how to treat ibd like an - cloudcme...2020/03/15 · samuel s, et al. clin gastroenterol hepatol...

How to treat IBD like an expertBruce E. Sands, MD, MS

Chief of the Dr. Henry D. Janowitz Division of Gastroenterology

Dr. Burrill B. Crohn Professor of Medicine

Icahn School of Medicineat Mount SinaiNew York, NY

Disclosures• AbbVie• American Academy of CME• American Gastroenterological Association• AGA Institute• Catrille & Associates Ltd.• Celgene• Focus Medical Communications, LLC• Forest Research Institute• Indiana University• Janssen Biotech• Jefferson University• Luitpold Pharmaceuticals• MedImmune• Millennium Pharmaceuticals/Takeda• Pfizer• Prometheus Laboratories• Salix Pharmaceuticals• Shire• Strategic Consultants International

Learning Objectives

• Summarize evidence‐based guidelines for treating IBD

• Recommend interventions associated with improved outcomes in IBD management

What is an expert?

“Make three correct guesses consecutively and you will establish a reputation as an expert.”

Laurence J. Peter

“My definition of an expert in any field is a person who knows enough about what's really going on to be scared.”

P.J. Plauger

“An expert is one who knows more and more about less and less.” Nicholas Butler

IBD: What’s the big deal?

The burden of inflammatory bowel diseases

• Prevalence of IBD is 1% in North America and some European countries

• Incidence of Crohn’s disease is still increasing in these countries

• Rapid increases in the incidence of IBD are nowbeing observed in Japan, South Korea, Australia,New Zealand and some regions of India and China

• IBD will emerge as a worldwide epidemic in thecoming years

Elkjaer M et al. Gut 2010;59:1652–61 Molodecky NA, et al. Gastroenterology 2012;142:46–54

Incidence of IBD in Rhode Island, 2008‐10

Sands BE, et al. Inflamm Bowel Dis. 2011;17(Suppl 1):S8

What do patients think? The IMPACT survey

• Online patient survey by EFCCA in 10 European languages • 24 European countries participated• 4,990 IBD surveys analysed• 63% of respondents had CD and 33% had UC• Most (68%) respondents were aged 19–44 years

Data from IMPACT. http://efcca.org/media/files/press‐Join‐Fight/3.PRESS_KIT_IBD_IMPACT_REPORT_BCN.pdf

18

6453

21

Waited over 5years fordiagnosis

Neededemergency carebefore diagnosis

Don't get todiscuss important

topics

Have suffereddiscrimination

020406080100

Patie

nts (%)

Work disability in IBDCD

patients receiving

DP (%

)

0

10

20

30

50

18–29 40–49 60–6750–5930–39

40

Age (years)

UC pa

tients receiving

DP (%

)0

10

20

30

50

18–29 40–49 60–6750–5930–39

40

DP because of CDDP because of other diagnosisDP in background population

DP because of UCDP because of other diagnosisDP in background population

Age (years)

Norwegian population‐based study of IBD patients (n=518)receiving disability pension (DP)

RR for DP: 2.0(95% CI 1.4–2.7)

RR for DP: 1.8(95% CI 1.4–2.3)

Hoivik M, et al. Gut 2012 [Epub ahead of print: doi:10.1136/gutjnl‐2012‐302311]

Crohn’s disease Ulcerative colitis

Estimates of mortality in IBD

• Mortality increased in the first year after diagnosis

• Intermediate and long‐termmortality increased by 10% in UC and 50% in CD

• Mortality from UC decreased from1982 to 2010, because of reducedmortalities from gastrointestinaldisorders and colorectal cancer

• Mortality from CD did not change

Risk of dying according to age at, and time since, IBD diagnosis(Denmark 1982–2010) 36,080 UC and 15,361 CD vs 2,858,096 matched controls

Jess T, et al. Clin Gastroenterol Hepatol 2013;11:43–8

02550

100

0 5 10 15 20 25

80+ years old

02550

100

0 5 10 15 20 25

60–79 years old

02040

0 5 10 15 20 25

40–59 years old

05

1015

0 5 10 15 20 25

20–39 years old

024

0 5 10 15 20 25

0–19 years old

Time since IBD diagnosis / date of matching (years)

Risk of d

eath (%

)

Control personsUlcerative colitisCrohn’s disease

So, you want to be an IBD expert!

