New Therapeutic Agents in the Treatment of Inflammatory Bowel Disease DAVIDL. GEIER,M.D., PHILIP B. MINER, JR., M.D., Kansas City,

Despite intense investigation the etiology of . mflammatmy bowel disease (IBD) remains unknowa Recent studies with new therapeutic agents provide insight into the pathogenesis of IBD through analy& of the clinical response to pharmacologic agents whose mechanism of action is understood. Until new agents are established, lBD will be treated with conventional drugsdirectedtowardmodifyingthei4ammatory responsea responsible for gastrointestinal mucoeal damage Sulfasahvine, mesalanke (5aminosalicylic acid), and corticosteroids will continue to be the mainstay of therapy for the foreseeable future. Antibiotics such as metronidazole and immunosuppressan ts such as 6-mercaptopurine and methotrexate are useful in Crohn’s disease and ulcerative colitis in selected casea Many new exciting agents are being investigated and show encouraging results in the treatment of IBD. Tbis article reviews the agents used in IBD with an emphasis on new therapeutic agents.

From the Division of Gastroenterology. The University of Kansas Medical Center, Kansas City, Kansas. Requests for reprints should be addressed to Philip 6. Miner, Jr.. M.D., Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66103. Manuscript submitted December 12, 1991, and accepted in revised form March 25,1992.

Kansas

I

nflammatory bowel disease (IBD) is broadly categorized into two different diseases, Crohn’s disease and ulcerative colitis. Treatment regimens have many similarities even though the diseases have widely different presenting symptoms and their response to treatment varies. The introduction of sulfasalazine in the 1930s was a major advance in the treatment of IBD, although there was not widespread acceptance of its value until the mid-1950s. Until recently, treatment was limited to sulfasalazine and high-level immunosuppression with corticosteroids. Allergy and intolerance to sulfasalazine and systemic side effects caused by corticosteroids have interfered with effective treatment. Over the past decade, new agents that have been utilized in IBD improve medical management by achieving a decrease in the medication-induced side effects and by increasing the number of patients entering and being maintained in remission. There are multiple potential steps in the inflammatory response where specific agents can be utilized to modify the tissue damage that occurs in IBD. T and B lymphocytes, polymorphonuclear leukocytes, mast cells, eosinophils, basophils, tissue macrophages, and monocytes all have a vital role in the cellular inflammatory response. The inflammatory response is an essential reaction to environmental stimuli, but, in the process of protection, many toxic compounds such as eosinophilic basic protein and oxygen-derived free radicals invoke damage to the gastrointestinal mucosa. Modifying the inflammatory response may by useful in limiting the tissue damage while not interfering with the beneficial aspect of inflammation (Figure 1). Many cells participate in the inflammatory process through a number of different molecular mechanisms. An important role is played by the arachidonic acid pathway, which gives rise to the leukotrienes and prostaglandins (Figure 2). Treatment of IBD has been targeted toward specific areas in this complex system to modify the immune response. Agents such as corticosteroids and mesalamine (5aminosalicylic acid, 5-ASA) influence several sites in the inflammatory response. Other agents work in only one site. Current research is investigating which of these sites are the most significant in the inflammatory response in IBD. The objective of this review is to identify the recent adAugust 1992 The American Journal of Medicine

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Figure 1. Cellular components of inflammation in inflammatory bowel disease (IBD): Multiple cellular components are involved in the inflammatory response in IBD. Many therapeutic agents inhibit various pathways in this immune response. Arrows wlth double lines = inhibits; circles = therapeutic agents; 6-MP = 6-mercaptopurine; MTX = methotrexate; IL-2 - interleukin 2; IL-1 = interleukin 1; LTB4 = leukotriene B4; PGD2 = prostaglandin De; PMN’s = polymorphonuclear leukocytes; GI = gastrointestinal.

