Comparative trial of remission prophylaxis in quiescent Crohn ' s disease with oral 4 ~ aminosalicylic acid versus S ~ aminosalicylic acid slow release tablets

S HOWALDT, A RAEDLER, H-C REINECKER, et al. Comparative trial of remission prophylaxis in quiescent Crohn's disease with oral 4-aminosalicylic acid versus 5-aminosalicylic acid slow release tablets. Can J Gastroenterol 1993;7(2):241-244. 4-Aminosalicylic acid (4-ASA) has been suggested co be effective in the treatment of active ulcerative colitis. Oral slow release tablets containing 4-ASA ( 1.5 g/day) were compareJ with those containing 5-ASA ( l.5 g/day) in the maintenance treatment of Crohn's disease in a one-year doubleblind, randomized study involving 60 patients with ileocolonic or colonic involvement. Patients were enrolled if in stable remission without active drugs for more than two months but less than one year. Total colonoscopy anJ ileoscopy were performed at enrollment and at the end of the study. The cumulative relapse rates at 12 months were 37% in the 4-ASA and 38% in the 5-ASA group. Clinical relapse, as defined by a rise in the C rohn's disease activity index (COAi) of more than 100 points co values higher than 150, was accompanied by a statistically significant rise m serum concentrations of soluble interleukin-2 receptor and by an increased percentage of activated peripheral blood T cells. There were no statistical differences between the 4-ASA and the 5-ASA goup regarding relapse rates, the rise in COAi during relapse or the increase of soluble interleukin-2 receptor concentrations. It is concluded that 4-ASA may be as effective as 5-ASA in the maintenance treatment of quiescent Crohn's disease and that there were no differences in the severity of relapse between both treatment groups. (Pour resume, voir page 242 )

4 -AMINOSALICYL!C ACID (4-ASA), also name<l para-aminosalicylic acid (PAS), is regarded as a relatively safe drug, following its use in the therapy of tuberculosis over many years.le is an isomer of 5-aminosalicylic acid (5-ASA), which is the active component of salazosulphapyri<line used in the treatment of inflammatory bowel disease (IBO).However, in comparison with 5-ASA, the sodium salt of 4-ASA is a more stable compound (1,2).Animal moJeb led to the conclusion char 4-ASA may have anti-inflammatory properties comparable to those of 5-ASA ( I ).Numerous clinical studies have shown that 4-ASA is highly effective in the topical treatment of u lccracive proctitis or left-sided ulcerative col itis (2)(3)(4)(5)(6).Moreover, 4-ASA slow-release tablets were shown to be effective in active ulcerative colitis (7).The results of a one year, double-blind, randomized and prospective tnal are reporte<l in which cnterically coaled 4-ASA was compared with a dose rate of 5-ASA at 0.5 g tid in the maintenance therapy of patients with inactive Crohn's colitis and ileocolicis.
On en concl ut quc le 4-A AS peuc ctre auss1 efficace quc le 5-AAS clan s le traitement J 'entre t1e11 de la maladic c.le Crohn s1lcncieu:se ct qu'il n ' y a c u aucune d iffe rence clans la gravitc J es rcch ut es ent re les deu.x groupes traitcs.

