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
Feb 23, 2016
Other Major Side Effects to Immunomodulators and/or
Biologics in Our IBD Patients
Edward V. Loftus, Jr., M.D.Professor of Medicine
Mayo ClinicRochester, 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 1.7 (0.9-3.1)– Serious AE 2.6 (0.9-7.1)
• AZA vs. 5-ASA– Study withdrawal due to AE 1.0 (0.4-2.5)– Serious AE 11.3 (0.6-205)
• AZA vs. IFX– Study withdrawal due to AE 1.5 (0.96-2.2)– Serious AE 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 N % Withdrawal Due to AE
Olmsted Co, MN 102 25%Canterbury, NZ 216 26%Oxford, UK 622 28%Groningen, NL 318 23%Nijmegen, NL 50 22%Loftus CG et al, Am J Gastroenterology 2003 abstractGearry et al, Pharmacoepidemiol Drug Safety 2004;13:563-7Fraser AG et al, Gut 2002;50:485-9Weersma RK et al, Aliment Pharmacol Ther 2004;20:843-50deJong DJ et al, Eur J Gastroenterol Hepatol 2004;16:207-12
Azathioprine/6-MercaptopurineToxicity
• Nausea• Allergic reactions• Pancreatitis• Bone marrow depression• Drug hepatitis
Blood Dyscrasias Are an Important SAE for 5-ASA Agents--More Likely with Sulfasalazine
Fatalities after developing a blood dyscrasia: Sulfasalazine 5% (7/129) Mesalamine 9% (5/51)
Ransford RAJ. Gut 2002;51:536-539.
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 Non-
Randomized 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.
0
2000
4000
6000
p < 0.05
Med
ian
6-M
MP
(pm
ol/8
x108 R
BC
)6-MMP and Hepatotoxicity
2213
5463
n=157Absent
n=16Present
HEPATOTOXICITYDubinsky MC et al, Gastroenterology 2002;122(4):904-15.
Allopurinol Therapy for Preferential 6-MMP Metabolism
Pre-allopurinol Post-allopurinol
Sparrow MP et al. Aliment Pharmacol Ther. 2005;22:441.
Allopurinol 100 mg added; 6-MP/AZA dose reduced to 25% to 50% of baseline
6-TG0
50100150200250300350400450
6-MMP0
2000
4000
6000
8000
10000
12000
•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
Allopurinol + AZA/6MP: Clinical Outcome
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
DeBoer NK et al, Scand J Gastroenterol 2008;43:604-8Seksik P et al, Inflamm Bowel Dis 2011;17:565-72.
• 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
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
Conclusions• TP use is not associated with increased
risk of congenital abnormalities • Increased incidence of LBW and
prematurity under TP was not significant and may correlate to the underlying disease
Coelho J, Gut 2011; 60:198-203.
IBD treatment Outcome
TPs (n=86)
Others (n=84)
None (n=45)
Births, n (%) 55 (64%)
56 (66.6%)
27 (60%)
Prematurity, n (%)*
12 (21.8%)
9 (16.0%)
4 (14.8%)
Low birth weight under 2500g, n (%)*
8 (14.5%)
7 (12.5%)
2 (7.4%)
Congenital abnormalities, n (%)*
2 (3.6%)
3 (5.3%)
1 (3.7%)
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
Khan N et al, Inflamm Bowel Dis 2012;18:359-67.
• Steatosis, steatohepatitis, hepatic fibrosis• Fortunately, risk of hepatotoxicity is low (0.9-1.4 per
100 person-months)
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/dose-related
– 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 p-y 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 CHFMann 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 anti-
histone
• 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 5-yr 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