discover the benefits of linked color imaging · 2020. 5. 21. · 5/21/2020 6 virtual grand rounds...

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Virtual Grand Rounds universe.gi.org

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Virtual Grand Rounds universe.gi.orgREGISTER NOW…ACG’s IBD School & Eastern Regional!

Are now VIRTUAL events, withOn‐Demand Presentations and LIVE Webcast Q&A sessions!

Visit meetings.gi.org to register for BOTH COURSES today!

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American College of Gastroenterology

5/21/2020

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Visit meetings.gi.org to register today!

Virtual Grand Rounds universe.gi.orgNEW!! ACG 2020 ABSTRACT SUBMISSION DEADLINE

EXTENDED 2 WEEKS!

NEW!! DEADLINE: JUNE 15, 2020 11:59pm Eastern

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Virtual Grand Rounds universe.gi.orgACG Virtual Grand RoundsJoin us for upcoming Virtual Grand Rounds!

Visit gi.org/ACGVGR to Register

Week 10: Colorectal Cancer Screening in a Post Covid World Renee L. Williams, MD, MHPE, FACGMay 28, 2020 at Noon EDT

NEW! Week 11: Non‐Alcoholic Steatohepatitis: Disease Burden, Diagnosis, and TreatmentZobair M. Younossi, MD, MPH, FACGJune 4, 2020 at Noon EDT

Week 12: Gastroparesis: Then, Now, and The Future – June 11, Noon Week 13: Health Maintenance for the Patient with IBD – June 18, Noon Week 14: EOE and EGID: Pearls and Pitfalls – June 25, Noon Week 16:Managing Complications of Cirrhosis – July 9, Noon


How to Receive CME and MOC Points

LIVE VIRTUAL GRAND ROUNDS WEBINAR

ACG will send a link to a CME & MOC evaluation to all attendees on the live webinar.

ABIM Board Certified physicians need to complete their MOC activities by December 31, 2020 in order for the MOC points to count toward any MOC requirements that are due by the end of the year. No MOC credit may be awarded after March 1, 2021 for this activity.

ACG will submit MOC points on the first of each month. Please allow 3‐5 business days for your MOC credit to appear on your ABIM account.

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MOC QUESTION

If you plan to claim MOC Points for this activity, you will be asked to: Please list specific changes you will make in your

practice as a result of the information you received from this activity.

Include specific strategies or changes that you plan to implement.THESE ANSWERS WILL BE REVIEWED.

Virtual Grand Rounds universe.gi.orgDisclosuresDr. Rubin: Consultant and/or Grant Support

• AbbVie• Abgenomics• Allergan, Inc.• Boehringer Ingelheim, Ltd.

• Bristol‐Myers Squibb• Celgene Corp/Syneos• Check‐cap• Dizal Pharmaceuticals• GalenPharma/Atlantica• Genentech/Roche

• Gilead Sciences• Ichnos Sciences S.A. (formerly GlenmarkPharmaceuticals)

• GSK (GlaxoSmithKline Services)

• Janssen Pharmaceuticals

• Lilly• Mahana Therapeutics• Narrow River Mgmt

• Pfizer• Prometheus Laboratories

• Reistone• Seres Therapeutics• Shire• Takeda• Target PharmaSolutions, Inc.

• Techlab, Inc

Dr. Shah has indicated no relevant financial relationships.

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Positioning of Old and New Therapies in IBD

David T. Rubin, MD, FACGJoseph B. Kirsner Professor of Medicine

Chief, Section of Gastroenterology, Hepatology and Nutrition

University of Chicago

@IBDMD

RubinLab.uchicago.edu


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Glasziou P, et al. BMJ. 2005;330(7492):644‐48.