PATIENTS AND METHODS
Study criteria: In order to he included in th e study, pa tie nt~ with C rohn's colit1 ~ or ilcocoliu:.h aJ to be in ~cable rem1ss1on for more than two months wirh a Cmhn's disease activ ity inJex (CDA I ) of le ss tha n 150 po m cs.
Patie nts we re not caking any ac tive drugs, 5-ASA , ~tero1ds or othe r im• munosupprcss1ves o ne week hefore entry en the study.Pnu ents with less than 30 cm of diseased bowe l were excl udeJ h orn the stuJy, as we re patie nts m stable re m1~s ion fo r lon ger than on e year or with bowel resec tions more tha n 50 cm.Furthe r exclusion crite ria were previous, unsuccessful treatment with 5-ASA, hype rsensit ivity to 5-A SA compounds, and pregnancy a nd/or lactation .A medically npprovcd plan of contraceptio n was required for a ll menstruating fe males.If 1t was fe lt tha t the medi ca l pro blems the p a ti e nt developed during the trial we re due to the progess1ve formatio n of ste nnse:s, the patient was dropped from the study.Defined endpoints were the end of the study period or a relapse m disc.iseactivity, ,ls dcfincJ hy a m l' of the C DAI of more than 100 po ints to a resultin g value greate r than 150.The trial was granted pnor approval by the 111stitu-t ion.11 review h1.,arJs of the U niversity of H amburg and a ll pattcnrs signed a n informed consen t.A placebo group was not included because of e thical reasons (be nefit by 5-ASA , which is licensed fo r t h e ma inte n a n ce o f re miss io n therapy m Germany).
Patients: S ixty pa tients see n at the IBO clinics of University of Hamburg we re entered into th e trial and were randomized co 5-ASA o r 4-ASA.G roups were comparabl e 111 age, sex, duration of disease, disease manifestation , length of present remission a nd previous treatment.Forty patie nts ( I 9 on 4-ASA and 21 on 5-ASA) reached the pre<lcfineJ s tud y e ndpoi n ts, three p a t ie nts developeJ progressive stenoses anJ the rc ma mmg 17 pattcn ts we re dropped from the trial because of unreliabiltty in keeping their appointments.N one of the pa tients re moved from the cnal developed a cl inical relapse withm four weeks fo llowing the exclusion from the study.Protocol: At 1he initial v1s1c, history, physical examination, colonoscopy a nd stool cxaminati1.m for ova, parasites a nd entcm .pathogens was carried out a nd blood was drawn for electrolyte assessment, Jifferenttal blood count, sequent ia l mul t ipl e a n a lys is (S MA 12), determination of acti vated T cells and ~erum soluble interle ukin (IL)-2 receptor concentration.O ffice visits we re re pea ted a t mo nrh ly tnte rvals.The patients kept daily diaries m which they recorded the numbe r of bowel move-ment~ and scores for hlood, muc us, urge n cy , a bdo minal pa in a nd the appearan ce of excramccstinal manifesta tion s.Eac h office v1s1c included a physical examma u on, scrum elec:.trolyces, diffe rential blood count a nd S MA 12.
Eve ry three mo nths assess me nt of 1iolublc IL-2 receptor a nd ac tivated T cells was repeated .Patients were randomly assigned to cake e ither 500 mg 4-ASA t1d (Recd and Carn1ck/Block Drug Co, N e w Jersey) or 500 mg 5-ASA rid (Claversal; Sm1chKline Beecham, Pennsy lva111a ) .T ablccs we re coated with Euc.lragit S/L <les1gned to d issolve at pH 6.8.Colonoscopy and ileoscopy were performed at enro llment and at the study e ndpo int hy an cndoscop1st unawa re of the tnal.Endoscopy result~ we re classified by a score shown m Ta hlc l .

RESULTS
The patients ra ndomized were compa rable with respect co age, sex, dura• cion of disease, disease act1v1ty, symptoms and adjunc tive medication.O f 60 patie nts, 21 receiving 5-ASA   ( 17).None of them left the study because of relapse.T he cumulative relapse rates are shown in Table 2.
No statistical difference was found between the 4-ASA anti the 5-ASA group.
To determine whether the clinical severity of relapse was different between patients treated with 4-ASA anJ those on 5-ASA, the average rise in COAl scores before and after relapse was assessed in both groups.The COAi values (mean±SEM) of the relapsing patients treated with 4-ASA increased by 132±36, whereas the 5-ASA group showed an average rise of 14 7±40.Moreover, average endoscopic scores (mean±SEM) in patients relapsing were not different between treatment groups (3.1±1.2 for 4-ASA and 3.5±0.9for 5-ASA treated patients).There was also little difference in the disease activ ity of patients maintaining remission with 4-ASA (83.3±29) in comparison with those receiving 5-ASA (60.9± 23.4).
Immunological parameters including ~crum soluble IL-2 receptor concentrations and activated peripheral blood T cells can be used co monitor disease activity in !BO (8)(9)(10)(11)(12)(13)(14).A difference in the immunological degree of activation would be indicative for differences in Jisease activity during relapse m either of the treatment groups.However, both the rise of serum soluble IL-2 receptor concentrations (mean±SEM) during relapse (286±48 U/mL and 242±54 U/mL) and of activ::ited T cells ( 10.1±3.4% and 13.5±4%) were similar in the 4-ASA and the 5-ASA group, respectively.The increase in soluble IL-2 recepror concentrations during relapse was statistically significant ( P<O.O l) compared with clinically quiescent patients reaching the one-ye::ir study enc.I point.

