inflammatory bowel disease: updates in...

Uma Mahadevan, MD, FACG

Inflammatory Bowel Disease: Updates in Therapy

Uma Mahadevan MDProfessor of MedicineProfessor of MedicineCo-Medical Director

UCSF Center of Colitis and Crohn’s Disease

’ULCERATIVE COLITIS AND CROHN’S DISEASE: THERAPEUTIC SIMILARITIES AND DIFFERENCES

ACG Western Regional Postgraduate Course - Las Vegas, NV Copyright 2015 American College of Gastroenterology

1


Therapeutic AgentsCrohn’s Only; UC Only

5 ASA CompoundsSulfasalazineO l 5 ASA f l ti

Biological Therapies PPD/HBV

Oral 5-ASA formulationsRectal 5-ASA

GlucocorticosteroidsSystemic steroidsTopically acting steroids (budesonide)

Antibioticsd l

/InfliximabAdlimumabCertolizumab pegolGolimumabNatalizumab (JCV Ab)Vedolizumab

Nutritional TherapiesEl t l dMetronidazole

Quinolones

ImmunosuppressivesAzathioprine or

6-mercaptopurine/TPMTMethotrexate

Elemental and polymeric formulas

Pre- and probiotics

Symptomatic AgentsAnti-diarrhealsAnti-spasmodics

Adapted from Rutgeerts PJ. Rev Gastroenterol Disord. 2004;4(suppl 3):S3-S9.

Evolving Goals of Therapy for IBD: Sustained Deep Remission and Better Long-term Outcomes

Goal Clinical Parameters Outcomes

Response

Remission

Symptoms

Endoscopy

Improved Quality of life

Hospitalization

Deep Remission Mucosal healing Avoidance of surgery Minimal/No Disability

SUSTAINED DISEASE CONTROLSame


2


Sequential Therapy for UC

Disease Severityat Presentation Colectomy

Corticosteroid

Anti-TNFVedolizumabCyclosporineSevere

Moderate

AminosalicylateThiopurine

Anti-TNF/VedoImmunomod.

Therapy is stepped up according to severity at presentation or failure at prior step

Aminosalicylate

Mild

AminosalicylateInduction

Maintenance

Corticosteroids: Short- and Long-term Efficacy

Complete Partial1-Month

Outcomes*(n=63)

Complete Remission

54%(n=34)

Partial Remission

30%(n=19)

No Response 16%

(n=10)

*30 days after initiating corticosteroid therapy.

Faubion W et al. Gastroenterology. 2001;121:255-260.

1-YearOutcomes

(n=63)

Steroid Dependent

22%(n=14)

Prolonged Response

49%(n=31)

Surgery 29%

(n=18)


3


Infliximab in UC: The ACT1 and ACT2 Trials

Placebo 5 mg of infliximab 10 mg of infliximab

ACT 1 ACT 2100 100

**

* **

*

100

80

60

40

20

0

100

80

60

40

20

0

Pat

ien

ts w

ith

Su

stai

ned

Res

po

nse

(%

)

23.1

48.845.9

14 0

38.836.9

15.4

41.3

53.3

Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.

Response at Weeks 8 and 30

Response at Weeks 8, 30, and 54

Response at Weeks 8 and 30

*P<.001 vs placebo

14.0 15.4

100

77

IFX+AZA (n=78)

IFX (n=77)

UC Success: Combination Therapy for UC

#

40

60

80

40

77

63

22

69

55

24

50

37

( )

AZA (n=66)

Pat

ien

ts (

%)

*

#

##

0

20

Steroid-free remission Response Mucosal healing

*P < .05 compared to IFX; # P < .05 compared to AZA

Panccione R, et al. DDW 2011; Abstract 835


4


Mucosal Healing and Time to Colectomy in Infliximab-treated Patients

1.00

Time to coloectomy infliximab use (weeks)

P<0.0001

endoscopy subscore = 0 endoscopy subscore = 2

0.75

0.5001 0 203 0 40 50

Colombel JF et al. Gastroenterology. 2011;141:1194-1201. 9

1 = MILD 2 = MODERATE 3 = SEVERE0 = NORMAL

endoscopy subscore = 0endoscopy subscore = 1

endoscopy subscore = 2endoscopy subscore = 3

Retrospective study of induction IFX 5mg/kg in patients who required hospitalization for acute

t id f t UC

Accelerated Infliximab Rescue Reduces Early Colectomy Rate in Acute Severe UC

severe, steroid-refractory UC

No difference in colectomy rate during IFX maintenance

Proportion of Patients Colectomy-Free Maintenance Induction

Accelerated dosing

10Gibson D, et al. Presented at DDW, May 3, 2014 Abstract 207.