• Avoid pitfalls in diagnosis• Treatment

- Judgment: Know best indications, timing, expected efficacy, sequence/combination, risk/benefit, when to move on

- Sometimes defy convention- Always have a back‐up plan

• Know “something extra” about the disease

Diagnosing IBD like an expert

NIDDK IBD Genetics Consortium Diagnostic Criteria for IBD

• Symptoms: one or more of– Diarrhea– Rectal bleeding– Abdominal pain– Fever– Complicated perianal disease– Extraintestinal manifestations– Weight loss– Failure to thrive

AND


• Symptoms on 2 or more occasions• Separated by at least 8 weeks OR ongoing for at least 6 weeks*

*If single episode of colitis (<6 wk) with colectomy, pathology should be consistent with idiopathic IBD and microbiology studies should be negative

AND

• Objective evidence on 1 or more of endoscopy, radiology, or histology


• Endoscopic– Mucosal edema*– Erythema*– Loss of normal submucosal vasculature*– Friability*– Ulceration– Stricture formation– Pseudopolyps

*Considered minor changes, and require mucosal biopsies to confirm IBD

OR


• Radiology– Mucosal thickening and/or nodularity*– Ulceration– Stricture– Pseudopolyps– Fistula formation– Pseudosacculation

*Considered minor changes, and not sufficient to make diagnosis

OR


• Histology– Mucosal erosion or ulceration– Architectural changes of crypts– Paneth cell metaplasia (in colon)– Transmural inflammatory infiltrate*– Fibrosis of muscularis propria*– Noncaseating granuloma*

*Changes consistent with Crohn’s disease

Unusual pathologic manifestations of other forms of colitis

• Acute self‐limited colitis• NSAID‐induced colitis mimicking IBD• Ischemia• Radiation• Microscopic colitis with features of IBD• Diverticular disease associated colitis• Diversion colitis• Other

1 = MILD

2 = MODERATE 3 = SEVERE

0 = NORMAL

Colombel JF, et al. Gastroenterology. 2011.

Endoscopic Appearance in UC:Modified Baron Score

“Rake ulcers” in Crohn’s disease

Lymphoid Hyperplasia or Cobblestoning?

Agreement between Junior and Senior Phenotypers using the NIDDK IBD Genetics Consortium Diagnostic Criteria

Variable Kappa (95% CI)

Diagnosis 0.83 (0.74‐0.90)

Crohn’s disease

Behavior 0.70 (0.59‐0.80)

Location

Esophagogastroduodenal 0.45 (0.25‐0.62)

Jejunal 0.73 (0.59‐0.85)

Ileal 0.67 (0.52‐0.80)

Colonic 0.60 (0.44‐0.75)

Perianal 0.53 (0.41‐0.64)

Ulcerative colitis

Disease extent 0.73 (0.57‐0.86)

Dassopoulos T, et al. Inflamm Bowel Dis 2007;13:975–983

Crohn’s Disease ‐ Distinguishing Features

GranulomaGranuloma

Focal lesionsFocal lesions

FistulizationFistulization

Perineal diseasePerineal disease

Small bowel involvementSmall bowel involvement

Endoscopic featuresEndoscopic features

Asymmetric involvementAsymmetric involvement

Skip lesionsSkip lesions

Rectal sparingRectal sparing

20-30% without gross bleeding20-30% without gross bleeding

StricturesStrictures

Beware of granuloma worship!

