Corticosteroid therapy for IBD : Old and new

GR GREENBERG, Corticosteroid therapy for IBO: Old and new. Can J Gastroenterol 1993;7(2):127-131. Corticosteroids remain the most effecttve treatment for the management of patients with acute inflammatory bowel disease (IBD). The superior efficacy of corticostcroiJs has been demonstrated when administered topically for distal ulcerative colitis or systemically for pancolitas, and for active Cmhn's disease of the small bowel alone or when combined with colonic disease. Notwithstanding the symptomatic benefit of prednisone in acti\'e Crohn's disease, however, only a minority of patients achieve endo~copic remission. Corticosteroids have a broad range of anti-inflammatory effects, including reductions of interleukin-I production by macrophages and interleukin-II synthesis by lymphocytes, inhibition of platelet-activating factor and decreased margmat1on of neutrophils. At pharmacological doses, corticosteroids also induce the synthesis oflipomodulin which, m tum, blocks phospholipase A2 and so ltm1ts availability of arachidonate for the production of leukotrienes and prostaglandins. Because corticosteroid treatment is associated with s1gmficant side effects, new agents have been sought to achieve equivalent efficacy but with a lower adverse event profile. This approach is predicated on structural changes to the basic hydrocortisone molecule to achieve potent topical anti-inflammatory effects, sufficient water and lipid solubility that allows dissolution within the inte~tinal lumen and rapid high-first pass metabolism by the liver to products with little or no biologic activity. Three steroid preparations JevelopeJ for rectal administration include ttxocortal pivalate, bcclomethasone and buJesonide. C.mcrolled trials undertaken in patients with active distal ulcerative colitis indicate each of these products has equivalent or superior efficacy when compared with hydrocortisone and without reductions of serum cortisol. Two preparations, t1uticasone and budesomde, have been developed for oral administration and preliminary studies suggest l.'fficacy for both drugs in patients with active ileal Crohn's disease. The first pass corticosteroids are potentially promising new therapeutic agents for the management of IBO.

B ECAUSE T HE ETIOLOGY OF INFLAM- ma tory bowel disease (IBO) remains unknown, the major objective of drug therapy is to optimize quality of life by suppressing the sympto ms of inflammation, without introducing major side effects.Although the the rapeutic armamenta rium for the man agement of patients with acute ulcerative colitis and C rohn's disease has expanded considerably over the last decade, corticoste ro ids continue to be the most effective treatment.The frequent side effects associated with the use of corticosteroids has, however, prompted the development of a new group of agents that may provide certain advantages over curre ntly available steroids by achieving equivalent or superior efficacy with a lower adverse eve nt profile.

