Preventing relapse in Crohn's disease - …downloads.hindawi.com/journals/cjgh/1993/576071.pdf · RECURRENCE AND ITS PREVENTION ~~~~~ Preventing relapse in Crohn's disease JEAN-PIERRE

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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JT, <!t .ii. National cooperative Crolrn', disease study; resulis of drug treatment. Gastroenrerology 1979; 77 :84 7-69.

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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Preventing relapse in Crohn's disease - …downloads.hindawi.com/journals/cjgh/1993/576071.pdf · RECURRENCE AND ITS PREVENTION ~~~~~ Preventing relapse in Crohn's disease JEAN-PIERRE