Crohn's Disease. The What, When, and Why of Treatment

Transcription

1 Crohn's Disease The What, When, and Why of Treatment Gary R. Lichtenstein, MD, FACG Professor of Medicine Director, Inflammatory Bowel Disease Program University of Pennsylvania Philadelphia, PA In my lecture today, I will be discussing off label use of several medications to treat Crohn s disease 1

2 Joseph 45 year old male with no significant PMH presents with 5 months of abdominal pain, 5 pound weight loss and diarrhea No recent travel or antibiotics FH: No FH of IBD SH: Smokes ½ ppd for 1 years 3 Joseph PE shows a well appearing male in NAD with probable fullness in the RLQ Stool samples negative Colonoscopy ulcerations in the distal 15 centimeters of terminal ileum with normal colon CTE short segment (15cms) of ileal inflammation Labs WBC 6.5K Hct 35% MCV 88 Platelets 4K CRP 3.5 mg/dl (nl <1.) 4 2

3 Joseph: Treatment Options 1. 5ASAs 2. Budesonide monotherapy 3. Budesonide and antimetabolite 4. Antimetabolite monotherapy 5. Anti TNF agent 5 Azathioprine / 6-Mercaptopurine and Methotrexate: Efficacy in CD Chronic active disease Induction of remission (for moderate to severe active disease) Maintenance of remission (for moderate to severe active disease) Steroid induced Remission For the intent of sparing of corticosteroids Long term maintenance following a biologic Prevention of immunogenicity to biologics Treatment of fistulizing Crohn s Disease 6 3

4 Induction of Remission: Azathioprine and 6-MP in CD Study Rhodes et al Klein et al Candy et al Part 1 NCCDS Group I Phase1 Ewe et al Number of Subjects Present et al Willoughby et al Group 1 Common Odds Ratio (2.27) Favors Placebo Favors Therapy Pearson DC, et al. Ann Intern Med. 1995;123(2): Maintenance Effects of Azathioprine and 6-MP in CD Study NCCDS Group II NCCDS Group I Phase 2 O Donoghue et al Rosenberg et al Willoughby et al Group 2 Candy et al Part 2 Number of Subjects Common Odds Ratio Pearson DC, et al. Ann Intern Med. 1995;123(2): (3.9) Favors Placebo Favors Therapy 8 4

5 SONIC Study Design Main Extension Visits Week * Week 2 Week 6 Week 1 Week 14 Week 18 Week 22 Week 26* Week 3 Week 34 Week 38 Week 42 Week 46 Week 5 Week 54 Azathioprine 2.5 mg/kg + placebo infusions Primary Endpoint (Corticosteroid free Remission at Week 26) Infusions * Endoscopy performed at Weeks & 26 Colombel JF, et al. N Engl J Med. 1;362(15): Randomization of Patients Infliximab 5 mg/kg + placebo capsules Secondary Endpoint (Week 5) Infliximab 5 mg/kg + Azathioprine 2.5 mg/kg 9 Clinical Remission Without Corticosteroids at Week 26 Primary Endpoint 1 p<.1 Proportion of Patients (%) 8 3 p=.6 44 p= /17 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel JF, et al. N Engl J Med. 1;362(15):

6 Clinical Remission Without Corticosteroids at Week 5 1 All Randomized Patients (N=58)* Percent of patients (%) p=.25 p< p= /17 67/169 94/169 AZA + placebo IFX + placebo IFX+ AZA * Patients who did not enter the Study Extension had Week 26 values carried forward Colombel JF, et al. N Engl J Med. 1;362(15): Patients in Corticosteroid-Free Clinical Remission at Weeks 26 & 5 All Randomized Patients (N=58)* * Patients who did not enter the Study Extension were treated as non responders Percent of Patients (%) Week 26 Week 5 AZA + Placebo (n=17) IFX + Placebo (n=169) IFX + AZA (n=169) Colombel JF, et al. N Engl J Med. 1;362(15):

