PERSONAGGI FAMOSI CON IBD - Giacomo Trallori · TERAPIA DELLA COLITE ULCEROSA ... PERSONAGGI FAMOSI...

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Malattie Infiammatorie Croniche Intestinali:TERAPIA DELLA COLITE ULCEROSA

Giacomo Trallori Venerdi 23 e Sabato 24 Marzo 2012

Firenze

PERSONAGGI FAMOSI CON PERSONAGGI FAMOSI CON IBDIBD

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Current PharmacotherapyCurrent Pharmacotherapy

Because no cure for UC has been foundBecause no cure for UC has been found, treatment of the disease consists of long-term pharmacotherapyDirected at controlling the symptoms of the diseaseThe ultimate goal is to achieve remission and avoid surgery

Traditional Approach To Traditional Approach To Therapy For Ulcerative ColitisTherapy For Ulcerative Colitis

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La terapia medica della La terapia medica della M.R.G.E.M.R.G.E.

Giacomo Trallori MDGiacomo Trallori MDGiacomo Trallori, MDGiacomo Trallori, MDAzienda Ospedaliera Azienda Ospedaliera CareggiCareggiFirenzeFirenze

Costi studio 2004Costi studio 2004

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COSTICOSTI

COSTICOSTI

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SulfasalazineSulfasalazine

Became available in the 1940’s when SvatzBecame available in the 1940 s when Svatz et al discovered that sulfasalazine, originally used to treat RA, was also noted to reduce colonic mucosal inflammation and bloody diarrhea


Is indicated for the treatment of mild toIs indicated for the treatment of mild to moderate UC, as adjunctive therapy in severe cases, and for prolongation of remissionIt is a prodrug comprised of mesalamine and sulfapyridine joined by a diazo bondand sulfapyridine joined by a diazo bondAbout 1/3 of the dose is absorbed in the small intestine

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Sulfasalazine Dose/ToxicitySulfasalazine Dose/Toxicity

100%100%

ResponseResponse

1G 2G 3G 4G

ToxicityToxicity

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Adverse events of sulfasalazine are of twoAdverse events of sulfasalazine are of two types: dose-related or hypersensitivityThe first group includes nausea, vomiting, abdominal discomfort, anorexia, and headache.Less common include hemolytic anemia, reticulocytosis, and methemoglobinemia


The second group are non dose dependentThe second group are non-dose dependent They include exfoliative dermatitis, aplastic anemia, hepatitis, pancreatitis, pneumonitis, autoimmune hemolysis, pericarditis, nephrotic syndrome, and severe exacerbation of symptoms of colitis

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SulfaSulfa--Free Oral MesalamineFree Oral Mesalamine

Studies have shown that mesalamine is theStudies have shown that mesalamine is the principal therapeutically active component of sulfasalazine, while sulfapyridine is the carrierRecognition that sulfapyridine is associated with dose-related adverse events led to efforts to develop sulfa-free productsdevelop sulfa free productsThese include Asacol (mesalamine), Dipentum (olsalazine), Pentasa (mesalamine), and Colazal (balsalazide)

Asacol (mesalamine)Asacol (mesalamine)

Asacol tablets were introduced to the US in 1992Asacol tablets were introduced to the US in 1992Unlike sulfasalazine, olsalazine, and balsalazine, Asacol is not a prodrug It contains a core of 400 mg of mesalamine coated with a pH-sensitive acrylic polymer call Eudragit-S which delays release of mesalamine until the

bl h i f H f 7 btablet reaches an environment of pH of 7 or aboveThe coating typically dissolves in the terminal ileum or colon

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55--ASA E AZIONE SUL ASA E AZIONE SUL COLONCOLON

ASA: More is BetterASA: More is BetterTreatment Success at Weeks 3 & 6

Pooled Moderate Population

ASCEND I, II

Pooled Moderate Population

58%53%

72%62%

30%40%50%60%70%80%

atie

nts

Impr

oved

2.4 g/day4.8 g/day

*

0%10%20%

Week 3 Week 6

% o

f Pa

p=0.0034p=0.058

N=223 N=223N=198 N=200

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Asacol (mesalamine)Asacol (mesalamine)

Asacol is indicated for the treatment ofAsacol is indicated for the treatment of mildly to moderately active UC and the maintenance of remission The usual dose is two 400-mg tablets to be taken three times a day for a total daily dose of 2 4 g for a duration of 6 weeksof 2.4 g for a duration of 6 weeksFor maintenance the recommended dose is 1.6 g daily, in divided doses