dosing protects

against early colectomy in acute severe

UC


5


Response: D 7Primary Objectives

Cyclosporine Versus Infliximab In Severe Acute Ulcerative Colitis Refractory To Intravenous Steroids: A Randomized Trial

p=0.97

85.4% 85.7%

40%

60%

80%

100%

Difference Cys vs. IFX: -0.3% (95%CI: -13.3 to 12.8%)

p=0.4960%

54%

40%

60%

80%

100% Difference Cys vs. IFX failure rates: -6.4% (95%CI: - 24.8 to 12.0%)

Response: Lichtiger score < 10 and decrease ≥ 3 points as compared to baseline

0%

20%

Cys (n=55) IFX (n=56)

0%

20%

Cys (n=55) IFX (n=56)

Laharie et al. Lancet. 2012 Dec

Clinical Response, Remission, Mucosal Healing at 6 Weeks

P<0.0001

P=0.0012

Vedolizumab for Ulcerative Colitis: Gemini

P=0.0009%

Δ 21.711.6, 31.7

Δ 11.54.7, 18.3

Δ 16.16.4, 25.995% CI:


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• Prospective, double blind RCT– 53 active UC patients (Mayo score ≥ 4 with

endoscopic Mayo subscore ≥ 1)– Negative for C. difficile

UC Patients Failed to Show Significant Improvement after Fecal Microbiota Therapy (FMT)

IBDQ at Week 6

g ff– 42% on steroids, 19% on immunomodulators,

and 9% on biologics– 6 weeks of once-weekly fecal microbiota therapy

delivered by retention enemas (n = 27) vs placebo delivered by water enemas (n=26)

• Results– No difference in remission between groups at

week 6 (assessed by Mayo score, IBDQ and EQ-5D)– No adverse events related to FMT

Mayo Score at Week 6

• Limitations– Short duration (6 weeks) – Small sample size

Moayeddi P, et al. Presented at DDW; May 5, 2014. Abstract 929c

Summary of UC Therapies• Mild to Moderate disease:

• Mesalamine (oral ± topical) induction and maintenance for mild-moderate disease (2.4-4.8 gm induction and maintenance)

• Topical Therapy

• Moderate to Severe disease:• Corticosteroid induction for moderate-severe disease

• Thiopurines maintain steroid-induced remission

• Anti-TNF agents for moderate to severe disease, steroid-refractory induction or steroid-dependent maintenance (± thiopurine)

• Vedolizumab: same indications as anti-TNF. Can be first line biologic

S Di• Severe Disease:• Intravenous steroids

• ? High dose infliximab

• ? Cyclosporine


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Biologic Agents in Crohn’s Disease: Dosing Recommendations

Agent RouteDosing Regimen

Induction MaintenanceInfliximab IV 5 mg/kg at weeks

0, 2, and 65 mg/kg every 8 weeks 10 mg/kg in lost response

Adalimumab SC 160 mg week 0, 80 mg week 2,40 mg week 4

40 mg every 2 weeks

g

Certolizumab SC 400 mg at weeks 0, 2, and 4

400 mg every 4 weeks

Vedolizumab IV 300 mg at weeks 0,2,6

300 mg every 8 weeks

Natalizumab IV --- 300 mg every 4 weeks

Safety of Starting Full Weight-Based Dosing vs Low-Dose Thiopurines in Normal Metabolizers (TPMT >25)

• Retrospective study of 134 adult CD patients with TPMT > 25

Complication Rates in Patients Starting Full-Dose Thiopurines vs. Controls (Gradual Increase)

CD patients with TPMT > 25 (normal metabolizers) and > 1 year follow-up

– Dose initiation at 2-2.5mg/kg AZA or 1-1.5 mg/kg 6MP (therapy) compared with gradual increase (control)

• Results– Overall similar rates of AEs

Adverse Event Comparison*

– 90% of complications in both groups occurred in first 3 months

Benmassauod A, et al. Presented at DDW; May 4, 2014. Abstract Su1416.

