Population Variations in Rheumatoid Arthritis Treatment and Outcomes, Northern California,

Transcription

1 credits ville for this rticle see pge 96. Popultion Vritions in Rheumtoid Arthritis Tretment nd Outcomes, Northern Cliforni, Lis J Herrinton, PhD; Leslie Hrrold, MD, MPH; Crig Slmn; Liyn Liu, MD, MS; Roert Goldfien, MD; Mrym Asgri, MD, MPH; Joel M Gelfnd, MD, MSCE; Jshin J Wu, MD; Jeffrey R Curtis, MD, MS, MPH Perm J 2016 Winter;20(1): ABSTRACT Ojective: To ssess vritions in rheumtoid rthritis tretment nd outcomes t the community level from 1998 through Methods: The study used computerized dt from 16 Kiser Permnente Northern Cliforni Medicl Centers. Mixed modeling ws used to ssess ptterns cross time nd clinic. The nlysis ccounted for ptient demogrphics, clustering of ptients within Medicl Centers, nd repeted mesures of ptients over time. The metric used to mesure drug use, months of use per ptient per yer, included oth users nd nonusers in the denomintor, to ccount for oth prevlence nd durtion of use. Results: Assessment ws performed of 28,601 ptients with rheumtoid rthritis, with ll levels of severity. From 1998 through 2009, methotrexte use douled in the typicl ptient to include 23% of the time they were oserved; sulfslzine nd hydrochloroquine use declined. By 2008 through 2009, leflunomide nd ntitumor necrosis fctor gents were used y the typicl ptient 4% nd 9% of the time, respectively. Between 1998 nd 2009, disese-modifying ntirheumtic drug use incresed in the typicl ptient from 38% to 63% of the time, nd orl prednisone use declined from 23% to 15% of the time, wheres opioid use initilly rose ut then fell to 23% of the time. No vritions over time were oserved for the rte of hospitlized pneumoni or opportunistic infection. Vrition cross clinics, mesured y the difference in drug use etween clinics t the 75th nd 25th percentiles, ws lowest for opioids (25% vs 20% of the time) nd gretest for inflixim (< 1% to 3%). Conclusion: Incresed use of disese-modifying ntirheumtic drugs nd declines in prednisone re encourging. Opioid use my need intervention. INTRODUCTION In recent decdes, the tretment of rheumtoid rthritis (RA) hs chnged sustntilly, with introductions in the 1980s of methotrexte nd sulfslzine nd in the 1990s of leflunomide nd ntitumor necrosis fctor (TNF) gents. In 2002, the Americn College of Rheumtology estlished qulity mesure specifying tht ptient with estlished RA e treted with disese-modifying ntirheumtic drug (DMARD) unless there ws contrindiction, inctive disese, or ptient refusl. 1,2 In 2005, the Ntionl Committee for Qulity Assurnce dopted the percentge of dult ptients with dignosis of RA who hve documenttion of DMARD s Helthcre Effectiveness Dt nd Informtion Set (HEDIS) mesure. 3 In 2012, the Americn College of Rheumtology revised its tretment recommendtions for RA, trgeting remission or low disese ctivity. 4,5 With these chnges, one expects popultion-level increses in use of therpies. In ddition, ecuse clinicl trils hve demonstrted the enefits of these therpies for reducing inflmmtion nd joint dmge nd improving functionl ility nd helth-relted qulity of life, 6,7 one further expects improved outcomes. We used computerized dt for more thn 28,000 ptients with RA who were memers of n integrted helth cre delivery system to explore chnges in RA prctice ptterns nd outcomes over time nd cross Medicl Centers. We sought to understnd the diffusion of new tretments nd their effects on outcomes t the popultion level. METHODS The study ws pproved y the institutionl review ords of the Kiser Foundtion Reserch Institute nd Kiser Permnente (KP) Northern Cliforni (KPNC). The outcomes used in the study prednisone nd opioid use nd rtes of pneumoni nd opportunistic infection were selected ecuse they re esily defined using the computerized clinicl dt tht were ville for the study. Although these outcomes re Lis J Herrinton, PhD, is Reserch Scientist for the Division of Reserch in Oklnd, CA. E-mil: lis.herrinton@kp.org. Leslie Hrrold, MD, MPH, is n Associte Professor in the Deprtment of Medicine t the University of Msschusetts Medicl School in Worcester. E-mil: leslie.hrrold@umssmed.edu. Crig Slmn is Dt Anlyst in Clinicl Eduction for the Americn Acdemy of Ophthlmology in Sn Frncisco, CA. E-mil: ndyc298@yhoo.com. Liyn Liu, MD, MS, is Senior Dt Consultnt for the Division of Reserch in Oklnd, CA. E-mil: liyn.liu@kp.org. Roert Goldfien, MD, is Rheumtologist t the Richmond Medicl Center in CA. E-mil: roert.goldfien@kp.org. Mrym Asgri, MD, MPH, is Dermtologist nd Reserch Scientist t Msschusetts Generl Hospitl in Boston. E-mil: msgri@prtners.org. Joel M Gelfnd, MD, MSCE, is Dermtologist t the University of Pennsylvni in Phildelphi. E-mil: joel.gelfnd@uphs.upenn.edu. Jshin J Wu, MD, is the Director of Dermtology Reserch for the Deprtment of Dermtology t the Los Angeles Medicl Center in CA. E-mil: jshin.j.wu@kp.org. Jeffrey R Curtis, MD, MS, MPH, is n Associte Professor of Medicine in the Division of Clinicl Immunology nd Rheumtology t the University of Alm in Birminghm. E-mil: jeffrey.curtis@ccc.u.edu. 4 The Permnente Journl/ Winter 2016/ Volume 20 No. 1

