I EDIC
`
`LIJAR.19.96
`
`f VOLUME 10 NUMBER3
`W1 AL375
`tr.
`1996
`NO.3 (cid:9)
`9 51 11 ------- SEQ: 5R0057930
`- 1
`(cid:9) ALIMENTARY PHARMACOLOGY
`07/01/96
`AND THERAPEUTIC: (cid:9)
`
`li
`
`CODEN APTHEN ISSN 0269-2813
`
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`411 C
`Pe
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`fkilkoiloituipotst1 jjoitorw ti Atoctikti
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`
`Blackwell
`Science
`
`Wyk EtRITOcgiAL
`LIBRARY OF
`MEDICINE
`
`this
`
`Lsws.
`
`Ex. 1083 - Page 1
`
`

`

`Alimentary Pharmacology & Therapeutics
`
`Editors
`Professor R E Pounder London
`Professor W L Peterson Dallas
`
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`Birmingham
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`
`It (cid:9) Yts'a• i=1 `.'
`
`Ex. 1083 - Page 2
`
`

`

`Alimentary
`Pharmacology
`& Therapeutics
`
`VOLUME 10 NUMBER 3 JUNE 1996
`
`Contents
`
`217 Letter from the Editors. R. E. POIINDER &
`W. L. PETERSON
`219 Review article: Renal circulatory changes in
`cirrhosis — pathogenesis and therapeutic prospects.
`E. H. FORREST, R. JALAN & P. C. HAYES
`233 Clinical economics review: gastrointestinal disease
`in primary care. R.11. JONES
`241 Ranitidine bismuth citrate: a novel anti-ulcer
`agent with different physico-chemical
`characteristics and improved biological activity to
`a bismuth citrate—ranitidine admixture.
`A. A. McCOLM, A. McLAREN, G. KLINKERT,
`M. R. FRANCIS, P. C. CONNOLLY, C. J. GRINHAM,
`C. J. CAMPBELL, S. SELWAY & R. WILLIAMSON
`251 Ranitidine bismuth citrate plus clarithromycin is
`effective for healing duodenal ulcers, eradicating
`H. pylori and reducing ulcer recurrence.
`W. L. PETERSON, A. A. CIOCIOLA, D. L. SYKES,
`D. J. McSORLEY, D. D. WEBB & THE RBC
`H. PYLORI STUDY GROUP
`263 Omeprazole—amoxycillin versus omeprazole—
`amoxycillin—clarithromycin in the eradication of
`Helicobacter pylori. J. C. DELCHIER, I. ELAMINE,
`D. GOLDFAIN, S. CHAUSSADE, P. BARTFIELEMY
`& J. P. IDSTROM
`269 Prospective evaluation of the macrolide antibiotic
`dirithromycin for the treatment of Helicobacter
`pylori. L. LAINE, C. STEIN, F. GARCIA,
`M. TRUJILLO & R. ESTRADA
`275 Comparison of two low-dose one-week triple therapy
`regimens with and without metronidazole for cure of
`H. pylori infection. B. H. JAUP & A. NORRBY
`279 A seven-day Helicobacter pylori treatment regimen
`using clarithromycin, omeprazole and tripotassium
`dicitrato bismuthate. M. J. WELDON,
`A. BROADBENT, S. CHAMBERS, R. MISTRY,
`L. RANGANATH & S. R. GOULD
`
`A
`1308 (4-61 137
`11(,
`03/26/9/ (cid:9)
`
`MRB
`
`Printed in Great Britain by the University Press, Camber o,at a i I
`
`Suaien 27 7 (cid:9)
`
`Laws
`
`285 Low-dose omeprazole plus clarithromycin and either
`tinidazole or amoxycillin for Helicobacter pylori
`infection. A. TURSI, G. CAMMAROTA,
`M. MONTALTO, A. PAPA, G. VENETO, L. CUOCO,
`F. TRUA, G. BRANCA, G. FEDELI & G. GASBARRINI
`289 Effect of proton pump inhibitors on the detection of
`Helicobacter pylori in gastric biopsies. W. DICKEY,
`B. D. KENNY & J. B. McCONNELL
`295 Pharmacokinetic and pharmacodynamic
`interactions between omeprazole arid amoxycillin
`in Helicobacter pylori-positive healthy subjects.
