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First Line Therapies for UC and Crohn s Disease Douglas C Wolf, MD
Ulcera've Coli's Crohn s disease Aminosalicyalates (ASA to mesalamine) Aminosalicyalates (?) oral therapy(diazo bond, ph, controlled release) topical rectal therapy( mesalamine suppository and enema) Cor'costeroids Cor'costeroid systemic-oral, IV ( prednisone) non-systemic-topical po./ rectal (budesonide MMX, Budesonide foam) Immunomodulators thiopurine(aza, 6MP) Mtx (?) Biologic AnM-cytokine: AnM-TNF(IFX, ADA, GOL) AnM-integrin(VEDO) I systemic-oral, IV (prednisone) non-systemic-topical po/ rectal budesonide EC, budesonide foam) Immunomodulators Thiopurine (AZA, 6MP) MTX Biologic AnM-TNF(CZP,IFX,ADA) AnM-integrin (VEDO)
Crohn s Disease Algorithm LOW RISK TERMINAL ILEUM+/- right colon COLON Sulfasalazine or Mesalamine NO Prednisone 4-6 weeks Response NO Budesonide Response yes yes yes (AZA/ 6 MP) or MTX Response yes +/- Maintenance Response NO +/- Maintenance yes NO Treat as high risk Maintenance ( AZA/6 MP) or MTX
Crohn s Disease Algorithm HIGH RISK Prednisone OR An9 TNF+/- ( AZA/6 MP) or MTX 4-6 weeks +/or Response no Response (AZA/ 6 MP) or MTX no yes no yes Response Maintenance ( AZA/6 MP) or MTX Maintenance anm TNF and (AZA/6MP) or MTX Dose escalate Switch AnM TNF Switch anm metabolite Natalizumab Clinical trial Surgery
Moderate-to-Severe Active UC Non-hospitalized Bressler B, Marshall JK, et al. Gastroenterology. 2015;148(5):1035-1058.
National Cooperative Crohn s Disease Study
Corticosteroids One of the most effecmve CD medicamons Always try to minimize use PotenMal side effects : Mood swings AsepMc necrosis InfecMon Cataracts Hypertension Weight gain Striae Diabetes mellitus Osteoporosis Cushingoid appearance Adrenal suppression(addisons if severe)
Antibiotics
Immunomodulators Rutgeerts P et al.rev Gastroenterol disord.2004;4(suppl 3):S3-S9) Korelitz BI,Present DH.NEJM.1995;333:600-601.
Early Crohn s Disease Therapy: Combined Immunosuppressive vs ConvenMonal
OpMmizing Thiopurine Therapy Thiopurine Nonresponder Groups Nonadherent Underdosing Thiopurine Resistant Thiopurine Refractory THIOPURINE METABOLITE MEASUREMENTS AND MANAGEMENT Metabolite Profile Low/absent 6-TGN Low/absent 6-MMP Low 6-TGN Low 6-MMP Low 6-TGN High 6-MMP High 6-TGN High 6-MMP Management Pa'ent educa'on Increase thiopurine dose Pa'ent educa'on Switch to another drug. Possibly add allopurinol (special monitoring)* Switch to another drug *WBC must be >4.5x10 4 Allopurinol dose is 100mg and thiopurine dose is reduced 25-50% from the original dose Chevaux J-P, et al. Inflamm Bowel Dis. 2011;17(6):1428-35.
Steroid Sparing and Toxicity of MTX in AcMve CD
Indication for Biologic Therapy
Indication for Biologic therapy
Biologic Induction and Maintenance Dosing
Optimizing biologic therapy InducMon- Give a loading dose Give in combinamon with a immunomodulator (6MP,AZA, MTX) OpMmize maintenance dosing Avoid episodic dosing TherapeuMc drug monitoring (TDM)
CHARM: Remission by Disease Duration with Adalimumab at Week 26 Placebo All adalimumab 70 60 59* % Remission 50 40 30 20 10 17 25 40 41** 14 0 <2 years N = 23, N = 39 <2-5 years N = 36, N = 57 5 years N = 111, N = 233 *P =.002, **P <.001, P =.014, P =.001 all vs placebo Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147. Abstract 985.
SONIC: CorMcosteroid-Free Clinical Remission at Week 26 Infliximab Naïve to IMM/anM-TNF/Short DuraMon CD Propor'on of Pa'ents (%) 100 80 60 40 20 0 P <.001 P =.009 P =.022 56.8 44.4 30.6 52/170 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel JF, Sandborn WJ, et al. N Engl J Med. 2010; 362: 1383-1395
PRECISE 2: Response and Remission by Disease DuraMon with Certolizumab Pegol at Week 26 Response Placebo response Remission Placebo remission 100 90 PRECiSE trial (certolizumab) 80 60 40 20 37 68 75 55 50 37 36 62 57 47 44 36 33 29 24 0 <1 year N = 19, 35, 19, 35 1-<2 years N = 20, 22, 20, 22 2-<5 years N = 45, 55, 45, 55 5 years N = 131, 98, 131, 98 Sandborn WJ, et al. Am J Gastroenterol. 2006;101:S454-455. Abstract 1109. Schreiber S, et al. N Engl J Med. 2007;357(3):239-250.
