Treatment algorithmsTreatment algorithmsThe standard patientThe standard patient

mildmild--toto--moderate left sided UC and UPmoderate left sided UC and UP

GerassimosGerassimos J. J. MantzarisMantzaris, MD, PhD, MD, PhDConsultant GastroenterologistConsultant Gastroenterologist

‘‘EvangelismosEvangelismos’’ GHAGHAAthens, GreeceAthens, Greece

DefinitionsDefinitions

Montreal classification of UCMontreal classification of UC

–– Extensive UCExtensive UC–– LeftLeft--sided UCsided UC–– Ulcerative Ulcerative proctitisproctitis

MildMild--to moderate UCto moderate UCTT--W criteriaW criteria

MildMild<4 Bowel motions<4 Bowel motions±± mucus/bloodmucus/bloodnormal normal HbHbESR <15ESR <15No constitutional No constitutional symptomssymptoms

ModerateModerate44--6 Bowel motions6 Bowel motionsmucus + bloodmucus + blood↓↓ HbHbESR: <30 mm/hESR: <30 mm/hNo constitutional No constitutional symptomssymptoms

Armamentarium Armamentarium for treating for treating

mildmild--toto--moderate moderate LSLS--UC and UPUC and UP

AminosalicylatesAminosalicylatesCorticosteroidsCorticosteroids–– ConventionalConventional

–– Topically actingTopically acting

Orally or rectally administeredOrally or rectally administeredMonotherapyMonotherapy and/or combinationand/or combination

ArmamentariumArmamentarium

55--ASA preparationsASA preparationsLiquid/foam/gel enemas (1Liquid/foam/gel enemas (1--4 g/60 ml)4 g/60 ml)Suppositories (0.5 Suppositories (0.5 –– 1 g)1 g)

CorticosteroidsCorticosteroidsHCHC-- enemas and 10% HC acetate foamsenemas and 10% HC acetate foamsPrednisolonePrednisolone SP enemas (30 mg/60 ml)SP enemas (30 mg/60 ml)BetamethasoneBetamethasone enemas (2 mg/100 ml) enemas (2 mg/100 ml) BeclomethasoneBeclomethasone DP enemas (3 mg/60 ml)DP enemas (3 mg/60 ml)BudesonideBudesonide (2 mg) liquid and foam enemas(2 mg) liquid and foam enemas

Liquid enemasLiquid enemas LSLS--UCUCFoam and gel enemasFoam and gel enemas UPSUPSSuppositoriesSuppositories UPUP

Topical therapyTopical therapy

55--ASA formulationsASA formulationsProPro--drugsdrugs

–– SASPSASP–– BalsalazideBalsalazide–– OlsalazineOlsalazine

pHpH--modified (delayed) release (modified (delayed) release (mesalazinemesalazine))–– EudragitEudragit –– S, andS, and–– EudragitEudragit –– L coatedL coated

Sustained releaseSustained release–– PentasaPentasa

Delayed and sustained releaseDelayed and sustained release–– MesalazineMesalazine pellets and MMX pellets and MMX mesalazinemesalazine

Corticosteroids Corticosteroids Conventional Conventional BudesonideBudesonide (??)(??)

Oral therapyOral therapy

Decision strategiesDecision strategies

patient preferences and compliance patient preferences and compliance foam/gel>liquid enemafoam/gel>liquid enema55--ASA supp>steroid suppASA supp>steroid supp

disease extent (UPdisease extent (UP→→UPSUPS→→LSLS--UC)UC)disease behaviour disease behaviour local availabilitylocal availabilitycostcostetc.etc.

