IBD: Adverse Events of Medical Therapyd2j7fjepcxuj0a.cloudfront.net/wp-content/uploads/2015/01/15ACG...Title: Microsoft PowerPoint - 9-Regueiro-IBD Adverse Events of Med Rx.ppt [Compatibility

Miguel D. Regueiro, MD, FACG

IBD: Adverse Events of Medical ThTherapy

Mi l R i M D

1

Miguel Regueiro, M.D.

Professor of Medicine

Associate Chief, Education

Clinical Head and Co-Director, IBD Ctr

University of Pittsburgh Medical Ctr

I’m going to focus my talk, a bit….

…..on a challenging topic that we f i tiface in our practices……

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

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Continuing or Discontinuing Immunosuppression in the PatientImmunosuppression in the Patient

with Infection or Malignancy?

Mi l R i M D

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Miguel Regueiro, M.D.

Professor of Medicine

Associate Chief, Education

Clinical Head and Co-Director, IBD Ctr

University of Pittsburgh Medical Ctr

I will give you my opinion on what to do with IMMs/antiTNFs when an AE occurs

we need to individualize this decision based on severity of IBD and AEy

I look forward to further discussion and your opinion.

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

EventFrequency Estimate

Stop therapy due to AE 11%

Allergic reactions 2%

Nausea 2%

Hepatitis 2%

Pancreatitis 3%

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

Serious infections 5%

non-Hodgkin’s lymphoma 0.04%-0.09% (4-9/10,000)

Adverse Events Associated with anti-TNF Treatment

Event Estimated Frequency

Stop therapy due to adverse event 10%

Infusion or injection site reactions 3%-20%

Drug related lupus-like reaction 1%

Serious infections 3%

Skin ? 1-20%

Siegel CA.. The inflammatory bowel disease yearbook, volume 6. 2009; Infliximab package insert; Vermeire, Gastro 2003; Cush, Ann Rheum Dis 2005; Lenercept study group, Neurology 1999; ATTACH trial 2003

Tuberculosis 0.05% (5/10,000)

Non-Hodgkin’s lymphoma (combo) 0.06% (6/10,000)

Multiple sclerosis, heart failure, serious liver injury

Case reports only


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Continue or Stop Rxent?Focus on two adverse event

categories – cases from my clinic

• Infections

• Malignancy

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Infections - Continue or Stop?

• 33 yo CD IFX/AZA recently relocated from Louisville to Pittsburgh.from Louisville to Pittsburgh.

• For the past month he had cough, myalgias, weight loss, and low grade fevers.

• PPD/Quantiferon negative, but CXR shows……..

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4


CXR – Reticulonodular infiltrate

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Bronchoscopy – what is the dx?

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5


Histoplasmosis

• Urine antigen also positive for• Urine antigen also positive for Histoplasmosis

• Stop AZA/IFX and rx ketoconazole

• Would you restart IFX/AZA after infxn clears?c ea s

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Increased Risk of Opportunistic Infections (Mayo) – AZA/antiTNF

Medication Odds Ratio (95% CI) P value

Any Medication(5-ASA, AZA/6-MP,

steroids, MTX, infliximab)

3.5 (2 - 6.1) <0.0001*

5-ASA 1.0 (0.6 - 1.6) 0.94

Corticosteroids 3.4 (1.8 - 6.2) <0.0001*

6-MP/azathioprine 3.1 (1.7 - 5.5) 0.0001*

Methotrexate 4.0 (0.4 - 44.1) 0.26

Infliximab 4.4 (1.2 - 17.1) 0.03

Toruner M et al, Gastroenterology 2008; 134:929-36.


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Older Age Is Associated with Opportunistic Infections

• Age at IBD diagnosis:–Odds Ratio (per 5 years), 1.1 (1.1-1.2)

• Age at first Mayo visit:– 0 – 23 1.0 (reference)–24 – 36 1.2 (0.5 – 2.8)–37 – 49 1.1 (0.5 – 2.5)( )– ≥ 50 3.0 (1.2 – 7.2)

Toruner M et al, Gastroenterology 2008; 134:929-36..

