New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and...

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New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for Crohn’s and Colitis Brigham and Women’s Hospital March 12, 2016

Transcript of New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and...

Page 1: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

New IBD Therapies Promise and Pitfalls

Frederick L. Makrauer, MD Center for Crohn’s and Colitis

Brigham and Women’s Hospital March 12, 2016

Page 2: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Conflicts of Interest and Disclosures

• None

Page 3: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Treatments we will discuss

• Antibiotics, prebiotics, probiotics

• Corticosteroids

• Azulfidine, 5-ASA’s

• Immunomodulators (AZT/6-MP, cyclosporine, tacrolimus)

• CAM (complementary and alternative therapy)

Today -

• anti- TNF’s (IFX, adlimumab, certolimumab, golimumab)

• anti-adhesion molecules (natalizumab, vedolizumab)

• Cytokine inhibitors (ustekinumab)

• Step-Up vs Step Down Rx

• Combination, Cessation and Resumption of Therapy

• Experimental therapies: fecal transplant, nutrients

Page 4: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

I. Patient Susan S. 2004

• 68 y teacher, L-sided UC x 2002, Mayo Score 0

• FHx: F- CRC, M-UC

• PMHx: Colonic adenoma 2003

• 5ASA 2.5 g/d, AZA 50 mg (metabolites good)

• Colonoscopy - L-sided mild scarring, inactive

• Is there anything else we should do?

Page 5: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

The Challenges to Proper IBD Rx

• Worldwide - increasing incidence/prevalence

• U.S. - UC 1:400, Crohn’s 1:500

• Proper study endpoint – ‘deep remission’

• No drug > 70 % effective

• Toxicity

• Insurance coverage

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Good IBD Care is Patient - Centered

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Individualized Rx Decisions

• Clinical Factors (‘phenotype’ and ‘activity’)

• Fertility, Pregnancy, Delivery and Lactation

• Genetic Factors (‘genotype’)

• Past Rxs & Response

• Drug Metabolism (assay)

• Insurance Coverage

• Goal of Therapy (patient vs provider) Siegel, 2014

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Page 9: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Monitoring The Patient

• Symptoms (activity indices)

• Labs: calprotectin, drug levels and antibodies

• Imaging (monitor radiation exposure)

• IBD Conference

• Support (patient & family)

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Supportive Care

• Oral/perineal hygiene and comfort • Anti-diarrheals • Pain control • Nutrition • Counseling, support, advocacy (CCFA)

Gerson and Triadafilopoulos 2000

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IBD in Pregnancy and Delivery

• A dedicated Ob/Gyn Service is recommended

• Sweden 1209 UC and 787 CD, with 10,773 controls

• DVT in UC OR 3.78

• Antepartum hemorrhage in CD OR 1.66

• Emergency C section in UC OR 1.39; in CD OR 1.50

Broms G et al. 2012

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Pregnancy Outcomes on Anti-TNF Therapy

Case-control study following 124 pregnant women over 133 pregnancies on anti-TNF therapy

Seirafi et. al. APT. 2014; 40(4): 363-373

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II. Susan S. 2006

• Rapid onset of cramps, diarrhea and urgency

• What questions need to be answered?

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Complications of Therapy

• Infection (disease activity, narcotic, CS, IFX)

• Hematologic

• Cancer – skin (melanoma), cervical, lymphoma

• Bone marrow, liver/pancreas, skin, hair, nerve, heart

• TREAT Registry

Page 15: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Why does IBD happen?

• Genetics + innate immunity + environment

• Genes - NOD2, ATG16L1, Arg381Gln, and > 150 others

• Innate Immunity - inappropriate response to invader

• Environment - Microbiome ‘dysbiosis’ (diet, antibio., hygiene)

Abreu 2015, Serban, 2015

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An Imbalanced Host-Microbiome Interaction

Kahng, 2009

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Gene Impact on Disease expression Only in 7.5 – 13.6 % patients

• NOD2/CARD15 – complicated CD course • ATG16L1, JAK2 – stenosis CD • IRGM, TNFS15 – need for surgery CD • IL23R, CDPRDM1 – fistulizing CD • TLR4 – pancolitis UC, colitis CD • IKBL – severity of UC Serban, 2015 from ncp.sagepub.com @ H.U.

