IBD therapy: Balancing risks and...

Maria T. Abreu, MD

IBD therapy: Balancing risks IBD therapy: Balancing risks and benefitsand benefits

Maria T. Abreu, MDMaria T. Abreu, MD

Reasons for complications in Reasons for complications in the established IBD patient the established IBD patient

Complications of the diseaseComplications of the disease•• Complications of the diseaseComplications of the disease

•• Complications of the treatmentComplications of the treatment

ACG/FGS Spring Symposium - Bonita Springs, FL Copyright 2014 American College of Gastroenterology

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Maria T. Abreu, MD

EyeEyeinflammation*inflammation*

Growth failureGrowth failurein childrenin children

IBD: Systemic ComplicationsIBD: Systemic Complications

Liver andLiver andbile ductbile ductinflammationinflammation

KidneyKidneystonesstones

LowerLowerbone density*bone density*

Subfertility*Subfertility*

GallstonesGallstones

OvariesOvaries

UterusUterus

Skin lesionsSkin lesions

Arthritis and Arthritis and joint painsjoint pains

*Higher incidence in women.*Higher incidence in women.

•• Biomechanical CT (BCT) can measure Biomechanical CT (BCT) can measure b i l d it (BMD) d bb i l d it (BMD) d b

CTE Can Also Be Used to CTE Can Also Be Used to Diagnose OsteoporosisDiagnose Osteoporosis

bone mineral density (BMD) and bone bone mineral density (BMD) and bone strength from non contrast CT imagesstrength from non contrast CT images

•• Clinical CTE provides hip BMD, TClinical CTE provides hip BMD, T--scores, scores, & clinical classifications comparable to & clinical classifications comparable to DXA DXA

•• For osteoporosis, CTE Sensitivity = 86%, For osteoporosis, CTE Sensitivity = 86%, Specificity = 98%Specificity = 98%

Combined with BCT CTE can identifyCombined with BCT CTE can identify

Densitydistribution

•• Combined with BCT, CTE can identify Combined with BCT, CTE can identify patients with osteopeniapatients with osteopenia

•• Ancillary analysis of CTE exams for BMD & Ancillary analysis of CTE exams for BMD & bone strength could improve osteoporosis bone strength could improve osteoporosis screening rates in IBD patients and may screening rates in IBD patients and may alter management plansalter management plans4

Regions of failure

Weber NK, et al. Presented at DDW; May 19, 2013. Abstract 475.


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Maria T. Abreu, MD

EMREMR--derived cohort of patients (n=3,217) assessed for association of derived cohort of patients (n=3,217) assessed for association of 25(OH)25(OH)--Vitamin D status on subsequent surgeryVitamin D status on subsequent surgery

Plasma 25(OH)Plasma 25(OH)--Vitamin D Is Associated Vitamin D Is Associated With a Reduced Risk of Surgery in IBDWith a Reduced Risk of Surgery in IBD

F ll U Vit i D

Surgery Hospitalizations

N t Not

Initial Vitamin D Level

Crohn’s UC

Surgery OR Surgery OR

>30 ng/dL 13% 10%

20-29 ng/dL 21% 1.54 (1.06 – 2.25) 12% 1.13 (0.68 – 1.86)

<20 ng/dL 24% 1.76 (1.24 – 2.51) 17% 2.10 (1.32 – 3.34)

Follow up Vitamin D examined for normalization and outcome in Crohn’s Disease

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Follow-Up Vitamin D Level

Not normalized Normalized

Not

Normalized Normalized

Crohn’s disease

Unadjusted 1.0 0.51 (0.32 – 0.82) 1.0 0.64 (0.44 – 0.96)

Adjusted 1.0 0.56 (0.32 – 0.98) 1.0 0.78 (0.51 – 1.25)

Limitations: no adjustment for severity/phenotype;

Ananthakrishnan AN, et al. Presented at DDW, May 18, 2013. Abstract 1.

