Managing Complications of IBD and Its Therapies David T. Rubin, MD, AGAF

Transcription

1 Managing Complications of IBD and Its Therapies David T. Rubin, MD, AGAF Joseph B. Kirsner Professor of Medicine Chief, Section of Gastroenterology, Hepatology and Nutrition University of Chicago Medicine

2 Disease-Related Complications

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5 Therapy-Related Complications: Infections

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7 Adjusted Odds Ratio Infections and Mortality in the TREAT Registry: 15,000 Patient-Years of Experience Mortality Steroids See update at DDW: Mo1800 Serious infections IFX AZA 6-MP MTX IFX AZA 6-MP MTX Steroids P<.001 P=.006 P= AZA = azathioprine; IFX = infliximab; MTX = methotrexate. LichtensteinGR, et al. Am J Gastroenterol. 2012;107(9):

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9 Suggestions for Managing IBD Therapy in the Setting of Infection* VIRAL EBV,HSV,CMV,HIV, HepB,HepC,HPV,VZV BACTERIAL Strep/Staph Mycobact FUNGAL Histoplasm Coccidio C.diff Thiopurine Stop Mayneedtostop+Rx virus Individualizeastowho torestart6mp/aza Stop+Rx thenindividualize Stop+RxthenRestart whencleared Continue Anti-TNF Continue Proboktocontinue, exceptactivehepb Stop+Rx thenindividualize Stop+RxthenRestart whencleared Continue Anti-Integrins Continue Continue Continue Continue *in addition to treating the underlying infection

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11 Therapy-Related Complications: Malignancies

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14 Lymphoproliferative Disorders with Thiopurines and anti-tnfs FDA Administration Adverse event Reporting System Data from Deepak P, et al. Am J Gastroenterol. 2013;108:

15 Lymphoma Risk Disappears After Discontinuing Thiopurines Khan N, et al. Gastroenterology. 2013;145(5):

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17 Lymphoma Risk Recommendations Understand risk factors: primarily thiopurine exposure and not anti-tnf therapy Accurate discussion of risk stratification and choice of therapies Consideration of non-thiopurine approaches (e.g. methotrexate) Evolving approach may involve discontinuation or de- escalation with some therapies to modify risk, but this is not defined yet

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19 Risk of Skin Cancers in IBD patients and Therapy Exposure Retrospective cohort and nested case-controlstudies using administrative data from the LifeLink Health Plan Claims Database N=108,579 patients with IBD matched to 4 individuals without IBD Long MD, et al. Gastroenterology. 2012;143:

20 Recommendations for Melanoma and NMSC Education of patients and physicians related to risk factors Fair skin pigmentation Overall UV exposure Thiopurines (NMSC) predominantly Personal or family history of melanoma Primary protection: Sun avoidance via sunscreen or sun-protective clothing1 Secondary prevention: Yearly dermatology screening of patientson immunosuppressives2 1Long MD, et al. Gastroenterology. 2012;143: Skin Cancer screening. (

21 Treating the Cancer Patient Who Also Has IBD If receiving cytotoxic chemotherapy, stop the IBD-related immune suppression After finishing the cytotoxic therapy, resume the immune suppressionneed to hold anti-tnf post cancer treatment If the patient had lymphoma, probably would not use thiopurines Organ-specific IBD treatments may have a role as cancer therapies become more specific

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23 Optimizing and switching IBD therapies: how do we decide? Maria T. Abreu, MD Director, Crohn s and Colitis Center Professor of Medicine, Microbiology and Immunology University of Miami Miller School of Medicine Miami, Florida

24 Which biologic first? Disease type Severity Co-morbidities

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28 Trafficking of inflammatory cells to the intestine

29 Vedolizumab blocks egress of effector T cells into the lamina propria

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32 Which biologic first? Anti-TNFs all work well and quickly Vedolizumab works well, esp in ulcerative colitis, but not as quickly Studies to look at steroid induction (Sands) Ustekinumab efficacy similar to anti-tnfs in Crohn s disease Not always/often our decision!

