Opportunistic Infections and Tuberculosis Risk Management

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1 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

2 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

3 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

4 Prednisone Sparing Effect Strangfeld A, et al. ARD

5 Yun H, et al. ARD

6 Risk of Serious Infection After an anti-tnf Associated Serious Infection (in RA) Biologics Referent 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 ( ) 0.87 ( ) 0.96 ( ) 0.94 ( ) 1.0 (Ref) Rituximab 0.85 ( ) 0.93 ( ) 1.03 ( ) 1.0 (Ref) Etanercept 0.83 ( ) 0.90 ( ) 1.0 (Ref) Adalimumab 0.92 ( ) 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

7 Secukinumab (anti-il17a) Candida Secu 300mg Secu 150mg ETN 22 (4.7%) 11 (2.3%) 4 (1.2%) Langley, et al. NEJM

8 Ixekizumab Griffiths CEM, et al.

9 IR (events/100 pt-yrs [95% CI]) 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 events/ 100 patient-years Rituximab events/ 100 patient-years Tocilizumab events/ 100 patient-years Etanercept 3.8 events/ 100 patient-years Abatacept events/ 100 patient-years Golimumab 5.09 events/ 100 patient-years to 6 6 to to to to to to 42 >42 Months Cohen S, Radominski SC, Gomez-Reino JJ, et al. Arthritis Rheumatol Jul 21. Slide prepared by CSF

10 Winthrop K, et al. ARD

11 SABER Non-viral OIs TNFi starters 270/100,000 Non-biologics 170/100,000 PJP crude incidence TNFi starters, 56/100,000 Baddley J, Winthrop KL, et al. Presented IDSA

12 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

13 OIs with Other Biologics Opportunistic Infection 1 Abatacept n=338 PY=486.5 Adalimumab n=1826 PY= Etanercept n=741 PY= Infliximab n=358 PY=511.2 Rituximab n=511 PY=650.8 Zoster Tuberculosis Pneumocystosis Legionellosis Coccidioidomycosis Histoplasmosis Non-tuberculous mycobacteria Salmonellosis Nocardiosis TOTAL OIs IR (95% CI) per 100 p-years Baddley, et al. ACR (0.4, 2.6) 1.6 (1.2, 2.2) 1.6 (1.0, 2.5) 0.8 (0.3, 2.1) Total N=3774 PY= (1.0, 3.2) 1.5 (1.2, 1.9) Incidence rate: 144/100,000 p-yrs

14 Tofacitinib and Opportunistic Infections (P2P3LTE) 60 OIs reported (IR 0.46/100 pys [ ]) 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

15 Hsia E, et al. Arth Rheum

16 QFT-Plus 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) Siegel S, et al. ATS Abstract

17 New Therapy Option INH and Rifapentine 3 months, once weekly (directly observed?) Sterling T, et al. NEJM

19 Environment? Host? Killer showerheads? Related to publication by Feazel et al: Opportunistic pathogens enriched in showerhead biofilms. PNAS 2009: 38:

20 Singing in the Shower Case #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 minute hot, steamy showers

22 What To Do? Wait and see vs. change the race-horse Stop TNF? Start MTX? Switch biologic? Stop taking showers? Treat her M. avium?

24 32 Year Old, Myositis, Rituximab, Disseminated M. Kansasii Forearm Nodules

25 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)

26 Environment? Host? Killer showerheads? Related to publication by Feazel et al: Opportunistic pathogens enriched in showerhead biofilms. PNAS 2009: 38:

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

28 Two weeks after last infliximab dose for uveitis

29 4 weeks later after receiving infliximab again

30 Hematogenous dissemination

31 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

32 (Adapted from Diestag, 2008)

33 Winthrop KL et al ARD 2011

34 Vaccines & Preventable Diseases Live BCG Influenza (nasal) Mumps/Measles/Rubell a Polio (oral) Rotavirus Shingles Smallpox Varicella Yellow Fever Typhoid (oral) Not-live Anthrax Hepatitis A Hepatitis B Influenza (IM) H. influenzae HPV Japanese Encephalitis Meningococcal Pneumococcal Poliomyelitis (IM) Rabies Tetanus/diptheria/pertussis (Td/Tdap) Typhoid (IM)

35 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

36 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

37 Freidman M, Winthrop KL. Curr Opin Rheum

38 PCV-13: CAPITA Trial PCV-13 Vs. placebo, Netherlands (n=85,000) Vaccine-type pneumococcal communityacquired pneumonia 45.6% (22%-62.5%) efficacy Vaccine-type invasive pneumococcal disease 75% (41-91%) efficacy MMWR / 63(37).

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

40 Influenza Inactivated annual vaccine for all rheumatologist patients High dose Flu-Zone? Quadrivalent Egg allergy not a contraindication vaccine A/California/7/2009(H1N1) A/Hong Kong/4801/2014(H3N2) B/Brisbane/60/2008 (victoria lineage) B/Phuket/3073/2013 (yamagata lineage)

42 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

43 Herpes Zoster (Shingles) Curtis J, et al. EULAR. abstract 2014.

44 HZ (Shingles) 1/3 lifetime risk 15% with post-herpetic neuralgia Ocular complications, stroke Calabrese L, et al. Arthritis and Rheum

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)

45 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 ( ) 1.00 (Ref) Rituximab ( ) 1.20 ( ) Tocilizumab ( ) 1.05 ( ) 142 Anti-TNF mechanism of action Adalimumab ( ) 1.04 ( ) Certolizumab ( ) 1.30 ( ) Etanercept ( ) 1.26 ( ) Golimumab ( ) 0.91 ( ) Infliximab ( ) 0.98 ( ) Prednisone None ( ) 1.00 (Ref) 7.5mg/day ( ) 1.55 ( ) > 7.5mg/day ( ) 2.35 ( ) Yun H, et al. Arth Car Res

46 Real World HZ with Tofa and Biologics Curtis JR et al. ARD 2016

47 Zostavax RA vaccination rate is low Safety and efficacy in RA? Jie J, et al. JAMA

48 Long Term Protection Wanes Hui Y, et al. ACR Abstract

49 Quillaja saponaria

50 Lal H, et al. NEJM

51 Chik-V (Alphavirus) 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 Sudeep AB. J Biosci

52 Move to Oregon while you still can Potential range of Zika, Chikungunya, and Dengue

53 Acknowledgments Colleagues from: American College of Rheumatology European Union League Against Rheumatism Oregon Health and Science University University of Alabama Birmingham (UAB)

JAK Inhibitors and Safety

JAK Inhibitors and Safety Kevin L. Winthrop, MD, MPH Associate Professor, Divisions of Infectious Diseases, Public Health, and Preventive Medicine Oregon Health & Science University Learning Objectives