miguel regueiro, m.d. professor of medicine associate chief, education

1

What adverse reactions to immunomodulators and biologics:

1) mandate discontinuation of therapy and

2) when can medications be continued?

Miguel Regueiro, M.D.

Professor of Medicine

Associate Chief, Education

Clinical Head and Co-Director, IBD Ctr

University of Pittsburgh Medical Ctr

Very little to no evidenced based data on this subject, so…

I called some friends for help.

2

Corey Siegel – after 1 minute of laughter, “I was asked to give this talk and turned

it down…good luck!”

3

David Rubin – “What are you kidding me?!?!”

4

Asher Kornbluth – “I’m sorry, I can’t

hear you.”

Ed Loftus – Clearly has gone over his own cliff…….

Jean Fred Colombel – yelled something in French about the color blue being

sacred, the rest I couldn’t understand.

7

So, with no help from my “friends”

8

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 AE.

I look forward to further discussion and opinion in the panel session.

9

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

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

EventFrequency Estimate

Stop therapy due to AE 11%

Allergic reactions 2%

Nausea 2%

Hepatitis 2%

Pancreatitis 3%

Serious infections 5%

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

Adverse Events Associated with anti-TNF Treatment

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

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%

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

Continue or Stop Rxent?Focus on three adverse event

categories – cases from my clinic

• Infections

• Malignancy

• Skin Complications

• Thank you Drs Siegel, Rubin, Loftus, Kornbluth, and Colombel for your slides

12

Infections - Continue or Stop?

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

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

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

13

CXR – Reticulonodular infiltrate

14

Bronchoscopy – what is the dx?

15

Histoplasmosis

• Urine antigen also positive for Histoplasmosis

• Stop AZA/IFX and rx ketoconazole

• Would you restart IFX/AZA after infxn clears?

16

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.

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..

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

• Bacterial•Tuberculosis•Atypical mycobacterial infection•Listeriosis

• Invasive Fungal•Histoplasmosis•Coccidioidomycosis•Candidiasis•Aspergillosis•Pneumocystosis

20

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

Case - Stop or Continue?

• 27 yo male with a h/o severe Crohn’s ds who 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 and affecting social life

23

What is the diagnosis?

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Warts (likely papillomavirus)

• 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?

25

Prospective study (n=230)Prospective study (n=230)

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

Thiopurines Increase the Incidence of Certain Viral Infections - Warts

Infe

ctio

n/p

atie

nt-

year

Infe

ctio

n/p

atie

nt-

year

2.02.0

1.51.5

1.01.0

0.50.5

00AZA+AZA+n=169n=169

AZA–AZA–n=61n=61

AZA+AZA+n=169n=169

AZA–AZA–n=61n=61

NSNS

**

Upper respiratory Upper respiratory tract infectionstract infections

Herpes virus flare-upsHerpes virus flare-ups

AZA+AZA+ AZA–AZA– AZA+AZA+ AZA–AZA–

Warts at the entryin the study

Appearance of increased Appearance of increased number of wartsnumber of warts

NSNS

**

Pat

ien

ts (

%)

Pat

ien

ts (

%)

2020

1818

1616

1414

1212

1010

88

66

44

22

00

NS = not significantNS = not significant

Case - Continue or Stop?

• 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”

• 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 patients

29

Case - Continue or Stop?

• 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……..

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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

Infections: Stop or Continue?What I do….Consult with ID..then..

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VIRALEBV, HSV, CMV, HIV, HepB, HepC,HPV

BACTERIALStrep/StaphMycobact

FUNGALHistoplasmCoccidio

OtherC Diff

Thiopurine

antiTNF

Infections: Stop or Continue?What I do….

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OtherC Diff

Thiopurine Stop if severe:

Individualize as to who to restart 6MP/AZA

antiTNF


36




OtherC Diff

Thiopurine StopMay need to stop + Rx virus


antiTNF Continue Prob ok to continue, except active Hep B

Infections: Stop or Continue?

37




OtherC Diff



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


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


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OtherC Diff



Stop + Rxthen individualize

Stop + Rx then Restart when cleared





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OtherC Diff





Probably continue




Probably continue

Malignancy

-Lymphoma

- Solid Tumors

40

Case – Stop or Continue?

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

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

41

Large periaortic LNs involving left renal cortex – diagnosis?

42

Non-Hodgkin’s Lymphoma

• What do you do now?

• Stop IFX and continue 6MP?

• Stop 6MP and continue IFX?

• Stop both?