The Five Phases of Chronic Disease Management

Pretreatment Assessment

Initial Titration (Induction)

MaintenanceMonitor and Re‐establish Control

Cessation


Prior Treatments for IBD: The “Really Old”• Intracolonic

insufflation of oxygen

• Gentian violet

• Tincture of iodine

• Sodium lauryl sulfate detergent to “destroy” trypsin or lysozyme

• Vaccines

• Azochloramid(“antibacterial” agent)

• Horse serum

• Copper sulfate

• Liver extracts

• Artificial fever therapy

• Hot (120°F) water enemas

• “Extracts” of hog intestine, stomach, and colon to “restore” an “intestinal protective agent”

• Zinc peroxide rectally

• Thiouracil drugs

• Hypnosis

• Neuroanalysis

From Kirsner, JB. Origins of the inflammatory bowel diseases, Oxford 2001.

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Positioning Therapies in IBD c1950‐1980s

Prednisone Sulfasalazine

Sulfasalazine Prednisone


Personalized Therapy with Old Drugs!

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Theory of Mechanistic Targeting in IBD Management

• Inflammation is a defense reaction to real or perceived threats to preserve self

‐ Layered, duplicitous and redundant

• Targeting a dominant pathway (or more than one) may reduce the inflammatory response and “reset” homeostatic control (healing)

‐ Persistent drive (antigenic?) may override this approach and result in “mechanistic escape” and loss of response to a specific target

Weisshof R, et al. Adv Ther. 2018;35(11):1746‐62.


Modern Treatments for IBD

Immune modification/suppression

– 5‐ASA (?)

– Steroids

– Thiopurines/methotrexate

– Anti‐TNFα therapies

– Anti‐integrin therapies

– Anti‐IL12/23

– JAK inhibitors

Microbiota manipulation

– Dietary therapies (exclusion diets)

– Antibiotics

– Prebiotics

– Probiotics

– Intestinal microbiota transfer

– Bacterial derived proteins

Surgery

– Resection of fibrostenosis

– Resection in medically resistant disease

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Treatment Options for Moderate‐to‐Severe IBD

Treatment Induction Maintenance Other Indications

Steroids CD, UC X

Thiopurines X CD, UC

Methotrexate CD CD

Anti‐integrin (natalizumab, vedolizumab)

Natalizumab CDVedolizumab CD, UC

Natalizumab CDVedolizumab CD, UC

Natalizumab MS

Anti‐p40 (ustekinumab) CD, UC CD, UC Psoriasis, PsA

Anti‐TNF (adalimumab1, certolizumab pegol2, golimumab3, infliximab4)

CD, UC CD, UCPsA, SpA, RA, uveitis,

etc

JAK inhibitor (tofacitinib) UC UC RA, PsA


Traditional Treatment Sequence in IBD

Aminosalicylate

Corticosteroids

Anti‐TNF

Aminosalicylate (UC)/Thiopurine (UC/CD)/MTX (CD)

Aminosalicylate

Anti‐TNF/Thiopurine/MTX

Induction

Maintenance

time

Cyclosporine/TacrolimusNatalizumab

Vedolizumab (CD, UC)Ustekinumab (CD, UC)

Fail first before stepping up

Assumption that induction dictates maintenance in all

patients

No predictive therapeutic biomarkers

EN, PEN PEN?

Doesn’t suggest that de‐escalation

is possibleTofacitinib (UC)

New therapies positioned agnostic to

existing ones

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1. Understand the Multiple Dimensions of Disease Control

Disease Control

Patient Factors

Disease Factors

Therapy Factors

• BMI

• Gender

• Nutritional status

• Pharmacogenomics

• Adherence

• Smoking

• Lag time before dx

• Phenotype

• Genotype

• Microbiome

• Immunology

• CRP

• Disability Index

• Resections

• Prior failed therapy

• Steroids

• Dose‐Response

• Half‐life

• Delivery

• Antibody complexes

Adapted from Rutgeerts P, et al. Dig Dis Sci. 2012;30:396–399.Bar‐Yoseph H, et al. Gastroenterology 2019;157:1338–1351.