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Pentasa (mesalamine)Pentasa (mesalamine)

Pentasa has been marketed in the US since 1993Pentasa has been marketed in the US since 1993Pentasa is also not a prodrugUnlike Asacol, the delivery system is made up of mesalamine microspheresIt is moisture activated, thus the capsules di i t t i th t h di i t ll ddisintegrate in the stomach, dispersing controlled-release microspheres into the small bowel and throughout the rest of the colon

Pentasa (mesalamine)Pentasa (mesalamine)

Pentasa is indicated for the induction ofPentasa is indicated for the induction of remission and for the treatment of mildly to moderately active UCThe recommended dose is four 250-mg capsules four times a day for a total daily dose of 4 0 gdose of 4.0 gTreatment duration is up to 8 weeksIs not indicated for maintenance UC

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Dipentum (olsalazine)Dipentum (olsalazine)

Dipentum was introduced to the US in 1990Dipentum was introduced to the US in 1990 and contains 250-mg of olsalazine sodiumIt is a prodrug consisting of two molecules of mesalamine joined by a diazo bond which is cleaved by bacterial action in the colon

Dipentum (olsalazine)Dipentum (olsalazine)

Dipentum is indicated for maintenance ofDipentum is indicated for maintenance of remission of UC in patients intolerant to sulfasalazineThe usual dose is two 250-mg capsules twice a day for a total daily dose of 1.0 gDipentum is not indicated for the treatment of acute ulcerative colitis

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Colazal (balsalazide)Colazal (balsalazide)

Colazal was introduced to the US in 2000Colazal was introduced to the US in 2000 and contains 750-mg of balsalazide sodiumIt is a prodrug and is delivered intact to the colon where it is cleaved by bacterial azoreduction to release mesalamine70% of patients intolerant of sulfasalazine are able to tolerate balsalazide

Colazal (balsalazide)Colazal (balsalazide)

The recommended dose of 6 75 g/dayThe recommended dose of 6.75 g/day contains 2.4 g of mesalamineIt is indicated for the treatment of mildly to moderately active ulcerative colitisThe safety and effectiveness of Colazal y Cbeyond 12 weeks has not been establishedIs not indicated for the maintenance of UC

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O r a l 5Oral 5--ASA Release SitesASA Release SitesCOLAZAL™COLAZAL™Pentasa® Pentasa® Asacol®Asacol®

StomachStomach

Small IntestineSmall Intestine

Large Large Large IntestineLarge Intestine

Azo bondAzo bondMesalamine in microgranulesMesalamine in microgranules

Mesalaminew/ eudragit-SMesalamine

w/ eudragit-S

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Fallingborg StudyFallingborg Study

pH of the gut lumen was measured in 39pH of the gut lumen was measured in 39 people with UC using a pH-sensitive, radiotransmitting capsuleThe location of the capsule was determined by X-rayThe pH was 5.7 in the cecum, but rose to 6.6 in the rectum


The low pH in the cecum is thought to beThe low pH in the cecum is thought to be caused by bacterial fermentation of non-absorbed carbohydratesIn 17 of the subjects, the pH decreased by 0.1-0.8 units while leaving the terminal ileum and entering the cecumileum and entering the cecumIn the cecum the pH dropped between 0.5-2.5 pH units to a median value of 5.7

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The pH levels ascending and transverseThe pH levels ascending and transverse colon had a median average of 5.6 and 5.7 respectivelyThe pH in the descending, the sigmoid, and the rectum average 6.6The median fecal pH was 6.5

Variance in Colonic pHVariance in Colonic pH

Ulcerative Colitis Patients

pH-dependent Delivery

Requirements

Fallingborg J, et al. Dig Dis Sci 1993;38(11):1989-1993.

0 2 4 6 8 10 12 14pH

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SteroidsSteroids

Corticosteroids such as prednisoneCorticosteroids, such as prednisone, methylprednisolone, and budesonide have been used to reduce inflammation in patients who do not respond to 5-ASA medsCan be given orally, intravenously, an enema or suppositoryenema, or suppositorySee improvement within daysAre a short term control of flare-up

SteroidsSteroids

Long term use increase likelihood of side effectsLong term use increase likelihood of side effects– Weight gain– Acne– Facial hair– HTN– OsteoporosisOsteoporosis– Diabetes– Mood swings– Risk of infection

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Corticosteroids: Dependency: Corticosteroids: Dependency: Short and Long Term EfficacyShort and Long Term Efficacy

Complete Partial1-Month Outcomes*(n=63)

Complete Remission

54%(n=34)

Partial Remission

30%(n=19)

No Response 16%

(n=10)

*30 days after initiating corticosteroid therapy Faubion W, et al. Gastroenterology. 2001;121:255.

