opportunistic infections and tuberculosis risk management · 2017-09-13 · opportunistic...
TRANSCRIPT
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)