vancesin the treatment of IBD with an emphasison fasalazineis a cornerstoneof medical therapy for new therapeutic agentsand their role in modifying patients with IBD. the immune response. During the 1966s,the mechanism of action of sulfasalazinewas unknown but suspectedto be reAMINOSALICYLATES lated to the antibiotic action of the sulfapyridine Sulfasalazineis an aminosalicylatecomposedof a moiety in sulfasalazine.Oral sulfasalazinereaches mesalaminemoleculeconnectedto sulfapyridine by the colon intact wherethe diazo bond is cleavedby a diazo bond. Nana Svartz first observedthe poten- colonic flora, liberating the me&amine and sulfatial utility of sulfasalazinewhen colonic symptoms pyridine. In 1977,Azad Khan et al [3] comparedthe improved in patients treated with sulfasalazinefor effectivenessof enemas of sulfasalazine,mesalatheir IBD-related arthritis [l]. The value of her ob- mine, and sulfapyridine in patients with left-sided servation was not completely understooduntil the colitis. They documented that sulfapyridine was 1959swhen trials with sulfasalazinedemonstrated not effective in inducing remission,whereasmesaits efficacy in inducing remission in patients with lamine was aseffective assulfasalazinein inducing chronic ulcerative colitis [2]. By the mid-196Os,sul- remission. Subsequently,mesalaminehas beenacfasalazinehad becomethe most important drug in cepted as an effective agent in treating IBD. Curmaintaining remission.Becauseof its efficacy, sul- rently, the theories on the mechanismof action of

n-6-fatly

acids

1 MEMBRANE

PHOSPHOLIPIDS

1

Figure 2. Molecular components of inflammation in inflammatory bowel disease (IBD): The arachadonic acid pathway is important in the inflammatory response in IBD. Many of the agents used to treat Crohn’s disease and ulcerative colitis modify this pathway as shown in this figure. Arrows wlth double liner = inhibits; clrcler = therapeutic agents; PAF = platelet-activating factor; = nonsteroidal anti-inflamNSAID’s matory drugs; 5ASA = mesalamine (Baminosalicylic acid); LTB4 = leukotriene B4; LTC4 = leukotriene C4; LTE4 = leukotriene E4.

PROSTAGIANDINS

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TREATMENT OF INFLAMMATORY BOWEL DISEASE / GEIER AND MINER TABLE I Aminosalicylate Enemas Drug

Dose

Clinical Situation

Mesalamine

4-g retention enema hs

Mild/moderate

Mesalamine

4-g retention enema hs

Mesalamine (Rowasa)

left-sided UC

Efficacy

Reference

93% clinical, 93% endoscopic, 77% histologic remission

f51

Left-sided UC

55% decrease in disease activity index, rapid response in 3 d

161

4-g retention enema hs

Left-sided unresponsive UC

80% remission at 34 wk

f71

Mesalamine (Rowasa)

l-g retention enema hs

Remission maintenance left-sided UC

Significant decrease in relapse

f81

4-ASA

2-g retention enema hs

Active left-sided UC

83% clinical, endoscopic, histologic improvement in 8 wk

no1

hs = at night; UC = ulcerative colitis; 4.ASA = 4.aminmalicyic acid.

mesalamineinclude: inhibition of natural killer cell activity, inhibition of antibody synthesis,inhibition of the cycle-oxygenaseand lipoxygenasepathways, impairment of neutrophil function, and ability to act asa potent scavengerof oxygenradicals [4] (Figures 1 and 2). Although sulfasalaxine is an effective agent in treating active colitis and in maintaining remission, many patients are allergic or intolerant to it. Most of the allergic or intolerant problems are due to the sulfapyridine moiety. This problem led to the development of experimental protocolsfor a variety of new medications designedto deliver mesalamineto the colonin ulcerative colitis and to the small bowel in Crohn’s disease.The challengefor the pharmaceutical industry is to deliver the maximum amount of mesalamine to the area of active diseasewhile limiting the absorption of mesalamine.

absenceof the sulfapyridine moiety and the low absorption of mesalamine from the rectum. Less than 20% is absorbedfrom the colon, acetylated, and excretedin the urine [9]. Four-ASA enemasare effective in treating distal ulcerative colitis, but they have receivedless attention than me&amine products [lo]. In summary, aminosalicylateenemas are efficaciousand safein treating active left-sided ulcerative colitis (Table I). Mesalaminesuppositoriesprovide a lower doseof active medicine to a smaller surfacearea of the colon than enemasand aremost useful in proctitis. In two double-blind, placebo-controlledtrials, 500-mg rectal suppositoriesgiven either two or three times per day showedsignificant improvement of proctitis overplacebo.There wasno statistical differences between500mg twice daily or 500mg three times a day [ll].

