Caroline Hwang, MD

Assistant Professor of Medicine

Division of Gastrointestinal & Liver Diseases

Keck/USC School of Medicine

November 8, 2017

Inflammatory Bowel Disease

Epidemiology

Approximately 1.5 million pts in U.S.

≈ Prevalence is 1 in 200

Classically a disease of industrialized nations

(N. America, NW Europe)

2 recent meta-analyses of global IBD trends

Growing incidence in developing nations

(Asia, S. America, Middle East)

Also higher rates in immigrants to western

countries (Indian/African in Europe,

Latinos/Asians in U.S.)

Pattern: UC incidence increases 1st, then CD

1. Molodecky et al: Gastro 2012

2. Ng S, et al: Gut 2013

Disease Costs

Annual direct healthcare costs for IBD ~ $11-20 billion / yr in U.S.

Does not account for indirect costs (work absence, decreased

productivity), impact on patients’ quality of life

Costs comparable to those for cardiac disease and cancer

Majority of IBD costs previously inpatient care / surgeries

shifting to costs of biologics

Pathogenesis

Multifactorial etiology Genetic component

20-30% CD, 6-18% UC

GWAS: 289 genes a/w IBD

Dysregulated immune function

Innate immunity

T-cell mediated (Th1/Th2, Th17)

Microbiome

IBD does not occur in

germ-free mouse models

Fecal diversion as Crohn’s tx

Genetic

Predispositi

on

Dysregulated

mucosal

immune

system

Environmental

trigger

Microbiome

Patterns of disease

Relapsing-Remitting Disease Course

55% UC, 43% CD

1% UC, 3% CD

6% UC, 19% CD 55% UC, 43% CD Crohn’s

Probability of Surgery for CD

Cumulative Bowel Damage

Differentiating IBD Subtypes:

Ulcerative Colitis

UC: Extent of Disease

UC: Severity of Disease

Clinical Assessment in between endoscopy

For flares, still use Truelove & Witt criterion (1950s)

Mild: <4BMs ±blood, nl ESR

Moderate: >4BMs, minimal toxicity

Severe: >6BMs, +toxicity

(low-grade fever, HR>90, anemia)

Fulminant: >10BMs, +toxicity,

abd distension/tenderness/dilated XR

UC: Severity of Disease

Characteristics of Crohn’s Disease

Perianal 30%

Wide Spectrum of Crohn’s

Disease Manifestations

Complications of Crohn’s Disease

SURGERY

IBD is a clinical diagnosis

- H&P / Labs - Radiology

- Endoscopy - Histology

Differential Diagnosis

- Infection - Appendicitis

(bacterial, TB, amebic) - Diverticulitis

- Ischemia - Irritable bowel syndrome

Diagnosis

Diagnosis

History

- ULCERATIVE COLITIS: Bloody diarrhea always

- CROHN’S: Diarrhea (±blood), Abdominal pain, Weight loss

Physical Exam

- Low-grade fever common

- Abdominal exam usually benign

if guarding/peritoneal signs, concern for complication

- Mouth ulcers, Perianal abnormalities (Crohn’s)

- Extraintestinal manifestations (both UC and Crohn’s)

Extraintestinal Manifestations

Musculoskeletal- Periphreal arthritis

- Sacroilitis

- Ankylosing spondylitis

Ocular- Uveitis

- Scleritis

- Episcleritis

Dermatologic- Erythema nodosum

- Pyoderma gangrenosum

Biliary- Primary sclerosing cholangitis

Endoscopy

Ulcerative

Colitis

Crohn’s Disease

- Rectal involvement

- Continuous pattern Ileal

ulcers

Rectal

Sparing

Patchy

Colitis

Deep

ulcers

Cobblestoning

Radiology

Often not necessary if diagnosis clear from endoscopy

Useful in certain situations:

- Imaging of small bowel (inflammation, strictures)

- CT or MR Enterography, SBFT

- Diagnosis of complications

- Toxic megacolon (UC, XR)

- Fistulas (CT pyelogram, MR pelvis)

- Perforations, Obstructions

Diagnosis:

Disease Severity

Fulminant Colitis / Toxic Megacolon

Toxic megacolon

Diagnostic criteria: Dilation of colon (total or segmental) > 6cm

Any 3 of: Fever >101, HR>100, WBC>10,

Anemia

Any 1 of: dehydration, electrolyte abnormalities,

hypotension, altered mental status

Poor Prognosis

47% underwent colectomy w/in 6 mo (38% urgent/emergent)

20% mortality in 1970s 4-5% currently

Surgical Emergency

Treatment of IBD

Goals of IBD Management

Induce remission

Maintain remission

Minimize steroid exposure over lifetime

Decrease short-term and long-term morbidity

Decrease hospitalization rates

Decrease surgical rates

Decrease risk of cancer

Medical Management

Ulcerative Colits Crohn’s Disease

Surgery

Biologic

Topical Steroids

(Budesonide)

Biologics

6MP/AZA

Steroids

Surgery

Severe

Moderate

Mild

Early

LateMesalamine, SSZ

(Budesonide)

(Antibiotics)

Steroids

6MP/AZA

Surgery

Biologic

Tailoring Treatment in UC:

Disease Stage

Mayo Score

Subjective: rectal bleeding, #BMs

Endoscopic Score (0-3)

Physician Global Assessment

Truelove & Witt criterion (1950s)