7 Azathioprine and 6-Mercaptopurine For Maintenance of Steroid Induced Remission In CD Study N Duration AZA/ Concomitant (Weeks) 6 MP Placebo P Dose Meds Candy /33 (73%) 19/3 (63%). AZA 2.5 mg/kg Tapering steroids 64 14/33 (42%) 2/3 (7%).1 Markowitz /27 (85%) 52 23/27 (85%) 24/28 (86%) 15/28 (54%) Markowitz study: 12 month prednisone use: 4,841 mg for 6 MP, 7,93 mg for placebo NS <.1 6 MP 1.5 mg/kg Tapering steroids Candy S, et al. Gut. 1995;37(5); Markowitz J, et al. Gastroenterology. ;119(4): Steroid Sparing and Toxicity of MTX in Active CD 5 39% P =.25 MTX 25 mg/wk IM (n = 94) Placebo (n = 47) % Patients 3 19% 17% P = % Able to Discontinue Steroids Unable to Tolerate Medication Feagan BG, et al. N Engl J Med. 1995;332(5):

8 Methotrexate Maintenance After Steroids in Crohn s Disease Multi center, randomized, controlled trial 76 steroid dependent patients In remission following methotrexate 25 mg IM x 16 weeks Randomized to 15 mg IM or placebo x weeks Remission (%) Estimation of one year efficacy: 65% of 39% responders = 26% overall Methotrexate Placebo n= 65% n=36 39% Weeks since randomization p=.4 Feagan BG, et al. N Engl J Med. ;342(22): Withdrawal of Immunosuppression in Crohn s Disease With Scheduled Infliximab Maintenance Methods: Controlled trial of pts with CD >6 mos after start of IFX (5 mg/kg iv) combined with immunosuppressives were randomized to: Continue (Con) or interrupt (Dis) immunosuppressives All pts received scheduled IFX maintenance therapy for 14 wks Primary end point was proportion of pts who required a decrease in IFX dosing interval or stopped IFX therapy Secondary end points included IFX trough levels, safety, and mucosal healing Van Assche G, et al. Gastroenterology. 8;134(7):

9 Withdrawal of Immunosuppression in Crohn s Disease With Scheduled Infliximab Maintenance Life table analysis (Kaplan Meier) of the patient outcomes (A) Analysis in both groups of the (B) Analysis in both groups of the need for early rescue IFX or need to stop further IFX therapy stopping IFX therapy P values are listed for the log rank test only (primary end point) Van Assche G, et al. Gastroenterology. 8;134(7): COMMITT: MTX plus IFX in CD Patients in Remission off Steroids (%) 1 8 p= p= Week 14 Week 5 MTX + IFX PBO + IFX No difference in ITT analysis, duration of disease <2 years, by CDAI score No difference in infectious AEs (58.7% MTX vs 61.9% PBO) Feagan BG, et al. Gastroenterology. 8;135:

10 Immunogenicity of TNF Antagonists Patients With Detectable Antibodies to a TNF Antagonist Percent of Patients Episodic Scheduled Maintenance Maintenance IMS IMS+ IMS IMS+ Infliximab 1 (CD 5 mg/kg) 11% 7% 38% 16% (ACCENT I) (CD 1 mg/kg) 8% 4% Infliximab 2 (UC 5 mg/kg) 19% 2% No data (ACT I & II) (UC 1 mg/kg) 9% 4% Certolizumab 3 (PRECiSE I) No data 1% 4% Certolizumab 4 (PRECiSE II) 24% 8% 12% 2% Adalimumab 5 (RA, all doses) No data 12% 1% Adalimumab 6 (CLASSIC II) No data 4% % IMS = immunosuppressant 1. Hanauer SB, et al. Clin Gastroenterol Hepatol. 4;2(7): Sandborn WJ, et al. DDW 7 Poster and abstract T Sandborn WJ, et al. N Engl J Med. 7;357(3): Schreiber S, et al. N Engl J Med. 7;357(3): Abbott Laboratories. July 7. Summary of product characteristics for adalimumab. 6. Sandborn WJ, et al. Gut. 7;56: Percent of Patients (%) SONIC: Immunogenicity Results At Week / /89 1/1 2/1 87/ /16 16/16 72/16 113/1 AZA + placebo IFX + placebo AZA + IFX Positive Negative Inconclusive Patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis. PK data at Week 3 were not available for 1 patient treated with AZA+placebo, 3 patients treated with IFX+placebo, and 4 patients treated with AZA+IFX. Colombel JF, et al. N Engl J Med. 1;362(15):