Different Release Sites and Release Mechanisms of 5-ASAs Stomach ph 6 Small Intes'ne ph 7 Large Intes'ne Mesalamine in microgranules Mesalamine w/ Eudragit-S Mesalamine MMX Granulated Mesalamine with Delayed and Extended Release Azo bond Oral and Rectal prepara'ons
Dose Response at Week 6: Delayed-Release Mesalamine (5-ASA) Patients With Treatment Success at Week 6 (%) 100 90 80 70 60 50 40 30 20 10 0 P=NS 51 ASCEND I P=.0384 57 Mild to moderate UC (N = 286) Moderate UC (N = 180) P=NS 56 P=.0384 2.4 g/day 4.8 g/day Delayed-Release Mesalamine 72 Hanauer SB, et al. Can J Gastroenterol. 2007;21(12):827-834.
MMX Mesalamine in Mild to Moderate UC Patients in Clinical and Endoscopic Remission at Week 8 (%) 100 90 80 70 60 50 40 30 20 10 0 22 13 Placebo P=.01* * P-values represent active treatment vs placebo 1. Kamm MA et al. Gastroenterology. 2007;132(1):66-75. 2. Lichtenstein GR, et al. Clin Gastroenterol Hepatol. 2007;5(1):95-102. 41 P<.001* 34 P=.007* 41 Kamm, et al 1 Lichtenstein, et al 2 P=.009* 29 2.4 g/day 4.8 g/day MMX Mesalamine Dose
Budesonide MMX in UC Induces Remission
Budesonide Foam is EffecMve for Mild and Moderate UlceraMve ProcMMs and ProctosigmoidiMs
METEOR: Methotrexate vs Placebo in Steroid-dependent UC Week 16: Primary Endpoint Week 16: Secondary Endpoints Baseline Characteris'cs Prednisone equiv. dose (mg/d) 30 25 Mayo score 4.0 4.0 Mayo Endoscopy score 1 1 Carbonnel F, et al. European Crohn s and ColiMs OrganisaMon, Inflammatory Bowel Diseases. Abstract OP023. February 21, 2015. clinicaltrials.gov/ct2/show/study/nct00498589
Infliximab in Ulcerative Colitis: Clinical Remission* Percent of Patients 50 45 40 35 30 25 20 15 10 5 ACT 1 39 37 34 32 15 16 Percent of Patients 50 45 40 35 30 25 20 15 10 5 ACT 2 34 28 11 6 26 P<0.001 P<0.01 36 0 8 Weeks 30 Weeks 0 8 Weeks 30 Weeks Placebo infusions 5 mg/kg infliximab 10 mg/kg infliximab *Clinical remission defined as Mayo score of 2 points, with no individual subscore >1. PaMents with baseline medicamon were conmnued on stable doses. Rutgeerts P, Sandborn WJ, Feagan BG, et al. N Engl J Med. 2005;353:2462-2476.
CombinaMon Therapy with Infliximab and Azathioprine Works Beqer than Either Alone in UC 100 IFX+AZA (n=78) IFX (n=77) AZA (n=66) 80 77 69 63 PaMents (%) 60 40 * 40 50 55 37 20 22 24 0 Steroid-free remission Response Mucosal Healing *P<.05 Panaccione R, et al. Gastroentreology. 2014;146(2):392-400.
Accelerated Infliximab Dosing in UC RetrospecMve analysis 50 hospitalized severe acute UC paments 35 received standard IFX 0,2,6 42 days 15 received 3 doses: median - 24 days Standard inducmon:14/35=40% colectomy Accelerated inducmon:1/15=6.7% colectomy Gibson, et al. CGH. 2015; 13:330-335.
Fecal Infliximab Loss Brandise JF, et al. Gastroenterology. 2015 Apr 24 [Epub ahead of print].
No Unanimity Regarding IFX Rescue Dosing for Severe UC Herfarth HH, et al. Clin Gastroenterol Hepatol. 2015;13(2):336-8.
Vedolizumab in UC Week 6 and 52 PaMents (%) Placebo (n=149) 100 80 60 40 20 0 [VALUE] % Week 6 Vedolizumab 300 mg (n=225) P<0.001 [VALUE] % Clinical Response: Week 6 Primary Endpoint Feagan B, et al. NEJM.2013;369:699-710. PaMents (%) PaMents (%) 100 80 60 40 20 0 100 80 60 40 20 0 Placebo (n=126) Vedolizumab 300 mg q8weeks (n=122) [VALUE] % P=0.008 [VALUE] % Clinical remission at both Weeks 6 and 52 Secondary Endpoint Placebo (n=126) Vedolizumab 300 mg q8weeks (n=122) [VALUE] % P<0.001 [VALUE] % Clinical response at both Weeks 6 and 52 Secondary Endpoint
What Is Our Treatment Target? Clinical - asymptomamc Biologic - normal labs, biomarkers Endoscopic - mucosal healing Histologic - deep remission Few of our paments are able to achieve it Cost Convenience Efficacy Side effects
What About Safety? Mesalamine rare issues, e.g. renal Immunomodulators Lymphoma, InfecMon Cyclosporine InfecMon AnM-TNF: Monotherapy vs. Dual InfecMon, Malignancy, Lymphoma (HSTL) Vedolizumab: Monotherapy vs. Dual InfecMon, Lymphoma (dual)
Conclusion ExisMng strategies are frequently ineffecmve at long term disease control PrognosMc factors are important to determine approach to therapy Careful disease and TherapeuMc Drug Monitoring improve outcomes Need for new agents in UC and CD