Local Mesalamine

Oral Mesalamine

The simplest delivery of high concentrationsof me&amine is met by providing local application to the rectal mucosa with enemas of mesalamine. Campieri and co-workers[5] comparedmesalamine enemaswith hydrocortisoneenemasin 86 patients with mild to moderately active distal ulcerative colitis. Patients receiving mesalamine had a significantly better clinical, endoscopic,and histologic response (Table I) [5]. In a multicentered trial, Sutherland et al [6] reported a 63%responsewith mesalamineenemascomparedwith a 29%response to placeboin ulcerative colitis patients (p = 0.001). Patients respondedrapidly to mesalamine with a decreasein rectal bleeding within 3 days.Biddle et al [7] demonstrated the efficacy of the long-term useof mesalamineenemasin inducing remission in 80%of patients by 34weekswho wereunresponsive or intolerant to conventionaltreatment. The toxicity of the mesalamine enema is low becauseof the

Oral me&amine is efficiently absorbedfrom the small bowel (52% to 93.1%renal excretion), and, therefore,high concentrationsdo not reachthe colon. Four novel delivery mechanismshavebeendevelopedto delay the releaseof mesalamineuntil it reachesthe colonicsite of inflammation. Theseformulations include: (1) mesalamineconjugatedto an inert molecule; (2) me&amine conjugated to another mesalamine molecule; (3) delayed-release coatingof mesalamine;and (4)pH-sensitive coating of the mesalamine molecule (Table II). The first oral drug approvedin the United Stateswas olsalazine,which combinestwo mesalaminemoleculestogetherby a diazobond. Olsalazinerequiresbacterial axoreductaseto break the bond between these two moleculesonce the compound reachesthe colon. This is a very effective medication in terms of delivery to the colon, since the renal excretion of oral mesalamine is similar to the renal excretion

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TABLE II Oral Aminosalicylates Drug (Trade Name)

Release Mechanism

% Renal Excretion

Dose

Use

52-93.1

NA

NA

23.9 (16.6-32.6)

2-4g

Active UC and CD, remission maintenance UC

Plain 5ASA

None

Sulfasalazine (Azulfidine)

Colon~bacterial

Olsalazine sodium (Dipentum)

Colonic bacterial cleavage of diazo bond

Mesalamine (Asacol)

Coated with Eudragit-S release at PH 7

Mesalamine (dlaversal, Salofalk)

Coatt6with

Mesalamine (Rowasa)

Coated with Eudragit-L-100

30

Mesalamine (Pentasa)

pH- and time-released

28

cleavage of diazo

27

(19-41) 20

Eudragit-L release at

lg 8OD-2,400

AC;; mg

-37

UC, remission maintenance

Ac;~;;~CU;CD,

remission mainte-

Ac;~;;~CU;CD,

remission mainte-

Currently not in use orally

1,500-4,000 mg

Active UC and CD, remission maintenance UC

5-ASA = mesalamine(5.amincsalicylic acid); NA = not available; UC = ulcerative colitis; CD = Cmhn’s disease.

after enemas of mesalamine [12]. Meyers et al [13] showed that 35% of patients receiving olsalazine improved clinically, compared with 16% of patients receiving placebo in a group that was sulfasalaxine intolerant. Unfortunately, 12.5% of patients using olsalaxine develop small bowel secretion resulting in diarrhea [14]. Balsalazide is similar to olsalaxine except the mesalamine moiety is conjugated to an inert compound instead of a second mesalamine molecule. It is activated through the same bacterial axoreductase that degrades the diaxo bond of sulfasalazine and olsalaxine [15]. The delayed-release coats of mesalamine fall into two broad categories: a time-release coating and a pH-dependent coating. Et&&-coated drugs release mesalamine at a defined pH (Table II). Generally, when the pill passes from the ileum into the colon, the pH changes and the drug is released. These drugs have been effective in treating active ulcerative colitis with very few side effects [16-X3]. Mesalamine encapsulated in a bead with a semipermeable membrane allows slow release from the bead. Release is dependent on the rate of water absorption and the pH-dependent solubility of the encapsulated mesalamine. This formulation, Pentasa, is also effective in ulcerative colitis and has the theoretical advantage of small bowel release, which may be desirable in Crohn’s disease [19]. The delayed release formulations are also effective in remission maintenance [20,21]. In an open trial, Rasmussen et al [22] showed that 500 mg three times a day of Pentasa improved the clinical course of 13 of 18 patients with active Crohn’s disease. In a subsequent trial, there was no significant difference between patients receiving 202

