient would fall exactly on the 45° diagonal. The
`degree of improvement.
`therefore.
`is .refleetec‘l by
`the distance at which a plotted point falls below
`the diagonal
`line. It will he noted that the aver-
`
`Table 2.——UndesirabIe Side Effects of Methctraxate in
`Treatment of 21 Patients with Psorlatic Arthritis
`ND. flf
`Pntlcnts
`
`.
`
`Side Effect
`tin 15 of 21 Bfltiantsl
`Ciaatrointustlnal
`lficcrcascd appetite
`Nausea
`Abdominal pain trnllnl
`oral ulceration
`' "
`Dermatological
`Burning sensation {chin}
`Bleeding From skin
`Mild hair loss
`Hematological tln 1' patients)
`WBC less than «HJDD.-"cu mm
`Platelets less than l0O.GDEli'¢u rnrn
`Hemoglobin less than 1!) xrnfis
`Disturbance In hepatic function
`Increase In ESP
`Transient elevation In EGO
`
`_
`
`-
`
`Page 3 of 5
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`
`.\1ET.I IDTIE lE.\'.-1. l'i".— Ii-I.,-'I.C.‘l\' ET AL
`
`IAMA. Seitt 7. mm
`
`in ROM of joints was oliseri-ed in
`p1'n\'eni-ent
`.-all patients during the study. The average perm-mt-
`age deficit in ROM decreased from 16.5 to 13.2 in
`l'l1r.= patients receiving the drug first, There tom;
`little change during the placebo period,
`the aver-
`i1.*I‘=‘
`‘5'l‘5’*"'.‘-l"'l.t‘5
`fl'0l'l‘|
`l3-3'75 {'0 12.7%. The secorul
`group of patients showed little change diiring the
`L':Ir'ly stage of the placebo period.
`the score vary-
`ing from 18% to 17.2%. During the drug phase the
`score changed from 17.2% to 15%.
`In
`The ESE was determined twice weelcly.
`group AB the average ESE fell from 55 to"39 mm
`per hour during methotrexate administration and
`changed from 43 to 45 mm per hour during the
`placebo period. In group BA the average E31’-I fell
`from 71 to 64 mm per hour during the placebo
`phase and from 64 to 48 mm per hour during the
`t'netl1otrexate phase.
`the
`Strrri.sticol Analy.sis.—Statistieal analysis of
`data was performed by Wilco.ron's ranl-zing meth-
`od." as modified by White,‘ to compare two treat-
`ments where the numbers in two groups are not
`necessarily the same. Since the response data are
`not normally distributed along the "bell-shaped"
`curve, conclusions drawn from an analysis of vari-
`ance based on normal distribution are invalid. Wil-
`t-o.ton’s test, however, mal-zes no assumptions as to
`the underlying distribution, and although there 1'.s
`some loss of information with "ranlcing,” the con-
`clusions are valid. The tables used in calculating
`the significance are those of Mainland.“
`The overall significance of treatment A (metho-
`trexate] was compared to treatment B (placebo) by
`ranking the difference in improvement scores of‘
`:._;roup AB (A minus B, which shoul'd be positive if
`A is eflecti.-Je_‘J and group BA (E minus A, which
`should be negative if A is eifective). The results
`were effect on the joints. p-=0.l}1'. effect on sltin.
`p-=:f0.0l,' effect on ESE, pa-.:U.U1; and eFr"cct on
`liO.‘ul_. p=D.Dl_. Response to treatment by metho-
`tresate was definitely superior to that from the
`placebo in all parameters measured.