1,324 patients in remission identified from the CCFA Partners Cohort Remission defined as Short Crohn’s Disease Activity Index <150 or Simple Clinical Colitis Activity Index ≤2

Higher Exercise Level May Reduce Risk of Relapse Higher Exercise Level May Reduce Risk of Relapse in Patients With IBDin Patients With IBD

Index ≤2Active disease after 6 months (relapse) in:

234 patients (17.7%) with CD and 141 (24.9%) with UC/IC

% R

elap

se

Baseline exercise status wasmeasured using the validatedGodin leisure time activityindex

Conclusion:A trend was observed that higher exercise level was associated with reduced likelihood of developing active disease (OR 0.87, 95% CI 0.67-1.12) after adjusting for age and global health

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index

Jones PD, et al. Presented at DDW; May 20, 2013. Abstract Mo1351.


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Maria T. Abreu, MD

University of Manitoba IBD Research Registry

High perceived stress levels in both Crohn’s disease and ulcerative

Stress in IBD Is Associated With Increased Symptoms, Stress in IBD Is Associated With Increased Symptoms, But Is Not Associated With Elevated Fecal CalprotectinBut Is Not Associated With Elevated Fecal Calprotectin

High perceived stress levels in both Crohn s disease and ulcerative colitis were associated with increased clinical indices

Crohn’s diseaseHBI ≥ 5 (OR 2.03, 95% CI 1.04-3.98)Active MIBDI (OR 2.48, 95% CI 1.30-4.74)

Ulcerative colitisPTI ≥ 5 (OR 2.33, 95% CI 1.09-5.01)Active MIBDI (OR 2.68, 95% CI 1.22-5.59)

High perceived stress levels were not associated with elevated fecal calprotectin (>250ug/g)

Crohn’s disease (OR 1.19, 95% CI 0.64-2.19)UIcerative colitis (OR 0.76, 95% CI 0.35-1.66)

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HBI, Harvey-Bradshaw Index;MIBDI, Manitoba IBD Index;

PTI, Powell-Tuck Index.Sexton KA, et al. Presented at DDW; May 20, 2013. Abstract 560.

toxicity of medicationstoxicity of medications

they almost never happen they almost never happen but good to be informedbut good to be informed


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Maria T. Abreu, MD

Comparative toxicity of various Comparative toxicity of various therapies for Crohntherapies for Crohn’’s diseases disease

Mortality associated with current and recent Mortality associated with current and recent corticosteroid use corticosteroid use –– adjusted HR (95% CI)adjusted HR (95% CI)

5

2.812.49

1

2

3

4

Haz

ard

Rat

io

Lewis JD, et al. Am J Gastroenterol. 2008;103:1428-1435.

0

1H

95% CI: (2.26-3.5) 95% CI: (1.65-3.75)

Recent use of corticosteroids

Current use of corticosteroids


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Maria T. Abreu, MD

Infections and mortality in the TREAT registry:Infections and mortality in the TREAT registry:15,000 patient15,000 patient--years of experienceyears of experience

Multivariate analysis4.5

M t lit S i i f ti

1.5

2

2.5

3

3.5

4

IFX

Od

ds

rati

o

Mortality Serious infections

AZA6-MPMTX

** IFXAZA6-MPMTX

****

Lichenstein GR, et al. Gastroenterology 2006;130(suppl 4):A-71Lichtenstein GR, et al. Clin Gastroenterol Hepatol 2006;4:621–630

*p=0.001 **p<0.00010

0.5

1Steroids Steroids

IFX = infliximab; AZA = azathioprine; MTX = methotrexate

Risk factors for opportunistic infections Risk factors for opportunistic infections in IBD: A casein IBD: A case--control studycontrol study

Odds Ratio (95% CI) P value

100 cases of opportunistic ınfections

1 medication 2.7 (1.5–4.8) 0.0014

2 medications 9.7 (3.3–28.2) < 0.0001

3 medications Infinite Overall P < 0.0001

Steroids alone 2.2 (1.1–4.8) 0.037

6-MP/AZA alone 2.5 (1.2–5.1) 0.015

IFX alone 11.2 (0.8–153.3) 0.07

6-MP/AZA + steroids 15.7(4.1–59.5) < 0.0001

6-MP/AZA + IFX 1.6 (0.1–18.7) 0.71

6-MP/AZA + IFX + steroids Infinite 0.0003

6-MP = 6-mercaptopurine; AZA = azathioprine; IBD = inflammatory bowel disease; IFX = infliximab.Toruner M, et al. Gastroenterology 2008;134:929-36.