1-YearOutcomes(n=63)

Steroid Dependent

22%(n=14)

Prolonged Response

49%(n=31)

Surgery 29%

(n=18)

ImmunomodulatorsImmunomodulators

Azathioprine (Imuran) and 6-mercaptopurine (6-Azathioprine (Imuran) and 6 mercaptopurine (6MP)Used to maintain remission of UC and decrease the need for steroidsCan take 3-6 months to produce effectivenessSide effects include nausea, vomiting, diarrhea, gpancreatitis, liver disease, and bone marrow disfunctionNeed CBC and LFT every few months

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20Patients

Cyclosporine in Patients withCyclosporine in Patients withSevere Ulcerative ColitisSevere Ulcerative Colitis

29

11

Cyclosporine

81

No Response:

surgery

Response

Elective colectom

y

Oral Cyclospori

neLichtiger S et al. NEJM 1994

IV Cyclosporine: Major ToxicityIV Cyclosporine: Major Toxicity

Renal insufficiency 23%

Infection 20%

Seizures 3%

hDeaths 2%

Anaphylaxis 1%

Sternthal J et al. Gastroenterol 1996

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Sequential TherapySequential Therapy

Rectosigmoid DiseaseRectosigmoid Disease

Induction of Acute DiseaseInduction of Acute Disease

STOP5-ASA Enema5-ASA Oral

Prednisone

Rectosigmoid DiseaseRectosigmoid Disease

Extensive DiseaseExtensive Disease

Tremaine WJ. (Bayless TM and Hanauer SB, eds.) Advanced Therapy

of Irritable Bowel Disease. 2nd ed. 2000:115-117.

STOP5-ASA Enema

5-ASA Oral

Prednisone

Extensive DiseaseExtensive Disease

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UTILIZZO ANTIUTILIZZO ANTI--TNFTNF

New Therapy for Treatment of New Therapy for Treatment of UCUC

Tumor necrosis factor-alpha is a chemicalTumor necrosis factor-alpha is a chemical produced by the bodyIt is responsible for recruiting immune cells to different tissue where they cause inflammation, swelling, pain, warmth, and erythemaHigh concentrations of TNF have been found in aHigh concentrations of TNF have been found in a variety of infections and inflammatory diseases such as UC

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Remicade (infliximab) to Treat Remicade (infliximab) to Treat Ulcerative ColitisUlcerative Colitis

Remicade is an anti TNF drugRemicade is an anti-TNF drugRemicade is a monoclonal antibody that is formed by combining portions of human and murine antibody moleculesIt targets and neutralizes TNF, thus g ,decreasing the inflammatory response


In a retrospective study by Sands et al 16 patientsIn a retrospective study by Sands et al, 16 patients with severe UC received a single 5-mg/kg infusion of remicadeClinical, endoscopic, and histological improvements were observed in 88% (14/16) of patients after initial treatmentpatients after initial treatment5 months later, 38% (6/16) of the patients received a second infusion to maintain remission

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Surgery was avoided in 6/7 patients whoSurgery was avoided in 6/7 patients who were previous surgical candidatesClinical remission was maintained in 14/16 patients for at least six months and in 4/16 for at least ten monthsMost of the patients were completely withdrawn from corticosteroid therapy

InfliximabInfliximab Rescue for Sick Unto Rescue for Sick Unto ColectomyColectomy??

•N=45 RCT: IFX 24 vs placebo 21•s/p 4d IV steroids if fulminant; s/p 6-8 d for severe or mod severe (by scoring system)•1º endpoint: Colectomy or death at 90d

•No deaths

•Colectomy: 7 IFX vs 14 placebo (p = .017)•More post-op complications seen with placebo•6 plus months f/u (none 12)

•Additional 2/24 IFX and 2/21 placebo have had a colectomy.

