Other Major Side Effects to
Immunomodulators and/or
Biologics in Our IBD
Patients
Edward V. Loftus, Jr., M.D.
Professor of Medicine
Mayo Clinic
Rochester, Minnesota, USA
Loftus Disclosures
• Research/grant
support
–
–
–
–
–
–
–
–
–
–
–
AbbVie
UCB
Janssen
Takeda
Amgen
Genentech
Pfizer
GlaxoSmithKline
Bristol-Myers Squibb
Santarus
Robarts Clinical Trials
• Consulting
–
–
–
–
–
AbbVie
UCB
Janssen
Takeda
Immune
Pharmaceuticals
Overview
• Thiopurines
– Adverse events and drug interactions
– Liver disease
• Methotrexate
• Calcineurin inhibitors
• Anti-TNF
– Infusion/injection site reactions
– Arthralgias and drug-induced lupus
– Demyelination
– Cardiomyopathy
AZA/6MP Adverse Events in Crohn’s
RCTs: Cochrane Meta-Analysis
• AZA vs. Placebo
– Study withdrawal due to AE
– Serious AE
1.7 (0.9-3.1)
2.6 (0.9-7.1)
• AZA vs. 5-ASA
– Study withdrawal due to AE
– Serious AE
1.0 (0.4-2.5)
11.3 (0.6-205)
• AZA vs. IFX
– Study withdrawal due to AE
– Serious AE
1.5 (0.96-2.2)
1.1 (0.8-1.6)
Chande N et al, Cochrane Database Syst Rev 2013;(4):CD000545.
“Real World” Experiences With
AZA/6MP in 2002-4
Setting
Olmsted Co, MN
Canterbury, NZ
Oxford, UK
Groningen, NL
Nijmegen, NL
N
102
216
622
318
50
% Withdrawal
Due to AE
25%
26%
28%
23%
22%
Loftus CG et al, Am J Gastroenterology 2003 abstract
Gearry et al, Pharmacoepidemiol Drug Safety 2004;13:563-7
Fraser AG et al, Gut 2002;50:485-9
Weersma RK et al, Aliment Pharmacol Ther 2004;20:843-50
deJong DJ et al, Eur J Gastroenterol Hepatol 2004;16:207-12
Azathioprine/6-Mercaptopurine
Toxicity
•
•
•
•
•
Nausea
Allergic reactions
Pancreatitis
Bone marrow depression
Drug hepatitis
Blood Dyscrasias Are an Important
SAE for 5-ASA Agents--More Likely
with Sulfasalazine
Ransford RAJ. Gut 2002;51:536-539.
Fatalities after developing a blood
dyscrasia:
Sulfasalazine 5% (7/129)
Mesalamine 9% (5/51)
Drug Interactions with AZA/6-MP: 5-ASA
• AZA and 6-MP may interact with 5-ASAs,
potentially causing leukopenia
– 5-ASA reversibly inhibits TPMT
– Low levels of TPMT causes accumulation 6-TGN,
active metabolite
– Increased 6-TGN leads to a decrease in WBC
– Patients with low baseline levels of TPMT who are
taking a combination of AZA/6-MP and 5-ASAs
are at risk of clinically significant leukopenia
Lowry P et al, Gut 2001; 49: 656
Concurrent 5 ASA & Immunomodulator Use
May Increase Myelosuppression: 8-Week NonRandomized Parallel Group Study
Lowry PW, et al. Gut 2001;49:656-664.
Drug Interaction Between
Thiopurines and Anti-TNF?
• Infliximab may cause transient increase in
6TGN metabolites in first few weeks, with
transient leukopenia, which normalizes
• No effect of adalimumab on thiopurine
metabolites over 12 weeks in 12 patients
Roblin X et al, Aliment Pharmacol Ther 2003;18:917-25.
Wong DR et al, J Crohns Colitis 2013 Online early
Hepatotoxicity with AZA/6MP
• Common cause of drug-induced liver
injury (DILI)(>3x ULN)
– 3rd most common cause of DILI in Iceland
2010-11 (4% of all cases, tied with infliximab)
– Absolute risk of DILI was 1 in 133 with AZA
• Spanish nationwide database of AZA
safety (n=3,931)
– 4% developed hepatotoxicity (>2x ULN)
– Dose-related
Bjornsson ES et al, Gastroenterology 2013;144:1419-26.
6-MMP and Hepatotoxicity
p < 0.05
Median 6-MMP
(pmol/8x108 RBC)
6000
5463
4000
2213
2000
0
n=157
Absent
n=16
Present
HEPATOTOXICITY
Dubinsky MC et al, Gastroenterology 2002;122(4):904-15.
