Managing IBD: Lessons I Have Learned Over the Past. Farraye s Tips

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1 Managing IBD: Lessons I Have Learned Over the Past 25 Years Francis A. Farraye, MD, MSc Clinical Director Section of Gastroenterology Boston Medical Center Professor of Medicine Boston University School of Medicine Farraye s Tips Assess extent of disease Assess response to treatment using objective measures Don t forget about natalizumab (JC virus testing) Maximizing thiopurines (6mp/allopurinol combination, qhs administration, split dosing) Consider methotrexate as alternative to 6MP/AZA Using 5ASAs; don t forget topical rx for UC Use steroids wisely Errors in managing the hospitalized IBD patient 1

2 Farraye s Tips Maximizing drug safety Vaccinations Lab monitoring i (CBC/diff, LFTS, BUN, creatinine) i PPD testing/quantiferon, HBsAG for anti-tnf eligible patients TPMT Learn chromoendoscopy Limit CT imaging Screen for depression Health maintenance and using checklists CCFA Resources New meds Assess Extent of Disease Look into the terminal ileum in all suspected cases of IBD and consider biopsy Take random biopsies throughout colon (proximal, descending, sigmoid and rectum) even in patient with distal disease Assess SB in Crohn s disease patients by CTE, MRE or in specific cases VCE 2

3 Assess Response to Treatment Using Objective Measures Don t abandon medications prematurely and without objective assessment of disease activity Options are flex sig, colonoscopy, ESR, CRP, fecal calprotectin, VCE or imaging Maximize dose of meds before switching agents especially anti-tnfs Consider superimposed IBS, SIBO, fistula, abscess, etc. Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in IBD Drug adjustment empirically based on clinical symptoms often is inaccurate and may lead to suboptimal outcomes Patient-related factors* may influence the pharmacokinetics of these agents Recent evidence shows that maintenance of an optimal therapeutic drug concentration is associated with improved clinical outcomes Incorporation of therapeutic tic drug monitoring into clinical practice may allow clinicians to optimize treatment by maintaining effective drug concentrations over time * Sex and/or body size, and disease severity, including TNF burden and serum albumin concentration Ordás I, Feagan BG, Sandborn WJ. Clin Gastroenterol Hepatol. 2012;10(10):

4 Management of Loss of Response to IFX Retrospective Mayo study of 155 patients Measured antibodies to infliximab (ATI) and infliximab i concentrations ti measured Testing performed in patients with: Loss of response to infliximab (49%) Partial response after initiation of infliximab (22%) Possible autoimmune delayed hypersensitivity reaction (10%) ATIs were identified d in 35 patients t (23%) Therapeutic infliximab concentrations identified in 51 patients (33%) Afif W, et al. Am J Gastroenterol. 2010;105(5): Measurement of IFX Levels and ATIs Test results impacted treatment in 73% of patients Subtherapeutic IFX Dose escalation Complete or partial response - 86% Subtherapeutic IFX Switch anti-tnf Response - 33% Therapeutic IFX No evidence of active inflammation in 62% of the patients ATIs + patients Switch anti-tnf Response - 92% ATIs + patients Dose escalation Response - 17% Increasing the infliximab dose in patients who have HACAs is ineffective, whereas in patients with subtherapeutic infliximab concentrations, this strategy may be a good alternative to changing to another anti-tnf agent. Afif W, et al. Am J Gastroenterol. 2010;105(5):

5 When Considering Your Third Anti- TNF for a CD Patient, Change MOA Don't forget about natalizumab and JC virus testing Natalizumab has different MOA than anti-tnfs JV Virus testing available- JC Stratify to Quest ENCORE trial (n = 509) with moderate to severe Crohn s disease and an elevated CRP were randomized to natalizumab 300mg IV given at 0, 4 and 8 weeks Natalizumab for Primary Non-Responder or when Considering a Third anti-tnf In a subgroup analysis in the natalizumab trials, there were no statistical differences in natalizumab treated patients who were primary nonresponders to infliximab and in those patients not exposed to infliximab Targan SR, et al. Gastroenterology. 2007;132(5):

