C33_rl"
`
`292
`
`THE NEW ENGLAND jDUENAL OF MEDICINE
`
`Feb. 2. l995
`
`METHOTREXATE FOR THE TREATMENT OF GRDHN’S DISEASE
`
`BRIAN G. Fascias, M.D.,JAMES RDCHDN, PH.D., Brennan N. FEDDMK. M.D., E. JAN IRVINE, M_D..
`Gator WILD, M.D._. LLOYD SUTl-IERLAND. MD. A. HILLARY STEINHART. M.D.. GORDON R. Gemstones, MD...
`RIC-HARD GILLIES. M.D.. Macrame Hornets. R.N., STEPHEN B. I'LANAUER. M.D.,
`AND JOHN W.D. MCIDONALD, M.D., roe THE NORTH AMERICAN Deer-Isis Srunv Grous- Iinn-3irrrrui'ross=t
`
`are
`corticosteroids
`Abstract Background. Although
`highly effective in improving symptoms of Crohn’s dis-
`ease,
`they may have substantial texicity.
`In some pa-
`tients. attempts to discontinue certieosteroids are unsuos
`cessfui.
`
`Methods. We conducted a double-blind, placebo-
`ecntrolied multicenter study of weekly injections of
`methotrexate in patients who had chronically active-
`Drohn's disease despite a minimum of three months of
`prednisone therapy. Patients were randomly assigned to
`treatment with intramuscular methotrexate {25 mg once
`weekly) or placebo for 16 weeks. The patients also re-
`ceived prednisone [ED mg once a day), which was is-
`pered over a period of to weeks unless their condition
`worsened. The primary outcome measure was clinical re«
`mission at the end of the 16—week trial. Fiemission was
`defined by the discontinuation of prednisone and a score
`of 55150 points on the Crohn’s Disease Activity index.
`Results. A total of 141 patients were randomly as
`signed in a 2:1 ratio to methotrexate (94 patients) or pia~
`ceioo (47 patients]. After 16 weeks. 3? patients (39.4 per-
`
`cent) were in clinical remission in the methotrexate group.
`as compared with 9 patients [19.1 percent) in the placebo
`group (P=o.oss; relative risk, 1.95: 95 percent confi-
`dence interval. 1.09 to 3.43). The patients in the metho-
`trexate group received less prednisone overall than those
`in the placebo group (P=ti.o.'ad). The mean (:SE) score
`on the Crohn’s Disease Activity Index alter to weeks of
`treatment was significantly lower in the methotrexate
`group (1621-12) than in the placebo group {204:17.
`P=0.002). The changes in quality-of-iiie scores and se-
`rum crosomucoid concentrations were similar.
`in the
`methotrexate group, 16 patients (17 percent) withdrew
`from treatment because of adverse events (including
`asymptomatic elevation of serum aminotransferase in
`7 and nausea in 6). as compared with 1 patient (2 per~
`cent) in the placebo group.
`Conclusions.
`in a group of patients with chronically
`active Drohn's disease. methotrexate was more effec-
`tive than placebo in improving symptoms and reducing
`requirements for prednisone.
`(N Eng! J Med 1995;332:
`292-7.)
`
`CRDHN’S disease is an inflammatory disorder that
`commonly involves the small bowel and colon. Aim
`though corticosteroids are highly effective in improv-
`ing Sy’t‘t‘tptot‘t‘ts,"2 attempts to discontinue therapy are
`unsuccessfid in approximately 20 percent of patientsa
`Patients treated with corticosteroids continue to have
`
`both complications of the disease and chronic toxicity
`from the therapyfl” Either mercaptopurine or aaathio~
`prine is sometimes prescribed to reduce the require-
`ments for corticosteroids, but the toxicity of these med—
`ications is of concern.5'IO Low—dose cyclosporine is not
`effective in this situation.“"3 Alternative treatments
`are desirable.
`
`Methotrexate. an antiinfiammatcry drug, has been.
`used to treat_rlteuma1.oid arthritis"=”’ and psoriasisdr’r”
`After a report of improvement in patients with Crohn's
`disease who were treated with mtart-hotrexaim,‘R we fur-
`ther assessed the efficacy of methotrexate therapy in
`chronically active Crohn.’s disease.
`
`From the Dennrtmnnt of Medicine. Division of Gastrocntcrology. University of
`Calgary. Calgary. Altit- (LSJ: th= Dapnrtn'lent of Medicine. Section of Gastrocn-
`urology. University of Chicago. Chicago (REEL); the Department of Medicine.
`Division of Gastrocnterology. University of Alberta. Edmonton (ENE); the De-
`pttrtn'lnnt of Medicine. DiViaion of Gastroentcrology. McMastcr University.
