Pro: Immunomodulators and AntiTNFs Must Be Stopped When a
Viral, Bacterial, or Fungal Infection
Occurs
Edward V. Loftus, Jr., M.D.
Professor of Medicine
Mayo Clinic
Rochester, Minnesota, U.S.A.
©2010 MFMER | slide-1
Loftus Disclosures (last 12 months)
• Research support
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AbbVie
UCB
Bristol-Myers Squibb
Shire
Genentech
Janssen
Amgen
Pfizer
Braintree
Takeda
GlaxoSmithKline
Robarts Clinical Trials
Santarus
• Consultant
•AbbVie
•UCB
•Janssen
•Takeda
•Immune
Pharmaceuticals
Case: 26 Year Old Man with Ulcerative
Colitis
• Diagnosed with proctitis 3 years ago
• Severe flare 1 year ago: now with extensive
disease
• Steroid-dependent
• Azathioprine 2.5 mg/kg body weight daily
• Still steroid-dependent after 3 months
• CXR, PPD negative
• Infliximab 5 mg/kg started, 3-dose induction and
scheduled maintenance
• Visit at 8 weeks: significant clinical improvement
Case: Steroid-Dependent UC
• Week 10: calls to report 10 days of
fever, myalgia, chest discomfort, dry
cough
• Seen urgently that day
• CXR: “negative”
• Chest CT: numerous tiny nodules
throughout lungs, mediastinal
lymphadenopathy
• ID: consistent with a granulomatous
infection such as histoplasmosis
• Histoplasma serology negative, no
clinical response to itraconazole
Case: Steroid-Dependent UC
• Referred to pulmonary
• Bronchoscopy, transbronchial biopsy/aspirate negative
• Original induced sputum from 2 weeks ago grew out
Mycobacterium tuberculosis
• Prednisone and infliximab and AZA all held
• Started on ethambutol, pyrazinamide, rifampin,
isoniazid: 9 months
• Developed arthralgias and fevers 2 weeks after starting
antimycobacterial therapy
• Eventually diagnosed as immune reconstitution syndrome
• Restarted on low-dose prednisone
• Serious flare of UC 1 year after TB
• Hospitalized
• Colectomy
Infection Definitions
• Opportunistic infection
•Infection by an organism which has limited
pathogenic capacity in ordinary circumstances
• Serious infection
•Infection resulting in need for intravenous
therapy or hospitalization, or which results in
disability or death
• Not all opportunistic infections are serious
and not all serious infections are
opportunistic
Immunosuppression in IBD
• Not all IBD patients are immunosuppressed
• Most important factors
•Increased age
•Malnutrition
•Comorbidities (e.g., COPD, DM)
•Medications: steroids, immunosuppressives, biologics
•Hospitalization
• Interplay of these factors results in variable amounts of
immunosuppression with same medications
• No clinical test available to measure “immunity”
Mayo Case-Control Study (n = 100 Trios):
Age Associated with Opportunistic Infection
• Age at IBD diagnosis:
•Odds Ratio (per 5 years), 1.1 (1.1-1.2)
• Age at first Mayo visit:
0 – 23
•24 – 36
•37 – 49
• ≥ 50
•
1.0 (reference)
1.2 (0.5 – 2.8)
1.1 (0.5 – 2.5)
3.0 (1.2 – 7.2)
Toruner M et al, Gastroenterology 2008; 134:929-36.