And know how this changes OVER TIME!


2. Employ Treat to Target

1. Initial treatment

2. Assessment of target

3. Adjustment of treatment


5. Target reached: continue monitoring

Treat to Target

Colombel JF, et al. Lancet. 2018;390:2779‐2789.

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2. Choose a Target that Is Individualized for Your Patient (and reliable)

1. Initial treatment


3. Adjustment of treatment


5. Target reached: continue monitoring

Treat to Target

Peyrin‐Biroulet L, et al. Am J Gastroenterol. 2015;110:1324‐38.

Composite PRO + endoscopy

Composite PRO + endoscopy

Growth and developmentGrowth and development

HemoglobinHemoglobin

CRPCRP

Calprotectin Calprotectin

CTE, MRI, Intestinal Ultrasound

CTE, MRI, Intestinal Ultrasound

Skin or eye inflammationSkin or eye

inflammation


3. Match Treatment Intensity to Inflammatory Burden

Inflam

matory burden

Time

Induction therapy continues at same dose as maintenance Th

erap

y intensity

Drug

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4. Choose Induction Therapies Wisely

• Based on disease activity and risk for bad outcomes

• Would surgery be best? (LIR!C)1

• Based on likelihood of rapid clearance or absorption issues (BMI, gender, CRP, albumin, prior immunogenicity)2

• Use organ‐selective therapies before systemic therapies3

• Based on prior treatment history that worked or did not (Cycle vs. Swap)4

• Based on co‐morbid illnesses (RA? Psoriasis? SpA? PsA? DM?)

1Ponsioen CY, et al. Lancet Gastroenterol Hepatol. 2017;2(11):785‐792.2Ordas I, et al. Clin Pharmacol Ther. 2012;91:635.

3Rubin DT, et al. Am J Gastroenterol. 2019;114:384‐413.4Yarur AJ and Rubin DT. Inflamm Bowel Dis. 2015;21(7):1709‐18.


Specific Scenarios for Choice of First IBD Therapy

Disease ModifierFirst drug

considerationReason

CD Perianal Anti‐TNFBest studied, on label

(IFX)

IBD Psoriasis Ustekinumab On label

IBD >60 yoVedolizumabUstekinumab

Older patients have higher risk of infections

UCSynovitisArthritis

Anti‐TNF or Tofacitinib

On label

UC Low albuminCyclosporineTacrolimusTofacitinib

Non‐protein‐basedtherapies

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5. Optimize Treatment

• Combine therapies:‐ Anti‐TNF with IMMs

‐ Anti‐TNF with antibiotics in perianal disease

• Judicious use of proactive therapeutic drug monitoring:‐ Post‐loading drug levels in high‐risk patients (infliximab week 8, adalimumabweek 4)

‐ Pediatrics: proactive monitoring of adalimumab beneficial (PAILOT)1

‐ 6‐thioguanine metabolites to assess thiopurines

• Match therapy to disease activity!

1Assa A, et al. Gastroenterology. 2019;157(4):985‐996.


Fecal Calprotectin Predicts Endoscopic Response to Therapy with VDZ and UST

• FC levels decreased as early as week 2 in responders

• FC<250 ug/g at week 8 predicts endoscopic response at week 16

Response to Vedolizumabin CD and UC1 (N=40)

Response to Ustekinumabin CD2 (N=38)

Endoscopic Non‐responders

Endoscopic Responders

1Pauwels RWM, et al. Gastroenterology. 2019;156(6 Suppl_1):S‐110.2Pauwels RWM, et al. Gastroenterology. 2019;156(6 Suppl_1):S‐874–S‐875.

