Risk and Prevention of Infection with Biologics and Small Molecular

Therapies

Kevin L. Winthrop, MD, MPH Professor, School of Public Health

Division of Infectious Diseases Oregon Health & Science University

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Disclosures

• Research funding from Pfizer, BMS• Scientific consultant work for Amgen, Abbvie,

Pfizer, UCB, Genentech, BMS, Lilly• Data safety monitoring boards for RCTs

conducted by UCB, Roche, Astellas, Lilly, Janssen, GalapagosOHSU

IMID Biologic Therapies• TNF-α 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: tocilizumab, sarilumab– Anti- IL12/IL23 antibody: ustekinumab– Anti-IL-17A: secukinumab, ixekizumab

• Small molecules (non-biologic)– JAK inhibitor: tofacitinib, baricitinib, upadacinitib

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“Low Dose” Corticosteroids and Infections

• Always a risk in observational studies– Limited RCT data suggests no increased risk

• What is the truth?– Confounding due to disease activity

versus true increased riskOHSU

George M et al. Annals Int Med (in Press)

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George M et al. Annals Int Med (in Press)

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Baddley J, Winthrop KL et al. Presented IDSA 2011

PJP crude incidenceTNFi starters, 56/100,000

SABER

Non-viral OIs

TNFi starters 270/100,000Non-biologics 170/100,000OHSU

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Psoriasis and TNFi

• Started on Adalimumab• Constitutional symptoms worsen• Worsened thumb abscesses• Cough and back pain

– Sputum grew M. tuberculosis

– Epidural abscess grew M. tuberculosis• Disseminated TB diagnosed

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Treatment and Course

• Treated with 4 drugs • Starting 2-3 months into therapy

– Para-spinal abscess at C6, T2, T6, T8– Required multiple drainage/laminectomies– Recurrent abscess at left thumb

• Over next 6 months with recurrent abscesses– Month 4---epidural abscess--AFB culture negative– Month 5---finger---AFB culture negative– Month 6 ---epidural abscess---AFB culture

negative

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QFT-Plus• Uses ESAT-6, CFP-10

– TB1 (CD4) and TB2 (CD8)• Specificity

– 98.1% (95% CI 95.6, 99.4)• Sensitivity (in active TB)

– 93% (95%CI 87.8, 96.5)• New result reporting

– TB1-nil >0.35 – TB2-nil >0.35

Horne D et al. IJTLD (In Press); Siegel S et al. ATS abstract 2016

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LTBI Treatment

MMWR (69), FEB 2020

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Environment? Host? Killer showerheads?

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

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Namkoong H et al. EID 2016

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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

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n (%) IR/100 p-y (95% CI)

Opportunistic infections* 45 (0.6)† 0.21 (0.15, 0.28)†

Bronchopulmonary aspergillosis 2 (<0.1) 0.01 (0.00, 0.03)Eye infection, fungal 3 (<0.1) 0.01 (0.00, 0.04)Oesophageal candidiasis 7 (0.1) 0.03 (0.01, 0.07)Fungal oesophagitis 1 (<0.1) 0.00 (0.00, 0.03)Pneumocystis jirovecii pneumonia 1 (<0.1) 0.00 (0.00, 0.03)Pneumonia pseudomonal 1 (<0.1) 0.00 (0.00, 0.03)Respiratory moniliasis 2 (<0.1) 0.01 (0.00, 0.03)Tuberculosis, including latent tuberculosis 17 (0.2)‡,§ 0.08 (0.05, 0.13)‡

• Cumulative abatacept exposure(N=7044; 21,335py)

Abatacept and Opportunistic Infection

(RCT and LTE)

Simon T et al. EULAR Oral abstract 2017

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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)

Baddley et al., ACR 2012

“OIs” with other Biologics

Incidence rate: 144/100,000 p-yrs

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RTX and Real World• Sunstone---989 patients open-label

– SIE incidence 8.8/100 pt-yrs– OI incidence 290/100,000 pt-yrs

• Among 4,479 patients receiving RTX– 87.5% had no IgG assessment

• 8.1% of those checked = hypo IgG– 33% with SIEs

Winthrop KL et al Arth Res Care 2018;Barmettler S et al. JAMA Open 2018

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Langley et al. NEJM 2014

Secukinumab

Secu 300mg Secu 150mg ETN

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

• Candida

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Anti-IL-23 Safety Profile

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761061s000lbl.pdf

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RTI and IL-23 Phase 3 studies PsO

Syed M et al. JAAD 2020

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Clark JD, et al. J Med Chem. 2014.

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Tofacitinib and “Opportunistic” Infections (P2P3LTE)

• 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

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Curtis J et al. ARD 2016

Real World HZ with Tofa and Biologics

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JAKs and TB Risk Similar to TNFi?

Winthrop KL et al. ACR oral abstract 2017

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HBcAB+/HBsAb-: 2 (14%) reactivated

HBcAB+/HBsAb+: 30 (15%) reactivated

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How to Mitigate Infectious Risk?

• Use lowest dose biologic/JAK possible• Avoid corticosteroids• Laboratory monitoring• Screen for TB, HBV, HCV• Vaccinate

– Influenza, pneumococcus, shingles

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VERVE Trial

• All active anti-TNF users (most RA)– N=617

• 1:1 live shingles vaccine versus placebo• Results

– Immunogenicity diminished as expected– Safety---No cases of vaccine HZ in 42 days

post-vaccination

Curtis J et al. ACR abstract 2019

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Quillaja saponaria

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Shingrix in RA?

Stevens E et al. EULAR abstract 2019

6.7% experienced flare13.4% vaccine-related side effects

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Influenza• Inactivated annual vaccine for all rheumatologist patients

– High dose flu vaccine or adjuvenated flu vaccine for “old” people?

– Quadrivalent versus trivalent– “Egg allergy” not a contraindication

• 2020-2021 egg-based vaccine– A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-

like virus – A/Hong Kong/2671/2019 (H3N2)-like virus – B/Washington/02/2019 (B/Victoria lineage)-like virus – B/Phuket/3073/2013-like (Yamagata lineage)

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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

Diaz Granados CA et al. NEJM 2014.

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HD in RA?

Colmegna I et al. ACR abstract 2018

• N= 279 RA

H3N2 B H1N1

HD SD HD SD HD SD

Seroprotection 49% 31% 61% 51% 80% 73%

Seroconversion

22% 8% 45% 29% 51% 30%

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https://www.fda.gov/media/132238/download

HD Quadrivalent

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COVID-19

https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200907-weekly-epi-update-4.pdf?sfvrsn=f5f607ee_2

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Richardson P et al. Lancet 2020

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Acknowledgements

• UAB colleagues

• ACR and EULAR colleagues

• Oregon Health Authority colleagues

• CDC colleaguesOHSU

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https://www.cdc.gov/covid-data-tracker/index.html

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ACR Guidance

https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-Patients-with-Rheumatic-Diseases.pdf

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https://www.idsociety.org/practice-guideline/covid-19-guideline-diagnostics/

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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 actionAbatacept 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 actionAdalimumab 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.

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