`W. POMMERIEN, M. BRAUN, J.-P. IDSTROM,
`M. WRANGSTADH & W. LONDONG
`303 Dose—response of omeprazole combined with
`amoxycillin on duodenal ulcer healing and
`eradication of Helicobacter pylori.
`W. POMMERIEN, V. SCHULTZE, B. BRADEN,
`B. LEMBCKE, M. WRANGSTADH & W. LONDONG
`309 Methotrexate for the treatment of refractory
`Crohn's disease. M. LEMANN, C. CHAMIOT-
`PRIEUR, B. MESNARD, M. HALPHEN, B. MESSING,
`J.-C. RAMBAUD, J.-P. GENDRE, J.-F. COLOMBEL
`& R. MODIGLIANI
`315 Picotamide inhibition of excess in vitro
`thromboxane B2 release by colorectal mucosa in
`inflammatory bowel disease. C. E. COLLINS,
`M. J. BENSON, W. R. BURNHAM
`& D. S. RAMPTON
`321 Strengths and limitations of the Crohn's disease
`activity index, revealed by an objective gut lavage
`test of gastrointestinal protein loss. S. ACCIUFFI,
`S. GHOSH & A. FERGUSON
`327 Distribution of mesalazine enemas in active arid
`quiescent ulcerative colitis. A. A. VAN
`BODEGRAVEN, R. 0. BOER, J. LOURENS,
`H. A. R. E. TUYNMAN & J. W. SINDRAM
`
`b
`
`Blackwell
`Science (cid:9)
`
`Continued on inside back cover
`
`0269-2813 (cid:9)
`
`99606 )10 : 3; 1-N
`
`Ex. 1083 - Page 3
`
`

`

`COOtinued from back cover
`
`333 How accurate is the determination of blood in
`gastric juice? Comparison of peroxidase and
`porphyrin methods. K. L. WOODS, C. KEIFE
`& D. Y. GRAHAM
`339 The role of acid in the pathogenesis of
`indomethacin-induced gastric antral ulcers in the
`rat. N. M. CLAYTON, I. OAKLEY, L. V. WILLIAMS
`& M. A. TREVETHICK
`347 High-dose ranitidine for the prevention of
`recurrent peptic ulcer disease in rheumatoid
`arthritis patients taking NSAIDs. S. TEN WOLDE,
`B. A. C. DIJKMANS, M. JANSSEN, J. HERMANS
`& C. B. FL W. LAMERS
`353 Diagnostic interpretation of the 24-hour
`intragastric pH-mctry using a pattern recognition
`method. B. HUNYADY, I. JURICSKAY,
`F. PAKODI, Cs. HORVATH & Gy. MOZSIK
`359 Twenty-four-hour intragastric pH profiles and
`pharmacokinctics following single and repeated
`oral administration of the proton pump inhibitor
`pantoprazole in comparison to omeprazole.
`M. HARTMANN, U. THEIE, R. HUBER,
`R. LUHMANN, H. BLIESATH, W. WURST
`& P. W. LUCKER
`367 The effects of omeprazole 20 and 40 mg twice daily
`on intragastric acidity in duodenal ulcer patients.
`V. SAVARINO, G. S. MELA, P. ZENTILIN,
`M. R. MELE, S. VIGNERI, C. MANSI & G. CELLE
`373 Ranitidine 300 mg twice daily and 150 mg four-
`times daily are effective in healing erosive
`oesophagitis. M. T. SILVER, R. H. MURDOCK Jai,
`B. B. MORRILL & S. 0. SUE
`3S 1 A trial of lansoprazole in refractory gastric ulcer.
