Prevention of relapse in ulcerative colitis using oral or topical 5-- arninosalicylic acid therapy

LR SUTHERLAND. Prevention of relapse in ulcerative colitis using oral or topical 5-aminosalicylic acid therapy. Can J Gastroenterol l 993:7(2):232236. Since ulcerative colitis as a clm1cal entity can be characterized by its propensity for recurrence or relapse, it should not be surprising that attention has focused on altering the frequency of episodes of colitis. Foremost among the strategies has been the initial assessment and subsequent use of 5-aminosalicylic acid (5-ASA) preparations for maintaining remission. Aside from the introduction of cort1coscer0tds, no ocher innovation in therapy has had greater impact for patient quality of life. Probahly more 5-ASA preparations are used for maintenance than for induction of remission. There are numerous trials of varying quality which have assessed the use of different oral preparations of 5-ASA, including sulphasalazine, in maintaining remission. The early trials using sulphasalazine suggested a 75% reduction in relapses for patknrs caking medication. Recent trials have generally compared the newer 5-ASA oral preparations with sulphasalazine. The efficacy of topical therapy (enemas and suppositories), already demonstrated to be effective in the treatment of active distal disease, has also been demonstrated for maintenance of remission. Questions remain as to the frequency of administration and dose requireJ. Ocher issues include the possibility of intermittent 5-ASA for maintenance of remission and whether or not there are alternatives for the 5-ASA sensitive patient.

T HE THERAPY OF ULCERATIVE colitis was advanced by the introduction of three strategies: the use of corticosteroids for severe disease; the use of 5-aminosalicylic ac id (5-ASA) containing preparations for the maintenance of remission; and the development of sphincter saving proce<lures when surgery is required.T he natural history of recurrence before the introduction of 5-ASA is reviewed here anJ c linical predictors of recurrence iden• tified.The maj or clinical m als of maintenance therapy for both oral anJ topical 5-ASA arc summarized and alternate strategies, including intcrmit• cent 5-ASA therapy, as well a, alternatives to 5-ASA discussed.

NATURAL HISTORY OF RECURRENCE
Ulcerative colitis has typi cally heen characterized by inevitable recurrent episodes of symptoms.ln fact the occurrence of a single attack of'coliris' in the remote past with no fu rther recurrence is often used as evidence chat the attack probably was Jue co infectious causes rather than ulcerative colitis.In their review of 250 new cases of ulcerative colitis seen at the Radcliffe Infirmary between 1938 and 1962, Edwards and T ruelovc ( 1) reported a one-year recur• rence race of approx imately 80%.The majority of patients in their study were probably nut on any form of maintenance therapy as sulphsalazine was qualite variable, Ont evalue l'utilisation J e differentes preparat ions orales Je 5-AAS, y compris la sulphasalazine cla ns le maintic n de la remission.Les essais initiaux sur la sulphasalazine demoncrenc une reduction de 75% des recidives c hez les patien ts qui prennent le medica ment.Des essais recencs ont compare Les preparations orales de 5-AAS plus recentes avec la sulphasalazine.Le t raitemenc topique ( la vemen t et supposi to ire) a deja demon t re son efficacite dans la malad ie distale ac tive pour le maintien d e la remission .Des question s demeurenc quant a la frequen ce de !'administration ct la J ose requise.D'autres questions con cernent la possibilitc d 'un traitemen t intermittent au 5-AAS pour le maintien de la remission e t a la misc au point de solution s de rt>change ch ez les patien ts sensibles au 5-AAS.not widely used until welt into th e 1950s.In a population-based study of patients routinely trea ted with sulph asalazine maintenan ce therapy, approximately 80% had a relapse by the end ot the second year of fo llow-up ( 2).
Meyers a nd Ja nowicz analyzed th e clinical recurren ces in 174 patients ranJomi~cJ to placebo m trials of 5-ASA for ma inten an ce of remission (3 ).Their data should be interpreted cautiously because the effect of caking any med ication, even a p lacebo, cannot be d ismissed completely.In four trials, each of six months du ratio n, up to 5 1 % of patients (range 29 to 51 %) remained in remission .In two trials of mainten ance th erapy for 12 mon ths, remission was maintained 111 only 25% of pa tients.T his figure is a reasonable approximation of the Edwa rds a nd T rue love study cited above ( l ).