Induction of remissionInduction of remission

Active mildActive mild--toto--moderatemoderateLeftLeft--sided ulcerative colitissided ulcerative colitis

(and (and proctosigmoiditisproctosigmoiditis))

Active LSActive LS--UCUCrectal rectal aminosalicylatesaminosalicylates

RCT & metaRCT & meta--analysis data analysis data

FirstFirst--line treatmentline treatmentEnemas: dose ranges 1Enemas: dose ranges 1--4 g 4 g noctenocte–– Clinical, Clinical, endoscopicendoscopic, and histological remission or response, and histological remission or response

~~80% of patients after 480% of patients after 4--6 wk6 wkRapid response Rapid response Effect is timeEffect is time-- but not dosebut not dose--dependentdependent

Superior to placebo and topical GCsSuperior to placebo and topical GCsProbably better than oral 5Probably better than oral 5--ASAASA

Active LSActive LS--UC and UP UC and UP rectal corticosteroidsrectal corticosteroids

RCT & metaRCT & meta--analysis dataanalysis dataSecondSecond--line treatmentline treatment–– Clinical, Clinical, endoscopicendoscopic, histological response/remission, histological response/remission

x 4x 4--5 superior to placebo 5 superior to placebo less effective than 5less effective than 5--ASAASA

–– BudesonideBudesonide enemasenemasdosed at 2mg for 4 wks dosed at 2mg for 4 wks equally effective to classical GCsequally effective to classical GCsno suppression of no suppression of CortisolCortisol..may substitute for classical GCs enemas may substitute for classical GCs enemas less effective than less effective than mesalazinemesalazine enemasenemas

Active LSActive LS--UCUCOral therapyOral therapy

SASP and 5SASP and 5--ASAASACochrane metaCochrane meta--analysis (2006)analysis (2006)

55--ASA ASA –– remission rates in extensive colitis: 50remission rates in extensive colitis: 50--75%75%

–– as effective in LSas effective in LS--UC UC –– at least twice more effective than placebo at least twice more effective than placebo –– tendedtended towards therapeutic benefit over SASPtowards therapeutic benefit over SASP

–– Effect is doseEffect is dose--dependent and much slower than GCsdependent and much slower than GCs–– SASP doses >4g/day intolerableSASP doses >4g/day intolerable

Oral SASP and Oral SASP and aminosalicylatesaminosalicylates

Effective dosesEffective doses–– SASP SASP 44--6g/day (6g/day (qidqid) ) –– MesalazineMesalazine

EudragitEudragit--S coatedS coated 2.42.4--4.8 g/day (4.8 g/day (tidtid) ) EudragitEudragit--L coated L coated 33--4.5 g/day (4.5 g/day (tidtid))

–– OlsalazineOlsalazine 1.51.5--3 g/day 3 g/day –– BalsalazideBalsalazide 6.5g/day (6.5g/day (tidtid), ), –– MesalamizeMesalamize pellets pellets 3 g/day (3 g/day (odod), ), –– MMX MMX mesalazinemesalazine 2.42.4--4.8 g/day4.8 g/day..

DoseDose--response effectresponse effect–– EudragitEudragit--S coated S coated mesalazinemesalazine–– BalsalazideBalsalazide. .

Mucosal healingMucosal healing–– SASP SASP –– Slow release 5Slow release 5--ASAASA–– MMX MMX mesalazinemesalazine Sandborn, Medscape 2006

LSLS--UCUCOral corticosteroidsOral corticosteroids

Mainstay for UC Mainstay for UC

? Role for LS? Role for LS--UC UC

? Newer, locally acting GCs? Newer, locally acting GCs–– LofbergLofberg et alet al

10w study, Bud 10 mg/d 10w study, Bud 10 mg/d vsvs PredPred 40 mg/d40 mg/d–– Angus et alAngus et al

4w study in LS4w study in LS--UC: Oral FP (5 mg UC: Oral FP (5 mg qidqid) ) vsvs placeboplacebo–– CampieriCampieri et alet al

4w study in E4w study in E--/LS/LS--UC: BDP (5 mg/day) UC: BDP (5 mg/day) vsvs 55--ASA (2.4 g/day)ASA (2.4 g/day)

–– RizzelloRizzello et alet al4w study in E4w study in E--/LS/LS--UC BDP (5 mg/d) UC BDP (5 mg/d) vsvs Placebo, 5Placebo, 5--ASA, 3.2 ASA, 3.2 g/dg/d]]

–– Negative or flawedNegative or flawed

PilotPilot--trial of oral Btrial of oral B--pHMRpHMRfor acute, steroidfor acute, steroid--dependent UCdependent UC

14 patients following a severe attack of UC.14 patients following a severe attack of UC.3mg 3mg tdstds BB--pHMRpHMR x 6 mo.x 6 mo.11 patients stopped classical GCs; CAI improved.11 patients stopped classical GCs; CAI improved.3 patients relapsed.3 patients relapsed.

