preventing relapse in crohn's disease · 2019. 8. 1. · results of mamtenance treatment mab arc j...
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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 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.
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IN ULCERA1 IVE COLITIS. MAINTEN anle treatment has been well csrnb-l1shcJ tor ., long ume. In contrnsc, prevcnung relapse in Crohn's disease remains an important therapeutic chal-lenge anJ should be discussed accord-mg 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 main-tenam;c therapeutic trials are very in-tercstmg 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 dif-ferent clm1cal sccnanos will be d is-cussed separately: patients m complete dm1c,1l rem1ss1on, patients clin1cally and 1m1eroscop1c,1lly m remission un-mediately after surgery ancl patients '" ith a chronic, mildly active Jiscasc. Patients in complete clinical remis-sion: In panents with complete cl1111cal rcm1~~ion, the ,um of treatment ob-viously 1~ to m,11ntam a long-stanJmg
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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 ac-tive disease; these drugs were not sig-111fitanth beneficial when used m macttve disease).
It has been suggested that ,ulpha-sabdnc 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 ( Pcn-tasa [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 (PmmeJ 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
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le
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
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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). Gawo-enterology 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
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