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,

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 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 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-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

RB

C)

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

50

100

150

200

250

300

350

400

450

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 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 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

Conclusions

• A wide variety of side effects can occur with our commonly used medications for IBD

• Regular monitoring necessary for many agents