Keller et al, Aliment Keller et al, Aliment PharmacolPharmacol TherTher 1997;11:10471997;11:1047--5252

LSLS--UCUCCombination or Combination or monotherapymonotherapy (oral or topical)?(oral or topical)?

Combination 5Combination 5--ASA therapyASA therapy–– Extensive UCExtensive UC–– No robust evidence for LSNo robust evidence for LS--UCUC

Trend for combined therapy over Trend for combined therapy over monotherapymonotherapy–– SafdiSafdi et al 1997et al 1997

Alternative combinationsAlternative combinations

Criteria for combined therapyCriteria for combined therapy–– More refractory patientsMore refractory patients–– Frequent relapsesFrequent relapses–– LSLS--UC UC vsvs proctosigmoiditisproctosigmoiditis

Induction of remissionInduction of remission

Active mildActive mild--toto--moderatemoderateulcerative ulcerative proctitisproctitis

FirstFirst--line treatment: line treatment: mesalazinemesalazine supp supp –– Superior to placebo, GCs supp, oral 5Superior to placebo, GCs supp, oral 5--ASA* ASA* –– Dose: 1g daily or 0.5 g twice dailyDose: 1g daily or 0.5 g twice daily–– ~~80% remission after 480% remission after 4--6 weeks6 weeks

Effect may be doseEffect may be dose--dependent dependent Rapid resolution of symptoms. Rapid resolution of symptoms. Gels, foams, even liquid enemas can substituteGels, foams, even liquid enemas can substitute

–– Alternative combinationsAlternative combinations

–– *Insufficient therapeutic amounts reach the rectum *Insufficient therapeutic amounts reach the rectum proximal colonic stasis, proximal colonic stasis, increased absorption, and increased absorption, and rapid transit through the inflamed colonicrapid transit through the inflamed colonic

Ulcerative Ulcerative proctitisproctitisrectal rectal aminosalicylatesaminosalicylates

MildMild--toto--moderate moderate LSLS--UC and UPUC and UP

Treatment algorithms for Treatment algorithms for induction of remission induction of remission

LSLS--UC: Induction of remissionUC: Induction of remission

Topical mesalazine(± oral 5-ASA)

remissionremission

maintenance

Prolonging inadequate Rx should be avoided.Prolonging inadequate Rx should be avoided.

Leads to refractory diseaseLeads to refractory disease

LSLS--UC: Induction of remissionUC: Induction of remission

Unresponsive to 2 wk Rx

Topical corticosteroidsTopical corticosteroidsClassical or Classical or budesonidebudesonide

enema/foam/gelenema/foam/gel

Combined topical RxCombined topical RxSteroids & Steroids & mesalazinemesalazine

Combined Rxoral SASP/5-ASA

+ rectal 5-ASA or GCs

Topical mesalazine(± oral 5-ASA)

remissionremission

maintenanceRelief of proximal

constipation

?

Still unresponsive ?

Oral GCsOral GCsMax oral SASP/5Max oral SASP/5--ASAASAtopical 5topical 5--ASA or GCsASA or GCs

Initial dose 40 mgTapered according to response

remission

maintenance

no response

LSLS--UC: Induction of remissionUC: Induction of remission

refractory

ConfirmedConfirmed UP: Induction of remissionUP: Induction of remission

Unresponsive to 2 wk Rx

Topical steroidsTopical steroidsclassical or classical or budesonidebudesonide

supp/foam/enemasupp/foam/enema

Combined topical RxCombined topical RxSteroids & Steroids & mesalazinemesalazine

Combined Rxoral SASP/5-ASA

+ rectal 5-ASA or GCs

Topical mesalazineSuppositoriesfoam/gel/enema remissionremission

maintenanceRelief of proximal

constipation

?

Still unresponsive ?

Combined treatmentCombined treatmentOral GCsOral GCs

Max oral SASP/5Max oral SASP/5--ASAASAtopical 5topical 5--ASA or GCsASA or GCs

Initial dose 20-40 mgTapered according to response

remission maintenance

refractoryrefractory

Re-confirm extent of diseaseSearch for other causes of

rectal inflammation

Still unresponsive ?