`C. J. VAN RENSBURG, J. A. LOUW, A. H. GIRDWOOD,
`A. E. SIMJEE & I. N. MARKS
`
`387 The management of refractory gastric ulcer using
`H,-receptor antagonists. G. S. RAJU,
`K. D. BARDHAN, C. ROYSTON & J. BERESFORD
`397 Efficacy and tolerability of pantoprazole 40 mg
`versus 80 mg in patients with reflux oesophagitis.
`C. J. VAN RENSBURG, P. J. HONIBALL,
`H. DE K. GRUNDLING, J. H. VAN ZYL, S. K. SPIES,
`F. P. ELOPE, A. E. SIMJEE, I. SEGAL, J. F. BOTHA,
`A. K. CARIEM, I. N. MARKS, I. THERON
`& T. D. BETHKE
`403 Symptomatic improvement with one-year
`cisapride treatment in neuropathic chronic
`intestinal dysmotility. M. CAMILLERI, R. K. BALM
`& A. R. ZINSMEISTER
`411 Effect of dexloxiglumide and spiroglumide, two
`new CCK-receptor antagonists, on gastric
`emptying and secretion in the rat: evaluation of
`their receptor selectivity in vivo.
`C. SCARPIGNATO, I. KISFALVI, M. D'AMATO
`& G. VARGA
`421 Effect of erythromycin on human biliary motility.
`T. WEHRMANN, C. PFELTZER & W. F. CASPARY
`427 Gastric emptying of pancreatin granules and
`dietary lipids in pancreatic insufficiency.
`P. NORREGAARD, J. LYSGAARD MADSEN,
`S. LARSEN & H. WORNING
`433 Pancreatin preparations used in the treatment of
`cystic fibrosis—lipase content and in vitro release.
`M. P. WALTERS & J. M. LITTLEWOOD
`441 Sucralfate gel versus placebo in patients with non-
`erosive gastro-oesophageal reflux disease.
`B. SIMON, G.-P. RAVELLI & H. COFFIN
`447 Letters to the Editors. V. SAVARINO, G. S. MELA
`& S. VIGNERI and J. HENDEL, L. HENDEL
`& S. AGGESTRUP
`
`al
`
`at • -
`
`i = - tL 3ws
`
`Ex. 1083 - Page 4
`
`

`

`Aliment Pharmacol Ther 1996: 10: 309-314.
`
`Methotrexate for the treatment of refractory Crohn's disease
`
`M. LEMANNt, C. CHAMIOT-PRIEURt, B. MESNARDt, M. HALPHEN§, B. MESSING§,
`J.-C. RAMBAUD§, J.-P. GENDRE1F, J.-F. COLOMBEL* & R. MODIGLIANIt
`Departments of Gastroenterology, t Hopital Saint-Louis, Paris, HOPital Claude Huriez, Lille, § HOpital Saint-Lazare and
`HOpital Rothschild, Paris, Prance
`
`Accepted for publication 3 January 1996
`
`SUMMARY
`
`Background: Previous studies suggested that
`methotrexate has beneficial effects in patients with
`Crohn's disease. We report our experience with this
`agent in patients with chronic active Crohn's disease
`who previously failed to improve with conventional
`treatment, including azathioprine in most cases.
`Methods: Between June 1988 and June 1992, 39
`patients with refractory Crohn's disease were treated
`with methotrexate. In patients with active disease,
`clinical remission was defined by a Harvey—Bradshaw
`index of less than 4. For patients also taking
`corticosteroids, the dates of remission and complete
`steroid withdrawal were recorded. For patients who
`
`achieved clinical remission, and those in clinical
`remission when methotrexate was started, the relapse
`rate on methotrexate therapy was noted.
`Results: In the 37 patients with active disease at
`methotrexate initiation, the probability of remission
`was 72% at 3 months. The probability of remission
`and steroid withdrawal was 42% at 12 months. In
`patients on clinical remission, the probability of relapse
`on methotrexate was 58% at 12 months. Twenty-two
`patients experienced side-effects, but these only
`warranted methotrexate discontinuation in four cases.