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Foods alter the activity of IBD

• Ant-inflam: fresh fruit & veggie’s, SCFA, S. boulardii, VSL-3, curcumin

• Eg., curcumin - UC mild to moderate

• Inflam: fat, refined sugars, alcohol. Gluten?

• Eg., emulsifiers, carrageenan, metals

Page 19: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

The’westernized’ diet’s impact on the microbiome

from breast milk to Burger King

• Herbivore to carnivore • Shift to hostile bacterial populations • Less fruit fiber, more refined CHO, fat, sulfur • Less intra-luminal SCFA*, and more H2S • N-6 FA’s > N-3 = more inflammation!

* short-chain fatty acids = n-3 PUFA (poly-unsaturated fatty acid)

Page 20: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s
Page 21: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

TNF II-1b IL-12/IL-18 IFN

Pro-inflammatory

Anti-inflammatory

IL-10 TGF IL-4/IL-13 IL-1Ra PGE2

Loss of Tolerance

Tolerance

Chronic inflammation vs mediator balance in IBD

Page 22: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Crohn’s disease

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Crohn’s - Esophagus

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Crohn’s - Rectum

Page 25: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

1 o’clock: incision site with a silk seton in place; drainage of pus. 3 o’clock: sinus tract with fistula opening

Crohn’s - Perineum

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Crohn’s - Perianal Abscess

Page 27: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Ulcerative Colitis

Page 28: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Ulcerative Colitis Endoscopic Spectrum of Severity

Normal

Moderate

Mild

Severe

Page 29: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

U.C. - Colonic Wall Thickening

Page 30: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Be sure it is IBD

• Infection • Mesenteric Ischemia • IBS (‘Irritable Pouch’) • Medication (NSAID, Cellcept, etc.) • Diverticulitis • Endometriosis • Radiation therapy • Lymphoma, leukemia, GVHD, cancer • Microscopic colitis • Diversion colitis

Page 31: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

III. Susan S. – 10/2009

• Flared with urgency, bleeding on prednisone + + imuran + 5-ASA

• Should we check any additional studies?

• Are there other treatment options?

Page 32: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Treatments We Will Discuss

• Antibiotics, prebiotics, probiotics

• Corticosteroids

• Azulfidine, 5-ASA’s

• Immunomodulators (AZT/6-MP, cyclosporine, tacrolimus)

• CAM (complementary and alternative therapy)

Today -

• anti- TNF’s (IFX, adlimumab, certolimumab, golimumab)

• anti-adhesion molecules (natalizumab, vedolizumab)

• Cytokine inhibitors (ustekinumab)

• Step-Up vs Step Down Rx

• Combination, Cessation and Resumption of Therapy

• Experimental therapies: fecal transplant, nutrition

Page 33: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Targeted Drug Therapy

Korzenik 2006; Sands 2002

Page 34: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Currently Approved Biologics For IBD

Initial cA2 (Infliximab) NEJM (1997)

Infliximab approved for Crohn’s disease (1998)

Infliximab approved for ulcerative colitis (2005)

Adalimumab approved for Crohn’s disease (2007)

Certolizumab Pegol approved for Crohn’s disease (2008)

Natalizumab approved for Crohn’s disease (2008)

Adalimumab approved for ulcerative colitis (2012)

CD

UC Golimumab approved for ulcerative colitis (2013)

Vedolizumab approved for ulcerative colitis (2014)

Vedolizumab approved for Crohn’s disease (2014)

Page 35: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

TNF Alpha

First described in 1975

Synthesized by activated macrophages and T cells as a transmembrane precursor protein

Binds to one of two receptors-TNFR1 and TNFR2

Stimulation of release of inflammatory cytokines (IL-1beta, IL-6, IL-8, and GM-CSF)

Upregulation of endothelial adhesion molecules (ICAM-1, VCAM-1, E-selectin) and chemokines

35 35

Page 36: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

anti-TNF’s

• Infliximab – CD and UC

• Adalimumab – CD and UC

• Certlizumab - CD

• Golimumab - UC

Page 37: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Anti-TNF Therapy in Crohn’s Disease

Infliximab, adalimumab, and certolizumab are approved for use in CD

Indications for Early Treatment:

Complex fistula

Deep ulceration on endoscopy

Young age

Steroid dependence/resistance

High risk anatomy

Severe disease activity (wt loss, low albumin, Hgb)

37

Page 38: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Clinical Response and Remission with Infliximab

Targan SR, et al. N Engl J Med. 1997.