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Maria T. Abreu, MD

AntiAnti--TNF Antibody ToxicityTNF Antibody Toxicity•• Immunogenicity (antibodies to infliximab, adalimumab, Immunogenicity (antibodies to infliximab, adalimumab,

certolizumab pegol)certolizumab pegol)•• Infusion reactions (infliximab)Infusion reactions (infliximab)

D l d h iti it ti (i fli i b)D l d h iti it ti (i fli i b)•• Delayed hypersensitivity reactions (infliximab)Delayed hypersensitivity reactions (infliximab)•• InjectionInjection--site reactions (adalimumab, certolizumab pegol)site reactions (adalimumab, certolizumab pegol)•• Autoantibody formation (predominantly infliximab, ? Autoantibody formation (predominantly infliximab, ?

adalimumab)adalimumab)•• DrugDrug--induced lupus (predominantly infliximab)induced lupus (predominantly infliximab)•• NonNon--HodgkinHodgkin’’s lymphomas lymphoma•• Hepatosplenic THepatosplenic T--cell lymphoma in children on anticell lymphoma in children on anti--TNF + TNF +

azathioprineazathioprineazathioprineazathioprine•• Skin cancerSkin cancer•• ? Solid tumors? Solid tumors•• Serious infectionsSerious infections•• Opportunistic infections (including tuberculosis, Opportunistic infections (including tuberculosis,

histoplasmosis, coccidiomycosis)histoplasmosis, coccidiomycosis)•• DemyelinationDemyelination

What are the main sideWhat are the main side--effects effects of 6MP/Azathioprine?of 6MP/Azathioprine?

EventFrequency

EventEstimate

Stop therapy due to adverse event 11%

Allergic reactions 2%

Nausea 2%

Hepatitis 2%

Siegel CA, et al. APT 2005 (weighted average); Siegel CA, et al. CGH 2009

Pancreatitis 3%

Serious infections 5%

non-Hodgkin’s lymphoma 0.04% (4/10,000)


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Maria T. Abreu, MD

MethotrexateMethotrexate

ToxicityToxicityToxicityToxicity•• RashRash•• Nausea, mucositis, diarrheaNausea, mucositis, diarrhea•• Bone marrow suppressionBone marrow suppression•• Hypersensitivity pneumonitisHypersensitivity pneumonitis•• Increased LFTsIncreased LFTs•• Hepatic fibrosis/cirrhosisHepatic fibrosis/cirrhosis

Lymphomas and infectionsLymphomas and infections


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Maria T. Abreu, MD

Epidemiology of NHLEpidemiology of NHL

•• 1960s1960s--1990s: NHL1990s: NHL1960s1960s 1990s: NHL 1990s: NHL increased 2%increased 2%--4% 4% annually annually

•• 5th most common in 5th most common in USUS

•• 10th most common 10th most common worldwideworldwide

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Treatment and Risk for Treatment and Risk for LymphomaLymphoma

•• Causality bias (ie incipient lymphomaCausality bias (ie incipient lymphoma•• Causality bias (ie, incipient lymphoma Causality bias (ie, incipient lymphoma present at time of initiating therapy)present at time of initiating therapy)•• 26 cases of lymphoma following treatment with 26 cases of lymphoma following treatment with

etanercept or infliximab in postmarketing etanercept or infliximab in postmarketing surveillancesurveillance

•• 81% NHL vs 19% Hodgkin, multiple subtypes81% NHL vs 19% Hodgkin, multiple subtypes

•• Median interval between initiating therapy and Median interval between initiating therapy and lymphoma = 8 weekslymphoma = 8 weeks

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Maria T. Abreu, MD

Risk of Lymphoma Associated Risk of Lymphoma Associated with Immunomodulatorswith Immunomodulators

•• 19,486 IBD patients19,486 IBD patients, p, p•• 30.1% currently receiving thiopurines30.1% currently receiving thiopurines

•• 14.4% discontinued thiopurines14.4% discontinued thiopurines

•• 55.5% never exposed to thiopurines55.5% never exposed to thiopurines

ExposureRate per

10,000 pt-years95% CI

Current use 9.0 5.0-14.9

Beaugerie et al, Lancet 2009;7:374.