33 Other factors Fistulizing disease Anti-TNFs Vedolizumab limited efficacy (Feagan 2015 #1261) Cancer history Vedolizumab Anti-TNFs safe (Shelton, E. et al. Gastro Apr) Multiple sclerosis Vedolizumab Ustekinumab Psoriasis Anti-TNFs (if not the cause) Ustekinumab

34 Optimizing therapies Its never as good as the first time!

35 When to start? Which to choose? And when do we need combination therapy? Immunomodulators: Thiopurines MTX Antibody-based biologics (immunogenic) Complementary MOAs Higher levels of biologic High inflammatory burden Moderate-to-severe disease Steroid-refractory disease Severe prognostic markers

36 When to start? Which to choose? And when do we need combination therapy? Immunomodulators: Thiopurines MTX Antibody-based biologics (immunogenic) Steroid-dependent disease (applies to both CD/UC) Low inflammatory burden Steroid-refractory disease Mild course/ prognostic markers Hi-risk for complications from combo therapy

37 Proportion of Patients (%) SONIC Combination Therapy With Infliximab and Azathioprine Works Better Than Either Alone in Crohn s Disease Mucosal Healing at Week 26 P<0.001 P=0.023 P= /109 28/93 47/107 AZA + placebo IFX + placebo IFX + AZA Colombel, J.F., et al., N Engl J Med (15): p

38 Median Serum Trough Levels (mg/ml) SONIC: IFX Trough Levels at Week 30* are Higher with Concomitant AZA n=97 IFX + Placebo n=109 IFX + AZA * Patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis Sandborn, W. et al. NEJM, 2010

39 µg/l Trough Concentration of Infliximab is Higher With Concurrent Methotrexate Infliximab plus MTX Placebo Feagan B et al. Gastroenterology Mar;146(3): e1.

40 Why Don t Patients Respond to Anti-TNFs? Dose not high enough: Dose of anti-tnf proportional to extent and severity of inflammation Tissue versus serum levels of drug Different mechanism driving inflammation: Could be different effector cytokines/ T cell subsets Could be epithelial dysfunction Microbial dysbiosis

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42 Yarur, AJ, et al. Inflamm Bowel Dis Feb;22(2): doi: / Serum Adalimumab (ADA) Levels and Anti-Adalimumab Antibodies (ATA) Correlate with Endoscopic Inflammation and Inflammatory Markers 13.3 vs 8.5 µg/ml 14.1 vs 9.2 µg/ml ADA level that best predicted mucosal healing was 7.5 µg/ml (ROC: 0.73 [p=0.02])

43 Adalimumab Levels and Mucosal Inflammation Mucosal Inflammation Mean ADA level 9.2 µg/ml Normal Mucosa Mean ADA level 14.1 µg/ml P=0.02 Yarur AJ. IBD Journal. 2016; In Press.

44 Tissue levels of the anti-tnf may be insufficient for the amount of TNF in the tissue Anti-TNF in tissue TNF in tissue Yarur A. et al. Gut Feb 10. pii: gutjnl doi: /gutjnl

45 Higher Infliximab Trough Levels Are Associated With A Higher Rate Of Perianal Fistula Healing In Patients With Crohn s Disease Yarur, A et al. #514 P< Fistula Healing 6.5 No Fistula Healing Infliximab level (μg/ml )

46 Vaughn B, et al (Cheifitz) Inflamm Bowel Dis Nov;20(11): doi: /MIB Active monitoring of anti-tnf levels may ensure durability of response Prospectively optimized IFX trough concentrations to a target range of 5-10ug/ml P=.0006

47 Switching therapies Assessing and managing loss of response

48 Treatment Algorithm Based on Drug Monitoring Subtherapeutic anti-tnf concentration Therapeutic anti-tnf concentration* Increase anti-tnf dose or frequency (add immunomodulator) Endoscopy/CTE/MRE with active disease Or elevated fecal calpro Endoscopy/CTE/MRE with inactive disease Change to a different anti-tnf if antibodies to the biologic Change to treatment with different mechanism of action (non anti-tnf agent) Investigate for alternate etiology of symptoms Vedolizumab or ustekinumab *If history compatible with early response then loss, I would still try higher dose of biologic in spite of therapeutic levels; we need higher levels than previously thought Afif W et al. Am J Gastroenteterol. 2010;105:

49 Positioning New and Established Medications for IBD Induction of Remission/ Active Disease Maintenance of Remission Vedolizumab (rapidity of response) Anti-TNFs Corticosteroids Budesonide 5-ASA Cyclosporine Tofacitinib (UC) Ustekinumab (CD) Ustekinumab (CD) Vedolizumab Anti-TNFs Methotrexate 6-MP/Azathioprine

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51 Immunomodulator and Biologic Therapy in IBD 2016 William J. Sandborn MD Professor and Chief, Division of Gastroenterology Director, UCSD IBD Center

52 Outline Azathioprine Methotrexate Cyclosporine Anti-TNF therapy Anti-integrin therapy Anti-interleukin 12/23 therapy Janus kinase (JAK) inhibitor therapy

53 Azathioprine

54 Patients (%) NCCDS: Cumulative Remission During Therapy With Azathioprine for Active Crohn s Disease Azathioprine 2.5 mg/kg (250 mg) Placebo NCCDS = National Cooperative Crohn s Disease Study. Summers. Gastroenterology Weeks After Randomization

55 Top Down Therapy With Azathioprine + Prednisone Versus Prednisone In Adults With Newly Diagnosed Crohn s Disease Sustained steroid free remission Survival free of relapse Panes J. Gastroenterology 2013

56 Chande 2014b AZA/6-MP versus Placebo Outcome = Maintenance of Clinical Remission

57 Estimate of Efficacy of AZA for Treatment Success in UC Patients: Meta-Analysis Pooled RR Estimate Across 5 Trials Study Ardizzone 2006 Sood 2002 Sood 2003 Sood 2000 Jewell 1974 Risk ratio (95% CI) 2.71 (1.30, 5.65) 1.72 (0.96, 3.07) 0.68 ( 0.31, 1.50) 1.06 (0.71, 1.58) 1.78 (0.89, 3.54) % Weight Overall (95% CI) 1.42 (0.93, 2.17) Risk ratio Leung Y et al. Dig Dis Sci. 2008;53:1455.

58 Proportion of Patients (%) SONIC: Clinical Remission Without Corticosteroids at Week 26 in Crohn s Disease 100 Primary End Point P<0.001 AZA + placebo IFX + placebo IFX + AZA P= P= /170 75/169 96/169 IFX, infliximab Colombel JF, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med Apr 15;362(15): Massachusetts Medical Society. All rights reserved.

59 Methotrexate

60 Patients (%) Methotrexate Induction in Steroid Dependant Crohn s Disease Multicenter, randomized, controlled trial 141 steroid-dependent patients Active disease despite treatment with prednisone mg/day Randomized to methotrexate 25 mg IM or placebo x 16 weeks P= Week 16 In remission and compete steroid withdrawal Placebo Methotrexate 25 mg/week Feagan. N Engl J Med 1995.

61 % Remission MTX: Efficacy as Maintenance Therapy* 39% Initial Responders Weeks Since Randomization MTX 15 mg IM once weekly (n=40) Placebo (n=36) p = 0.04 *Time to relapse after induction of remission with MTX 25 mg IM once weekly. Feagan BG et al. N Engl J Med. 2000;342:1627.

62 Cyclosporine

63 Cyclosporin Versus Infliximab in Acute Severe Ulcerative Colitis Refractory to Intravenous Steroids Primary Endpoint: Treatment Failure 100% 80% 60% Difference Cys vs. IFX failure rates: -6.4% (95%CI: to 12.0%) 60% p= % 40% 20% 0% Cys (n=55) IFX (n=56) Laharie D. Lancet 2012

64 Colectomy-free survival Cyclosporin Versus Infliximab in Acute Severe Ulcerative Colitis Refractory to Intravenous Steroids Time to Colectomy p=0.66 Colectomy rate Cys: 18 ± 5% IFX: 21± 5% Cys IFX 0.2 % of patients at risk Days since randomisation Laharie D. Lancet 2012

