Disclosures. Evidence Based Medicine. Infections in SLE and LN Patients. Aim

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1 Serious Infection Rates among Patients with Systemic Lupus Erythematosus Receiving Corticosteroids and Immunosuppressants None Disclosures Candace H. Feldman, MD, MPH 1,2 Linda T. Hiraki, MD, SM, ScD 3 Wolfgang Winkelmayer, MD, ScD 4 Francisco M. Marty, MD, MS 5 Jun Liu, MD, MPH 6 Jessica M. Franklin, PhD 6 Daniel H. Solomon, MD, MPH 1,6 Seoyoung C. Kim, MD, MSCE 1,2,6 Karen H. Costenbader, MD, MPH 1,2 1 Brigham and Women s Hospital, Division of Rheumatology, 2 Harvard School of Public Health, 3 Hospital for Sick Children, Division of Rheumatology, 4 Stanford School of Medicine, Division of Nephrology, 5 Brigham and Women s Hospital, Division of Infectious Disease, 6 Brigham and Women s Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics Evidence Based Medicine Danza A, Ruiz-Irastorza G. Infection risk in systemic lupus erythematosus: susceptibility factors and preventive strategies. Lupus 2013; 22(12): Petri M. Infection in systemic lupus erythematosus. Rheum Dis Clin North Am May; 24(2): Ward MM. Development and Testing of a Systemic Lupus-specific Risk Adjustment Index for In-Hospital Mortality. J Rheumatol 2000; 27:6, Schneeweiss S, Robicsek A, et al. Veteran s affairs hospital discharge databases coded serious bacterial infections accurately. J Clin Epidemiol Apr;60(40: Schneeweiss S, Setoguchi S, et al. Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum 2007 Jun;56(6): Infections in SLE and LN Patients Serious infections are a leading cause of hospitalization and mortality in SLE patients Up to 50% have a severe infection during disease course Lupus nephritis (LN) patients may be particularly vulnerable Likely related both to impaired immune function and to immunosuppressant use Little known about the sociodemographic distribution of serious infections in SLE and LN patients Many serious bacterial, fungal, viral and mycobacterial infections described in SLE patients, but few populationbased studies with power to examine incidence rates in setting of medication use Feng et al. J Rheumatol. 2011; Lee et al. Rheumatology. 2013; Sciascia et al. Autoimmun Rev. 2012; Zandman-Goddard et al. Autoimmunity. 2011; Duffy et al. J Rheumatol. 1991; Petri M. Rheum Dis Clin North Am. 1998; Danza et al. Lupus Infections and Medication Use Previous RCTs and small academic cohort studies describe increased infection rates in SLE associated with corticosteroids and other immunosuppressants Prior studies limited by: small sample sizes exclusions by disease severity restrictions on concurrent medication use short follow-up self-reported data primary focus on drug efficacy Precedent in RA to use nationwide administrative databases to examine infection risk factors, but no parallel large cohort studies to date in SLE Aim To examine the sociodemographics and incidence rates of serious infections requiring hospitalization in a nationwide cohort of SLE and lupus nephritis patients newly starting SLE-specific medications Petri et al. J Rheumatol. 1992; Staples et al. Arthritis Rheum. 1974; Yuhara et al. Intern Med. 1996; Kimberly et al. Medicine.1981; Chakravarty et al. Lupus. 2013; Solomon et al. Arthritis Rheum. 2008; Dixon et al. Arthritis Rheum. 2006; Grijalva et al. JAMA. 2011; Curtis et al. Arthritis Care Res. 2012; Schneeweiss et al. Arthritis Rheum,

2 Methods: Study Population Medicaid Analytic extract (MAX): billing claims and demographics for all Medicaid enrollees from 47 states and Washington, DC from Medicaid is largest public health insurance program in U.S., covering >60 million lowincome individuals Methods: Patient Identification Prevalent SLE Defined as age with >3 ICD-9 codes for SLE (710.0) each > 30 days apart from hospital discharge diagnoses or physician visit claims Prevalent lupus nephritis (LN) Defined by >2 ICD-9 codes for nephritis, proteinuria and/or renal failure, on or after SLE diagnosis and >30 days apart PPV 80% Feldman CH. et al. Arthritis Rheum. 2013; Chibnik L. et al. Lupus Methods: New Users Patients identified with prevalent with of with no use of SLE-specific drug during that period - new users : Hydroxychloroquine (HCQ) alone Oral or intravenous corticosteroids (CS) + HCQ Immunosuppressants (IS): mycophenolate mofetil, mycophenolic acid, oral or intravenous cyclophosphamide, azathioprine, cyclosporine, or tacrolimus + HCQ CS + IS simultaneously + HCQ New use of CS, IS, or CS+IS regardless of preexisting HCQ use Methods: Covariates Demographics Age and sex Race/ethnicity (,,,, ) U.S. geographic region Area-level socioeconomic status (SES) Previously validated county-level composite measure using U.S. Census variables at the ZIP code level SLE-specific risk adjustment index A SLE-specific severity of illness index using ICD-9 codes for comorbidities; superior to Charlson index in stratifying SLE patients by in-hospital mortality risk Covariates assessed (HCQ, CS, IS, or CS+IS, with no use in prior 6 months) (HCQ, CS, IS, or CS+IS, with no use in prior 6 months) Ward MM. J Rheumatol 2007; Ward MM. J Rheumatol Methods: Outcome Definition Serious infections requiring hospitalization Defined using ICD-9 discharge diagnoses: Bacterial: cellulitis, endocarditis, pneumonia, pyelonephritis, septic arthritis, osteomyelitis, bacteremia, listeriosis Viral: cytomegalovirus, influenza, herpes zoster Fungal: Systemic candidiasis, cryptococcosis, aspergillosis, histoplasmosis, pneumocystosis Mycobacterial: TB, atypical mycobacteria Previously validated in an administrative database (PPV>80%) Methods: Assessment of Outcome Cohort of SLE and LN new users of HCQ, CS, IS, or CS+IS Exposure lag and extension periods of 7 days each Censored after first infection, drug switch, death, dis or end of follow-up period Covariates assessed Lag period (HCQ, CS, IS, or CS+IS, with no use in prior 6 months) Follow-up time on drug At risk for serious infection Extension period Schneeweiss S. et al. J Clin Epidemiol