`Hamilton. Ont. [El-L); the Dopnn'rnenta of Medicine (B.G.F.. J.W.D.M.. NIH.)
`and Epidemiology and Bioarariarica (BEE. J.Et.). University orWosiei-n Onto-to.
`London. Ont: die Department of Medicine. Division of Gnnrrnenterniegy. McGili
`University. Montreal (G.W.): the Department of Medicine. Division of Gastrono-
`terology. University cri'Toronto.Temn1ri (Aim... G.R.G.)-. and the Department of
`Madieinc. University of Ottawa. Ottawa. Clnt. (Perl). Address reprint requests to
`Dr. Feagan at.
`i5 CJF 12 University Hospital. 339 Mndeme’re Rd., London. ON
`NoA 5A5. Canada.
`Supported by mater-ch grants from the Medical Research Council of Canada.
`the Crohn's and Colitis Foundation of America dtrough donations from the David
`and Minnie Berk Foundation. and the Crcl'in‘s and Colitis Foundation of Canada.
`"The persons and institutions participating in the North American Crnhn'n
`Study Group are listed in the Appendix.
`
`METHODS
`
`A randomized. double-blind. placebowcontrelled study was con-
`ducted at seven university medical centers between November 1992
`and February l99'i. The protocol was approved by the investigations]
`review board at each center. All the patients gave written informed
`consent.
`
`Patients
`
`The medical records of potentially eligible patients were reviewed
`by a clinician. it radiologist, and a pathologist to confirm the diagno-
`sis ofClt‘ohn’s disease. Eligible patients had chronically active disease
`with at least three months of symptoms clespitn daily doses of at least
`12-5 ms of prcdnisonc with at least one attempt to discontinue treat-
`t‘fil‘tt'tt. Patients who had received long-term prcdnisone therapy at low
`closes (5910 mg pct“ day) were ineligible. as were critically ill patients.
`Patients With the following title Factors for methotrexatc toxicity”
`were ineligible: preexisting hepatic disease [biopsy-proved cirrhosis,
`chronic active hepatitis, or Serum aspartatc aminotransi'crase, bilirn-
`bin, or alkaline photphatasc concentrations at least twice the upper
`limit of” normal). renal dysfunction (scrum crcatinine concentration
`greater than 1.7 mg per deciliter [150 iamo] per literj). clinically im-
`portant lung disease as determined subjectively. systemic infection,
`pregnancy or a desire to become pregnant, history of cancer, high
`alcohol consumption (more than seven drinks per week), hypersensi-
`tivity to mcthotrcaatc, ct‘ytht‘ocfic macrocytosis, body weight 40
`percent higher than normal, diabetes mellitus. a requirement For non-
`steroidal antiinl'iamn'iatnry drugs, or the use of immunoaupprcasivc
`drugs in the past three months. Patients with an estimated survival
`of less than one year and. those Who were unwilling to comply with
`the protocol were also ineligible For the study.
`Base-Line Studies
`
`Three Weeks before randomization, potentially eligible patients
`wcrc instructed in the use of' a diary card to score the Crohn’s Dis-
`case Activity index.m'i' This index incorporates eight items: the num-
`ber oi liquid or very soil stools. abdominal pain. general well-being.
`catraintcatina] manifestations of Crohn’s disease, the use of opiates
`to treat diarrhea, abdominal mass, hematocrit, and hotly weight;
`these yield a composite score ranging from D to approximately 600.
`Higher scores indicate more disease activity; patients with scores or
`
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`Vol.. 332 No. 5
`"'
`' 4v
`
`METHDTREXATE FOR THE TREATMENT OF QROHN'S DISEASE
`
`293
`
`150 or less are considered to have inactive disease, whereas those
`with scores above 4.50 are critically iii. A clinic visit was scheduled
`one week later (two weeks before randomization}, at which time a.