Yantis RK, Odze RD. Am J Gastroenterol 2007;102:890–904

Defining the genetic architecture of CD vs. UCIB

D v

s. c

ontr

ol o

dds

ratio >1.5

1.3

1.4

1.2

1.1

0.67 1.0 >1.5

IL23R

NOD2

PTPN22

CD vs. UC odds ratio

30 CD specific

loci

23 UC specific

loci

110 IBD loci

MHC

Courtesy of Dr. Judy Cho

Differentiating CD and UC:Twelve exceptions to the rules

1. UC following oral or enema medical therapy2. Pretreatment presentation of UC in children3. Cecal inflammation and left‐sided colitis (with

sparing of the ascending and/or transverse colon)4. Appendiceal inflammation in patients with subtotal

or left‐sided colitis5. “Fulminant” UC6. Crohn’ s‐like aphthous ulcers in UC


Differentiating CD and UC:Twelve exceptions to the rules

7. Ileitis in UC8. Upper GI Tract Involvement in UC9. CD involving the mucosa in a UC‐like pattern with

minimal or no submucosal inflammation10. CD with continuous disease involving the entire

colon (pancolitis)11. Rectovaginal fistula in UC12. Anal fissure in UC


Key Reasons to Use Cross‐Sectional Imaging in IBD

• To identify presence and activity of small bowel disease

• To identify complications of disease (stricture, fistula, abscess) in Crohn’s disease

• To monitor for progression of Crohn’s disease• To monitor response to therapy in Crohn’s disease

CTE or MRE?

CT Enterography• Non‐invasive• Provides information on

intramural and extramural features

• Ionizing radiation• Tissue penetration and

radiation dose are related

MR Enterography• Non‐invasive• Provides information on

intramural and extramural features

• Lacks ionizing radiation• High tissue penetration

Siddiki HA. AJR 2009;193:113–121

Single CT Scan: Lifetime Attributable Risk of Cancer Death By Age*

•Assumes linear‐no threshold model of cancer riskBrenner DJ, Hall EJ. N Engl J Med. 2007;357:2277‐2284.

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0 10 20 30 40 50 60 70 80

Estimated Lifetime

Attributable Risk of Death from Cancer

(%)

Age at Time of CT Study (yr)

TotalDigestiveOtherLeukemia

Samuel S, et al. Clin Gastroenterol Hepatol 2012;10:1253–1259

Enterography is complementary to ileocolonoscopy in evaluating Crohn’s disease

TI normal on ileoscopy

43.8% (n=67)

Active SB Crohn’s disease based on reference standard

53.7%(n=36)

Skipping of distal TI on CTE 30.6% (n=11)

Intramural TI disease on CTE 63.9% (n=23)

Upper GI Crohn’s 5.6% (n=2)

Treating IBD like an expert

US survey about prevention of DVT in hospitalized IBD patients (n=591 physicians)

● 29% were unaware of any recommendations addressing pharmacological prophylaxis included in ACG IBD guidelines

● 35% would give pharmacological VTE prophylaxis to a hospitalized patient with severe ulcerative colitis

Tinsley A, et al. J Clin Gastroenterol 2013;47:e1‐6

Grainge MJ, et al. Lancet 2010;5:657–63

Adherence to guidelines on prevention of venous thromboembolism

Case‐fatality rates and occurrence of C.difficilein small or large bowel Crohn’s disease

Ricciardi R. Dis Colon Rectum 2009; 52: 40Y45

Data from the Nationwide Inpatient Sample

Goals of Therapy

• Induce symptomatic remission• Maintain steroid‐free remission• Enhance quality of life• Prevent/treat complications of disease• Avoid short and long term toxicity of therapy

How to achieve goals of therapy?