Starting thiopurines at full weight-based dosing in patientswith TPMT > 25 appears safe


8


Risk of Lymphoma Returns to Normal after Stopping Thiopurines

• 36,891 VA patients with UC with a median f ll f 6 7 d di f 60follow up of 6.7 years and a median age of 60 years at inclusion –4,734 patients using thiopurines; median duration

of exposure : 0.97 years

Thiopurine use Incidence Rate (per 1000 py)

Unexposed 0.6

During 2.3

After stopping 0.3

• 142 confirmed lymphomacases

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Methotrexate

• 25 mg SQ weekly shorter onset of efficacy25 mg SQ weekly, shorter onset of efficacy– 39% MTX vs 19% placebo CR (p=.025)

• Monitor CBC, liver enzymes, ?liver biopsy• Folic Acid 1 mg QD• 15 mg maintenance, 65% vs 39% (p=.04)

– Maintain with 15-25 mg q week

• Avoid use in obese, ETOH, DM, conception• **12.5 mg orally weekly as concomitant

immunomodulator (UC or CD)Feagan N Engl J Med. 2000 Jun 1;342(22):1627-32


9


Induction and Maintenance of Response and Remission

Primary Endpoint100

SONIC: Corticosteroid-Free Clinical Remission at Week 26

30.6

44.4

56.8

40

60

80

100

rtio

n o

f P

atie

nts

(%

)

P<0.001

P=0.006 P=0.022

0

20

Pro

po

r

AZA + placebo IFX + placebo IFX+ AZA

52/170 75/169 96/169

Colombel N Engl J Med 2010; 362:1383-1395


10


Gemini 2 and 3: Vedolizumab for Maintenance of CD

• Responders randomized 1:1:1 VDZ Q4W Q8W placebo from 6–VDZ Q4W, Q8W, placebo from 6–52 weeks

– Open-label VDZ Q4W if no clinical response at 6 weeks compared to placebo

– Extension of induction trial for 6-week responders

• Maintenance at week 52

21

– Cohorts 1+ 2– Among those with Clin Rem at

week 6, still in Clin Rem at week 52

Sandborn N Engl J Med. 2013 Aug 22;369(8):711-21

VDZ is effective as maintenance therapy in Crohn’s disease. Induction therapy may

take longer than 6 weeks.

• 21 patients with anti-TNF antibody-induced psoriasis prospectively recruited from 434 anti TNF treated IBD patients; Genotyping for IL23R and IL12B variants performed

Anti-TNF Antibody-Induced Psoriaform Skin Lesions Respond to Ustekinumab

anti-TNF treated IBD patients; Genotyping for IL23R and IL12B variants performed

• Results:– 19/331 CD – 5.7% , 2/103 UC patients – 1.3%– Predictors of skin lesions using multivariate analysis:

• Smoking ( OR 4.24, 95%CI 1.55-13.6; P=0.007)• Increased BMI (OR 1.12, CI 1.01-1.24; P=0.029)

– 7/21 with severe skin lesions and/or alopecia treated with ustekinumab – 100% response

l• Conclusions:– Anti-TNF antibody-induced psoriasiform skin lesions are not uncommon– Smoking and increased BMI are predictors– Ustekinumab can be used to successfully treat severe cases– Dose effect in development of psoriasiform lesions were not analyzed, and no dose or frequency

reduction was attempted– Genetic factors predict severe cases – IL23R and IL12B variants

Tillack C, et al. Gut. 2014 Apr;63(4):567-77


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Treatment Algorithm in IBD Patients With Clinical Symptoms (Infliximab and HACA Concentrations)

Subtherapeutic IFX Therapeutic IFX Positive HACA

Change to another anti-TNF agent

persistent disease

Increase infliximab dose or

frequency

Change to different anti-TNF

agent

concentrationconcentration

Active disease on endoscopy/radiology?

Change to Investigate

yes no

Change to non–anti-TNF agent

Change to non–

anti-TNF agent


agent


agent

Investigate alternate etiologies

Afif W et al. Am J Gastroenterol 2010;105:1133Slide Courtesy of Dr. EVL

Do you need to use full dose azathioprine for immunogenicity prevention?

• Cross-sectional study of IBD patients (N=72, 63% CD) receiving IFX in combination with a thiopurine for ≥4 months

Comparison Between Groups Withand Without Detectable Antibodies to IFX (ATI)

Correlation Between 6-TGN and IFX C t ti and Without Detectable Antibodies to IFX (ATI)IFX Concentrations

Higher 6-TGN levels correlate with higher IFX trough concentrations but levels of 125 may maximize IFX levels

Patients with detectable IFX abs had significantly lower 6TGN levelsYarur A, et al. Presented at DDW, May 5, 2014 Abstract 788.


