Psychiatry Overview

Inflammatory Bowel DiseaseSonia Friedman MD

Associate Physician, Brigham and Women’s Hospital

Division of Gastroenterology, Department of Medicine

Associate Professor, Harvard Medical School

Sonia Friedman, MD

• Yale Medical School• Medicine Residency @ Hospital

of the University of Pennsylvania• Gastroenterology Fellowship @

Mount Sinai Medical Center • Associate Professor of Medicine

@ HMS– Clinical focus: Crohn’s disease and

ulcerative colitis– Research focus: IBD and

reproduction

Conflict of Interest

• No conflicts of interest

Key Learning Objectives

• Diagnosis and evaluation of inflammatory bowel disease type and severity

• Medical management of inflammatory bowel disease

Overview of Inflammatory Bowel Disease (IBD)

INDETERMINATECOLITIS2

10%-20% of IBD patients

Colitis32%

Ileitis22%

Ileocolitis45%

CROHN’SDISEASE3

Pancolitis47%

Left-sideddisease

25%

ULCERATIVE1

COLITIS

IBD>1.6 million persons in US

Proctitis28% % at time

of diagnosis

1. Loftus EV, et al. Gut. 2000;46:336-343; 2. Marion JF, et al. In: Kirsner JB, ed.

Inflammatory Bowel Disease. 5th ed. Philadelphia, Pa: WB Saunders Co; 2000:315-

325; 3. Loftus EV, et al. Gastroenterology. 1998;14:1161-1168.

Ulcerative Colitis Crohn’s Disease

Age-Specific Incidence of IBD*

*Per 100,000 population

Reprinted with permission from Lashner BA. In: Stein SH and Rood RP, eds. Inflammatory Bowel Disease: A Guide for Patients and Their Families. Philadelphia, Pa: Lippincott-Raven Publishers; 1999:23-29.

10

0

2

4

6

8

0 20 40 60 80

10

0

2

4

6

8

0 20 40 60 80

Age (yrs) Age (yrs)

UC: Presenting Symptoms

• Bloody diarrhea

• Abdominal cramping

• Tenesmus

• Weight loss

• Fevers

• Symptoms depend upon extent and severity of inflammation

Endoscopic Spectrum of SeverityUC – Spectrum of Disease

Normal

Moderate

Mild

Severe

Reprinted with permission from AGA Clinical Teaching Project. IBD. 3rd ed. 2002.

Classification of UC Severity

MILD• <4

stools/day ± blood

• Normal ESR• No signs of

toxicity

MODERATE• ≥4

stools/day± blood

• Minimal signs of toxicity

SEVERE• >6 bloody

stools/day

• Fever

• Tachycardia

• Anemia or ESR

FULMINANT• >10 stools/day• Continuous bleeding• Toxicity• Abdominal

tenderness/distension• Transfusion requirement• Colonic dilation on x-ray

Truelove SC, Witts LJ. Br Med J. 1955;2(4947):1041-8; Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105(3):501-23.

CD: Presentation

• Diarrhea

• Chronic abdominal pain and tenderness

• Weight loss

• Fever

• Perianal disease

• Symptoms vary with location of disease

CD: Clinical Features

⚫ Abdominal pain

⚫ Tenderness

⚫ Diarrhea

⚫ Weight loss

⚫ Cramps

⚫ Distention

⚫ Vomiting

⚫ Diarrhea

⚫ Pain

⚫ Air/feces in urine

⚫ Types– Enteroenteric– Enterovesical– Retroperitoneal– Enterocutaneous

Inflammation Obstruction Fistulization

Adapted with permission from AGA Gastroenterology Teaching Project. 3rd ed. 2002.

Crohn’s Disease: Severity• Remission: Asymptomatic either spontaneously or after medical or

surgical intervention and not on steroids.

• Mild to moderate: Ambulatory and able to tolerate an oral diet, no dehydration, toxicity, abdominal tenderness, mass, obstruction, or > 10 percent weight loss.

