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  • Treatment Algorithms in Ulcerative Colitis

  • Premise and PreviewIn Most Clinical Scenarios of Ulcerative ColitisTherapy is Sequential

  • Goals of Therapy for IBDInducing remissionMaintaining remissionRestoring and maintaining nutritionMaintaining patients quality of lifeSurgical intervention (selection of optimal time for surgery)

  • Inflammatory Bowel DiseaseUC is limited to the mucosa of the large bowel.CD is transmural and may affect any portion of the GI tract.Some patients exhibit signs and symptoms of both and up to 25% of patients with IBD do not separate cleanly into either classification. UC and CD can exhibit extraintestinal manifestations (i.e., symptoms that involve organs other than the intestines).

  • Environmental Risk FactorsSmoking UC , CD. CHO & sugar CD. Oral contraceptives CD. - The relative risk of CD is reported to be (8.0) in women who have used oral contraceptives for > 5 yrs - Relative risk of (1.2) in women who have not used oral contraception.Breastfeeding CD.diarrheal illness during infancy UC.NSAIDs CD. ( 5-fold)IBD is not caused by stress. stress may alter the immune system and increase the susceptibility to disease.

  • EpidemiologyNorthern countries have the incidence of IBD; Southern European countries have a incidence.In the U.S., incidence of IBD is reported to be in African Americans than in Caucasians.Migrants who move from an area of lower incidence to an area of higher incidence develop a higher incidence of IBD.UC and CD are more frequent in populations of higher socioeconomic class.IBD the highest peak occurring in people age 1530 yrs of age & a smaller peak occurring in people 6080 yrs of age.

  • Anatomic Comparison of UC to CD

  • The Sigmoidoscopic / Colonoscopic

  • Ulcerative ColitisSymptoms of UC:Constipation.Rectal bleeding.Urgency.Diarrhea.Abdominal discomfort. Decreased appetite, & weight loss. Bloody stools.

  • Remission & Relapse of UC

    Completely relapse-free course is only 18.4% after 5 yrs & Completely relapse-free course is only 10.6% after 25 yrs. The probability of unrelenting disease is 0.1%.The annual chance of experiencing a year in remission after a relapse is 30%. Factors associated with a relapse: 1. Aspirin & other NSAIDs. 2. Respiratory illness. 3. Enteric infection (e.g. ,Campylobacter jejuni) 4. Antibiotics, oral contraceptives, & psychological stress.

  • Complication of U.C.Massive hemorrhage. Toxic megacolon.Perforation. Strictures. Sclerosing cholangitis, Cholangiocarcinoma.Extraintestinal symptoms [ acute arthropathy sacroiliitis, ankylosing spondylitis, ocular complications,& hepatobiliary disease]. Colon cancer. The cancer risk is highest in patients with UC > 10 years. The annual incidence of colon cancer in patients with UC of > 10 years is 0.81%

  • Referral Population Cohort:Disease Distribution at Presentationn = 1116Farmer RG, Easley KA, Ranking GB. Dig Dis Sci 1993;38(6):1137-1146

    Classification of Severity of IBD

  • > 30> 30< 30ESR Transfusion required 90> 90NormalPulse> 37.5> 37.5NormalTemperature (C)ContinuousFrequentIntermittentBlood in stool>10>6
  • UC: Natural History020406080100Disease ActivityPatients with UC (%) Disease Severity at PresentationMild Activity (20%)Moderate Activity (71%)Severe Activity (9%)Mild Activity: < 4 stools daily No systemic disturbance ESR: Nl Moderate Activity: > 4 stools daily Minimal systemic effects Severe Activity: > 6 stools daily Bloody stools Fever Tachycardia Anemia ESR > 30 mm/hrHendriksen C, Kreiner S, Binder V. Gut 1985;26:158-163

  • UC Natural HistoryDisease course one year after diagnosis

  • Natural Course of Ulcerative ColitisLangholz E et al.Scand J Gastroenterol. 1996;31:260-266.Based on a multivariate analysis.Proctitis Left-Sided Pan-colitis ProgressionSurgeryRegression

  • Treatment of IBDPharmacological Management:Aminosalicylates.Cortisone or Steroids. Immunomodulatory and Immunosuppressive Agents [Azathioprine and 6-MP, Methotrexate, Cyclosporine]Infliximab.Antibiotics.Miscellaneous Therapies (Heparin).

  • Therapeutic Pyramid for Active UCSevereModerateMildSystemic CorticosteroidsAminosalicylatesSurgeryOral SteroidsAZA/6-MP CyclosporineInfliximab

  • Sequential IndicationsInduction of remissionTreatment of acute disease Maintenance of remission Medical maintenanceSteroid-sparing

  • Ulcerative Colitis: Induction of RemissionMild diseaseAminosalicylateTopical therapy (distal disease)Oral therapy (extensive disease)

  • Chemical Structure of 5-Aminosalicylate (Mesalamine) and Its Pro-Drugs: Sulfasalazine, Balsalazide, and Olsalazine

  • Oral 5-ASA Release SitesMesalamine in microgranulesPentasa

  • Comparative Doses:Mild to Moderate UC

    RecommendedTreatment DoseEquivalent5-ASA doseSulfasalazine3-4 grams1.2-1.6 gramsMesalamine2.4 grams2.4 gramsBalsalazide6.75 grams2.4 grams