`Arloerse Side Effects and One Dc-cth.—Side ef-
`fects observed in the group of patients during
`treatment with methotrexate fall
`in four general
`categories and are listed in Table 2. Gastrointes-
`tinal symptoms occurred in 16 ‘of the 21 patients:
`<_lccrea.~:e in appetite was the most frequent com-
`plaint, and nausea occurred in 13 patients. Two
`patients had mild abdominal pain and two others
`developed buccal ulcerations. Ten patients
`re-
`ported a burning sensation of the involved skin
`areas during the 24- to 48-hour period following in-
`jection of methotrexate. The sensation was relative-
`ly mild in all but four patients who experienced
`bleeding from the slcin at the site of previous psori-
`atic plaques. One patient had mild hair loss, a
`symptom which gradually decreased after the last
`dose of the drug. Seven patients showed a decrease
`it‘:
`‘WEE? count to less than -I-.000/cu mm;
`in one
`
`patient the leultocytc count fell to less than 1,000/-
`t-I.1 mm and platelets to below l_O0,0()i');’cu mm, In
`all cases the changes were transitory and recovg-_j-V
`was complete within one week. In three patients
`an elevation in SCOT levels was observed. This
`was transient, returning to normal within ten days
`Following the injection. One patient showed an
`increase in 135.1?‘ retention to 20%, detected. six days
`following an intravenous injection of 100 mg of
`methntrexatc. In spite of this abnormality math”.
`trcrtate was administered on three subsequent oc-
`Cil-‘=l'OI'I3 {twice in a dosage of 150 mg) and three
`days after the last injection, the BSP retention was
`only 7%.
`One patient, a 39-year-old male, died during the
`period of methotrexate administration.
`‘This pa-
`tient had had psoriasis for 13 years and arthritis
`for. six months. During the eight months preceding
`the patient's admission he had received predat-
`sone, 30 mg daily, for his psoriasis. Threenoses
`(50 mg, 100 mg‘, and 150 mg) of methotrexate were
`administered intravenously at ten-day intervals. On
`the day prior to the third close, the pat-ient’s WBC
`count was 9,il(_lO/cu mm, SCOT, 8 units, and plate-
`lets, normal value. Four days after the injection
`the WBC count fell to 1,200,-’cu mm, on the sixth
`day to 600/cu. mm, reaching 400/cu mm on the
`seventh day. Platelets fell to .‘2i3.0UO;’cu mm. At this
`time the patient developed abdominal pain, and
`aspirate from the stomach was dark brown and
`contained blood (guaic-positive). Two WBC trans-
`fusions from donors with chronic rnyelogcnous leu-
`kemia and platelet transfusions were administered.
`There was a progressive rise in the WBC count to
`5.400/Cl! mm on the tenth post-injection day,
`8,400/cu mm on the next day, and 13.000/cu mm
`on the 12th day. The SGOT value during this
`period reached a peak of 200 units. Cortisone ace-
`tate was given, .300 mg daily intrarnuscularly, dur-
`ing this period of stress. On the 13th post-injee-
`tion day, the patient had an episode of hematcme-
`sis and died. In addition to generalized pustular
`psoriasis and chronic arthritis, autopsy revealed
`a single massive and rnultiple small pulmonary em-
`boli. The marrow showed a Ieulternoid reaction.
`Subacute ulccrative esophagitis was found, with
`-.u1 estimated 500 ml of blood in the bowel. Focal
`areas of central Iobular necrosis were observed in
`the liver. Death was believed to be due to the
`large pulmonary embolus. rtlthough a primary rela-
`tionship between the administration of methotrene
`ate and his death could not he established (the
`bone marrow was observed to have fully recov-
`ered prior to the patient's death). the fact remaI'I'IS
`that this death did follow immediately after a pro-
`folmd and serious reaction to the drug.
`Follow-Up .
`
`The subsequent course of the 21 patients who
`have been treated with r_netl1ntre.\tate in the double-
`
`Page 4 of 5
`
`
`
`Vol 189. No [0
`
`.
`
`blind study is of
`to the death alre
`died of cerebral
`pletion of the stu _
`gcd therapy
`Tm?‘
`_
`i
`intramuseuIarli'
`with ll‘!
`EV”? 10 *0 14 Cl-'t_V-'5: they have been observed over
`a six- and eight—month period,
`respectively_ and
`ha“? EXP!‘-rienced no recurrence of their skin or
`joint manifestations.
`treatment was
`For the remaining 1'? patients.