Receiving thiopurines vs. never exposedReceiving thiopurines vs. never exposedHR 5.28 (2.01HR 5.28 (2.01--13.9)13.9)

Discontinued 2.0 0.2-7.2Never exposed 2.6 1.0-5.7

Cesame TrialCesame Trial19,486 patients with IBD in a nationwide French cohort from 5/04-6/05

Beaugerie L et al. Lancet. 2009;374:1617-1625.

Multivariate Hazard Ratio for Lymphoproliferative Disorder From Thiopurine Use = 5.28 (2.01-13.9)


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Maria T. Abreu, MD

Risk of NH Lymphoma with antiRisk of NH Lymphoma with anti--TNF + TNF + IM treatment for CrohnIM treatment for Crohn’’s Diseases Disease

MetaMeta--analysis Resultsanalysis Results

•• 8905 patients representing 20,602 pt8905 patients representing 20,602 pt--years of exposureyears of exposure

•• 13 Non13 Non--HodgkinHodgkin’’s lymphomass lymphomas6 1 per 10 000 pt-years•• 13 Non13 Non--HodgkinHodgkin s lymphomas s lymphomas

•• Mean age 52, 62% maleMean age 52, 62% male

•• 10/13 exposed to IM* (really a study of combo Rx) 10/13 exposed to IM* (really a study of combo Rx)

NHL rate per 10,000

SIR 95% CI

SEER all ages 1.9 - -

6.1 per 10,000 pt-years

SEER all ages 1.9 IM alone 3.6 - -Anti-TNF + IM vs SEER 6.1 3.23 1.5-6.9

Anti-TNF+ IM vs IM alone 6.1 1.7 0.5-7.1

Siegel et al, CGH 2009;7:874. *not reported in 2

36,891 VA patients with UC with a median follow up of 6.7 years and a median age of 60 years at inclusion

4 734 i i hi i

Risk of Lymphoma Returns to Normal After Risk of Lymphoma Returns to Normal After Stopping ThiopurinesStopping Thiopurines

Thiopurine Use Incidence Rate4,734 patients using thiopurines; median duration of exposure: 0.97 years

142 confirmed lymphoma cases

Thiopurine Use Incidence Rate (per 1,000 person-years)

Unexposed 0.6

During 2.3

After stopping 0.3

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Khan N, et al. Presented at DDW; May 20, 2013. Abstract 641. VA, Veterans Affairs


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Maria T. Abreu, MD

Risk of Developing NH LymphomaRisk of Developing NH LymphomaPatient receiving anti-TNF + Immunomodulator Therapy for 1 year

Siegel et al, CGH 2009;7:874.


Risk without medication



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Maria T. Abreu, MD


Risk without medicationRisk with IM monotherapy



Risk without medicationRisk with IM monotherapyRisk with combination therapy



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Maria T. Abreu, MD

1,979 patients, more than 80% on concomitant immunomodulatorsLymphoma rate of pediatric IBD patients exposed to anti-TNF agents: 2.3/10,000

f f ll

Serious Infection and Lymphoma Risk With AntiSerious Infection and Lymphoma Risk With Anti--TNF TNF Therapy for Pediatric IBD: Systematic ReviewTherapy for Pediatric IBD: Systematic Review

patient-years of follow-upBaseline incidence

(per 10,000 PY)SIR for anti-TNF, P value,

(95% CI)Lymphoma (general pediatric population) 0.58 3.88, P=0.15, (0.38-21.7)

Immunomodulators (pediatric use) 4.5 0.52, P=0.54, (0.04-7.1)Pediatric Anti-TNF

(per 10,000 PY)Adults Anti-TNF (per 10,000 PY)

Serious infection 332 654

Conclusion:Risk of serious infection, lymphoma, and death with anti-TNF in pediatric IBD is very low, and much lower than in adults

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Serious infection 332 654Lymphoma 2.3 6.1Death 5.8 21

Dulai PS, et al. Presented at DDW; May 20, 2013. Abstract 640.