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Optimizing Response to Thiopurines

6‐TG 6‐MMP Possible cause Recommendation

Undetectable UndetectableNon‐adherent or underdosed

Understand why pt not taking med or increase dose

Low (<230)Low orundetectable

Non‐adherentor underdosed

Discuss adherence, increase dose

Low (<230) High (>5700) 6‐MMP shunter1. Consider allopurinol, or2. Switch agents

“Therapeutic” (>230‐<400) or High (>400)

Normal range or high

Primary non‐responder

1. Assess disease2. Switch agents

Understand TMPT and NUDT15

Sparrow MP, et al. Clin Gastroenterol Hepatol. 2007;5(2):209‐14.Dubinsky MC. Curr Gastroenterol Rep. 2003;5(6):506‐11.


Optimizing Response to Thiopurines

6‐TG 6‐MMP Possible cause Recommendation

Undetectable UndetectableNon‐adherent or underdosed

Understand why pt not taking med or increase dose

Low (<230)Low orundetectable

Non‐adherentor underdosed

Discuss adherence, increase dose

Low (<230) High (>5700) 6‐MMP shunter1. Consider allopurinol, or2. Switch agents

“Therapeutic” (>230‐<400) or High (>400)

Normal range or high

Primary non‐responder

1. Assess disease2. Switch agents

Understand TMPT and NUDT15

Sparrow MP, et al. Clin Gastroenterol Hepatol. 2007;5(2):209‐14.Dubinsky MC. Curr Gastroenterol Rep. 2003;5(6):506‐11.

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Optimizing Response to Biologics

• CD patients with short disease duration treated with anti‐TNF:

‐ Respond better1

‐ Lose response less often2

‐ Have less surgery3

• Your first therapy will work better

‐ Vedolizumab

‐ Ustekinumab

‐ Tofacitinib1Schreiber S, et al. J Crohns Colitis. 2013;7(3):213‐21.

2Schreiber S, et al. Am J Gastroenterol. 2010;105(7):1574‐82. 3Rubin DT, et al. Inflamm Bowel Dis. 2012;18(12):2225‐2231.

4Sandborn WJ, et al. N Engl J Med. 2013;369(8):711‐721. 5Feagan BG, et al. N Engl J Med. 2013;369(8):699‐710.

6Sandborn W, et al. Gastroenterology. 2016;150(4 Suppl 1):S157‐S158.7Paschos P, et al. Ann Gastroenterol. 2018;31(5):572‐82.


Comparative Effectiveness Studies in IBD Favor Anti‐TNF (mostly infliximab) Combined with IMMs…

UC SUCCESS Trial2SONIC Trial (CD)1

1Colombel JF, et al. N Engl J Med. 2010;362(15):1383‐95.2Panaccione R, et al. Gastroenterology. 2014;146(2):392‐400.

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…BUT, Infliximab Level is A More Important Predictor of Remission Than Combination Therapy

SONIC Post‐hoc Analysis

Colombel JF, et al. Gastroenterology. 2017;152(5):S37‐38.

23.555.8 58.8

73.1

76.544.2 41.2

26.9

0%

20%

40%

60%

80%

100%

Q1 Q2 Q3 Q4Proportion of Patients (%)

IFX Concentration at Week 30 (µg/mL)

IFX+AZA IFX

(N=51) (N=52) (N=51) (N=52)

Q1: <0.84 µg/mL; Q2: 0.84‐2.36 µg/mL; Q3: 2.36‐5.02 µg/mL; Q4 ≥5.02 µg/mL.


It is Safe to Stop 5‐ASA in Patients Escalated to Biological Therapy

• Analysis of clinical trials of infliximab and golimumab in moderate‐severe UC1

• Health claims data of UC and CD2,3

Risk of major adverse outcomes according to 5‐ASA use

OutcomeAdjusted OR (95% CI)

p‐value Outcome

Clinical Remission

0.67 (0.45‐1.01) 0.06 Clinical Remission

Clinical Response

0.89 (0.60‐1.33) 0.58 Clinical Response

Endoscopic Remission

1.12 (0.82‐1.51) 0.48Endoscopic Remission

Biochemical Remission

0.94 (0.61‐1.46) 0.79Biochemical Remission

5‐ASA vs. no concomitant 5‐ASA in TNFi‐treated patients

1Singh S, et al. Am J Gastroenterol. 2018;113(8):1197‐1205. 2Ungaro RC, et al. Gut. 2019;68(6):977‐84.

