Trends in inflammatory bowel disease therapy: A meta

Trends in inflammatory boweldisease therapy:

A meta-analytic approachGREGORY W WHITING BA, JOSEPH LAU MD, BRUCE KUPELNICK BA, THOMAS C CHALMERS MD

META-ANALYSIS IS MORE THAN A

statistical technique for poolingdata from multiple primary research re-ports. It is a wholly new and precise dis-cipline for gathering and transferringthe results of primary research projectsinto a valid and understandable formatso that they can be applied to patientcare by physicians and those who setmedical policy.

Crohn’s disease is a perfect exampleof the serious problem physicians andhealth care policy-makers face whentrying to keep up with the potential im-pact of research on medical practice. Ina disease of unknown etiology, espe-cially one with acute and chronicmanifestations, there is bound to be anincreasing explosion of importantclinical trials. Publication of review ar-ticles written by clinical experts hasbeen the classical way of keeping every-body informed. That route has been in-creasingly found to be flawed becauseof evidence of nonthorough literaturesearches and of bias in the selection andinterpretation of published trials inmany fields; there is no reason to thinkthat Crohn’s disease meta-analysis isany different. Compared with those whoprepare meta-analysis, the writer of re-views and textbook chapters does notpresent all evidence on which opinionsand recommendations are based.

The purpose of this paper is to illus-trate the application of all aspects ofthe technique of meta-analysis to thepharmacological treatment of acute at-tacks of Crohn’s disease, a commonclinical problem requiring frequent up-dates of therapeutic advances.

IBD – CRITICAL APPRAISAL OF CLINICAL TRIALS

GW WHITING, J LAU, B KUPELNICK, TC CHALMERS. Trends in inflamma-tory bowel disease therapy: A meta-analytic approach. Can J Gastroenterol1995;9(7):405-411.

OBJECTIVE: To illustrate the current meta-analytic approach to extracting clini-cally useful information from the glut of randomized controlled trials (RCTs) ofthe treatment of acute attacks of Crohn’s disease.PROCEDURE: Acceptable RCTs were classified in a matrical format so that thefeasibility of a meta-analysis of each treatment could be quickly determined.Each potential inclusion was then photocopied after blinding the source and out-come to minimize bias by the investigators.RESULTS AND CONCLUSIONS: The search was started in 1990, when a previousmeta-analysis was completed. Over 100 citations in MEDLINE contained 21 RCTsof the treatment of acute attacks of Crohn’s disease, and 11 more were culled fromthe references of recent papers. The meta-analysis most indicated by the matrixwas a comparison of several different immunosuppressive regimens with a pla-cebo. The previously demonstrated statistical significance was confirmed and thepoint made that it is no longer justified to compare any new treatments with aplacebo. Cumulative meta-analysis, the process of performing a new analysisevery time a new trial is published, revealed the importance of employing bothrandom and fixed effect models when heterogeneity of treatment results is appre-ciable, as in this case.

Key Words: Crohn’s disease, Immunosuppression, Meta-analysis, Therapy

Tendances du traitement de la maladie inflammatoire de l’intestin :approche méta-analytique

OBJECTIFS : Illustrer l’approche méta-analytique actuelle d’extraction desdonnées cliniquement pertinentes à partir de l’amas d’essais contrôlés ran-domisés (ECR) qui ont porté sur le traitement des poussées aiguës de maladie deCrohn.PROCÉDURES : Les ECR acceptables ont été classés sous forme de matrice pourque la faisabilité de la méta-analyse puisse être rapidement déterminée pourchaque traitement. Chaque essai potentiel a ensuite été photocopié après que lasource et le résultat en aient été biffés, afin de minimiser tout risque de biais de lapart des investigateurs.

