Preventing relapse in Crohn's disease -...

RECURRENCE AND ITS PREVENTION ~~~~~~~~~~~~~~~~~~~~~~~~

Preventing relapse in Crohn's disease

JEAN-PIERRE Gl'NDRE, MD

J,P GENDRE. Preventing relapse in Crohn'!> disease. Can J Gastroenterol 1993;7(2):237,240. Prcvcncmg rd.1pse rcm:uns a main challl.'nge in Crohn's di~eru.c. Three Jifkrcnt clinical situations should be cons1dcreJ separately. Fm,t, in patients in clinILal remission, the most useful drugs might be ~ulphasalazinc and its dcnvarivcs. Only 5-aminosalicylic acid ( 5-ASA ) has hecn l>hown to be l'ffectlvc m such pat 1enrs. lt b likely that 5-ASA, at a Jl)sc from 2 co 3 g per day, reduces the rdapSl' rate, particularly when used l.!arly ,1trer achic\'ing remission. \Vhat is che proper dosage? How long must the treamwnt last? Must patients with a long-standing remission be treated? The three question:, remam unans\\ercJ. Second, in patients clinically :md macro:,copically in remission seen immediately after surgery, then.· is no evidence of any drug dticacy co prevent clinical and/or endoscopic recurrence, but there is a slight trend in favl.1ur of 5-ASA. Third, in patients with chronic, mildly active discasl, when surgery must be ,\V\.lldcd because of anttdparcd dis:1bling con~cqul'l1Ct's, unmuno-supprcssants such as azathtoprme anJ/1.x 6-mcrcaptopurine seem the most appropn,1te anJ cffccnve Jrugs. Usctulness <1f methtotrexate and/or cyclosporine needs evaluation.

Key Words: 5-Ammosalicylic acid, Crohn's disease, lmmunosu[,prressives, Main­tenance creatmeru, Pharmacochera/)'\·

Prevention des redicts de la maladie de Crohns

RESUME: La prcventton Jes rcchures de la malad1e de Crohn <le-meure Lm problcmc mal rc:>olu. Trms situations dmi-ques diffcrentcs doivcnt etre cnvisagccs. I/Chez !cs mal,1des en remission dmique, yu'ils ail'nt ete ou non opcrc,:;. auparav:mt, les pwduits le:, plus utilcs sont la sulfapyridmc et ses derives. Seul le 5-ASA s'csr averc efficacc chez de tel, ma lades. II scmble crabli qu'a une posologie Je 2 a 3 g/j, le 5-ASA est capahlc Jc rcdmre la frfa;iuence des rcchutes, en particulicr chcz les ma lades qui v1cnnent d'etre mis en rcm1ss1on. Qucllc est la meillcure po~1.1logie? Comh1en de temps faut•il prulonJc!er le tra1rement? Faur-ii traitcr les malaJcs en remission dcpuis lungtcmps? Ces trots 4uestions restcnt pour !'instant sans rcponse. 2/Chcz Jes malades en remissilm clirnque ct macro­scopiqul' au decours J'une mtcrvent1on chirurgica lc, .1ucun rraill.'·ment n 'a fatt

De/>aroncm of Gmcroecnerology. Ho/1Hal Rothschikl. Paris. Fnmcc Corres/1oruknce anJ rc/>mm I )1 Jean-J>rcrrc l ii:n,lr,•. Dc/)(lrrmnu of Gmcrocnrcrnlo!!;i.

1-foprtal RuthKhild. 33 , Bcmlcnml Jc l'ic/111\. J'iQ 12 1',m.,. Franco'

C\NjG:\',11,t)ENHRl)l Vol 7NtlZ H1ml ,\R) Il)l)\

IN ULCERA1 IVE COLITIS. MAINTEN

anle treatment has been well csrnb­l1shcJ tor ., long ume. In contrnsc, prevcnung relapse in Crohn's disease remains an important therapeutic chal­lenge anJ should be discussed accord­mg to some ti( ll s relevant aspects, the most 1mporrnnc of whH:h 1s the cl1scase's natural hbtory The data collected from l he place ho groups in main­tenam;c therapeutic trials are very in­tercstmg m this respect. Clt111cal rdapscs occur ,lt a rate of 40 to 65% over ,I 12- to 24-month period ( 1-3 ). Results of mamtenance treatment mab arc J 1tficult to interpret in patients with 4u1cscent Crohn's disease because the patients arc not homogeneous with respect co their relapse risk. The easiest way tn ,malyze the results and/or straufy the pattt!nts in dm1cal cnals 1s prohably to take mm account rheir predous cl inical history. The typl' of remission ts .1bn of great value. Thcrctore, three dif­ferent clm1cal sccnanos will be d is­cussed separately: patients m complete dm1c,1l rem1ss1on, patients clin1cally and 1m1eroscop1c,1lly m remission un­mediately after surgery ancl patients '" ith a chronic, mildly active Jiscasc. Patients in complete clinical remis­sion: In panents with complete cl1111cal rcm1~~ion, the ,um of treatment ob­viously 1~ to m,11ntam a long-stanJmg