• Risk stratification• Optimize each medication• Monitor for and act upon objective evidence of inflammation

Medications for IBD

Infliximab Adalimumab

Certolizumab pegol

Vedolizumab

MethotrexateMercaptopurine/Azathio

prine

CorticosteroidsBudesonide CIR

Antibiotics

Crohn’s Disease

CyclosporineInfliximab AdalimumabGolimumab

Vedolizumab

?MethotrexateMercaptopurine/Azathiopri

CorticosteroidsBudesonide MMXBudesonide foam5‐Aminosalicylates

Ulcerative Colitis

Biologics

Immune Modulators

Corticosteroids

Anti‐TNF Abs

Anti‐α4β7 integrin Ab

• Penetrating disease• Post‐operative

prophylaxis

Severe acute UC

5‐Aminosalicylates

• Small clinical benefit in CD1

• Effective for induction of remission in UC2; generally in 2 to 8 weeks• No difference in rates of induction of remission among various

preparations2

• High dose not more effective than moderate dose in mild disease; possibly more effective in moderate disease and those exposed to prior therapy3

• Once daily as effective as split dosing and better adherence4

• Combination of oral and rectal 5ASA more effective in distal and extensive disease5,6

• All doses effective for maintenance of remission2

1Clin Gastroenterol Hepatol 2004;2:379‐3882Cochrane Database of Systematic Reviews, 17 OCT 2012 DOI: 10.1002/14651858.CD000543.pub33Sandborn WJ, et al. Gastroenterology 20094Lichtenstein GR, et al. Clin Gastroenterol Hepatol 20075Safdi M, et al. Amer J Gastroenterol 1997;92:18676Marteau P, et al. Gut 2005;54:960–965

Modified from Kane S. Curr Gastroenterol Rep. 2010;12:502.

Patient meets criteria for IS

therapy

Update vaccination status

Steroids Immunomodulators Biologics

Calcium/vitamin D DEXA

“Exit strategy”

TPMT for thiopurines, CBC, liver enzyme

monitoring

HBV testing, TB testing,monitor for infection

IS, immunosuppressant; TPTM, thiopurine methyltransferase; DEXA, dual‐energy x‐ray absorptiometry; CBC, complete blood count; TB, tuberculosis; HBV, hepatitis B virus

Corticosteroids: Topical and Budesonide

Steroid enemas, foam, suppositories effective for induction of remission in mild to moderate UCo Hydrocortisone enema less effective than mesalamine enema

Budesonide effective for induction of remission in mild to moderate ileocolonic CD (CIR), UC (MMX), proctitis/proctosigmoiditis (foam)o Limited role in maintenance of remission

Corticosteroids: Oral

• Effective for induction of remission, no role in maintenance Indicated for those failing 5ASAs, budesonide, moderately

severe disease Poor side effect profile May be used in combination with an anti‐TNF to induce

remission in moderate to severe CD Doses >60 mg/d not more effective Effective in 1 to 3 weeks Anticipate steroid dependence in ~25% of patients

IV Steroids• Indicated for severe flare, not responding to oral steroids,

other therapies• No need to give more than 60 mg methylprednisolone or 300

mg hydrocortisone• Can give once daily• Response generally occurs within 5‐7 days!• ~60% of patients completely respond to IV steroids

Truelove SC, Jewell, DP. Lancet 1974Truelove SC et al. Lancet 1978Jarnerot G, et al. Gastroenterology 1985Gustavsson A, et al. Am J Gastroenterol 2007

Thiopurines: Mercaptopurine and Azathioprine

• Indicationso Steroid‐dependence/refractorinesso As part of combination therapy with biologicso Post‐operative prophylaxis (CD)o Fistulas (CD)

• TPMT testing advised before starting• Dosing

o Mercaptopurine: 1 – 1.5 mg/kgo Azathioprine: 2 – 3 mg/kg

Onset of effect: 8 – 16 weeks Metabolite testing helpful in inadequate response

Pearson DC et al. Ann Intern Med. 1995;1203:132.