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1,500 mg Pentasa or placebo [23]. Using larger doses of Pentasa, 4 g/d, compared with placebo, Hanauer et al [24] demonstrated statistically significant reductions in the Crohn’s disease activity index (mean reduction of 78 with a p = 0.0072) in 199 patients with active Crohn’s disease. In summary, the new oral mesalamine products are very useful in the sulfasalazine intolerant or allergic patient with ulcerative colitis and may be useful in patients with Crohn’s disease. Acetyb5Aminosalicylic Acid The colonic mucosa converts 5-ASA (mesalamine) into acetyl-5-ASA, raising the important possibility that acetyl-5-ASA is an important metabolite for the treatment of IBD. In 1980, Willoughby et al [25] reported an early trial suggesting that acetyl-5-ASA was effective in inducing remission. Although this early study was optimistic, more recent evaluations by Binder et al [26] and Van Hogezand et al [27] dismissed acetyl-5-ASA as an active metabolite since the clinical response was no different than that of placebo controls. Remission Maintenance Both topical and systemic forms of mesalamine have been effective in maintaining remission in ulcerative colitis. Biddle et al [S] studied the effectiveness of l-g mesalamine enemas or placebo in 25 patients with left-sided ulcerative colitis in remission. After 1 year of follow-up, 11 of 13 patients receiving placebo experienced relapse, whereas only 3 of 12 receiving mesalamine enemas experienced relapse [8]. Oral sulfasalazine is effective as a single agent in maintaining remission in ulcerative colitis, 93

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with a relapserate of 14%at 6 months (21.Olsala- TABLE III zine (500mg twice a day) resulted in a 23%relapse rate at 6 months comparedwith a 44.9%relapserate Topical Corticosteroidsin IBD in a placebo group [14]. Both Asacol and Pentasa Established New:LowSystemicAvailability havebeen effective in maintaining remission in ulBeclamethasone diproprionate Hydrocortisone cerativecolitis, with fewer sideeffectsthan sulfasaBetamethasone Prednisolone metasulfobenzoate sodium laxine [20,21].Although mesalamine products are useful in remission maintenancein ulcerative coliBudesonide Prednisolone41-ohosphate tis, fewer data are available for remission mainteTixocortol pivalate nancein Crohn’s disease.With the delayed-release compounds, it is postulated that improved small bowel delivery of mesalaminemay result in effective remission maintenance in Crohn’s disease. responsein four of six versussix of six), whereas only the beclomethasoneenemasdid not have an CORTICOSTEROIDS adverseeffect on the hypothalamic pituitary axis as From the early 1950suntil the early 198Os,corti- assessedby the cosyntropin test [29]. In two trials, costeroids were considered the most important prednisolone metasulfobenzoate sodium enemas drugs for the managementof ulcerative colitis and were aseffective asprednisolone-21-phosphateenCrohn’s disease.Initially hydrocortisone,then cor- emasand producedlower plasma prednisolonelevticotropin, and later prednisoneand prednisolone, els [30,31].In a recent study, Danielssonet al [32] were shownto improve symptoms in patients with showedthat budesonideenemaswere superior to ulcerative colitis and Crohn’s disease.Corticoste- prednisolonedisodium phosphateenemasin 64 paroid action in IBD involves multiple nonspecific tients with active left-sided ulcerative colitis (52% anti-inflammatory and immune response-modify- endoscopichealing versus24% endoscopichealing ing mechanisms (Figures 1 and 2) [4]. The site of at 4 weeks).No suppressionof plasma cortisol levels action most important in IBD is unknown. Current occurredin the budesonidegroup.Tixocortol pivapractice limits the role of corticosteroids in the late, a locally active anti-inflammatory steroid with treatment of IBD to patients in whom sulfasalaxine no effect on the hypothalamic pituitary axis, was or mesalaminefails or to patients who areseriously shownto be as effective as hydrocortisoneenemas ill. When feasible,corticosteroidsshouldbetapered in left-sided ulcerative colitis in 125 patients [33]. as quickly as possible (about 0.5 to 1 mg/d) while These new topical corticosteroidswith diminished maintaining remission with an aminosalicylate. systemiceffectswill undoubtedly be helpful for the The widespreadphysiologic effectsof corticoste- long-term managementof IBD either in the form of roids result in a predictable array of side effects. enemasor delivery by the newer pharmaceutical Strategiesto decreasethe side effectsof corticoste- technologysimilar to the systemssuggestedfor meroids include: (1) useof well-defined,rapid tapering salamine delivery (Table III). schedules;(2) useof every-other-dayschedules[28]; (3) substitution of rectally administered steroids IMMUNOSUPPRESSANTSI for oral steroids; and (4) the development of new IMMUNOMODULATORS ’ agentswith low systemicbioavailability. The useof Specific immunosuppressantsand immunomotopical rectal corticosteroids decreasesthe most dulators act at distinct points in the immune redisconcerting symptoms of IBD such as tenesmus sponse.Many have proven useful in the treatment and the urgent call to stool by suppressinginflam- of IBD (Figures1 and 2). Immunosuppressivethermation in the rectum and in the sigmoid colon. apy hasbeenimportant in Crobn’s disease,and inSymptoms usually improve even though colitis formation on efficacy is emerging in the manageabove the rectum may continue to be active. ment of patients with ulcerative colitis. Several Systemic availability of corticosteroid prepara- trials with variousimmunosuppressantshave demtions can bediminished by active metabolism at the onstrated efficacy in treating active IBD, in decolonic mucosal surface or by effective fiit-pass creasing corticosteroid doses,in healing perineal hepatic clearance. Beclomethasone dipropionate disease,and in maintaining remission. has beenusedasa topical corticosteroidin asthmatics. When given as an enema for IBD, it has low Azathioprineand &Mercaptopurine(6MP) systemic bioavailability becauseof high first-pass Axathioprine is an immunosuppressantthat inclearance.In one trial comparing beclometbasone terfereswith puke biosynthesis.It is useful in redipropionate enemaswith traditional betametha- nal transplant managementand has beenteatedin soneenemas,similar efficacy was observed(clinical IBD. Data from the National CooperativeCrohn’s August