6 Appropriate Use of Thiopurines Measure TPMT before starting therapy Closely monitor CBCs frequently in the first 8 weeks of therapy, less closely thereafter Consider dose optimization strategies in selected populations Recommend use of sunscreen and hats Regular dermatology exams Counsel about risk of lymphoma, but no proven strategies to reduce this risk Avoid combination therapy in specific patient subsets Maximizing AZA/6MP Give QHS in patients with nausea/dyspepsia Consider 6MP/Allopurinol in patients with preferential 6MMP metabolism Allopurinol 100 mg PO daily Reduce 6MP and AZA to 25 50% of original dose 1 st month: weekly CBC 2 nd month: qow CBC, periodic metabolite levels 6TGN 6MMP Sparrow. MP, et al. Aliment Pharmacol Ther 2005, Sparrow. MP, et al. Clin Gastroenterol Hepatol 2007, Bradford K, et al. World J Gastro

7 Allopurinol + Azathioprine Combo N=72 AZA dose (mg/kg) 6MP dose (mg/kg) 6TGN * P<0.05 6MMP Mono ,110 Combo * 265* Reduce thiopurine to 25-33% of original dose and add allopurinol 100 mg daily 77 patients (36% resistance, 35% hepatotoxicity, 15% both, 9% other toxicity) Myelosuppression (WBC<3.5) in 16 of 72 (21%) but none required permanent discontinuation 5 year persistence on drug 65% Hoentjen F. Inflamm Bowel Dis Feb;19(2): Dose Splitting Shih DQ, et al. Aliment Pharmacol Ther Sep;36(5):

8 Learn How to Use Methotrexate Steroid Sparing and Toxicity of MTX in Active CD % P =.025 MTX 25 mg/wk IM (n = 94) Placebo (n = 47) % Patients % 17% P = % Able to Discontinue Steroids Unable to Tolerate Medication Feagan BG, et al. N Engl J Med. 1995;332(5):

9 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 40 weeks Remission (%) Estimation of one year efficacy: 65% of 39% responders = 26% overall Methotrexate Placebo n=40 65% n=36 39% Weeks since randomization p=0.04 Feagan BG, et al. N Engl J Med. 2000;342(22): Methotrexate Toxicity Rash Nausea, mucositis, diarrhea Bone marrow suppression Hypersensitivity pneumonitis Increased liver enzymes Hepatic fibrosis/cirrhosis Known abortifacent No documented increased risk of lymphoma or skin cancer Alfadhli A. Cochrane Database Syst Rev. 2005; 25(1):CD

10 Optimize Use of 5ASAs Do not need to be given tid or qid-ok to give qd or bid Remember idiosyncratic exacerbation of UC related to 5ASAs Monitor renal function on 5ASA as well as CBC if on sulfasalazine Don t Forget Topical Rx 10

11 Treatment of Distal UC: Oral and Rectal Mesalamine Therapy Patients Reporting No Rectal Bleeding (%) 100 Oral (2.4 g/d) Rectal (4 g/d) Combined * *P<0.05 vs oral alone * * 0 1 Week 2 Weeks 3 Weeks 6 Weeks Safdi M, et al. Am J Gastroenterol. 1997;92:1867. Extensive Mild/Moderate UC: Oral and Rectal Mesalamine Therapy Mesalamine* 4 g total PO (in divided doses; 2 g BID) + mesalamine enema 1 g HS (N=71) Mesalamine 4 g total PO (in divided doses; 2 g BID) + placebo enema HS (N=56) No. of Patients (%) P=NS Remission Week 4 P= Improvement *Controlled-release mesalamine Marteau P, et al. Gut. 2005;54:

12 Misuse of Steroids Use up to 60mg/day Have an exit strategy when starting steroids Side effects of steroid therapy were reviewed with the patient including but not limited to infections, diabetes, glaucoma, aseptic necrosis of bones, etc were discussed with the patient Give vitamin D and calcium BMD in selected patients Steroid Dosing Oral prednisone shows a dose-response effect between 20 and 60 mg per day, with 60 mg per day modestly more effective than 40 mg per day but at the expense of greater side effects Intravenous steroid in a daily dose equivalent to 300 mg hydrocortisone or 60 mg methylprednisolone if the patient has received steroids in the previous month. There is no benefit to treatment with a much higher daily dose of steroids, which exposes the patient to a higher potential rate of side effects. Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:

13 Errors in Managing The Hospitalized IBD Patient Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501. Predictors of IV Steroid Failure Travis et al, % failure rate on day 3 if: >8 BM/d or CRP>45mg/l 60% failure rate on day 7 if: >3 BM/d or Blood still visible Higher failure rate if: Severe ulcerations present on sigmoidoscopy Ho et al, 2004 Over first 3 days Points Mean # BMs Mean # BMs Mean had an # BMs 85% risk >9of medical 4 failure. Albumin <3.0 g/dl 1 Colonic dilatation 4 Failure of Medical Therapy Score 0 1 = 11% Score 2 3 = 43% Score 4 = 85% Travis S, et al. Gut. 1996;38:905. Ho GT, et al. Aliment Pharmacol Ther. 2004;19:

14 CsA vs Infliximab in IV Steroid- Refractory UC- CYSIF Study Patients (%) Response Rates at Day % 86% CsA Infliximab N=111 (55 CsA; 56 infliximab) CONCLUSION: CsA is not more effective than infliximab in achieving short-term remission and avoiding urgent colectomy in IV steroid-refractory acute UC Laharie D, et al. Lancet. 2012;380(9857): Management of the Patient with Severe UC Patient admitted with severe ulcerative colitis Conduct: Assays of stool samples for C. difficile and bacterial pathogens Abdominal X-ray Flexible sigmoidoscopy Chest X-ray and tuberculosis testing Treat with intravenous corticosteroids Responders Switch to oral corticosteroids Add AZA or 6-MP or 5-ASA Assess response at 3 days Intravenous cyclosporine or infliximab Non-responders Surgery or second-line medical therapy Total or subtotal colectomy with end ileostomy Responders Assess response at 5-7 days Non-responders If cyclosporine: switch to oral cyclosporine then initiate AZA or 6-MP If infliximab: additional induction does at 2 and 6 weeks, then maintenance therapy Bitton A, et al. Am J Gastroenterol Feb;107(2): Total or subtotal colectomy with end ileostomy AZA = Azathioprine 6-MP = 6-mercaptopurine 5-ASA = 5-aminosalicylic acid 14

15 Safely Using IBD Medications Safely Using IBD Medications All IBD meds should be refilled by gastroenterology Only give 3 months of immunomodulators or biologics at a time Only give 3 months of 5ASAs for first prescription and then 12 months when on maintenance Monitor labs CBC with diff, LFTs q 6 weeks for MTX CBC with diff, LFTs q 12 weeks for thiopurines CBC with diff, LFTS? interval for anti-tnfs CBC, creatinine for 5ASAs 6, 12 and 52 weeks and then yearly CBC, creatinine regularly for sulfasalazine 15

16 Vaccination Summary IBD patients can mount a response to vaccines Diminished immune response in patients on combination therapy of immunomodulator and anti-tnf agent Ideally vaccinate on diagnosis and prior to initiation of immunosuppressive agents IBD disease activity will not be affected by vaccinations Gastroenterologists should take a more proactive role in assuring that patients are vaccinated appropriately Screening for TB Tuberculin skin test or interferon-gamma release assay Interferon-gamma release assay preferred: Patients who have received BCG or Patients who are immunosuppressed Specificity >95% for diagnosis of latent TB Chest x-ray in patients with positive test and referral to infectious disease for treatment Perform yearly TB risk assessment Retest selectively due to exposure or travel to endemic areas BCG, Bacillus Calmette Guérin 16

17 Medications: Be Cognizant of Triple Immunosuppression Patients at highest risk of infectious complications when patients are triple immunosuppressed Monitor absolute lymphocyte count Consider PCP/PJP prophylaxis in selected patients Patient meets criteria for IS therapy Update vaccination status Steroids Immunomodulators Biologics Calcium/vitamin D DEXA Exit strategy Monitor for infection TPMT for thiopurines, CBC, liver enzyme Monitor for infection HBV testing TB testing Monitor for infection IS, immunosuppressant, TPMT, thiopurine methyltransferase, DEXA, dual-energy x-ray absorptiometry, CBC, complete blood count, TB, tuberculosis, HBV, hepatitis B virus Modified from: Kane S. Curr Gastroenterol Rep. 2010;12:

18 Selected Monitoring Parameters 5-ASAs Corticosteroids Immunomodulators (MTX, 6MP/AZA) Biologics CBC x x x x Liver enzymes x x x Creatinine/Urinalysis/BUN Eye examination Opportunistic infections (TB, Hep B, varicella, etc) x x x x x Immunizations x x x x TPMT Bone mineral density for > 3 months x x Learn To Perform Chromoendoscopy 18