Jarnerot G Gastro. 2005;128:1805–1811

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In a second study 11 patients with severeIn a second study, 11 patients with severe UC were randomized to either receive a single infusion of remicade or a placeboOf the 8 patients receiving the remicade, 4 experienced a clinical response at 2 weeksOf the 3 patients receiving the placebo, all 3 experienced no response


Some of the most common symptoms as with anySome of the most common symptoms, as with any drug, are headaches, nausea, vomiting, URI, dizziness, and rashesMore serious complications include TB, pneumonia, sepsis, herpes zoster, leukemia, and lymphomalymphomaAdditionally, some people were noted to become ANA and anti-double-stranded DNA positive

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Complications of UC SurgeryComplications of UC SurgeryMortality (<0.5%)1

10 yr post-opAge

3-10 stools/24 hrs 1

Impotence (1.5%)2

Pouchitis (10-60%)1

SBO (20%)1

10 yr post-op<45

46-55

56-65 >65

% Never Incontinent

56 46 42 33

% Noct. Seepage 39 48 39 60

( )▼♀ fertility (56-98%)3-5

Pouch-vag fistula (4%)1

1Sagar PM, Pemberton JH. In Satsangi J, Sutherland L, et al, eds. Inflammatory Bowel Diseases. Spain: Elsevier Limited; 2003:491 511. 2Pemberton JH, et

al. Ann. Surg. 1987;206(4):504-513. 3Olsen, KO, et al. Gastroenterology. 2002;122:15-19. 4Johnson P, et al. Dis Colon

Rectum. 2004;47;1119–1126. 5Gorgun E, et al. Surgery. 2004;136(4):795–803.

Delaney CP Ann Surg. 2003;238:221-228.

EFFETTI AVVERSIEFFETTI AVVERSI

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Anti Anti -- TNFTNF

AntiAnti-- TNFTNF

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moderatemoderate--toto--severesevere ulcerative ulcerative colitiscolitis 20102010

HUMIRA (ADALIMUMAB)HUMIRA (ADALIMUMAB)Infezioni segnalate includono:Tubercolosi attiva (TB), compresa la riattivazione della tubercolosi latente. I pazienti con TB sono spesso presentati con malattia disseminata o extrapolmonare. I pazienti devono essere testati per la tubercolosi latente prima di HUMIRA (adalimumab) uso e durante la terapia. Il trattamento per la tubercolosi latente deve essere iniziato prima di HUMIRA (adalimumab) uso.Infezioni fungine invasive, tra cui istoplasmosi, coccidioidomicosi, candidosi, aspergillosi, blastomicosi e pneumocistosi. I pazienti con istoplasmosi o altre infezioni fungine invasive possono presentare diffusiistoplasmosi o altre infezioni fungine invasive possono presentare diffusi, piuttosto che localizzata, malattia. Test antigene e anticorpo per istoplasmosi può essere negativo in alcuni pazienti con infezione attiva.Empirica terapia antimicotica dovrebbe essere considerata nei pazienti a rischio di infezioni fungine invasive che sviluppano una grave malattia sistemica.Infezioni batteriche, virali e altre dovute ad agenti patogeni opportunistici.

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IBD Drugs in Pregnancy IBD Drugs in Pregnancy

5-ASAs and corticosteroids low risk for use during d b f di

gpregnancy and breast-feedingImmunosuppressants– AZA/6-MP appear low risk during pregnancy– Methotrexate contraindicated

Antibiotics– Ampicillin and cephalosporins are low risk– Ciprofloxacin and metronidazole should be avoided for

longterm uselongterm useBiologics: – Anti-TNF agents low risk. Infliximab and likely

adalimumab cross placenta in third trimester

Natural RemediesNatural Remedies

www copingwithcolitiswww.copingwithcolitisSeasilver: 100% plant-based nutritional supplement 1-STARCat’s Claw: Helps normalize the balance of beneficial microbes and reverse conditions of intestinal inflammation 5-STAR

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Ulcerative Colitis: Mild to ModerateUlcerative Colitis: Mild to ModerateAcute flare

Exclude entericpathogen

Extensive

Oral 5-ASA

Responseadequate

Responseinadequate

MaintainResponse adequate Consider

Consider rectal therapy(5-ASA and/or steroid)

Patient willing totake rectal therapy

Patient unwilling to take rectal

therapy

L sided

Maintainoral 5-ASA

adequate Considerincreased dose

Responseinadequate

Oral steroidResponse inadequate

Oral 5-ASA Response inadequate

Responseadequate

Maintain

Ulcerative Colitis: Moderate to SevereUlcerative Colitis: Moderate to Severe

Moderate

Inadequate response ConsideInadequate response

Severe

Oral steroid

Taper

Successfu

Adequate response

Unsuccessful

IV Steroid

6MP/AZA

Succes

Response

Failure

rCyA

No response

Inflixim

No response

l

Maintain on

5-ASA and observe

s

Maintain6-MP/AZA

Colectomy

InfliximabResponse

Maintaininfliximab

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Final PointsFinal PointsThere is no “one size fits all” to IBD therapy– Therapy and decision making are tailored to the py g

individualAlgorithms are based upon available evidence– Evidence is in constant flux