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DiseaseStudy did not showa significant difference betweenaxathioprineand placeboin treating active Crohn’s disease,and great concernover sideeffects emergedwhen2 of 54patients developedpancreatitis [34]. Discouraging results with axathioprine shifted researchemphasisto 6-MP, which is an active metabolite of axathioprine. It has been evaluated in severalrecent trials. 6-MP is known to inhibit purine bioeynthesisand thus results in decreasedinflammatory cell proliferation [4]. In an important trial in unresponsiveCrohn’sdiseasepatients, Present and colleagues[35] observedsignificant clinical improvement, fistula closure,and discontinuation or reduction of corticosteroiddoseusing 6-MP ascomparedwith placebo.The onsetof responseto 6-MP wasoften delayed,with a meanresponsetime of 3.1 months. Adverseside effectsoccurredin 10% of patients and wereall reversible.Alder and Korelitx [36] reported IS-year follow-up data on 158patients receiving 6MP and confirmed efficacy in eliminating corticosteroids(67%)and in healingabscessesand fistulas. Korelitx et al [37] reportedimprovement in fistulas in 34 patients with Crohn’s disease.Thirteen patients had complete closureof their fistulas, while another9 patients showedobviousimprovement in a mean of 3.1months [37].Perrault and colleagues[38] at the Mayo Clinic retrospectivelyobservedthat of 19patients with Crohn’s disease,47%showeda complete or partial response to 6-MP. One retrospective study measuring the effectivenessof 6MP in 81 patients with recalcitrant ulcerative colitis showed favorable results with respect to eliminating or reducing steroids (61%) [39]. Toxicity associatedwith 6MP has been an important concern.Present et al [40] retrospectively reviewed 396 patients who received the drug for IBD. Follow-up data for a mean of 60.3months was obtained. Pancreatitis occurredin 3.396,bone marrow suppressionin 2%,allergic reaction in 296,and drug-inducedhepatitis in 0.3%.All reportedtoxicities were reversible,and there were no deaths.Because of encouragingresults with 6MP and the manageableside effects,it should be consideredin the treatment of patients with refractory Crohn’s diseaseor in those patients who are intolerant to arninosalicylatesor corticosteroids.

ceived25 mg methotrexateintramuscularly weekly for 12 weeksand then were switched to oral tapering schedules. Sixteen patients (11 of 14 with Crohn’s diseaseand 5 of 7 with ulcerative colitis) improved when assessedby the diseaseactivity index. In addition, patients with Crohn’s diseaseand ulcerative colitis wereable to decreasetheir prednisonedosefrom 21.4mg to 5.5mg and 38.6mg to 12.9 mg, respectively. Side effects included transient leukopeniain one patient, mild increasesin aspartate aminotransferaselevels in two patients, and nauseaand diarrheafor 24hours after injections in two patients [42]. Larger controlled trials will be needed before methotrexate can be widely recommended. Cyclosporine