4,343 patients enrolled; 2,586 were exposed to anti-TNF biologics, 2,503 received IFX and 1,757 received non-biologic therapies

Serious Infection in Children Receiving IBD Therapies: Serious Infection in Children Receiving IBD Therapies: A Multicenter, Prospective, Pediatric (The DEVELOP) A Multicenter, Prospective, Pediatric (The DEVELOP) Registry Registry

Identified patients (mean age= 13) within 90 days of anti-TNF exposure whoexperienced a serious infectionAbsolute rate of serious infections per 100 patient-years of follow-up

Anti-TNF exposed = 5.82 versus 2.89 for anti-TNF unexposed (P<0.05)Anti-TNF monotherapy = 3.51 versus 8.09 for anti-TNF + IM combination therapy

Factors associated with a higher risk of time to first serious infection include:Prior hospitalization within 1 year, age, infliximab use, immunomodulator use, higher physician global assessment

Conclusion:Pediatric patients receiving anti-TNF therapy have an increased risk of superficial infections, abdominal abscesses, and viral infections

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Baldassano R, et al. Presented at DDW May 2013. Abstract Sa41.


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Maria T. Abreu, MD

Malignancy event rates from DEVELOP were compared with the expected event rates using the SEER database; adjusted for age, gender, and race

ll d

Malignancies in Children Receiving IBD Therapies:Malignancies in Children Receiving IBD Therapies:A Multicenter, Prospective, Pediatric (The DEVELOP) A Multicenter, Prospective, Pediatric (The DEVELOP) Registry Registry

4,343 patients enrolled2,586 exposed to anti-TNFs (2,503 to IFX); 1,757 received non-biologic therapies

No malignancies in patients without prior immunomodulator exposure

Infliximab + immunomodulator (N=2)

Infliximab Adalimumab + Immunomodulator (N=2)

Immunomodulator only (N=3)

Basal cell carcinomaMelanoma

Acute monocytic leukemiaParotid gland adenocarcinoma

Haematophagic histiocytosisHodgkin’s disease

Malignant lymphohistiocytosisMedication use Observed Rate of Malignancies Standardized Incidence

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Medication use Observed Rate of Malignancies(per 10,000 patients)

Standardized Incidence Ratio (95% CI)

Anti-TNF + immunomodulator combination 10.7 5.73 (1.56-14.70)

Immunomodulator monotherapy 12.4 7.12 (1.47-20.80)

Anti-TNF monotherapy 0 0 (0-21.40)

Neither Anti-TNF nor immunomodulator 0 0 (0-17.90)

Colletti RB, et al. Presented at DDW; May 20, 2013. Abstract 833.

It is a subgroup of patients at It is a subgroup of patients at higher risk for infections and higher risk for infections and

lymphomaslymphomasOlderOlder•• OlderOlder

•• Average age = 63 (systematic Average age = 63 (systematic review); 67 (Mayo)review); 67 (Mayo)

•• Multiple coMultiple co--morbiditiesmorbidities

•• Concomitant steroids and/or narcoticsConcomitant steroids and/or narcotics

•• LongLong--standing disease standing disease

Siegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006; Toruner, Gastro 2008

Young “healthy” patients are not in the clear, but probably much less at risk


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Maria T. Abreu, MD

Retrospective cohort study of 292 patients, 146 patients ≥ 65 years

Age ≥ 65 Is A Predictor of Infectious Complications Age ≥ 65 Is A Predictor of Infectious Complications in IBD Patientsin IBD Patients

Incidence Rate

Conclusions:

Ratio 95% CI

Elderly IBD patients 1.58 1.14-2.18

Elderly IBD patients on corticosteroids 3.15 1.55-6.41

Elderly IBD patients on corticosteroids and immunomodulator therapy

10.58 1.27-87.91

Elderly IBD patients on corticosteroids and anti-TNF therapy 10.64 1.95-58.10

Conclusions:Increasing age is associated with an increased risk for infection in IBD patients on corticosteroids, immunomodulators, and anti-TNF therapiesCorticosteroids had the highest incidence rate ratio for infection as compared to all other therapiesInfectious risk is increased when corticosteroids are added to an immunomodulator or to an anti-TNF

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Tofani C, et al. Presented at DDW; May 20, 2013. Abstract 642.

