Ulcerative Colitis

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

Chief, Section of Gastroenterology, Hepatology, and NutritionCo-Director, Digestive Diseases Center

@IBDMD

Disclosures(Last 24 months)• Consultant and Grant Support:

– Abbvie– Amgen– Cellgene– Janssen– Pfizer– Prometheus– Takeda– UCB

Learning Objectives

At the conclusion of this presentation, participants will:• Recognize the common presentation and progression

of ulcerative colitis• Understand the appropriate treatment options for

ulcerative colitis.

Case• 18 year old male• 4 months of rectal

urgency and frequency• Nocturnal symptoms• Blood with bowel

movements• One episode of

incontinence• Nausea

• SH: – Senior in high school– “stressed”– No tobacco

• FH:– No GI or immune

problems– Sister with IDDM

• PSH: – none

Case continued• Physical examination:

– BMI: 21– Abdomen:

• Minimal tenderness in the left lower quadrant

• Tympany on the right side of the abdomen

– Perianal area: • Normal

• Labs:– Hemoglobin 11.1 g/dL– CRP 3.0 mg/L– Albumin 3.4 g/dL– Stool studies: negative

for O and P, C. difficiletoxin

• A diagnostic test is performed

Diffuse, prominent crypt architectural distortion and mucosal atrophy, with foci of crypt dropout.

No granulomas.

Diagnosis: ulcerative colitis

Distal Left-Sided Pancolitis

18%44% 36%*Based on regional cohort of 1,161 patients diagnosed from 1962 to 1987.

Langholz EP, et al. Scand J Gastroenterol. 1991;26:1247.

Anatomic Extent of Disease:Disease Involvement at Diagnosis*

Major Symptoms of UC are Due to an Inflamed Rectum

85% 83% 78%

63%

0%

20%

40%

60%

80%

100%

Urgency Increaseddefecationfrequency

Incompleteevacuation

Tenesmus

Patie

nts,

%Symptom prevalence

Rao SS, et al. Gut. 1988;29:342-345.

Disease Behaviors of Ulcerative Colitis

Solberg IC, et al. Scand J Gastroenterol. 2009;44(4):431-40.

Environmental Associations of UC

• Protective against UC– Appendectomy (for appendicitis)1

– Dietary omega-3-fatty acids2

• Increase UC risk– Dietary linoleic acid (your lunch today?)3

– Ex-smoking4

– Gut infections5

– Possibly antibiotic exposure6

1. Andersson RE, et al. N Engl J Med. 2001;344:808-814.2. Sneha J, et al. Gastroenterology. 2008;134(Suppl 1):A-4.a3. Hart AR, et al. Gut. 2009. 58(12):1606-1.

4. Rubin DT, Hanauer SB. Eur J Gastroenterol Hepatol. 2000;12:855-862.5. Ohkusa T, et al. Int Med. 2004;43:534-539.6. Shaw SY, et al. Am J Gastroenterol. 2011; 106(12):2133-42.

How can we treat our patient’s UC?

Historical Treatment Strategies in IBD

• Symptom-based• Expectant management• Unclear if changed natural history of the disease or

quality of life• Imprecise (“Dirty therapy”)

Historical Treatment StrategiesSymptom Based, Short Term Goals

Disease severityat presentation?

Severe

Moderate

MildAminosalicylate

Corticosteroids

Anti-TNFAnti-integrin

Thiopurine(UC)/Thiopurine/MTX (CD)

Aminosalicylate

Anti-TNF (UC)/Thiopurine/MTX (CD)Anti-integrin

Induction

Maintenance

time

Cyclosporine/TacrolimusSurgery

Modern Goals of IBD Management

Induction of Remission

•Turning “off” the inflammation•Feeling well•Normalization of labs, growth, development and nutrition

Maintenance of Remission

•Stable disease control and optimization of therapy•NO STEROIDS•Prevention of relapse over time (sustained and durable)•Changing the natural course of the disease