Mild: <4BMs ±blood, nl ESR

Moderate: >4BMs, minimal toxicity

Severe: >6BMs, +toxicity

(low-grade fever, HR>90, anemia)

Fulminant: >10BMs, +toxicity,

abd distension/tenderness/dilated XR

Outpt

Intpt

Ulcerative Colitis

Severe

Moderate

MildMesalamine, SSZ

(Budesonide)

(Antibiotics)

Steroids

6MP/AZA

Surgery

Biologic

Ulcerative Colitis

Mild (50-80%)- <4 BM’s/d- Aminosalicylates mainstay

Mesalamine, SSZ

(Budesonide)

(Antibiotics)

Steroids

6MP/AZA

Surgery

Biologic

Oral

Sulfasalazine 2-3g/day divided TID

Mesalamine 2.4-4.8g QD

Topical

Canasa suppositories (<15cm)

Rowasa enemas (>15cm)

- Induction RCTs show:4.8g/day superior to 2.4g/day

Oral + topical superior to either

alone

Mild Ulcerative Colitis

Aminosalicylates remains mainstay tx for majority of UC

(50-80%)

Sulfasalazine first 5-ASA used (1965)

- Mesalamine developed 1980s->lacks sulfa moeity so better tolerated

- Different formulations available with different targeted sites of release

Possible mechanisms of action:

- Inhibition of cyclooxygenase/lipoxygenase pathways->reduced

production of prostaglandins and leuokotrienes

- Disrupts transcription of inflammatory mediators that are important

in proliferative effects of TNF-alpha on intestinal cells

Mild-Moderate UC

Rowasa

Canasa(Cortifoam)

Oral Aminosalicylates Sulfasalazine

- Oldest, sulfa + 5ASA

- Poorly tolerated

Asacol- Eudragit coated

- pH-dep release in TI/cecum

Pentasa- Ethylcellulose-coated microgranules timed release in small/large bowel

Colazol- Newer azo-bonded formulation release in colon

Lialda- Multimatrix formulation touted for slower/more homogenous release in colon/

rectum, higher dose / pill (1.2gm)

Ulcerative Colitis

Severe

Moderate- <6BM’s/day

- Anemia, CRP

Mild

Mesalamine, SSZ

(Budesonide)

(Antibiotics)

Steroids

6MP/AZA

Biologics

Surgery

Biologic

Ulcerative Colitis

Severe>8 BM’s/day -or-

no response/

intolerant of

6MP/AZA

Moderate

Mild

Mesalamine, SSZ

(Budesonide)

(Antibiotics)

Steroids

6MP/AZA

Biologics

Surgery

Biologic

Biologic Therapies in IBD

Van Schouwenburg PA et al: Nature Reviews 2013; 9:164-72

Anti-TNF

Anti-Integrins

Medical Management

Ulcerative Colits Crohn’s Disease

Surgery

Biologic

Topical Steroids

(Budesonide)

Biologics

6MP/AZA

Steroids

Surgery

Severe

Moderate

Mild

Early

LateMesalamine, SSZ

(Budesonide)

(Antibiotics)

Steroids

6MP/AZA

Surgery

Biologic

Clinical Considerations

• Prognostic factors

– Age of diagnosis (<40yo)

– Penetrating disease

– Fistulas/perianal disease

– Steroids for first flare

• Severity of flare – hospitalized or outpatient, steroids, CRP

• History of Surgery/Postoperative Prevention

• Extraintestinal Manifestations

-

Early/Mild Crohn’s Disease

Early

Late

Surgery

Biologic

Topical Steroids

(Budesonide)

Mesalamine (little evidence)

Biologics

6MP/AZA

Steroids

Surgery

Early

Late

Mild diseaseNormal labs

mild syptoms

Budesonide

Mesalamine

controversial

Crohn’s Disease

Early

Late

Surgery

Biologic

Topical Steroids

(Budesonide)

Mesalamine (little evidence)

Biologics

6MP/AZA

Steroids

Surgery

Early

Late

Moderate &

Severe

Disease

SONIC Study:

AZA vs IFX vs Combination%

Cort

icoste

roid

-Fre

e

Rem

issio

n @

26 w

eeks

0

30%

45%

AZA IFX

100

AZA +IFX

57%

P=0.00

9

P=0.02

2

P<0.00

1

% M

ucosa

l H

ealin

g a

t 26

wks

0

16.5%

30%

AZA IFX

100

AZA +IFX

44%

P=0.02P=0.02

2

P<0.00

1

Ustekinumab

Risks/Complications of IBD

- Colon cancer- Iron deficiency- B12 deficiency- Vitamin D deficiency- Thromboembolism

- Infection - Osteoporosis - Lymphoma - Vit D deficiency - Skin cancer - Folatedeficiency- Cervical cancer - Leukopenia

Preventative Care in IBD Patients

Many IBD patients are young and/or have few other

• comorbidities May not have a PMD

In survey studies, many primary care providers not comfortable

• providing routine preventive care to IBD patients

General preventive care 63%

Giving vaccinations 70%

IBD patients receive general preventative care at lower rate

• than non-IBD patients seen by internists/FPs

1. Selby et al: Dig Dis Sci 20112. Selby et al: IBD 2008

Preventative Care in IBD Patients

Vaccines

Smoking cessation

Osteoporosis screening/prevention

Nutritional deficiency screening/treatment

Cancer screening- Colorectal

- Skin

- Cervical