237

GrNPRI

prcuve J'activite :.au! unc lcgcrc tcn-dam:e en favcur du 5-ASA. 3/Chez le:, malades ,wee une fonne chmniquc moderemt·nt active lorsque la chirur-gic drnt crre cvitcc du fait de :,es consequences mvaltdantes prdvi:,1hles, l'azathiopr111e et/ou la 16-mercaptopurinc constituent les pmdu1ts !cs plus .1pproprics ct lcs plus cff1caccs. L'interet Ju mctho-tn:xate et/ou Jc la cyclo~porint· reste A etablir.

rcmbs1on with a wdl-tt1lcrated and easy-to-rah· drug.

The treatment of the a..:ute phase nf Cmhn's disease may 1nfluenLe , he fur ther clin1rnl course; thus, rt·miss111n Ill duced by an clenll'ntal du.:t has been sh(iwn to be shllfler than rcmiss,nn in duu:d hy stcnHds (4,5). In faLt, sus rained trcarmenr usu,11ly 1, advised.

Miscdlanc(>Us drugs such as oral BCG (6), levam1z(1le 0) or rifampic1n and ethambutol (7) have nnt heen found ltl he effeuin· m clinical rnab.

The most commonly ust'd drugs ,ire cmticostero,ds, and sulphas,1lazim: and ns Jcnvat1vcs. All controlled 1hera peuttc tnals ( 1,8-1 L) hut one ( 2) han· failed co show any hcnetit from either low dtlsc steroid or sulphasalazmc (and even 10 char stuJy (2), steroids alone or m cllmhmat1on with sulphasahmne were only effective in patients who rcsponJcd mitially tll treatment ot ac­tive disease; these drugs were not sig-111fitanth beneficial when used m macttve disease).

It has been suggested that ,ulpha­sabdnc efficacy was limited hy its side effects and therefore 5-ammosal,cyltc acid (5-ASA) might be useful when used at equivalent or higher dosage. ln accordance w,rh clinical results in acute phases, fl\·c controlled trials ( L 2-L 6) have been conducted tt1 test the effectiveness of 5-ASA as maintenance treatment. The results of these studies arc somewhat contradictory. Two of them (LZ,16) showed neg.itivc results. In hoth gmups, I ht: do~c was low ( Pcn­tasa [Brocade~ Pharma] I or 2 g per day, respect1vclv) and the rnal was of short duration (four months). In the first (L2), tlw number of patients mduded was only 46. Despite a greater number of patients ( 101 m each group) and a higher dose ( Pentasa 3 g per/Jay) m I he seconJ study ( 16), the cumulauvc per centage of relapses over 18 months was the same (29%) m the 5-ASA and the placebo groups, hut the durauon nf

rl'm1ss1on hdorl' l'ntry w.is nor r,1ken mto ,Knlunt. The thrL'l' orher trials found results in favour tlf 5-ASA.

In an 111tl'rnat1onal muluu:nrn .. trial ( I 3) (209 p,nicnts), the c:.umulauve pl'rCL'ntage of relapses llVer 12 mtmths was 22.2°0 on l'la\'ers,tl (Sm,chKlme hench) (1 5 g per day) ,·ersus 42.tNn on placeho (P<0.05). with the J,ffcrt·ncc more "1gmf,canr 111 partents with deal disease location ( L 3 ). In rhe FrenLh tnal condut.tcd hy the Groupe d'Etudc Thcrapl'UtllJUes lks Affectllll1S lntl,un­matoires du tuht· d,gcstif (C,ETAIL1) (14). 161 pat1enb were mduJed ma controlled trial of Pentas,1 ( 2 g per day) \'ersus placebo ti,·er two years. They were strat ified into two strata, presumed to hm c a different relapse risk: a low relapse risk ~tratum (LRRS) h>r patients 111 remtss1on from threl' to 24 months and a high rcl,1pse risk stratum (HRRS) for patients 111 rcm1s­s1on for less than three months. L1fetahlc analysis showed no s1g111f1Lant difference hctween treatment groups m the LRRS, but nnted a s1g111hcant J1f­fl'n~ncc in the HRRS ( P<0.00 3); in this ~tratum, the LUmularivc percentage of relapse in the Pentasa group was 28 and 5 5 at one and two years, resp,xti\ cly versus 68 and 71 m the placeho group. This d1ftcrence between the two strata was not confirmed by the Italian study ( 15 ); 111 that trial, Asarnl (G1uliarn and Bracco) (2.4 g per day) w.ts significant­ly better than placebo in a group of patienrs in remission for more than three months; the cumulative relapse r,1tes were 34% versus 55°0, respec­tively, m 12 months (P= 0.02).