• Moderate to severe: Failed treatment for mild to moderate or prominent symptoms such as fever, weight loss, abdominal pain and tenderness, intermittent nausea or vomiting, or anemia.

• Severe-fulminant disease: Persisting symptoms despite conventional glucocorticoids or biologics as outpatients or individuals presenting with high fevers, persistent vomiting, intestinal obstruction, significant peritoneal signs, cachexia or evidence or an abscess

Indications for Biologic Therapy in IBD

Indications for Early Treatment in Crohn’s Disease (CD)

• Complex fistula

• Deep ulceration on endoscopy

• Young age (Age<30)

• Steroid dependence/resistance

• High risk anatomy

• Severe disease activity (weight loss, low albumin and/or hemoglobin)

Indications for Early Treatment in Ulcerative Colitis (UC)

• Moderate to Severe UC

• Steroid-dependent, refractory UC

• Refractory Pouchitis

• Maintenance of disease in remission

The image demonstrates a new gastrocolic fistula (solid white arrows). Multifocal involvement of the small bowel and terminal ileum is also present (dashed white arrows).

39 year-old male with Crohn’s disease MRI shows a defect in the internal sphincter at the 6:00 position of the mid anal canal (open white arrow) communicating with a 1.1 cm intersphincteric collection (black arrow). Wide defect in the external sphincter at the 7:00 position (solid white arrow) leads to a moderate sized perianal abscess in the ischioanal fossa.

Newer Management Concepts For Moderate to Severe IBD

• Treat early in disease

• Treat aggressively with “top down” biologics

• Check drug levels

• Dual therapy (immunomodulator + biologic)

• Aim for deep remission (histologic and endoscopic remission)

What are the data on efficacy and safety of biologic agents?

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)

Golimumab approved for

ulcerative colitis (2013)

Vedolizumab approved for

Crohn’s Disease (2014)

Vedolizumab approved for

ulcerative colitis (2014)

Ustekinumab approved for

Crohn’s Disease (2017)

Ustekinumab approved for ulcerative colitis 2019

Anti-TNF Therapies – Approved for IBD

• Infliximab (IFX): chimeric mouse/human anti-TNF-⍺ antibody • 75% human IgG1 isotype

• Adalimumab (ADL)/Golimumab (GOL): fully human monoclonal anti-TNF-⍺ antibodies• 100% human IgG1 isotype

• Certolizumab pegol (CIMZIA): antigen-binding fragment (Fab') of a humanized monoclonal antibody coupled to polyethylene glycol (No Fc portion)

• 95% human IgG1 isotype

CD and UC CD UC

Clinical Remission in UC

0%

40%

30%

20%

10%

Infliximab 10 mg/kg

Infliximab 5 mg/kg

Placebo

ACT: Infliximab 8 Weeks1

0%

40%

30%

20%

10%

Infliximab 10 mg/kg

Infliximab 5 mg/kg

Placebo

ACT: Infliximab 54 Weeks1

0%

40%

30%

20%

10%

Golimumab 100 mg

Golimumab 50 mg

Placebo

PURSUIT: Golimumab 54 Weeks4

0%

40%

30%

20%

10%

Golimumab 400/200 mg

Golimumab 200/100 mg

Placebo

PURSUIT: Golimumab 6 Weeks3

0%

40%

30%

20%

10%

Adalimumab Placebo

ULTRA 2 Adalimumab 8 Weeks2

0%

40%

30%

20%

10%

Adalimumab Placebo

ULTRA 2: Adalimumab 52 Weeks2

1Rutgeerts P, et al. N Engl J Med. 2005;353(23):2462-76; 2Sandborn WJ, et al. Gastroenterology. 2012;142(2):257-65; 3Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95; 4Sandborn WJ, et al. Gastroenterology. 2014;146(1):96-109.