2 Popultion Vritions in Rheumtoid Arthritis Tretment nd Outcomes, Northern Cliforni, cliniclly importnt, they serve s surrogtes for clinicl disese ctivity (prednisone) nd pin (opioid), or they re side effects of ggressive tretment (infection). We used these surrogtes ecuse clinicl disese ctivity mesures, such s the Helth Assessment Questionnire, were not ville. 8 Nonetheless, the informtion we present increses understnding of how chnging therpeutic pproches hs dvnced outcomes in the community setting. Furthermore, where vrition results in underuse, overuse, or inpproprite use of therpy, it my e possile to improve outcomes y further stndrdizing ptient selection for therpy. Setting This study ws conducted mong 3.2 million memers of KPNC, which provides prepid, comprehensive, integrted helth cre. KP physicins re on stff, nd their compenstion is unrelted to their ptients utiliztion of services. Memers receive cre t 1 or more of the Medicl Centers of their choosing, generlly one nerest home nd/or work. Every Medicl Center contins Deprtment of Rheumtology, nd referrl to rheumtologist is through the primry cre physicin. Etnercept hs een the preferred first-line nti-tnf therpy t KPNC, nd over time, dlimum hs replced inflixim s the second-line nti-tnf therpy. Becuse it is infused nd not injected, inflixim is sometimes prescried preferentilly for ptients whose out-of-pocket drug costs re high, such s those receiving Medicre without supplementl coverge. Becuse cre is prepid, no finncil incentive exists for using inflixim over other nti-tnf gents. KP enforces strict conflict-of-interest rules through contrct provisions, so tht representtives of phrmcy compnies my not py for food, gifts, or eductionl events for KP clinicins. According to the Helth Pln s rules, only specilists nd not primry cre physicins cn prescrie nti-tnf gents. Primry cre physicins my prescrie noniologic drugs used to tret RA nd my modify these regimens. Specilty RA clinics do not exist, nd no other tretment guidelines were in plce; nor were systemwide process improvement ctivities implemented to shift clinicl prctices. Over time, the Helth Pln hs offered wider vriety of insurnce products, ut during most of the study period, ptients pid $5 to $20 copyment for drugs, including injected nti-tnf, with similr-sized copyment for visits to the infusion clinic. Medicre ptients were covered under risk contrct, nd those without supplementl insurnce pid the so-clled donut hole (Medicre Prt D coverge gp). We re not wre of ny other pressures on tretment decision mking tht re relevnt to this study. Study Design A conceptul model guided the study design nd nlysis (Figure 1). We sought to compre, t the popultion level, tretments nd outcomes over time nd cross Medicl Centers while ccounting for confounding differences in ptientlevel chrcteristics, especilly disese ctivity. Similr to our previous report, the study used hierrchicl mixed methods design, 9 with time nd Medicl Center treted cross-sectionlly t the higher level nd ptient chrcteristics treted longitudinlly t the lower level. To ssess vritions over time, we divided the study period into six 2-yer windows nd pplied the sme eligiility criteri to ech window. To ssess vrition cross Medicl Centers, we grouped Medicl Centers nd medicl offices into 12 ctegories on the sis of their geogrphic seprtion; we pplied the sme ptient eligiility criteri to ech of the 12 Medicl Center groupings. For ech ptient nd ech 2-yer time window, we ssigned Medicl Center nd computed the follow-up time, numer of outptient visits (visits per ptient per yer, known s ptient-yer ), drug use (months of use per ptient-yer), nd rtes of hospitlized pneumoni nd opportunistic infection (events per ptient-yer). Figure 1. Conceptul model: predictors, ptterns of cre, nd outcomes. DMARD = disese-modifying ntirheumtic drug. The Permnente Journl/ Winter 2016/ Volume 20 No. 1 5

3 Popultion Vritions in Rheumtoid Arthritis Tretment nd Outcomes, Northern Cliforni, Although ptient demogrphics nd comoridity were not the focus of nlysis, we djusted for these vriles in ll nlyses. Disese ctivity ws presumed to influence ptterns of cre nd outcomes, ut the informtion ws not ville for djustment; thus, we designed the study to minimize is from disese ctivity. This ws done y including the entire census of RA-ffected ptients t ech Medicl Center, including those with mild disese, nd y focusing the nlysis t the level of the popultion, not the individul. Specificlly, we ssumed tht the verge seline disese ctivity did not vry cross time windows or Medicl Centers except through differences in the use of therpy. To minimize ny ssocition of disese ctivity with Medicl Center resulting from migrtion cross Medicl Centers, we linked ptients to their home Medicl Center (primry cre physicin or ddress) to eliminte is stemming from referrl of ptients with more severe disese