`Conclusions: Methotrexate appears effective in most
`patients with refractory Crohn's disease and its short-
`term toxicity is acceptable, but the long-term benefit
`seems more limited.
`
`INTRODUCTION
`
`Methotrexate is one of the oldest cytototoxic drugs which
`acts as a potent inhibitor of folic acid, an essential
`cofactor for de novo purine synthesis. Because of its anti-
`inflammatory and immunosuppressant properties, it has
`been used at low doses to treat various non-neoplastic
`immunologically mediated diseases, including psoriasis,
`rheumatoid arthritis and polymyositis/dermatomyositis.
`It was also recently proposed for the treatment of
`inflammatory bowel disease.' The results of preliminary
`studies suggest that methotrexate may have beneficial
`effects in patients with refractory chronic ulcerative
`colitis or Crohn's disease.1-5 A recent placebo-controlled
`study in patients who had chronically active Crohn's
`
`Correspondence to: Dr M. Le771111111, Service de Gastroenterologie, Hopital
`Saint-Louis, 1 Avenue Claude Vellefaux, F75010, Paris, France.
`
`disease demonstrated that intramuscular methotrexate
`(25 mg once a week) for 16 weeks was more effective
`than placebo in improving symptoms and reducing
`requirements for steroids.'
`We report here on our experience with methotrexate in
`the management of patients with chronic active Crohn's
`disease who previously failed to improve with conven-
`tional treatment, including azathioprine in most cases.
`
`PATIENTS AND METHODS
`
`Patient population
`
`Between June 1988 and June 1992, 39 patients with
`Crohn's disease (23 females and 16 males) were treated
`with methotrexate in the four French hospital centres
`participating in this study. The 39 patients represented
`3% of the patients with Crohn's disease seen in these
`
`© 1996 Blackwell Science Ltd
`
`309
`
`Thia rata ial as ::sia3
`
`Laws
`
`Ex. 1083 - Page 5
`
`

`

`310 (cid:9) M. LEMANN et al.
`
`centres during the same period. Their charts were all
`reviewed by the same physician (C.C-P.). Diagnosis of
`Crohn's disease was based on clinical, endoscopic,
`radiological and histological criteria.' The mean age of
`the patients was 29.2 ± 8.4 years (range, 17-43 years).
`The mean duration of disease was 6.4 + 3.7 years. One
`patient had jejunitis (2 %), two had ileitis (5%), 22 had
`ileocolitis (56%) and 14 had colitis (36%). Twelve
`patients (31 %) had also had perianal lesions, but only
`four of them had active lesions at the time of metho-
`trexate initiation. Twenty-two patients (56%) had under-
`gone prior small bowel, ileocolonic and colonic resection
`(n = 11, 8 and 3, respectively). All patients had been
`treated with corticosteroids for a mean period of 7.3 ± 4.7
`months, but, at the time of methotrexate initiation, only
`24 patients (62 %) were still taking prednisolone at a
`mean daily dose of 20.5 ± 21.0 mg (range, 5-
`70 mg/day). Fifteen of them were dependent on
`steroids and nine were resistant to steroids ; six of these
`nine were having concomitant parenteral nutrition
`(n = 3) or enteral nutrition (n = 3) at the time of
`methotrexate initiation. Fifteen patients (38%) were not
`given corticosteroids when methotrexate started, in order
`to avoid a new course of steroids. Thirty-six patients
`(92 %) had previously taken azathioprine, but were no
`longer on this therapy because of drug intolerance
`(n = 16) or clinical failure (n = 20). All the patients had
`been previously treated with sulphasalazine or had
`mesalazine treatment during the course of their disease,
`and some of them had been treated with metronidazole,
`but none of them were still taking these drugs at the time
`of methotrexate initiation.