EFFICACY OF CONVENTIONAL CORTICOSTEROIDS
Ulcerative colitis: In acute ulce rative colitis, the value of systemic corticostero ids was demonstrated by True love and Witts ( 1) in a controlled trial comparing oral cortisone aga inst placebo.Subsequently Le nnard-Jones e t al (2) confirmed the superior efficacy of prednisone over sulph asalazine and placebo in ac hieving clinical re mission.To re m ain asy mpto matic , occas io n al pa tients with chron ic relapsing ulcerative colitis may benefit from alternate day ste ro ids (3 ), but neither cortisone nor prednisolone has been shown to be effecti ve fo r the maintenance of remission when compared to placebo ( 4 ).
The intrarectal administra tion of de maladie de Crohn cvolutive au niveau du petit intcstin sculc ou avcc atteinte colique.Malgre les avancages de la prednisone pour les symptomes clans la maladie de Crohn active, cependant, seulemenc une minorite de patients connattront une remission a !'endoscopic.Les corticostero"ides ont un large spectre d'effets anti-inflammatoires, y compris la reduction de la production d'interleukine-1 par les macrophages et de la syn these de l'interlcukine-2 par les lymphocytes, l'inhibition du facceur d'activacion des plaquettes et la diminution de la margination des neutrophiles.A des doses pharmacologiques, les corticostero'ides induisent egalement lasynthese de lipomoduline qui en retour inhibe la phospholipasc A2 pour limiter la disponibilite d'arachidonatc dans la production de leucotrienes et de prostaglandines.).In contrast to the NCCS, the Eu ropean tria l also showed that prednisolone was effective fo r colonic Crohn's disease and fu rther indicated that once remission had been achieved fo r either ilea! or colonic disease, a low dose of steroids may have benefit in maintaining remission for up to two years.Indeed, co maintain clinical remission after administration of steroid therapy in Crohn's disease, up co two-thirds of pat ients may become steroid-<lependent.Both studies (9, 10) de mo nstrated that in patients with quiescent disease the prophylactic use of steroids is of no benefit in preventing recurrence.No twithstanding the benefit of prednisolone for achieving clinical remission in active C rohn's disease, only a minority (29% ) of patients also achieve endoscopic remission ( 11 ).
T he administration of sulphasalazine, in addition to prednisone, for patients with active C rohn's disease causes a more rapid initial improvement, but after 16 weeks' therapy sulphasalazine plus prednisone is no t significantly better than prednisolone alone for the control of symptoms related to inflammation (1 2).In vitro studies indicate that prednisolone blocks the synthesis OI lipooxygenase and cyclooxygenase products by inducing the synthesis of lipomodulin.le has been proposed that lipomodu lin, in turn, reduces phospholipase-A2 production, thereby limiting the availability of arachidonate fo r the synthesis of leukotriene 84 (a lipooxygenase product), prostaglandiru and thromboxane A2 (products of the cyclooxygenase pathway).Whethe1 corticosteroids have a similar effect m IBO patients is less clear.In a reccm study, administration of long-tern prednisolone did not alter mucosa phospholipase A2 activity in chi neoterminal ileum of patients wit! recurrent active Crohn's disease (1 4) the unaffected phospholipase A2 ac tivity in the mucosa!biopsies was as, sociated with the presence of activ inflammation at endoscopy.Corcic()I steroids also enhance absorption water and electrolytes from the gut and improve nutrient intake by stimulating appetite.

MECHANISMS OF ACTION
Although all of these actions by 1tero1ds could po tentially contnbute to the suppression of inflammation and rrovide symptomatic relief, 1t remains uncertain which of these mechanisms predominate in achieving improved clinical outcome for patients with IBO.
Inhibition of ncutrophil and monocyte migration into inflamed intestinal tis-;ue has been suggested as the most important factor contributing to the therapeutic efficacy of corticosteroids m IBD ( 13 ).Perhaps most no teworthy 1~ that elucidation of various mechan-11ms whereby corticosteroids ace has provided little insight into the basic cuology of lBD.