`physical examination and blood tests were performed and base-line
`demographic information, scores on the Crohn's Disease Activity In-
`dex, and data on prednisonc use were obtained. Quality of life was
`measured with the Inflammatory Bowel Disease Questionnaire, a
`prcViously validated instrument with four parts (on bowel fitnction,
`emotional status, systemic symptoms, and social function); the total
`score on this index ranges from 32 to 2‘24. with higher scores indicat-
`ing better quality of life. The scores of patients in remission usually
`range from li'D to 19032-23 Patients were then treated with 2|] mg of
`prednisone once daily. A uniform dose was chosen to control for the
`effects of a primary determinant of disease activity and to permit a
`common starting point from which to measure differences in predni-
`some use between B'mupis,
`Randomizatlon
`
`The patients were randomly assigned, in a 2:1 ratio, to receive ei—
`thet 25 mg of methotrexate (Rheumatrcs, Lederle Laboratories,
`Pearl River, NY.) or a placebo weekly for 16 weeks if they had not
`required increases in their prednisone dose to 20 mg daily in the pre-
`ceding two weeks. Medication was given by intramuscular injection
`to ensure drug absorption and minimise nausea. The placebo was
`identical in appearance to the active drug. Between each patient’s
`visits to the study clinic, the injection was administered by a family
`physician. The investigators were unaware of the treatment assign-
`ments. Patients who were receiving 20 mg or more of prednisone dai-
`ly two weeks before randomization were randomized in a separate
`stratum (the highwprednisone stratum) from those who had their
`close increased to 20 mg (the low-prednisone stratum), Stratification
`was used because we predicted that patients who had required higher
`prednisone doses in the past to control symptoms would have a worse
`prognosis.
`
`Prednisons Therapy
`
`For two weeks after randomization. no attempt was made to de-
`crease the prcdnisone dose. After the first follow—up visit {at week 2),
`the daily dose of prcdnisone was decreased by 2.5 mg each week.
`Prednisonc was discontinued by week 12 of the study if the patient’s
`condition remained stable or improved. Patients whose condition
`worsened had their prednisone dosage increased to a maximal daily
`dose of 40 mg. After a dose increase, prednisone tapering was re-
`sumed at a rate of .5 mg a week until a daily dose of 20 mg was
`reached. The tapering regimen described above was then begun
`again.
`
`Other Twain-tents for Crohn’s Disease
`
`The patients were not permitted to use aminesalicylares, buoeso—
`nide,
`immunosuppressive agents, antibiotics {or pcrianal disease,
`tube feeding, parenteral nutrition. or topical aminosalicylatcs or our-
`ticosteroids. The use of hydrocortisone ointment was allowed for
`perianal disease.
`
`Follow-up
`
`Patients were seen 2 and a weeks after randomization and every
`‘1- wccka thereafter for 15 weeks. At each visit, the patient’s scores on
`the Crohn’s Disease Activity Index and the Inflammatory Bowel Dis-
`ease Questionnaire were calculated, and the serum orosomucoid con-
`centration (a laboratory measure of inflammatory activity) and the
`total prednisone dose were measured. Patients who discontinued
`their medication because of adverse reactions or treatment failure
`were followed in the same way as those who continued to receive in-
`jections.
`A PhYSician who had no contact with patients and did not assess
`outcomes. but who was aware of the group assignments, monitored
`serum aminotransferase concentrations each month and complete
`blood counts every two weeks. These results were not made available
`to the attending physicians and nurses. If letdtopenia developed
`{white-cell count, £3.8Xllli' per liter), the study drug was withheld
`for one week and the daily dose was decreased to 17.5 mg the follow
`ing week. The study drug was discontinued if persistent lcukopcnia
`developed. An identical algorithm was Followed if the serum amino-
`
`transferase concentrations increased to twice the upper limit of nor-
`mal. Matching dose adjustments were made in the placebo group.
`Outcome Measures
`
`The primary outcome measure was the presence or clinical masts.
`sion. as defined by the discontinuation of prednisone therapy and a
`score on the Crohn’s Disease Activity Index of =52l5i] points at the
`end of the trial [15 weeks). Secondary outcomes were the daily dose
`'of prednisone, the mean scores on the Crohn's Disease Activity Index
`and the Inflammatory Bowel Disease Questionnaire, and the mean .
`scrum orosomucoid concentrationmzi
`
`Statistical Analysis
`
`Statistical comparisons were made with 3A5 softwarcflfi A two-
`siclcd P value of 0.05 was the criterion for statistical significance. All
`analyses were performed according to the intention—ro-treat princi-
`ple. The medical center and stratum of the prednisone dose were
`used as the stratification variables. Ease-line characteristics megs.
`urcd on a nominal or ordinal scale were compared by Fisher's exact:
`test or the chi-square test, and continuous variables were compared
`by analysis of variance.
`the proportions of patients in the two
`In the primary analysis,
`study groups who successfully discontinued prednisone and remained
`in remission at Hi weeks were compared with use of the Mantel—
`Hfltl‘lml chi-“quart test Differences between the high-ptednisone
`and low-prcdnisono strata with regard to this outcome we“: mm-
`pared by logistic regression analysis. The daily prednisone dose,
`scores on the Crohn's Disease Activity Index and the Inflammatory
`Bowel Disease Questionnaire, and the mean serum otosomucoid con-
`centrations were compared by repeated-measures analysis of vari-
`ance.” In these analyses the overall effect of treatment was assessed
`by comparing trends over time; differences between study groups at
`the end of follow-up were assessed by comparing the values predicted
`for the two groups in linear modds. The distribution of prednisone
`use was skewed toward higher daily doses; repeated-measures analm
`ysis performed on ranks was used to analyze these data.
