Download Azathioprine: Long-Term Side Effects

Azathioprine: Long-Term
Side Effects
Edward V Loftus, Jr, MD
Division of Gastroenterology and Hepatology
Mayo Clinic College of Medicine
Rochester, MN
Overview
• “Real world” experiences with AZA
• ITPA polymorphisms
• Hematological – Drug interactions
• Teratogenicity/Pregnancy Safety
• Hepatic
• Infectious
– Combination therapy with infliximab
• Neoplastic (e.g., lymphoma)
AZA/6MP Tolerance: RCT
Experience
• Experience in RCTs for Crohn’s disease
generally favorable
• Pooled odds ratio of study withdrawal
due to AZA/6MP adverse events was 5.3
(95% CI, 2.2-12.6)
• Withdrawals due to adverse events
ranged from 0% to 15%
– Average rate was 9% (vs. 2% in placebo)
Pearson DC et al, Ann Intern Med 1995;123:132-42
“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
Inosine Triphosphate Pyrophosphatase
(ITPA): Role in AZA/6MP Metabolism
6-thio-IDP
6-thio-ITP
6MMP
ITPA
TPMT
AZA
6MP
HPRT
6-thio-IMP
XO
6-thio-uric acid
IMPDH
TPMT
Me-6-thio-IMP
Marinaki et al, Pharmacogenetics 2004;14:181-7
6-TGNs
Inosine Triphosphate Pyrophosphatase (ITPA)
Polymorphisms May Explain Some
“Idiosyncratic Reactions” to AZA/6MP
• 62 IBD pts with adverse reactions to
AZA, 68 pts who tolerated > 3 months
• ITPA polymorphism (94C>A)
significantly associated with adverse
events overall
• 94C>A 17% allele frequency vs. 4% in
controls (OR, 4.2, 95% CI 1.6-11.5)
– Flu-like symptoms: OR 4.7, 1.2-18.1
– Rash: OR, 10.3, 4.7-62.9
– Pancreatitis: OR, 6.2, 1.1-32.6
Marinaki et al, Pharmacogenetics 2004;14:181-7
Do ITPA Polymorphisms Account for
Leucopenia Following AZA/6MP?
• 41 CD patients with leucopenia and 100
controls tested for ITPA mutations
– Prevalence of 94C>A was 15% in leucopenia
group vs. 10% in controls
• 254 IBD patients and 129 healthy volunteers
tested
– Leucopenia seen in 11% of IBD pts
– 94C>A seen in 25% of leucopenic pts but only
10% of controls
– 94C>A did NOT predict hepatotoxicity or
pancreatitis
Allorge D et al, Gut 2005;54:565
Zelinkova Z et al, Gut 2004;53(Suppl VI):A49 (UEGW abstract)
Hematological Adverse Events
• Variations in TPMT activity may explain
only a small proportion of leucopenia,
usually only early events
• TPMT deficiencies explained only 27%
of leucopenic events in a French study
• Role of ITPA mutations remains unclear
• Continued indefinite need for periodic
monitoring of WBC even if counts have
been stable
Colombel JF et al, Gastroenterology 2000;118:1025-30.
AZA/6MP Drug Interactions:
Sulphasalazine and 5-ASA
• 34 Crohn’s patients on stable doses of
•
AZA/6MP with serial 6TGN levels before and
after introduction of SASP or 5ASA
Leucopenia (WBC < 3.5) occurred over the
next 8 weeks in:
– 5/10 mesalamine 4 g/d (50%)
– 6/11 sulphasalazine 4 g/d (54%)
– 2/10 balsalazide 6.75 g/d (20%)
• Serum 6-TGN levels rose significantly after
introduction of mesalamine or sulphasalazine
Lowry et al, Gut 2001;49:656-64.
AZA/6MP Drug Interactions:
Infliximab
• 32 Crohn’s patients with serial 6TGN serum
•
levels before/after infliximab
Median AZA dose 2.8 mg/kg (0.6–3.6)
TGN
WBC
MCV
Before
277
4.3
96.1
1-3 Weeks
442 †
3.6 †
98.3 †
† p<0.01 compared to other 2 time points
Roblin et al, Aliment Pharmacol Ther 2003;18:917-25.
3 Months
279
4.1
95.3
AZA Effects on Fertility in Males
• 18 men with IBD on AZA for > 3 months
– Semen quality as measured by total
sperm county, density, motility, and
morphology was normal
• 11 men with IBD started on AZA after
first semen analysis
– Baseline parameters slightly decreased
– No worsening in parameters after mean
11 months AZA treatment
• 6 men on AZA fathered 7 healthy
children
Dejaco et al, Gastroenterology 2001;121:1048-53.