Success of algorithms depends upon optimization of each step of therapy andoptimization of each step of therapy and considerable judgment about each outcome– Skillful application of medical therapy makes all the

difference in outcomes

THERAPY ULCERATIVE THERAPY ULCERATIVE COLITISCOLITIS

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SummaryW lki d dWalking wounded– More is better for ASA (dose, route)– Expanding role for biologic agents

Shrinking role for steroidsColorectal surgery consult at 1st course

Sick unto colectomy– Biologic therapy edging into CSA pool– Bx for CMV

Optimism for drug development

More More isis better for ASA (dose, better for ASA (dose, route)route)

Il nuovo prodotto che ha il marchioIl nuovo prodotto, che ha il marchio Mesavancol, è l'unico che utilizza la tecnologia del triplo meccanismo Multi Matrix System (MMX). La tecnologia MMX è il primo sistema che consente il rilascio di 5-ASA anche nella parte finale del colon utilizzando una matrice lipofila, una matrice idrofila e un rivestimento pH dipendente.

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More More isis better for ASA (dose, better for ASA (dose, route)route)

La tecnologia MMX costituisce una formulazione aLa tecnologia MMX costituisce una formulazione a rilascio prolungato ad alto dosaggio (1,2 g di mesalazina per compressa), che consente una distribuzione uniforme nel colon nelle 24 ore, rendendo possibile la monosomministrazione. Ciò significa che i pazienti devono assumere solo 2-4 compresse una volta al giorno, per rispettare il dosaggio raccomandato di 2,4 o 4,8 g/die. Con p gg gle attuali formulazioni si arriva ad assumere anche sei compresse da 800 mg, suddivise in tre somministrazioni giornaliere.

MESAVANCOLMESAVANCOLSTUDIO PILOTA CU RANDOMIZZATI 79STUDIO PILOTA CU RANDOMIZZATI 79

5-ASA MMX 40 CLISMI 39

8 settimane remissione clinica

60%

8 settimane remissione clinica

50%60%Remissione endoscopica45%

50%Remissione endoscopica36,8%

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Rilievi sull’uso dei vari farmaci nella terapia delle IBD

Mesalazina

55--ASA può essere utile nella prevenzione della progressione ASA può essere utile nella prevenzione della progressione

displasiadisplasia--cancro?cancro?

55--ASA può essere utile nella prevenzione della progressione ASA può essere utile nella prevenzione della progressione

displasiadisplasia--cancro?cancro?

I ll l i liI ll l i liI ll l i liI ll l i li

????????????????????????????????

55--ASA & chemoprevezione in IBD.ASA & chemoprevezione in IBD.Carcinogenesi colica in IBD.Carcinogenesi colica in IBD.


DNA oxydative damageDNA oxydative damageDNA oxydative damageDNA oxydative damage

Intacellular signalingIntacellular signalingIntacellular signalingIntacellular signaling

ProliferationProliferationProliferationProliferation ApoptosisApoptosisApoptosisApoptosis

Tumor growthTumor growthTumor growthTumor growth

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Tumor growthTumor growthTumor growthTumor growth

L’L’evidenzaevidenza sperimentalesperimentale dimostra che l’attività dimostra che l’attività

h i di 5h i di 5 ASA i liASA i li

L’L’evidenzaevidenza sperimentalesperimentale dimostra che l’attività dimostra che l’attività

h i di 5h i di 5 ASA i liASA i li



chemopreventiva di 5chemopreventiva di 5--ASA si esplica attraverso:ASA si esplica attraverso:chemopreventiva di 5chemopreventiva di 5--ASA si esplica attraverso:ASA si esplica attraverso:

Modificazione del disequilibrio apoptosi/proliferazione,Modificazione del disequilibrio apoptosi/proliferazione,

Blocco dell’attivazione di effettori intracellulariBlocco dell’attivazione di effettori intracellulariBlocco dell attivazione di effettori intracellulari,Blocco dell attivazione di effettori intracellulari,

Diminuzione del danno ossidativo al DNA.Diminuzione del danno ossidativo al DNA.

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ANCORA ANCORA 0 0 MINUTI !!!MINUTI !!!

Questions?Questions?

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GRAZIE !!!GRAZIE !!!

PERSONAGGI FAMOSI CON IBD - Giacomo Trallori · TERAPIA DELLA COLITE ULCEROSA ... PERSONAGGI FAMOSI...

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