3 Methods: Statistical Analyses Stratified serious infections requiring hospitalization by medication use, infection subtype and sociodemographic factors Calculated incidence rates (IR) of serious infections and incident rate ratios (IRR) with 95% CI adjusting for covariates, using Poisson regression Results: Baseline Characteristics SLE (n=28,803) LN (n=5,140) Sex Female N (%) (93.6) 4637 (90) Age (years) Mean (SD) 38.9 (9) 34.2 (9) - N (%) - N (%) New Users- N (%) HCQ CS IS CS+IS (34.8) (38.9) 4371 (15.2) 1294 (4.5) 424 (1.5) 6532 (22.7) (39) 4520 (15.7) 6497 (22.6) 8016 (27.8) (56) 3165 (11) 1486 (5.2) 1125 (21.9) 2467 (48) 881 (17.1) 60 (1.2) 15 (0.3) 1089 (21.2) 2034 (39.6) 864 (16.8) 1153 (22.4) 807 (15.7) 3272 (63.7) 665 (12.9) 396 (7.7) Results: Serious Infections 28,803 SLE patients (23,671 person-years follow-up) - 3,502 (12.2%) with serious infections 93% Bacterial 4% Fungal 2% Viral 1% Mycobacterial 5,140 LN patients (3,600 person-years follow-up) - 1,348 (26.2%) with serious infections 92% Bacterial 5% Fungal 3% Viral <1% Mycobacterial Predominant infections Bacterial- pneumonia, cellulitis and bacteremia; fungalsystemic candidiasis; viral- herpes zoster; mycobacterialtuberculosis Sociodemographics of Infections Total Infections: SLE N (% of stratified cohort) Total Infections: LN N (% of stratified cohort) Overall N=28, (12.2) 1348 (26.2) Sex Age (years) SLE-Specific Index Female Male (12) 258 (14) 998 (9.3) 1608 (13.1) 896 (15.6) 1138 (11.8) 1657 (14.8) 357 (8.2) 84 (6.5) 63 (14.9) 729 (11.2) 1513 (13.4) 742 (16.4) 519 (8) 1750 (13.2) 1501 (11.1) 1268 (7.5) 2234 (18.6) 1228 (26.5) 120 (23.9) 481 (17.3) 553 (33.4) 314 (45.1) 337 (30) 721 (29.2) 163 (18.5) 43 (12.6) 19 (24.4) 320 (29.4) 515 (25.3) 318 (36.8) 195 (16.9) 619 (26.6) 628 (25.3) 492 (15.7) 856 (42.6) SLE New Users Incident Rates of All Serious Infections # of Infections Person-Years IR/100* (95% CI) IRR** (95% CI) HCQ (n=8016) ( ). CS (n=16136) ( ) 4.2 ( ) IS (n=3165) ( ) 1.5 ( ) CS+IS (n=1486) ( ) 2.1 ( ) LN New Users HCQ (n=807) ( ). CS (n=396) ( ) 2.6 ( ) IS (n=665) ( ) 0.8 ( ) CS+IS (n=396) ( ) 2.9 ( ) *Incidence rates (IR) per 100 person-years **Incidence rate ratios (IRR), adjusted for age, sex, race/ethnicity, region, area SES, and SLE-specific index Adjusted IRRs by Sociodemographic Group Sex Age (years) SLE-Specific Index Female Male SLE IRR* (95% CI) 1.1 ( ) 0.9 ( ) 0.8 ( ) 1.2 ( ) 0.8 ( ) 0.8 ( ) 1.5 ( ) 1.2 ( ) 1.4 ( ) 1.6 ( ) 1.1 ( ) 1.2 ( ) LN IRR*(95% CI) 0.9 ( ) 1.2 ( ) 1.1 ( ) 1.2 ( ) 0.9 ( ) 0.9 ( ) 1.3 ( ) 1.4 ( ) 1.3 ( ) 1.5 ( ) 1.1 ( ) 1.1 ( ) *Incidence rate ratios (IRR) for all serious infections also adjusted for HCQ, CS, IS or IS+CS use 3