*P<.05 vs. placebo; **P <.01 vs. placebo

*

****

** **

**

** **

**

Patients failing 5-ASA/Steroids/Immunomodulators

Cyclosporine vs. Infliximab for Severe UC

There were no significant differences between IFX and cyclosporine in adverse drug-related events, post-operative complications, or mortality.

Narula N, et al. Am J Gastroenterol. 2016;111(4):477-91.

Efficacy of Anti-TNF Therapies for Crohn’s Disease

*5 mg/kg dose.**Maintenance trial with 80/40 mg induction dosing. Randomized responders = CR-70 at week 4. Week 26 remission among randomized responders on 40 mg every other week dosing.

ACCENT I*(infliximab)2

Pa

tie

nts

(%

)PRECISE 2

(certolizumab)3P

ati

en

ts (

%)

CHARM**(adalimumab)1

24

60

40

0

20

40

60

80

Week 4 Response Week 26 Remission

Overall Remission Week 26

Pa

tie

nts

(%

)

1Colombel JF, et al. Gastroenterology. 2007;132(1):52-65; 2Hanauer SB, et al. Lancet. 2002;359(9317):1541-9;

3Schreiber S, et al. N Engl J Med. 2007;357(3):239-50.

Anti-TNF Agents: Adverse Events

• Immunogenicity

• Injection site reactions

• Infections

• Bacterial, viral, fungal and granulomatous (TB, histo, Listeria, etc)

• Lymphoproliferative disorders

• Autoimmunity

• Lupus-like symptoms

• Psoriasiform lesions

• Demyelinating disorders

• Worsen or de novo congestive heart failure

• Hepatotoxicity (rare)

• Malignancies

• T cell lymphoma (young men thiopurine combo therapy)

• Lymphoma (patients seronegative for EBV)

• Cutaneous

• Reactivation of:

• Latent TB

• HBV

• Herpes zoster

Di Sario A, et al. Curr Drug Saf. 2016;11(1):55-61; Murdaca G, et al. Expert Opin Drug Saf. 2015;14(4):571-82.

Adalimumab SC 160/80/40 mg Vedolizumab IV 300 mg

VARSITY Results: Overall Clinical Remission at Week 52 in UC

CI, confidence interval; IV, intravenous; SC, subcutaneous; TNF, tumour necrosis factor.aClinical remission: Complete Mayo score of ≤2 points and no individual subscore >1 point. bData from full analysis set, which includes all randomized patients who received at least 1 dose of study drug. cAnti-TNF subgroup analysis was prespecified and produced nominal p values.

Schreiber S et al. J Crohns Colitis. 2019;13(Suppl 1):S612–3. Abstr OP34. ECCO 2019 [oral presentation].

Overall clinical remissiona at week 52b

Pa

tie

nts

, %

OverallPrimary analysis

Anti-TNF naïvec

Subgroup analysisAnti-TNF exposure/failurec

Subgroup analysis

P=0.0061

∆ = 8.8% (2.6%, 15.0%)

P=0.0070

∆ = 9.9% (2.8%, 17.1%) ∆ = 4.2% (-7.7%, 16.1%)

P=0.4948

VARSITY: Mucosal Healing at Week 52 in UC

Adalimumab SC 160/80/40 mg Vedolizumab IV 300 mg

Mucosal healinga at week 52b

Pa

tie

nts

, %

OverallPrimary analysis

Anti-TNF naïvec

Subgroup analysisAnti-TNF exposure/failurec

Subgroup analysis

P=0.0005

∆ = 12.0% (5.3%, 18.6%)

P=0.0005

∆ = 13.6% (6.0%, 21.1%) ∆ = 5.6% (-7.6%, 18.8%)

P=0.4136

CI, confidence interval; IV, intravenous; SC, subcutaneous; TNF, tumour necrosis factor.a Mucosal healing defined as Mayo endoscopic subscore of ≤1 point. bData from full analysis set, which includes all randomized patients who received at least 1 dose of study drug. cAnti-TNF subgroup analysis was prespecified and produced nominal p values.

