©2010 MFMER | slide-1

Edward V. Loftus, Jr., M.D.

Professor of Medicine

Mayo Clinic

Rochester, 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 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

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

Od

ds

rat

io

Mortality Serious infections

AZA6-MPMTX

Steroids

* IFXAZA6-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/p

atie

nt-

year

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

*

Pat

ien

ts (

%)

20

18

16

14

12

10

8

6

4

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 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 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