4%

16%

48%

81%

0

20

40

60

80

100

4-week Clinical

Response

4-week Clinical

Remission

Placebo (n=25)

REMICADE 5 mg/kg

(n=27)

P<0.001

P<0.001

% P

atie

nts

38

Page 39: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Long-term endoscopic remission 5 year follow up data

Regueiro M, et al. Clin Gastro Hep. 2014.

Page 40: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Infliximab Prevents CD Recurrence After Ileal Resection

Regueiro M, et al. Gastroenterology. 2009. 40

Page 41: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

CD: Primary Non-Responder

Individuals who fail induction within 12 weeks

Approximately 35-40% of patients in anti-TNF clinical trials are primary non-responders

For primary non-responders

Add an antimetabolite (6MP/AZA/methotrexate) for patients not previously on these agents

Switch to second anti-TNF Switch to natalizumab/vedolizumab Surgery may be an option to consider in patients with

limited disease

Lichtenstein G, et al. Am J Gastroenterol. 2009. Yanai H et al. Am J Gastroenterol. 2011.

41

Page 42: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

SONIC: Mucosal Healing at Week 26 secondary endpoint

42 Colombel JF, et al. NEJM. 2010.

Page 43: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

SONIC: IFX Trough Levels Wk 30 Higher with Concomitant AZA M

ed

ian

Se

rum

Tro

ug

h

Le

ve

ls (

mg

/ml)

1.6

3.5

0

2

4

6

8

10

IFX + placebo IFX + AZA

(N=97) (N=109)

Sandborn W, et al. NEJM. 2010. 43

Page 44: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

CD: Secondary Non-Responder

Improve after initial induction but lose response

Between 10-15% lose response annually

For secondary non-responders

Measure drug levels and antibodies Escalate the dose Switch to another anti-TNF Switch to natalizumab/vedolizumab Work up for infections or other pathological

processes

44

Page 45: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Afif W, et al. Am J Gastroenterol. 2010; Brandse, J et al. Clin Gastro and Hep 2016

Clinical Utility of Measuring Anti-TNF Trough and Antibody Levels

45

Page 46: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Anti-TNF Therapy in Ulcerative Colitis

Indications:

Moderate to severe UC

Steroid-dependent UC

Refractory pouchitis

Maintenance of disease in remission

Infliximab, adalimumab, and golimumab are approved for use in UC

46

Page 47: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Rates of Sustained Clinical Remission in ACT 1 and 2

ACT 2 ACT 1

Remission at Week 8 and 30 Week 8 and 30 Week 8, 30, and 54

Remission

P<0.001

P=0.001

P=0.002

P=0.002

P<0.001

P<0.001

Sustained Clinical Remission

Pa

tie

nts

(%

)

Pati

en

ts (

%)

Placebo Infliximab 5 mg/kg Infliximab 10 mg/kg

8.3 6.6

23.1 19.8 26.2

20.5

0

20

40

60

80

100

2.4

14.9 22.5

0

20

40

60

80

100

Rutgeerts P, et al. NEJM. 2005. 47

Page 48: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

UC: Non-Responder

• Enhanced clearance with

– High BMI – Male – Lack of concomitant immunosuppression – Low albumin – Severe Inflammation

• Loss of proteins, lytes, minerals via ulcerated mucosa

48

Page 49: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

ULTRA 1 and ULTRA 2

49 Sandborn WJ, et al. Gastroenterology. 2012.

Page 50: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s
Page 51: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s
Page 52: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

IV. Susan S. -11/2009

• Hair loss!

• Mayo Score 0, colonic mucosa healed.

• What might be causing her hair loss?

• What should we do next?