`.
`The number of patients withdrawn from therapy because of ad-
`verse reactions or treatment failure was compared between study
`groups by Fisher‘s exact test. The number of achrsc events was com-
`pared with the use of a Poisson regression model.”
`We anticipated that 20 percent of the patients receiving placebo
`would remain in remission. The randomisation of 135 patients al-
`lowed 80 percent power to detect an absolute difference ol" 9.5 percent
`in this outcome between study groups.
`
`RESULTS
`
`Between September 1992 and November 1993, 193
`patients were assessed to determine whether they were
`eligible for the study. The most common reasons for
`exclusion from the study were an inability or unwill-
`ingness to give informed consent
`(10 patients),
`the
`presence of risk factors
`for methotrcxate toxicity
`(8 patients), and a requirement for a contraindicated
`medication (7 patients). Sixteen patients were excluded
`for other reasons, leaving a total of 152 eligible pa-
`tients. Eleven of these patients were not randomized
`because of a refusal to participate by the patient or the
`patient’s physician (eight. patients), an increase in the
`prcdnisone dose above 20 mg before randomisation
`(two patients), or the occurrence of a new illness (deep
`venous thrombosis in one patient). The patients who
`were eligible but who were not randomized did not dif-
`fer significantly with respect to age, sex, and duration
`of disease from the patients who entered the study. Of
`the 14-] study patients, 94 were randomly assigned to
`receive methotrcxate and '47 to receive placebo. Eighty-
`nine patients (59 assigned to the methotrexate group
`and 30 to the placebo group) were included in. the high-
`
`
`
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`

`QEi'lv
`
`THE NEW ENG-LAND JOURNAL OF MEDICINE
`
`W.
`.
`
`d
`
`Feb. 2, 1.395
`A
`1..
`
`I Placebo
`
`H Mothotrexate
`
`50
`
` PercentageinRemissionits}
`
`P = 0.025
`
`P = 0.00:3“
`P = 0.92400-
`390-
`
`
`
`
`
`
`
`25
`
` O
`All Patients
`Low-Stratum
`High-Stratum
`Prsdniscna
`Prednisona
`
`prednisone stratum, and 52 patients (35 in the metho-
`trexate group and 17 in the placebo group) were in-
`cluded in the low-prednisone stratum. The base-line
`characteristics of the groups Were similar (Table 1).
`Primary Outcome
`
`No patients were lost to follow-up. The same propors
`tion of patients in the two groups (28 percent) was
`withdrawn from treatment prematurely (26 of 94 re-
`ceiving methotrexate, as compared with. 13 of 41-? re-
`ceiving placebo; P=0.99). The proportion of patients
`withdrawn because of treatment failure was significant—
`ly lower in the methotrexatc group (7 of 94 receiving
`methotrexate [7 percent], as compared with 11 of 4-7
`_ receiving placebo [23 percent]; P=0.014-). After
`l6
`weeks (Fig. 1) the proportion of patients who had dis-
`continued prednisone therapy and remained in remis—
`sion was higher in the methotrexate group than in the
`placebo group: 37 of 94- (39 percent) as compared with.
`.9 of =1?
`(19 percent; P=0.025; relative likelihood of
`entering remission, 1.05; 95 percent confidence inter-
`val, 1.09 to 3.48). In the high—prednisone stratum, this
`outcome occurred in 23 of 59 patients receiving meth-
`otrexate (39.0 percent), as compared with 3 of 30
`patients receiving placebo (10.0 percent; P=0.003;
`relative likelihood of entering remission, 3.013; 95 perm
`cent confidence interval, 1.00 to 9.4-3). In contrast,
`1‘1 of 35 patients receiving methotrexatc in the low-
`prednisone stratum (40 percent) had this primary
`outcome, as compared with 6 of 17 receiving placebo
`(35 percent; P=0.92; relative likelihood of entering rc»
`mission, 0.96; 95 percent confidence interval, 0.4-3 to
`2.17). When the percentage of response in the placebo
`group was subtracted from that in thc methotrexate
`group, the difference in therapeutic gain betWeen the
`prednisone strata (20 percent in the high-prednisone
`
`Table 1. Base-Line Characteristics of the Study Pationts.*%
`ME't‘Horrtrou'i-E
`Pmcsso
`[Ni-9+)
`(N m1?)