to Medicl Centers perceived to offer higher-qulity cre. Study Popultion Ptients ged 18 to 89 yers with 12 or more months of memership during the 1998 through 2009 study period were eligile. To identify ptients with suspected RA, we identified those with 1 or more relevnt ssignments of Interntionl Clssifiction of Diseses, Ninth Revision (ICD-9) dignosis code of 714 in computerized clinicl encounter dt. In rndom smple of 210 ptients, we used mnul chrt review to confirm the dignosis nd identify the est-performing csefinding lgorithm using computerized dt lone. As descried in the Results section, the est-performing lgorithm ws 2 or more physicin-recorded dignoses of RA, recorded t ny time, without regrd to use of DMARD. For the full study, ptients were required to hve 2 or more dignoses of RA during the 48 months tht strted 2 yers efore nd ended t the conclusion of ech 2-yer period under study. Dt from 1996 through 1997 were used to identify RA in those ptients who were included in the 1998 through 1999 period. Dt Collection Ptient-level informtion ws otined from computerized clinicl dtses to estimte proportions nd rtes cross the six 2-yer time windows nd 12 Medicl Centers. During 1998 through 2004, the dt were recorded in informtion systems (eg, outptient encounters, inptient encounters, phrmcy, nd lortory) y helth cre physicins nd dministrtors for mesuring utiliztion nd qulity, not for sumitting clims. Beginning in 2004, the Helth Pln egn implementing n electronic medicl record tht ws fully estlished y 2006; during oth the legcy systems nd the electronic medicl record were in use. By 2006, ll deprtments used the electronic medicl record exclusively. Although few outside clims were processed, we lso included these in the study. The phrmcy dt were integrl to this study, nd single phrmcy system ws used throughout the study period. In ddition, for 210 ptients, we performed chrt review using trined medicl record strctor, stndrdized instrument, nd procedure mnul. Independent Vriles Ptient ge, sex, nd enrollment history were otined from memership files. During the study period, the Helth Pln did not sk memers for their rce or ethnicity; however, this informtion ws ville for 94% of the RA cohort. From the chrt review of 108 ptients, we lso otined ffected joints nd joint counts. We djusted our nlyses for comoridity using the Chrlson Comoridity Index on the sis of dignoses recorded during the 12-month period preceding the second recorded RA dignosis tht qulified the ptient for the study. 10 Age nd comoridity were recomputed for ech 2-yer time window. The Helth Pln ssigns ech ptient to home Medicl Center on the sis of the loction of his/her primry cre visits or, if there is none, his/her residentil ddress. However, ptients fce no rrier in using whichever Medicl Center they choose. For this study, we linked the ptient to his/her home Medicl Center in ech two-yer window. This decision ensured comprility of RA severity cross Medicl Centers. We scertined ll outptient visits to rheumtology or primry cre physicins for which the primry reson for the visit ws RA (ICD-9 Code 714). The visit rte ws computed s the numer of visits in the 2-yer window divided y the ptients enrollment time during tht window. The physicin recorded the reson for the visit t the time of the visit using dignosis code for the primry purpose of trcking utiliztion nd qulity. For ech Medicl Center nd two-yer time window, we estimted from computerized phrmcy dt the verge use of DMARD in months of use per ptient per yer; this ws expressed in months per ptient-yer. In keeping with the study s focus on mesuring popultion-level utiliztion, the denomintor included oth users nd nonusers of ech drug; thus, the mesure ccounted for oth prevlence of use nd durtion of use mong users. To compute this mesure, we scertined the dys supply of DMARD dispensed per ptientyer. For dispensings extending efore or fter the two-yer window, only the dys supply ville within the two-yer window ws counted. The clcultion ccounted for the recommended dosing of inflixim t two weeks initilly nd every eight weeks therefter. We did not exmine golimum ecuse the drug ws not used pprecily in our Helth Pln. Outcome Mesures Four outcome mesures were computed for ech twoyer time window nd ech Medicl Center: 1) use of orl prednisone nd 2) use of opioid, ech in months of use per ptient-yer, nd 3) rtes of hospitlized pneumoni nd 4) rtes of opportunistic infection, ech in events per ptientyer. We focused on orl prednisone ecuse of our interest in long-term glucocorticoid use; orl prednisone ccounted for 98% of dispensings of orl glucocorticoids in the popultion. As descried in the previous prgrph for DMARD, the denomintor included oth users nd nonusers of ech drug; thus, the mesure ccounted for oth prevlence of use nd durtion of use mong users. The four outcomes 6 The Permnente Journl/ Winter 2016/ Volume 20 No. 1