R ISK FACTORS FOR RECURRENCE
There a rc few studies on potential risk facto rs or marke rs which would indicate which pattencs arc at greate r risk of rec urrence.Most reports arc retrospective.A recent prospective study of 92 patien ts with ulcerative colitis in remission curre ntly taking either sulphasalzine or 5-ASA (A sacol; Procte r & Gamble ) fo und that 38% had a relapse during the n ext year ( 4 ).Patients who relapsed were c ha racterized as being more likely to h ave h ad a relapse during the year before entry into the study (97 ve rsus 56%, P<0.00 1).T h ey we re also noted to have been in remission fo r a shorte r pe riod of time compared with those who re mained in re mission (seven ver-sus 12 months, P<0.0 1).T he authors d id not find an y association between recent stressful life events, a ntibiotic ingestion or upper respiratory trac t infec tions and recu rren ce.They noted a seasonal variatio n; the majority of relapses occurred between August and February, with a peak in Septe mbe r and October.O the r investigators have reported that many flare-ups of ulcerative colits arc associa ted wirh upper respiratory tract infection (5 ).

ORAL 5-ASA AND MAINTENANCE
T he first tria l d emo n~tra ting tha t 5-ASA (sulphasalazine) alte red t he relapse risk was reported by Misiewicz a nd colleagues.During a I 2-month period, 24 of 34 patien ts ( 71 %) raking 2 g/day of sulphasalazme remained in remission compared wi th nine of 33 placebo-treated pa tients (27%) (6) .A subsequent study by Dissan ayakc and T ruelove (7) recommended th at sulph asa laz ine therapy be continued indefini tely.
Azad Khan and assoc iates perfor med a J ose ranging study o f 1, 2 and 4 g/day sulphasalazine in l 70 pa tients c urrently in remission ( mainly on 2 g/day) (8).They found significa nt diffe rences in recurrence related to the dose of 5-ASA given.A lthough patie nts given sulph asalazine 4 g/day h ad fe wer recurre nces than chose on 2 g/day, approximately I 0% of patients on the 4 g/day dose had to wi thdraw because of side effects.T wenty-one of th e 56 patie nts randomized co 4 g/day sulphasalaz inc reported adverse reactiom .This emphas izes the concept chat many side effects associated with sulphasalaz ine a re dose related as t he maJ,Hity of these patients had previously tolerated 2 g/day sulphsalazine.
T he mechanism of action by which 5-ASA is effective in mamce nam..c of remission is not clear.Its efficacy m active disease has been related to effects on leukotriene metabolism (9, I 0), oxygen free rad ical scavenging ( 11 -13) or other mecha nisms not yet described.Two scena rios are possible to explam the role of 5ASA in ma intain mg rcm i~sion .One possibility is that 5-ASA ts n ecessary to constantly either suppress the infla mmation or scavenge oxygen free rad icals when they are produced.T he other is that contin uous 5-ASA is effective hy being present when wha tever facto r(s) which trigger an acute episode appear(s) .
W ith the knowledge that 5-ASA was the active agent of sulphasalazine ( 14,15 ), t he nex t step was co develop d ifferent delivery systems for the su lpha-scns it1ve patient (16).Using Asacol, Dew was able to con tinue maintenance therapy with 5-A SA m L he maJon ty of previously sulphasalazine mtolerant pa tients.Of interest, I 0% of sulphasalazine intolerant patients were also intolerant to 5-ASA.

TOPICAL 5-ASA AND MAINTENANCE OF REMISSION
Th e efficacy of 5-ASA the rapy used as a n enema in the treatment of ulcerative proccosigmoiditis 1s well establish ed (27)(28)(29)(30).It is also effective when given as a suppository for patients with localized d isease (31)(32)(33).
Topica l therapy can be used to susta in remission (3 4-37).Sutherla nd and Marci n (34) compared the relapse rate in 29 patien ts who had already achieved remiss ion using 4 g 5-ASA ene mas.Patients were randomly assigned to either 2 or 4 g 5-ASA enemas taken at bedtime.Sixty-six per cent of patients remained in remission for the next six months.There were no differences in relapse rates between the two groups.Biddle and associates (3 5) studied 25 patients rando mized to either l g 5-ASA enemas ( 12 patients) or placebo (1 3 patients).O verthe next year only two placebo-treated patients remained in remission ( 15%) compared with 75% in the 5-ASA group.
D'Arienzo and a group of Italian investigators (3 7) demo nstrated tha t 5-ASA suppositories (400 g bid) compared with placebo in 30 patients with distal ulcerative proctitis were effective in maintaining remission .Ninety-two per cent of patients on 5-ASA were relapse-free at the end of a year compared with 21 % of placebo-treated patients.