MetaWorks, Inc; and the Division of Clinical Care Research, New England Medical Center,Boston, Massachusetts, USA

Correspondence and reprints: Dr Thomas C Chalmers, MetaWorks, Inc, 470 Atlantic Avenue,Boston, MA 02210, USA. Telephone 617-368-3575, fax 617-368-3591

This paper was presented at the Trends in Inflammatory Bowel Disease Therapy meeting, April6 to 9, 1994, held in Victoria, British Columbia. This paper has also been published in SutherlandLR, et al, eds. Inflammatory Bowel Disease: Basic Research, Clinical Implications and Trends inTherapy. Boston, Dordrecht and London: Kluwer Academic Publishers, 1994

voir page suivante

CAN J GASTROENTEROL VOL 9 NO 7 NOVEMBER/DECEMBER 1995 405

CRITERIA FOR A GOODMETA-ANALYSIS

If meta-analyses are to be reliableconduits of original medical informa-tion they must be reliably performed.Calling something a meta-analysis or‘structured’ review calls into play cer-tain methodological rules, which if ne-glected could and should lead torejection by editors or peer reviewers ofthe whole effort. This protection of thereader only works if there is reasonableagreement about the characteristics ofan acceptable meta-analysis. Thesearch for original data must be as com-plete as possible, bias must be mini-mized by blinding papers beforedecisions are made by the investigatorsand all steps must be carried out in du-plicate to minimize errors. These initialsteps are illustrated schematically inFigure 1. Once a subject has been se-lected, references are sought in reviewarticles and recent randomized con-trolled trials (RCTs). Medical subjectheading terms and key words for a MED-

LINE search are gleaned from a recoveryof the first articles in MEDLINE. How-ever it has been demonstrated at leastseven times (1) that a MEDLINE searchfor clinical trials only recovers about50% of the articles found by othermeans (two-thirds in this case). Mostof the clinical trials found elsewhereare actually in MEDLINE when anauthor search is carried out, so the de-fect lies in subject cataloguing.

The conscientious clinical investi-gator will also have been perusing Cur-

rent Contents each week for inflamma-tory disease trials. As for other diseases,there are also special publications ofbibliographies and abstracts; in this case,Trends in Inflammatory Bowel Disease

Therapy, published in June 1993 (2).Once a number of candidate papers

have been logged in, a preliminaryscreening is carried out and the reviewarticles and uncontrolled trials re-jected. A matrix of comparisons is thenconstructed and a decision is madeabout which meta-analyses to under-take. A technician blots out all infor-mation in the selected papers relativeto the sources, dates and therapeuticregimens of each trial before photo-copying (‘differential photocopying’).

RÉSULTATS ET CONCLUSIONS : La recherche a commencé en 1990 alors qu’uneméta-analyse précédente arrivait à terme. Plus de 100 citations tirées de MED-LINE renfermaient 21 ECR sur le traitement des poussées aiguës de maladie deCrohn et 11 autres provenaient de la bibliographie d’articles récents. La méta-analyse mise en évidence par la matrice était une comparaison de différentsschémas immunosuppresseurs avec placebo. La portée statistique précédemmentdémontrée a été confirmée et il n’est plus justifié de comparer les nouveaux traite-ments avec placebo. La méta-analyse cumulative, le processus d’analyse exigé pourchaque nouvel essai publié, a révélé l’importance d’employer des modèles d’essaisrandomisés et fixes lorsque l’hétérogénéité des résultats des traitements est appré-ciable, comme c’est le cas ici.

Figure 1) Diagram of a meta-analytic process designed to ensure that all relevant published articlesare included, that bias is minimized by blinding information that might influence selection of papers andextraction of data, and that errors are minimized by duplicate performance. RCT Randomized con-trolled trial; UI Unique identifier. Reproduced with permission from reference 1