Dt•sp1re these trials, a number of quesuons ahnut 5-ASA as mamte­nance treatment Crohn's disease remain without answer. What dose llf 5-ASA slrnuld be recommended, even ,fa dose of 2 1>r 3 g per day 1s used widely m prauice I Mamtenance treatment must prohahly be started as soon as pos­"'hk a!tcrcllh1ev111g rcmiss1tm, hut doc~

5-ASA faultt,tte steroid wcanmg 111

patients nch1e\ mg rem1ss1on on ,tcroids? HO\\ long should the treat­ment laM? One or two years? For the pauem\ life? Or, can trl'a tment he Stl ippcd afrer two or three years without rcl,1pse? b 5-ASA rnmpktcly sate llVer ,1 pml1mged period? Furtht·r tnals arc w.irrantcd to heir amwer rhe,e ques I i1ms.

Patients clinically and macroscopical, ly in rembsion immediately after surgery: If ,d i mauosc.opically patholog,cal tissue has been rt>mmeJ surgically, then the nsk pf anawm1c,1I ret. urrc1Ke has heen sho\, n to read1 80% over the n rst year ( I 7). Therefore, thi, group of patients provides a ver} acLuratc model tO test the efficacy pf different drugs, espec 1ally 1 ( the surgical procedure ,1llows endl1scop1L control ot the anasronws1s. No study h.1s <lemomrratcJ defi111te efficacy of an} drug tested (9.1 L,18-20). Nevenheless, in one trial (20) there was a slight trend in favour of 5-ASA co prevent endo­scopic. recurrence m ,1 three-month period after surgery: 50\}o on Clavcrsal (3 g per da}) \'ersus 63°1ii on placeho (P=0.16). Others trials arc needed to confirm these preluninary results.

Patients with chronic, mildly active disease: Patients with chrome milJly active disease arc usually stero,d-Je. pendent, bur dcspue steroid therapy they arc not totally symptom-free, and they relapse as soon as steroids arc dl'c rcased below the threshold ot stermd dependence.

If the level of steroid dependence " low (about LO mg per day), n is likely acceptahle to 01ntmue the same dost., especially if the patient has only a few symptoms. On the contrary, if 1t 1s higher than LO to 15 mg per day, the aim of treatment is nor only to achieve a complete rcnussion, but also to allow steroid sparing and/or weaning.

Bowel rest has heen proven to he effective either as total parenteral nutrition or as a total e lemental Jiet, but the results are often short-lived (21,22).

LymphlKyte aphercs1s remam.s con­troversial. It has been suggested to be of great promise 111 prcl,mmary uncontml-

238 l ,\NJ llASTR\)ENTERt)l VOi 7 Nt) 2 FFHRUARY 1991

le<l stu<lies (23 ), b u t in o ne controlle<l

Lrial it <lid not prevent early relapse

(24 ). lmmunosuppressants have prob­

ably their best indication in steroid-de­

pendent patients, when anticipated

consequences of surgery, such as exten­

sive small bowel resection resulting in

severe short bowel syndrome or proc­

tocolcccomy with permanent ileo­

stomy, arc like ly to be disabling.

Methotrcxatc is likely Lo he a useful

drug (25) but there is no controlled

tria l of its efficacy and cyclnsoprine has

no proven efficacy as maintenance

treatment (26,27). So the most often

used immunosuppressant d rugs are aza-

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2. Malchow H, Ewe K, Brandes JW, et al. European cooperative Cwhn 's di:,ease study (ECCDS); results of drug treatment. Gastroenterology l 984;86:249-66.