`
`Methotrexate therapy
`
`The planned regimen was to give patients one intra-
`muscular injection of 25 mg methotrexate per week for
`at least 3 months. If improvement was evident by the end
`of that time, the dose was given orally and tapered to a
`minimum of 7.5 mg per week, according to the scheme
`proposed by Kozarek et a1.1 For patients still taking
`corticosteroids when methotrexate was started, an at-
`tempt was made to reduce the daily dose as soon as
`possible, depending on their clinical status.
`
`Evaluation of treatment outcome
`
`Patients were seen regularly and none was lost to
`follow-up. At each visit, clinical status was recorded and
`
`Thit:
`att-
`
`a physical examination performed. Laboratory investi-
`gations included blood cell counts and liver function
`tests. Disease activity was judged according to the
`Harvey—Bradshaw five-item Clinical Activity Index,'
`ranging from 0 (no disease) to 15 (severe disease). In the
`37 patients with active disease at the start of metho-
`trexate (Harvey—Bradshaw index 4), clinical remission
`was defined by a Harvey—Bradshaw index of less than 4.
`Partial response was defined as a decrease in the index
`without clinical remission. For the 24 patients who were
`taking corticosteroids at the start of methotrexate, the
`dates of clinical remission and complete steroid with-
`drawal were also noted. For patients who achieved
`clinical remission on methotrexate, and those who were
`in remission on steroids at the start of methotrexate
`(n = 2), the relapse rate on methotrexate maintenance
`therapy was recorded, as well as in 11 patients who
`stopped the treatment for reasons other than relapse.
`Lastly, the achievement of the specific therapeutic goals
`listed below was also evaluated according to the method
`proposed by Present et al.° and modified by O'Brien et al.1°
`based on the definition of specific therapeutic goals for
`each patient. For the present series, these goals com-
`prised: (a) control of active disease, (b) steroid sparing for
`patients who required more than 10 mg/day of pred-
`nisone when the methotrexate was started (the aim was
`to reduce the dose to less than 10 mg/day), (c) prevention
`of clinical relapse for patients who had achieved complete
`remission, (d) perianal fistula healing and (e) control of
`extraintestinal manifestations.
`
`Statistical analysis
`
`For patients with active disease at the start of metho-
`trexate treatment, the probability of complete remission
`was calculated using the Kaplan—Meier method."
`Follow-up began on the day methotrexate was started
`and continued until clinical remission, until the last
`examination or until the day of methotrexate with-
`drawal. For patients on methotrexate maintenance
`therapy, the probability of relapse was calculated using
`the same method. Follow-up began for them on the day
`of clinical remission, and continued until clinical relapse
`(Harvey—Bradshaw index 4), the last examination or
`the day of methotrexate withdrawal. Probabilities were
`expressed with their 95 % confidence interval (95% CI).
`Quantitative data were expressed as means ± standard
`deviation. The characteristics of the patients who re-
`lapsed were compared with those of the patients who
`
`© 1996 Blackwell Science Ltd, Aliment Pharmacol Ther 10, 309-314
`
`Ex. 1083 - Page 6
`
`

`

`remained on remission, using the x2 test. A P value of less
`than 0.05 was considered significant.
`
`RESULTS
`
`Methotrexate dose and duration
`
`Initially, all patients were given methotrexate as an
`intramuscular injection, at a weekly dose of 25 mg for 36
`of them, and of 20 mg for the remaining three. After 3, 6
`and 12 months of treatment, the average weekly doses of
`methotrexate were 23.0 + 2.1, 17.5 + 7.2 and
`12.5 ± 6.1 mg, respectively, and the proportions of pa-
`tients given methotrexate orally were 3, 69 and 100%,
`respectively. The median duration of methotrexate ther-
`apy was 5.5 months (range, 2 weeks-24 months). Only
`six patients were treated for more than 1 year. Metho-
`trexate therapy was stopped for the following reasons :
`treatment failure in 20 patients, either primarily (n = 4)
`or after an initial improvement (ri = 16), side-effects in
`four patients; other reasons in eight patients.