Schreiber S et al. J Crohns Colitis. 2019;13(Suppl 1):S612–3. Abstr OP34. ECCO 2019 [oral presentation].

Vedolizumab: Maintenance in Crohn’s

Feagan BG, et al. N Engl J Med. 2013;369(8):699-710.

P values vs. placebo

GEMINI IIWeek 52

Where do we position Vedolizumab?

• In patients unresponsive or intolerant to conventional therapies and anti‐TNF agents → however, can be used first-line

• In patients with unusual or other immune conditions such that additional systemic immune modification may be relatively contraindicated– Organ transplant patients– Hereditary or acquired immune deficiencies– Elderly patients– Cancer patients (skin cancers)

• Probably not patients with certain extraintestinal manifestations given gut selectivity

Ustekinumab for UC

NEJM 2020.

Ustekinumab: Maintenance for Crohn’s Disease

Primary and Major Secondary End Points in IM-UNITI

Feagan BG, et al. N Engl J Med. 2016;375(20):1946-60.

Pa

tie

nts

(%

)

Where should we position Ustekinumab?

• Possibly 1st line therapy in CD?

• After failures of anti-integrins or anti-TNFs?

• In patients with concomitant Psoriasis?

Safety Pyramid for IBD medications

VDZ

UST

Anti-TNF (monotherapy)

Thiopurines

Combination Therapy (Anti-TNF + Thiopurine)

Steroids

Safest

Advantages of Small Molecules in IBD

• Low-molecular weight

• Oral administration

• Resist gastric degradation

• Rapidly enter the systemic circulation

• Short half-life

• Lack immunogenicity

• Easier to manufacture than biologics, which may improve cost effectiveness

• Bind to specific intracellular targets.

Tofacitinib in UC: OCTAVE Phase 3 TrialClinical Response and Remission: Week 8

TNF Rxed

80

60

40

20

0Placebo Placebo10 mg

BIDTNF

Naive

Tofacitinib 10 mg BID

32.

8

59.

9

8.2

25.

212.

6

P<.01

P<.00

1

Clinical Remission

Clinical Response

OCTAVE 1

Placebo

80

60

40

20

0Placebo10 mg

BIDTNF

NaiveTNF Rxed

Tofacitinib 10 mg BID

29

55

4

22.

112

P<.001

P<.00

1

Clinical Remission

Clinical Response

OCTAVE 2

Sandborn WF, et al. NEJM. May 2017.

Tofacitinib Has A Rapid Effect As Early As 3 Days in UC Induction

aP<0.01 vs placebo; bP<0.001 vs placebo.Hanauer S et al. Clin Gastroenterol Hepatol. 2019;17:139-47.

Pa

tie

nts

, %

Reduction from baseline stool

frequency subscore of ≥1 point

Pa

tie

nts

, %

Reduction from baseline in both

Mayo stool frequency and Mayo

rectal bleeding subscore of ≥1 point

Day Day

a

bb

b b b b bb b

b b b

a

bb

b b b b bb b

b b b

Placebo Tofacitinib

Herpes Zoster (Shingles) in Tofacitinib-Treated UC Patients

Among 1157 (1612.8 PY) patients treated with tofacitinib

• 65 (5.6%) developed HZ on tofacitinib, IR - 4.07 (95% CI: 3.14–5.19)

– 51 (74%) involved 1 or 2 adjacent dermatomes

– 12 events in 11 patients were multidermatomal

– 6 events in 6 patients were disseminated

▪ 3 diffuse cutaneous rashes

▪ 2 ocular and skin lesions

▪ 1 HZ encephalitis

• 43% women

• Median age = 52 years (18-80)

• Median time to develop HZ = 324 days (13-1185)

• Dose-dependent (highest in 10 mg BID group)

BID, twice daily; CI, confidence interval; HZ, herpes zoster; IR, incidence rate; PY, patient-years.Winthrop KL et al. Inflamm Bowel Dis. 2018. 24(10):2258-2265.

Tofacitinib Boxed Warning

Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and. Accessed December 11, 2020.