MEDLINE titles and

UI numbers

References from

completed

papers

Current Contents

Abstracts Collected papers logged in

Rejects

Non-RCT rejects Screened

Rejects Matrix constructed

Copied three times

Copy 1 of full paper and

blinded paper in separate

folders to reader 1

Differentially

photocopied

Copy 2 of full paper and

blinded paper in separate

folders to reader 2

Quality scored using form B

for blinded methods, form C

for blinded results with full

paper and form A for

blinded data extraction

Master file with full

paper

Quality scored using form B for

blinded methods, form C for

blinded results with full paper

and form A for blinded data

extraction

Rejected if found not to meet

screening requirements

Data extracted Rejected if found not to meet

screening requirements

Readers have a consensus conference to determine final quality

score and data extraction – first from blinded,

then full papers

Statistical analysis

Manuscript

Always publish

406 CAN J GASTROENTEROL VOL 9 NO 7 NOVEMBER/DECEMBER 1995

WHITING et al

The sources and dates are left blankwhile the therapeutic regimen is en-coded A or B, or X or Y. One copy ofthis blinded paper is placed in the mas-ter file with the original and one copy isgiven to each investigator, along withan unaltered copy to be consultedwhen all questions that could be an-swered from the blinded copy are an-swered. Pertinent data are extracted byeach investigator, and quality ques-tionnaires are filled using only the‘Methods’ and ‘Results’ sections (3). Aconsensus conference is then held toiron out the differences, which typi-cally occur 15 to 21% of the time.There are occasional exceptions to theabove process, as when a few papers arewell known to all and others are addedlate, but an attempt is made to do eachstudy properly. Because those familiarwith the field will easily recognize a fewpapers, an attempt is made in each in-stance to include a methodologist orstudent as one of the investigators, inaddition to the expert in the field.

After the consensus conference, ta-bles of results are constructed in a stan-dard format and the statistical analysescarried out by more than one method.

Unfortunately there is no quantita-tive system for scoring quality to reflectthat bias might distort the results, sothe confidence intervals are notweighted by the quality scores. Insteadthe included RCTs are listed in order ofdescending quality score so that the in-vestigators or readers can do their ownsensitivity analyses by omitting theworst papers to see whether the resultsare inordinately influenced by theworst research. Other sensitivity analy-ses can then be carried out, such as re-moving studies with outlyingtreatments or unusual patients. Sub-group analyses can be done at thisstage, but with great caution to avoidthe accusation of data-dredging.

CUMULATIVEMETA-ANALYSIS:

AN EXCITING INNOVATIONIf a new meta-analysis is performed

every time a new study is published orfound, critical new information is pre-sented. As an example, a standard for-mat meta-analysis of RCTs comparing

Figure 2) A meta-analytic approach – fixed effects model (Mantel-Haenszel) – to randomized con-trolled trials of the efficacy of perioperative antibiotics in reducing the operative death rates from sur-gery for colon cancer. The standard chart on the left reveals that none of the individual trials wasstatistically significant and the cumulative meta-analysis on the right reveals that statistical signifi-cance was achieved by 1975. In this case, heterogeneity is not significant, so the random and fixed ef-fects models give the same results. �Odds ratio: under 1.0 favours the antibiotics. The horizontallines are the 95% CIs around each ratio. The end-point is perioperative death. Pts Patients. Refer-ences listed in this figure can be obtained in full from the corresponding author

TABLE 1Therapy comparison matrix of randomized controlled trials of therapy for acute at-tacks of Crohn’s disease

Experimental therapy

Comparison therapy

A

Placebo

B

Sulfasalazine

C

Steroids

D

Diet

E

Other

F

Total

1. Immunosuppression 26?, 72++, 42+,

12+, 15+, 42++,

134?

3? 37++,

36?

10

2. T cell stimulants 33+, 9?, 19?, 21? 4

3. Sulfasalazine 26++, 54++ 42–,

23?

4

4. 5-ASA 12?, 67+ 30+, 23? 4

5. Antibiotics 20+, 100++,

52++, 7?

72+,

52?

6

6. Steroids 47++, 38++,

85++

38+ 38+ 5

7. Diet 36++ 6+,

7+, 9?

19?,

10++,

36?,

16?,

28+,

20++

10

8. Combination 56++, 20+,

163++

163– 21++ 72++ 6

9. Other 55?, 18?, 29?,

199+, 21+, 16?,

18?

80++,

22?

9

10. Totals 33 3 7 7 8 58

Numbers in cells refer to the number of subjects in a specific trial. ++Statistically significant in favour of ex-

perimental therapy; +Trend in favour of experimental therapy; ?No clinically interesting difference; –Trend in

favour of control therapy. 5-ASA Aminosalicylic acid. Based on reference 5


Meta-analysis and therapy of Crohn’s disease

perioperative antibiotics with placeboor no antibiotics in patients undergo-ing colorectal surgery, usually for can-cer of the colon, is presented in Figure2. Although most studies favoured theantibiotics, no study, by itself, was sta-tistically significant. The trials also re-ported postoperative infection rates, inwhich control rates were higher anddifferences more often significant. How-