Don’t forget about Corticosteroids when discussing Infections

4.0

4.5Mortality Serious infections

1.0

1.5

2.0

2.5

3.0

3.5

IFX

Od

ds

rati

o

AZA6-MPMTX

Steroids

* IFXAZA6-MPMTX

Steroids

**

Lichenstein GR et al, Gastroenterology 2006;130(Suppl 4):A-71.Lichtenstein GR et al, Clin Gastroenterol Hepatol 2006;4:621-30..

**P<0.00010.0

0.5

IFX = infliximab; AZA = azathioprine; MTX = methotrexateIFX = infliximab; AZA = azathioprine; MTX = methotrexate

*P=0.001


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The type of infections more prevelant with anti-TNFs (granulomatous)

• Bacterial•Tuberculosis•Atypical mycobacterial infection•Listeriosis

• Invasive Fungal•Histoplasmosis•CoccidioidomycosisC•Candidiasis

•Aspergillosis•Pneumocystosis

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Lee JH et al. Arthritis Rheum. 2002;46:2565-70Velayos FS et al. Inflamm Bowel Dis. 2004;10:657-60Bergstrom L et al. Arthritis Rheum. 2004;50:1959-66

Geographic Distribution of Histoplasmosis and Coccidioidomycosis in Older Americans, 1999-2008:

Medicare Sample

HisHistoplasmosis Coccidiodomycosisp Coccidiodomycosis

Baddley JW et al, Emerging Infect Dis 2011;17:1664-9.

Cases per 100,000 person-years


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Reminder on Tuberculosis Screening

• Average risk: tuberculin test

• Residents of endemic areas and/or those h i d BCGwho received BCG

–Interferon gamma release assay (QuantiFERON)

• Latent infection: INH for 6-9 months, can start anti-TNF after 3 weeks

• Active infection: do not start or reinitiateActive infection: do not start or reinitiate anti-TNF until a minimum of 2 months of anti-TB therapy

Case - Stop or Continue?

• 27 yo male with a h/o severe Crohn’s ds h i i i i f 4 6MPwho is in remission for 4 years on 6MP

1 mg/kg.

• Over the past year he has had recurrent “bumps” over his hands and arms.

• Not painful but aesthetically displeasing• Not painful, but aesthetically displeasing and affecting social life

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What is the diagnosis?

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Warts (likely papillomavirus)

• Despite treatment he continues to have• Despite treatment he continues to have problems with warts.

• The 6MP is lowered but it is not until 6MP is stopped that his warts resolve.

• Can 6MP be started again in the future?Ca 6 be s a ed aga e u u e

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Prospective Prospective studystudy (n=230)(n=230)

Thiopurines Increase the Incidence of Certain Viral Infections - Warts

NSNS

**2020

tio

n/p

atie

nt

tio

n/p

atie

nt--

year

year

2.02.0

1.51.5

1.01.0

**

NSNS

Pat

ien

ts (

%)

Pat

ien

ts (

%)

1818

1616

1414

1212

1010

88

66

Seksik P et al. Aliment Pharmacol Ther 2009;29:1106Seksik P et al. Aliment Pharmacol Ther 2009;29:1106--13.13.

Infe

ctIn

fect

0.50.5

00 AZA+AZA+n=169n=169

AZAAZA––n=61n=61

AZA+AZA+n=169n=169

AZAAZA––n=61n=61

Upper respiratory Upper respiratory tract infectionstract infections

Herpes virus flareHerpes virus flare--upsups

AZA+AZA+ AZAAZA–– AZA+AZA+ AZAAZA––

Warts at the entryin the study

Appearance of increased Appearance of increased number of wartsnumber of warts

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22

00

NS = not significantNS = not significant

Case - Continue or Stop?