Allopurinol Therapy for Preferential
6-MMP Metabolism
Pre-allopurinol
Post-allopurinol
12000
450
400
350
300
250
200
150
100
50
0
10000
8000
6000
4000
2000
0
6-TG
6-MMP
Allopurinol 100 mg added; 6-MP/AZA dose reduced to 25% to 50% of baseline
Sparrow MP et al. Aliment Pharmacol Ther. 2005;22:441.
Allopurinol + AZA/6MP: Clinical Outcome
•20 6MP/AZA nonresponders with high
6MMP levels (12 CD, 6 UC, 2 IC)
•Mean AZA = 200 mg 6MP = 87 mg
Treatment
•Decrease AZA/6MP to 25-50%
original dose
•Allopurinol = 100 mg/day
Sparrow MP et al. Clin Gastroenterol Hepatol 2007;5:209-214
Allopurinol Plus AZA/6MP
• Might prevent non-hepatic adverse
events as well (nausea, myalgia,
fatigue): 88% success in one small
study
• Needs to be done with extreme
vigilance
– 100 mg allopurinol
– Dose reduce to 25% of original dose
– Weekly CBC for 4 weeks then monthly
– Periodic metabolites
Ansari A et al, Aliment Pharmacol Ther 2010;31:640-7.
Gearry RB et al, J Gastroenterol Hepatol 2010;25:649-56.
Long-Term AZA/6MP Hepatotoxicity
• Much less common but much more serious:
• Nodular regenerative hyperplasia: 1.2% at 10 years of AZA (but
there may be a baseline of NRH in thiopurine-naïve IBD
• Veno-occlusive disease of liver
• Male gender and
extensive SB
resection may be risk
factors
• Much higher incidence
of these events with
high-dose thioguanine
(>40 mg/day)
• Watch for
thrombocytopenia
Reticulin stain
DeBoer NK et al, Scand J Gastroenterol 2008;43:604-8
Seksik P et al, Inflamm Bowel Dis 2011;17:565-72.
Nausea Only with AZA: Switch to 6MP!
• If nausea with AZA is the rate-limiting side effect,
it’s worth trying 6-MP; many will tolerate
• Olmsted County 1940-2001
– 102 patients treated with thiopurines
– 73 treated with AZA
• 12 of 24 who stopped AZA were treated with 6-MP, and
exactly 50% tolerated it
• Edinburgh: 149 pts intolerant of AZA treated with
6MP
– Overall 58% tolerated
– More likely to tolerate if AZA issue was GI symptom
or LFTs compared to flu-like
Loftus CG et al, Am J Gastroenterol 2003;9 (Suppl):S242.
Kennedy NA et al, Aliment Pharmacol Ther 2013;38:1255-66.
Pregnancy Outcome in Crohn’s Disease for Women
Treated with Thiopurines: Cohort from the CESAME
Study
•
215 pregnancies (204 women) in the
CESAME cohort 3/04 -12/07.
•
3 exposure groups compared:
– TP (TP only or associated with
another treatment: 5-ASA, CS or
anti-TNF)
– A drug other than TP
– No medication
IBD treatment
Outcome
TPs
(n=86)
Others
(n=84)
None
(n=45)
Births, n (%)
55
(64%)
56
(66.6%)
27
(60%)
12
(21.8%)
9
(16.0%)
4
(14.8%)
8
(14.5%)
7
(12.5%)
2
(7.4%)
2
(3.6%)
3
(5.3%)
1
(3.7%)
Prematurity, n
(%)*
Conclusions
•
•
TP use is not associated with increased Low birth
weight under
risk of congenital abnormalities
2500g, n (%)*
Increased incidence of LBW and
prematurity under TP was not
significant and may correlate to the
underlying disease
Congenital
abnormalities, n
(%)*
Coelho J, Gut 2011; 60:198-203.
Methotrexate Toxicity
• Rash, alopecia
• Nausea, mucositis, diarrhea
– Folate mitigates much of this
– Ondansetron before MTX injections
•
•
•
•
Bone marrow suppression
Hypersensitivity pneumonitis
Increased LFTs
Hepatic fibrosis/cirrhosis
MTX Hepatotoxicity
• Risk factors:
– Obesity
– Alcohol
– Diabetes
• Screen for
HBC/HCV
• Monitor LFTs,
adjust dose
accordingly
• Steatosis, steatohepatitis, hepatic fibrosis
• Fortunately, risk of hepatotoxicity is low (0.9-1.4 per
100 person-months)
Khan N et al, Inflamm Bowel Dis 2012;18:359-67.