Cyclosporine is an immunosuppressant widely used in the organ transplant arena. It selectively affectsT-lymphocyte-mediatedimmune responses. In 71 patients with active Crohn’s diseaseresistant to corticosteroida,59%of patients receiving5 to 7.5 mg/kg/d of cyclosporine for 3 months responded comparedwith a 32%improvement in the placebo group (p = 0.032)[43]. In follow-up data, however, Brynskov and co-workers [PQ]determined that a short courseof cyclosporinedoesnot result in longterm improvement in Crohn’s disease.Lichtiger et al [45] investigatedcyclosporine’sefficacy in ulcerative colitis. Ten patients with severerefractory ulcerativecolitis in whom 10to 14 days of corticosteroids failed were given cyclosporineintravenously in dosestitrated to keep serum levels between400 and 600 ng/mL. Six patients showedmarked improvement, with a mean responsetime of 9.7 days. Doees,duration of treatment, efficacy, and side effects of long-term cycloaporineuse such as renal impairment need to be evaluatedby properly conducted trials. Levamisole

Levamisole is an immunostimulant that enhancesspecific and natural immunity and hasbeen postulated to have a beneficial effect on maintaining remission in ulcerative colitis. In light of the relative successof immunosuppressionin IBD, this hypothesis seemsparadoxical. Hermanowicx et al [46] randomized 50 patients with quiescent ulcerative colitis to 150mglwk of levamisoleor placebo. Methotrexate No significant differencewasseenbetweenthe two Methotrexate is a folic acid antagonist that has groupswith respectto relapse.Similar discouraging molecular homologyto interleukin-1 (IL-l) and in- results with levamisole in treating patients with terfereswith IL-l’s inflammatory actions[41].In an Crohn’a diseasehave been reported [47]. Unless opentrial, 21patients with refractory IBD (14with other promising data emerge, levamisole has no Crohn’s diseaseand 7 with ulcerative colitis) re- place in the treatment of IBD.

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ANTIBIOTICS There are two possible roles for antibiotics in IDD: (1) as treatment for an intercurrent infection and (2) asprimary treatment for IBD. There is considerableevidencethat intercurrent infections can causeflares in IBD [48]. Some of the pathogens capableof causinga flare in IBD are listed in Table IV. It is prudent to maintain a high level of suspicion for thesepathogensand to treat appropriately when they are present. Infections such as Campylobucter jejuni and Yersinia enterocolitica can mimic IBD. The similarity of Crohn’s diseaseand ulcerative colitis to infectious colitis hasstimulated the hypothesisthat IBD is an infectious disease.Although proof of an infectious origin is lacking, antibiotics have been tried as primary treatment of IBD. In an uncontrolled clinical trial with antibiotics in Crohn’s disease,Moss et oZ [49] found that continuous treatment with a variety of broad-spectrumantibiotics such as ampicillin and tetracycline resulted in symptomatic improvement in 41 of 44 (93%) patients with Crohn’s disease.Coincident with this study, metronidaxole was being successfullyused for the treatment of perianal Crohn’s diseasein the United States. In Sweden,it was being compared favorably with sulfasalaxinefor the long-term managementof Crohn’s disease[50]. Metronidazole has many clinical effects including antibacterial properties and immune-modulating properties,and it improves wound healing(Figures 1 and 3) [4]. With these combined effects, metronidaxolemay work in IBD through a mechanism independentof its antimicrobial properties.In the CooperativeCrohn’s DiseaseStudy in Sweden, 800mg/d of metronidaxolewascomparedwith 3 g/d

piiEzzq

TABLE IV lnfecBons Asseciited Wii Ulcerative Colitis Relapse Clostridium difficile Bacterial enteric pathogens CMV Enteroviruses hfycoplasma pneumonia and upper respiratory viruses Entamoeba histolytica Aemmonas CMV = cylorrEgalovinls.