Favors TherapyFavors Placebo

Odds Ratio of ResponseOdds Ratio of Response

AZA and 6‐MP: Clinical Response in Crohn’s Disease

Study Year # Pts

Rhodes 1971 12

Klein 1974 26

Candy Part 1 1994 63

NCCDS Group 1 1979 136Phase 1

Ewe 1993 42

Present 1980 72

Willoughby Group 1 1971 12

Common odds ratio 367

0.1 0.2 0.5 1 2 5 10 100

6‐Mercaptopurine & Azathioprine: Adverse Effects

• GI intolerance• Bone marrow suppression• Infection• Liver function abnormality / frank hepatitis• Pancreatitis• Hypersensitivity syndrome (serum sickness)• Lymphoma• Squamous cell skin cancer, cervical cancer

TPMT genotype associated with early but not late severe myelosuppression

0

2

4

6

8

0.5 1 1.5 2 3 4 5 6 7 8 9 10 11 12 18 26 27 35 46 55 87Months

Patie

nts

High methylatorsIntermediate methylatorsLow methylators

Colombel JF, et al. Gastro. 2000;118:1025‐30.

6‐MP dose does not correlate with clinical response

0%

25%

50%

75%

100%

Freq

uenc

y of

Res

pons

e

0.4-1.0 1.0-1.3 1.4-1.5 1.6-2.4

6-MP DOSE QUARTILES

p = 0.6

Dubinsky M, et al. Gastro. 2000;118:705-13.

Interpreting Thiopurine Metabolites6TGN

6MMP

235

450

3,500Non‐compliance

Gearry RB et al. J Gastroetnerol Hepatol 2005; 20(8):1149‐57

Under-dosing


6MMP

235

450

3,500



6MMP

235

450

3,500

Thiopurine Resistance(if not responding)


Thiopurine resistance6MMP:6TGN > 12


6MMP

235

450

3,500



6MMP

235

450

3,500

Liver Tox


Exposure to Thiopurines and Lymphomas in IBD

Beaugerie L et al. Lancet. 2009;374:1617.

6

4

1

2

0

Year

ly In

cide

nce

Rat

e (p

er 1

,000

pat

ient

-yea

rs)

5

3

5

0 0 6 1 2 4 1 4

0.370 0

2.58

0.660.40

5.41

1.88 1.68

Cases of Lymphoproliferative Disorders

<50 years 50–65 years >65 years

Thiopurine therapyContinuingDiscontinuedNever received

Patient-years 13,595 7,924 15,732 2,325 1,524 4,965 739 533 2,375

Overall rate on therapy:0∙90 per 1000 (95% CI 0∙50–1∙49) patient‐years

Methotrexate• Indications

o Steroid‐dependenceo Steroid‐refractoryo As part of combination therapy with biologics

• Dosingo SC or IM: 25 15 mg weeklyo PO: 7.5 ‐ 15 mg weekly

Onset of effect: 8 – 16 weeks Anticipate nausea (folate, ondansetron) Effective contraception needed Monitor AST, ALT, bilirubin, albumin

Feagan BG, et al. N Engl J Med 1995;332:292‐7.

Moderate–Severe CD: Efficacy of MTX

Feagan BG et al. N Engl J Med. 1995;332:292‐297.

p = 0.025 p = 0.003 p = 0.092

Placebo

MTX 25 mgIM weekly

35.3%40.0%39.0%

10.0%

39.4%

19.1%

50

25

0All patients 20 mg/day

Treatment group

Remission (%

)

20 mg/day

Mucosal healing in Crohn’s diseasewith anti‐TNF antibody (infliximab)

Van Dullemen HM et al. Gastroenterology 1995

The most influential paper of the last 20 years in IBD

Anti‐TNF Antibodies

• CD: infliximab, adalimumab, certolizumab pegol• UC: infliximab, adalimumab, golimumab• Indications

o Moderate to severe diseaseo Steroid‐dependent/refractory diseaseo Refractory to immune modulatorso Severe, IV steroid‐refractory UCo Fistulizing CDo Selected patients with early CDo ?Post‐operative prophylaxis of CD

Onset of effect: 2 ‐6 weeks

Evidence for Combination Therapy in Immunosuppressant‐Naive Patients

Corticosteroid-free clinical remission at Week 26Colombel JF et al. N Engl J Med. 2010;362:1383.