ever, by the time 200 patients had beenrandomized in 1971, the differenceswere statistically significant, and al-though fluctuating in degree, the confi-dence intervals never crossed the unityline in the ensuing 20 years. The finalillustrative Z and P values were highlysignificant (2P=0.0016) in 1987 whenthe last study in this series was re-ported. The term ‘illustrative P’ value is

used because we have not corrected thecritical P value with each calculation,as some strict frequentist biostatisti-cians would have us do. Cumulativemeta-analysis has brought to the fore-front the importance of prior clinicaltrials in planning and stopping clinicaltrials. A Bayesian approach (4) seemsmore appropriate when dealing with avast array of published RCTs.

CROHN’S DISEASETREATMENT AND THE NEEDTO FIND EFFICIENT WAYS TO

DEAL WITH RCT GLUTThree years ago we developed a ma-

trical approach to the large number ofavailable clinical trials of drugs and dietfor the treatment of acute attacks ofCrohn’s disease for the Online Journal of

Current Clinical Trials (5). The differ-ent drugs and diets considered by theauthors of each RCT to be the experi-mental approach were placed in therows, and the control treatments ofeach RCT were the columns. Into theappropriate cells were placed eachstudy, identified by the number of pa-tients randomized and a code for theoutcome chosen by the authors as theprincipal one (Table 1). This processenabled the author and the reader tokeep close track of the papers appearingin each cell so that the need for meta-

TABLE 2Results of a MEDLINE search for citationsrelated to the treatment of Crohn’s dis-ease between January 1990 and April1994

Type of study

Number of ci-

tations

Review articles 22

RCTs

Acute treatment 21 (11*)

Maintaining remission 12

Total 33

Nonrandomized and

uncontrolled

7

Meta-analysis of RCTs 1

Total clinical trial citations 96

*Randomized controlled trials (RCTs) of acute treat-

ment are expanded by 11 additional ones culled

from the reference lists of recent publications. A full

list of the combined 32 trials appears in Appendix 1

TABLE 3Matrix of randomized controlled trials of treatment of acute attacks of Crohn’s dis-ease published from January 1990 to March 1994

Experimental therapy

Comparison therapy

A

Placebo

B

Sulfasalazine

C

Steroids

D

Diet

E

Other

1. Immunosuppression 71++, 28+

2. Sulfasalazine 26++

3. 5-ASA 14++, 67+ 55––

4. Metronidazole 56++ 78?

5. Steroids 310++, 84? 96?, 54+ 78++, 21? 37?

6. Diet 32?, 42?,

29?, 15?,

24?, 19?

14––, 30++,

51?, 28+,

24?, 30?

107––

7. Combination therapy 49+, 18+,

42++

17+

8. Mesalamine 34?

9. Sulfasalazine and

prednisone

60+

Cells contain number of patients in each randomized controlled trial and results of major end-point chosen

by author. Numbers plotted are comparisons, not individual papers, due to some papers comparing more

than two treatments. ++Statistically significant in favour of experimental therapy; +Trend in favour of experi-

mental therapy; ?No clinically meaningful difference; ––Statistically significant in favour of control therapy.

5-ASA Aminosalicylic acid

Figure 3) Random effects model (DerSimonian and Laird) showing nine randomized controlled tri-als of immunosuppressive therapy versus placebo for acute attacks of Crohn’s disease. Results are ex-pressed as odds ratio; experimental treatment was better than placebo when the odds ratio was lessthan one. Studies ordered by year of publication: standard on left and cumulative on right. �Oddsratio: under 1.0 favours the immunosuppressive therapy. The horizontal lines are the 95% CIsaround each ratio. The end-point is clinical improvement (response rates). References listed in this fig-ure can be obtained in full from the corresponding author. Pts Patients


WHITING et al

analysis could be determined. For in-stance, a pooling of the trials of an im-munosuppressant drug summarized incell A1 was clearly indicated and wascarried out (5). The success rate of thecombined different immunosuppres-sant drugs in short term studies of vary-ing duration was significantly betterthan the success rate of placebo. CellsA2 and A4 bear watching, and A3 andA5 appear to be statistically significantbut could be checked with a meta-analysis. Cells under columns B to E arecomparisons of one active treatmentwith another, and because of a lowerfailure rate among controls will requiremany more studies before meta-analysis is indicated. The diet studiesare going to require individual analysisbecause most are studying differentmodifications. Use of the proposed ma-trical format facilitates a quick surveyof the randomized controlled trialsituation with regard to the nonsurgicaltreatment of acute attacks of Crohn’sdisease.