`
`Ci-mmcrsmsrie
`
`Age .._ yr
`Male sex
`Disease site
`
`Colon
`Small bowel
`Both
`Months since diagnosis
`Months of continuous disease activity
`Abdominal mass
`Previous surgery for Crohn‘s disease
`Cigarette smoker
`CDAI score
`IBDQ score
`Semi-n orosomucoid concentration —- 1113(le
`White-cell count —- Xlfl'h‘litcr
`Hemoglobin — gflirs-r
`Platelet count, — x]0”°.-'1iter
`
`34:1
`51 (54)
`
`15 (16}
`30 (32)
`45‘ [52)
`9323
`151-4
`13 (111)
`44 [47)
`46 (49]
`181211.
`16213.4
`93:10
`11.7203
`135=L6
`367111
`
`36 3:2
`26 (55)
`
`9 (15‘)
`B (11')
`.30 {54)
`931-12
`9.31:5
`3 (IS)
`22 {47)
`22 (47)
`190214
`15915.2
`95:5.0
`[1.51115
`1351,25
`2163:14-
`
`*E‘lus-mlnul values are means 151-1. and all other vniues are numbers of patients followed
`in parentheses by the percentage of patio-nu in the group. Pro-MD ror nil paired comparisons
`between star-Ins. CUM denotes the Crohn's Disease Activity Indian, and timid dis Inflammn-
`tory Bowel Disease Questionnaire. Higher scores on the CDM indicate greater disease activity,
`anti higher scores on the [BBQ indicate better quality oi‘tife.
`TBerun-I nrrwnrnucoiti concentratinnn inert-me with inflnmmmlun The nnn'nnl rnnge is 3: no
`Sit mg per tleeiiiter.
`
`Figure 1. Percentages of Patients in Fismiseion at Week 16. Ac-
`cording to Study. Group and Stratum of Daily Prednisona Dose
`.
`before Entry into the Study.
`The high-prednisone stratum was receiving a daily dose or more
`than 20 mg of prednisone, and the low~prseinisone stratum a dei-
`iy dose of 20 mg or less, more than two weeks before random-
`ization. Tho actuai percentages are shown above the bars. P vai-
`uas were derived by the Mantai—Hssnszei chi-square test, with
`adjustment tor study center. For the definition of remission, sea
`the Methods section under "Outcome Measures".
`
`stratum minus 5 per0ent in the low-prednisone stra-
`tum) was significant (P2004).
`Characteristics associated with the primary outcome
`Were examined by stepwise logistic regression with the
`variables of age, sex, prednisone stratum, site of dis-
`ease, scores on the Crohn’s Disease Activity Index and
`the Inflammatory Bowel Disease Questionnaire, serum
`orosomucoid concentration, and smoking status. The
`base-line score on. the Crohn’s Disease Activity Index
`was inversely associated with the probability of dis-
`continuing prednisone and remaining in remission
`(P = 0.04; relative likelihood of entering remission, 1.30
`for each 50npoint decrease in the score on the index).
`The other characteristics were not significantly associ-
`ated with the primary outcome.
`Pradnisone Use
`
`The patients in the methotrexate group used less
`prednisone overall
`than those in the placebo group
`(P=0.025). The difference in prednisone use was de-
`tectable in the 90th percentile of the distribution (high-
`er prednisone dose) by week 4 and in the 50th percen-
`tile by week 12 (Fig. 2). This difference Was due to the
`increased use of high-dose prednisone therapy in the
`patients assigned to receitre placebo whose condition
`worsened in the later weeks of the study. The difference
`was greatest from. week 12 through week 16.At the end
`of the study, the 50th, 75th, and 90th percentiles of the
`daily prednisone dose in the methotrcxate group were
`0, 12.5, and 20 mg, respectively, as compared with 5,
`20, and 30 mg in the placebo group (P=0.003).
`Disease Activity
`
`The average of the mean (ISE) scores on the
`Cirohn’s Disease Activity Index (Fig. 3) over the entire
`follow-up period was significantly lower in the metho-
`
`
`
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`

`METHDTREXATE FOR THE TREATMENT OF GRDHNE DISEASE
`
`295
`
`v1 332 No.5
`or
`,_
`
`_
`50th Percentile
`
`30
`25
`
`ED
`
`15
`
`the mean quality-of—Iilie scores was higher in the moth"
`otrexate group (methotrexate, lSEiQ; placebo, 155:3;
`PfiOflL—ll). At 15 weeks the mean values were lfiQi‘l- in
`the methotrexate group and 1.51 :6 in the placebo
`group (Pf-10.002). Improvement in, quality of life was
`evident in. all four parts of the Inflammatory Bowel Dis—
`ease Questionnaire (Pa‘ODI for all comparisons).
