Annual Rheumatology & Therapeutics Review for Organizations & Societies

Transcription

1 Annual Rheumatology & Therapeutics Review for Organizations & Societies

2 Opportunistic Infections and Tuberculosis Risk Management

3 Learning Objectives Define the risks of TB and non-tb opportunistic infections, identifying the differences depending on the type of TNF inhibitor Identify which patients have the highest risk for infection

4 Biologics in Rheumatoid Arthritis Agent Biologic Target Construct Infliximab TNF Chimeric MAb Etanercept TNF IgG-p75 receptor Adalimumab TNF Human MAb Goliumumab TNF Human MAb Certolizumab TNF Peg-Fab Abatacept T-cell costim IgG-CTLA4 fusion Rituximab B-cells Chimeric MAb Anakinra IL-1 IL-1 Recpt antag Tocilizumab IL-6 Anti-IL6 Recept MAb * Tofacitinib is NOT a Biologic

5 Scope of Infections Associated with Biologic Use Anti-TNF Anakinra Abatacept Rituximab Tocilizumab Tofacitinib NSIE SIE Bacterial TB & Myco * * * Fungal & Opportunistic * * Hepatitis B * * Hepatitis C * H. Zoster * * * PML * Increased risk from PI, RCTs & Registries * Few cases reported NSIE: nonserious infectious events (URI, etc) SIE: serious infectious events PML: progressive multifocal leukoencephalopathy

6 The Problem with Steroids 30-60% of RA patients take prednisone Demonstrable clinical and radiographic benefits Steroids significantly increase the odds of: Non-serious infections Serious bacterial infections Mycobacteria (TB, NTM) Other opportunistic infections (eg, PCP, Zoster) Dose-dependent risk factor. Risk increased even at lowest doses (<5mg/day) Blunt/obscure fever, signs/sxs Used frequently long term Recommended for short term use

7 Prednisone and Tuberculosis General Practice Research Database, UK TB cases and controls Current glucocorticoid use *OR 4.9 ( ) <15mg/day *OR 2.8 ( ) >15mg/day *OR 7.7 ( ) *Adjusted for smoking, BMI, lung disease, diabetes, anti-rheumatic therapy, other TB risk factors Controls matched for age, sex, residence, time clinically followed Jick et al. Arthritis Rheum 2006

8 Global TB Epidemiology Courtesy of World Health Organization

9 TB Risk Risk of prior TB exposure Prior contact to case 30 Relative Risk RA +TNF Birth or extended living (>3 months) in countries where TB is endemic Regions other than North America, Western Europe, Australia/NZ Living or working in Homeless shelters 9 RA +TNF RA No TNF Jail/prison Health care settings (where TB is seen) Increased risk of TB disease varies 5-10 fold or more TB risk # /100,000pt-yrs 2 RA No TNF NL NL 1. Winthrop K. EULAR 2005, #SP0005; 2. Askling J, et al. Arthritis Rheum 52: , Seong SS, et al Apr;34(4): Singh JA, etl. Cochrane Reviews 2011 Baronnet et al. / Joint Bone Spine 78 (2011) Sweden Korea

10 Cumulative Incidence UK Biologic Registry 1% Incident TB Nelson-Aalen plot ADA 0.5% INF ETA 0% DMARD Drug Dixon WG et al. Ann Rheum Dis 2010:69: Days since registration Registration (entry to study) 1 year (365 days) 2 years (730 days) 3 years (1095 days) 4 years (1460 days) DMARD ETA INF ADA

11 Table 1. Crude incidence rates of tuberculosis and nontuberculous mycobacterial disease (NTM) among anti-tnf users, Kaiser Permanente Northern California, Crude incidence rate (95% CI)* Tuberculosis NTM 1 All Anti-TNF users 49 (18-79) 74 (37-111) a Etanercept users 17 (0-41) 35 (1-69) b Infliximab users 83 (10-156) 116 (30-203) c Adalimumab users 61 (0-145) 122 (3-241) 2 Anti-TNF users 50 years old 64 (26-132) 118 (63-202) *rate per 100,000 patient years (95% confidence interval) 1 All anti-tnf users: 10 Tuberculosis cases/20,409 person-years, 15 NTM cases/20,270 person-years; a Etanercept users: 2 Tuberculosis /11,765 person-years, 4 NTM cases/11,429 person-years; b Infliximab users: 5 Tuberculosis cases/6,024 person-years, 7 NTM cases/6,035 person-years; c Adalimumab users: 2 Tuberculosis cases/3,279 person-years, 4 NTM cases/3,279 person-years; 2 Anti-TNF users 50 years old; 7 Tuberculosis cases/11,011 person-years, 13 NTM cases/11,017 person-years Winthrop K et al. ARD 2013