• 58 yo in remission on IFX monotx for• 58 yo in remission on IFX monotx for 5yrs (first 1.5 yrs on 6MP as well).

• Due for IFX infusion in 3 weeks.

• 1 wk ago developed severe pain along back, “thought kidney stone”bac , oug d ey s o e

• 4 days ago developed “blisters” along back (very painful)

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Diagnosis? Give IFX in 3 weeks?

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Does Zoster mandate stopping?

• If pt due for antiTNF and active zoster, I wait for blisters to “dry/scab”

• In this case she received IFX on schedule as her lesions resolved

• Side Note: Shingles vaccine is live and contraindicated in immunosuppressed patientspatients

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Case - Continue or Stop?

• 41 yo UC in remission on Adalimumab• 41 yo UC in remission on Adalimumab 40mg qow and 6MP 50mg/d for 3 yrs

• 2 weeks ago worsening diarrhea – no bleeding, but “feels like flare”

• Colonoscopy shows……..Co o oscopy s o s

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What is your dx and would you change the ADA/6MP?

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Clostridium difficile Infection and IBDIncreasing percentage of C. diff Increasing percentage of C. diff

infections are IBD patientsinfections are IBD patients

Increasing number of Increasing number of hospitalizations in IBD hospitalizations in IBD

patients with patients with C. diffC. diff

Issa M, et al. Clin Gastroenterol Hepatol 2007; 5: 345-51.

•Classic risk factors disappearing•Pseudomembranes usually not present•Low threshold for checking in IBD patients with flares

•Should you stop immunosuppression? Conflicting data

antiTNFs and IMM infections

• antiTNF tend to be associated with• antiTNF tend to be associated with fungal, bacterial (granulomatous-forming) infection

• 6MP/AZA tend to be associated with viral infections

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Infections: Stop or Continue?What I do….

VIRALEBV, HSV, CMV, HIV, HepB,

BACTERIALStrep/StaphMycobact

FUNGALHistoplasmCoccidio

OtherC Diff

, p ,HepC,HPV

y

Thiopurine

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antiTNF





OtherC Diff

, p ,HepC,HPV

y

Thiopurine Stop if severe:

Individualize as to who to restart 6MP/AZA

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antiTNF


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OtherC Diff

, p ,HepC,HPV

y

Thiopurine StopMay need to stop+ Rx virus

Individualize as to who to restart

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to who to restart 6MP/AZA

antiTNF ContinueProb ok to continue, except active Hep B

Infections: Stop or Continue?VIRALEBV, HSV, CMV, HIV, HepB, HepC,HPV



OtherC Diff


Individualize as to who to restart 6MP/AZA

Stop + Rxthen individualize(if typical bact,eg strep, often can rx through)

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antiTNF Continue Prob ok to continue, except active Hep B

Stop + Rxthen individualize(if typical bact,eg strep, often can rx through)


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OtherC Diff

, p ,HepC,HPV

y



Stop + Rxthen individualize

Stop + Rx then Restart when cleared

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OtherC Diff

, p ,HepC,HPV

y





Probably continue

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Probably continue


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Malignancy

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Important questions in pts who develops cancer on IBD meds:

1. Did the medicine cause the cancer?

2. What is the risk of:

- continuing the med in terms of worsening cancer orworsening cancer or

- discontinuing the med in terms of worsening IBD?

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Let’s consider three types of cancer:

-Skin Cancer

-Lymphoma

- Solid Tumors

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Case

• 50 year old male

• 30 year history of small bowel Crohn’s30 year history of small bowel Crohn s

• 1 prior bowel resection

• Current meds – 6MP + Adalimumab

• 3 BM per day

• Colonoscopy – few scattered aphthousColonoscopy few scattered aphthous ulcers (i1) in the neo-TI


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Case (cont)

• 2 years prior diagnosed with Non Melanoma Skin Cancer (Basal Cell Ca)

• 2 weeks ago newly diagnosed with Squamous Cell Cancer

Do GI’s know Skin?