of sulfasalaxinein patients with active Crohn’s disease.Patients received each respectivedrug for 4 months and then were crossedover. No significant difference was seenin the Crohn’s diseaseactivity index in the first 4 months, but significant benefit wasfound in the patients with persistentactive diseasein the sulfasalaxinegroup that crossedover to metronidazole[50].Recently, a multicenter trial assessedthe efficacy of 20 mg/kg and 10 mg/kg of metronidaxole versusplacebo in patients with active Crohn’sdisease.Crohn’s diseaseactivity index scoresweresignificantly improved in both metronidaxolegroupsover placebo,but there were no differencesin remission rates betweenmetronidazole and placebo [51]. Metronidazole has been promising in treating perineal Crohn’s disease.In an open trial, 21 patients with unremitting perineal Crohn’sdiseasereceived20 mg/kg/d of metronidaxole.Drainage,erythema, and induration improved in all patients. Ten of 18 who completed the trial had complete healing [52]. The probable efficacy of metronidaxole in treating perineal Crohn’s diseaseis emphasized by frequent relapse after discontinuing the

+

Cloatndium diioile Flgurs 3. Infectious agents: Multiple infectious agents and toxins have been implicated in contributing to small bowel and colonic inflammation in inflammatory bowel disease. Therapeutic agents shown in this figure have the potential to modify this inflammatory response. Arrows with double Ilnes - inhibits; clroles = therapeutic agents.

Yersinia Aeromonos Campylobacter Sfrlmonella Myoobausrlum sp. 4+Viral agents

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drug. This problem is easilymanagedby reinetituting the drug at full dose [53]. Side effects with metronidazoleare dosedependent and include a metallic taste, gastrointestinal upset, dark urine, and peripheral neuropathy [52]. Long-term follow-up by Brandt et al [53] with metronidaxolein IBD revealedthat the only major side effectsareparesthesias,which occurin about50%of patients at a mean time of 6.5months. Paresthesias appear to be dose related, since they are rare in dosesunder 1,000mg/d. Although metronidaxolehas an important role in the treatment of Crohn’s disease,it hasno effect in ulcerative colitis exceptin the treatment of concurrent infections, particularly Clostridium difficile. This is illustrated by a comparativestudy of metronidaxole and sulfasalaxinein active ulcerative colitis. Over a 28-daytreatment course,only 28%of the metronidaxolegroup respondedwhereas68%of the sulfasalaxinegroup responded[54]. Various reports haveimplicated mycobacteriaas having a possiblerole in IBD [55]. Shaffer et al [!%I pursuedthe possibility that Mycobacterium kansasii might be an etiologic agentin Crohn’sdiseaseby randomizing 27patients to a a-yeartrial with rifampicin plus ethambutol againstplacebobut found no significant difference betweenthe two groups.Another small open trial demonstrated more promising results with antimycobacterials when six patients with refractory Crohn’s disease showed improvement while taking rifabutin and streptomycin [57]. It would be necessaryfor a large controlled trial to demonstrateefficacy of the antimycobacterialsbefore their use can be advised.This seemsunlikely unless a specific organism can be isolated that causesIBD.

tis. Stool frequencydecreasedto two stools or less per day in 64%of the sodium cromoglycategroup and in 84%of the prednisolonegroup at 8 weeks. Rectal bleedingdecreasedto 38%and lO%,respectively, in the cromoglycateand prednisolonegroups [So].Oral forms of disodium cromoglycatehavenot been as efficacious.Binder et al [61] found no differencebetweenoral cromoglycateand placebo in 25 patients with Crohn’s disease.Interestingly, we have found that 60%of our patients with IBD have increasednumbersof mast cells [59]. This group of patients may be able to be separatedby histologic examination into groupsthat may respondto disodium cromoglycate.

OTHERAGENTS Aminosalycylates, corticosteroids, antibiotics, and immunosuppressantaall haveestablishedroles in the treatment of IBD. Many new agentshave been introduced and are being evaluated in the treatment of IBD. These agentswork at multiple different points in the immune response(Figures 1 through 3) and will be outlined below.

Chloroquine

Sucralfate

Sucralfate is a mucosally active, cytoprotective mucopolysaccharideeffective in healinggastric and duodenal ulcers. Since the mucosa in IBD often contains ulcers and erosions, sucralfate enemas were tried in 15 patients with active left-sided ulcerative colitis in an open trial. Sucralfate enemas showeda progressivehealingeffect in most patients over a l- to g-week period [62]. In a subsequent prospective,randomizedtrial, 50patients with distal active ulcerative colitis receivedsucralfate enemas,mesalamineenemas,or placebofor 1 month. Sucralfate was no better than placebo by clinical, endoscopic,or histologic criteria [63]. In another randomized control trial, sucralfate enemaswere associatedwith significant improvement in distal ulcerative colitis but were significantly less effective than prednisoloneenemas[64]. Therefore,despite initial encouragingdata, unless other trials showa benefit with sucralfate,it probably will not be useful in treating IBD.

