Contemporary Views of the Impact of Biologic Therapy on Infection Risk

Transcription

1 Contemporary Views of the Impact of Biologic Therapy on Infection Risk Cezarina Mindru, M.D. Assistant Professor of Medicine Baylor College of Medicine VA Michel E. Debakey, Houston, TX Faculty Disclosures Dr. Mindru has listed an affiliation with: Consultant Gilead Sciences, Inc. However, no conflict of interest exists for this conference. Special thanks to Dr. John W. Baddley, UAB. 1

2 Objectives Describe the frequency of infectious complications associated with TNF alpha inhibitor use Measures we can take to mitigate those risks Discuss few cases TNF alpha: the good and the bad Tsiodras et al. Mayo Clin Proc 2008;83:

3 Nature Reviews: Immunology 3

4 Traditional TNF alpha inhibitors Drug Brand Mechanism Approval Indications infliximab Remicade Chimeric anti-tnf mab etanercept Enbrel Soluble TNF- receptor fusion protein adalimumab Humira Human anti-tnf mab golimumab Simponi Human anti-tnf mab certolizumab Cimzia Pegylated Fab frag humanized mab IBD, RA, AS, PsA, plaque Ps 1998 RA, AS, JIA, PsA, plaque ps 2008 IBD, RA, AS, JIL, PsA, plaque ps, HS, uv UC, RA, AS, JIA, PsA 2008 CD, RA, AS, PsA Other agents Drug Brand Mechanism Approval Indications rituximab Rituxan Anti CD RA, lymphoma, CLL, polyangiitis anakira Kineret IL-1 rec.antagonist 2001 RA abatacept Orancia CTLA-4 ligand, select 2005 RA Tcell costim. ustekinumab Stelara Ab anti IL-12,IL psoriasis tocilizumab Acterma Ab anti-il-6 reeptor 2010 RA, JIA belimumab Benlista Ab anti B-cell act. fact 2011 SLE tofacinib Xelianj JK inhibitor 2012 RA 4

5 - Risk of infections with use of TNF alpha inhibitors increased risk for granulomatous inf. TB (reactivation) theoretically increase susceptibility to intracellular pathogen- bacteria (Listeria, Salmonella spp.) viruses (HBV, VZV, JC) may cause neutropenia- increase IFI dependent on agent Clinical trials not powered to detect adverse events such as rare infections high rate of co-morbidities in patients immunosuppressant use associated with disease severity (confounding) patients receiving many immuno-supressants (impact of prednisone?) Case 38 yo man with severe IBD, currently on po steroids, is being evaluated for biologic therapy. A TST was 11 mm and a Quantiferon test is borderline. Patient is a healthcare worker and states he has been always allergic to PPD and CXR yearly was negative. He was told that BCG he received in his country of origin would make PPD positive for ever. What do you recommend? 5

6 LTBI and TNF alpha inhibitor use What is the best strategy for LTBI screening? Single step TST followed by ELISA based IGRA Is the systematic retesting needed while on anti TNF? Not if risk is low Unclear in highly endemic area- yes in RA, annually, if ongoing or future risk (21-29% converts at least one LTBI screening assay during the first year of therapy - but no active TB noted) When do we start biologics after initiation of LTBI treatment? At least a month Sing JA et al, ACR, Arthritis care 2012 Hatzara C et al, AnnRheum Dis 2015 Cantini F, et al, Autoimmun Rev (2015) LTBI and TNF alpha inhibitor use LTBI- 4x increase in risk of developing active TB Screening and treatment LTBI reduced but not completely eliminated risk of reactivation -age, comorbidities, previous/concurrent DMARDs -cumulative steroid use* -disease itself (RA 2-8.9x; PsAx 3.1, AS x3.9) -defective/incomplete compliance with guidelines 7x -etarnecept has the lowest risk -IBD 2-2.5xrisk of developing active TB 6

7 Case 56 y.o. male with severe seropositive RF, nodular RA with vasculitis 2009 Abnormal CT lung small caseating granuloma in his lung by bx; no cultures sent!; not felt to be caused by TB On Humira since 2012 with dramatic improvement in symptoms; 1/2017: Weight loss, poor appetite, night sweats, cough, dyspnea 2/2017: T spot positive. Sputum sent, BAL; 1/3 +M.fortuitum. 3 small nodules RUL on CT chest 2/2017: Candida esophagitis -responded splendidly to fluconazole 3/16/2017: 2/3 M. fortuitum Case points? Do we treat LTBI (positive T-spot)? Do we consider M. fortuitum pathogenic? Do we restart biologic (poor QOL)? 7

8 Case (con t) 3/30/2017: seen, prescribed Bactrim, moxifloxacin and tedizolid ; INH/B6 6/22/2017: doing well, completely quit smoking; minimal cough, no hemoptysis; main issue is lower back pain; wants surgery for QOL. 6/30/2017: AFB + in broth week 1, smear negative, result reported 7/19/2017 M. fortuitum 9/2017 :AFB+ 1/3 M. fortuitum, growth week 2- broth. Smear negative 7/24/2017: CT chest: 2/3 nodules stable, one mildly improved; quit smoking 8/23/2017: sputum 3/3 growth, smear negative but 3/3 MAC! 9/18/2017: had surgery of the lumbar spine, with improvement in QOL, pain Other case points? Changed to azithromycin/ethambutol/rifampin M. fortuitum?... Had spine surgery- when do we restart the biologic? For how long do we treat? 8