11 SONIC: Infliximab Trough Levels At Week 3 1 Median Serum Trough Levels (mg/ml) (n=97) IFX + placebo Patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis. 3.5 (n=19) IFX + AZA Colombel JF, et al. N Engl J Med. 1;362(15): SONIC: Clinical Remission at Week 26 Without Corticosteroids by Immunogenicity Primary Endpoint 1 Positive Negative Inconclusive Patients (%) /16 12/18 133/185 IFX and IFX+AZA patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis. Colombel JF, et al. N Engl J Med. 1;362(15):

12 SONIC: Clinical Remission Without Corticosteroids By Trough IFX Concentration at Week 26 Primary Endpoint Patients (%) /32 13/23 43/59 36/49 31/43 > 1 >1 3 >3 6 >6 IFX Concentration (mg/ml) at Week 3 IFX and IFX+AZA patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis. Colombel JF, et al. N Engl J Med. 1;362(15): SONIC: Corticosteroid-free Clinical Remission at Week 5 All Randomized Patients (n=58)* 1 8 Patients (%) p=.28 35% p=.35 46% 24% 41/17 59/169 78/169 AZA + Placebo IFX + Placebo IFX + AZA * Patients who did not enter the Study Extension were treated as non responders Sandborn WJ, et al. Gastroenterology. 9;136(Suppl 1):A

13 MTX vs AZA for Prevention of ATI ATI Formation and Immunomodulation Therapy 1 P=NS % Patients No IS (n=59) MTX (n=29) AZA (n=65) Treatment Group ATI - ATI + ATI Indet Vermeire S, et al. Gut. 7;56(9): Oral 6-MP/AZA in Fistula Closure 1. Several studies document benefit of 6 MP/AZA over placebo in healing all types of Crohn s disease fistulas 2. Dose of 6 MP mg/kg/day, AZA mg/kg/day 3. Response correlates with duration of therapy, usually requires 3 6 months 26 13

14 Azathioprine/6-Mercaptopurine in Fistulizing Crohn s Disease * Meta analysis of 5 Controlled Trials 1 % Patient Response 8 21% 54% 6/29 Placebo 22/41 AZA/6 MP *Primary endpoint of these studies was the treatment of active inflammatory CD Complete healing or decreased discharge Pearson DC, et al. Ann Intern Med. 1995;123: Methotrexate Therapy for Fistulizing Crohn s Disease 35 3 % Response % 31% n=33 Complete Response Potential Response Mahadevan U, et al. Aliment Pharmacol Ther. 3;18(1):

15 Azathioprine / 6-Mercaptopurine and Methotrexate: Efficacy in CD Chronic active disease Induction of remission (for moderate to severe active disease) Maintenance of remission (for moderate to severe active disease) Steroid induced Remission For the intent of sparing of corticosteroids Long term maintenance following a biologic Prevention of immunogenicity to biologics Treatment of fistulizing Crohn s Disease 29 Budesonide: Efficacy in CD Enteric coating (resistant up to ph 5.5) Rate limiting polymer (ethylcellulose with budesonide) Budesonide is delivered and absorbed primarily in the ileum and ascending colon inert core Granule ~1 mm budesonide capsules Absorbed budesonide is subject to first pass metabolism in the liver Only 1% % of budesonide reaches the systemic circulation Edsbacker S, et al. Clin Pharmacokinet. 4;43(12):

16 Clinical Remission Rates With Budesonide vs Prednisolone a Patients Achieving Clinical Remission, % % P=NS 37% P =NS % % Budesonide 9 mg once daily (n=58) Prednisolone a mg taper (n=58) Week 2 Week 8 a Not FDA approved for the treatment of Crohn s disease in the US Campieri M, et al. Gut. 1997;41(2): Glucocorticosteroid (GCS)-Related Adverse Events Patients in the Study Reporting AEs, % Budesonide 9 mg once daily (n=427) Prednisolone a mg taper (n=145) Placebo (n=17) Adverse Event Acne 15 b Bruising easily Moon face 11 b 37 4 Swollen ankles Hirsutism Buffalo hump Skin striae 1 2 Pooled 8 week data from 4 short term active disease trials with varying comparators a Not FDA approved for the treatment of Crohn s disease in the US b P<.5, budesonide vs prednisolone 1. Sandborn WJ, Feagan BG. Aliment Pharmacol Ther. 3;18(3): ENTOCORT EC (budesonide) Capsules (package insert). Wilmington, DE: AstraZeneca, April