UP: Induction of remissionUP: Induction of remission

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LSLS--UC: remission maintenanceUC: remission maintenanceRemission induced by

Topical 5-ASA Continue

Oral 5-ASA mono-Rx

5-ASA (Oral + intermittent topical)

5-ASA (Oral + topical) Continue5-ASA (Oral + intermittent topical)

Topical steroids Switch to Topical 5-ASA± oral 5-ASA

Oral steroids Taper off max oral+topical 5-ASA

Rx as refractoryRelapse ?

UP: remission maintenanceUP: remission maintenanceRemission induced by

Topical 5-ASAsupp/foam/enema

5-ASA supp 1 g/d

↓ to 0.5 g/d or eod or tiw

5-ASA (Oral+topical)

5-ASA (oral + supp)

Topical steroids Switch to 5-ASA supp± oral 5-ASA

Oral steroidsand topical Rx Taper off

max 5-ASAoral+topical

Rx as refractoryRelapse ?

↓ to min topicalor oral Rx

Red

uce

to m

in e

ffect

ive

treat

men

t

Maintenance of remissionMaintenance of remission

LSLS--UC and UPUC and UP

Oral and topical corticosteroids Oral and topical corticosteroids

IneffectiveIneffectiveAdverse eventsAdverse events

LSLS--UCUCoral therapyoral therapy

SASP and 5SASP and 5--ASA preparations are effective ASA preparations are effective Lowest effective dosesLowest effective doses–– SASPSASP 2 g/day.2 g/day.–– mesalazinemesalazine

EudragitEudragit--S coated S coated 2.42.4--3.2 g/day 3.2 g/day EudragitEudragit LL--coated coated 1.51.5--3.0 g/day3.0 g/day

–– olsalazineolsalazine 1 g/day 1 g/day –– balsalazidebalsalazide 33--6 g/day6 g/day–– MMX MMX mesalazinemesalazine 2.4 g/day 2.4 g/day

–– MesalazineMesalazine pelletspellets not yet evaluatednot yet evaluated

55--ASA effective as ASA effective as monotherapymonotherapy

Even intermittently administered.Even intermittently administered.–– Two maintenance studies (2 years)Two maintenance studies (2 years)–– DD’’ AlbasioAlbasio, et al 1990, et al 1990

Oral SASP (2 g/day) Oral SASP (2 g/day) equally effectiveequally effective to to mesalazinemesalazineenemas (4g x 7 d/month).enemas (4g x 7 d/month).

–– MantzarisMantzaris, et al 1994, et al 1994MesalazineMesalazine enemas (4g enemas (4g tiwtiw) ) at least twice more at least twice more effectiveeffective than oral than oral mesalazinemesalazine (1.5 (1.5 g/dg/d).).

LSLS--UC (UC (inclincl UPS)UPS)topical therapytopical therapy

More refractory casesMore refractory casesMore effective than oral or topical More effective than oral or topical monotherapymonotherapy

DD’’ AlbasioAlbasio, et al 1991, 1997, et al 1991, 1997

–– mesalazinemesalazine oraloral (1.6 g/day) (1.6 g/day) vsvs enemasenemas (4g (4g biwbiw) or placebo) or placebo–– RR after 1 year: 69% RR after 1 year: 69% vsvs 39% (p=0.036). 39% (p=0.036).

MantzarisMantzaris, et al 1994, et al 1994

–– Patients with >2 annual relapsesPatients with >2 annual relapses–– mesalazinemesalazine oraloral (1.5 (1.5 g/dg/d) and ) and enemasenemas (4g (4g tiwtiw))–– After 1 year only 6/32 patients relapsed (17.14%).After 1 year only 6/32 patients relapsed (17.14%).