`
`Clinical response in patients with active disease
`
`Twenty-six of 37 patients with active disease at metho-
`trexate initiation achieved clinical remission. After 1 and
`3 months of treatment, the probabilities of remission
`were 53% (95% CI, 36-69%) and 72% (95% CI,
`57-88 %), respectively (Figure 1). The period required to
`achieve remission ranged from 2 weeks to 6.5 months,
`but most patients who achieved remission did so within
`3 months. Six patients exhibited a partial response. Two
`
`100 -
`90 -
`80 -
`70 -
`60 -
`50 -
`40 -
`30 -
`20 -
`10-
`0 (cid:9)
`
`
`.0
`"(T)) E
`0
`0
`
`.0
`0 a-
`
`2 3 4 5 6 7 8 9 10 11 12
`Months
`
`Patients
`at risk (cid:9)
`37 (cid:9)
`15
`Figure 1. Probability of clinical remission (Harvey—Bradshaw
`index < 4) in 37 Crohn's disease patients with active disease
`when methotrexate started.
`
`7 (cid:9)
`
`6 (cid:9)
`
`3 (cid:9)
`
`2 (cid:9)
`
`0
`
`METHOTREXATE IN CROHN'S DISEASE 311
`
`100 -
`90 -
`80 -
`70
`60
`50
`40
`30
`20 -
`10-
`0 (cid:9)
`
`1 2 3 4 5 6 7 8 9 10 11 12
`Months
`
`24 22 16 8 5 4 1
`
`Patients
`at risk
`Figure 2. Probability of clinical remission and steroid withdrawal
`in 24 Crohn's disease patients taking corticosteroids when
`methotrexate started.
`
`of the five patients considered as failures had surgery :
`one of them underwent colectomy at week 2 because of
`colonic perforation, and the other failed to improve on
`methotrexate and underwent colectomy at month 8.
`Figure 2 shows the probabilities of clinical remission and
`steroid withdrawal for the 24 patients who were taking
`steroids at methotrexate initiation. After 3, 6 and 12
`months on methotrexate, these probabilities were 17%
`(95% CI, 6-25%), 33% (95% CI, 13-53%) and 42%
`(95% CI, 19-67%), respectively.
`
`Relapses in patients on maintenance treatment with
`methotrexate
`
`Twenty-eight patients were treated with methotrexate in
`order to maintain clinical remission. This group included
`the 26 patients who had previously achieved a clinical
`remission on methotrexate, and two patients who were
`in remission on steroids at the start of methotrexate. For
`this group of 28 patients, the probabilities of relapse on
`methotrexate at 3, 6 and 12 months were 13% (95% CI,
`0-27%), 38% (95% CI, 15-62%) and 58% (95% CI,
`30-85%), respectively (Figure 3). For the 10 patients
`who experienced a relapse, the average weekly dose of
`methotrexate at the time of relapse was 14 + 6.4 mg
`(range, 7.5-25 mg) and the drug was administered orally
`in nine of the 10 cases. For the 18 patients who remained
`on clinical remission, the average weekly dose of metho-
`trexate at last follow-up was similar (17.7+ 6.3 mg ;
`range, 7.5-25 mg; P > 0.05) but a smaller proportion
`(11 out of 18) was treated orally (P < 0.01). The average
`daily dose of steroids in patients who had a relapse was
`
`© 1996 Blackwell Science Ltd, Aliment Pharmacol Ther 10, 309-314
`
`This (cid:9)
`att•-•E
`
`z
`
`Ex. 1083 - Page 7
`
`

`

`Table 1. Success rate for achieving specific therapeutic goals
`with methotrexate
`
`Indication for methotrexate (cid:9)
`
`No. of
`No. of (cid:9)
`success
`patients (%)
`
`Control of active disease
`Steroid sparing*
`Prevention of clinical relapse
`Perianal fistula healing (cid:9)
`Control of extraintestinal manifestations
`Totalt
`
`37
`y-) (cid:9)
`28 (cid:9)
`
`93
`
`26 (70)
`15 (68)
`18 (64)
`2 (50)
`1 (50)
`62 (67)
`
`* The goal was to reduce the dose to less than 10 mg predni-
`sone-equivalent per day.