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Plantar Psoriasis

Nodular Pigmented BCC

Basal Cell Cancer

Squamous Cell Ca

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Is skin cancer caused by or are patients at increased risk from…

-azathioprine/6MP

-Methotrexate

-antiTNFs

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Thiopurines and Skin Cancer

NMSC MELANOMA

Long M. Gastroenterology 2012:143:390-9. Singh H Gastroenterology 2011:141:1612-20Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: 10.1038/ajg.2012.181

Timing of Thiopurines and NMSC (esp. older ages)

CESAME

R a

nd 9

5% C

I

Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8

SIR


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Anti-TNF and Skin Cancer (IBD data)

NMSC MELANOMA

NR

Long M. Gastroenterology 2012:143:390-9. Singh H Gastroenterology 2011:141:1612-20Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: 10.1038/ajg.2012.181

Clinical Questions

• Is skin cancer risk increased by therapy?therapy?– Thiopurines – yes

– Methotrexate – don’t know, probably not

– Biologics – no NMSC, maybe melanoma

• If so, does the risk of continuing therapy outweigh the benefits?– In this case – consider stopping thiopurine Uncertain if risk will decline

– Annual skin exam and regular use of sunscreen and hats


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Skin: Stop or Continue? What I do-Consult with Dermatology and then.….

NMSC – Basal Cell Squamous Cell Melanoma

ThiopurineThiopurine

antiTNF

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antiTNF



Thiopurine Continue or start:Active or Past, as long as Dermatology monitoringMTX prob ok

Stop:Only if significant recurrence or potential for disfiguring sequelae

antiTNF

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Thiopurine

antiTNF Continue or start:Active or Past, as long as Dermatology

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monitoring

Stop:NO, rarely necessary to stop


NMSC – Basal Cell Squamous Cell

Melanoma

Thiopurine Start:-eradicated/resected/no metseradicated/resected/no mets-melanoma free for > 1 yrStop/Restart: -Hold for new onset?-Maybe ok to continue -Restart if melanoma free-Stop for metastatic ds

antiTNF

50


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NMSC – Basal Cell Squamous Cell

Melanoma

Thiopurine

antiTNF Start:-eradicated/resected/no mets

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eradicated/resected/no mets-melanoma free for > 1 yrStop: -New Onset-?Restart if melanoma free > 1 yr-Do not restart <1yr or mets

Lymphoma

52


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Questions

Does immunosuppressant therapy pp pyincrease the risk of lymphoma?

Do the benefits outweigh the risks?

What do you do when a lymphoma develops in the setting of IBD meds?

AZA/6-MP are probably related to Lymphoma (Meta-analysis): SIR 4.06

AuthorAuthor ObservedObserved ExpectedExpected

ConnellConnell 00 0 520 52ConnellConnell 00 0.520.52

KinlenKinlen 22 0.240.24

FarrellFarrell 22 0.050.05

LewisLewis 11 0.640.64

FraserFraser 33 0 650 65FraserFraser 33 0.650.65

KorelitzKorelitz 33 0.610.61

TotalTotal 1111 2.712.71

SIR = 4.06, 95% CI 2.01 – 7.28Kandiel A et al. Gut. 2005:54:1121-25


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CESAME – 6MP/AZA OnlyLymphoma: HR 5.3

At cohort entry

N # Lymphomas

HR (95% CI)

N 10 810 6 R fNever exposed to thiopurines

10,810 6 Reference

On therapy with thiopurines

5,867 16 5.3 (2.0 – 13.9)

Previously discontinued thiopurines

2,809 2 1.0 (0.2 – 5.1)

Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7

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

13 Non Hodgkin’s lymphomas

Risk of NH Lymphoma with anti-TNF + IM treatment for Crohn’s Disease: A Meta-Analysis

6 1 per 10 000 pt ears• 13 Non-Hodgkin s lymphomas

• Mean age 52, 62% male

• 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

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


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

13 Non Hodgkin’s lymphomas

Risk of NH Lymphoma with anti-TNF + IM treatment for Crohn’s Disease: A Meta-Analysis