Prop

ortio

n of

pat

ient

s (%

) P<0.001P=0.006 P=0.022

51/170 75/169 96/169

30.0

44.4

56.8

0

20

40

60

80

100

AZA + placebo IFX + placebo IFX + AZA

AZA, azathioprine; IFX, infliximab

SONIC

Pragmatic Approach to Combination Therapy

• Combination therapy is most effective, least risky induction therapy

• Limited data on benefits and risks of combination therapy with biologic therapies other than infliximab

• Infection risk driven more by steroids• Neoplasia risk driven more by thiopurines• Consider reducing to monotherapy for

– Young males– Individuals in deep, sustained remissions

• Can be re‐treated with combination therapy

Symptoms (Crohn’s Disease Activity Index) vs Endoscopic Findings (Crohn’s Disease Endoscopic Index of Severity)

CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s Disease Endoscopic Index of Severity

0

100

200

300

400

500

600

5 10 15 20 25 30 350

Correlation of CDAI vs CDEIS at D0 (n=142)CDEIS

R=0.13 ; NS

Modigliani R et al. Gastroenterology. 1990;98:811.

CD

AI

Poor Correlation Between Clinical Remission and Mucosal Healing

Week 8 Week 30 Week 54

*

**

**

*

Infliximab5 mg

(n=121)

Placebo(n=121)

Placebo(n=121)

Infliximab5 mg

(n=121)

Placebo(n=121)

Infliximab5 mg

(n=121)*P≤0.001 vs placebo based on a two-sided Cochran-Mantel-Haenszel chi-square testMucosal healing = Mayo score 0 or 1

Patie

nts (%)

100

0

Patie

nts (%)

100

0

Patie

nts (%)

100

0

34%

15%

62%

39%

25%16%

50%

34%

18%16%

45%35%

Mucosal healing Clinical remission

Rutgeerts P et al. N Engl J Med. 2005;353:2462.

Treatment of UC with infliximab (ACT 1)

Causes of Symptoms Other Than Active Inflammation in Patients With Crohn’s Disease

• Disease complications– Strictures– Fistulas– Abscesses

• Complications of surgical resection– Bile salt diarrhea– Steatorrhea– Small intestine bacterial overgrowth

• Infection– Clostridium difficile– Cytomegalovirus

• Irritable bowel syndrome (with/without mood disorder)

“Trust, but verify.”

Mucosal Healing in the Management of IBD

• Severe endoscopic disease is associated with a worse clinical course

• Mucosal healing is associated with improved outcomes

• Endoscopy can be helpful in confirming active disease and guiding clinical decisions

• Need to define mucosal healing

• Validated endoscopic indices exist—but not easy to use!

• Mucosal healing cannot consistently be obtained with currently used therapies

Currently, insufficient evidence to support an increase in therapy for all patients in clinical remission that continue to have

endoscopic evidence of ongoing inflammation.

Mehrotra N, et al. International Journal of Impotence Research (2009) 21, 107–115.

Pharmacokinetics 101: Drug levels matter!

Steroid‐free Clinical Remission at Week 26 by Median Trough Infliximab Concentration at

Week 30 (SONIC)

19/32 31/43

Prop

ortio

n of

Pat

ient

s (%

)

43/59 36/4913/23

IFX + placebo or IFX/AZA-treated patients who had serum samples collected prior to infusion atWeek 30 (N=206)

Colombel JF et al. N Engl J Med. 2010;362:1383-1395.