In 1994, four years after completionof the previous literature search, it wastime for a repeat, and one was carriedout for the Trends in InflammatoryBowel Disease Therapy meeting heldin Victoria, British Columbia in April1994. Table 2 presents the results of theliterature search. Ninety-six clinicaltrial citations were found by a MEDLINE

search, 22% of which were RCTs ofacute treatments. Search of publishedreferences and other databases revealed11 more RCTs, an additional one-third.

A matrix of the RCTs published fromJanuary 1990 to March 1994 is pre-sented in Table 3. An updated meta-analysis that includes the two new tri-als of an immunosuppressant versusplacebo is presented in Figures 3 to 6. Itis apparent that the additional trials didnot need to be undertaken to establishthat short term treatment was effective.It may be argued, and indeed it proba-bly was, that additional trials were nec-essary to determine duration of optimaltherapy, drug regimen or span of sideeffects, which were not apparent fromthe few completed studies. Once theoverall question is answered it shouldno longer be ethical to assign new pa-

tients to placebo, but the other ques-tions must be answered and the onlyethical way to accomplish this is to em-ploy the seemingly best regimen as thecontrol thereafter. This requires alarger number of acute Crohn’s diseasepatients because of the smaller differ-ences being sought, but that should notbe difficult. The optimal duration oftherapy can be determined by random-izing the stopping time earlier versus

later depending on the extent of the re-sponse.

Figures 3 to 6 reveal various statisti-cal approaches to pooling the data inthe nine RCTs. Figures 3 and 4 illustratethe advantages of employing both thefixed and random effects models. Theresults of the trials are heterogeneous(P<0.01) and the cumulative meta-analyses best illustrate the differencesresulting from widening the confidence

Figure 4) Random effects model (DerSimonian and Laird) showing nine randomized controlled tri-als of immunosuppressive therapy versus placebo for acute attacks of Crohn’s disease. Results are ex-pressed as absolute percentage difference. Studies ordered by year of publication: standard on left andcumulative on right. �Odds ratio: under 1.0 favours the immunosuppressive therapy. The horizon-tal lines are the 95% CIs around each ratio. The end-point is clinical improvement (response rates).mRate of failure in placebo-treated groups. References listed in this figure can be obtained in full fromthe corresponding author. Pts Patients

Figure 5) Fixed effects model (Mantel-Haenszel) showing nine randomized controlled trials of im-munosuppressive therapy versus placebo for acute attacks of Crohn’s disease. Studies ordered by yearof publication: standard on left and cumulative on right. �Odds ratio: under 1.0 favours the immu-nosuppressive therapy. The horizontal lines are the 95% CIs around each ratio. The end-point isclinical improvement (response rates). Note on the right that significance at the P<0.05 level isachieved by 1980 instead of in 1989 as in the random effects model. References listed in this figure canbe obtained in full from the corresponding author. Pts Patients



intervals with the random effectsmodel. The reduction in the odds ratiosis statistically significant (confidenceintervals no longer crossing one) from

1980 onwards in the fixed effects modeland only after 1989 in the random ef-fects model. In Figure 5 the random ef-fects model units are different; absolute

percentage change and the varyingcontrol rates of failure are shown. InFigure 6 the order of the trials waschanged from ascending year to de-scending control rate to illustratesomething we have found almost uni-versally in meta-analyses: a direct cor-relation between response rate and therate of events in the control group (un-published data).

The above procedures are new andmay be somewhat disturbing to bothgastroenterologists and biostatisticians,and considerable thought and dialogueare indicated. But such are the conse-quences of the very large number of tri-als of Crohn’s disease treatment. Thesituation actually would be more acutewere clinicians to randomize the ‘firstpatient’ (6-9), as they should as long asthe optimal treatment of the acute dis-ease has not been discovered. That isnot likely to occur unless the exact eti-ology is known, and a large number ofpatients will have to have presentedthemselves for treatment before thathappens.

