Management of Moderate to Severe Ulcerative Colitis

Transcription

1 Management of Moderate to Severe Ulcerative Colitis Neilanjan Nandi, MD Assistant Professor of Medicine Associate Program Director Division of Gastroenterology Drexel University College of Medicine Hahnemann University Hospital Philadelphia, PA Disclosures Speaker s Bureau: Janssen Biotech 1

2 Ulcerative Colitis Natural History Langholz E, et al. Gastroenterology. 1994:7:3. y/o Female w/ulcerative Pancolitis Previously mild-moderate disease maintained on 5-ASA PO/PR Now with: Diffuse abdominal pain BM: 8x/day Bloody diarrhea in majority of stools Urgency, Tenesmus What do you do? 2

3 Prognostic Factors: Poor Response or Surgery Stool Frequency > 8 or > 5 w/3d of IV Tx Percentage bloody stools HR > 9 bpm Temp > 37.5 C Inpatient status Active infection Prolonged flare Disease duration Severe endoscopic lesions Hgb <.5 g/dl Bandemia Elevated ESR\CRP Low Albumin Transverse colon dilation, > 5cm Ananthakrishnan AN et al, AJG 8;3(11): Stage Severity, Rule Out Infection Colonoscopy In Severe UC, colonoscopy CONTRAINDICATED, Perforation risk HIGH Perform Flex Sig to rectum r/o CMV (biopsy center of ulcer) r/o C difficile Minimize insufflation, Consider water immersion or CO2 NO retroflexion Minimize sedation Avoid narcotics 3

4 MILD MODERATE SEVERE BM: 1-2/d + baseline Less than daily blood/pus No systemic symptoms BM: 3-4/d + baseline Daily blood/pus Systemic symptoms BM: 5/d + baseline Only blood Systemic symptoms % 71% 9% % % % 6% 8% % Ulcerative Colitis Patients (%) Erythema Mild loss of vasculature Mild edema, granularity Mild friability Significant erythema Absent vasculature Grossly granular Friable Erosions Spontaneous bleeding Ulcerated Langholz E, et al. Scand J Gastroenterol. 1991:26: Endoscopic Severity Correlates with Colectomy SEVERE COLITIS MODERATE COLITIS PROGRESSION TO COLECTOMY 93 % 23% Carbonnel F, et al. Dig Dis Sci. 1994;39:155. 4

5 y/o Female w/ulcerative Pancolitis (-) C difficile assay No CMV UC Therapeutic Pyramid SEVERE MODERATE Surgery CSA/Tacro IFX/Vedo ± IMM? Anti-TNF/Alpha-Integrin Systemic CS Topical Steroid IMM 6-MP AZA MTX? MILD Topical Steroid (PR,Budesonide-MMX) 5-ASA CSA = Cyclosporine, Tacro = Tacrolimus, IFX= Infliximab, Vedo = Vedoluzimab, IMM = Immunomodulator, 6-MP = 6-Mercaptopurine, AZA = Azathioprine, MTX = Methotrexate, CS = Corticsteroid, 5-ASA = Mesalamine 5

6 How Good Are Our Options? Surgery Steroids Anti-TNF Cyclosporine Tacrolimus Thiopurines? Methotrexate? Not a timely option as monotherapy Is the verdict in? Anti-Alpha-Integrin IV Corticosteroids for Severe UC Study Year CS Remission/Response D # 15 Chapman, et al MP 7% Mantzaris GJ, et al HC 65% Panes J, et al. MP 69% D Haens G, et al. 1 MP 53% Mantzaris GJ, e al 1 HC 78% Sood A, et al. 2 Dx 93% CS = Corticosteroid MP = Methylprednisolone HC = Hydrocortisone Dx = Dexamethasone Steroids work, but. 6

7 Immediate Response 1 Year Outcome After Initial Response Complete Remission 54% No Response 16% Partial Remission % 1 year Prolonged Response 49% Surgery 29% Steroid Dependence Early Steroid Requirement Associated With Increased Rate of Colectomy Faubian WA, et al. Gastroenterology. 1;121: Moderate-Severe UC Induction in Anti-TNF Naive Delta vs Placebo (%) mg/kg, ACT 1/2, Week 8 ADA 16/8, ULTRA 1/2, Week 8 GLM /, PURSUIT- SC, Week 6 5 Clinical Remission Clinical Response Mucosal Healing Note: Studies are not comparable. Delta between outcome and placebo compared here 7

8 Moderate-Severe UC Maintenance in Anti-TNF Naive Delta vs Placebo (%) mg/kg, ACT 1/2, Week 54 ADA mg EOW, ULTRA 2, Week 52 GLM q4week, PURSUIT-M, Weeks & 54 Clinical Remission Clinical Response Mucosal Healing Note: Studies are not comparable. Delta between outcome and placebo compared here But in clinical practice, IFX doesn t always work! Danese S, et al. Ann Intern Med. 14;16: Reasons for Low Infliximab (IFX) Efficacy Immunogenicity Antibodies to Infliximab Luminal IFX loss Fecal losses 8