Biologics in the Elderly
Adverse Events
Older Cohort
(n=89)
Younger Cohort (n=178)
Events
N
Patients
N (%)
Events
N
Patients
N (%)
Adverse Event
61
40 (45)
67
41 (23)
Serious Adverse Events
32
24 (27)
29
17 (10)
Serious Infections
27
20 (22)
26
15 (8)
Older age, HR unadjusted 1.9 (1.2 – 3.1)
HR adjusted 1.7 (1.1 – 2.8)
Bhushan A et al, DDW Abstract 2010
Mayo Case-Control Study (n = 100 Trios):
Immunosuppressive Medications Were
Associated with Increased Risk of
Opportunistic Infections
Odds Ratio (95% CI)
P value
Any Medication
(5-ASA, AZA/6-MP,
steroids, MTX,
infliximab)
3.5 (2 - 6.1)
<0.0001*
5-ASA
1.0 (0.6 - 1.6)
0.94
Corticosteroids
3.4 (1.8 - 6.2)
<0.0001*
6-MP/azathioprine
3.1 (1.7 - 5.5)
0.0001*
Methotrexate
4.0 (0.4 - 44.1)
0.26
Infliximab
4.4 (1.2 - 17.1)
0.03
Toruner M et al, Gastroenterology 2008; 134:929-36.
Risk Factors for Opportunistic Infections in
IBD: A Case-Control Study
Odds Ratio (95% CI) P value
1 medication
2.65 (1.45-4.82)
0.0014
≥2 medications
14.5 (4.9-43)
<0.0001
Toruner M et al, Gastroenterology 2008; 134:929-36.
Infections and Mortality in the TREAT
Registry: 15,000 Patient-Years of Experience
Multivariate analysis
4.5
Mortality
4.0
Serious infections
Odds ratio
3.5
3.0
2.5
2.0
1.5
1.0
IFX
AZA
6-MP
MTX
*
IFX
Steroids
AZA
6-MP
MTX
**
Steroids
0.5
0.0
*P=0.001
**P<0.0001
IFX = infliximab; AZA = azathioprine; MTX = methotrexate
Lichenstein GR et al, Gastroenterology 2006;130(Suppl 4):A-71.
Lichtenstein GR et al, Clin Gastroenterol Hepatol 2006;4:621-30.
Infliximab Dose and Serious Infection: RCT in
RA (n = 1084)
• RCT of placebo vs 2 doses of
infliximab in RA
• Relaxed entry criteria to allow
co-morbidities
• Group 1: placebo to wk 22,
then 3 mg/kg q 8
• Group 2: 3 mg/kg to wk 22,
then escalate by 1.5 mg/kg
PRN
• Group 3: 10 mg/kg throughout
• Primary endpoint: risk of serious
infection at week 22
4.5
Group 1
Group 2
Group 3
4
3.5
P = 0.013
3
2.5
2
1.5
1
0.5
0
Relative Risk
Serious Infection
Westhovens R et al. Arthritis Rheum. 2006;54:1075-86
# TB Cases
Week 54
Risk of Hospitalization for Serious Infection
After Starting Medication for IBD (n=2,323
Pairs Matched on Propensity Score)
• Incidence
rates:
• Anti-TNF:
10.9 per 100
PY
• AZA/6MP:
9.6 per 100
PY
• Adjusted
hazard ratio:
1.1 (0.8-1.5)
Grijalva CG et al, JAMA 2011 Online Early
AZA Increases the Incidence
of Certain Viral Infections
Prospective study (n=230)
NS
*
20
18
NS
16
2.0
*
1.5
Patients (%)
Infection/patient-year
14
1.0
12
10
8
6
4
0.5
2
0
0
AZA+
n=169
AZA–
n=61
Upper respiratory
tract infections
AZA+
n=169
AZA–
n=61
Herpes virus flare-ups
AZA+
AZA–
Warts at the entry
in the study
AZA+
Appearance of increased
number of warts
Seksik P et al. Aliment Pharmacol Ther 2009;29:1106-13.
NS = not significant
AZA–
Cervical Dysplasia in IBD
• Some (not all) studies suggest that cervical
dypslasia is more common in women with IBD
• Presumably mediated through HPV reactivation
• Immunosuppressive medications
• Cigarette smoking
• Recommend annual screening for cervical
dysplasia in women with IBD, especially those
who smoke and are on immunosuppressives
Bhatia J et al, World J Gastroenterol 2006;12:6167-71.
Kane S et al, Am J Gastroenterol 2008;103:631-6.
