Opportunistic Infections

and Tuberculosis Risk

Management

Kevin L. Winthrop, MD, MPH Associate Professor, Divisions of Infectious

Diseases, Public Health, and

Preventive Medicine

Oregon Health & Science University

Learning Objectives

• Identify which patients have the highest

risk for infection and how this is modified

by DMARDs

• Define the risks of specific types of

opportunistic infections, and identify

appropriate screening and mitigation

strategies of these and other infectious risks

IMID Biologic Therapies

• TNF- inhibition

– Infliximab, adalimumab, golimumab, certolizumab

(monoclonal antibodies)

– Etanercept (soluble p75 receptor)

• Other Biologics

– CD4 co-stimulation modulator: abatacept

– B-cell (CD20+) antibody: rituximab

– Anti-IL-6 receptor antibody: tocilizumab

– Anti- IL12/IL23 antibody: ustekinumab

– Anti-IL-17A: secukinumab, Ixekizumab

• Small molecules (non-biologic)

– JAK inhibitor: tofacitinib

Prednisone Sparing Effect

Strangfeld A, et al. ARD. 2011.

Yun H, et al. ARD. 2015.

BiologicsReferent Group

Infliximab Adalimumab Etanercept Rituximab Abatacept

Crude IR Per 100

years (n/pys†)33.8 (1,382/4,087) 34.9 (497/1,423) 36.1 (661/1,831) 28.5 (38/133) 26.5 (88/333)

Adjusted HR (95% CI) ‡

Abatacept 0.80 (0.64-0.99) 0.87 (0.68-1.11) 0.96 (0.75-1.23) 0.94 (0.64-1.37) 1.0 (Ref)

Rituximab 0.85 (0.62-1.18) 0.93 (0.66-1.30) 1.03 (0.73-1.43) 1.0 (Ref)

Etanercept 0.83 (0.72-0.96) 0.90 (0.76-1.07) 1.0 (Ref)

Adalimumab 0.92 (0.79-1.07) 1.0 (Ref)

Infliximab 1.0 (Ref)

*Biologic exposure was defined as the days’ supply from filled prescriptions or assigned days’ supply based on recommended

dosing frequency, plus a 30-day ‘extension’ period to each exposure.

† Person years

‡Adjusted for the decile of disease risk score, specific anti-TNF biologic at the time of the index hospitalization, steroid use

during baseline, methotrexate use during baseline, infection type for the index hospitalization, and coexisting medication

exposures during follow up.

Yun H, et al. ARD. 2015.

Risk of Serious Infection After an anti-TNF Associated Serious Infection (in RA)

Secukinumab (anti-IL17A)

Secu 300mg Secu 150mg ETN

22 (4.7%) 11 (2.3%) 4 (1.2%)

• Candida

Langley, et al. NEJM. 2014.

Ixekizumab

Griffiths CEM, et al.

Incidence Rates of Serious Infections by 6-Month Intervals

• Overall rate of serious infection

reported with tofacitinib:

– 3.1 events/100 patient-years

• Rates previously reported in clinical

trial safety analyses of other

RA drugs:

– Adalimumab 3.9–5.1 events/

100 patient-years

– Rituximab 3.9–4.3 events/

100 patient-years

– Tocilizumab 3.8–5.1 events/

100 patient-years

– Etanercept 3.8 events/

100 patient-years

– Abatacept 2.0–3.1 events/

100 patient-years

– Golimumab 5.09 events/

100 patient-years

Cohen S, Radominski SC, Gomez-Reino JJ, et al. Arthritis Rheumatol. 2014 Jul 21. Slide prepared by CSF

0

1

2

3

4

5

6

0 to 6 6 to 12 12 to 18 18 to 24 24 to 30 30 to 36 36 to 42 >42

IR (

even

ts/1

00 p

t-yrs

[95%

CI]

)

Months

Winthrop K, et al. ARD. 2015.

PJP crude incidence

TNFi starters, 56/100,000

Non-viral OIs

TNFi starters 270/100,000

Non-biologics 170/100,000

Baddley J, Winthrop KL, et al. Presented IDSA. 2011.

SABER

Tocilizumab and Opportunistic Infection

• Schiff et al meta-analysis

– 230/100,000 (TB/NTM, candida, crypto, pneumocystis)

– No cases in control groups (n=1,550)

• Japan observational study

– TB, 130/100,000

– NTM 440/100,000

– Pneumocystis, 370/100,000

– Zoster, 22/1,000

Schiff MH, et al. ART. 2011; Koike T, et al. J Rheum. 2014.