`The mean. serum orosomucoid concentrations de-
`creasod in the methotrexate group and increased in the
`placebo group (Fig. 3). The average of the mean proso-
`mucoid concentrations in patients treated with metho-
`trexatc was 8822 mg per deciliter, as compared with
`97:3 mg per deciliter in patients receiving placebo
`(P= 0.007). There were significant differences between
`the groups from 4 weeks onward; at 16 weeks, the val-
`ues were 82i3 in the methotrcxate group and Qimfi in
`the placebo group (P =0.003).
`Adverse Effects
`
`Among 94 patients treated with methotrcxate, 15 (l 7
`percent) withdrew from treatment because of adverse
`events, as compared with ] of 4,7 patients receiving
`placebo (2 percent, P=0.012). The patient in the pia-
`cebo group had an episode of polyneuropathy that
`required hospitalization. The reasons for withdrawal
`in the methotrexate group were as follows: asympton
`matic elevation of serum aminotransfcrasc concentra—
`tions (seven patients), nausea (six), skin rash (one),
`pneumonia probably due to myeoplasma (one), and op-
`tic neuritis (one). Table 2, shows the frequency of drug-
`related adverse events that were not severe enough to
`warrant discontinuation of the study drug. The patients
`in the methotrexate group had 2.5 such events per pa-
`tient, as compared with 2.9 events per patient in the
`placebo group (P=0.35).
`
`DISCUSSION
`
`We found that methotrexatc was an effective and
`well-tolerated treatment for patients with chronically
`active Cirohn’s disease. At the time of randomization,
`the patients had moderately active disease despite re-
`ceiving 20 mg of prednisone each day. After treatment
`with methotrexate, significantly more patients were
`able to discontinue prcdnisone use than were patients
`receiving placebo. Because long-term. prednisone ther-
`apy is associated. with a variety of harmful consequenc-
`es, methotrcxate represents an alternative treatment
`for patients who do not tolerate prednisone or in whom
`symptoms of Crohnis disease persist despite a modera
`ately high dose of prednisone.
`Although they received less prednisone, the patients
`who received methotrexate had improvement with re‘
`gard to disease activity and were more likely to enter
`clinical remission. After 15 weeks of treatment,
`the
`mean score on the Crohn's Disease Activity Index
`(1621—12) approximated that in. patients with inactive
`disease (5.150). Improvement in symptoms as assessed
`by the Crohn’s Disease Activity Index and the Inflam-
`matory Bowel Disease Questionnaire was detectable by
`six weeks. This rapid response is in. contrast to the rcl~
`ativcly slow onset (three to six months) of therapeutic
`
`1D
`PrednisoneDose{mg}
`Daily
` : Placebo
`
`
`'I' Methotrexate
`
`
`oa4ss1o12141s
`
`Weeks since Flandornization
`
`Figure 2. The 50th. 75th. and 90th Percentiles of the Daily Predn
`nisone Dose in the Study Patients, According to Group.
`The daily prednieone dose was 20 mg for all patients from week
`2 before randomization until week 2 after randomization. when it
`was tapered by 2.5 mg each week. Patients whose condition im-
`proved or remained stable discontinued prednisone therapy at
`week 12. Patients whose condition worsened at any time during
`the study were treated with highndose prednisone [20 to 4-D mg
`daily). The use of higher daily doses in these patients skewed
`the distribution of prednisone doses toward higher values, mak-
`ing a comparison based on means inappropriate. The overall
`Pvalue was 0.026 by a repeated-measures log-rant: test; the
`P value at week 16 was 0.003 by the log-rank test.
`
`-
`
`than in the placebo group
`trexate group (170:?)
`(193i1?, P=0.003). There were significant differences
`from week E- onward; at the end of the study; there was
`a difference of 4-2 points ([52:12 in the methotrcxatc
`group vs. 204i” in the placebo group, P=0.002).
`At base line, the groups’ mean quality—oF-life scores
`were similar (methotreJ-tateJ 152:17; plaeeimJ 159:5).
`After four weeks of therapy, a. significant difference be-
`tween.
`the groups developed (Fig. 3). The average of
`
`
`
`Page 4 of 6
`
`Page 4 of 6
`
`

`

`2'95
`
`THE NEW ENGLAND JOURNAL or" MEDICINE
`
`p.313 2 1995
`a-
`
`Table 2. Adverse Events in the Study Patients Ae-
`cordlng to Gi‘i‘siip.t
`METHGMEKATt:
`.