Singh H et al, Gastroenterology 2009;136:451-8.
Lees CW et al, Inflamm Bowel Dis 2009;15:1621-9.
ECCO Guidelines for Managing
Opportunistic Viral Infections
Virus
Screen?
Vaccinate?
Withdraw?
HCV
Not necessary
N/A
No
HBV
Yes
Yes
No but treat preemptive
HIV
Consider testing
N/A
No if counts OK
CMV
No
N/A
Yes
HSV
No
N/A
Only for severe
VZV
Yes if no hx
Yes
Only for severe
EBV
No
N/A
Only for severe
HPV
Cervical ca
Yes
Only for severe
JCV
Yes
N/A
Yes
Rahier JF et al, J Crohns Colitis 2009;3:47-91
©2010 MFMER | slide-17
Clostridium difficile Infection and IBD
Increasing percentage of C. diff
infections are IBD patients
Increasing number of
hospitalizations in IBD
patients with C. diff
•Classic risk factors disappearing
•Pseudomembranes usually not present
•Low threshold for checking in IBD patients with flares
•Should you stop immunosuppression? Conflicting data
Issa M, et al. Clin Gastroenterol Hepatol 2007; 5: 345-51.
Granulomatous Infections After TNF
Blockade
• Bacterial
•Tuberculosis
•Atypical mycobacterial infection
•Listeriosis
• Invasive fungal
•Histoplasmosis
•Coccidioidomycosis
•Candidiasis
•Aspergillosis
•Pneumocystosis
•Others
Lee JH et al. Arthritis Rheum. 2002;46:2565-70
Velayos FS et al. Inflamm Bowel Dis. 2004;10:657-60
Bergstrom L et al. Arthritis Rheum. 2004;50:1959-66
Geographic Distribution of Histoplasmosis and
Coccidioidomycosis in Older Americans, 1999-2008:
Medicare Sample
Histoplasmosis
Coccidiodomycosis
Cases per 100,000 person-years
Baddley JW et al, Emerging Infect Dis 2011;17:1664-9.
Fungal Infections and Anti-TNF Therapy:
MEDLINE and PubMed Until 2007
Tsiodras S et al, Mayo Clin Proc 2008;83:181-94.
Long-Term Outcome of Patients Treated With IV
Cyclosporine for Severe UC (n=86)
• Aspergillus pneumonia
60 yr old man, IV Steroids,
AZA, cyclosporine
• Aspergillus pneumonia
57 yr old man, IV Steroids,
cyclosporine, surgery
• Pneumocystis jiroveci
32 yr old man, Steroids,
cyclosporine, AZA
Arts J et al. Inflamm Bowel Dis 2004;10:73-8.
Tuberculosis Screening
• Average risk: tuberculin test and chest Xray
• Residents of endemic areas and/or those
who received BCG
•Interferon gamma release assay
(QuantiFERON)
• Latent infection: INH for 6-9 months, can
start anti-TNF after 3 weeks
• Active infection: do not start or reinitiate
anti-TNF until a minimum of 2 months of
anti-TB therapy
ECCO Guidelines for Managing Fungal Infections,
Bacterial Infections and Tuberculosis
Organism
Screen?
Vaccinate?
Withdraw?
Fungal
No
N/A
Individualize
TB
Yes
N/A
Latent: wait 3
weeks
Active: yes wait 2
months
Screen at flare
N/A
Individualize
No
N/A
Individualize
C diff
Various bacterial
Rahier JF et al, J Crohns Colitis 2009;3:47-91
©2010 MFMER | slide-24
Conclusions
• Serious and opportunistic infections occur in
IBD patients
• Risk factors include older age, hospitalization,
corticosteroids, immunosuppressives, anti-TNF
agents
• Overall risk of serious infection with anti-TNF
probably no higher than with thiopurines
• Pay close attention in the elderly
• Stay vigilant
• Weigh benefit to risk ratio in each patient
• Decision to stop immunosuppression in most
cases is individualized-get I.D. support