Transcript Pro: Immunomodulators and Anti-TNFs Must Be Stopped When a
Pro: Immunomodulators and Anti TNFs 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 • AbbVie • • • • • • • • • • • • UCB Bristol-Myers Squibb Shire Genentech Janssen Amgen Pfizer Braintree Takeda GlaxoSmithKline Robarts Clinical Trials Santarus • Consultant • AbbVie • UCB • Janssen • Takeda • Immune Pharmaceuticals
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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
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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) Adverse Event Serious Adverse Events Events N 61 32 Patients N (%) 40 (45) 24 (27) Events N 67 29 Patients N (%) 41 (23) 17 (10) Serious Infections 27 20 (22) 26
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
15 (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 6-MP/azathioprine 3.4 (1.8 - 6.2) 3.1 (1.7 - 5.5) Methotrexate 4.0 (0.4 - 44.1) Infliximab 4.4 (1.2 - 17.1)
Toruner M et al, Gastroenterology 2008; 134:929-36.
<0.0001* 0.0001* 0.26
0.03
Risk Factors for Opportunistic Infections in IBD: A Case-Control Study
1 medication ≥2 medications
Odds Ratio (95% CI) P value
2.65 (1.45-4.82) 0.0014
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 Serious infections 4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
IFX AZA 6-MP MTX * Steroids *P=0.001
IFX **P<0.0001
AZA 6-MP MTX ** Steroids 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
4 3.5
3 2.5
2 1.5
1 0.5
Group 1 Group 2 P = 0.013
0 Relative Risk Serious Infection Westhovens R et al. Arthritis Rheum. 2006;54:1075-86 Group 3 # 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 2.0
1.5
1.0
0.5
* 10 8 6 4 2 20 18 16 14 12 NS * 0 AZA+ n=169 AZA – n=61 Upper respiratory tract infections NS = not significant 0 AZA+ n=169 AZA – n=61 Herpes virus flare-ups AZA+ AZA Warts at the entry in the study – AZA+ Seksik P et al. Aliment Pharmacol Ther 2009;29:1106-13.
AZA – Appearance of increased number of warts
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.
Virus
HCV HBV HIV CMV HSV VZV EBV HPV JCV
ECCO Guidelines for Managing Opportunistic Viral Infections Screen?
Not necessary Yes Consider testing No No Yes if no hx No Cervical ca Yes
Vaccinate?
N/A Yes N/A N/A N/A Yes N/A Yes N/A
Withdraw?
No No but treat pre emptive No if counts OK Yes Only for severe Only for severe Only for severe Only for severe Yes Rahier JF et al, J Crohns Colitis 2009;3:47-91 ©2010 MFMER | slide-17
Clostridium difficile Infection and IBD Increasing number of Increasing percentage of C. diff infections are IBD patients hospitalizations in IBD patients with C. diff
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Classic risk factors disappearing
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Pseudomembranes usually not present
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Low threshold for checking in IBD patients with flares
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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)
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Aspergillus pneumonia
60 yr old man, IV Steroids, AZA, cyclosporine
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Aspergillus pneumonia
57 yr old man, IV Steroids, cyclosporine, surgery
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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 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
Fungal TB C diff Various bacterial
Screen?
No Yes Screen at flare No
Vaccinate?
N/A N/A N/A N/A
Withdraw?
Individualize Latent: wait 3 weeks Active: yes wait 2 months Individualize Individualize Rahier JF et al, J Crohns Colitis 2009;3:47-91 ©2010 MFMER | slide-24
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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