Since the development of sulfa -salazine, drugs containing 5-

aminosalicylic acid (5-ASA) haveplayed a pivotal part in the manage-ment of ulcerative colitis (UC). Themechanism of action of 5-ASA isnot clearly understood but relies onthe drug being delivered intralumi-nally to affected areas of the gastro -intestinal tract. 5-ASA drugs havebecome widely used in the treat-ment of inflammatory bowel dis-ease (IBD). They are generally safewith few significant adverse events,require simple monitoring and arevery well tolerated.

While the collective opinionfrom national and international

guidelines supported by a wide evi-dence base recommends their usein the treatment of UC, thereremains controversy about the ben-efits of 5-ASA therapy in the man-agement of Crohn’s disease (CD).

The aims of this article are todiscuss possible prescribing indica-tions for 5-ASAs in the manage-ment of CD and debate whetherthis use is justified by the availableevidence and current guidance.

Management of an acuteflare and induction ofremissionCD is characterised by periods ofremission followed by episodes of

relapse. Despite limited evidence,5-ASAs remain widely used in CD.It is, therefore, important toaddress the evidence supportingthis and summarise the currentguidance regarding their use.

Two landmark trials of sulfa -salazine conducted over 20 yearsago1,2 showed some benefit overplacebo in inducing remission inCD. The National CooperativeCrohn’s Disease Study2 demon-strated that, while sulfasalazine wassuperior to placebo, it was not aseffective as corticosteroids in induc-ing remission.

The only patients to benefitappeared to be those with colonic

42 Prescriber 5 September 2012 www.prescriber.co.uk

Current issues

5-ASAs in Crohn’s disease: are

they any better than placebo?Shuvra Ray BSc, MRCP and Peter Irving MA, MD, FRCP

5-ASAs are widely employed

in the management of

Crohn’s disease despite lim-

ited evidence for their effec-

tiveness. Here, the authors

assess the evidence base

and current guidance for

their use in inducing and

maintaining remission in CD.

Figure 1. Crohn’s disease in the transverse colon; although there is a wide evidence

base for the use of 5-ASAs in ulcerative colitis, the evidence supporting their use in

Crohn’s disease is inconsistent and contradictory

SP

L

involvement, sulfasalazine being nomore effective than placebo in ilealdisease. This may be due to therelease characteristics of the drug,which rely on cleavage of its azobond by colonic bacteria to releasethe 5-ASA from its carrier, sul-phapyridine. In addition the highincidence of sulphapyridine-associ-ated side-effects limits its tolerabil-ity and use.

Accordingly, sulfasalazine is nowgenerally only used in patients whohave IBD-associated arthropathy(which is thought to be improvedby the sulphur moiety).

Subsequently, four randomisedcontrolled trials have been con-ducted looking at the use ofmesalazine preparations (withsome small bowel-release character-istics) in inducing remission inmild to moderate CD.3,4,5,6 A meta-analysis of three of these studiesshowed a statistically significant butsmall improvement in CD activityindex (CDAI) scores in patientstaking Pentasa 4g daily overplacebo (63 versus 43 point reduc-tion). Such a small difference inCDAI is of questionable clinical sig-nificance.7

A more recent meta-analysis con-curs with this conclusion but alsonoted that dichotomous data from amuch larger trial were not included.Had these data been included it islikely that there would have been nosignificant difference betweenmesalazine therapy and placebo ininducing remission in CD.8

Routine use of 5-ASAs in activeCD is therefore not included inrecently published clinical guid-ance. European Crohn’s andColitis Organisation (ECCO) 2010guidelines state ‘mesalazineshould be considered clinically nomore effective than placebo foractive ileal or colonic Crohn’s dis-ease’.9 British Society of Gastro -enterology (BSG) 2011 guidancereferring to patients with active

Crohn’s ileocolitis states ‘the useof aminosalicylates as first linetherapy in this group is not justi-fied by the evidence’.10

However, a recent trial has chal-lenged this dogma. In a noninferi-ority study in patients with mild tomoderate CD comparing high-dosemesalazine granules (4.5g per day)with budesonide, the current first-line treatment in these patients,there was no difference in remis-sion rates. Sixty-two per cent ofpatients receiving mesalazineachieved clinical remission aftereight weeks of treatment comparedwith 69 per cent in the budesonidegroup (see Table 1).11

While these results are of inter-est, they must be interpreted inlight of the fact that this was not aplacebo-controlled trial and ques-tions regarding its design andpower have been raised.

Maintenance of medicallyinduced remissionOne of the key aims of manage-ment in CD it to maintain steroid-free remission in the long term.The evidence that mesalazine iseffective in maintaining medicallyinduced remission is inconsistent.

A recent meta-analysis of 15clinical trials concluded that theefficacy of aminosalicylates in main-

taining remission is equivocal atbest.8 This is supported by a 2005Cochrane meta-analysis that con-cluded that there was no evidenceto suggest 5-ASAs were superior toplacebo in maintaining medicalremission.12 However, other meta-analyses have identified benefitwhen 5-ASA is used for this indica-tion.13,14

We can conclude that the evi-dence base is inconsistent and con-tradictory, but that strong evidenceof benefit of 5-ASAs for this indica-tion is not available.