IBD, TNFIBD, TNF--αα Antagonists and Antagonists and Hepatosplenic THepatosplenic T--Cell Lymphoma Cell Lymphoma

(HSTCL)(HSTCL)•• Kotlyar et al (DDW Abstract S1133)Kotlyar et al (DDW Abstract S1133)•• Kotlyar et al (DDW Abstract S1133)Kotlyar et al (DDW Abstract S1133)

•• 24 cases of HSTCL in patients with IBD24 cases of HSTCL in patients with IBD

•• Nearly all maleNearly all male

•• Nearly all deadNearly all dead

•• Nearly all <40 years oldNearly all <40 years old

•• 90% had90% had ≥≥3 years of AZA/63 years of AZA/6--MPMP90% had 90% had ≥≥3 years of AZA/63 years of AZA/6 MPMP

•• 75% exposed to TNF75% exposed to TNF--αα antagonistsantagonists

•• HSTCL not reported in other autoimmune HSTCL not reported in other autoimmune populations treated with TNFpopulations treated with TNF--ααantagonists and purine analogsantagonists and purine analogs


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Maria T. Abreu, MD

Aims: identify genetic and clinical factors associated with Cl idi diffi il (C diff) i C

Female Gender and Pancolitis Are Associated With Female Gender and Pancolitis Are Associated With an Increased Risk of an Increased Risk of Clostridium difficile Clostridium difficile in UCin UC

Clostridium difficile (C. diff) in UC

Methods: single-center registry, 2005-2012

Results: 319 UC patients, 29 of which had C. diff8 known IBD genetic loci are associated with C. diffMultivariate analysis revealed 4 clinical variables associated with C. diff:

Female gender (OR 3 07 95% CI 1 26 – 7 52)Female gender (OR 3.07, 95% CI 1.26 – 7.52)Pancolitis (OR 2.52, 95% CI 1.03 – 6.17) Age >55 years (OR 0.21, 95% CI 0.05 – 0.90) Anti-TNF use (OR 0.29, 95% CI 0.12 – 0.76)

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Ananthakrishnan AN, et al. Presented at DDW; May 20, 2013, Abstract 835.

Single center study: 173 patients experienced 200 thromboembolic events over an 11-year periodDVT 48%; PE 12%; thrombophlebitis 12%; mesenteric venous thrombosis 4%; coronary ischemia

Thromboembolic Risk in Hospitalized IBD PatientsThromboembolic Risk in Hospitalized IBD Patients

DVT 48%; PE 12%; thrombophlebitis 12%; mesenteric venous thrombosis 4%; coronary ischemia 6%; stroke/TIA 5%

Risk Factor Proportion of patients

Surgery (IBD related / unrelated) 30% / 6%

Malignancy (past or current) 17%

Estrogen use 9%

Personal / family history of TE 20% / 25%

Smoking 11%

IdentifiedProthrombotic State

Number of patients,total tested = 44 (%)

Antiphospholipid Ab 3 (7)

Factor VIII mutation 3 (7)

Hyperhomocysteinemia 3 (7)

Lupus anticoagulant 9 (20)

Protein S deficiency 2 (5)

Prophylaxis was documented in only 40% of inpatients prior to the diagnosis of the thromboembolic event

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Smoking 11%

Prothrombotic state 12% (20 of 44 patients tested)

Protein S deficiency 2 (5)

Total 20 (45)

Levy A, et al. Presented at DDW; May 20, 2013. Abstract Mo1242.


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Maria T. Abreu, MD

Retrospective single center cohort study 229 patients discharged following hospitalization for severe UC

30 day readmission 11 7%

Extensive Colitis Predicts Early Hospital Readmission in Extensive Colitis Predicts Early Hospital Readmission in Patients With Severe Ulcerative ColitisPatients With Severe Ulcerative Colitis

30-day readmission 11.7%90-day readmission 20.5%

47% of early readmissions were for urgent colectomyPredictors of 30-Day Readmission

Odds Ratio (OR (95% CI)

Predictors of 90-Day Readmission

OR (95% CI) P value

Extensive colitis 3.59 (1.41-9.13) Extensive colitis 2.43 (1.21-4.89) 0.01

Albumin on first admission 0.63 (0.38-1.00) 0.07

Being admitted to a 2 12 (1 09-4 11) 0 03

Rate of 90-day readmission by discharge medications:Steroids only > cyclosporine or biologic monotherapy > combination cyclosporine or biologic plus immunomodulator

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Being admitted to a housestaff service

2.12 (1.09-4.11) 0.03

Tinsley A, et al. Presented at DDW; May 20, 2013. Abstract Mo1370.