4 Popultion Vritions in Rheumtoid Arthritis Tretment nd Outcomes, Northern Cliforni, were evluted in seprte nlytic models, with ech ptient counted no more thn once per event. Dignoses of pneumoni were otined from inptient ICD-9 dignosis Codes , 484.3, 484.5, 485, 486, nd 513. Hospitlized opportunistic infections included Slmonell (ICD-9 Code 003), Mycocterium tuerculosis ( ), Listeriosis (027.0), other mycocteri (031), Actinomycosis (039), progressive multifocl leukoencephlopthy (046.3), herpes zoster (053), Coccidiomycosis (114), Histoplsmosis (115), Blstomycosis (116), Aspergillosis (117.3), Cryptosporidiosis (117.5), Toxoplsmosis (130), pneumocystis pneumoni (136.3), Cryptosporidiosis meningitis (321.0), Legionnire s disese (482.84), nd pneumoni in other mycoses (484.7). Entry nd Exit into Follow-up For ech 2-yer time window, ptients were included if they hd t lest 2 RA dignoses during the current or immeditely preceding 2-yer time window (with inclusion in the time window on the sis of dignosis recorded during ). For ech 2-yer window, entry into follow-up ws determined from the ltest of the following dtes: 1) the ptient s 18th irthdy; 2) for RA identified in the current 2-yer window, the dte of the first primry or secondry RA dignosis; 3) for RA identified in the preceding 2-yer window, the strting dte of the current 2-yer window; or 4) for ptients who hd disenrolled in the Helth Pln efore the window s strt dte, the strt of their next enrollment period within the window. For ech 2-yer window, exit from follow-up ws determined from the erliest of the following dtes: 1) the end of the 2-yer window; 2) the first dte of disenrollment within the window; 3) the 90th irthdy, nd 4) the deth dte. Anlytic Methods Dt nlyses used SAS Version 9 softwre (SAS Institute Inc, Cry, NC). We used mixed modeling, which provided flexile pproch for dtsets tht contined repeted mesures over time nd spce. Correltions within sujects nd Medicl Centers could e modeled using rndom nd fixed vriles to elucidte the simultneous effects of Medicl Center nd time window on outptient visit rtes, drug use, nd infections. 11 Mixed modeling is useful when repeted mesures re ville for clustered settings. An open-ccess rticle explining mixed-methods design nd nlysis for the generl reder ws written y Minlu nd collegues. 12 Every model included ptient ge (18 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, nd 70 to 89 yers), sex, rce/ethnicity (Asin, lck, Hispnic, white, unknown), nd Chrlson Comoridity Index (none, 1, nd 2 or more conditions). To test whether the clss vrile period improved the model s fit, we compred less prsimonious model contining the vrile period with more prsimonious model tht did not. Where the vrile improved the model fit to sttisticlly significnt degree (p < 0.05) s indicted y the likelihood rtio test, we inferred tht period ws importnt. Becuse the vrile ws coded s clss vrile, it ws not necessry tht the fit e monotonic or liner; rther, the model tested for significnt chnges etween periods s well s for overll trends, with the null hypothesis eing no chnge. To ssess the role of the 2-yer time window, oth Medicl Center nd 2-yer time window were coded s clss vriles nd treted s fixed effects, with p vlues for ech of these eing otined from Type 3 F-sttistics. Ech of these models ws tested for n interction etween Medicl Center nd 2-yer time window; the interction term ws retined when it ws significnt t p < We used similr pproch to test whether the vrile Medicl Center improved the model, ut in this instnce, we used shrinkge method to pull estimtes for smller centers towrd the men to ccount for their lower stility. 13 To ssess the role of Medicl Center nd to estimte the interqurtile rnges cross the Medicl Centers, we treted Medicl Center s rndom effect. RESULTS Vlidtion of Rheumtoid Arthritis The est-performing cse-finding lgorithm for detecting RA ws 2 or more physicin-recorded dignoses of RA (ICD-9 Code 714) without regrd to use of DMARD (Tle 1). The lgorithm hd sensitivity of 97% nd positive predictive vlue of 77%. In the full study popultion of 28,601 ptients with RA, the length of enrollment ws 1 to 3 yers in 14% of the cohort, 4 to 6 yers in 16%, 7 to 9 yers in 18%, nd 10 to 12 yers in 52%. Tle 2 shows ptient chrcteristics for the 108 persons included in the chrt review s well s the 28,601 ptients included in the full study. The full cohort ws older (p = 0.01) Tle 1. Sensitivity nd positive predictive vlue of dignoses for confirming rheumtoid rthritis Dignostic codes DMARD dispensings Using chrt review s gold stndrd (N = 210) Strtified smple, no. True-positives, no. Flse-positives, no. Sensitivity, % Positive predictive vlue, % > The sensitivity, positive predictive vlue, is weighted to reflect the smpling frctions. By definition. DMARD = disese-modifying ntirheumtic drug. The Permnente Journl/ Winter 2016/ Volume 20 No. 1 7