`Phil-CEBU
`[N H 941
`(N _ 117)
`
`ADVERSE. Evflrri'
`
`no. afpfl'i'irni's' (”It ofgroup]
`
`Nausea and vomltlng
`Symptoms of cold
`Abdominal pain
`Hendnche
`Joint pain or anlirsigis
`Fatigue
`influenza-like illness
`Dim-rhea
`Abdominal bloating or distension
`Skin rash
`Insomnia
`Other
`
`40 {42]
`22 (2.3)
`17 (13)
`16 (1'7)
`1.5 (16)
`15 (16)
`10 [11)
`'i‘ (7)
`6 (t5)
`5 (15)
`2 (2)
`41 (45)
`
`13 (33}
`9 (19]
`i2 (26)
`5 [I 11
`G [13)
`5 (ll)
`IS (13)
`4 (3)
`3 (6}
`2 (4)
`'2 (4)
`20 [42)
`
`“Adverse events related to treatment wlth the study drug (MI; were not
`severe annual! tn warrnnr. discontinuation ofthe study drug it“! shown. Put
`limit may have had more than one adverse event.
`
`the occurrence of this complication in one of our pa-
`tients was probably due to chance, further study of pa-
`tients with Clrchns disease treated with methotrexate
`will be needed to exclude a causal relation. The risk
`
`of liver disease with long-term methotrexate therapy
`in patients with Crohn’s disease is not known. To mine
`imize the risk of hepatic toxicity, we discontinued.
`treatment if patients had persistently elevated serum
`aminotransferaacs, but this may have been unneces-
`sary. ‘It might have been possible, for example, to re—
`duce the close of medication and follow the patients.Em
`However, in the absence oi“ data specific to patients
`with Crohn’s disease, we believe that the reeommem
`dations for the use of methotrexate in rheumatoid ar-
`thritis should be followed. 3' 32 These recommendations
`
`include not using. the drug1n patients with risk factors
`for hepatic toxicity (alcohol abuse, obesity, or preex-
`isting liver disease), monitoring serum aminotransfer~ ‘
`ass and albumin. concentrations at monthly intervals,
`and performing a liver biopsy in. patients with perv
`sistent enzyme elevations or‘ hypoalbuminemia. Addi—
`tional risks associated with methotrexate are those of
`
`hypersonsitivity pneumonitisf:1 bone marrow depres-
`sion,“ and teratogenicity.35
`Effective drug therapy to maintain clinical remission
`in patients with Clrohn’s disease is currently unavail-
`able.5m Maintenance therapy is a research priority. Boa-
`desonide,“ the new aminesalicylates,BB and methotrcx-
`etc should be evaluated in this regard. We are studying
`the efficacy and safety of 15 mg of methotrexate once
`weekly for the prevention of relapse of Crohn’s disease
`in patients with quiescent disease.
`In conclusion, in cut group of patients, methotrexatc
`improved symptoms rapidly and reduced the require-
`ment for prcdnisonc in patients with chronically active
`Crohn’s disease.
`
`We are indebted to the patients who participated in the study, to
`Karen Taylor‘i'flolmer For assistance in preparing the manuscript. to
`Beckman Scientific for providing orosomucoid-assay kits, to Lederie
`Laboratories For mctl'lotrexatc, and to the Upjohn Company of Can-
`ada for predniscne.
`
`Figure 5. Disease Activity as Assessed by the Crohn'e Disease
`Activity index (CDAI) the Inflammatory Bowel Disease Quee-
`
`tionnaire (IBDQ). and the Serum Drosomucoid Concentration.
`According to Study Group.
`Values are means iSE. Higher scores on the CDAI indicate
`worse disease; scores of 15:1 or less are found in patients in re-
`mission. Higher scores on the 18121121 indicate better quality of life.
`P values for the overall comparisons between groups were de-
`rived by a repeated-measures analysis of variance; those at 16
`weeks were derived by a simple analysis of variance. All analy-
`see were adjusted for base-line values.
`
`
`
`Page 5 of 6
`
`effect with the antimetabolites aza1Lhiopri1-1e and mer~
`captoputinc.
`There was a significantly greater benefit of treatment.
`in the high—prednisonc stratum and in patients with
`lower scores on the Grohn’s Disease Activity Index at
`base line. It was not, however, our hypothesis before
`the study that methotrexatc would have such a differ-
`ential effect, and these analyses of subgroups should be
`interpreted with caution.
`Methotrexatc treatment appeared to be safe .in this
`group of patients. A previous case report described
`optic neuritis in association with methotrexatc thera~
`py in a patient with psoriasis.29 Although we believe
`
`P:- 0.0
`P OJ!