Meta-analysis” using MOOSE (Meta-analysis of Observational Studies in Epidemiology) criteria

Endoscopic Surveillance After Resection of Polypoid Endoscopic Surveillance After Resection of Polypoid Dysplasia in Ulcerative Colitis Is Safe and EffectiveDysplasia in Ulcerative Colitis Is Safe and Effective

10 constituent published studies looking at nonsurgical management after resection of dysplastic polyps in ulcerative colitis

Pooled Case series and not randomized trials

Pooled resultsRate of CRC is 6.7 (3.5-12.9) per 1000 patient yearsRate of CRC or high grade dysplasia is 9 0 (5 1-15 8) per 1000 patient yearsRate of CRC or high grade dysplasia is 9.0 (5.1 15.8) per 1000 patient yearsRate of any dysplasia is 60 (48-71) per 1000 patient years

Patients may continue with every 6 month surveillance provided that polyp(s) are completely resected

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Wanders L, et al. Presented at DDW; May 21, 2013. Abstract Tu981.


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Maria T. Abreu, MD

Skin issues related to IBDSkin issues related to IBDSkin issues related to IBD Skin issues related to IBD treatmenttreatment

New psoriasis after antiNew psoriasis after anti--TNF TNF therapytherapy

•• Hundreds of casesHundreds of casesHundreds of casesHundreds of cases

•• Appears in 50% within 6 months, but can occur Appears in 50% within 6 months, but can occur up to several years after antiup to several years after anti--TNF useTNF use

•• Adalimumab (5X) > etanercept (4X) > infliximab Adalimumab (5X) > etanercept (4X) > infliximab (3X) increased risk(3X) increased risk

•• Usually new onset but can worsen existing Usually new onset but can worsen existing i ii ipsoriasispsoriasis

•• Palmoplantar pustulosis (32%)Palmoplantar pustulosis (32%)

•• Can be severe scalp involvement or genitalCan be severe scalp involvement or genitalRoux, CH et al. J Rheumatol. 2007 Feb;34(2):434-7.

Ko JM, et al. J Dermatolog Treat. 2008 Oct 16:1-8.


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Maria T. Abreu, MD

Palmoplantar psoriasisPalmoplantar psoriasis

Palmoplantar psoriasisPalmoplantar psoriasis


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Maria T. Abreu, MD

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

AntiAnti--TNF AntibodyTNF Antibody--Induced Psoriasiform Skin Induced Psoriasiform Skin Lesions Respond to UstekinumabLesions Respond to Ustekinumab

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

Conclusions:Conclusions:Anti-TNF antibody-induced psoriasiform skin lesions are not uncommonSmoking and increased BMI are predictorsUstekinumab can be used to successfully treat severe casesDose effect in development of psoriasiform lesions were not analyzed, and no dose or frequency reduction was attemptedGenetic factors predict severe cases – IL23R and IL12B variants

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Tillack C, et al. Presented at DDW; May 20, 2013. Abstract 639.

Systematic review and meta-analysis: 12 studies (9 population based, 2 large administrative databases, 1 hospital-based)

172 837 patients with IBD – 92 208 with CD and 79 360 with UC

IBD Is Associated With an Increased Risk of IBD Is Associated With an Increased Risk of Melanoma Independent of Biologic UseMelanoma Independent of Biologic Use

172,837 patients with IBD – 92,208 with CD and 79,360 with UC118 cases of melanoma from 1940-2009

Sub-groups CategoriesNo. of studies

RR 95% CI

Type of IBDCrohn’s Disease 7 1.51 1.14-1.98

Ulcerative Colitis 7 1.23 1.01-1.50

Biologic era(1998 onwards)

Pre-biologic 8 1.52 1.02-2.25Biologic era 2 1.08 0.59-1.96

Crude incidence rate of melanoma 27.5 / 100,000 person-yearsRelative risk (RR) of melanoma in IBD: 1.43 (95% CI 1.08 – 1.88)

No increased risk with thiopurines (RR 1.10, 95% CI 0.71-1.36) or biologics (RR 1.08, 95% CI 0.59-1.96)

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(1998 onwards)Across both eras 2 1.56 0.86-2.84

Singh S, et al. Presented at DDW; May 20, 2013. Abstract Mo1252.