Disease Monitoring and

Prevention

•Monitoring for early relapse•Monitoring therapies•Prevention of infections•Cancer prevention

Medical Treatment Options for Patients With UC

• Aminosalicylates– Mesalamine– Azo-bonded prodrugs

• Sulfasalazine• Olsalazine • Balsalazide

• Corticosteroids– Systemic steroids– Budesonide

• Thiopurines– AZA– 6-MP

• Cyclosporine• TNF-α inhibitors

– Infliximab– Adalimumab– Golimumab

• Anti-integrin therapy– Vedolizumab

5-ASA Therapies

• Mesalamine with different delivery systems– various pH-release mesalamines

– controlled-release mesalamine

– rectal preparations

• Pro-drugs– azo-bonded sulfasalazine, olsalazine, and balsalazide

• Oral PLUS topical (rectal) therapy is better than either alone for induction of remission (distal and extensive)

Advantages of 5-ASA for Mild to Moderate UC

• Efficacy for induction of response is 50% to 70%

• Efficacy for induction of remission is 15% to 40%

• Excellent safety profile

Hanauer SB, et al. Ann Intern Med. 1996;124:204.Hanauer SB, et al. Am J Gastroenterol. 1993;88:1188.Hanauer SB, et al. Am J Gastroenterol. 2005;100:2478.

Levine DS, et al. Am J Gastroenterol. 2002;97:1398.Sninsky CA, et al. Ann Intern Med. 1991;115:350.

5-ASA Safety Considerations

• Mesalamine intolerance: Rare but important1

• Pancreatitis1

• Pneumonitis2

• Renal insufficiency3,4

1Kornbluth & Sachar, Am J Gastroenterol.2004; 99: 1371–85.2Foster, et al. Inflamm Bowel Dis.2003; 9: 308–15.3Van Staa, et al. Gastroenterology. 2004; 126: 1733–9.4Gisbert, et al. Inflamm Bowel Dis. 2007; 13: 629–38.

.

Current use

Recent use

Past use

Risk of renal events with 5-ASA3

Adjusted odds ratio

0 1 2 3 4 5

Increased risk vs non-use

Oral (2.4 g/d)Rectal (4 g/d)Combined

Focus on the RectumTreatment of Distal UC:

Oral and Rectal Mesalamine Therapy

6 Weeks

*

0

Patie

nts

Rep

ortin

gN

o R

ecta

l Ble

edin

g (%

)100

40

60

20

80

*P<0.002 vs oral alone, P=0.04 vs topical alone

Adapted from Safdi M, et al. Am J Gastroenterol. 1997;92:1867.

Case continued

• Treated with 5-ASA therapy topically and rectally

• Improvement for 3 months– then non-adherence

• Recurrent diseaseAminosalicylate

Corticosteroids

Anti-TNFAnti-integrin

Thiopurine(UC)/Thiopurine/MTX (CD)

Aminosalicylate

Anti-TNF (UC)/Thiopurine/MTX (CD)Anti-integrin

Induction

Maintenance

time

Cyclosporine/TacrolimusSurgery

Importance of Adherence: Sustained Remission of IBD

Kane S, et al. Am J Med. 2003;114:39.

Patie

nts W

ith

Qui

esce

nt U

C (%

)

0 300

Adherent to 5-ASA therapy

Nonadherent to 5-ASA therapy*

Time (months)

100

75

50

25

10 20

*P<0.001

Lesson learned: maintenance therapy is needed, patients should

be educated

Case continued

• Recurrent symptoms, given steroids– Prednisone 40 mg PO QD

• Steroid sparing therapy initiatedAminosalicylate

Corticosteroids

Anti-TNFAnti-integrin

Thiopurine(UC)/Thiopurine/MTX (CD)

Aminosalicylate

Anti-TNF (UC)/Thiopurine/MTX (CD)Anti-integrin

Induction

Maintenance

time

Cyclosporine/TacrolimusSurgery

Treatment Revolution: Steroids for UC Reduce Mortality

40

30

20

10

0

Mor

talit

y (%

)

1938–1952

1953–1962

1963–1972

1973–1982

1983–1987

Edwards FC, et al. Gut. 1963;4:299.