`
`03 overall
`02 at week 15
`
`
`
`
`Cl
`
`2
`
`4
`
`B
`
`B
`
`in
`
`12
`
`1d
`
`16
`
`Petaooi overall
`F'fitiflm at week 16
`
`250
`
`225
`
`200
`
`E 8
`
`ED
`
`E 11's
`1:1
`'0
`
`150
`
`125
`
`200
`
`on
`E 175
`o
`co
`
`
`
`2
`
`4
`
`1'3
`
`13
`
`10
`
`12
`
`14
`
`15
`
`CI
`
`150
`
`125
`
`110.
`
`100
`
`F' = 0.00? overall
`P “e (1003 at week 1EI
`
`//‘l\
`
`‘ .... l
`
`I Placebo
`I Meihotreieate
`
`1—6—1
`
`I‘d—q
`
`
`D
`2
`4
`6
`8
`‘ID
`1 2
`14
`16
`
`Weeks since Randomization
`
`so
`mC:
`
`'-lO
`
`8E
`
`
`
`SerumUrosomueolcl[mgi'dii
`
`Page 5 of 6
`
`

`

`Vol, 332 No. 5
`-5-
`
`METHOTRE‘XATE FOR THE TREATMENT OF GRUHN‘S DISEASE
`
`297
`
`.APPENDIX
`The Following persons and institutions participated in the North
`American Crohn's Study Group.
`Steering Committee: E. .Feagan (chair). RN. Fedorak, G. Greenborg,
`S. Hat-inner. EJ. IrtdntJ.W.D. MoDoualciJ. Roohon, A.H. Steinhart.
`I... Sutherland, G. Wild. and M. Hopkins. Adjudication Committee.-
`B. Fettgan, R. Gillies, and 1WD. McDonald (chair). Operations Com-
`mittee: B. Feagsrt (ehnir),,I.W.D. MeDonaid,j. Reel-ion, and M. Hop-
`kins. Extemais'ldoimgr Committee: R. Kozarck. A. Laupacis,J. Single-
`tort. o. Sackett {chair}, r. Tugwcll, and G. Wells. Unbt'indnd clinicians.-
`V Bsin, G. Geller. C. Ghent (their). 13.}. Heatheott, J. Lemairt,
`G. Sweeney, and C. Watts. Com‘dt'nnting crates: L. Cameron, M. Hop-
`kins, E. Seglenielts, and K. Taylor-Dolmen
`Investigators {listed atone-ring to center and number grfiatie'nts enrolled).-
`University ofAlhtrta, Edmonton (3 l) ._ KN. Parlor-nit, T. Alexander.
`D. Fisher, L. Jewell, P. Kirdeikis, E. Lalor, S. Maeiejko, M. Millan,
`D. Sadowslti, .E. Semiaeher, R. Shel-haniult, A. Thomson, and B. Ya-
`cyfihi'n; University of Western Ontario, London, Ont. (30) — P. Ade
`urns, W Barnett, IVI. Bolsheit-n. D. 1Bondy, R. Eberhard, B. Fcagtm,
`P. Gilmore, M. Hopkins, j. Howard. D. Lloyd. J.W.D. McDonald,
`L. Meyer. T. Ponich, H. Preiirsaitis, I. Frolropiw, it. Reynolds. 1'... Val-
`herg, and W. Watson; McMaster University, Hamilton, Ont. (l9) —
`M. Castelli, 3. Collins, K. Croitotu, M. Donnelly. R. Hunt, EJ. Irvine,
`B. Lumb, D. Morgan, R. Rosstnnrt. B. Selena. and T. Staten: MeGil]
`University, Montreal (19) — E. Alpert, DP. Cleland, D. Daly. M.-C.
`Dugout, M. Jahlosri, D. Kinnear. M. Lithter. D. Mills, 5. Mishitin,
`P. Mlynarylt, H. Vaupshns, and G. Wild; University of Calgary, Dal-
`gsry, Alta.
`(16) — N. Hershfielcl, K. MaeCisnnell. _]'. Meddings,
`L- Price, N. RaCiCQIl. E. Shaffer, and I... Suthefland; Ufijwrsity at" Tap.
`(into, Toronto (.14) —_]'. Baker, 1.. Cohen, G. Greenberg, K. Jccjeeb-
`boy. 3. Mikelainis. A. Newman, 3. Pearen, F. Saihil. and AH. Stein-
`hart; University of Chicago. Chicago (l2) — I. Hanan, S. Hanauer,
`P. Schultz, andJ. Young.
`
`REFERENCES
`
`l. Summers kW. Swim DM. Sessions .TT' Jr. et el. Nntionnl Cooperntive
`Crohn's Disease Shitty: results of drug treatment. Gash-oenterology 1979:
`77