9 The Nontuberculous Mycobacteria and TNF alpha inhibitors Incidence of TB (per 100,000 p-years) Incidence of NTM (per 100,000 p-years) Relative Risk (NTM/TB) All Anti-TNF Users 49 (95% CI 18-79) 74 (95% CI ) 1.5 Anti-TNF >59 y/o 64 (95% CI ) 118 (95% CI ) 1.8 RA Anti-TNF Users 56 (95% CI ) 112 (95% CI ) patients Winthrop et al., Ann Rheum Dis 2013;72:37-42 Other serious bacterial infections Occur early (<6 months) after staring anti-tnf 2-14/100 person years Probably an increase of 2-3 infections/100 person-years with a biologic (relative increase of %) compared to non-biologic DMARDS monoclonals (ada/inflix)- more risky versus etanercept/abatacept underlying disease confers an increased risk for specific infection (septic arthritis in RA, intra-abdominal abscess in IBD) 2015: 2x risk of serious infections 2016: in IBD no increased risk; it seems CD activity index and steroids/dmadrs are more important! Steroids and co-morbidities important contributors Singh JA et al, Lancet 2015 Bonovas et al, Clin. Gastroenterology 2016 Osterman et al, Am J. Gastroenterology 2016 Baddley et al,

10 Fungal infections and TNF alpha inhibitors Numerous case reports Meta-analysis (RA): -only 9 cases of non-pjp IFI (5 IA)*; no increased risk of IFI with biologics Infections occur within 1-6 months of starting the biologic Advanced disease; high morbidity and mortality (FDA black box warning) Pneumocystosis (0.5/100,000) Histoplasmosis (2-19/100,000) Coccidioidomycosis (1-5/100,000) French study : /100,000 p-yrs (PJP, crypto, Aspergillus) 41 non-tb OIs were identified Risk factors for OIs: steroid therapy (>10mg/d) and monoclonal TNF antibodies Kourbeti et al., Clin Infect Dis 2014 Salmon-Ceron et al., Ann Rheum Dis ,309 pt screened 33, 324 TNF 80 OIs 16 PJP Crude rate (/1000 p-yrs) Adjusted Rate Comparator 1.7 (1.2, 2.5) ref TNF users 2.7 (2.2, 3.4) 1.6 (1.0, 2.6) Baseline steroids 2.5 (1.5, 4.0) Baddley et al., Ann Rheum Dis

11 Management of IFIs Stop the biologic: beware of IRIS (42% in Histoplasmosis study) Standard course of antifungal therapy Document clinical resolution of infection Re-start the biologic? Chronic suppressive therapy/secondary prophylaxis? Histoplasmosis: Restarted in 4/15; 1 had recurrence Coccidioidomycosis : 44 cases (9 disseminated), treated x9mo avg., restarted after 10 months, no recativation Candida : Candida infections in 4.7% on secukinimab (IL-17 pathway), greater than etanercept 1.2% (no need to stop therapy) Need more data regarding re-starting biologics and duration of antifungal therapy Hage, C. et al. Clin Infect Dis 2010;50:85-92 Olson et al BMC ID 2011 Taroumian et al., Arthritis Care and Research, 2012 Langley et al, NEJM 2014 Viral Infections and TNF alpha inhibitor use Reactivation of varicella-zoster virus Reactivation of hepatitis B HSV (severe cases) JC virus (PML)-rituximab WNV (1 case) Risk of EBV, CMV controversial (steroids*) HCV infection is not worsening on therapy Baddley, JW et al., CMI

12 Case 62 y.o woman with RA on tofacinib presents to her rheumatologist with 2 days of low grade fever and a rash. Did she need VZV vaccination? VZV infection and TNF inhibitors Year Published Source HR for VZV 2009 German, RABBIT registry US, Veterans Affairs French, RATIO registry US, 4 databases British, BSRBR database US, 4 databases, tofacinib (JAK i) 4.4 (if max +GC) Novasad and Winthrop, Clin Infect Dis 2014 Winthrop el al, Arthritis Rheumatol

13 Case 32 y.o man born in Vietnam is being treated for IBD. He failed few courses of DMARDs and is planned to start infliximab. Hepatitis B serology shows positive HBsAg, positive HBcAb, negative HBsAb. ALT, AST, bilirubin, INR, albumin are normal. Abdominal US is unremarkable. What is the next test you perform? If deciding to treat, what would you choose? HBV reactivation and biologics all rheumatic disease patients who are scheduled to start treatment with biological and/or non-biological DMARDs should receive screening for HBV infection. :HBsAg, anti-hbc, and anti-hbs If HBsAg + and DNA high- start antiviral If only isolated HBc Ab+- the data is not clear except rituximab 13

14 Risk of HVB reactivation Bessone F. et al, World Journal of Gatroenterorogy 2016 Conclusions Biologics are here to stay Biologics are associated with increased incidence of infections, and often with increased severity of disease Mycobacterial diseases, bacterial infections and zoster are the most important No benefit from antibacterial/antifungal/antiviral prophylaxis Age appropriate use of vaccines (inactive, some live vaccines) important Newer drugs will bring new challenges Baddley, JW, et al., ESCMID Study Group, Clin Microbiology and Infection

15 Thanks! if any questions 15