3Ungaro RC, et al. Clin Gastroenterol Hepatol. 2019. [Epub ahead of print].

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More Anti‐TNF is Not Always Better

• Meta‐analysis: accelerated dosing of infliximab in acute severe UC does not prevent colectomy1

• High‐dose adalimumab (160 mg qw x 4) not better than standard dosing (160 mg week 0 then 80 mg week 2) in induction of remission in UC2

1Nalagatla N, et al. Clin Gastroenterol Hepatol. 2019;17:502‐509.2Panes J, et al. United European Gastroenterology Week 2019. Abstract OP216.


6. Choose Maintenance Therapies Wisely

• Based on induction therapy

• Don’t forget adherence issues!

• Don’t forget changes that may occur over time: MONITOR for LOR

• Are symptoms stable between doses?

• Objective assessment over time

Louis E, et al. Gastroenterology. 2012;142(1):63‐70.De Suray N, et al. Gastroenterology. 2012;142(5):S‐149.

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Can You De‐intensify Therapy?Inflam

matory burden

Time

Induction therapy continues at same dose as maintenance Th

erap

y intensity

Drug Drug

How long?


Examples of “De‐Intensification” of Therapy

• Steroid induction steroid‐sparing maintenance therapy

• 5‐ASA• 4.8 g induction can be reduced to 2.4 g maintenance (IF ENDOSCOPIC IMPROVEMENT)1

• Concomitant IMM + anti‐TNF therapy • Possibility of withdrawing IMM (IMM experienced)2

• Possibility of withdrawing anti‐TNF (Crohn’s disease)3 (IF DEEP REMISSION)

1Rubin DT, et al. J Crohns Colitis. 2016;10(8):925‐33. 2Van Assche G, et al. Gastroenterol. 2008;134(7):1861‐8.

3Louis E, et al. Gastroenterol. 2012;142(1):63‐70.

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7. Planning for De‐escalation in IBD

1. Discuss WHY this might be reasonable (Is the patient healthy because of your therapy or in spite of it?)

2. Confirm deep remission (mucosal healing), preferably for >1 year

3. Confirm optimization of drug (make SURE it’s working)

4. De‐escalate

5. Have a monitoring strategy (Serial labs, fecal calprotectin, scope)

6. Know your rescue plan (Resume prior therapy or Move on to next strategy)

Buisson A, et al. J Crohns Colitis. 2019;13(8):1012‐24.


Disease ModifierFirst drug

considerationReason

UC/CDAnti‐TNF‐induced lupoid

reactionNon‐anti‐TNF

Not reported with non‐anti‐TNF drugs

UC/CD Joint pain+ vedolizumabAnti‐TNF (UC+CD)Tofacitinib (UC)

On label

UC/CDAnti‐TNF‐induced psoriasis or palmar plantar pustulosis

Ustekinumab (CD)Tofacitinib (UC)

Vedolizumab (UC+CD)

On labelNot reportedCase Reports1

UC/CD Cancer (solid tumor)None during Chemo

VedolizumabUstekinumab

Safety

8. Reasons to Switch Therapies and What to Choose

1Rubin DT. Gastroenterol Hepatol. 2017;13(11):688‐90.

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9. Be Smart About Loss of Response

1. Confirm adherence

2. Rule out infection

3. Confirm inflammation

4. Assess drug

5. If anti‐drug antibodies, take precautions on the next treatment (use combination therapy)

Roblin X, et al. Inflamm Bowel Dis. 2018;24(9):2078‐85.Kennedy NA, et al. Lancet Gastroenterol Hepatol. 2019;4(5):341‐53.