Opportunistic

Infection1

Abatacept

n=338

PY=486.5

Adalimumab

n=1826

PY=2727.4

Etanercept

n=741

PY=1180.6

Infliximab

n=358

PY=511.2

Rituximab

n=511

PY=650.8

Total

N=3774

PY=5538

Zoster 5 38 16 2 4 65

Tuberculosis 0 0 2 0 1 3

Pneumocystosis 0 0 0 0 3 3

Legionellosis 0 3 0 0 0 3

Coccidioidomycosis 0 0 1 0 2 3

Histoplasmosis 0 1 0 1 0 2

Non-tuberculous

mycobacteria 0 1 0 0 1 2

Salmonellosis 0 1 0 0 1 2

Nocardiosis 0 0 0 1 0 1

TOTAL OIs 5 44 19 4 12 84

IR (95% CI) per

100 p-years

1.1(0.4,

2.6) 1.6 (1.2, 2.2)

1.6 (1.0,

2.5)

0.8 (0.3,

2.1) 1.8 (1.0, 3.2) 1.5 (1.2, 1.9)

Incidence rate: 144/100,000 p-yrsBaddley, et al. ACR. 2012.

“OIs” with Other Biologics

• 60 OIs reported (IR 0.46/100 pys [0.36-0.59])

– TB (n=26)

– PCP (n=4)

– CMV (n=6)

– Candida Esophagitis (n=9)

– Cryptococcus (n=3)

– NTM (n=2)

– HZ, multi-dermatomal (n=8)

– BK encephalopathy (n=1)

– Toxoplasmosis (n=1)

Winthrop K, et al. ARD. 2015.

Tofacitinib and “Opportunistic” Infections (P2P3LTE)

Hsia E, et al. Arth Rheum. 2012.

QFT-Plus

Siegel S, et al. ATS Abstract. 2016.

• Uses ESAT-6, CFP-10

– TB1 (CD4) and TB2 (CD8)

• Specificity study

– No risk TB (n=212)

– No risk TB with Pulmonary NTM (n=51)

• 5 positives (1 in NTM, 4 in no risk TB)

– Only 3 with concordant + in TB1/TB2

• Specificity

– 98.1% (95% CI 95.6, 99.4)

New Therapy Option

• INH and Rifapentine

– 3 months, once weekly (directly observed?)

Sterling T, et al. NEJM. 2011.

Environment? Host? Killer showerheads?

Related to publication by Feazel et al: Opportunistic pathogens enriched in showerhead biofilms. PNAS 2009: 38: 16393-16399

Singing in the ShowerCase #1

• 50 year old female, RA

– Met Opera Singer

– Prednisone 7.5mg, etanercept

• Recent increase in cough

– Bronchoscopy with Mycobacterium avium X1

– Recent switch from baths to 30-45 minute hot,

steamy showers

What To Do?

• Wait and see vs. “change the race-horse”

– Stop TNF? Start MTX?

– Switch biologic?

• Stop taking showers?

• Treat her M. avium?

32 Year Old, Myositis, Rituximab, Disseminated M. Kansasii Forearm Nodules

55 Year Old Male, Dermatomyositis, Rituximab, M. avium

Contrast enhanced chest CT showing bilateral pleural effusions with extensive pleural enhancement (white arrows) and passive atelectasis

(black arrows)

Related to publication by Feazel et al: Opportunistic pathogens enriched in showerhead biofilms. PNAS 2009: 38: 16393-16399

Environment? Host? Killer showerheads?

Winthrop KL, et al. Ann Rheum Dis. 2012; Winthrop KL. Nat Rheum Rev, in press.

Two weeks after last infliximab dose for uveitis

4 weeks later after receiving infliximab again

Hematogenous dissemination

Histoplasmosis and TNFi

N=98 cases, retrospective review

• 20 centers, endemic region US

• Median onset, 15.5 months

(range, 1-88 mo)

Therapy

• All but one treated with

anti-fungals

• TNFi stopped in 97%

• 9.2% with IRIS, med.

6 wks (1-45)

• 34% resumed TNFi during

or after anti-fungal therapy

(3 recurrences)

• Death 3.2%Vergidis P, et al. CID. 2015.

(Adapted from Diestag, 2008)

Winthrop KL et al ARD 2011

Live Not-live

BCG

Influenza (nasal)

Mumps/Measles/Rubell

a

Polio (oral)

Rotavirus

Shingles

Smallpox

Varicella

Yellow Fever

Typhoid (oral)

Anthrax

Hepatitis A

Hepatitis B

Influenza (IM)

H. influenzae

HPV

Japanese Encephalitis

Meningococcal

Pneumococcal

Poliomyelitis (IM)

Rabies

Tetanus/diptheria/pertussis

(Td/Tdap)

Typhoid (IM)

Vaccines & Preventable Diseases

Case Study

• 52 year old female with rheumatoid

arthritis (RA)

• Current therapy (visit date October 2015)

– Methotrexate 25mg week

– Prednisone 10mg daily

• RA disease severity with little change

– Considering biologic therapy

Her Feelings About Vaccines

• Patient not enthusiastic about vaccinations

– “Have egg allergy”

– “My husband gets the flu from the flu shot”

– “They have mercury in them that can cause

Alzheimers disease”

Freidman M, Winthrop KL. Curr Opin Rheum. 2016.