12 Survival (%) Log 10 cfu Survival (%) Log 10 cfu Granuloma Penetration A 100 Survival of acutely infected mice B 9.0 Bacterial burden in the lungs MP6-XT22 hi mtnfr2-fc hi lgg1 hi MP6-XT22 lo mtnfr2-fc lo lgg1 lo MP6-XT22 mtnfr2-fc lgg Days after injection Days after injection D Survival of chronically infected mice Bacterial burden in lungs mg/dose MP6-XT mg/dose mtnfr2-fc 0.5 mg/dose mtnfr2-fc 60 7 Control C MP6 0.5 mg/dose mtnfr2-fc 0.2 mg/dose mtnfr2-fc 0.5 mg/dose Control Days after first injection Days after first injection Plessner HL et al JID 2007

13 Mycobacteria with Newer RA Biologics Rituximab Cases of TB and NTM reported in case-series fashion. Most on prednisone Abatacept Clinical trial program, 7 TB cases reported (rate 60/100,000) Tocilizumab Clinical development program, 10 TB cases (rate 100/100,000). Post-marketing surveillance in Japan, 4 cases (rate 220/100,000) Simon TA et al. Arth Res Ther 2010; Koike T et al. ARD 2011; Winthrop K et al. CID 2009

14 Tofacitinib in RA JAK 1/3 inhibition Tuberculosis rate = 173/100,000 37/100,000 (North America/Western Europe) Most cases at 10mg BID dose All cases screened negative prior to trial entry Mechanism? Macrophage control of TB Interferon signaling? Winthrop et al abstract, American College of Rheumatology (ACR), Washington DC, Nov 2012

15 Interferon-gamma Release Assays (IGRAs)

16 IGRAs Specificity ESAT CFP M.tuberculosis + + M. africanum + + M. bovis + + BCG substrain Gothenburg - - Moreau - - Tice - - Tokyo - - Danish - - Glaxo - - Montreal - - Pasteur - - Andersen, et al. Lancet 2000;356(9235):1099. ESAT CFP M. abcessus - - M. avium - - M. branderi - - M. celatum - - M. chelonae - - M. fortuitum - - M. gordonii - - M. intracellulare - - M. kansasii + + M. malmoense - - M. marinum + + M. oenavense - - M. smegmatis - - M. scrofulaceum - - M. szulgai + + M. terrae - - M. vaccae - - M. xenopi - -

17 Comparison of LTBI Screening Methods TST in vivo Poor specificity of PPD False positives with BCG 2 patient visits results in 2-3 days Difficult to place and read read in hrs false negative results occur in immunosuppressed IGRA in vitro Higher specificity in those with BCG 1 patient visit results in 24 hrs lab variability IND and false negative results occur in immunosuppressed

18 Relative Sensitivity of IGRA Case-control study, Peru 80% BCG use in both groups High prednisone use among RA group RA (n = 101) Controls (n = 93) TST+ 27 (27%) a 61 (66%) QFT-IT+ 45 (45%) 55 (59%) Ponce de Leon D et al. J Rheumatol. 2008;35:

19 Golimumab and TB N= 2,282 RA, PsA, AS development program Screened with TST and QFT-IT 5 patients developed active TB All 5 screened negative at baseline 2 with TST of 5mm or 15mm (negative by local standards) 317 screened positive INH and golimumab No TB cases Hsia E et al. Arth Rheum 2012

20 B C TST TST QFT-GIT + 71 QFT-GIT + 72 Figure 1. Overlap of screening test results and rates of positivity from the tuberculin skin test (TST) and an interferon-γ release assay (i.e., the QuantiFERON-TB Gold In-Tube [QFT-GIT] test) for the detection of latent tuberculosis infection in all patients (A), bacillus Calmette-Guérin (BCG)- vaccinated patients (B), and non-bcg-vaccinated patients (C). Hsia E et al. Arth Rheum 2012

21 IGRAs in the Immunocompromised Anergy with TST and IGRAs IGRAs less affected by prednisone? False negative with IGRA in patients already receiving anti-tnf therapy 1 Indeterminate results 2 QFT-IT and T-SPOT.TB in 2-5% LTBI sensitivity 2 QFT-IT similar to T.SPOT.TB (and probably greater than TST) 1. Hamdi H et al. Arthritis Res Ther. 2006;8:R Lalvani A, Millington KA. Autoimmun Rev Epub ahead of print.