5 Popultion Vritions in Rheumtoid Arthritis Tretment nd Outcomes, Northern Cliforni, Tle 2. Chrcteristics of ptients with rheumtoid rthritis, Chrcteristic Ptients with chrt review, % (n = 108) Ptients with computerized dt, % (n = 28,601) Sex Men Women Age group, yers Rce/ethnicity White Hispnic Blck 10 8 Asin 12 8 Unknown/other 8 11 Antiody positivity Rheumtoid fctor positive 69 Anticyclic citrullinted peptide 24 ntiody positive Rdiogrphic evidence Juxt-rticulr osteopeni 15 Soft-tissue/fusiform swelling 4 Joint spce nrrow 17 Perirticulr erosions 14 Suluxtions 7 Comorid gout 6 Joint involvement Shoulder, elows 12 Knees 20 Ankles 18 Metcrpophlngel (MPT) joints 27 Proximl interphlngel joints 32 Second through fifth MPT joints 17 Wrist 37 Hnds 15 Feet 6 Not recorded 27 Numer of involved smll joints Not recorded 33 Disese durtion, yers Unknown 6 p = p < = not ville. nd included more women (p = 0.16) thn the chrt review. From the chrt review, we scertined the loction of joint involvement, numer of involved smll joints, disese durtion, nd rdiologic findings s of Decemer 31, 2009 (Tle 2). Vritions over Time All vritions over time were significnt t p < unless otherwise stted. Between 1998 nd 2009, the djusted nnul visit rte to the Rheumtology Deprtment decresed y 3%; visits to primry cre physicins with the primry reson for visit eing RA incresed y 47% (Figure 2). Drug use ws mesured in months of use per ptient-yer, including oth users nd nonusers. This mesure ccounted for oth prevlence of drug use nd durtion of use mong users. The use of nti-tnf gents incresed from essentilly zero to n verge 3% of the follow-up time (including oth users nd nonusers; Figure 3). Etnercept use incresed consistently from its introduction in 1998 through the period, ut then declined slightly. Adlimum use incresed consistently from the time of its introduction through the end of the study period. Inflixim use peked in Methotrexte use nerly douled, from 13% to 23% of the time per ptient-yer in , ut then declined slightly. Use of sulfslzine nd hydrochloroquine incresed from to , ut then declined through Leflunomide did not come into use until 2000; y , the verge ptient with RA used leflunomide 4% of the time. Across these gents, DMARD use incresed for the verge RA-ffected ptient, in months per yer, from 38% in to 65% in , ut then declined to 63% in Between 1998 to 1999 nd 2008 to 2009, use of orl prednisone decresed from 23% to 15% of the time (Figure 4). The dose of orl prednisone declined s well. Opioid use incresed from 18% in to 25% of the time in , ut then declined to 23% of the time in Across the study period, 60% of opioids were prescried y rheumtologists nd 23% y primry cre physicins. The incidence rtes of hospitlized pneumoni (verge, 73.3 cses per 1000 ptient-yers) nd opportunistic infection (2.9/1000 ptient-yers) did not vry over time (p vlues = 0.59 nd 0.27, respectively). The primry metric used in the present study ws months of drug use in reltion to months of oservtion with RA, which cptures dherence with DMARD. In contrst, pst studies hve focused on the percentge of ptients who received t lest 1 dispensing of DMARD in ech yer; in the present study, we oserved 75% to 83% of ptients to hve received t lest 1 dispensing (or inflixim infusion) in ech yer. Differences cross Medicl Centers Adjusted rtes of outptient visits to rheumtology (rtio of 75th to 25th percentile, 1.5) nd primry cre (rtio, 1.3) differed cross the 12 Medicl Centers, s did verge months of use per ptient-yer (including oth users nd nonusers) of DMARDs, prednisone, nd opioid per ptient 8 The Permnente Journl/ Winter 2016/ Volume 20 No. 1

6 Popultion Vritions in Rheumtoid Arthritis Tretment nd Outcomes, Northern Cliforni, Figure 2. Trends in rtes of visits to rheumtology nd primry cre physicins., All results for 28,601 ptients with rheumtoid rthritis were djusted for ge, sex, rce/ethnicity, comoridity, nd Medicl Center. p vlues for chnge over time were < 0.01 for ll visit types. Figure 3. Trends in verge drug use (months per ptient-yer) of disese-modifying ntirheumtic drugs mong users nd nonusers., All results for 28,601 ptients with rheumtoid rthritis were djusted for ge, sex, rce/ethnicity, comoridity, nd Medicl Center. All p vlues were < except for hydrochloroquine (p = 0.47) nd sulfslzine (p = 0.34). TNF = tumor necrosis fctor. Figure 4. Trends in prednisone nd opioid exposure mong users nd nonusers., All results for 28,601 ptients with rheumtoid rthritis were djusted for ge, sex, rce/ethnicity, comoridity, nd Medicl Center. p vlues were < The Permnente Journl/ Winter 2016/ Volume 20 No. 1 9