Figure 6) Random effects model (DerSimonian and Laird) showing nine randomized controlled tri-als of immunosuppressive therapy versus placebo for acute attacks of Crohn’s disease. Results are ex-pressed as absolute percentage difference. Studies are arranged in descending order according to therate of failure in the control group. �Odds ratio: under 1.0 favours the immunosuppressive therapy.The horizontal lines are the 95% CIs around each ratio. The end-point is clinical improvement (re-sponse rates). mRate of failure in placebo-treated groups. References listed in this figure can be ob-tained in full from the corresponding author. Pts Patients

ACKNOWLEDGEMENTS: This studywas supported in part by a grant from theAgency for Health Care Policy and Re-search, R01HS07782.

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C J G V 9 N 7 N D 1995 405


APPENDIX 1: References to the 32 randomized controlled trials in the matrix ofnew trials (Table 2) listed by cell in the matrix

D5 Riordan AM, Hunter JO, Cowan RE,et al. Treatment of active Crohn’sdisease by exclusion diet: EastAnglican multicentre controlled trial.Lancet 1993;342:1131-4.

C6 Gorard DA, Hunt JB, Payne-James JJ,et al. Initial response and subsequentcourse of Crohn’s disease treated withelemental diet or prednisolone. Gut1993;34:1198-202.

C6 Gonzalez-Huix F, de Leon R,Fernandez-Banares F, et al. Polymericenteral diets as primary treatment ofactive Crohn’s disease: a prospectivesteroid controlled trial. Gut1993;34:778-82.

A5 Singleton JW, Hanauer SB, GitnickGL, et al. Mesalamine capsules forthe treatment of active Crohn’sdisease: results of a 16-week trial.Pentasa Crohn’s Disease StudyGroup. Gastroenterology1993;104:1293-301.

C5 Landi B, Anh TN, Cortot A, et al.Endoscopic monitoring of Crohn’sdisease treatment: a prospective,randomized clinical trial. The Grouped’Etudes Therapeutiques desAffections Inflammatoires Digestives.Gastroenterology 1992;102:1647-53.

C6 Sanderson IR, Udeen S, Davies PS,Savage MO, Walker-Smith JA.Remission induced by an elementaldiet in small bowel Crohn’s disease.Arch Dis Child 1987;61:123-7.

A4 Sutherland LR, Singleton J, SessionsJ, et al. Double-blind placebocontrolled trial of metronidazole inCrohn’s disease. Gut 1991;32:1071-5.

B4 Ursig B, Alm T, Barany F, et al.A comparative study of metronidazoleand sulfasalazine for active Crohn’sdisease: the cooperative Crohn’sdisease study in Sweden. II. Result.Gastroenterology 1982;83:550-62.

D6 Harries AD, Jones LA, Danis V, et al.Controlled trial of supplemented oralnutrition in Crohn’s disease. Lancet1983;i:887-90.

D6 Park RH, Galloway A, Danesh BJ,Russell RI. Double-blind trialcomparing elemental and polymericdiet as primary treatment for activeCrohn’s disease. Gut1989;30:A1453-4. (Abst)

Al Brynskov J, Freund L, Rasmussen SN,et al. A placebo-controlled,double-blind, randomized trial ofcyclosporine therapy in activechronic Crohn’s disease. N Engl JMed 1989;321:845-50.

A5 Bergman L, Krause U. Postoperativetreatment with corticosteroids and

salazosulphapyridine (Salazopyrin)after radical resection for Crohn’sdisease. Scand J Gastroenterol1976;11:651-66.

A8 Brillanti S, Biasco G, Azzaroni D,et al. Pentasa versus sulphasalazinetablets in the treatment of activeCrohn’s ileocolitis. Scand JGastroenterol 1989;158(Suppl):129-30.

D6 Greenberg GR, Fleming CR,Jeejeebhoy KN, Rosenberg IH, SalesD, Tremaine WJ. Controlled trial ofbowel rest and nutritional support inthe management of Crohn’s disease.Gut 1988;29:1309-15.