22 Figure American College of Rheumatology recommandations update for tuberculosis (TB) screening with biologic agent use. Depending on a patient's current therapy. the management may begin at an appropriate rectangle in the figure. rather than only at the top of the figure. The level of evidence supporting each recommendation for TB reactivation was "C." except for initiation of biologic agents in patients being treated for latent TB infection, where the level of evidence was "B." Anergy panel testing is not recommended. t Interferon-?-release assay (IGRA) is preferred if the patient has a history of BCG vaccination. Risk factors for TB exposure are defined based on a publication from the US Centers for Disease Control and Prevention as: close contacts of persons known or suspected to have active TB: foreign-born persons from areas that have a high incidence of active TB (e.g.. Africa. Asia, Eastern Europe. Latin America, and Russia): persons who visit areas with a high prevalence of active TB. especially if visits are frequent or prolonged: residents and employees of congregate settings whose clients are at an increased risk for active TB (e.g.. correctional facilities, long-term care facilities, and homeless shelters): health care workers who serve clients who are at an increased risk for active TB: populations defined locally as having an increased incidence of latent Mycobacterium tuberculosis infection or active TB, possibly including medically undersorved. low-income populations, or persons who abuse drugs or alcohol: and infants, children. and adolescents exposed to adults who are at an increased risk for latent M tuberculosis infection or active TB (14). If the patient is immunosuppressed and false-negative results are more likely. consider repeating screening testis) with tuberculin skin test (TST) or IGRA. I Chest radiograph may also be considered when clinically indicated in patients with risk factors. even with a negative repeat TST or IGRA. * Obtain respiratory (e.g., sputum, bronchoalveolar lavage fluid) or other samples as clinically appropriate for acid-fast bacilli (AFB) smear and culture and consider referral to a TB specialist for further evaluation and treatment. * In a patient diagnosed with latent or active TB. consider referral to a specialist for the recommended treatment Patients who test positive for TST or IGRA at baseline often remain positive for these tests even after successful treatment of TB. These patients need monitoring for clinical signs and symptoms of recurrent TB disease, since repeating tests will not allow help in diagnosis of recurrent TB.

23 Screening in the Biologics Setting: Words to Live by A priori probability reigns supreme If they should be positive, then they probably are If they shouldn t be positive, they probably aren t If risk factors and immunosuppressed, consider using two screening tests Maximize sensitivity If you don t believe your test result, REPEAT it!

24 Rate per 100 patient-years TB Screening Lowers TB Rates >80% Pre-screening Adalimumab RA Clinical Trials Post-screening Phase 1 2 Phase 3 and extension ReACT All cases No. of cases Exposure (pt yrs) + = *Through December 2003 Biobadaser ,729 RA pts (7,825 pt-yrs TNFi Rx) Before screening guidelines: 32/6,126 TB rate 522/100,000 PY After screening guidelines: 2/1,699 TB Rate 117/100,000 PY Carmona L. Arthritis Rheum.2005;52:

25 Physicans who follow TB test guidlines, % Rheumatologists are Smartest Rheumatologists Gastroenterologists Dermatologists 92% 85% 80% 76% 73% 76% G5 Non-G5 Figure 2 Percentage of rheumatologists, gastroenterologists and dermatologists who reported following guidelines for TB testing of their patients prior to prescribing anti-tnf agents: G5 vs. non-g5 EU member countries, TB = tuberculosis; G5 = the five foremost industrialized economies; TNF = tumor necrosis factor; EU = European Union. Smith MY et al. IJTLD 2012

26 Treatment of LTBI Duration (mos) Evidence Completion Hepatitis Risk INH 9 A 45-60% INH 6 B 55-57% 3.8% RIF 4 B 69-78% 0.7% INH/RIF* Hi dose weekly 3 B 75% Unknown INH: Isoniazid; RIF: Rifampin *Horsburgh CR, Rubin EJ, NEJM 2011: 364:15