3. Modigliani R. Pieddeluup C. Hccketsweiler P. et al. Effet du levamizole sur la prevention des poussees evolutives de la maladic de Crohn quiescents: un essai prospectif multiccntrique controle sur I 55 rnalades. Gastroenterol Clin Biol 1983;7:683-92.

4. Gorard DA, I lune JB, Payne-James JJ, et al. Early response and subsequent rel::ipse rates in Croh n's disease treated with elemental diet or predn1solonc. A controlled trial. Gastroenterology I 99 l ;l00:A213. (Abst)

5. Seidman EG, Lohoues Mj, Turgeon), Boutillier L, Morin CL Elemental diet versus prednisone as initial therapy in Crohn's disease: Early ancl long term results. Gastroenterology 1991 ;JOO: A250. (Absc)

6. Burnham WR, Lennard-Jones JE, Hcckctsweilcr P, Colin R. Geffroy Y. Oral BCG vaccine in Crohn 's disease. Gut !979;20:229-33.

7. Shaffer JL, Hughes S, Lmaker BO, Baker RD, Turn berg LA. Controlled trial of rifampicin and echambutol m Crohn's disease. Gut l 984;25:302-5.

8. Baron JH, Bennet PN, Lennard Jones, et al. Sulphasalazine in asymptomatic Crohn's disease; a multicentrc trial. Gut 1977;18:69-72.

9. Bergman L, Krause U. Postoperative treatment with con 1cosreroids and salazosulphapyridine (Salazopyrinc) after radical resection for Crohn', disease. Scand J Gc1strocnteml 1976; l l :65 L-6.

thioprine and 6-mercaptopurine.

When used at the right dose (2 mg/kg per day for azathioprine, 1.5 mg/kg per

day for 6-mercaptopurine), the results

arc very encouraging, even 1f they arc

delayed, with a median time to an ef­

fective response of three months ( 15

days to nine months) (28). As a whole,

total remission (including steroid

weaning) is observed in about 50% of

the patients, with a partia l response

( improvement with reduction of

steroid dosage) in 25% additional cases

(28-31 ). When treatment is contmued,

the percentage of maintenance in

remission reaches 85% l)VCr one year

10. Smtth RC. Rhodes J, Heatley RV, ct al. Lnw Jose steroids and cl in Kai rdap:,e in Crohn':, disease: A controlled trial. Gut 1978; 19:606-10.

11. Wcnkert A, Kristensen M, Eklund AE, et al. The ltmg-term prophylactic effect of salazosulphapyridine (Salazopyrine) m primarily re:,ectcd patients with Crohn':, disease; a controlled douhlc-bl111d trial. Scand J Gastnienterol 1978; 13: 161-7.

12. Brignola C. Relapse prevenuon with Pentas;1 in Crohn's dise,1se. Proceedings of an 111ternat1onal work;,hop on inflamm::itory bowel diseases; I 987;Bolognc, 30-1.

13. Thomson ABR. lncernational Mesalazinc St uJy Group. Coated oral 5-ammosahcylic acid versus placebo 111

maintaining remission of inactive Crohn's disease. Aliment Pharmacol Therap 1990;4:55-64.

14. Gcndre JP ct le GET AID: Oral mesalamine (Penrnsa) as mamtenance treatment in Crohn':; disease: A multicentre placebo-controlled study. Gastroetncrology. (In pre&,)

15. Pallone F, Prantera C, Cottone M, Brunene G, Miglioli Mand an Italian study group. Ma111tenancc treatmcnr of Crohn's disease with oral 5-ASA (Asacol). Resu Its of a muluccntre nmtrolled crial. Gastroenterology 199l;LOO:A237. (Ahst)

16. &mdesen S, and the Danish 5-ASA-group. Mesalazmc (Pcntasa) as prophylaxis in Crohn's disease. A multicentre, controlled trial. ScandJ Gamocntcrol 199 l ;26(Suppl 183 ):F44. (Alm)

17. Rutgcerrs P, Gchocs K, Vantrappcn G, BeylsJ, Kerrcmans R, Hielc M. Pred1ctahility nf postlipcrnt1vc cuur-;c of Crohn\ disease. Uastroenterolugy I 990;99:956-6 3.