Page 53: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Anti-TNF Adverse Effects

Neutropenia

Infections

Demyelinating disease

Heart failure

Cutaneous reactions, including psoriasis

Malignancy

Induction of autoimmunity

53

Page 54: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Anti-TNF Opportunistic Infections

Toruner M, et al. Gastroenterology. 2008 54

Most Frequently Reported Organisms: Herpes Zoster Candida albicans Herpes simplex Cytomegalovirus Epstein-Barr virus Histoplasma capsulatum

Page 55: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Association of Immunosuppressive Medication Combinations with Opportunistic Infection

Number of Immunosuppressive Medication Combinations

OR (95% CI)

None 1.0 (reference)

1 2.9 (1.5 to 5.3)

2 or 3 14.5 (4.9 to 43)

55 Toruner M, et al. Gastroenterology. 2008.

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Italian study of patients over 65 with IBD receiving infliximab or adalimumab

Two control groups: < 65 with anti-TNF and > 65 with IBD but no biologics

Outcome of interest: serious infection, neoplasm or death

Advanced Age and Anti-TNF Side Effects

Age/Years Infection (%) Neoplasm (%) Death (%)

> 65 11 3 10

< 65 Control (anti-TNF)

2.6 0 1

> 65 Control (no biologics)

0.5 2 2

Cottone M, et al. Clin Gastroenterol and Hepatol. 2011. 56

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Skin Cancer Among Patients with IBD

Long MD, et al. Gastroenterology. 2012. 57

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Hepatosplenic T-Cell Lymphoma

• Rare and usually fatal lymphoma, that primarily affects men <35 years old

• As of 2013, 37 reported cases of HSTCL among patients with IBD

• In a systematic review of the first 36 cases, no cases were associated with anti-TNF therapy alone

– 20 occurred with combination therapy with infliximab and a thiopurine

– 16 occurred with thiopurine monotherapy

Kotylar DS, et al. Clin Gastro Hep. 2011. Selvaraj, et al. Systematic Reviews. 2013. 58

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Stopping Anti-TNF Alpha Therapy

One study1 : 115 CD patients in remission IFX & AZA > 1 yr, remission for 6 mo

IFX stopped; followed for 1 yr; 39% relapsed

Similar study2 : 84% CD relapsed in 5 yr

In Crohn’s, relapse after stopping IFX > 6MP/AZA

1. Louis E et al. Gastroenterology. 2009. 2. Schnitzler F et al. Gut. 2009. 59

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Summary anti-TNF Points

• Anti-TNF - CD perianal fistulas, post-op prevention

• Combo therapy (IFX + IM) better for CD and UC

• Lymphoma: Imm only 4/103pt-yr; Imm + IFX 6/103pt-yr

• Combination therapy = higher IFX levels

60

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Leucocyte Adhesion Molecule Inhibitors

• Natalizumab - CD, anti-alpha 4 integrin (gut and CNS)

• Vedolizumab – CD + UC, anti-alpha4B7 integrin (gut only)

• FDA-approved after failure of AZT, CS, anti-TNF’s

• Future: Etrolizumab UC anti beta7 integrin (gut only)

• AJM300 anti-alpha-4 integrin antibody.

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Natalizumab

Humanized IgG4 monoclonal antibody that blocks the adhesion and subsequent migration of leukocytes into the gut

Antibody is directed towards alpha 4 integrin

α4β1 and α4β7 antibody

Natalizumab is approved for the treatment of moderate to severe CD.

62

Page 63: New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for rohn’s and Colitis righam and Women’s

Progressive Multifocal Leukoencephalopathy

63 Wenning W, 2009

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Natalizumab-Associated PML

Factors Associated with Increased Risk

Positive status – anti-JC virus antibodies

Increased duration of natalizumab treatment: greatest risk occurred after 2 years of therapy (25-48 months in this study)

Prior use of immunosuppressants

Bloomgren G, et al. NEJM. May 2012. 64

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• Vedolizumab - humanized, monoclonal α4β7 antibody

– blocks lymphocyte trafficking to gut, but not CNS

• The α4β7 integrin is variably expressed on circulating B and T lymphocytes

– interacts with addressin-cell adhesion

molecule 19 (MAdCAM-1) on intestinal vasculature

Vedolizumab

65

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Vedolizumab for Crohn’s GEMINI 2

Maintenance phase Sandborn W, 2013. 66

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New ‘Orphan’Biologics

Ulcerative Colitis Tofacitinib – JAK inhibitor (rheumatoid arthritis)

Crohn’s Disease Ustekinumab - ab to p40 unit IL’s -12, -23 (psoriasis) Wils, 2016 retrospective, 122 pts 2011-14, 20 centers, steroid-free.