27 New Therapy Option INH and Rifapentine 3 months, once weekly (directly observed) Table 2. Number of Subjects with Tuberculosis and Event Rates.* Population and Study Group No. of Subjects Subjects with Tuberculosis Difference in Cumulative Rate Upper Limit of 95% Cl for Difference in Cumulative Rate No. No. per patient-yr Cumulative rate Modified intention-to-treat analysis Isoniazid only Combination therapy Per-protocol analysis Isoniazid only Combination therapy *Combination therapy consisted of 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus Isoniazid (900 mg). Isoniazid-only therapy consisted of 9 months of self-administered daily isoniazid (300 mg). Data are shown for a period up to 33 months after study enrollment. The difference is the rate in the combination-therapy group minus the rate in the isoniazid-only group Sterling T et al. NEJM 2011

28 Nontuberculous (NTM) Disease Environmental mycobacteria Drinking water and soil Lung, skin/soft tissue, disseminated disease M. avium, M. kansasii Rapid growers M. abscessus Pulmonary NTM Elderly female predominance Underlying lung disease (e.g. RA) No defined way to screen for NTM Suspect in elderly women with unexplained chronic cough

29 FDA MedWatch Reported Characteristics of Anti-TNF Therapy Associated Nontuberculous Mycobacterial (NTM) Cases Pulmonary (n=59) Extrapulmonary (n=46) M. avium 43 (73%) 9 (20%) RGM* 6 (10%) 15 (33%) Age (years) Sex (female) 41 (73%) 25 (54%) RA ± 48 (81%) 25 (54%) Infliximab 40 (68%) 33 (72%) Etanercept 13 (22%) 12 (26%) +p value < 0.05 for comparison between pulmonary and extrapulmonary disease *Rapidly growing mycobacteria (RGM) ±Rheumatoid arthritis (RA) Winthrop KL Emerg Infect Dis 2009

30 Crude incidence rate per 100,000 patient years Figure NTM Tuberculosis 95% Cl General population General population 50 years old RA population, no anti-tnf use RA population, no anti-tnf therapy exposed Winthrop KL et al. Ann Rheum Dis 2012; Winthrop KL Nat Rheum Rev 2013

31 Many Other Types of Opportunistic Infections Reported with DMARDs mtb ntm Clostridial Salmonella Nocardia Legionella Listeriosis Hepatitis B, Hepatitis C Herpes simplex virus HIV Varicella Zoster CMV Ebstein-Barr virus Human papilloma virus TNF Inhibitors Histoplasmosis Coccidioidomycosis Candidiasis Aspergillosis Cryptococcosis Pneumocystis Toxoplasmosis Strongyloidosis Leishmaniasis Rituximab Rare TB, mycobacterial JC Virus (PML) Reactivation HBV New/reactivated viral infx; CMV, HSV, Parvo B19, VZV, W. Nile, Hep C Abatacept TB, Reactivation HBV Aspergillosis, candidiasis Tocilizumab TB, reactivation HBV Tofacitinib H.Zoster TB, CMV, BK virus Ustekinumab mycobacteria, Salmonella, and Bacillus Calmette-Guerin (BCG) Ali T, et al. Drug Healthc Patient Saf. 2013; 5:

32 Population-based Estimates of OI Risk Table 2. The biologic era: rates and risks of opportunistic infections in RA patients Using anti-tnf therapy from European and North American observational cohort studies. Crude Incidence per 100,000 pt-yrs. Crude Incidence per 100,000 pt-yrs. Country/year Outcome studied Anti-TNF treated Non-biologic comparator Adj. RR (95% CI) 33 UK, 2006 OI NR 93 France, 2006 OI 152* NR NR 92 US,2010 OI ( ) * Rate adjusted for age and sex Cohorts restricted to RA patients + Rate not published, but rather estimated using data provided within paper OI outcomes did not include tuberculosis NR, not reported; UNDEF, undefined Winthrop K, Rheum Clin North Am 2012

33 SABER Non-viral OIs TNFi starters 270/100,000 Non-biologics 170/100,000 PJP crude incidence TNFi starters, 56/100,000 Table 2. Distribution of non-viral opportunistic infections (n=80) all disease indications Infection Frequency (%) Pneumocystosis 16 (20) Nocardiosis/Actinonmycosis 12 (15) Tuberculosis 10 (12.5) Histoplasmosis 9 (11.3) Nontuberculosis Mycobacteria 9 (11.3) Salmonellosis 8 (10) Listeriosis 4 (5) Legionellosis 4 (5) Cryptococcosis 3 (3.8) Endemic Fungal Infection 1 1 (1.3) Toxoplasmosis 1 (1.3) Coccidioidomycosis 1 (1.3) Baddley J, Winthrop KL et al. Presented IDSA 2011 Baddley/Winthrop et al. ARD 2014 Blastomycosis 1 (1.3) Aspergillosis 1 (1.3)