`t Most patients had more than one specific goal.
`
`Side-effects
`
`Table 2 shows the frequency of adverse events encoun-
`tered during methotrexate treatment. Of the 39 patients,
`22 (56%) experienced side-effects, and these effects were
`severe enough in four patients (10%) to warrant dis-
`continuation of the drug. Of note, gastrointestinal symp-
`toms occurred in six patients after they were switched to
`the oral methotrexate. None of the patients experienced
`severe adverse haematological, liver or pulmonary ef-
`fects, or serious infection during methotrexate treatment.
`A liver biopsy was performed in four patients after they
`had received a total dose of 1500 mg of methotrexate.
`Two patients had a normal biopsy, one patient had
`peliosis and one patient had a granulomatous hepatitis.
`
`DISCUSSION
`
`In this work, we report our experience of the use of
`methotrexate in 39 patients with Crohn's disease re-
`sistant to conventional treatment. Before being given
`methotrexate, all patients had been taking steroids ; 24 of
`them (59%) were still doing so and exhibited either
`steroid dependence or resistance when methotrexate
`treatment started. Twenty-two patients (56%) had had
`previous surgery. In 36 patients (92 %), azathioprine had
`been tried but had failed, either because of poor
`intolerance or the absence of improvement.
`Our short-term results are comparable to those reported
`by other authors.'" Clinical improvement was obser-
`ved in 90% of our patients and two-thirds of them
`achieved complete clinical remission within 3 months of
`methotrexate therapy. These rates of improvement are
`
`© 1996 Blackwell Science Ltd, Aliment Pharmacol Ther 10, 309-314
`
`312 (cid:9) M. LNANN et al.
`
`1 2 3 4 5 6 7 8 9 10 11 12
`Months
`
`100 —
`90 —
`80 —
`70 —
`60 —
`50 —
`40 —
`30 —
`20 —
`10 —
`0
`
`Probability of relapse (%)
`
`Patients 28 26 15 10 7 5 4
`at risk
`Figure 3. Probability of relapse (Harvey—Bradshaw index ,..>... 4) in
`28 Crohn's disease patients on maintenance treatment with
`methotrexate, including 26 patients who previously experienced
`a clinical remission on methotrexate and two patients who were
`in remission when methotrexate started.
`
`1 2 (cid:9)
`
`4 5 (cid:9)66 7 8 9 10 11 (cid:9)12
`Months
`
`100 -
`90 -
`80 -
`70 -
`60
`50 -
`40 -
`30 -
`20 -
`10-
`0 (cid:9)
`
`
`Probability of relapse (%)
`
`5 (cid:9)
`
`2 (cid:9)
`
`1 (cid:9)
`
`Patients
`11 (cid:9)
`at risk
`Figure 4. Probability of relapse (Harvey—Bradshaw index ?.. 4) in
`11 Crohn's disease patients who stopped methotrexate for
`reasons other than failure.
`
`1 (cid:9)
`
`1
`
`8.3 ± 9.4 mg (range, 0-30 mg), compared with
`5.6 + 10.4 mg (range, 0-40 mg) in patients still in
`remission at their last visit (P > 0.05). Eleven of the
`18 patients maintained in complete remission stopped
`methotrexate for reasons other than relapse. For these
`patients, the probabilities of relapse at 1, 3 and 6 months
`after methotrexate withdrawal were 39, 80 and 90%,
`respectively (Figure 4).
`
`Specific therapeutic goals
`
`The overall success rate for achieving specific therapeutic
`goals for the patients in the present series was 67%. The
`rates for each goal are given in Table 1.