Abnormalities in antigen processinghave been proposedas a possibleetiologic factor in IBD [65]. Preliminary in vitro data showedthat chloroquine can slow antigen processingand therefore could be useful in the treatment of IBD. In an open trial, Mayer et al [66] treated 10patients with ulcerative colitis and 4 patients with Crohn’s diseasewith 300 mg chloroquine per day. Eight of the 10 patients Disodium Cromoglycate with ulcerativecolitis improvedafter 3 to 8 weeksof Becausemast cell hyperplasia is known to occur treatment. There was a less impressive effect in in IBD both during activediseaseand during remis- patients with Crohn’s disease[66]. sion [58,59],it is not surprising that attempts to alter mast cell-mediated immune responseshave 5-Lipoxygenase Inhibitors been made. Disodium cromoglycateinhibits mast 5-Lipoxygenaseis the first important enzymein cell degranulationand eosinophildegranulation.In the production of leukotrienes (Figure 2). Leukoone trial, sodium cromoglycateenemasand pred- trienes are known to amplify the immune response nisolone enemasdemonstrated comparablethera- by increasingneutrophil migration, promoting neupeutic effects in patients with distal ulcerativecoli- trophil and monocyteaggregation,and releasingly-

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sosomal enzymes. Leukotriene B4 (LTBd levels are high in rectal dialysis fluid in patients with active IBD, and levels decrease during remission. Laursen et al [67] gave 10 patients with active ulcerative colitis 800 mg of the 5-lipoxygenase inhibitor A64077. Rectal dialysate fhrid was measured before and after treatment. The median LTB4 level fell from 4.9 ng/mL before treatment to 1.6 ng/mL after treatment. Clinical correlation with this drug is needed. n-3 Fatty Acids (Fish Oil) Manipulation of precursor fatty acids that supply the arachidonic acid cascade can interfere with the inflammatory response by changing the type of leukotrienes produced. Arachidonic acid relies on n-6 fatty acids. With the addition of n-3 fatty acids to the diet, fewer n-6 fatty acids are available for the arachidonic acid cascade (Figure 2). Lorenx et al [68] treated 39 patients with active IBD with 3.2 g/d of n-3 fatty acids or placebo for 7 months. In the patients with Crohn’s disease, clinical activity was unchanged. In the ulcerative colitis patients, disease activity declined, but this did not reach statistical significance. Clonidine Clonidine is a centrally acting a-2 agonist commonly used in hypertension. There is some evidence that clonidine may affect distal colon motility. Lechin et al [69] randomized 45 patients with active ulcerative colitis to 0.3 mg of clonidine three times a day, 1.5 gm of sulfasalaxine three times a day, or 20 mg of prednisone three times a day. Both clonidine and prednisone were more effective than sulfasalazinc. Patients had decreased sigmoidal tone during relapse; therefore, the authors postulate that clonidine may have a beneficial effect in ulcerative colitis via central control of sigmoid colon motility. Nonsteroidal Anti-Inflammatory Agents (NSAIDs) The role of prostaglandins in the inflammatory process makes the idea of inhibiting the cyclo-oxygenase pathway an attractive possibility for the treatment of IBD. A major mechanism of action of the NSAIDs is inhibition of prostaglandin synthesis by the inhibition of cycle-oxygenase. Unfortunately, studies have shown that NSAIDs may actually exacerbate IBD. In one trial, 14 patients with active ulcerative colitis were given either 50 mg four times a day of flurbiprofen, prednisolone enemas, or oral sulfasalazine for 1 week. Patients in the flurbiprofen group had significantly worse rectal bleeding and endoscopic appearance [70]. These data suggest that NSAIDs should probably be avoided in patients with IBD.

OF INFLAMMATORY

BOWEL

DISEASE / GEIER AND MINER

CONCLUSIONS Although sulfasalazine and corticosteroids continue to be very important drugs in the management of IBD, many new agents are emerging as useful alternatives, especially in the intolerant or allergic patient. The new mesalamine products have been shown to be effective in IBD. Metronidazole has proven efficacy in Crohn’s disease. Various immunosuppressants, especially 6-MP, are helpful in recalcitrant Crohn’s disease. Until more is understood about the etiology of IBD, a cure will not be possible and nonspecific treatment with the various classes of agents discussed above will be the only defense against Crohn’s disease and ulcerative colitis.

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