34 Number of Cases Histoplasmosis Infections with anti-tnf FDA analysis prompted by reports of histoplasmosis deaths in patients receiving anti-tnf Rx; Medwatch AERS thru 2/29/08 N=240 cases (207 IFX; 16 ETN; 17 ADA) Complete data on 21 cases All (21) Dx and Rx delayed 5 died without Rx; 7 neg. C/S Pulm. 10%, disseminated 76% Death occurred in 45/240 (19%) 85% of cases occurred in endemic areas (OH/MS river valley) Concern about delayed diagnosis of fungal infection in anti-tnf Rx pts Summary: Patients living in endemic areas are at risk FDA conclusion: Clinicians should consider initiating empiric fungal therapy while evaluating at-risk individuals with undiagnosed systemic illnesses Unrecognized Histoplasmosis Cases Total cases Death cases Infliximab Etanercept Adalimumab Diak P et al., FDA 2008

35 Herpes Zoster (Shingles) Reactivation of varicella zoster virus (VZV) Prior exposure to VZV ubiquitous in those >40 years Lifetime risk of reactivation = 33% 0.4 and 1.1 events per 100 patient-years depending on age Decline in VZV-specific cell-mediated immunity Acute and chronic pain, dermatomal rash Post-herpetic neuralgia (15%), visual loss Disseminated disease (1%) RA patients Risk elevated 2-3 fold Vs. non-ra VZV vaccination is recommended, but rare (1%) Harpaz et al. MMWR 2008; Yawn et al. Mayo Clin Proc 2007 ; Levin et al. J ID 2003; Weinberg et al. J ID 2009; Smitten et al. Arthritis Rheum 2007;chmajuk et al. JAMA 2011; Zhang et al. ART 2011

36 Age, gender standardized incidence rate for herpes zoster/1000pys Figure: Age standardized incidence rate for herpes zoster per 1000pys (standardized to the U.S census) Healthy SLE IBD RA PsA PsO AS Gout Diabetes Curtis J et al, EULAR abstract 2014

37 European and US Studies Differ re: HZ risk with TNFi Author N Rate & TNFi BSRBR Strangfeld McDonald , Wolfe , Smitten , Winthrop Galloway , Hazard Ratios for VZV Infection BSRBR Strangfeld Smitten Wolfe McDonald & IIRR per 1000 pt-yrs (Population rate ~5/1000 PY*) Statistically significant p < All TNFi ETN ADA INF H.Zoster (VZV) infections are increased w/ TNF blockade, age, steroid, comorbidities Galloway J. #421 ACR 2010 Strangfeld A. JAMA 2009; 301:737 Smitten A&R : McDonald. Clin Infect Dis :1364 Wolfe F. Rheumatology 2006; 45:1370 Winthrop JAMA 2013 Galloway Ann Rheum Dis 2013; 72:229

38 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 ( ) Anti-TNF mechanism of action Adalimumab ( ) 1.04 ( ) Certolizumab ( ) 1.30 ( ) Etanercept ( ) 1.26 ( ) Golimumab ( ) 0.91 ( ) Infliximab ( ) 0.98 ( ) Other RA Medications Methotrexate No ( ) 1.00 (Ref) Yes ( ) 1.07 ( ) Oral Glucocorticoids (prednisoneequivalent dose) None ( ) 1.00 (Ref) 7.5mg/day ( ) 1.55 ( ) > 7.5mg/day ( ) 2.35 ( ) Yun H et al, Arth Car Res, In Press

39 Herpes Zoster and Tofacitinib Table 4. Crude incidence rates of HZ overall and by geographic region of Enrollment in the phase II, phase III, and long-term extension studies HZ events Patient-years of exposure HZ incidence rate (95% CI)* Global rheumatoid arthritis program 239 5, ( ) By region US/Canada/Australia 40 1, ( ) Western Europe ( ) Eastern Europe 43 1, ( ) Latin America ( ) Asia 107 1, ( ) Within Asian countries Japan/Korea ( ) India ( ) Thailand/Malaysia/Philippines ( ) China/Taiwan ( ) *The crude incidence rates of herpes zoster (HZ) events, with 95% confidence intervals (95% CIs), are expressed per 100 patient-years. Winthrop et al Arth and Rheumatol 2014 Winthrop K et al Arth and Rheumatol 2014