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Maria T. Abreu, MD

Patient Population Patient Population for Model Developmentfor Model Development

•• 796 well796 well--characterized pediatric CD patientscharacterized pediatric CD patients796 well796 well characterized pediatric CD patients characterized pediatric CD patients

•• Enrolled from 21 centers from North AmericaEnrolled from 21 centers from North America

•• Demographic, clinical, genetic, and immune Demographic, clinical, genetic, and immune response data were response data were prospectivelyprospectively collected collected

•• Treatment data collectedTreatment data collected•• Steroids, immunomodulators (IMs), antiSteroids, immunomodulators (IMs), anti––tumor necrosis tumor necrosis

factor (antifactor (anti TNF) agentsTNF) agentsfactor (antifactor (anti--TNF) agentsTNF) agents

•• Timing in relationship to a disease complicationTiming in relationship to a disease complication

•• Model concordance index (HarrellModel concordance index (Harrell’’s C = 0.81)s C = 0.81)

Siegel CA et al. Inflamm Bowel Dis. 2011;17:30.

16-year-old girl, small bowel and perianal disease, QSS group = 4

Control Panel and OutputControl Panel and Output

Risk of Complication100100

75

50

Notreatment

25

00 1 2 3

Year From Present

EarlyIM treatment

Siegel CA et al. Inflamm Bowel Dis. 2011;17:30.


22

Maria T. Abreu, MD

52 l /115 ti t

Maintaining Remission on Antimetabolites Maintaining Remission on Antimetabolites After Stopping Infliximab in CrohnAfter Stopping Infliximab in Crohn’’s s

Disease: A Prospective Cohort StudyDisease: A Prospective Cohort Study

STORI

Kaplan-Meier Curve of Relapse

• n=52 relapses/115 patients• Median follow-up 28+/- 2 months

• Median time to relapse: 16.4 months

Louis E, et al. Gastroenterology. 2012 Jan;142(1):63-70

Predictive Model for TimePredictive Model for Time--toto--RelapseRelapseKaplan Meier timeKaplan Meier time--toto--relapse curves according to multivariate models and scores relapse curves according to multivariate models and scores

generated through Cox model using multiple imputations methodgenerated through Cox model using multiple imputations method

0 8

1.0No. of deleterious factors

<4

0.0

0.4

0.6

0.2

0.8

0 6 12 18 24 30

Pro

po

rtio

nw

ith

ou

t re

lap

se

4

5–6

>6

Months since infliximab withdrawal

Deleterious factors were: • No previous surgery• Steroid use within 12-6 months before

infliximab withdrawal• Male gender• Haemoglobin ≤14.5 g/dl

• leukocyte count >6 109/l • hsCRP ≥5 mg/l• faecal calprotectin ≥300 µg/g• CDEIS >0• infliximab trough ≥2 mg/l

Louis E, et al. Gastroenterology. 2012 Jan;142(1):63-70


23

Maria T. Abreu, MD

What should doctors do to minimize What should doctors do to minimize riskrisk

•• Routine laboratory monitoringRoutine laboratory monitoring

•• Age and risk: olderAge and risk: older men and younger menmen and younger men andandAge and risk: older Age and risk: older men and younger men men and younger men and and thiopurinesthiopurines

•• Vaccinate patients:Vaccinate patients:•• Seasonal fluSeasonal flu

•• HPV (young women)HPV (young women)

•• Pneumococcal vaccinePneumococcal vaccine

•• Avoid live vaccines if already onAvoid live vaccines if already on•• Avoid live vaccines if already on Avoid live vaccines if already on immunomodulatorsimmunomodulators::

•• VaricellaVaricella

•• MMRMMR

•• Skin exams yearlySkin exams yearly

•• Develop a simple checklistDevelop a simple checklist


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