➢ Tofacitinib should be reserved for use following a TNF antagonist

Interim Data From Ongoing Rheumatology Trials: Tofacitinib

Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and. Accessed December 11, 2020.

Tofacitinib 10 mg BID Anti-TNF

Pulmonary embolus19 cases in

3,884 patient-years3 cases in

3,982 patient-years

All-cause mortality45 cases in

3,884 patient-years25 cases in

3,982 patient-years

FDA Approves Ozanimod (Zeposia) for Ulcerative Colitis

(Zeposia) for Ulcerative ColitisUlcerative Colitis• Ozanimod (0.92 mg), an oral medication taken once daily, is

the first sphingosine-1-phosphate (S1P) receptor modulator approved for moderate to severe UC.

• Reduces lymphocyte migration into the intestine

• Reduces the # of lymphocytes in the peripheral blood

• For induction and maintenance of UC

• Clinical remission week 10 vs placebo 18% vs 6%, (p <0.0001)

• Clinical remission week 52 vs placebo 37% vs 19% (p <0.0001)

Abstract LB02, UEG Research Prize 2020 Session and Abstract LB10 from True North study

Non-response: Definitions

• Primary non-response: A patient does not respond to a loading dose of a biological agent when he/she receives it for the first time. Is this patient a non-responder to all drugs targeting the same pathway?

• Secondary non-response: A patient has responded to biological therapy at onset, but loses response or becomes intolerant to the molecule. This patient may respond to dose adjustment or is likely to benefit from other agents targeting the same pathway. If antibodies to initial drug, can switch within class.

Drug antibody negative

Sub-therapeuticInfliximab/Adalimumab

concentration

Reactive Testing Algorithm: Anti-TNF Therapy

Secondary loss of response (disease activity confirmed)

Change drug class or surgery

Dose escalate

Drug antibody positive

Therapeutic infliximab/adalimumab

concentration

High level of antibody

Consider dose escalation, addition of immunomodulator, or

change anti-TNF

Low level of antibody

Change to different anti-TNF

Modified from Khanna R, et al. Aliment Pharmacol Ther. 2013;38(5):447-59.

Positioning of Biologics in UC and CD

• The earlier the better…

• In the patients that need them…

• With (short-term?) combination therapy…

• And therapeutic drug monitoring

Eye

inflammation*

Liver andbile duct

inflammation

Skin lesions

Arthritis and joint pains

Kidney

stones

Growth failurein children

Lower

bone density*

Subfertility*

IBD: Systemic Complications

*Higher incidence in women.

Gallstones

Ovaries

Uterus

Musculoskeletal Disorders in IBD

•Sacroiliitis

•Peripheral arthritis

•Ankylosingspondylitis

Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, copyright 1991, 1995, 1997. Used by permission of the American College of Rheumatology.

Reprinted with permission from Berens DL. Roentgen Features of Ankylosing Spondylitis. Clin Ortho.1971;74:20-33.

AGA Recommendationsfor Managing Osteoporosis

IBD patient:

Any of:

-Prolonged steroid use

(>3mo consec or recurrent

courses)

-Low trauma, fragility fracture

-Postmenopausal or male age

>50

-Hypogonadism

DXA

T score >-1

Basic Prevention:

-Ca/Vit D

-exercise

-smoking cessation

-avoid alcohol

-minimize

corticosteroids

-treat hypogonadismT score -2.5 to -1

Prevention and:

-repeat DXA 2 years

-Prolonged CS consider BP

and DXA 1 year

T score <-2.5

Vert Fracture

Regardless of DXA

Prevention and:

-Screen other causes low BMD

-Bisphosphonate therapy or

-Refer to bone specialist

Gastroenterology 2003;124:795-841

Relative Risk of Colon Cancer Based on Extent of UC (and Crohn’s colitis)

0

20

2

10

14

18

ProctitisAll Cases

6

Left-Sided Pan-colitis

8

12

16

4

Ekbom A, et al. N Engl J Med. 1990;323:1228-1233.