19 Controlled Studies on the Use of Chromoendoscopy in Patients with Ulcerative Colitis Study Number of patients Dye MB=methylene blue IC=IndigocarmineI i Number of lesions Difference (x-fold) Kiesslich et al. (2003) 165 MB 42 (32 vs 10) 3.07 Hurlstone et al. (2004) 324 IC and magnification 93 (69 vs 24) 3.81 Rutter et al. (2004) 100 IC 7 (7 vs 0) 4.50 Kiesslich et al. (2007) 153 MB and Confocal Endomicroscopy 23 (19 vs 4) 4.75 Marion et al. (2008) 102 MB 20 (17 vs 9) 5.66 Kiesslich R, et al. Endoscopic Surveillance in UC: Smart biopsies do it better. Gastro 2007;133: Kiesslich R, et al. Is chromoendoscopy the new standard for cancer surveillance in patients with ulcerative colitis? Nat Clin Pract Gastroenterol Hepatol Mar;6(3): Deleterious Effects of Excess Imaging Brenner D, Hall E. N Engl J Med 2007;357:

20 Estimated Number of CT Scans Performed Annually in the United States Brenner D, Hall E. N Engl J Med 2007;357: Estimated Lifetime Radiation-Induced Risk of Cancer on Age at Exposure Brenner D, Hall E. N Engl J Med 2007;357:

21 Risk of radiation is higher in children and young adults Over 24 months in a study of 965 children with CD and 628 with UC, 34 % of CD subjects and 23 % of UC subjects were exposed to moderate diagnostic radiation This high utilization may impart long term risk Palmer L, Herfath H, Porter CQ, et al. Diagnostic ionizing radiation exposure in a population-based sample of children with inflammatorry bowel disease. Am J Gastroenterol 2009;104: Depression May affect as many as 15-35% of patients with IBD Predisposing factors: chronic relapsing nature of IBD and some medications used as treatment Appropriate p medical treatments are available and well tolerated CCFA Fact Sheet: Health Maintenance Moscandrew M, Mahadevan U, Kane S. General health maintenance in IBD. Inflamm Bowel Dis. 2009;15(9):

22 Depression 1. Over the past month, have you felt down, depressed, or hopeless? 2. Over the past month, have you felt little interest or pleasure in doing things? Nimalasuriya K, Compton MT, Guillory VJ. Screening adults for depression in primary care: A position statement of the American College of Preventive Medicine. J Fam Pract 2009;58: Depression Screening Scores are rated as normal (0-2), mild (3-5), moderate (6-8), and severe (9-12) 22

23 Health Maintenance and Using Checklists Health Maintenance Vaccinating the IBD Patient Surveillance for Colorectal Neoplasia Risks of Cervical and Skin Cancer Bone Health Smoking Cessation Screening for Depression Risks of Radiation Ophthalmologic Evaluation 23

24 CCFA Resources Patient education brochures Webcasts for patients Webcasts for MDs, NPs/Pas, RNs Appeal letters letters/ Lots more 48 24

25 CCFA Appeal Letters Accommodations School Accommodations Employment Accommodation Private Dorm and Bathroom Disability Social Security Disability Resources Life Insurance Financial Resources Mental Health Benefits Ostomy Patient Assistance Medication/Treatment Certolizumab Pegol Boost Pediatric Adalimumab Therapy Off Labeling Adalimumab Dosing Adalimumab for UC Infliximab Dose Escalation Tests/Procedures Calprotectin Capsule Endoscopy Metabolite Level Testing Infliximab & HACA TPMT 49 Waiting For New Meds 25

26 Vedolizumab for UC (Induction Week 6) * 53 N=374 * P< ** P = ** Remission Response Vedo Anti-TNF Naïve - Vedo Placebo Feagan B, et al. NEJM. 2013;369(8): Vedolizumab for UC (Maintenance Week 52) 45* 42* 52* 57* N=373 * P< Remission Response Vedo q 4 weeks Vedo q 8 weeks Placebo Feagan B, et al. NEJM. 2013;369(8):

27 Tofacitinib (JAK3 inhibitor) in UC- Results 90 Placebo n= mg BID n= mg BID n=33 Patients (%) mg BID n=33 15 mg BID n= Clinical Response Endoscopic Response Clinical Remission Endoscopic Remission Sandborn et al. NEJM 2012; 367: UC Medications Available and in Clinical Trials Danese S. Gut 2012;61:

28 CD Medications Available and in Clinical Trials Danese S. Gut 2012;61: Work every day to improve the quality of care you deliver to your IBD patients 28