PCV-13: CAPITA Trial

• PCV-13 Vs. placebo, Netherlands (n=85,000)

• Vaccine-type pneumococcal community-

acquired pneumonia

– 45.6% (22%-62.5%) efficacy

• Vaccine-type invasive pneumococcal disease

– 75% (41-91%) efficacy

MMWR. 2014 / 63(37).

MMWR, October 12, 2012; 61(40):816-9.

Influenza

• Inactivated annual vaccine for all

rheumatologist patients

– High dose Flu-Zone®?

– Quadrivalent

– “Egg allergy” not a contraindication

• 2016-2017 vaccine

– A/California/7/2009(H1N1)

A/Hong Kong/4801/2014(H3N2)

B/Brisbane/60/2008 (victoria lineage)

B/Phuket/3073/2013 (yamagata lineage)

https://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm

High Dose (HD) Flu > 65 Years Old

• HD Vs. Standard Dose (SD) (N=31,989)

• Outcome = lab-confirmed flu

– 228 (1.4%) HD Vs. 301 (1.9%) SD

– Relative efficacy, 24.2%

– Higher percentage of protective titers with HD

• SAEs similar between groups

– (8.3%) HD Vs. (9.0%) SD

DiazGranados CA, et al. NEJM. 2014.

Curtis J, et al. EULAR. abstract 2014.

Herpes Zoster (Shingles)

HZ (Shingles)

Calabrese L, et al. Arthritis and Rheum. 2016.

• 1/3 lifetime risk

• 15% with post-herpetic neuralgia

• Ocular complications, stroke

142

Table 2: Events, absolute incidence rate and adjusted hazard ratio of Herpes Zoster infection by

different types of biologics and other RA Medication

Biologic Exposures Events

Person

years

(pys)

Absolute incidence rate

per 100 pys (95% CI)

Adjusted hazard ratio*

(95% CI)

Non-Anti TNF mechanism of action

Abatacept 142 7614 1.87 (1.58-2.20) 1.00 (Ref)

Rituximab 82 3611 2.27 (1.83-2.82) 1.20 (0.88-1.63)

Tocilizumab 18 839 2.15 (1.35-3.40) 1.05 (0.60-1.84)

Anti-TNF mechanism of action

Adalimumab 46 2638 1.74 (1.31-2.33) 1.04 (0.72-1.51)

Certolizumab 19 774 2.45 (1.57-3.85) 1.30 (0.77-2.23)

Etanercept 48 2229 2.15 (1.62-2.86) 1.26 (0.87-1.81)

Golimumab 11 683 1.61 (0.89-2.91) 0.91 (0.47-1.76)

Infliximab 57 3135 1.82 (1.40-2.36) 0.98 (0.69-1.39)

Prednisone

None 128 8548 1.50 (1.26-1.78) 1.00 (Ref)

≤ 7.5mg/day 209 9841 2.12 (1.85-2.43) 1.55 (1.25-1.93)

> 7.5mg/day 86 3134 2.74 (2.22-3.39) 2.35 (1.81-3.04)

Yun H, et al. Arth Car Res. 2014.

Curtis JR et al. ARD 2016

Real World HZ with Tofa and Biologics

Zostavax ®

• RA vaccination rate is low

– Safety and efficacy in RA?

Jie J, et al. JAMA. 2012.

Hui Y, et al. ACR Abstract. 2015.

Long Term Protection Wanes

Quillaja saponaria

Lal H, et al. NEJM. 2015.

Chik-V (Alphavirus)

Sudeep AB. J Biosci. 2008.

• Chikungunya, Ross River

• 48% with arthritis up to 6 months

post-infection

– Subset develop chronic arthritis

• Rash, fever, edema of face, LFT elevation,

thrombocytopenia

• Treatment with steroids,

NSAIDS, MTX, HCQ, TNFi

Potential range of Zika,

Chikungunya, and Dengue

Move to Oregon

while you still can

Acknowledgments

• Colleagues from:

– American College of Rheumatology

– European Union League Against Rheumatism

– Oregon Health and Science University

– University of Alabama Birmingham (UAB)