A3 Rasmussen SN, Lauritsen K, Tage-Jensen U, et al. 5-aminosalicylic acidin the treatment of Crohn’s disease.A 16-week double-blind, placebo-controlled, multicentre study withPentasa. Scand J Gastroenterol1987;22:877-83.

A1 Arora S, Katkov WN, Cooley J, et al.A double-blind, randomized, placebo-controlled trial of methotrexate inCrohn’s disease. Gastroenterology1992:102:A591. (Abst)

D6 Giaffer MH, North G, HoldsworthCD. Controlled trial of polymericversus elemental diet in treatment ofactive Crohn’s disease. Lancet1990;335:81 6-819.

E5 Saverymuttu S, Hodgson HJ,Chadwick VS. Controlled trialcomparing prednisolone with anelemental diet plus non-absorbableantibiotics in active Crohn’s disease.Gut 1985;26:994-8.

C6 Hunt JB, Payne-James JJ, Palmer KR,et al. A randomized controlled trial ofelemental diet and prednisoloneas primary therapy in acuteexacerbations of Crohn’s disease.Gastroenterology 1989;96:A224.(Abst)

A2 Van Hees PA, Van Lier JH, VanElteren PH, et al. Effect ofsulphasalazine in patients with activeCrohn’s disease: a controlled double-blind study. Gut 1981;22:404-9.

D5 O’Morain C, Segal AW, Levi AJ.Elemental diet as primary treatmentof acute Crohn’s disease: a controlledtrial. BMJ 1984;288:1859-62.

A3 Griffiths A, Koletzko S, Sylvester F,Marcon M, Sherman P. Slow-release5-aminosalicylic acid therapy inchildren with small intestinalCrohn’s disease. J PediatrGastroenterol Nutr 1993;17:186-92.

D6 Raouf AH, Hildrey V, Daniel J, et al.Enteral feeding as sole treatment for

Crohn’s disease: controlled trial ofwhole protein vs amino acid basedfeed and a case study of dietarychallenge. Gut 1991;32:702-7.

D6 Rigaud D, Cosnes J, Le Quintrec Y,et al. Controlled trial comparing twotypes of enteral nutrition intreatment of active Crohn’s disease:elemental versus polymeric diet.Gut 1991;32:1492-7.

B9 Rijk MC, van Hogezand RA, vanLier HJ, van Tongeren JH.Sulphasalazine and prednisonecompared with sulphasalazine fortreating active Crohn’s disease.A double-blind, randomized,multicentre trial. Ann Intern Med1991;114:445-50.

C7 Ewe K, Press AG, Singe CC, et al.Azathioprine combined withprednisolone or monotherapy withprednisolone in active Crohn’sdisease. Gastroenterology1993;105:367-72.

E6 Lochs H, Steinhardt HJ,Klaus-Wentz B, et al. Comparison ofenteral nutrition and drug treatmentin active Crohn’s disease. Results ofthe European Cooperative Crohn’sDisease Study. IV. Gastroenterology1991;101:881-8.

C6 Thomas AG, Taylor F, Miller V.Dietary intake and nutritionaltreatment in childhood Crohn’sdisease. J Pediatr Gastroenterol Nutr1993;17:75-81.

C6 Lindor KD, Fleming CR, BurnesD7 JU, Nelson JK, Ilstrup DM. AC7 randomized prospective trialC7 comparing a defined formula diet,C7 corticosteroids and a defined formulaC7 diet plus corticosteroids in activeC7 Crohn’s disease. Mayo Clin ProcC7 1992;67:328-33.C7 Afdhal NH, Long A, Lennon J,

Crowe J, O’Donoghue DP.Controlled trial of antimycobacterialtherapy in Crohn’s disease.Clofazimine versus placebo. Dig DisSci 1991;36:449-53.

C5 Brignola C, De Simone G, IannoneP, et al. Influence of steroidtreatment’s duration in patients withactive Crohn’s disease. AgentsActions 1992;Spec No:C90-2.

C3 Jenss H, Hartmann F, Scholmerich J,German ASA-Study Group.5-aminosalicylic acid versusmethylprednisolone in the treatmentof active Crohn’s disease – firstresults of double-blind clinical trial.Scand J Gastroenterol 1989;158(Suppl):136.

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Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Documents

Trends in inflammatory bowel disease therapy: A meta