Infliximab Concentration and Clinical Outcome in Adult Patients with Moderate to Severe UC (ACT 1 & ACT 2)

*Data presented for the 5 mg/kg groups in ACT 1 & ACT 2

<21.3≥21.3‐<33.0

≥21.3‐<33.0

≥33.0‐<47.9

≥33.0‐<47.9>47.9 >47.9

N=230P<0.0001

N=230P=0.008

Reinisch W, et al. Presented at DDW; May 20, 2012. Abstract 566.

<21.3

* 6 discontinued IFX, 3 continued same dose 3, 3 proceeded to surgery, 5 patients could not be assessed

Clinical outcomes in patients with detectable HACA (n=35)*

* 10 continued same dose, 9 discontinued IFX, 8 proceeded to surgery and 7 patients could not be assessed

Clinical outcomes in patients with sub-therapeutic concentrations (n=69)*

Increasing Dose of Infliximab in the Presence of ATI Formation is Inferior to Changing Anti‐TNF

Com

plet

e / p

artia

l res

pons

e (%

)

P<0.004

Com

plet

e / p

artia

l res

pons

e (%

)

P<0.016

Afif W, et al. Am J Gastroenterol 2010;105:1133-9.

Management of loss of response to anti‐TNF antibodies

Adapted from Vermeire S, Gils A. Frontline Gastroenterology 2013;4:41–43

Symptoms suggestive of relapse

Trough levels

detectable

Trough levels

undetectable

Endoscopy shows

inflammation

Endoscopy shows no

inflammationAntibodies high No or low

antibodies

Switch to drug with different

mode of action

R/O stenosis, consider

treating IBSSwitch within

class

Optimize within same anti-TNF (dose

intensify, add IMMOD)

Therapeutic Drug Monitoring (TDM) of Anti‐TNF Antibodies

• Minimum effective concentration roughly definedo IFX trough ~3 μg/mL1

o ADA trough ~5 μg/mL2

• Role of TDM best established in assessing loss of response• Growing interest in early TDM to dose optimize in severe

disease (especially UC)3,4

• TDM appears to be cost effective when dose‐reduction incorporated into treatment algorithm, but will be highly dependent upon cost and frequency of assay5

1Bortlik M, et al. J Crohns Colitis 2013;7:736‐743.2Roblin X, et al. Am J Gastroenterol 2014;109:1250‐6.3Murthy S, et al. Presented at DDW; May 19, 2012. Abstract Sa2047.4Vande Casteele N, et al. Gastroenterology 2015, in press.5Steenholdt C, et al. Gut 2014;63:919‐27.

Vedolizumab

• Indicationso Active UC or CD despite corticosteroids, immune modulators, or anti‐TNF1,2

o Effective in steroid sparing1,2

• Dose: 300 mg IV weeks 0, 2, 6 and every 8 wk• Onset of effect

– as early as 2 weeks– 6 to 8 weeks more typical– at least 10 weeks needed in CD with prior anti‐TNF3

• Consider using in combination with immune modulator

1Sandborn et al, N Engl J Med 2013;369:711‐212Feagan et al, N Engl J Med 2013;369:699‐7103Sands BE, et al. Gastroenterology 2014;147:618–627

Putting it together in specific clinical situations

• Acute severe UC• New diagnosis CD: top‐down?

Prognostic factors in ulcerative colitis

• Greater extent of disease• Failure of 5ASA/need for corticosteroids (especially for first

flare)• Deep ulceration• High CRP, ESR• Low albumin

Severe acute ulcerative colitis

• Switch from oral to IV steroids may be effective• Stop 5ASAs• Decision for next steps in 3 days (not more than 5)• Cyclosporine and infliximab roughly same efficacy1

• Infliximab: consider induction doses higher than standard 5 mg/kg at weeks 0, 2 and 6

1Laharie D, et al. Lancet 2012; 380: 1909–15

240228216204192180168156144132120108968472604836241200

10

20

30

40

50

60

70

80

90

100

Cum

ulat

ive

Prob

abili

ty (%

)

Patients at risk: Months2002 552 229 95 37N =

Penetrating

Cosnes J et al. Inflamm Bowel Dis. 2002;8(4):244-250.