IDEAL STRUCTURE-ACTIVITY PROFILE FOR CORTICOSTEROIDS
Treatment with conventio na l corticosteroids 1s associated with significant side effects.In the NCCS, prednisolone administered for l 7 weeks caused ma1or adverse events in over 50% of patients, including 'moon face', acne, ecchymosis and hypertension (15).A 1()% incidence of osteoporosis has also been reported in patients receiving corncostcroids for lBO ( 16).Risk facto rs nclude severe small intestinal disease, intestinal resection and premature menopause, as well as high dose steroid therapy.Osteonecrosis has been reported in 4.3% of patients treated with corticosteroids for IBO over a 10-\l'ar period ( 17).Because admm1strauon of conventional corticosteroids 1s a.\SOCiated with a significant adverse \'Cnt profile, several avenues have been sought to achieve equivalent efficacy with a lower incidence of side effects.Whether the concomitant ad-11m1stration of 5-ASA products (12), other immunosuppressive agents (18), certain antibiotics or the addition of nutntiona l therapy (19), will achieve this objective requires clarification.An alternate approach to treatment of r,1rients with IBO is predicated on changes to the basic hydroco rtisone "Olecular structure to achieve a more ,rumal structure-activity profile.
Compared with hydrocortisone, this ideal struc ture-activity profile inc ludes three maj o r characterisucs.First, there should be relatively selective glucocor-tic01d activity with very potenr to pical anti-inflammatory effects.A double bond in the A -ring between posmons l and 2 increases the affinity for the glucocorticoid but no t the mineralocomco id receptor, while an oxygen function at position I J in the C-ring is required for glucocorticoid receptor binding.Enhanced topical anti-inflammato ry potency can be achieved by the introduc tion of lipo philic constituents into the 17a and/or the 16a or 17a posm ons of the corticosteroid D-ring; esterification in the l 7a position markedly enhances glucocorcico1d activity (20).Second, when administered o ra lly o r rec tally there should be rclan ve srab1ltty with sufficient water and lipid solubility to a llow dissolution, as well as effective absorption into the gut wall.Conventional corticosteroids such as prednisolone arc rapidly absorbed fro m the gastrointestinal tract, and up to 80% of the drug becomes systemically bioavailable.ln active small intestinal Crohn's disease the absorption of prednisolo ne may be delayed but the total amount absorbed is unc hanged ( 21).Thus, the third characten scic 1s that o nce absorbed there should be rapid metabo lism of the steroid to products with little or no biologic activity.As the liver 1s the major site for steroid metabolism, this breakdown is referred to as high -first pass hepatic metabolism, which can be achieved by estenficatton at l he 2 1 position of the D-ring.