UPS UPS combined therapycombined therapy

RCTRCT55--ASA supp much more effective than oral 5ASA supp much more effective than oral 5--ASAASAProlongs remission; reduces relapsesProlongs remission; reduces relapses

HanauerHanauer, et al 2000, et al 2000

DoseDose--response relationshipresponse relationshipDD’’ AlbasioAlbasio, et al 1998, et al 1998

Even intermittent treatment is effectiveEven intermittent treatment is effectiveMarteauMarteau, et al 1998, et al 1998

UP UP topical therapytopical therapy

Topical therapy is not easily tolerated Topical therapy is not easily tolerated Compliance is compromised with prolongation of Compliance is compromised with prolongation of treatment treatment –– local irritation, local irritation, –– discomfort, and discomfort, and

–– inconvenience.inconvenience.

Routine clinical practiceRoutine clinical practice

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LSLS--UCUCOral corticosteroidsOral corticosteroids

Mainstay for UC Mainstay for UC ? Role for LS? Role for LS--UC UC ? Newer GCs? Newer GCs–– LofbergLofberg et alet al

9w study in E9w study in E--/LS/LS--UCUCBud 10 mg/d Bud 10 mg/d vsvs PredPred 40 mg/d 40 mg/d Similar improvement in Similar improvement in endoscopyendoscopy but not histology scoresbut not histology scores

–– Angus et alAngus et al4w study in LS4w study in LS--UC: Oral FP (5 mg UC: Oral FP (5 mg qidqid) ) vsvs placeboplacebonegative.negative.

–– CampieriCampieri et alet al4w study in E4w study in E--/LS/LS--UC: BDP (5 mg/day) UC: BDP (5 mg/day) vsvs 55--ASA (2.4 g/day)ASA (2.4 g/day)DAI reduced by BDP only in extensive UC.DAI reduced by BDP only in extensive UC.

–– RizzelloRizzello et alet al4w in E4w in E--/LS/LS--UC: BDP (5 mg/d) UC: BDP (5 mg/d) vsvs Placebo [5Placebo [5--ASA, 3.2 ASA, 3.2 g/dg/d] ] combined Rx more effective irrespective of disease extentcombined Rx more effective irrespective of disease extent

LSLS--UCUCtopical therapytopical therapy

RCT & metaRCT & meta--analysis data analysis data Topical 5Topical 5--ASA: ASA: FirstFirst--line treatmentline treatment–– Enemas: dose ranges 1Enemas: dose ranges 1--4 g 4 g noctenocte

Rapid; timeRapid; time-- but not dosebut not dose--dependentdependentClinical response/remission Clinical response/remission ~~80% after 480% after 4--6 wk6 wkSuperior to placebo and topical GCsSuperior to placebo and topical GCsProbably better than oral 5Probably better than oral 5--ASA ASA

–– Topical corticosteroids Topical corticosteroids x 4x 4--5 superior to placebo; less effective than 55 superior to placebo; less effective than 5--ASAASABudesonideBudesonide equally effectiveequally effective

–– No suppression of No suppression of CortisolCortisol (2mg/day for 4 wks).(2mg/day for 4 wks).

Active mildActive mild--toto--moderate LSmoderate LS--UC UC Oral corticosteroidsOral corticosteroids

Mainstay for UC; Mainstay for UC; ? Role for LS? Role for LS--UC; ? Newer GCsUC; ? Newer GCs–– LofbergLofberg et alet al

Bud 10 mg/d Bud 10 mg/d vsvs PredPred 40 mg/d x9w (E40 mg/d x9w (E--/LS/LS--UC)UC)Similar improvement in Similar improvement in endoscopyendoscopy but not histology scoresbut not histology scores

–– Angus et alAngus et alOral FP (5 mg Oral FP (5 mg qidqid) ) vsvs placebo x4w (LSplacebo x4w (LS--UC)UC)negative.negative.

–– RizzelloRizzello et alet alBDP (5 mg/d)+5BDP (5 mg/d)+5--ASA (3.2 ASA (3.2 g/dg/d) ) vsvs Plac/5Plac/5--ASA x 4w (EASA x 4w (E--/LS/LS--UC)UC)Combined Rx more effective irrespective of disease extentCombined Rx more effective irrespective of disease extent

–– CampieriCampieri et alet alBDP (5 mg/day) BDP (5 mg/day) vsvs 55--ASA (2.4 g/day) x 4w (EASA (2.4 g/day) x 4w (E--/LS/LS--UC)UC)DAI reduced by BDP only in extensive UC.DAI reduced by BDP only in extensive UC.