`suspended upon completion of
`the douhle—bIind
`study. Recurrence of skin and joint manifestations
`occurred in all—in 12 patients, within one to four
`months. Among the other five patients the shortest
`interval of remission was two weeks and the long-
`est was 15 months. Six of these 17 patients have
`received intermittent doses of 40 to 60 mg of
`methotrexate following recurrence of their disease.
`In three of these six patients it was possible to re-
`duce concomitant corticosteroid therapy by at least
`50%. They were observed for periods of 1 to 12
`months and in each case suppression of disease
`was maintained.
`
`147
`_
`METEIOTHEN.-"iTE—BL.-\Cl~£ ET AL
`this latter instance a direct causal relationship l1.-is
`I101.‘ liettn establislietl.
`The clinical response in most patients treated by
`us was quite impressive. but nevertheless pallia-
`t.ive, since the drug merely suppressocl the cliscasi-.
`Helapses occurred in all cases after variable inter-
`vals following a course oi‘ three injections given at
`10-day intervals. Fortunately, almost all patients
`continued to respond well
`to repeated courses.
`Although many totally disabled patients ‘Lvt-re rt‘-
`stored to an ambulatory and employable .“il‘i'Il‘I.'.
`there is as yet no evidence that the course of the
`disease was altered by methotrexate.
`The authors are currently engaged in develop-
`ing and evaluating a relatively safe,
`long—term
`regimen of treatment of severe psoriatic arthritis
`with antifolic acid agents. The fact that extensive
`cutaneous disease has been safely controlled with
`methotrexate administered at regular intervals for
`periods up to several years new suggests that this
`may be feasible."
`
`Comment
`
`The biochemistry and mechanism of action of
`the folic acid antagonists has been reviewed re-
`cently by Holland." The mechanism of action of
`these agents depends on inhibition of folic reduc-
`tase, the enzyme which catalyzes the conversion.
`of folic acid to citrovorum factor. Folic acid antag-
`onists exert a potent inhibitory effect u_pon cell re-
`production in rapidly growing tissue such as the
`bone marrow and certain neoplasms, especially
`choriocarcinoma.
`The hazards of administration of folic acid an-
`tagonists—both reported and potentiale-are of con-
`siderable magnitude. This type of therapy there-
`lere requires unusual caution—a conservative cal-
`culation of risks versus expected benefits. judicious
`selection of patients, -and very close and alert ob-
`servation of
`the patient during treatment. The
`dosage schedule adopted by us, consisting of rela-
`tively small individual and aggregate doses.
`long
`intervals between injections, and parenteral admin-
`istration, was designed to minimize inc.idence and
`severity of toxic reactions. They were not elimi-
`nated, however, and one patient in our group died
`after a series of three injections of methotrcxate.
`Sodium aminopterin has been used to induce
`abortions. In those cases in which pregnancy con-
`tinued, some newborns exhibited anomalies.’ Folic
`acid antagonists are,
`therefore, contraindicated in
`pregnancy. These drugs also cause oligosperrniaf
`Some leukemic children treated with these agents
`have developed fibrosis of the liver; " hepatic fibro-
`sis has also been reported in an adult following
`methotrexate therapy for psoriasis,” although in
`
`i
`
`Clinical Center, National Institutes of Health. Bethesda.
`Md 20014 (Dr. Blaclc).
`Dr. Donald Mainland, Professor of Medical Statistics at
`the School of Medicine, New York University, assistctl
`in
`the statistical design and interpretation of this study.
`Generic and Trade Names of Drugs
`Soclitun .'1minopterin—-Amilmprerin Sodium.
`Chloroquine phosphatc—A:-also Pliosphate.
`Triamcinolone-Aristocorr, Kenaeort.
`F‘reclnisonc—-Deltcsnne, Deltra, Metienrten, Pcmce-rt.
`Cortisonc
`acctate—Cortisone Acetate, Cortogcn Acetate.
`Corinne Acetate.
`
`‘References
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`Page 5 of 5