65 Ant-TNF Therapy

66 Patients (%) Patients (%) Patients (%) Patients (%) Net Remission at 6 Months: Certolizumab Pegol, Adalimumab, Infliximab Certolizumab pegol PRECISE 21 Infliximab ACCENT I2 100 Pbo CzP 100 Pbo IFX Open-Label Induction Week 6 Week 26 Remission Net Remission Week 26 0 Open-Label Induction Week 2 Week 30 Remission Net Remission Week 30 Certolizumab pegol PRECISE 14 Adalimumab CHARM Pbo CzP Pbo ADA Net Remission Week Open-Label Induction Week 4 Week 26 Remission Net Remission Week Schreiber S et al. N Engl J Med. 2007;357: Hanauer SB et al. Lancet. 2002;359: Colombel JF et al. Gastroenterology. 2007;132: Sandborn WJ et al. N Engl J Med. 2007;357:228.

67 Patients (%) Patients (%) Infliximab Induction and Maintenance Therapy in Patients With Ulcerative Colitis: Clinical Response ACT 1 ACT 2 Placebo IFX 5 mg/kg IFX 10 mg/kg * 69 * * * * * 65 * * * 47 * weeks 30 weeks 54 weeks weeks 30 weeks *P<0.001vs placebo P vs placebo Rutgeerts P et al. N Engl J Med. 2005;353:2462.

68 Proportion of Patients (%) SONIC: Clinical Remission Without Corticosteroids at Week 26 in Crohn s Disease 100 Primary End Point P<0.001 AZA + placebo IFX + placebo IFX + AZA P= P= /170 75/169 96/169 IFX, infliximab Colombel JF, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med Apr 15;362(15): Massachusetts Medical Society. All rights reserved.

69 Innovator Infliximab (IFX) versus CT-P13 Biosimilar for Active Rheumatoid Arthritis:Mean (±SD) Serum ConcentrationsVersus Time By Treatment Note:Values below the lower limit of quantification (LLoQ) have been set equal to LLoQ. ParkW,et al.ann Rheum Dis.2013;72:

70 Ant-Integrin Therapy

71 Patients (%) Vedolizumab for Ulcerative Colitis: Induction at Week 6 by TNFα Antagonist Failure Patients With Prior Anti-TNF Failure 39.0 Patients Without Anti-TNF Exposure 53.1 Placebo Vedolizumab Clinical Response % CI: 3.9, Clinical Remission , Clinical Response , Clinical Remission , 30.2 Feagan B, Sandborn WJ. New England Journal of Medicine 2013

72 Patients, % Vedolizumab for Ulcerative Colitis: Maintenance at Week 52 by TNFα Antagonist Failure Prior Anti-TNF Antagonist Exposure (n=149) VDZ/PBO VDZ/VDZ Q8W VDZ/VDZ Q4W Clinical Remission Durable Clinical Response Patients Without TNF Antagonist Exposure (n=224) 65.3 Clinical Remission Durable Clinical Response Mean % vs VDZ/PBO (95% CI) VDZ/VDZ Q8W: 25.4 (5.1, 43.8) VDZ/VDZ Q4W: 29.7 (10.3, 47.7) 24.9 (7.1, 42.6) 27.0 (9.4, 44.6) 26.8 (12.4, 41.2) 29.0 (14.6, 43.3) 38.7 (24.0, 53.4) 29.6 (14.6, 44.6) Feagan B, Sandborn WJ. New England Journal of Medicine 2013

73 Patients, % Vedolizumab for Crohn s Disease: Induction at Week 6 by TNF α Antagonist Failure Patients With Anti-TNF Exposure (n=183) Patients Without Anti-TNF Exposure (n=185) Sandborn W. N Engl J Med 2 95% CI: Δ , 22.1 Δ , 11.9 Δ , 17.9 Δ , 25.8