17 Summary Chronic active disease Induction of remission (for moderate to severe active disease) Maintenance of remission (for moderate to severe active disease) Steroid induced Remission For the intent of sparing of corticosteroids Long term maintenance following a biologic Prevention of immunogenicity to biologics Treatment of fistulizing Crohn s Disease Budesonide as alternative to corticosteroids in pts with mild moderate ileocolonic Crohn s Disease 33 Minimizing Steroid Toxicity Assess for risk factors for osteoporosis and perform DEXA if appropriate Supplement Vit D, calcium daily 1 mg Calcium 8 IU vitamin D Monitor fasting glucose levels Have an exit strategy for steroid use Kane S. Curr Gastroenterol Rep. 1;12(6):

18 Azathioprine/6-Mercaptopurine Toxicity Nausea Allergic reactions (fevers, arthralgias) Pancreatitis Bone marrow depression Drug induced hepatitis Infectious complications Lymphoma, non melanoma skin cancer Present DH, et al. N Engl J Med. 198;32(18): Lymphoma Risk and Thiopurines CESAME cohort 19,486 patients in France with IBD Outcomes based on drug exposure 23 new cases of lymphoproliferative disorders diagnosed HR 5.28 ( ) for lymphoproliferative disorder with thiopurine exposure Beaugerie L, et al. Lancet. 9;374(971): Kotlyar K, et al. Am J Gastroenterol. 1; 15;S

19 Minimizing Toxicity from Thiopurines Check TPMT first to rule out those with low enzyme activity Schedule regular CBC, liver enzymes Educate patient on symptoms to watch for Dosing at night anecdotally alleviates some complaints of nausea Vaccinate patients for age appropriate diseases prior to initiation Kane S. Curr Gastroenterol Rep. 1;12(6): Methotrexate Toxicity Rash Nausea, mucositis, diarrhea Bone marrow suppression Hypersensitivity pneumonitis Increased liver enzymes Hepatic fibrosis/cirrhosis Known abortifacient No documented increased risk of lymphoma or skin cancer Alfadhli A. Cochrane Database Syst Rev. 5; 25(1):CD

20 Minimizing Methotrexate Toxicity Regular counseling regarding birth control 1 mg Folic acid supplementation daily Monitor CBC, liver enzymes monthly Evaluate risk factors for liver disease Diabetes Obesity Alcohol abuse Liver biopsy no longer recommended Alfadhli A. Cochrane Database Syst Rev. 5; 25(1):CD Anti-TNF Agents: Adverse Events Immunogenicity Infection Granulomatous (TB, histo, Listeria) Viral, fungal Autoimmunity Lymphoproliferative dx? Neoplasm Skin Pediatric tumors Psoriaform lesions Demyelinating disorders true causal??? Worsen or de novo congestive heart failure Hepatotoxicity (rare) true causal?? Stallmach A, Hagel S, Bruns T. Best Pract Res Clin Gastroenterol. 1;24(2):

21 Minimizing Toxicity for Anti-TNF Therapy Rule out evidence for TB prior to initiation If immunocompromised, PPD and Quantiferon may be negative Rule out active infection prior to initiation Abscess C difficile CMV Vaccination for age appropriate diseases Kane S. Curr Gastroenterol Rep. 1;12(6): Minimizing Toxicity for Anti-TNF Therapy Check serologies for Hepatitis B Assess for signs/symptoms of: Uncontrolled heart failure Demyelinating disorders (MS) Skin cancers/suspicious moles Kane S. Curr Gastroenterol Rep. 1;12(6):

22 Summary Safety Slide Corticosteroids appear to be associated with many adverse events and side effects Patients on antimetabolites need to be monitored for short and long term side effects Biologics can cause immune as well as infectious type of complications Balance risk and benefit for each patient 43 Joseph: Followup Started on budesonide 9mg daily Received appropriate vaccinations TPMT enzyme activity normal and started on 6MP 1.5mg/kg with monitoring of CBC/LFTs Patient improved and budesonide discontinued after 12 weeks Continues to do well 18 months after presentation 44 22