4 Results Summary Significant burden of serious infections requiring hospitalization: 12.2% of SLE patients and 26.2% of LN patients; predominately bacterial infections Prevalence highest among year-olds, s, African Americans, s, patients from lower SES areas and with higher SLE-specific risk adjustment indices Incidence rates of serious infection highest among CS users > 20 infections/100 person-years among SLE patients > 40 infections/100 person-years among LN patients In SLE patients, 4.2 times higher rate, and in LN a 2.6 times higher rate of infections among CS users compared to HCQ Infection rates among SLE patients on IS were 1.5 times higher and among LN patients on CS+IS, 2.9 times higher than those on HCQ alone Limitations Confounding by indication and contraindication No clinical information available on disease activity Possible misclassification of drugs and exposure risk windows, however minimized given new use design Separate IS drugs were not investigated individually Relatively short follow-up time among IS users and IS and CS combined users income population with high burden of disease; may not be globally generalizable Conclusions In this large, nationwide, diverse cohort of SLE patients, we found a significant burden of serious infections, particularly bacterial, and among patients with LN First documentation of infection rates in a SLE cohort this size; found to be strikingly high Compared to RA patients on CS in a similar size cohort, we found nearly 5 times higher IRs among SLE patients and 10 times higher IRs in those with LN Demonstrated an increased rate of infection among SLE new users of IS, and SLE and LN new users of CS+IS Further research needed to examine infection risk by specific IS drug, and by infection subtype Future Directions Propensity score-adjusted analyses to compare incidence rates of serious infections by specific medication use Further assessment of corticosteroid use according to administration route, dose and duration Examination of medication switchers in addition to new users Schneeweiss S. et al. Arthritis Rheum, Thanks Mentors: Dr. Karen Costenbader, Dr. Daniel Solomon, Dr. Seoyoung Kim Funded by the Lupus Foundation Career Development Award and the NIH-NIAMS T32 AR

5 SLE Characteristics by Medication Use HCQ (n=8,016) CS (n=12,136) IS (n=3,165) CS+IS (n=1,486) Age- mean (SD) 39.7 (12.1) 38.9 (12.3) 38.1 (12.8) 35.7 (12.4) Follow-up, mean months (SD) 10.8 (14.4) 10.9 (15.4) 5 (8.2) 3 (3.7) Sex- N (%) Female 7576 (94.5) (93.7) 2910 (91.9) 1354 (91.1) 3052 (38.1) 2881 (35.9) 1206 (15) 349 (4.4) 100 (1.3) 2051 (25.6) 2955 (36.9) 1851 (23.1) 1159 (14.5) 3677 (50) 3680 (50) 5489 (34) 6586 (40.8) 2343 (14.5) 672 (4.2) 237 (1.5) 3413 (21.2) 6653 (41.2) 3419 (21.2) 2651 (16.4) 7462 (49) 7646 (51) 1105 (34.9) 1135 (35.9) 514 (16.2) 169 (5.3) 66 (2.1) 701 (22.2) 1156 (36.5) 821 (25.9) 487 (15.4) 1526 (52) 1409 (48) 371 (25) 592 (40) 308 (20.7) 104 (7) 21 (1.4) 367 (24.7) 490 (33) 406 (27.3) 223 (15) 867 (61.8) 525 (38.2) LN Characteristics by Medication Use HCQ (n=807) CS (n=3,272) IS (n=665) CS+IS (n=396) Age- mean (SD) 36.6 (13.2) 34.4 (12.8) 32.9 (12.5) 29.9 (11.2) Follow-up, mean months (SD) 7.7 (11.4) 10.1 (13.6) 4.3 (6.7) 3.1 (3.7) Sex- N (%) Female 739 (91.6) 2949 (90.1) 599 (90.1) 350 (88.4) 291 (27.1) 353 (43.7) 125 (15.5) 52 (6.4) 13 (1.6) 161 (20) 307 (38) 207 (25.7) 132 (16.4) 367 (49.6) 373 (50.4) 709 (21.7) 1650 (50.4) 538 (16.4) 191 (5.8) 44 (1.3) 699 (21.4) 1345 (41.1) 662 (20.2) 566 (17.3) 1555 (50.7) 1512 (49.3) 132 (19.9) 286 (43) 135 (20.3) 60 (9) 15 (2.3) 131 (19.7) 261 (39.3) 182 (27.4) 91 (13.7) 327 (52.5) 296 (47.5) 65 (16.4) 178 (45) 83 (21) 39 (9.9) (24.8) 121 (30.6) 102 (25.8) 75 (18.9) 233 (61.3) 147 (38.7) 5