DISCUSSION
This pilot trial indicates that oral 4-ASA may be as effective as 5-ASA in maintaining remission in quiescent Crohn's disease.Relapse races were not different between patients treated with 4-ASA and those treated with 5-ASA.Moreover, the relapse rates observed under l.5 g/day 5-ASA were similar co those observed 111 another trial studying maintenance of remission under 2.4 g/ Jay 5-ASA and using similar study inclusion criteria (15).This trial also included a placebo group, showing a spontaneous relapse rate of more th::in 50%.The height l)f the relapse rate is hest explained by the selection criteria Ir is possible that the severity of relapse would be different under treatment with 4-ASA compareJ with 5-ASA.However, ne ither by clinical (COAi, endoscopic score) nor by immunological parameters (serum soluble IL-2 receptor, activated T cells) could any difference in disease activity during relapse he found.Moreover, clinical disease activities (COAi) of patients mamtamed in remission were similar whether treated by 4-ASA or by 5-ASA.
4-ASA differs from 5-ASA in that it is more stable than 5-ASA , which is substituted in the meta position and therefore hreaksdown more rapidly in a watery solution ( 1,2).In contrast co 5-ASA no nephrocoxicity related to 4-ASA has been reported.The only ocher study which compared these two compounds examined the response to topical treatment in left-sided colitis ::ind showed that 4-ASA and 5-ASA were equally effective (6).
The anti-inflammatory mechanism by which the aminosalicylates exert their therapeULic action is unknown.5-ASA is a potent inhibitor of arachidonic acid metabolism, decreasing the synthesis of both leukotrienes and proscaglandins (16)(17)(18).Moreover, 5-ASA is a potent scavenger of free radicals (19)(20)(21).In contrast, 4-ASA does not seem to have an inhibitory effect of the lipooxygenacion of arachidonic acid and is ineffective as a radical scavenger (22).However, both drugs mhibit in vitro ::ictivation of T and B lymphocytes by pokeweed mitogen in a Jose-dependent manner (8,23 ).Animal models suggest that 4-ASA may be as effective as 5-ASA in terms of in vivo anti-inflammacory properties (1).These observations suggest that the use of either drug in IBO may decrease the heightened state oflamina propria lymphocyte activation as a part of their therapeutic action.Moreover, mechanisms not affecting arachidonic acid metabolism anti superoxide release may conrrihute to the therapeutic potential of both drugs in IBD.
4-ASA, which has been previously named para-aminosalicylic acid, has been used in the treatment of tuberculosis using resorbable oral doses ranging from 8 to 12 g/day.Consequently, considerable data on the drug's side effect profile have been generated from a large number of patients.The most common side effects include nausea, vomiting and epigastric pain.In a small number of cases, fever, joint pains, skin eruptions and hepatitis h ave been reported, which all may be attributed to hypersensitivity reactions (24 ).Very rarely seen arc more seriou~ side effects such as leukopenia, thrombocytopenia and agranu locytcosis (22).It may, therefore, be possible to use 4-ASA at much higher doses in a slow release formulation, perhaps resulting in greater therapeutic efficacy.It is concluded that oral 4-ASA therapy may be as effective as 5-ASA in CAN J GASm OENTEROL VOL 7 No 2 FERRUARY 1993 4-ASA for maintenance in Crohn's colitis used m the mal hy Pallone et al ( 15) ::inti in the present study inclutling only patients who had reached remission recently.

TABLE 1
Endoscopy score used to assess disease activity

TABLE 2
maintenance of remission 111 C rohn's disease.Moreover, several studies h:we shown that 4-ASA may be effective in the treatment of active Crohn's dbease or ulcerative colitis both as a topical formulation (enema) or as an oral ~low release tablet.Additional placebo controlled triab, mvolving a large number of patients, are warranted to investigate further this prom1s1ng compound. the