  • 5-ASA Delivery SystemsPENTASAASACOLSASP/OLS/BALSENEMASUPPJEJUNUM / ILEUM / ASC / DES / SIG / RECT

  • SPD476 uses MMX technology to deliver 5-ASA to the entire colon Delayed and extended drug release formulation containing 1.2g 5-ASAHighest 5-ASA drug loading per tabletMMX = MMX Multi Matrix System

  • Sulfasalazine Dose/Toxicity 1G 2G 3G 4G100%

  • Aminosalicylate Dosing for Reductionof Signs/SymptomsDose-Response without Intolerance% Response Schroeder, Tremaine, Ilstrup, 1997; Hanauer, 1993; Sninsky, 199101020304050607080PLACEBO1.6G2G2.4G4G4.8G

  • ASCEND I & II:Pooled DataTwo Phase III, multi-center, randomized, double-blind controlled studies423 analyzable patients with moderately active UC randomized to oral mesalamine 4.8 g/day (800 mg tablets) or 2.4 g/day (400 mg tablets) x 6 weeksTreatment with 4.8 g/day provided a statistically significant efficacy benefit over 2.4 g/day in moderately active diseaseBoth doses of mesalamine had similar safety profiles, and both were well toleratedHanauer et al. DDW 2005

  • ASCEND I & II:Treatment Success at Weeks 3 & 6 P=0.0034 P=0.058n=223n=223n=198n=200*Pooled Data: Moderately Active UC58%53%72%62%020406080Week 3Week 6% of Patients Improved2.4 g/day4.8 g/day

  • Oral (2.4 g) vs. Rectal (4 g)Mesalamine for Distal UC% Response Safdi. Am J Gastroenterol 199701020304050607080901001 week2 weeks3 weeks6 weeksOral RectalCombined

  • Addition of Rectal Mesalamine to Oral Mesalamine in PancolitisMarteau, P et al. Gut 2005;54:960-965

    Percentage of patients achieving remission (ulcerative colitis disease activity index (UCDAI) of 0 or 1) or improvement (decrease in UCDAI >2 points).

  • Marteau, P et al. Gut 2005;54:960-965 Remission and improvement rates

  • Maintenance Therapies for Ulcerative ColitisAminosalicylatesAzathioprine/6-MP

  • Aminosalicylate: Maintenance TherapySulfasalazineDose-response limited by intoleranceConventional dose-reduction based on balance of efficacy/toxicity

  • Oral Mesalamine Dosingfor UC Maintenance% RemissionMonths Hanauer. Ann Intern Med 1996020406080100120123456789101112

  • Oral vs. Topical Mesalaminefor Maintenance of Distal UC% RemissionMonths DAlbasio. Am J Gastroenterol 1997 02040608010012024681012141618202224

  • Frequency of Topical Mesalamine for Maintenance of Distal UCMiner. Gastroenterol 1994;106:A736% Remission01020304050607080906 wks 12 wks 24 wks

  • Combined Oral + Topical Mesalamine for Maintenance of Distal UCDAlbasio. Am J Gastroenterol 1997Months% Remission0204060801001201234567891012

    *IN05594?

    *P

  • Aminosalicylates Side effects: Dose-dependent side effects:Headache.Dyspepsia.N, V, anorexia.Alopecia.

    Idiosyncratic reactions:Hypersensitivity reactions (rash).Dronchospasm.Hemolytic anemia.AgranulocytosisHepatitis, pancreatitis.Male infertility.Interstitial nephritis.

    CorticosteroidM.O.A: Anti-inflammatory effects and suppress the immune system. production of some pro-inflammatory cytokines Directly inhibit many leukocyte functions.Dose: prednisone (4060 mg/day), hydrocortisone(100 mg q 68 hrs), methylprednisolone (40-60 mg/day), Budesonide (9-15 mg/day).Adverse Reactions: sleep disturbances, mood alterations, adrenal suppression, glaucoma, cataracts, osteoporosis.Monitoring Parameters: BP, Blood glucose, electrolytes, Ca+2 correct level.

    Azathioprin and 6-MPM.O.A:Inhibiting the synthesis of protein, (RNA,DNA).Direct anti-inflammatory properties Inhibit cytotoxic T cell and natural killer cell function.Dose: azathioprine (1.53.0 mg/kg/day), 6-MP (11.5 mg/kg/day).Adverse Reactions: leukopenia, pneumonia, thrombocytopenia, pancreatitis, lymphoma, bone marrow toxicity.Monitoring Parameters: CBC, Platelet counts, total bilirubin, alkaline phosphatase, TPMT phenotype before therapy.

    *IN05594?

    Controlled Trial of AZA in Management of Chronic UC - ResultsRosenberg J, et al. Gastroenterology. 1975;65:96-99.

    *IN05594?

    Controlled Trial of AZA in Management of Chronic UC - Results23.222.213.62.3051015202530Placebon=20Azathioprinen=24Mean Activity ScoreP

  • 20Patients281911Cyclosporine in Patients with Severe Ulcerative ColitisCyclosporineNo Response: surgeryResponseElective colectomyOral CyclosporineLichtiger S et al. NEJM 1994

  • IV Cyclosporine: Major Toxicity Renal insufficiency 23%

    Infection20%

    Seizure

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