7 Popultion Vritions in Rheumtoid Arthritis Tretment nd Outcomes, Northern Cliforni, A comngement y generlists nd suspecilists hs not een comprehensively evluted, lthough previous studies suggest lower use of DMARD mong ptients in primry cre, likely reflecting lower disese ctivity. (ll p vlues < ; Tle 3). The lrgest difference ws in the use of inflixim, which differed y fctor of 13.9 cross the interqurtile rnge. However, the incidence rtes of pneumoni (p = 0.40) nd opportunistic infection (p = 0.61) did not differ significntly cross Medicl Centers. One center hd disproportionte numer of Africn Americns, nd nother hd disproportionte numer of Asin Americns; otherwise, the Medicl Center popultions were similr in ge, sex, rce, nd comoridity; djustment for these vriles did not chnge the estimtes to n importnt degree. DISCUSSION Prctice vritions cn e used to identify trgets for the development of guidelines, qulity mesures, nd qulity improvement. KP s community-sed setting nd detiled computerized clinicl dt provide n excellent opportunity to ssess prctice vritions. During 12-yer period, 28,601 dults with RA showed shifts in tretment ptterns, including n incresing rte of primry cre visits nd incresing use of DMARDs. Totl DMARD use incresed for the verge ptient with RA to 63% of follow-up in Similr to previous findings in the Veterns Affirs popultion, 14 this increse ws predominntly relted to higher rtes of continution of methotrexte nd Tle 3. Interqurtile rnges cross 12 Medicl Centers of visits, drugs, nd outcomes mong ptients with rheumtoid rthritis, Chrcteristic 25th percentile Medin 75th percentile Rtio of 75th percentile to 25th percentile Outptient visits per ptient-yer Rheumtology Primry cre Averge nti-tnf gent use c Any d Etnercept d Adlimum d Inflixim d Averge noniologic use Hydrochloroquine Sulfslzine Methotrexte Leflunomide Glucocorticoid Opioid Infection events per ptient-yer Hospitlized pneumoni e Opportunistic infections e Adjusted for ge, sex, rce/ethnicity, comoridity, nd clendr yer in ll 28,601 ptients. p vlues < c In months of use per ptient-yer, including users nd nonusers. d Per 1000 ptient-yers. e p vlue for hospitlized pneumoni ws 0.40, nd for opportunistic infections ws TNF = tumor necrosis fctor. incresed uptke of nti-tnf gents. Nerly hlf of ll visits coded for RA were to primry cre physicins, with the rte of these visits incresing nerly 50% over the study period. A comngement y generlists nd suspecilists hs not een comprehensively evluted, lthough previous studies suggest lower use of DMARD mong ptients in primry cre, likely reflecting lower disese ctivity. 6 Comngement nd temsed cre of RA re importnt topics for further reserch. We further oserved importnt vritions in use of inflixim nd dlimum, with more modest vritions in etnercept nd noniologic DMARDs. We suspect tht clinic-sed vrition in use of nti-tnf therpy my hve een consequence of the drugs reltively recent introduction, resulting in differences in rheumtologists knowledge, ttitudes, nd preferences towrd use. In ddition, ecuse inflixim is infused nd not injected, it ws not suject to the Medicre donut hole, with some rheumtologists using it for tht reson. The pproch to ddressing ptients cost rriers my hve vried from Medicl Center to Medicl Center. The study results suggest opportunities for stndrdizing DMARD use cross settings. This study ws designed to ssess vritions t the popultion level. The incresed use of methotrexte, leflunomide, nd nti-tnf gents together with the declining use of hydrochloroquine nd sulfslzine suggest more ggressive pproch to therpy. However, incresed dherence nd continution of therpy mong ptients receiving prescription remins n importnt topic for future reserch. Furthermore, rief ptient-reported outcomes, such s might e dpted from the Helth Assessment Questionnire, will ecome fesile to ssess during routine clinicl cre, nd these outcomes will e vlule for future reserch studies. Pst studies of vritions in cre for RA hve een conducted in popultion-sed studies, cohorts of insured ptients (through dministrtive dt), nd rheumtology cohorts, with the ltter hving high levels of DMARD use s expected. 6 We oserved 75% to 83% of ptients to hve received t lest 1 dispensing of DMARD. The frequency of DMARD use (numer of ptients with t lest 1 dispensing in ech yer) rnged from 16% to 87% in 245 Medicre mnged cre plns ( ), compred with 75% to 83% in the present study. 15 In the Ntionl Amultory Medicl Cre Survey, , DMARD ws exmined t the unit of the visit nd not the ptient, with 47% of 859 visits cross the entire study period hving documenttion of DMARD use. 16 In the TennCre popultion, the proportion of ptients with RA (N = 23,342) who received t lest 1 dispensing of nti- TNF or noniologic DMARD incresed from 1995 through 2004, from 62% to 71%. 17 The TennCre study ws similr to ours in finding reduction in glucocorticoid prescriing nd n increse, through 2004, of opioid prescriing. In the West Virgini Medicid dt in 2003, the proportion of ptients with RA ged 50 to 64 yers (N = 143,211) with nrcotic dispensing ws quite high t 68%; glucocorticoid use ws 48%; DMARD use ws 40%; nd use of iologic gent, 12% The Permnente Journl/ Winter 2016/ Volume 20 No. 1