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In contrast: Hepatosplenic T cell lymphoma – enlarged spleen, otherwise

nonspecific

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

AuthorAuthor ObservedObserved ExpectedExpected

ConnellConnell 00 0.520.52

KinlenKinlen 22 0.240.24

FarrellFarrell 22 0.050.05

LewisLewis 11 0.640.64

FraserFraser 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

CESAME – 6MP/AZA OnlyLymphoma: HR 5.3

At cohort entry

N # Lymphomas

HR (95% CI)

Never 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

• Mean age 52, 62% male

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

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

NHL rate per 10,000

SIR 95% CI

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

6.1 per 10,000 pt-years

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

Therapy Patients # Lymph SIR 95% CI

Never thiopurine or TNF

22,706 6 1.5 0.5 – 3.2

Current thiopurine without TNF

14,729 13 6.5 3.5 – 11.2

Current thiopurine + TNF

1,929 2 10.2 1.2 – 36.9

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

Case Continue or Stop?

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

• Just diagnosed with intraductal breast CA (T1N0MX)

• Strong FHx breast CA, pt opts for bilateral mastectomy

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

49

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,

breast, cervical755 NO

…..but DO seem associated with increased risk of skin cancers and lymphoma

Malignancy: Stop or Continue? What I doConsult with Oncology and then.….

51

LYMPHOMA HSTC Lymphoma SOLID TUMORS

Thiopurine

antiTNF


52


Thiopurine Continue or start:Previously Rx’d and inactive >1 yr

antiTNF Continue or start:Previously Rx’d and inactive >1 yr


53



Stop:New Lymphoma, esp EBV on 6MP


Stop:New Lymphoma?Restart


54




Must Stop:

-Has been a fatal lymphoma.

-Even if eradicated, avoid future 6MP




55




Must Stop:





Must Stop:-Has been a fatal lymphoma.

-Even if eradicated, avoid future antiTNF?


56




Must Stop:



Continue or start:

-Previously Rx’d

-even active (non-EBV) solid tumors ok to continue






57




Must Stop:



Continue or start:

-Previously Rx’d






Start: Previously Rx’d


58




Must Stop:



Continue or start:

-Previously Rx’d






Start: Previously Rx’d

Stop:Active cancer (but unless mets, ok to restart once rx’d?)

I think skin AEs are increasing and becoming

most problematic

Skin AEs secondary to Meds

- Malignancy

- Immune mediated

-Thank you, Jean Fred for your slides

60

Do GI’s know Skin?

61

62

Plantar Psoriasis

Nodular Pigmented BCC

Basal Cell Cancer

Squamous Cell Ca

Take home message:

Get Dermatology involved!

63

What’s the dx? Stop or Cont ADA?

• 67 yo m CD remission 3 yrs ADA – has 15 of these lesions removed over past 2 years

64

Stop or Continue – Basal Cell CA

• 67 yo m CD remission 3 yrs ADA – 15 basal cells removed over past 2 years

• He opts to continue ADA given good CD response.

• He follows closely with derm – for smaller lesions topical 5FU has been effective.

65

What is this? What do you do?

• 59 yo f CD sun exposure entire life – deep remission on 6MP for 15 years

• Last 2 yrs has had Moh’s surgery x 2 to remove these lesions from face – 3 from neck

66

Stop or Continue – Squamous Cell cancer

• The 6MP is stopped and in the next 2 years she has had 1 more SCC but her CD remains in remission

67

Yea

rly

inci

den

ce r

ate

(per

1,0

00

pat

ien

t-ye

ars)

32 incident NMSC: 20 BCC and 12 SCC

Continuing

Discontinued

Never received

<50 years

50-65 years

>65 yearsThiopurine therapy

Cases of NMSC (n)

Patient-years

039 336 233

15736792413590 496815302319 2383526743

6

3

4

5

1

2

0

High Rates of BCC and SCC in IBD pts exposed to thiopurines – active or previous exposure

Peyrin-Biroulet. Gastroenterology 2011

• Prospective observational registries and studies

• Patients with RA, PsA or ankylosing Spondylitis receiving TNFi therapy

Patients treated with TNFi have a significantly

increased risk ofdeveloping an NMSC

(1.45, 95% CI 1.15 to 1.76).

Mariette X. Ann Rheum Dis. 2011

Anti-TNFs also associated with Basal Cell and Squamous Cell Cancers

• Retrospective cohort (and nested case-control) study

• LifeLink claims database 108,518 IBD pts• Crohn’s (but not UC) associated with

increased risk of melanoma (IRR 1.45, 95% CI 1.13-1.85)

• Biologics increased risk of melanoma

Melanoma and anti-TNF therapy in IBD

Long M, et al. Gastroenterology 2012. Epub ahead of print.

