1. Rochester, Minnesota, USA
Understanding Contraindications to the Use of Immunomodulators and Biologics for Inflammatory Bowel Disease
Edward V. Loftus, Jr., M.D.
Professor of Medicine
Mayo Clinic
Rochester, Minnesota, USA

2. Loftus Disclosures (last 12 months)
Research support
AbbVie
UCB
Bristol-Myers Squibb
Shire
Genentech
Janssen
Amgen
Pfizer
Takeda
GlaxoSmithKline
Robarts Clinical Trials
Consultant
AbbVie
UCB
Janssen
Takeda
Immune Pharmaceuticals
MedImmune
Celgene
Progentec Biosciences
Theradiag

3. Overview of Contraindications
Thiopurines
Methotrexate
Calcineurin inhibitors (tacrolimus, cyclosporine)
Anti-TNF agents
Infliximab
Adalimumab
Certolizumab pegol
Golimumab
Anti-integrins
Natalizumab
Vedolizumab

4. Contraindications to Thiopurines (Azathioprine, Mercaptopurine)
Known hypersensitivity to drug
Examples: fever, pancreatitis, influenza-like symptoms
Not necessarily nausea/vomiting: half of IBD patients with nausea on AZA will tolerate 6MP
Homozygous deficiency to TPMT (1 in 300)
TPMT testing is recommended in prescribing information of Purinethol®
Active untreated infection
Young male who has negative EBV serology?
Higher risk of hemophagocytic syndrome if primary EBV infection occurs while on thiopurine?

5. Possible/Relative Contraindications to Thiopurines
Concurrent use of allopurinol (unless dose of thiopurine is reduced to 25% of normal weight-based dose and CBC is monitored CLOSELY)
Other possible drug-drug interactions
Trimethoprim-sulfamethoxazole
Angiotensin converting enzyme inhibitors
5-ASA’s cause partial inhibition of TPMT

6. Contraindications to Methotrexate
Known hypersensitivity to MTX or an ingredient in the formulation
Pregnancy
Can result in fetal death, embryotoxicity, abortion or teratogenicity
Childbearing women, unless they understand the serious risk to the fetus should they become pregnant
Breastfeeding
Alcoholism, alcoholic liver disease, other chronic liver disease

7. Relative Contraindications to MTX
Drug-drug interactions
Concurrent NSAIDs may potentiate bone marrow suppression, aplastic anemia, gastrointestinal toxicity
Use with caution if there is already a hematologic abnormality, MTX may cause bone marrow depression in all cell lines
Chronic hepatitis B or C infection
Active infection

8. Contraindications to Anti-TNF Therapies
Previous severe hypersensitivity reaction to the drug
Doses >5mg/kg infliximab in moderate to severe heart failure
Active serious infections including invasive fungal infections (histoplasmosis, coccidioidomycosis, aspergillosis, blastomycosis, and pneumocystosis)
Recent serious histoplasmosis, consider 3 months prophylaxis itraconazole
Hepatitis B virus infection
Chronic or recurrent infection

9. Contraindications to Anti-TNF (cont)
Latent TB—start treatment for TB before starting anti-TNF
Duration of anti-TB treatment before anti-TNF start is unclear
Personal history of multiple sclerosis, optic neuritis, or other demyelinating disease
Concurrent use of anakinra or abatacept
“Consider the risks and benefits of TNF-blocker treatment prior to initiating therapy in patients with known malignancy other than a successfully treated non-melanoma skin cancer”

10. Who Is Most at Risk for Dying From Sepsis Related to Anti-TNF?
Older
Average age = 63 years (systematic review); 67 years (Mayo first 500 on IFX)
Multiple co-morbidities
Concomitant medications (steroids, narcotics)
Long-standing disease
Young “healthy” patients are not in the clear, but probably less at risk
Siegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006

11. Infections and Mortality in the TREAT Registry: 15,000 Patient-Years of Experience
Serious infections
Steroids
AZA 6-MP MTX
Steroids
AZA 6-MP MTX
IFX
IFX
P<.001
P=.006
P=.002
AZA = azathioprine; IFX = infliximab; MTX = methotrexate.
Lichtenstein GR et al. Am J Gastroenterol. 2012;107:

12. Meta-Analysis of Safety of Anti-TNF Agents in CD: Placebo-Controlled Trials
21 studies, N=5356
Mortality: no difference
Malignancy: no difference
Serious infection: no difference
Peyrin-Biroulet L et al. Clin Gastroenterol Hepatol. 2008;6:

13. Hospitalization, Follow-up, Abscess Size, and Recurrence
Medical Management
n = 55
Surgical
Management
n = 40
p-value
Median length of hospitalization, days (range)
5 (0-36)
16 (2-169)
< 0.001
Median length of follow-up after abscess resolution, months (range)
45 (6-130)
43 (6-120)
0.72
Abscess size, maximum diameter (cm)
6.9 ± 3.2
7.4 ± 3.7
0.59
Abscess recurrence during follow-up
a) Total
b) Within 3 months of resolution
c) After 3 months of resolution
17 (31%) 14 3
8 (20%) 5
0.25
Nguyen DL et al, Clin Gastroenterol Hepatol 2012;10:400-4

14. Medical Therapy and Abscess Recurrence
Pharmacologic Therapy* at Abscess Resolution
(n=95)
Recurrence
(n=25)
Hazard Ratio for Abscess Reoccurrence (95% CI)
p-value
No therapy
(n=13) 13
1.00 (reference)
Overall
< 0.01
Immunomodulator monotherapy
(n=44) 10
0.42 ( )
0.059
Any anti-TNF therapy (n=38) 2
0.10 ( )
0.001
*Therapy assessed as a time dependent covariate for association with abscess recurrence.
Nguyen DL et al, Clin Gastroenterol Hepatol 2012;10:400-4

15. Medical Therapy and Abscess Recurrence on Anti-TNF Therapy
Pharmacologic Therapy* at Abscess Resolution
(n=38)
Recurrence
Hazard Ratio for Abscess Reoccurrence (95% CI)
p-value
Anti-TNF monotherapy
(n=18) 2
0.32 ( )
0.14
Combination therapy
(n=20)
0.00
< 0.001
*Therapy assessed as a time dependent covariate for association with abscess recurrence.
Nguyen DL et al, Clin Gastroenterol Hepatol 2012;10:400-4

16. Other Neurologic Side Effects Reported with Anti-TNF Therapy
Guillain-Barre syndrome
Peripheral neuropathy
Aseptic meningoencephalitis
Leukoencephalopathy
Transverse myelitis
Chronic inflammatory demyelinating polyneuropathy
Progressive multifocal leukoencephalopathy
Posterior reversible encephalopathy syndrome
Singh S et al, Inflamm Bowel Dis 2013; 19:

17. Congestive Heart Failure and Anti-TNF Therapy
Etanercept trials to treat CHF were negative
Infliximab trial of CHF: highest mortality rate in IFX 10 mg/kg arm
Adalimumab: event rate of CHF <0.26 per 1000 p-y
Use with caution in patients with CHF or reduced LVEF
IFX contraindicated at doses >5mg/kg in NYHA Class III/IV
Consider ECHO ± Cards consult in those with suspected CHF
Mann DL et al, Circulation 2004; Chung ES et al, Circulation 2003; Schiff MH et al, EULAR 2005; Kent JD et al, ACR 2005.

18. Hepatotoxicity with Anti-TNF
Most commonly described with infliximab but has been describe with all
PI contains warning
Hepatocellular > cholestatic injury, often with autoimmune characteristics
Slowly improves after drug cessation
Rare cases of hepatic failure/liver transplant
Ghabril M et al, Clin Gastroenterol Hepatol 2013;11:

19. Contraindications to Natalizumab Therapy
Known hypersensitivity to natalizumab
Known or suspected progressive multifocal leukoencephalopathy
Positive JC virus serology is relative contraindication
Concomitant immunosuppressants are not allowed, and steroids need to tapered within 6 months

20. Natalizumab and PML Risk Based on anti-JC Virus Antibody Status
Anti-JCV Antibody Status
Negative
< 0.11/1000
Positive (and prior IS use)
0-2 years
2/1000 (1 in 500)
2+ years
11/1000
(≈1 in 100)
To ORDER anti-JC Virus antibody test:
Quest Labs test # 90257, JC Virus Antibody with Reflex Inhibition Assay
About 50% of Crohn’s patients will be positive
Bloomgren, et al. NEJM 2012;

21. Natalizumab: Adverse Events Beyond PML
Headache
Infusion reactions, generally mild
Hepatotoxicity
Rare but severe cholestatic liver injury reported

22. Contraindications to Vedolizumab
Known hypersensitivity to vedolizumab
Active severe infections (until controlled)
History of recurring severe infections
Consider screening for TB
Warning about PML in prescribing info, but no cases of PML observed
Discontinue drug in face of rising transaminases and bilirubin

23. Conclusions
A wide variety of side effects can occur with our commonly used medications for IBD
Many of the contraindications relate to infectious risks
Screen for latent TB and chronic viral hepatitis in all patients starting a biologic