IS THERE A ROLE FOR
'PRN' 5-ASA?Since the mode of action of 5-ASA is not known, it is not clear as to whether continuous 5-ASA is required co maintain remission .An alternative hypothesis would be that early treatment of relapse is the key issue and that continuous therapy is effective only because it ensures that 5-AS A is on hand when the colitis flares.Dickinson and associates (38) explored this hypo thesis in a clinical trial of 2 g/day sulphasalazine versus 3 g sulphasalazine taken at the first sign of relapse.During the trial approximately the same proportion of patients on either treatme nt regimen relapsed but the statistical power of the trial was low and the possibility of a type II error remains.Rectal biopsies fro m bo th treatment groups were reviewed blindly and the pathologist could not differentiate between those patients on continuo us 5-AS A and those on intermittent therapy.D'Albasio and associates (36) compared the efficacy for maintenance of remission for 4 g 5-ASA enemas taken fo r the first week of every month compared with 2 g sulphasalazine taken daily by mouth in 60 patients with distal colitis.A minor criticism would be that the trial was not conducted in a double-dummy fashion.Using lifecable analysis, the investigators demo n-stratec.lthat the relapse rates were similar for both groups.

lS THERE AN ALTERNATIVE FOR THE 5-ASA SENSITIVE PATIENT?
Approximately l 0% of patients who report adverse reactions while taking sulphasalaz ine will also be intolerant to 5-ASA preparations.A variety of alternatives to 5-ASA have been assessed , including corticosteroids (39-42), azathioprine (43,44) , met ronidazole (45 ), cromoglycate (46) and levamisole ( 4 7) .Interpretation of these studies is often difficult as the sample sizes are generally small and the statistical power is low.
Soon after the initial reports that corticosteroids were effective in t he therapy of active ulcerative colitis (39,48 ), a variety of studies assessed the efficacy of steroids for maintenance therapy, given e ither as an enema twice weekly (39) or taken each day by mouth either as 50 mg cortisone ( 40 ) or 15 mg prednisone ( 41) .These trials fa iled to demonstrate any efficacy fo r corticosteroids in maintaining remission .Powell-Tuck and associates (42) hypothesized that steroid therapy, if given in a high enough dose, could be effective.They speculated that an alternate day regimen would allow the use of a higher dose of corticosteroid ( 40 mg prednisolone) and alter the side effect profile.They performed a crossover trial in 3 1 patients in remission, the majority of whom continued sulphasalazine.Using life table analys is, significant differences in recurrence rates were identified in the 24 patien ts who completed both treatment cycles.A greater percentage of prednisolonetreated patients remained in remission compared with placebo-created patients (80% versus 46%, 0.05>P>0.02).
Azathioprine has been assessed, generally in combination wi th corticosteroids, in the treatment of active ulcerative colitis and fo und to offer little benefit (43 ).However, Jewell and Truelove, in the maintenance phase of their trial, fo und fewer relapses m patients with a past history of recurrence who continued on azathioprine (2.5 g/kg), but the diffe rence in relapse did not qui te reach statistical sign ificance.Hawt horne and col leagues ( 44) recen tly reportec.lpreli minary results of an azathioprine withd rawal trial for patients t hough t to have responded to azachioprine.Patients were randomly ass igned to continued azathioprine or placebo.Recurrence was reported more frequently for placebo-treated patients compared with those remaining on active therapy (56 versus 33%, P=0.04).
Metronidazole is not effective in the treatment of active ulcerative colitis either as monotherapy ( 49) or adjunctive therapy in comhinarion with corticostero id (50).G ilat and colleagues ( 45) compared the efficacy of metro-n1dazole (600 mg dail y) and su lphasalazine (2 g/Jay) in mamtaining remission for 12 months.The relapse rate was high in bo th groups, with 12 <if the 15 sulphasalazi ne-treated pattents relapsing compared wi th 11 of the 20 metro nidazole treated patients.Statistically significan t differences, however, cou ld be detected using life-cable analysis.T he study resu lts should be in terpreted cautiously as t he rclapM~ rate fo r t he sulphasa lazi nc-treatcd patients was unusually high.
Sodium cromoglycate is effective m type l hypersensitivity reactions, perhaps through its ability to stabilize mast celk S ince masr cells may be important in ulcerative colitis, cromoglycate ha, been assessed for both active ulcerative colitis and for ma intenance of remission.A group of British gastroenterolo• gists compared the remission sustaining properties of cromoglycate in pa tients stratified by concurrent use of sulphasalazine (46).T here was no benefit fo r t he combinabon of SLilphasala:inc plus cromoglycate compared with sulphasalazine alone.ln a small group of patients who were not tak ing concurrent sulphasalazine (18), fewer relapses occurred on patients ra ndomized to cromoglycate (400 mg qid) compared with placebo-created patients, but this <lid not reach statistical significance.
Levamisole has also been assessed ,b a potential agen t fo r maintenance of remission.In a placebo-controlled, two-year study of this immuno~timulan t, no c.l ifference in relapse rates could be identified (47).
In conclusion, the use of 5-ASA containing preparations has a ltered the natural history of ulcerative colitis by prolonging the time in remission.It would appear chat the 5-ASA preparations are effective in ma intaining re mission.Topical therapy is effective and there is preliminary evidence co suggest that intermittent use of 5-ASA may be poss ible.A lternatives co 5-ASA for the 5-ASA sensitive patient have no t heen idenrified.