OR 1.88 (95% CI 1.08-3.29)

What is your dx? How do you rx?• 27 yo female CD on ADA in remission

for 3 yrs but over past 6 mos develops progressive skin lesions over ears and scalp (with hair loss)

74

Anti-TNF psoriaform lesions – in my opinion the most common and

difficult antiTNF AE to manage

• She sees dermatology who tries topical treatment (steroids, dapsone) without benefit.

• They recommend adding MTX but she wants to have children soon

• She stops the ADA. Her skin improves and 1 yr later she is pregnant but is beginning to have CD sx’s.

75

What about this case? Fungal? Other?

• 25 yo male UC on IFX in remission but over past 6 mos has patchy skin lesions under the arms and gluteal cleft

76

“Inverse Psoriasis” from antiTNF• His skin improves with topical steroids/dapsone but

not completely

• After adding MTX 10mg per week the lesions resolve.

77

Psoriasis associated with Anti-TNF therapy

• Described with all the anti-TNF: class effect

• Described in patients receiving treatment for diverse indications (RA, IBD, psoriasis, psoriatic arthritis, ankylosing spondylitis)

• Often leads to therapy discontinuation

• First IBD case reported in 2004 in a CD patient treated with infliximab

Verea MM. Ann Pharmacther 2004; (1) G. Fiorino. APT 2009; (2) Cullen G. In press 2011

November 2008 (1) August 2011 (2)

Increasingly recognised side-effect of anti-TNF

therapy in the IBD literature

Psoriasis associated with Anti-TNF therapy

FDA WARNING

Psoriasis associated with Anti-TNF therapyWhat is the magnitude of the problem in IBD patients?

Cullen G. APT 2011

Psoriasis associated with Anti-TNF therapy in IBD: a new series and review of 120 cases from the Literature

Case reports (50) + current series(30) + GETAID Series (62)150 cases for analysis

Psoriasis details

Location: •Palmoplantar - 42%•Scalp - 42%•Trunk – 31%•Flexures – 31%•Facial – 16%

When you see this –think antiTNF mediated Psoriasis

• Several phenotypes:• Palmoplantar pustular psoriasis: form most commonly associated

with anti-TNF therapy (even in patients treated for plaque psoriasis)

JF Rahier.CGH 2010; Courtesy of Franck Delesalle

….or this……antiTNF Psoriasis

•Several phenotypes:• Inverse psoriasis (type of psoriasis in plaques)

In Psoriasis – Manson publishing; Courtesy of Franck Delesalle

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

87

NMSC – Basal Cell Squamous Cell

Melanoma PSORIASIAS-like(Immune mediated)

Thiopurine

antiTNF


88



Thiopurine Continue or start:Active or Past, as long as Dermatology monitoring

Stop:Only if significant recurrence or potential for disfiguring sequelae

antiTNF


89





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

Stop:Rarely necessary


90





Continue/start:-eradicated-melanoma free for > 1 yr-no mets

Stop: New Onset?




91






Stop: New Onset?




Stop: New Onset


92






Stop: New Onset?

Continue or start:

-any psoriasis, past or present

- MTX may be useful in rxing antiTNF-mediated skin ds




Stop: New Onset


93






Stop: New Onset?

Continue or start:

-any psoriasis, past or present

- MTX may be useful in rxing antiTNF-mediated skin ds




Stop: New Onset

Continue:Mild, <5% skin, responds to topical tx or MTX

Stop:>5%, nonresponsive to psoriasis tx

Summary: Stop or Continue Rx?• IMMs and biologics are associated with rare, but potentially

serious AEs

• Most AEs do not mandate IMM/antiTNF cessation – individualize the decision

• I would stop/hold IMM/antiTNF for:– Active opportunistic infections (rare)– Lymphoma/Cancer (very rare)– Recurrent skin cancers– Non-responsive psoriasis to antiTNF– Allergic/idiosyncratic drug rxns

• Once AE resolves, usually restart meds

94

UPMC IBD Center: Physicians and Staff

When you go out tonight, beware of:When you go out tonight, beware of:

97Bill Sandborn and Jean Fred Colombel

miguel regueiro, m.d. professor of medicine associate chief, education

Documents

drs siegel

corey siegel

adverse event10

adverse events

adverse reactions

infectionslichenstein

lichtenstein gr et

serious infections5