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• 115 Crohn’s disease patients on combination therapySt id f i i f t l t 6 th

Can you stop anti-TNF? The STORI Trial

• Steroid-free remission for at least 6 months• Infliximab therapy stopped, immunomodulator continued

1.0

0.4

0.6

0.8

0.2po

rtio

n W

ith

ou

t R

ela

ps

e 1.0

0.4

0.6

0.8

rtio

n W

ith

ou

t R

elap

se

Number ofdeleterious

factors

2

3

4

Louis E, et al. Gastroenterology. 2012;142(1):63.

• Deleterious factors included: steroids within the year; no prior surgery; male; hemoglobin ≤ 14.5; white blood cell count > 6.0; any endoscopic activity; hsCRP ≥5; infliximab trough ≥ 2; fecal calprotectin ≥ 300μg/g

0.00 3318

Months Since Infliximab Withdrawal

Pro

p

12 309 276 243 2115

0.2

0.00 3318

Months Since Infliximab WithdrawalP

rop

o12 309 276 243 2115

4

>4

115 3849 1559 2979 32100 3247No. at risk

• 113 patients with luminal CD treated with > 1 year IFX/IS combination in stable steroid-

Close Monitoring of CRP and Fecal Calprotectin is Able to Predict Clinical Relapse in Patients with CD in Remission after Infliximab Withdrawal: A Sub-Analysis of

the STORI Study

95%

CI/µ

g/g

) 30

20

25

15

P<0.001

Non-relapsersR l

CRP Evolution

free remission for > 6 months (STORI), with discontinuation of IFX

• 51 (45%) with relapse at median of 10 months

• In relapsers, higher median CRP and calprotectin during follow-up but also a sudden

CR

P (

mea

n,

-14Time before relapse or end of follow-up (months)

-6 00

10

5

15

N patients withCRP measurement inrelapsers/non-relapsers

-12 -10 -8 -4 -2

3/33 6/36 5/34 12/39 14/44 27/45 31/49 41/50

Relapsers

CI/

µg

/g)

1200

1000

P=0.001

Calprotectin Evolution

pand pronounced increase in CRP and calprotectin during 4 months prior to relapse

• CRP of 6.1mg/L and calprotectin of 305mcg/g best for prediction of relapse

De Suray N, et al. Presented at DDW; May 21, 2012. Abstract 864.

Cal

pro

(m

ean

, 95%

C

-14Time before relapse or end of follow-up (months)

-6 00

400

800

200

600

N patients withCalpro measurement inrelapsers/non-relapsers

-12 -10 -8 -4 -2

4/35 6/39 6/39 9/41 11/36 27/43 33/43 37/45

Non-relapsersRelapsers

IFX, infliximab; IS, i t


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• Aim: Assessing efficacy and tolerability of adalimumab

Can you switch the anti-TNF?CD patients in remission

(HBI score <8) for >6 months on IFX (n=29)

tolerability of adalimumab (ADA) therapy after an elective switch from infliximab (IFX) in CD patients in remission. (Open-label single-center study)

• Primary endpoint: Dose intensification or termination of ADA therapy

Switch to ADA(Mean follow-up 50 weeks)

8/29 (28%) discontinued ADA therapy (50% due

to AE and 50% lost response)

21/29 (72%) remained in remission (1 patient

needed dose intensification)

of ADA therapy

4 patients were re-started on IFX (2 patients lost response;1 patient needed dose intensification)

Hoentjen F, et al. Presented at DDW; May 19, 2012. Abstract 268.

An elective switch from IFX to ADA carries the risk of losing response to IFX in a subset of patients.

AE, adverse eventHBI, Harvey-Bradshaw Index

Summary of Crohn’s Therapy

• Mesalamine does not work for CD (mild colonic ok)• Steroids/Budesonide: induction• Azathioprine/Methotrexate: steroid sparing and

concomitant immuomodulator– Full dose Aza (?), 12.5 weekly MTX

• Anti-TNF (infliximab, adalimumab, certolizumab) induction and maintenance of remission in moderate to severe disease (+/- immunomodulator)

• Vedolizumab for induction/maintenance of remission in moderate-severe Crohn’s (+/- immunomodulator)

• Natalizumab in JCV (-) patients failing anti-TNF/Vedo• Ustekinumab anecdotal evidence


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THANK YOU!


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