8 Popultion Vritions in Rheumtoid Arthritis Tretment nd Outcomes, Northern Cliforni, In the yers tht opite use ws rising in the present study, KPNC ws engged in n ggressive progrm to limit the use of cyclooxygense 2 inhiitors nd other nonsteroidl nti-inflmmtory drugs, prticulrly mong older ptients, who were deemed pproprite for low-level opioids such s hydrocodone-cetminophen (Vicodin). Opioid use my e relted to RA or comoridities; incresing use reflects ntionl trends. 19 We cnnot comment on whether this increse ws pproprite ecuse we did not nlyze ptient-level dt on the indiction for opioid use. Optiml use of opioids remins n re for intervention. The use of prednisone for tretment of RA is controversil 20 ; in the US, mny physicins try to void using the drug, prticulrly t higher doses. Recent studies using dministrtive dt hve oserved incresed risk of serious infection, even with low doses of corticosteroid. 21,22 We oserved declining use of prednisone during the study period; however, this decline ws not linked to reduction in the rtes of pneumoni nd opportunistic infection. A difference etween this nd erlier studies ws the design; we did not compre prednisone users with nonusers, which is suject to is y disese severity, ut rther exmined chnges in oth prednisone use nd infection risk over time in the popultion of users nd nonusers. A minor limittion of the study is the inclusion of persons without RA in the study popultion. The positive predictive vlue of the cse-finding lgorithm we used, 77%, ws similr to the vlue of 76% reported in Cndin study using criteri more pproprite to helth cre utiliztion in Cnd. 23 Inclusion of persons without RA would depress the overll prevlence of outcomes nd use of tretment. A more importnt limittion ws lck of informtion on disese severity. However, our design minimized this limittion. Also, the vrition in prctice within KP most likely is lower thn outside KP. Bsed on dt from the 2003 Cliforni Helth Interview Survey, the KP dult memership is very similr to the non-kp popultion with helth insurnce pln other thn Medicid with regrd to eduction nd helth; it differs y hving fewer non-hispnic whites nd fewer memers with very low nd very high household incomes. 24 Finlly, the study cohort of 28,601 persons ws somewht older thn expected, possily reflecting greter use of medicl cre mong older persons nd the greter opportunity to record dignoses of RA. CONCLUSION This study demonstrted trend of more ggressive tretment in RA, consistent with tretment recommendtions from the Americn College of Rheumtology. It is encourging tht use of prednisone decresed. Opioid use remins n importnt topic for investigtion nd intervention. Vrition cross Medicl Centers ws high for inflixim nd dlimum, suggesting physicin differences nd opportunities to further stndrdize use of newer gents. Despite incresed use of DMARDs nd decresed use of orl prednisone, we did not find evidence for chnge in the risk of infection. We recommend further reserch to etter understnd comngement nd tem-sed cre of RA, nd to etter stndrdize use of nti-tnf gents nd opioids in RA. v Disclosure Sttement Dr Herrinton hs received reserch grnts from Genentech, South Sn Frncisco, CA; Procter & Gmle Co, Cincinnti, Ohio; nd MedImmune, Githersurg, MD. Dr Hrrold hs reserch contrct with the Consortium of Rheumtology Reserchers of North Americ (CORRONA), Southorough, MA. Dr Asgri hs reserch contrcts with Vlent, Lvl, Queec, Cnd; nd Pfizer Inc, New York, NY. Dr Gelfnd hs served s consultnt for nd received honorri from AVie, North Chicgo, IL; Amgen Inc, Thousnd Oks, CA; Celgene Corp, Summit, NJ; Coherus Biosciences, Cmrillo, CA; Eli Lilly nd Co, Indinpolis, IN; LEO Phrm, Bllerup, Denmrk; Merck, Kenilworth, NJ; Jnssen Biotech Inc (formerly Centocor), Horshm, PA; Novrtis Corp, Bsel, Switzerlnd; nd Pfizer; he hs hd grnts or hs pending grnts from Amgen; Jnssen Phrmceuticls Inc, Titusville, NJ; AVie; Novrtis; Eli Lilly; nd Pfizer. Dr Wu hs received reserch grnts from AVie; Amgen; Coherus Biosciences; Eli Lilly; Jnssen Phrmceuticls; Merck; Novrtis; Pfizer; Regeneron, Trrytown, NY; nd Sndoz Interntionl, Holzkirchen, Germny; he is consultnt for AVie; Amgen; Celgene; DUSA Phrmceuticls Inc, Wilmington, MA; Eli Lilly; nd Pfizer. Dr Curtis hs received reserch funding from Genentech; UCB, Brussels, Belgium; AVie; Jnssen Phrmceuticls; Bristol-Myers Squi Co, New York, NY; nd Amgen. Other uthors hve reported no competing interests. The Ntionl Institute for Allergy nd Infectious Diseses did not ply role in the design, nlysis, or interprettion of the study. Acknowledgments This reserch ws funded y grnt (1RC ) from the Ntionl Institutes of Helth (NIH), Ntionl Institute for Allergy nd Infectious Diseses, Bethesd, MD. Dr Herrinton ws supported y NIH Grnt R01 HS19912 nd Agency for Helthcre Reserch nd Qulity Grnts U18 HS010391, U18 HS017919, nd R01 HS Dr Curtis receives support from NIH Grnt K23 AR nd Agency for Helthcre Reserch nd Qulity Grnt R01 HS Dr Hrrold ws supported y NIH Grnt K23 AR Dr Gelfnd ws supported y NIH Grnt K24 AR Dr Asgri ws supported y NIH Grnts R01 CA nd R03 AR Kthleen Louden, ELS, of Louden Helth Communictions provided editoril ssistnce. References 1. Khnn D, Arnold EL, Penchrz JN, et l. Mesuring process of rthritis cre: the Arthritis Foundtion s qulity indictor set for rheumtoid rthritis. Semin Arthritis Rheum 2006 Fe;35(4): DOI: semrthrit McLen CH, Sg