9 Weeks, 2, 6 Fecal samples collected over 14 days Clinical Response 3 mo s IFX in all stools Maximally observed within first few days post-infusion Brandse JF, et al. Gastroenterology 15; 149: Steroid Refractory UC Patients 15 pts, Accelerated 5 mg/kg, 3 doses w/in 3 weeks Median time: ~ 24 days 35 pts, Standard 5 mg/kg, Wks, 2, 6, q8 Rate of Colectomy.% 35.%.% 25.%.% 15.%.% 5.%.% 6.7% Accelerated % Standard Gibson DJ, et al. Clinical Gastro Hep. 15;13:

10 ULTRA2: Adalimumab by IFX Exposure 8 8 Patients (%) Anti-TNF Naïve 3.2 Anti-TNF Exposed Patients (%) 6 P= Anti-TNF Naïve P= Anti-TNF Exposed Week 52, remission Placebo ADA Week 52, response Placebo ADA Sandborn WJ et al. Gastroenterology. 14;142: UC SUCCESS: Mod-Severe UC w/inadequate Steroid Response Week 16 AZA + PBO IFX + PBO IFX + AZA Remission Response Mucosal Healing Previously Anti-TNF naïve AZA exposure prior to 3 mo s was permitted Pannacione R, et al. Gastroenterology 14.

11 Long-Term Decreased Colectomy Rate in UC Receiving CSA 12 year follow-up of CSA receiving patients Those on 6-MP demonstrated more than 5% less rate of colectomy Chung PY, et al. Am J Gastro. 3(98):S IFX naïve and IV CS refractory UC patients randomized in unmasked fashion to CSA(2 mg/kg/d) or IFX Wk,2,6) Responders received D#7 Failure: CSA 35/58 (6%) IFX 31/57 (54%) CSA level optimized IFX/ATA not evaluated Laharie D, et al. Lancet.38, Dec

12 Cyclosporine (CSA) Baseline electrolytes (Ca, Mg, Ph), LCT s, Cholesterol, Uric acid Cyclosporine continuous mg/kg/hr (2 mg/kg/d); Round off in 5 mg intervals Steady state: 2-3 days, so levels drawn and subsequent dose adjustments require careful consideration and accurate timing Oral absorption difficult due to poor and unstable enteric absorption. Common Side Effects: Mortality 1-2 % HTN, Nephrotoxicity, Electrolyte abnormality Seizures, Paresthesias, Headache Gingival hyperplasia Opportunistic infection (CMV, PCP) Remember prophylaxis! 62 patients total Placebo 32 Tacro 2 week trial Titration goal: -15 ng/ml Extension to 12 week Outcomes 2 week Outcomes More questions than answers right now Ogata H, et al. Inflamm Bowel Dis. 18:5, May

13 MTX vs Placebo MTX vs Sulfasalazine MTX vs 5-ASA Conclusion: No evidence that MTX has a role in maintenance therapy for ulcerative colitis. MTX vs Thiopurine Wang Y, et al. Cochrane Database Sys Rev. 15 August 11. CD756 MERIT-UC 76 patients successfully enrolled and completed open label induction period at 16 weeks Steroid Free Response Remission MERIT-UC, Interim results. Clinical trials.gov 13

14 Anti-Integrin Therapy Natalizumab Anti-α4-β7 Vedolizumab Anti-α4-β7 & Anti-α4-β1 PML (Gut specific) Vedoluzimab A humanized monocloncal antibody (mab) that binds specifically to α4β7 integrin and blocks the interaction of α4β7 with MAdCAM-1 which is mainly expressed on gut endothelial cells. PML = Progressive Multifocal Encephalopathy GEMINI I: Vedoluzimab in UC, Week 6 Vedoluzimab mg IV at Weeks, 2, 6, then q8 weeks Response Remission MH Feagans B, et al. NEJM 13; 369:

15 GEMINI I: Vedoluzimab in UC Anti-TNF Exposed Anti-TNF Naive PBO Vedo PBO Vedo.6 Response Remission 26.3 Response Remission Anti-TNF naïve patients responded at a greater rate than those previously exposed. GEMINI I: Vedoluzimab in UC PBO Vedo Steroid Free Remission Response Week 6 Remission Week 52 Steroid Free Remission was achieved with Vedo over Placebo Feagans B, et al. NEJM 13; 369:

16 Tobacco Conflicting benefit in studies in mild-moderate disease No known reduction in rate of colectomy Role in moderate to severe colitis not established Not clear if nicotine is the active therapeutic or perhaps another unidentified molecule within tobacco smoke But Do desperate times call for desperate measures? Moderate to Severe Ulcerative Colitis Flexible sigmoidoscopy ONLY, Rule out CMV, C difficile Early surgical consult, Avoid narcotics IV steroids but if no improvement by ~ 3-5 days, then consider: IFX CSA/Tacro MTX Vedoluzimab Accelerated dosing warranted, consider kg/mg Measure trough levels to guide dosing and decision making Experienced center, Cumbersome For CSA, then better outcomes with thiopurine for maintenance Previous data not convincing Recent data suggests benefit but be cautious as it is only preliminary Especially if anti-tnf failure and/or steroid dependent/refractory 16

17 Neilanjan Nandi, MD (215) Assistant Professor of Medicine Associate Professor of Medicine Division of Gastroenterology Drexel University College of Medicine Hahnemann University Hospital 17