NEWER CORTICOSTEROIDS
Severa l new preparations h ave been developed that begin to approach t his o ptimal structure-act1v1ry profile for corticosteroids.Three preparations deve lo ped for rec ta l admmistra t1on include tixicorcal pivalate, beclomethasone a nd budesonide, while two preparations, fluticasone and budesonide have been developed for oral administration.Tixocortal pivalate: This synthetic steroid 1s a derivative of hydrocmt1sone , \N j GASTROENTEROL VOL 7 NO 2 FEBRUARY 1993 Corticosteroid therapy for IBD where t he 2 1-hydroxyl group on the D-ring 1s replaced hy a 21-thwl gruup esterifi eJ with p1valmic acid.Thi~ change 111 structure co1weys h1gh-f1N pass metabolism, but docs not enhance g lucocort1co1J receptor affinity or poten cy when compared tn hyJnicl1r-t1sone ( 22).The efficacy of tixncnrral pivalatc m patients with left-s1Jed ulcerative col ms has been studu:J in three controlled trials 111 the Un1ted States compnsing 337 patients where three weeks' adm 101st rdt1on \lf 250 mg tixocortal pivalate enemas were compared to l 00 mg hy<lrocortisonc enemas (23 ).C li nical 11nprovcmi::nt was observed in 68l1'o of pauenn, after nxoconal p1valace and 75% after hydrocortbonc.without scrum LOrt1sol n:Juct1ons 111 e ither group.A Jose response study of 250 mg, 500 mg anJ 1000 mg tixi<.:ortalp1valate enemas did not, however, J emomtrate any improved efficacy at the higher doses.Notwithstand ing the absence of steroid side effects, thL' low topical potency uf this agent and the absence of superior efficacy over hydrocortisone suggests that tixocortal pivalate wi ll have a limited role a:, a top ical agent fo r left-sided ulcerntive colitis and is unlikely to be of value as an oral agent for the treatment of more extensive ulcerative coli ti:.or Crohn 's disease.Beclomethasone dipropionate: This 1s a l 7a substituted glucocort1co1~l with a topical potency about 80-fold greater than h ydrocortisone, wh1Lh 1s 1nacuvaced hy hepat1L first pass mcrnbol1sm.RanJom1.:cd,Jouhle-blinJ trial-h,1,•e assessed the effeLl of 0. 5 mg bet,1 methasone Jiprop1onate enemas when comparL'd with 5 mg hed11methas11ne phmphate in patients with distal ul-ceratiVl' C1)lit1s (24)(25)(26).The overall therapc11t1L response was c4u1vaknt 111 the two treatment groups.Suppression of aJrenocortical !unction was found m the ma1ority of patients receiving het,1 methasone phosphate hut d1J n1)t occm 111 any of the patients receiving heclomethasone J 1prop1onate.The h10availahil I ty nt hedomethasone J1prop1onate when administL'reJ rectally or ornlly m humam has nnt been studied.Fluticasone pro pionate: This 1s a I 7u propionate with an S-fluo romethyl carbothioate side c hain in the l7~ position.The topical potency of this new steroid 1s about 200-fold greater than h ydrocortisone, and the altered ring structure conveys biotransformacion in the liver to metabolites oflow glucocorticoid potency (20).Ora l bioavailability of fluticasone is very low, likely reflecting not only hepatic first pass metabolism, but also poor absorptio n from the gastroinrcst inal tract because of low solubility.When given in a single o ra l dose to patients with a well-established ileostomy, 72.7% of the drug was recovered in the ileostomy effluent (27).Oral fluticasone 20 mg/day has been studied in 12 patients with mild to moderately active Crohn's disease.After three weeks treatment, fluticasone caused a significant fall in the Crohn's disease activity index (COAT) from 193±84 to 122±5 1 and improved 1111 l . .
n eucocyte scan images m seven patients, without changes in plasma cortisol (28).Fluticasone 20 mg/day has also been administered to 12 patients with uncreated cel iac disease (29).
After s ix weeks of treatment, a mean 2 kg weight gain, a rise in a lbumin, improvement in the lactulose/mannitol excretion ratio and improved histology was reported.Two of the patients in chis latter study (29) had suppressed cortisol va lues to synacchen after the six weeks of therapy.Oral fluticasone is n ot, however, effective treatment for active distal ulcerative colitis.A doub le-blind randomized tria l comparing 30 patients who received fluticasone 20 mg/day versus 29 patients who received placebo found similar clinical, sigmoidoscopic and histologic responses in the two groups (27).Budesonide: This is a nonhalogenated glucocorticoid which is structurally related to l 6a.-hydroxyprednisolone.This drug is a 1: l mixture of two epimers designated 22R and 22S with the 22R epimer about three times more potent than the 22S epimer (20).Budesonide h as a topical potency about 200-fold greate r than hydrocortisone, a water solubility that is approximately 100times higher than fluticasone and undergoes hepatic first pass metabolism into metabolites with low glucocorticoid effects.A multicentre randomized trial comparing budesonide 2 mg/100 mL enemas with prednisolone disodium phosphate 3 l.25 mg/100 mL enemas administered for four weeks in 64 patients with active distal ulcerative col itis indicated 52% h ea ling in patients receiving budesonide versus 24% h ealing in patients receiving prednisolone enemas (30) 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proccosigmoiditis and proctitts.Gastroencerology 1987;92: l 894-8.9. Summers RW, Switz OM, Se551onsJT, nisolonc 20 mg/100 mL enemas (31).and to 5-ASA 4 g/160 mL enemas (32), without causing adrenal suppression Budesonide 0.5 mg suppo~itories given three times daily have a lso been reported co be effective tn the symptomatic treatment of patients with pouchitis, caus ing a reduction rn leukotrienc 84 and proscaglandin Ei levels in fecal dialysates (33 ); however, 60% of patients relapsed within eight weeks of stopptng therapy.Three preliminary reports (34-36) have ap• peared on the efficacy of a slow relca~e oral preparat ion of budesonide 9 mg/day administered to patients with active Crohn's disease.The comporne results comprising 4 7 patients indicated a significant reduction of CDAI.without changes in serum cortisol levels o r side effects.Multicenrre randomized trials compa rin g oral budesoniJe against placebo a nd against preJnisone in patients with active Crohn's disease are currently in progress.

SUMMARY
The development of new glucocorcicoids characterized by high topical anti-inflammalOry activity and first pass hepatic metabolism represent a1 potentiall y promising new approach to the management of patients with IBO.
Whether long-term administration oi these agents will maintain sympro, matic improvement without systemtC or local side effects requires careful!prospective evaluation.