Can you Go Back to a Therapy That Had Worked and Stopped Working?

Circling Backwards

• If the inflammatory pathway is reactivated: YES

• If prior loss of response was due to anti‐drug antibodies: NO

• After surgery:

‐ Did the patient just need surgery anyway, and that was the reason for the lack of response to therapy? YES

‐ Did the patient progress right through the prior therapy? NO

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Novel Treatment Considerations – 1Two Step Management

1Ananthakrishnan AN, et al. Cell Host Microbe. 2017;21(5):603‐610.2Lombardo M, et al. Open Forum Infect Dis. 2015;2(Suppl_1):S149.

INDUCTION MAINTENANCE

Cytokine inhibition:• TNFi• IL23• JAKinib

Cellular inhibition:• Anti‐integrin• S1P1 receptor modulator• Thiopurine

Microbiota “pre‐treatment”:• Intestinal microbiota transfer1

• Antibiotics2

Microbiota maintenance:• Diet• Prebiotics• Bacterial products• Antibiotics?

Surgery:• Ileocecectomy ”curative resection”• Diverting ileostomy


Novel Treatment Considerations – 2Combination Approaches

• Biological combinations

• Small molecule and biological combinations

‐ To prevent immunogenicity

‐ To combine mechanisms of action

• Antibiotics and immune suppressives

• Diet plus immunobiological therapies

Biocycle. www.biocycle‐project.eu. Accessed July 3 2018.Clinical Trials. https://clinicaltrials.gov (NCT02764762) Accessed April 23 2019.

Yang E, et al. Aliment Pharmacol Ther. 2020. [In Press].

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Calcineurin Induction Therapy Followed by Maintenance on Vedolizumab in IBD

Author/Center Design NWeek 14 Clinical

RemissionWeek 52 Clinical

Remission

Christensen B/UChicagoCGH 2019Ollech J/UchicagoAPT 2019

Retrospective20

71

55%

50%

45%

43% (28% at 2 y)

Pellet G/GETAIDCGH 2019

Retrospective 39 38% ‐‐

Tarabar D/SerbiaUEGW 2018

Prospective 17 93% 79%

Christensen B, et al. Clin Gastroenterol Hepatol. 2019;17(3):486‐93.Ollech J, et al. Aliment Pharmacol Ther. 2020 Mar;51(6):637‐643.Pellet G, et al. Clin Gastroenterol Hepatol. 2019;17(3):494‐501.

Tarabar D, et al. United European Gastroenterol J. 2018;6(8S1):A457.


The Ongoing Search for Therapeutic Biomarkers

Schmechel S, et al. Inflamm Bowel Dis. 2008;14(2):204‐12.

0

10

20

30

40

50

60

70

Placebo DNase Sensitive pANCA+

pANCA–

Response Rate (%

)

NS

P<0.006

Taylor KD, et al. Gastroenterology. 2001;120(6):1347‐55. Vermeire S, et al. Lancet. 2014;384(9940):309‐18.

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Clinical Prediction ToolsExample: Vedolizumab Use in Crohn’s Disease

Dulai PS, et al. Gastroenterology. 2018;155(3):687‐695.


Future of Personalized Management of IBD

Immune panel

Inflammation and response to therapy measured

Patient achieves remission

Ongoing monitoring occurs

Immune panel is repeated

New dominant pathways identified

ORSubclinical

inflammation detected

Therapy changed/ optimized

PK Dashboard

PK Dashboard

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Virtual Grand Rounds universe.gi.orgREGISTER NOW…ACG’s IBD School & Eastern Regional!

Are now VIRTUAL events, withOn‐Demand Presentations and LIVE Webcast Q&A sessions!

Visit meetings.gi.org to register for both today!

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discover the benefits of linked color imaging · 2020. 5. 21. · 5/21/2020 6 virtual grand rounds...

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