AZA/6-MP Teratogenicity
• Metabolites can cross the placenta
• Biggest/best studies in transplant and
•
rheumatology (SLE) literature
146 kidney transplant recipients on
AZA/steroids or AZA alone
– Low birth weights in 39%
– Premature births in 52%
– Congenital anomalies in 4% (background
rate = 3%)
• IBD-specific studies are hampered by
small numbers
Armenti et al, Transplantation 1994
AZA/6MP During Pregnancy in IBD
New York 1950s-1997
A
B1
B2
C
Pregnancies, n
84
61
15
165
Full term (%)
63%
72%
67%
75%
5%
5%
27%
4%
23%
16%
7%
19%
15%–40%
Congenital abnormalities (%)
4%
3%
7%
4%
2%–5%
Neonatal/child infections(%)
1%
2%
13%
1%
2%–12%
Neoplasia in child
0%
2%
0%
0%
0.1/106/yr
Prematurity (%)
Spontaneous abortion (%)
Normal
7.1%
Multivariate analysis: successful pregnancy outcome on 6MP, 0.8 (0.5-1.5)
A=conceived after 6-MP; B1=stopped 6-MP when pregnant; B2=continued
6-MP while pregnant; C=pregnancy before starting 6-MP(control)
Francella et al.Gastroenterology 2003;124:9-17
Pregnancy Following 6MP, New York, 1982-97
Group 1
n = 29
Pregnancies
72
Live Births
51 (71%)
Spont Abs
16 (22%)
Stillbirths
1 (1%)
Ectopic
2 (3%)
Prematurity
4 (8%)
Low Birth Weight 4 (8%)
Cong Anomaly
3 (6%)
Fetal demise
29%
Complications
15%
Group 2
n = 75
140
120 (86%)
18 (13%)
2 (1%)
0
8 (7%)
8 (7%)
4 (3%)
14%
10%
Zlatanic J et al, J Clin Gastroenterol 2003;36:303-9.
Gen pop
85%
12%
1%
2%
11%
7%
5%
15%
16%
Azathioprine and 6MP in PregnancyNorth Jutland, Denmark, 1991-2000
Low
Birth weight
Pre-term
Birth
Congenital
Anomalies
Perinatal
Death
First Entire
Not
Trim. Preg Exposed
n=9
n=10 n=19,418
OR, All
Controls
(95% CI)
22%
30%
4.4%
3.8 (0.4-33)
2.3 (0.4-14)
22%
30%
5.5%
6.6 (1.7-26)
2.8 (0.4-19)
22%
20%
3.7%
20 (2.5-161)
3.2 (0.2-57)
11%
10%
0.6%
6.7 (1.4-32)
7.7 (0.6-102)
Norgard et al, Aliment Pharmacol Ther 2003;17:827-34
OR, AZA/6MP
Controls
(95% CI)
AZA/6MP: Infectious Complications
• Lenox Hill Hospital 1980-99 (n = 410)
• Infections, not necessarily related to
leucopenia, may occur in up to 14%
• Pneumonia 4%
• Herpes zoster 3%
• Cytomegalovirus infections (colitis,
hepatitis, systemic illness) < 1%
• Upper respiratory infections 7%
Warman JI et al, J Clin Gastroenterol 2003;37:220-5.
Combination Purine Analog and Anti-TNF
Therapy: Does It Synergistically Increase
Infection Risk?
• Many centres advocate combination therapy to
•
•
reduce formation of antibodies to infliximab
Does this increase infection risk?
217 IBD patients from Stockholm
– 18 severe infections (8%)
– 2 sepsis deaths
• 500 Crohn’s patients from Mayo
– 41 infections (8%)
– 2 sepsis deaths, 2 pneumonia deaths
Ljung T et al, Gut 2004
Colombel JF et al, Gastroenterology 2004
AZA/6MP Hepatotoxicity
• Overall prevalence of biochemical
abnormalities: 3-4%
• Most of these are dose-dependent
– Related to over-accumulation of 6MMP
due to high TPMT? Controversial
– May resolve spontaneously or with dose
reduction
• 6-thioguanine: fewer allergic side
effects, more hepatotoxicity (up to 26%)
Dubinsky MC et al, Gastroenterology 2002;122:904-15
Dubinsky MC et al, Gastroenterology 2003;125:298-303
AZA/6MP Hepatotoxicity
Less common but more serious:
Nodular regenerative hyperplasia
Veno-occlusive disease of liver
True incidence of
these events
remains unknown
Reticulin stain
Holtmann M et al, Dig
Dis Sci 2003
Daniel F et al, Gut
2004;53
(Suppl VI):A221
Baseline Risk of Lymphoma in IBD
• Studies from referral centers indicate
a twofold to six fold increase in risk
– Referral bias?
– Risk increases with increased
severity?