- @ 3 mo 65% responders; with immunosuppressive OR 5.43

- @ 12 mo 68% responders.

67

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Janus Kinase (JAK) Inhibitors Tofacitinib

• Oral inhibitor of JAK kinases 1-3

• Reduced cytokine production

• FDA-approved only for rheumatoid arthritis

• UC (off-label)

• Elevates of LDL

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Sandborn W, et al. ,2012. 69

Tofacitinib

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IL-12 & IL-23 Receptor Inhibitors Ustekinumab

• Blocks IL-12 & IL-23 rec on T lymph, Ag-presenting cells • FDA-approved only for psoriatic arthritis. • CD (off label) after failure of anti-TNF agents • 6 wk (6 mg/kg iv), U 39.7 % vs placebo 23.5 % (p = .005) • 22 wk (90 mg sc q 8wks) - clinical response U 41.7 % vs placebo 27.4 % p < 0.03

- mucosal healing - equal - clinical remission U 69.4 % vs placebo 42.5 % p < 0.001

• Serious infection: @ induction 6/7; @ maintenance 4/11 • Cancer - basal cell 1

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V. Susan S. – 04/2013

• 2010-2013 flares respond to 5 ASA boosts

• But, multiple skin ca’s, hematuria and,

• Low bone density, increased glucose

• Urology – transitional cell ca of renal pelvis

• What are our treatment options?

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Oral Therapies Present and future

A. Non-targeted (today) i. induction: CS, 5-ASA, CSA, tacrolimus

ii. maintenance: thiopurines, MTX, 5-ASA, tacrolimus

B. Targeted (breakthrough agents)

i. Anti-TNF’s, anti-integrins, IL 12/23 inhibitors (Stelara off label)

ii. Synthetic

1. jakinibs: reduce inflammatory CK production (Tofacitinib off label)

2. anti-integrins: block circ lymphocyte entry into mucosa (AJM300)

3. sphingosine-1-phos (S1P): blocks nodal lymphocytes (Ozanimod)

4. anti-sense nucleotide: normalizes TGF B1 signaling (Mongersen)

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The ‘Promise’

• Bio-engineered E. coli Nissl (IL-10) - anti-inflammatory

• n-3 PUFA, curcumin

• Fecal Transplant - under investigation

• Oral Therapies

• Pre-Rx tissue ‘signatures’ - ‘personalized care’

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The ‘Pitfalls’

• Is it really an IBD flare? (infection, IBS)

• Underestimating disease activity

• Under-treating (bottom-up, mono Rx)

• Non-responders

• Drug toxicity

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Good IBD Care is Collaborative

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Acknowledgements

• Our patients

• Our professional organizations: SGNA, CCFA

• Our Colleagues: Crohn’s & Colitis Center

• Our Trainees: Edward L. Barnes, Rachel W. Winter

• Our Teachers: Dr. Peter A. Banks.

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Bibliography

• Genetics and Environmental Interactions Shape the Intestinal Microbiome to Promote Inflammatory bowel Disease Versus Mucosal Homeostasis Gastroenterology 2010;139:1816-19

• Inflammatory Bowel Disease: Role of Diet, Microbiota, Lifestyle Translational Research 2012;160:29-44

• Combinatorial Effects of Diet and Genetics on IBD Pathogenesis Inflamm Bowel Dis 2015; 21: 912-922

• Mechanism of Probiotic Action: Implications for Therapeutic Applications in IBD Inflamm Bowel Dis 2008;14:1585-96

• Guidelines for Management of Growth Failure in Childhood IBD Inflamm Bowel Dis 2008;14:839-849

• DNA-driven Nutritional Therapy of IBD Nutrition 2009;25:885-91