High Potential Low Potential

InflammatoryStricturing

Impact of Therapy Depends on Degree of Structural Damage and Velocity of Progression

CDAI: Crohn's Disease Activity Index; CDEIS : Crohn’s Disease Endoscopic Index of Severity; CRP: C-Reactive Protein

Pariente B et al. Inflamm Bowel Dis 2011;17(6):1415-22

Progression of digestive disease damage and inflammatory activity

Pre-clinical Clinical

Inflamm

atory Activity

(CD

AI, C

DEIS, C

RP)

Surgery

Stricture

Stricture

Fistula/abscess

Diseaseonset

Diagnosis Early disease

Dig

estiv

e D

amag

e

90%

75%

62%57%

68%

55%47% 44%

33%36%

50%

37%

24%29%

36%37%

0

10

20

30

40

50

60

70

80

90

100

<1 Year 1 to <2 years 2 to <5 years ≥5 years

% in

CD

AI R

espo

nse

or R

emis

sion

Response Placebo ResponseRemission Placebo Remission

n=35

n=19

n=35

n=19

n=22

n=20

n=22

n=20

n=55

n=45

n=55

n=45

n=98

n=13

1

n=98

n=13

1

Data from the PRECiSE 2 study

Schreiber S. et al. Am J Gastroenterol. 2010;105:1574-1582.

Response and remission to certolizumabpegol in Crohn’s disease vs disease duration

Schreiber S et al. Journal of Crohn’s and Colitis (2012), doi: 10.1016/j.crohns.2012.05.015

Placebo All adalimumab

Rem

issi

on (%

)

<2 yearsn=23, n=39

<2-5 yearsn= 36, n=57

≥5 yearsn=111, n=233

Remission by disease duration with adalimumab at week 26

P=0.008P=0.56

P<0.001

Evolving treatment strategies for Crohn’s disease

Sandborn WJ, et al. J Crohn’s Colitis. 2014;8:927‐35.

Early disease: Who should get top‐down?Early Crohn’s Disease (Moderate To Severe)

High risk for rapid progression to bowel damage and disability

Potential predictors from literature‐ Early onset (<40 yrs)‐ Small bowel involvement‐ Perianal disease at diagnosis‐ Endoscopic severe lesions

Potential predictors in clinical practice‐ Diagnosis age <40 yrs‐ Extensive anatomic involvement‐ Perianal or severe rectal disease‐ Deep ulcers‐ Prior surgical resection‐ Stricturing and/or penetrating behavior

Early top-down IMM + TNF antagonist

Accelerated step-careIMM + TNF antagonist

TNF antagonist ± IMM

YES NO

Fail to respond

Sandborn WJ, et al. J Crohn’s Colitis. 2014;8:927‐35.

Management of Crohn’s disease: from the start

Antues O, et al. Best Pract & Res Clin Gastroenterol 2014;28:473–483

Active SymptomsActive Symptoms

Objective evidence of inflammation

Objective evidence of inflammation

New treatment begunNew treatment begun

YesCONTINUETreatment

Appropriate treatment duration

t0

t1

New approach to treatment of IBD:Treat to target

Symptoms

improved?

Symptoms resolved?

Inflammation improved?

Yes

No

SymptomaticTreatment

SymptomaticTreatment

Reassess for symptoms And objective inflammationReassess for symptoms

And objective inflammation

ANo

Periodic reassessment of symptoms

and inflammation

Periodic reassessment of symptoms

and inflammation

STOPTreatment

Optimize dosing

BNo

Summary

• Finer points of diagnosis• Knowing how and when to combine medications is key

• Objective monitoring of disease activity/response to therapy, and judicious use of drug level monitoring very helpful in achieving best long‐term results

how to treat ibd like an - cloudcme...2020/03/15 · samuel s, et al. clin gastroenterol hepatol...

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