18 McLeod RS, Wolff BG, Baker J, et al. Prcvcntion of Crohn's d1,easc (CD) follu\\'mg sur!c(ical re,ccri,,n: interim

CAN J GA~"TROENTEROJ Vl1L 7 NO 2 FEBRUARY 1993

Preventing relapse in CD

(29). On Lhc other hand, 111 the only

published controlled trial (31 ), the

relapse rate uver one year after ran­

domized withdrawal of azathioprine

was 41 'Xi on placebo versus 5% m patients continuing azarhiopnne. The

results could he different for pat1cnb in

remission nn ,1wthioprine for a longer

period (two or three years). At

present, there are no data availahle to

recommend how long the treatment

must be conLinued. The therapeutic

value of azaLhioprine and/or 6-mcr­

captnpurinc must be halanccd against

a 10% rate of potentia l adverse ef­

fects.

report ('fa randomized controlled trial (RC..'T). Gamoenrerolugy 1990;98:A 191. ( Abst)

19. Fia,.st' R, Fontaine F, Vanhcuwrzwyn R. Prevention of Crohn's di:sca,c recurrences after intestinal resectinn w11h Eudr,1gn-L-cl,atcd 5-ammn-s;:il1cylic auJ. Preliminary results ,if a ,me year d,luble-blind placebo concrnlk·d ,tudy. Gastroentcrnl,)gy 1991: 100:A208. (Ahst)

20. Florene C. Cnrtor A, Qu::indale P, et al. Placeh,1-wntrollcd mat of C laversal (C) 111 che prevenuon of early end,1scop1c rl'l,1pse ::iftcr "curative" resection for Crnhn':; Disease (CD) G,1,rrncnterology 1992; 102:A. (Ahst)

21. Lerehour, E, Messing, Chevallic r B, Bone, C, Colin R, Bernier JJ. An evaluation of tlltal parenteral nutntton 111 the management of :,tcmid-dependent and steroiJ-rcsbtant pauents with Crohn's disease. J Parent Ent Nutr 1986; I 0:274-8.

2Z. Le Qumtrec Y, Cosnl!~ J, Le Quincrec M. ct al. L\d11nencation cnterale clcmcncaire exclusive dam les formes lOrtlCO-rCSIStantes et CllflK()•

dcpcndantc, de l.1 maladic de Crohn. Gastroentt•ml Clm RIOI 1987;11:477 82.

23. B1Lb RO, Grmh,1rt KW. The trc:it· mcm of chronic a<.:tiw Crohn's disca,c hy T -lymphncytc, aphercsis (TLA) Gastroen terol,igy 1990;98:A 160. (Ahsc)

24. Lerebours E and the GET AID. Controlled tnal of the efficacy of lymphocyte aphcrcs1s 111 preventing rclap,c m Cmhn's disease patient,. Gastroemcrolo1-,,y J 99l;100:A224. (Abst)

l.1. Ko:arck RA, Patterson DJ, Gelfand MD, Bowman VA, Ball TTJ, Wd,ke KR. Mechotrexate induces clm1cal and h1swk1gi( r,'mi:;s1on 111 patient:, with refractory inflamm,Hory bowel d1sea~c. Ann Intern Med 1989;110:353-6.

26. Lohn AJ, Juby LO, Rurhwell J, Poole

239

GEN DRE

TW, Axon AT. Long-term treatment of Crohn's disease with cyclosporine: The effect of a very low dose on maintenance of remission. J Clin Gastroenterol 1991;13:42-5.

27. Archambault A, Feagan B, Fcdorak R et al. The CanaJian Crohn's relapse prevention cnal (CCRPT). Gawo­enterology 1991;100:Al93. (Abst)

28. Present DH, Korclicz Bl , Wisch N, Glass JL, Sachar DB, Pasternack BS.

240

T rearment of Crohn's disease with 6-mercaptopurine. A long term, randomized, double-blind study. N Engl ] Med 1980;302:981-7.

29. Lemann M, Bonhomme P, Bitoun A, Messing B, Modigliani R, Rambaud JC. Traitemem de la maladie de Crohn par l'azathioprine ou la 6-mercaptopurine; etude retrospective chcz 126 mala<les. Gastrocnterol Clin Biol 1990; 14:548-54.

30. O'Brien JJ, Bayless TM, Bayless JA. Use of azachioprine or 6-mercapw­purine in the treatment ofCrohn's disease. Gastroenterology 1991;101:39-46.

31. O'Donaghue DP. Dawson AM, Powell-Tuck), Bwwn RL, Lennard-Jones JE. Double-blind withdrawal trial of azathioprinc as maintenance treatment for Crohn 's disease. Lancet I 978;ii:955-7.

CAN J GASTROENTtROL VOL 7 No 2 FEBRUARY 1993

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