The ECCO 2010 guidelinesacknowledge the inconsistency inthe evidence base and conclude ‘5-ASAs are not recommended formaintenance of medically inducedremission in Crohn’s disease’,9 andthe BSG 2011 guidelines state‘There is no evidence that 5-ASA issuperior to placebo for the main-tenance of medically inducedremission’.10

Maintenance of surgicallyinduced remissionDespite significant improvementsin the medical management of CD,many patients undergo surgery fortheir condition. However, surgeryis far from being a cure for CD:most patients with ileocaecal CDwho undergo resection will develop

www.prescriber.co.uk Prescriber 5 September 2012 43

Current issues

Table 1. Noninferiority of budesonide vs mesalazine in active CD; CDAI = CD Activity

Index (after reference 11)

Median time to response 7 days 9 days not significant

(70-point drop in CDAI)

Median time to remission 11.5 days 13 days not significant

(CDAI <150)

Therapeutic benefit 89% 79.1% not significant

Complete remission 69.5% 62.1% 0.001 (for

noninferiority)

Budesonide Mesalazine p value

9mg/day 1.5g tds

(n=154) (n=153)

44 Prescriber 5 September 2012 www.prescriber.co.uk

Current issues

recurrence in the neoterminalileum. Endoscopic evidence ofrecurrence is found in 73 per centat one year and 85 per cent at threeyears.15

Relatively small trials performedin the 1990s assessed the efficacy of5-ASAs in reducing postsurgicalrecurrence and demonstrated effi-cacy over placebo.16,17 However, amore recent and much largerEuropean collaborative study didnot find overall benefit in the 5-ASA group versus placebo,although a suggestion of benefit inpatients with isolated small boweldisease was noted (see Table 2).18

A subsequent updated meta-analy-sis also suggests slight benefit.19

ECCO 2010 guidance states‘High-dose mesalazine is an optionfor patients with an isolated ilealresection’. However, it goes on tostate ‘Given mesalazine’s limitedeffect, no prophylactic treatment isan option in some asymptomaticlow-risk patients’.20

BSG 2011 guidance states thatmesalazine has a modest effect onpreventing relapse after surgery,with increased efficacy in patientswho have had a small bowel resec-tion. However, it also states that dueto cost and pill burden, mesalazine

should only be used in selectedpatients once more effective meas-ures have been implemented.10

SummaryThe evidence underlying the use of5-ASAs in CD is inconsistent andcontradictory. They are likely tohave a mildly positive benefit insome patients over placebo, butmore effective treatments shouldbe used for patients with anythingother than mild disease. They arerelatively safe and well-tolerateddrugs.

National and internationalguidelines have largely removed 5-ASAs as treatments for inducingand maintaining remission exceptin selected postsurgical patients,although recent data may chal-lenge this.

References1. Summers RW, et al. Gastroenterology1979;77:847–69.2. Malchow M, et al. Gastroenterology1984;86:249–66.3. Rasmussen SN, et al. Scand JGastroenterol 1987;22:877–83.4. Singleton JW, et al. Gastroenterology1993;104:1293–301.5. Mahida YR, et al. Digestion 1990;45:88–92.6. Tremaine WJ, et al. J Clin Gastroenterol

1994;19:278–82.7. Hanauer SB, et al. Clin GastroenterolHepatol 2004;2:379e88.8. Ford AC, et al. Am J Gastroenterol2011;106(4):617–29.9. Dignass A, et al. Journal of Crohn’s andColitis 2010;4:28–62.10. Mowat C, et al. Gut 2011;60(5):571–607.11. Tromm A, et al. Gastroenterology2011;140(2):425–34.12. Akobeng AK, et al. Oral 5-aminosal-icylic acid for maintenance of med-ically-induced remission in Crohn’sdisease (review). Cochrane Database SystRev 2005, CD003715.13. Messori A, et al. Am J Gastroenterol1994;89:692–8.14. Steinhart AH, et al. AlimentPharmacol Ther 2007;25:1389–99.15. Rutgeerts P, et al. Gastroenterology1990;99:956–63.16. Caprilli R, et al, Gruppo Italiano perlo Studio del Colon e del Retto (GISC).Aliment Pharmacol Ther 1994;8:35–43.17. Brignola C, et al. Gastroenterology1995;108:345–9.18. Lochs H, et al, ECCDS. Gastro -enterology 2000;118:264–73.19. Cottone M, et al. Gastroenterology2000;118:597.20. Van Asche G, et al. Journal of Crohn’sand Colitis 2010;4:63–101.

Declaration of interestsDr Ray, none to declare; Dr Irvinghas received honoraria fromFerring, Warner Chilcott and Shireas a speaker and for sitting on advi-sory boards.

Dr Ray is clinical research fellow and Dr Irving is consultant gastro -enterologist in the Department ofGastroenterology, Guy’s and StThomas’ NHS Foundation Trust,London

Table 2. Relapse rates at 18 months in postoperative CD (after reference 18)

All postoperative Crohn’s 31.4% (n=170) 24.5% (n=154) 0.1

Crohn’s involving colon 25.6% 26.3% not significant

(n=194)

Crohn’s not involving 38.7% 21.8% 0.002

colon (n=124)

Placebo Mesalazine p value

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