`
`rhis- - (cid:9)
`
`
`
`Ex. 1083 - Page 8
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`Table 2. Adverse events in patients treated with methotrexate
`
`No. of
`events
`(0/0)
`
`10 (26)
`
`5
`3
`7 (18)
`5 (13)
`2 (5)
`2 (5)
`2 (5)
`1
`1
`2 (5)
`1 (3)
`1 (3)
`22 (56)*
`
`Methotrexate
`withdrawal
`(no. of
`patients)
`
`3
`
`0
`1
`1
`0
`0
`1
`0
`
`0
`0
`0
`4
`
`Gastrointestinal symptoms
`nausea and vomiting
`diarrhoea
`abdominal pain
`Abnormal liver function tests
`Headache, dizziness
`Fatigue
`Skin rash
`Infections
`herpes zoster
`candidiasis
`Gynaecomastia
`Leukopenia ( < 3000/mL)
`Cough
`Total
`
`* Number (%) of patients with at least one adverse event.
`
`close to those reported by Kozarek et al.' in 14 patients
`(78%) and by Baron et al.' in 10 patients (80 %). In the
`placebo-controlled North American trial,' the percentage
`of improvement was not stated, but the proportion of
`patients in complete remission after 16 weeks of treat-
`ment was 39 %. However, in the latter study, clinical
`remission was defined both as a drop in the Crohn's
`Disease Activity Index to below the threshold of 150 and
`as the complete cessation of corticosteroids. In our series,
`seven of the 24 (29 %) cortico-dependent or cortico-
`resistant patients stopped taking steroids after 4 months
`on methotrexate. In Kozarek et al.'s series,' 30% of
`patients had stopped taking steroids after 12 weeks on
`methotrexate, and in Baron et al.'s series,' the rate was
`20% after 18 weeks.
`In our study, 42 % of patients on maintenance metho-
`trexate treatment were still in remission after 1 year.
`These results are less favourable than those reported by
`Kozarek et al.,' who stated that 51 % of their patients
`taking methotrexate were still in remission after a mean
`follow-up of 69 weeks. In the randomized study by Arora
`et al.,' who compared the results of 15 mg per week of
`oral methotrexate for 1 year with those for a placebo, the
`proportion of patients maintained in remission was 54%
`in the methotrexate group compared with 20% in the
`placebo group (P < 0.05). However, 23% of their
`patients had stopped taking methotrexate because of
`side-effects, so that only 31 % were in fact still in
`
`(C.) 1996 Blackwell Science Ltd, Aliment Pliarinncol Ther 10, 309-314
`
`METHOTREXATE IN CROHN'S DISEASE 313
`
`remission after 1 year of treatment. Taken together, the
`long-term results for methotrexate in Crohn's disease
`therefore seems less favourable than those reported for
`azathioprine'" or 6-mercaptopurine." It is possible
`that the scheme of treatment proposed by Kozarek et al.,'
`and used in our patients, was not sufficient to prevent
`relapse, because it involved both passing from intra-
`muscular to oral administration of the drug after 3
`months, and tapering of the doses. In our patients, the
`mean dose for methotrexate at the time of relapse was
`comparable to those at the time of the last visit of patients
`who did not have a relapse. On the other hand, 90% of
`patients who did have relapse were taking methotrexate
`orally, compared to only 61 % of those who had no
`relapse. This result suggests that the efficacy of metho-
`trexate could be influenced by the route of admini-
`stration of the drug.
`Side-effects were often observed amongst our patients
`during methotrexate treatment, but they were mostly
`moderate, and the treatment had to be stopped in only
`10% of the patients. This proportion is smaller than those
`reported in previous studies.3• 6 None of our patients were
`given supplements of folic acid, which has been shown to
`reduce methotrexate toxicity without affecting its efficacy
`in rheumatoid arthritis.' There was no case of hyper-
`sensitivity pneumopathy in our series, and only one
`patient develo