Download - Edward V. Loftus, Jr., M.D. Professor of Medicine Mayo Clinic Rochester, Minnesota, U.S.A
©2010 MFMER | slide-1
Edward V. Loftus, Jr., M.D.Professor of Medicine
Mayo ClinicRochester, Minnesota, U.S.A.
Pro: Immunomodulators and Anti-TNFs Must Be Stopped When a
Viral, Bacterial, or Fungal Infection Occurs
Loftus Disclosures (last 12 months)• Consultant
•AbbVie•UCB•Janssen•Takeda•Immune Pharmaceuticals
• Research support• AbbVie• UCB• Bristol-Myers Squibb• Shire• Genentech• Janssen• Amgen• Pfizer• Braintree• Takeda• GlaxoSmithKline• Robarts Clinical Trials• Santarus
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 1.0 (reference)•24 – 36 1.2 (0.5 – 2.8)•37 – 49 1.1 (0.5 – 2.5)• ≥ 50 3.0 (1.2 – 7.2)
Toruner M et al, Gastroenterology 2008; 134:929-36.
Biologics in the ElderlyAdverse Events
Older Cohort (n=89)
Younger Cohort (n=178)
EventsN
Patients N (%)
EventsN
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)
Bhushan A et al, DDW Abstract 2010
Older age, HR unadjusted 1.9 (1.2 – 3.1)HR adjusted 1.7 (1.1 – 2.8)
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 value1 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
Lichenstein GR et al, Gastroenterology 2006;130(Suppl 4):A-71.Lichtenstein GR et al, Clin Gastroenterol Hepatol 2006;4:621-30.
Multivariate analysis
**P<0.00010.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
IFX
Odd
s ra
tio
Mortality Serious infections
AZA6-MPMTX
Steroids
* IFX AZA6-MPMTX
Steroids
**
IFX = infliximab; AZA = azathioprine; MTX = methotrexate
*P=0.001
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
P = 0.013
Westhovens R et al. Arthritis Rheum. 2006;54:1075-86
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Relative RiskSerious Infection
# TB CasesWeek 54
Group 1 Group 2 Group 3
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
Prospective study (n=230)
Seksik P et al. Aliment Pharmacol Ther 2009;29:1106-13.
AZA Increases the Incidence of Certain Viral Infections
Infe
ctio
n/pa
tient
-yea
r
2.0
1.5
1.0
0.5
0
AZA+n=169
AZA–n=61
AZA+n=169
AZA–n=61
NS
*
Upper respiratory tract infections
Herpes virus flare-ups
AZA+ AZA– AZA+ AZA–
Warts at the entryin the study
Appearance of increased number of warts
NS
*
Patie
nts
(%)
20181614
12
10864
2
0
NS = not significant
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 pre-emptive
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
©2010 MFMER | slide-17
Rahier JF et al, J Crohns Colitis 2009;3:47-91
Clostridium difficile Infection and IBD
Increasing percentage of C. diff infections are IBD patients
Increasing number of hospitalizations in IBD
patients with C. diff
Issa M, et al. Clin Gastroenterol Hepatol 2007; 5: 345-51.
• Classic risk factors disappearing• Pseudomembranes usually not present• Low threshold for checking in IBD patients with flares• Should you stop immunosuppression? Conflicting data
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;46:2565-70Velayos FS et al. Inflamm Bowel Dis. 2004;10:657-60Bergstrom L et al. Arthritis Rheum. 2004;50:1959-66
Geographic Distribution of Histoplasmosis and Coccidioidomycosis in Older Americans, 1999-2008:
Medicare Sample
Histoplasmosis Coccidiodomycosis
Baddley JW et al, Emerging Infect Dis 2011;17:1664-9.
Cases per 100,000 person-years
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 pneumonia57 yr old man, IV Steroids, cyclosporine, surgery • Pneumocystis jiroveci32 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 X-
ray• 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
C diff Screen at flare N/A Individualize
Various bacterial No N/A Individualize
©2010 MFMER | slide-24
Rahier JF et al, J Crohns Colitis 2009;3:47-91
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