MTX Pulmonary Toxicity
• Approximately 1-8% of
treated patients
• Various forms
– Hypersensitivity
pneumonitis
– BOOP
– Interstitial pneumonia
– Pleuritis/effusion
• Risk factors
–
–
–
–
Age>60
RA with pulmonary
Low albumin
Diabetes
• Can present as culture
negative pneumonia
• Subacute dry cough with
dyspnea
• Up to 50% have peripheral
eosinophilia
• Abnl PFTs in subacute
presentation: restrictive
pattern, ↓DLCO
• Sometimes BAL ± lung bx
needed
• Rx: hold MTX, consider
steroids
Agent
Published Guidelines For Monitoring
CBC
Oral 5 ASA Agents
• Package insert sulfasalazine:
• Q2 wk x 1st 3 mo, then qmo x 3 mo, then
q3mo
Thiopurines
• AGA & ACG:
• TPMT
• Q2 wk “while adjusted” then ≤3 mo
• Package insert
• Q1 wk x 1 mo, q2wk x3 mo, the “then
monthly or more frequently if dosage
alterations or other therapy changes are
necessary”
Methotrexate
• AGA “routine” CBC
• ACR recommends CBC q 4-8 wk for RA
patients
• Package insert & Internal Recommendations
• Monthly
Anti-TNF
• British Society of Rheumatology recommends
“regular monitoring” in RA patients
Cyclosporine and Tacrolimus Toxicity
• Nephrotoxicity:
– Acute azotemia, usually reversible/doserelated
– Rarely chronic progressive
• Hypertension: may require Ca++ channel
blocker
• Neurotoxicity
– Tremor common
– Seizures rare (more common with low lipids)
• ↓K+, ↓Mg++, ↑glucose
Adverse Events with Anti-TNF
Therapies
•
•
•
•
•
•
Neurologic
Cardiac
Hepatic
Rheumatologic
Infusion reactions
Injection site reactions
– Usually minor
Neurologic Side Effects: Demyelination
•
Confusing since there is a baseline association
between IBD and multiple sclerosis (Olmsted,
Manitoba, GPRD)
– MS is between 50% more and 3 times more
common in IBD than general population
• Lenercept caused increased MS exacerbations in a
group of MS patients
• Over 150 cases of demyelination after anti-TNF therapy
reported to FDA AERS (2000-09)
–
•
Optic neuritis, MS-like presentation
Spanish registry of anti-TNF therapy estimates
incidence at 0.2 per 1000 p-y for IFX and 1 per 1000 py for ADA
Kimura K et al, Mayo Clin Proc 2000; Bernstein CN et al, Gastroenterology 2005; Gupta G
et al, Gastroenterology 2005; Lenercept MS Study Group, Neurology 1999; Deepak P et al,
Aliment Pharmacol Ther 2013; Ramos-Casals M et al, Autoimmune Rev 2010.
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; 19:864-72.
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.
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;11:558-64.
Lupus-Like Reactions with Anti-TNF
• Most are women
• Virtually all have
arthritis/arthralgias
• Rash is common
• Serositis
• ANA positive
• Anti-ds-DNA often
positive
• Don’t forget to check antihistone
• Treatment is anti-TNF
cessation
• Sometimes steroids
needed, rarely
hydroxychloroquine
• Recurrence with a 2nd
anti-TNF is relatively low
• One study from U of C
suggested cumulative 5yr incidence over 10% in
women on anti-TNF
Wetter DA & Davis MDP. Mayo Clin Proc 2009;84:979-84.
Subramanian S et al, Inflamm Bowel Dis 2011;17:99-104.
Yanai H et al. Inflamm Bowel Dis 2013;19:2778-86.
Infliximab Infusion Reactions
• Acute infusion
reactions
– Associated with
antibodies to infliximab
– Mild reactions treated
with acetaminophen,
diphenhydramine and
slowing of infusion rate
– Severe reactions
require cessation,
steroids, or
epinephrine
• Delayed
hypersensitivity
reactions
– Not necessarily
associated with ATI
– Arthralgias 1 to 5 days
after infusion
– Sometimes require
steroids
– More common on
monotherapy episodic
Natalizumab: Adverse Events
Beyond PML
• Headache
• Infusion reactions, generally mild
• Hepatotoxicity
– Rare but severe cholestatic liver injury
reported
Conclusions
• A wide variety of side effects can occur
with our commonly used medications for
IBD
• Regular monitoring necessary for many
agents