Corticosteroids introduced in 1952

• Steroids subsequently associated with worst outcomes in IBD, are used short-term only!

• Initiation of steroids should always prompt an exit strategy (steroid-sparing therapy).

Corticosteroid Therapy in UC

StudyDisease

StateSteroid/

DoseResponse (%)*

Steroid PlaceboTruelove1

(6 weeks)Active Cortisone

≥100 mg69

(n=109)41

(n=101)

Lennard-Jones2

(6 months)Maintenance Prednisone

15 mg 38

(n=32)40

(n=30)

Truelove3

(5 days)Severely

activePrednisolone

40–60 mg (Total n=49)

73 N/A

* Response defined as: Truelove: Patients who improved and/or were in remission Lennard-

Jones: Maintenance of remissionTruelove: Patients in remission

1. Truelove SC, et al. Br Med J. 1955;2:1041.2. Lennard-Jones JE, et al. Lancet. 1965;1:188.3. Truelove SC, Jewell DP. Lancet. 1974;1:1067.

Corticosteroids: Short- and Long-Term Efficacy for UC

*30 days after initiating corticosteroid therapy

Faubion W, et al. Gastroenterology. 2001;121:255.

1-month outcomes*(n=63)

1-yearoutcomes(n=63)

Prolonged response

49%(n=31)

Steroid dependent

22%(n=14)

Surgery 29%

(n=18)

Complete remission

54%(n=34)

Partial remission

30%(n=19)

No response 16%

(n=10)

Budesonide MMX for active ulcerative colitis odds ratios for different endpoints

US trial: 9 mg vs placeboOR (95%CI)

Remission 2.71 (1.19, 6.16)

Clinical improvement 1.52 (0.87, 2.65)

Endoscopic improvement 1.43 (0.85, 2.42)

Symptom resolution 2.01 (1.08, 3.73)

Histologic healing 0.60 (0.19, 1.88)

EU trial: 9 mg vs placeboOR (95%CI)

Remission 4.49 (1.47, 13.72)

Clinical improvement 1.44 (0.80, 2.57)

Endoscopic improvement 1.59 (0.88, 2.86)

Symptom resolution 2.47 (1.12, 5.46)

Histologic healing 2.74 (1.04, 7.22)

Placebo better MMX 9 mg better 0.1 1 10

Placebo better MMX 9 mg better 0.1 1 10010

Sandborn, et al. Gastroenterology. 2011. 142(2):257-65.

Case continued

• Thiopurine therapy started (azathioprine)

• TPMT enzyme activity obtained prior to dosing

Aminosalicylate

Corticosteroids

Anti-TNFAnti-integrin

Thiopurine(UC)/Thiopurine/MTX (CD)

Aminosalicylate

Anti-TNF (UC)/Thiopurine/MTX (CD)Anti-integrin

Induction

Maintenance

time

Cyclosporine/TacrolimusSurgery

Frequency Enzyme Activity Allele89% normal to high TPMTH/TPMTH

11% intermediate TPMTH/TPMTL

0.33% low to absent TPMTL/TPMTL

TPMT Polymorphism and Metabolism of Azathioprine/6-MP

Azathioprine

6-Methyl-mercaptopurine

6-Mercaptopurine Thioinosinicacid

6-Thioguaininenucleotides

6-Thiouricacid

TPMT

HPRT

XO

Chan GL, et al. J Clin Pharmacol. 1990;30:358.

Use of Metabolites to Optimize Thiopurine Therapy

6-TG 6-MMP Possible cause

undetectable undetectable Non-adherentorunderdosed

Low (<230) Low or undetectable Non-adherent or underdosed

Low (<230) High (>5700) 6-MMP shunter

“Therapeutic” (>230-<400) orHigh (>400)

Normal range or high Primary non-responder

Dubinsky. Curr Gastroenterol Rep. 2003;5(6):506-11.