Risk Factors for Colon Cancer in IBD

• Strictures that cannot be passed

• Extensive colitis

• Long duration of disease

• Active disease

• Primary sclerosing cholangitis

• Family history of colon CA

Take Home Messages

• Treat early

• Treat aggressively for moderate to severe IBD

• Use dual therapy

• Use drug levels to guide therapy

• Treat to endoscopic and histologic remission

• The risk of a serious side effect is much less than the risk of a complication from the IBD itself

Question• A 22 y/o man recent diagnosed with Crohns’ disease presents

to your clinic to discuss treatment options. He is a non-smoker and does not drink alcohol. His only medication is Lialda. A recent endoscopy reveals superficial aphthae limited to the terminal ileum. He describes rare, intermittent abdominal pain and 2-3 BMs daily. Recent labs suggest a CRP of 2.8mg/dL (nl<3mg/dL), serum albumin: 4.8. He denies a history of perianal complications.

Which of the features of his disease puts him is considered high risk?A. Young ageB. Non-smoking statusC. Superficial ulcersD. Terminal ileal diseaseE. Serological markers

Question• A 22 y/o man recent diagnosed with Crohns’ disease presents

to your clinic to discuss treatment options. He is a non-smoker and does not drink alcohol. His only medications is Lialda. A recent endoscopy reveals superficial aphthae limited to the terminal ileum. He describes rare, intermittent abdominal pain and 2-3 BMs daily. Recent labs suggest a CRP of 2.8mg/dL (nl<3mg/dL), serum albumin: 4.8. He denies a history of perianal complications.

Which of the features of his disease puts him is considered high risk?A. Young ageB. Non-smoking statusC. Superficial ulcersD. Terminal ileal diseaseE. Serological markers

Age < 30 is a risk factor for increased disease severity

Question Which of the therapies for IBD has the highest risk for immunogenicity (drug antibody development)?

A. Vedolizumab

B. Ustekinumab

C. Infliximab

D. Adalimumab

E. Golimumab

Question Which of the therapies for IBD has the highest risk for immunogenicity (drug antibody development)?

A. Vedolizumab

B. Ustekinumab

C. Infliximab

D. Adalimumab

E. Golimumab

Infliximab is 25% mouse protein and thus has the highest immunogenicity

QuestionA 38 year old man with a medical history notable for Crohn’s disease, currently on infliximab at 5mg/kg every 8 weeks, presents in follow up with worsening abdominal pain, frequent bowel movements up to 15 daily, to discuss next options. Serum CRP is 56mg/dL. Infliximab trough level obtained prior to his last infusion was 12μg/mL (adequate therapeutic level is >5μg/mL); no antibody level detected.

After providing induction therapy, what would be the next best therapeutic option in managing his disease?

A. Start azathioprineB. Increase the infliximab dose to 10mg/kgC. Discontinue infliximab and start the biosimilar: inflectraD. Discontinue infliximab and start ustekinumabE. Decrease interval between infliximab infusions to every 4 weeks

QuestionA 38 year old man with a medical history notable for Crohn’s Disease, currently on Infliximab at 5mg/kg every 8 weeks, presents in follow up with worsening abdominal pain, frequent bowel movements up to 15 daily, to discuss next options. Serum CRP is 56mg/dL. Infliximab trough level obtained prior to his last infusion was 12μg/mL (adequate therapeutic level is >5μg/mL); no antibody level detected.

After providing induction therapy, what would be the next best therapeutic option in managing his disease?

A. Start azathioprineB. Increase the infliximab dose to 10mg/kgC. Discontinue infliximab and start the biosimilar: inflectraD. Discontinue infliximab and start ustekinumabE. Decrease interval between infliximab infusions to every 4 weeks

IFX does not work here even when the level is therapeutic so it is

necessary to switch drug class

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• Singh S, Allegretti JR, Siddique SM. AGA technical eview on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158(5):1465-1496.

•