• Population-based studies indicate
little or no increased risk, with few
exceptions
Population-Based Studies of Lymphoma in IBD
Author
Ekbom
Persson
Karlen
Loftus
Palli
Bernstein
Lewis
Askling
Setting
Uppsala
Patients
CD 1655
UC 3121
Stockholm
CD 1251
Stockholm
UC 1547
Olmsted Co
CD 216
UC 238
Florence
CD 231
UC 689
Manitoba
CD 2857
UC 2672
GPRD, UK
CD 6605
UC 10391
Mult Swedish CD 20120
cohorts
UC 27559
RR
0.4
1.2
1.4
1.2
2.4
0
2.5
9.3*
2.4
1.0
1.4
1.2
1.3
1.0
(95% CI)
(0 - 2.4)
(0.5 - 2.4)
(0.4 - 3.5)
(0.3 - 3.5)
(0.1 - 13)
(0 - 6.4)
(0.3 - 9)
(2.5 - 24)
(1.2 - 5)
(0.5 - 2.2)
(0.5 - 3.4)
(0.7 - 2.1)
(1.0 - 1.6)
(0.8 - 1.3)
* Hodgkin lymphoma (RR not signif elevated for non-Hodgkin)
Ekbom, Cancer 1991; Persson, Gastroenterology 1994; Karlen, Am J Gastroenterol 1999;
Loftus, Am J Gastroenterol 2000; Palli, Gastroenterology 2000; Bernstein, Cancer 2001;
Lewis, Gastroenterology 2001; Askling, Gut 2005
Lymphoma Risk in IBD Patients on
AZA/6MP: Meta-Analysis
Study
Setting
N
Obs
Exp
SIR
(95% CI)
Kinlen
U.K.
321
2
0.16
12.5
(1.2 - 46)
Connell
London
755
0
0.52
0
Farrell
Dublin
238
2
0.05
37.5
(3.5 - 138)
Fraser
Oxford
626
3
0.65
4.6
(0.9 - 13.7)
Korelitz
New York
486
3
0.61
4.9
(0.9 - 14.5)
Lewis
GPRD
1465
1
0.64
1.6
(0.001 - 9)
3891
11
2.63
4.2
(2.1 - 7.5)
Pooled
Sensitivity analyses: when papers with highest or lowest SIRs were
excluded, results remained significant (range, 3.5 - 5.2)
Kandiel et al, DDW abstract 2004 and Gut 2005 (in press)
Epstein-Barr Virus and Lymphoma
B-cell lymphoma
EBV in-situ hybridization
Dayharsh et al, Gastroenterology 2002;122:72
EBV Virus Load
138 Crohn’s patients
with serial EBV viral
load measurements
2 pts had viral loads in
dangerous range (i.e.,
risk for lymphoma)
No clear relationship
between immunosuppressive therapy
and EBV loads
Reijasse et al, Inflamm
Bowel Dis 2004;10:85
Risk-Benefit of AZA/6MP for
Crohn’s: Decision Analysis
• Markov model of quality-adjusted life year gain of AZA
•
•
•
for Crohn’s in a 35 year-old patient
Base case assumed 3 fold increased lymphoma risk
and a 50% reduction in Crohn’s related mortality
10 years of AZA resulted in gain of 1.25 qualityadjusted months
AZA was no longer beneficial if:
–
–
–
–
Risk of death from severe flare < 0.06%
Lymphoma risk is > 8 times normal
Background risk of lymphoma in Crohn’s > 4 times normal
Fear of AZA-related lymphoma results in > 1% decrease in
utility (proxy for QOL)
Lewis JD et al, Gastroenterology 2000;118:1018-24.
Does Prolonged Leukopenia
Increase Cancer Risk With 6MP?
• 600 IBD pts treated with 6MP at Lenox Hill
•
•
•
Hospital, New York
31 pts developed sustained leukopenia (WBC
< 4 for at least 2.5 wks)
93 matched controls without leukopenia
8 developed cancers (26%) versus 8% in
controls (p = 0.017)
– Leukemia in 2
– Non-Hodgkin lymphoma in 1
– No colorectal cancers
DiSanti et al, Am J Gastroenterol 2004;99:S252 (ACG abstract)
Risk of Other Cancers With AZA/6MP
• Non-melanoma skin cancer, especially
squamous cell cancer
– In transplant literature, RR is 6 to 65
– Might increase further with addition of
ciclosporin
• Many IBD cohort studies show
increased risk of colorectal cancer
following AZA/6MP, but this is to be
expected given the extent and duration
of colitis
Conclusions (1)
• Tolerance of AZA/6MP in the “real world” may
•
•
•
not be as good as RCT data (22 – 28%
withdrawal rates)
“Newer” polymorphisms such as ITPA may
explain some toxicity such as fever and
pancreatitis – data are conflicting
Drug interactions between AZA/6MP and 5ASA or infliximab may result in leucopenia
Data on safety in pregnancy are sparse – may
be a small but real risk of adverse outcome –
discuss with the patient
Conclusions (2)
• Most hepatotoxicity is mild and
reversible but rarely more serious injury
may occur
• Most population-based studies of
lymphoma in IBD suggest little to no
increased relative risk
• Relative risk of lymphoma with AZA/6MP
use is likely increased, up to fourfold absolute risk remains low
• Epstein-Barr virus typically found in
lymphomas in IBD pts on AZA/6MP