6 1 per 10 000 pt ears• 13 Non-Hodgkin s lymphomas

• Mean age 52, 62% male

• 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

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

Hepatosplenic T Cell Lymphoma

• 41 cases from FDA AERS among patients with IBD1

Thi i l 17– Thiopurine alone 17

– Anti-TNF alone 1

– Combination therapy 23

• Characteristics2

– Median age 22.5 (12 – 58)

– 93% male

– Median time since initiation of thiopurines ~6 years

1. Deepak P. Am J Gastroenterol 2013; 108:99–1052. Kotlyar D. Clin Gastroenterol Hepatol 2011;9:36–41


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CESAME – Combo 6MP/AZA and antiTNF: SIR = 10.2

Therapy Patients # Lymph SIR 95% CITherapy Patients # Lymph SIR 95% CI

Never thiopurineor TNF

22,706 6 1.5 0.5 – 3.2

Currentthiopurinewithout TNF

14,729 13 6.5 3.5 – 11.2

Current 1,929 2 10.2 1.2 – 36.9Current thiopurine + TNF

1,929 2 10.2 1.2 36.9

Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7

Clinical Questions

• Does immunosuppressant therapy i th i k f l h ?increase the risk of lymphoma?– Thiopurines – yes, but risk may revert after

discontinuation

– antiTNFs – Probably not

– Combination – Yes and probably more than thmonotherapy


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Risk:Benefit Ratio

61

Lymphoma - Number Needed to HarmMales Only 15-19 y.o. M

(per 105)20-24 y.o. M

(per 105)

Lymphoma other than HSTCL

A l i id NHL HD USA 5 2 7 0Annual incidence NHL + HD USA 5.2 7.0

Annual incidence NHL + HD with thiopurines (x4‡) 20.8 28.0

Annual mortality from lymphoma without thiopurines* 1.3 1.75

Annual mortality from lymphoma with thiopurines* 5.2 7.0

Excess deaths from thiopurine induced lymphoma 3.9 5.25

NNT to cause one death / year 25,641 19,074

‡ Kandiel A et al. Gut. 2005:54:1121-25* 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example

‡ Kandiel A et al. Gut. 2005:54:1121-25* 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example


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What to do if lymphoma develops while taking IMM/antiTNF?

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Case – Stop or Continue?

• 39 yo male CD in remission on 6MP/IFX• 39 yo male CD in remission on 6MP/IFX for 8 yrs.

• Now with weight loss, sweats, and low grade fevers

64


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Case – Stop or Continue?

• 39 yo male CD in remission on 6MP/IFX• 39 yo male CD in remission on 6MP/IFX for 8 yrs.

• Now with weight loss, sweats, and low grade fevers

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Crohn’s ds case: NHL while taking 6MP/IFX.

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After consulting with the oncologist….g

…we stopped the 6MP/antiTNF, but after 3 months of chemorx, the

antiTNF was resumed We didantiTNF was resumed. We did not restart the 6MP.

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On CT: Hepatosplenic T cell lymphoma –enlarged spleen, otherwise nonspecific.

Thiopurine must be stopped!

68


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Solid Tumors

69

Case Continue or Stop?

• 58 yo female with severe UC who has been on IFX/6MP (50mg/d) for past 1yrbeen on IFX/6MP (50mg/d) for past 1yr

• Just diagnosed with intraductal breast CA (T1N0MX)

• Strong FHx breast CA, pt opts for bilateral mastectomy y

• After consultation with oncology, the decision is to cont meds

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No clear association between thiopurines/antiTNFs and solid tumors

in IBD

Study Types of cancer

Number of patients

Statistically significant

Armstrong 2010 lung, breast 1955 NO

Fraser 2002breast,

bronchial, renal6262 NO

Connell 1994gastric, lung,

755 NOConnell 1994g , g,

breast, cervical755 NO

Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….