74 Patients, % Vedolizumab for Crohn s Disease: Maintenance at Week 52 TNF α Antagonist Failure Patients With Prior Anti-TNF Failure (n=237) Patients Without Prior Anti-TNF Failure (n=224) Clinical Remission CDAI-100 Response Clinical Remission CDAI-100 Response 95% CI Q8wk: 95% CI Q4wk: , , , , , , , , 29.0 Sandborn W. N Engl J Med 2013

75 Ant-Interleukin 12/23 Therapy

76 Fraction of patients (%) Fraction of patients (%) Ustekinumab Induces Clinical Response (CR-100) Through Week 8 Clinical Response* ( 100 Point CDAI Reduction) UNITI-1 UNITI-2 *All p-values < 0.05, any UST vs. PBO Sandborn et al. CCFA 2015, Abstract O-001 Feagan et al. UEGW 2015, Abstract OP054

77 Fraction of patients (%) Ustekinumab Induces Clinical Remission Through Week 8 Clinical Remission** (CDAI < 150) UNITI-1 UNITI-2 **All p-values < 0.05 except 130 mg dose at Week 3, any UST vs. PBO Sandborn et al. CCFA 2015, Abstract O-001 Feagan et al. UEGW 2015, Abstract OP054

78 Janus Kinase (JAK) Inhibitor Therapy

79 Percentof patients withmucosal healing Percentof patients withmucosal healing Percentof patients withremission Percentof patients with remission Tofacitinib (JAK Inhibitor) for Induction of Moderate to Severe Ulcerative Colitis: Remission and Mucosal Healing at Week 8 60 OCTAVE Induction 1 OCTAVE Induction 2 Remission Remission = =13.5 = = Yes Prior TNFi exposure No 0 0 Yes Prior TNFi exposure No 60 Mucosal healing = Mucosal healing = = = Yes Prior TNFi exposure No 0 Yes Prior TNFi exposure No Sandborn WJ. Journal of Crohn s and Colitis 2016 (Abstract)

80 Conclusions The role of traditional immunosuppressive agents, azathioprine, methotrexate, and cyclosporine, has and is evolving towards greater use as part of combination therapy regimens, largely due to questions regarding the robustness of efficacy as monotherapy agents Anti-TNF therapy has become the dominant treatment for moderate to severe IBD, the first biosimilar anti-tnf was recently approved in the United States The role of new agents including anti-integrin therapy with vedolizumab, anti-interleukin 12/23 therapy with ustekinumab and JAK inhibitor therapy with tofacitinib as first, second or third line agents in moderate to severe IBD is still evolving

81 The Postoperative IBD Patient: Management of Postoperative Crohn's and IPAA-Related Disorders Miguel Regueiro, M.D. Professor of Medicine Associate Chief for Education IBD Clinical Medical Director Senior Medical Director of Specialty Medical Homes University of Pittsburgh Medical Center

82 Postoperative management of Ulcerative Colitis 2

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85 The different faces of Pouchitis

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88 Postoperative management of Crohn s disease 8

89 Medical Management of Postop Crohn's Disease: Early Treatment Versus Watchful Waiting

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92 The Natural Course of postop CD Recurrence is clinically silent initially Histologic Endoscopic Radiologic Clinical Surgical Within 1 week 70-90% by 1 yr Tissue damage 30% 3 yr 60% 5 yr 50% by 5 yrs Surgery [1] D Haens G, Geboes K, Peeters M, et al. Gastroenterology 1998;114: [2] Olaison G, S medh K, Sjodahl R. Gut 1992;33: [3] Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99: [4] Sachar DB. Med Clin North Am 1990;74:

93 Early Treatment: Medications for Preventing Postoperative Crohn s Disease

94 Summary of Postop RCTs 5ASA, Nitroimidazoles, AZA/6MP Postop Prevention RCTs ClinicalRecurrence Endoscopicrecurrence Placebo 25% 77% 53%-79% 5ASA 24%-58% 63%-66% Budesonide 19%-32% 52%-57% Nitroimidazole 7%-8% 52%-54% AZA/6MP 34% 50% 42 44% Regueiro M. Inflammatory Bowel Diseases. 2009

95 % patients Infliximab (n=11) Placebo (n=13) Infliximab vs placebo p= /11 11/13 Recurrence Regueiro et al. Gastroenterol 2009 Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i4.