40 Zostavax RA vaccination rate is low Safety and efficacy in RA? Table 3. Herpes Zoster Incidence Rate for Unvaccinated and After Vaccination a >42 Days Since Vaccination Unvaccinated HZ Cases, No. HZ IR HZ Cases, No. HZ IR Overall ( ) ( ) Medications, mutually exclusive groups b Biologics, regardless of oral glucocorticoids ( ) ( ) Anti-TNF therapies ( ) ( ) DMARDs, without biologics but regardless of oral glucocorticoids ( ) ( ) Oral glucocorticoids alone ( ) ( ) Abbreviation: DMARDs, disease-modifying antirheumatic drugs; HZ, herpes zoster; IR, incidence rate per 1,000 person-years; TNF, tumor necrosis factor. a More than 42 days after vaccination. b Classified using the following hierarchy: biologics with or without nonbiologic DMARDs or oral glucocorticoids; nonbiologic DMARDs with or without oral Glucoccorticoids; oral glicocorticoids only. Jie J et al. JAMA 2012

41 ACIP and ACR Recs for Zostavax Recommended in >60 years old Licensed > 50 years Not contra-indicated MTX (<0.4mg/kg/wk), Prednisone (<20mg daily), azathioprine (<3.0mg/kg/day) Contraindicated Biologics Tofacitinib not specifically discussed (pre-approval) MMWR. November 11, ; ;

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43 Reactivation of Hepatitis B During Immunosuppressive Therapy: Potentially Fatal Yet Preventable RHEUMATOLOGISTS USA % routinely screen before non-biologic DMARD 69% before biologic DMARD 7% observed reactivation event IDEAS AND OPINIONS Anna S.F. Lock, MD; John W. Ward, MD; Robert P. Perrillo, MD; Brian J. McMahon, MD; and T. Jake Liang, MD Stine JG, et al. Arthritis Care Res. 2010;62:

44 Table 1c. Proposed functional HBV categorization of patients based on screening test results Screening test results Risk of progression during biologic therapy Management considerations Never infected HBV vaccinated Resolved HBV* Chronic HBV HBcAB negative HBsAg negative, HBsAb negative HBcAB negative HBsAg negative, HBsAb positive HBcAB positive HBsAg negative, HBsAb positive HBcAB positive HBsAg negative, HBsAb negative HBsAg positive (regardless of other results) None None + Immunity suggested Low risk (but not zero) γ Immunity not clear. Low to moderate risk of progression High Consider HBV vaccination if at risk for acquiring HBV N/A Obtain baseline HBV DNA If positive: -patient has chronic HBV. If negative: -periodic monitoring of HBV DNA levels and liver function tests during biologic therapy - If biologic therapy is not avoidable, then refer to GI or ID specialist for concurrent and appropriate anti-hbv therapy - Periodic monitoring of HBV DNA levels and liver function tests during biologic therapy + Patient s with HBsAb positivity have likely cleared their virus, although there still exists a small risk of seroreversion and reactivation during immunonosuppression[8]. γ In the case of HBsAb negativity, this substantially increases the risk that a patient has not cleared their HBV infection. Some proportion of these patients have either occult viremia (detectable serum HBV DNA) or can reactivate later during immunosuppression in which HBV DNA and/or surface antigen will become detectable. *Patients in this category may also rarely be antihbs positive in isolation

45 HBV Reactivation Reported with ALL biologics Risk probably highest with RTX Extrapolation from lymphoma literature Patients with prior exposure who lack surface antibody at highest risk Screen periodically (LFTs, HBV DNA) If reactivation Concomitant anti-viral with biologic appears safe Winthrop KL, Calabrese LH. Ann Rheum Dis. 2011;70:1701-3

46 PML Incidence among IMID without HIV or malignancy 0.2/100, confirmed cases of PML in IMID 17 SLE, 10 RA, 7 other 14 RTX, 6 TNFi Only 1 RTX treated case lacked other potential cause Concomitant drugs, lymphopenia, cancer There is no rationale for screening prior to biologic use in rheumatology patients Bharat A et al. Arth Res Care 2012; Molloy ES et al Arth Rheum 2012