Hepatosplenic TCNo relation to EBV

After acute EBVInitially EBV -

PTLD-likeInitially EBV +

Thiopurine

antiTNF

72


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Thiopurine Young Males

Extremely rare (<.0001%)

Usually in combo with anti-TNFs

Not with MTX/antiTNF

Fatal

73

antiTNF





Thiopurine Young males

Hemophagocyticlymphohistiocytosis

Very rare (<.001%)

Should we check EBV prior to starting in our young males?

74

antiTNF


37






Thiopurine Older pts, long duration of 6MPduration of 6MP

Rare (<.01%)

Males > Females

antiTNF

75





ThiopurineStopStop

Never Restart

antiTNF

76


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ThiopurineStop lymphomaStop, lymphomamay regress

Never Restart

antiTNF

77





ThiopurineStop lymphomaStop, lymphoma may resolve

Never Restart

antiTNF

78


39






Thiopurine

antiTNFStop probably

79

Stop, probably never restart





Thiopurine

antiTNFStop but restart

80

Stop, but restart once lymphoma resolves


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Thiopurine

antiTNFContinue only stop

81

Continue, only stop if progression of lymphoma

Solid Tumor: Stop or Continue? Consult with Oncology and then.….

Solid Tumors, e.g. Breast, Lung, RenalProbably no relationship to IBD meds

Thiopurine -Continue if curative resection, no need to stop

antiTNF -Continue if curative resection, no need to stop

82


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Thiopurine-Stop if metastatic ds and/or chemotherapyStop if metastatic ds and/or chemotherapy

antiTNF-Stop if metastatic ds and/or chemotherapy

83

Stop if metastatic ds and/or chemotherapy



Thiopurine-Restart once chemo done and no active cancer (? > 1 yr)Restart once chemo done and no active cancer (? > 1 yr)

antiTNF-Restart once chemo done and no active cancer (? > 1 yr)

84

Restart once chemo done and no active cancer (? > 1 yr)


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Should we continue or stop IBDShould we continue or stop IBD meds if an infection or malignancy

develops?

Depends on the severity of IBD

85

What about the patient in Deep Remission?

If in deep remission, maybe t i IBD d i k d tstopping IBD meds is ok and not

restarting them

86


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Thank you!

87

Not in deep remission or disabling IBDSkin Cancer

• Basal or Squamous Cell• Resected/Controlled

CONTINUE ll d– CONTINUE all meds

• Not controlled and/or disfiguring

– STOP azathioprine/6MP

– CONTINUE anti-TNFs

• MelanomaR t d/E di t d 1• Resected/Eradicated > 1 year

– CONTINUE all meds

• Multiple Skin Sites/Rapid Recurrence/Mets

– STOP anti-TNFs

– CONTINUE – 6MP/AZA/MTX?88


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Not in deep remission or disabling IBDLymphoma

• Acute EBV and lymphoma: • STOP AZA/6MP

• CONTINUE anti-TNF, after lymphoma resolved (may not even need to stop?)

• Hepatosplenic T Cell lymphoma:• STOP AZA/6MP and anti-TNF

• PTLD-like lymphoma (likely EBV):• STOP AZA/6MP

• CONTINUE anti-TNF, after lymphoma resolved (may not even need to stop?)

89

Not in deep remission or disabling IBDSolid Tumors

6MP/AZA:

- CONTINUE 6MP/AZA/MTX

- Stop during chemo

Anti-TNFs- CONTINUE if tumor resected/eradicated

- STOP if metastatic ds or chemorx

- RESTART once cancer eradicated/chemorx stopped

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UPMC IBD Center: Physicians and Staff


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Documents

IBD: Adverse Events of Medical Therapyd2j7fjepcxuj0a.cloudfront.net/wp-content/uploads/2015/01/15ACG...Title: Microsoft PowerPoint - 9-Regueiro-IBD Adverse Events of Med Rx.ppt [Compatibility