KG, Solomon DH, Morton SC, Smpsel S, Klippel JH. Mesuring qulity in rthritis cre: methods for developing the Arthritis Foundtion s qulity indictor set. Arthritis Rheum 2004 Apr 15;51(2): DOI: 3. Disese modifying nti-rheumtic drug therpy in rheumtoid rthritis [Internet]. Wshington, DC: Ntionl Committee for Qulity Assurnce; 2014 [cited 2015 July 20]. Aville from: teofhelthcrequlity/2014tleofcontents/dmards.spx. 4. Singh JA, Furst DE, Bhrt A, et l updte of the 2008 Americn College of Rheumtology recommendtions for the use of disese-modifying ntirheumtic drugs nd iologic gents in the tretment of rheumtoid rthritis. Arthritis Cre Res (Hooken) 2012 My;64(5): DOI: org/ /cr Americn College of Rheumtology. Rheumtoid rthritis qulity indictors [Internet]. Atlnt, GA: Americn College of Rheumtology; c2014 [cited 2013 Oct 10]. Aville from: 6. Schmjuk G, Solomon DH, Yzdny J. Ptterns of disese-modifying ntirheumtic drug use in rheumtoid rthritis ptients fter 2002: systemtic The Permnente Journl/ Winter 2016/ Volume 20 No. 1 11

9 Popultion Vritions in Rheumtoid Arthritis Tretment nd Outcomes, Northern Cliforni, review. Arthritis Cre Res (Hooken) 2013 Dec;65(12): DOI: 7. Hrrold LR, Peterson D, Berd AJ, Gurwitz JH, Briescher BA. Time trends in mediction use nd expenditures in older ptients with rheumtoid rthritis. Am J Med 2012 Sep;125(9):937.e9-15. DOI: mjmed Lillegrven S, Kvien TK. Mesuring disility nd qulity of life in estlished rheumtoid rthritis. Best Prct Res Clin Rheumtol 2007 Oct;21(5): DOI: 9. Herrinton LJ, Liu L, Firemn B, et l. Time trends in therpies nd outcomes for dult inflmmtory owel disese, Northern Cliforni, Gstroenterology 2009 Aug;137(2): DOI: gstro Deyo RA, Cherkin DC, Ciol MA. Adpting clinicl comoridity index for use with ICD-9-CM dministrtive dtses. J Clin Epidemiol 1992 Jun;45(6): DOI: The MIXED procedure [Internet]. Cry, NC: SAS Institute Inc; c2015 [cited 2013 Oct 10]. Aville from: sttug/63033/html/defult/viewer.htm#mixed_toc.htm. 12. Minlu G, Aerts M, Coenen S, et l. Appliction of mixed-effects models to study the country-specific outptient ntiiotic use in Europe: tutoril on longitudinl dt nlysis. J Antimicro Chemother 2011 Dec;66 Suppl 6:vi DOI: Cops JB. Using regression models for prediction: shrinkge nd regression to the men. Stt Methods Med Res 1997 Apr;6(2): DOI: / Ng B, Chu A, Khn MM. A retrospective cohort study: 10-yer trend of disesemodifying ntirheumtic drugs nd iologicl gents use in ptients with rheumtoid rthritis t Vetern Affirs Medicl Centers. BMJ Open 2013 Apr 5;3(4). pii: e DOI: Schmjuk G, Trivedi AN, Solomon DH, et l. Receipt of disese-modifying ntirheumtic drugs mong ptients with rheumtoid rthritis in Medicre mnged cre plns. JAMA 2011 Fe 2;305(5): DOI: /jm Solomon DH, Aynin JZ, Yelin E, Shykevich T, Brookhrt MA, Ktz JN. Use of disese-modifying medictions for rheumtoid rthritis y rce nd ethnicity in the Ntionl Amultory Medicl Cre Survey. Arthritis Cre Res (Hooken) 2012 Fe;64(2): DOI: Grijlv CG, Chung CP, Stein CM, Mitchel EF Jr, Griffin MR. Chnging ptterns of mediction use in ptients with rheumtoid rthritis in Medicid popultion. Rheumtology (Oxford) 2008 Jul;47(7): DOI: rheumtology/ken Khnn R, Smith MJ. Utiliztion nd costs of medicl services nd prescription medictions for rheumtoid rthritis mong recipients covered y stte Medicid progrm: retrospective, cross-sectionl, descriptive, dtse nlysis. Clin Ther 2007 Nov;29(11): DOI: clinther Cmpell CI, Weisner C, Leresche L, et l. Age nd gender trends in longterm opioid nlgesic use for noncncer pin. Am J Pulic Helth 2010 Dec;100(12): DOI: Kirwn JR. Comintion therpy including glucocorticoids: the new gold stndrd for erly tretment in rheumtoid rthritis? Ann Intern Med 2012 Mr 6;156(5): DOI: Widdifield J, Berntsky S, Pterson JM, et l. Serious infections in popultionsed cohort of 86,039 seniors with rheumtoid rthritis. Arthritis Cre Res (Hooken) 2013 Mr;65(3): DOI: Grijlv CG, Chen L, Delzell E, et l. Initition of tumor necrosis fctor-α ntgonists nd the risk of hospitliztion for infection in ptients with utoimmune diseses. JAMA 2011 Dec 7;306(21): DOI: /jm Widdifield J, Berntsky S, Pterson JM, et l. Accurcy of Cndin helth dministrtive dtses in identifying ptients with rheumtoid rthritis: vlidtion study using the medicl records of rheumtologists. Arthritis Cre Res (Hooken) 2013 Oct;65(10): DOI: memer helth survey [Internet]. Oklnd, CA: Kiser Permnente Division of Reserch; 2011 [cited 2015 Mr 24]. Aville from: org/externl/dorexternl/mhs/index.spx. Indiscriminte The chronicl [sic] differs from the cute rheumtism in eing joined with little or no fever, in hving duller pin, nd commonly no redness, ut the swellings re more permnent, nd the disese of much longer durtion; for if the cute species hve continued some months, the other hs continued for mny yers. Both kinds of the rheumtism ttck indiscrimintely mles nd femles, rich nd poor. Commentries on the History nd Cure of Diseses, Willim Heerden, , English physicin 12 The Permnente Journl/ Winter 2016/ Volume 20 No. 1