6-TG 6-MMP Possible cause

undetectable undetectable Non-adherentorunderdosed

Low (<230) Low or undetectable Non-adherent or underdosed

Low (<230) High (>5700) 6-MMP shunter

“Therapeutic” (>230-<400) orHigh (>400)

Normal range or high Primary non-responder

Dubinsky. Curr Gastroenterol Rep. 2003;5(6):506-11.

Use of Metabolites to Optimize Thiopurine Therapy

Case continued

• Doesn’t respond to “optimized” azathioprine

• Flexible sigmoidoscopy shows worsening mucosal disease

• C. difficile and CMV ruled out

Severity of Disease Correlates With Colectomy

Severe EndoscopicColitis(n=46)

Moderate EndoscopicColitis(n=39)

Carbonnel F, et al. Dig Dis Sci. 1994;39:1550.

100

80

60

40

20

0

Patie

nts

(%)

Deep/Extensive

Ulcers

93%

MucosalDetachment

30%

LargeMucosal

Abrasions

26%

Well-likeUlcers

17%

93% underwentcolectomy

100

80

60

40

20

0

Patie

nts

(%)

SuperficialUlcers

77%

Deep ButNonextensive

Ulcers

8%

23% underwentcolectomy

Case continued

Aminosalicylate

Corticosteroids

Anti-TNFAnti-integrin

Thiopurine (UC)/Thiopurine/MTX (CD)

Aminosalicylate

Anti-TNF (UC)/Thiopurine/MTX (CD)/Anti-integrin

Induction

Maintenance

time

Cyclosporine/TacrolimusSurgery

• An anti-TNFα therapy is now added to his azathioprine

24% 22%

40%

0

20

40

60

80

100

AZA (N=76) IFX (N=77) IFX+AZA (N=78)

Perc

ent o

f Pat

ient

s (%

)

n=18 n=17 n=31

P=0.017

P=0.813

P=0.032

Panaccione, et al. Gastroenterol. 2014; 146:392-400.

Combination of Thiopurines and Anti-TNF is Superior to Monotherapy

week 16 steroid-free remission

Case continued

• After loading doses of infliximab, feeling better, starts maintenance dosing

• Responds well- feeling good…for six months….

• Calls us to say he is not well again

Aminosalicylate

Corticosteroids

Anti-TNFAnti-integrin

Thiopurine (UC)/Thiopurine/MTX (CD)

Aminosalicylate

Anti-TNF (UC)/Thiopurine/MTX (CD)/Anti-integrin

Induction

Maintenance

time

Cyclosporine/TacrolimusSurgery

What happened?

Possible Reasons for Loss of Response to Infliximab and Azathioprine in our Patient• Non-adherence to his therapies (again)

• “Feeling good” not the same as actually healed

• pK issues of monoclonal antibodies: – Development of anti-drug antibodies– Progression of disease (getting worse instead of better)

• Role of loss of protein from bowel– Weight gain (getting better, eating more)

• “Mechanistic escape”

Case continued

• Infliximab level: 40 mcg/mL (very high)• Anti-infliximab antibodies not present

• Hgb 9.5 g/dL• CRP 12 mg/L• Albumin 3.0 g/dL

• Consider a different mechanism of management

Leukocyte Trafficking Inhibition

Action of Adhesion molecules (eg. Integrins) in the intestinal endothelium

Lobatón T, et al. Aliment Pharmacol Ther.2014; 39:579-594.

Vedolizumab

Our patient on vedolizumab plus azathioprine therapy

Now What?

Disease monitoringTherapeutic monitoring

Maintenance care, cancer prevention

Download Cornerstones’ Checklist for IBD Patients by visiting: cornerstoneshealth.org/checklist/

Summary: Ulcerative Colitis

• Know the disease activity of your patient• Choose therapies wisely, and target the areas of

activity• Understand the reasons for loss of response• Monitor disease, treatment and enroll in prevention

programs

Thank you