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97 Infliximab for Prevention of Recurrence of Post-Surgical Crohn s Disease Following Ileocolonic Resection: a Randomized, Placebo-Controlled Study (PREVENT) M Regueiro1, BG Feagan2, B Zou3, J Johanns3, M Blank4, M Chevrier3, S Plevy3, J Popp4, F Cornillie5, M. Lukas6, S. Danese7, P Gionchetti8, M Molenda4, SB Hanauer9, W Reinisch10, WJ Sandborn11, D Sorrentino12, P Rutgeerts13 1University of Pittsburgh Medical Center, 2Robarts Research Institute, University of Western Ontario, 3Janssen Research and Development, LLC., 4Janssen Scientific Affairs, LLC., 5MSD International, 6Charles University, 7Istituto Clinico Humanitas, 8DIMEC, S. Orsola-Malpighi Hospital, University of Bologna, 9Northwestern Feinberg School of Medicine, 10McMaster University, 11University of California San Diego, 12Virginia Tech Carilion School of Medicine, 13Catholic University of Leuven This study was supported by Janssen ScientificAffairs, LLC.

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100 .ok, that was the early treatment approach, but what about Watchful Waiting and Treat Postoperative Crohn s recurrence?

101 Crohn s disease management after intestinal resection: a randomized (postoperative Crohn s endoscopic recurrence POCER) trial De Cruz P, Kamm M, et al. Lancet 2014

102 Study Design Primary endpoint: 18 month endoscopic recurrence in Crohn s disease pts after bowel resection Design: After surgery pts randomized to: (active care) 6 month colonoscopy with step-up rxent for endoscopic recurrence (> i2) (standard care) no 6 month colonoscopy

103 Treatment Stratified by Risk All pts: metronidazole 400mg bid x 3 mos. (if not tolerating, then 200mg bid or stop) High risk for recurrence: >1 factor smoking, perforating ds, previous resection AZA 2mg/kg or 6MP 1.5mg/kg (if intolerant: Adalimumab 160/80/40qow) Low risk for recurrence: 0 risk factors metronidazole and no other rxent

104 Results

105 49% vs. 67% endoscopic recurrence at 18 months in active vs. standard care pts 67% 49% 18 months

106 By scoping at 6 mos and intensifying rx 18% lower rate of endoscopic recurrence 67% 49% 18 months

107 6 month Endoscopic Recurrence in Thiopurine and Adalimumab treated pts 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% * 45% 21% 6 months Thiopurine Adalimumab *6 mos. rates only include active care group Study not designed to compare endoscopic recurrence between thiopurines and adalimumab

108 This means that waiting on antitnf and giving thiopurine, nearly half of the pts had recurrence at 6 months 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% * 45% 21% 6 months Thiopurine Adalimumab *6 mos. rates only include active care group Standard care group only had 18 mos. Colonoscopy Study not designed to compare endoscopic recurrence between thiopurines and adalimumab

109 2 Possible Approaches to Postop Crohn s disease 1. Watchful Waiting for low risk pts, but treat high risk pts with IMM and/or antitnf 2. Treat All but lowest risk immediately after surgery - The main difference is how risk is defined.

110 Relative Risk Factors Early age of surgery (<30) Short time to first surgery Ileocolonic disease Active cigarette smoking Progressed to surgery despite immunomodulators Penetrating (fistulizing) disease History of prior resection

111 The Watchful Waiting Approach based on POCER..

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113 My Approach Almost All of my patients start a med after surgery but NOT necessarily an antitnf - take into account Risk Factors for Recurrence

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115 IBD Surgery - Summary Surgery is an important treatment for IBD, should not be considered failure ~1/2 Crohn s pts and 1/4 UC pts Types of surgery (most common types) CD primary resection and anastomosis UC proctocolectomy and ileal pouch anal anast. Postoperative management CD based on risk factors decide on meds UC technically cure, but pouchitis common 35