Rheumatoid arthritis (RA) is a chronic, progressive, and

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1 RESEARCH Evlution of Rel-World Experience with Compred with Adlimumb, Etnercept, nd Abtcept in RA Ptients with 1 Previous Biologic DMARD: Dt from U.S. Administrtive Clims Dtbse Jmes Hrnett, PhrmD, MS; Robert Gerber, PhrmD; Dvid Gruben, PhD; Andrew S. Koenig, DO; nd Connie Chen, PhrmD ABSTRACT BACKGROUND: Rel-world dt compring tofcitinib with biologic disese-modifying ntirheumtic drugs (bdmards) re limited. OBJECTIVE: To compre chrcteristics, tretment ptterns, nd costs of ptients with rheumtoid rthritis (RA) receiving tofcitinib versus the most common bdmards (dlimumb [ADA], etnercept [ETN], nd btcept [ABA]) following single bdmard in U.S. dministrtive clims dtbse. METHODS: This study ws retrospective cohort nlysis of ptients ged 18 yers with n RA dignosis (ICD-9-CM codes 714.0x-714.4x; ) nd 1 previous bdmard filling 1 tofcitinib or bdmard clim in the Truven MrketScn Commercil nd Medicre Supplementl clims dtbses (November 1, 2012-October 31, 2014). Monotherpy ws defined s bsence of conventionl synthetic DMARDs within 90 dys post-index. Persistence ws evluted using 60-dy gp. Adherence ws ssessed using proportion of dys covered (PDC). RA-relted totl, phrmcy, nd medicl costs were evluted in the 12-month pre- nd post-index periods. Tretment ptterns nd costs were djusted using liner models including common set of cliniclly relevnt vribles of interest (e.g., previous RA tretments), which were ssessed seprtely using t-tests nd chi-squred tests. RESULTS: Overll, 392 ptients initited tofcitinib; 178 ptients initited ADA; 118 ptients initited ETN; nd 191 ptients initited ABA. ptients were older versus ADA ptients (P = ) nd hd lower proportion of Medicre supplementl ptients versus ABA ptients (P = ). Twelve-month pre-index bdmard use ws greter in tofcitinib ptients (77.6%) versus bdmard cohorts (47.6%-59.6%). ptients hd greter 12-month pre-index RA-relted totl costs versus bdmard cohorts (ll P < ) nd gretest index use of monotherpy (P = vs. ABA). A similr (ll P > 0.10) proportion of ptients were persistent with tofcitinib (42.6%) versus ADA (37.6%), ETN (42.4%), nd ABA (43.5%). Men PDC ws 0.55 for tofcitinib versus 0.57 (ADA), 0.59 (ETN), nd 0.44 (ABA; P = ). Adjusted nlyses generted similr findings to the undjusted tretment ptterns. hd lower djusted 12-month post-index men RA-relted totl costs ($23,568) versus ADA ($29,278; P < ), ETN ($26,885; P = ), nd ABA ($30,477; P < ). CONCLUSIONS: In this study, tofcitinib ws more commonly used s monotherpy nd yielded t lest comprble persistence nd dherence with lower djusted men RA-relted totl costs versus ADA, ETN, nd ABA. Further nlysis is wrrnted given the greter 12-month pre-index bdmard use nd RA-relted costs for tofcitinib versus bdmards. J Mng Cre Spec Phrm. 2016;22(12): Copyright 2016, Acdemy of Mnged Cre Phrmcy. All rights reserved. Wht is lredy known bout this subject is n orl Jnus kinse inhibitor for the tretment of rheumtoid rthritis (RA). A network met-nlysis of rndomized controlled tril dt hs demonstrted tht tofcitinib hs similr efficcy to biologic disese-modifying ntirheumtic drugs (bdmards) in improving the signs nd symptoms of RA in ptients with n indequte response to tumor necrosis fctor inhibitors. Wht this study dds Although most ptients received conventionl synthetic DMARD (csdmard) in the 12-month pre-index period, substntil proportion strted bdmard, or more commonly, tofcitinib monotherpy; those receiving tofcitinib monotherpy hd the lowest proportion inititing csdmards in the 12-month follow-up period (i.e., styed on monotherpy) versus those receiving bdmards. ptients were more likely to hve received bdmard in the 12-month pre-index period nd hd t lest comprble persistence nd dherence versus ptients receiving bdmards. Totl RA-relted costs in the 12-month post-index period djusted for demogrphics nd prior enrollment history, clinicl chrcteristics, prior RA-relted tretments, use of monotherpy regimen, nd pre-index RA-relted costs were significntly lower for ptients receiving tofcitinib versus ptients receiving bdmards. Rheumtoid rthritis (RA) is chronic, progressive, nd disbling utoimmune disese ffecting 1.5 million people in the United Sttes. 1 The economic burden of RA is substntil. Dt from U.S. dministrtive clims dtbses covering privtely insured nd Medicre/Medicid beneficiries reported RA costs of $19.3 billion nnully, when intngible costs were excluded, nd $39.2 billion when these costs were considered. 2 U.S. Medicl Expenditure Pnel Survey dt suggest n nnul cost of $22.3 billion. 3 The current gol of RA tretment is to chieve low disese ctivity or remission. 4,5 The Americn Rheumtism Assocition erly response criteri included remission definition; 6 however, t tht time, therpies were rrely ble Vol. 22, No. 12 December 2016 JMCP Journl of Mnged Cre & Specilty Phrmcy 1457

2 to chieve such low ctivity levels. In contemporry prctice, there is greter bility to limit or eliminte clinicl signs nd symptoms, s exemplified in the Americn College of Rheumtology/Europen Legue Aginst Rheumtism (ACR/EULAR) Boolen response criteri. 7 The minsty of initil disese-modifying ntirheumtic drug (DMARD) therpy is methotrexte (MTX), which reduces signs nd symptoms of RA nd slows progression of joint dmge. However, intensive MTX monotherpy chieves remission in only one third of ptients. 8 Administering MTX with biologic DMARDs (bdmards) cn optimize efficcy, s mesured by clinicl, functionl, ptient-reported, nd rdiologic outcomes The introduction of bdmards hs improved the lives of mny RA ptients; however, only one third chieve clinicl remission. 14 bdmards include the following: tumor necrosis fctor inhibitors (TNFi): dlimumb (ADA), etnercept (ETN), infliximb (IFX), certolizumb pegol (CZP), nd golimumb (GOL); n interleukin (IL)-6 receptor inhibitor: tocilizumb (TCZ); n IL-1 receptor inhibitor: nkinr (ANK); B-cell depleting nti-cd20 monoclonl ntibody: rituximb (RTX); nd co-stimultion blocker of cytotoxic T lymphocyte ntigen 4: btcept (ABA). TNFi cn be ineffective in some ptients becuse of individul vritions in pthophysiologicl response or differences in the dominnt cytokine mediting the disese process. 15 Ptients my develop secondry loss of efficcy following uto-ntibody production necessitting concomitnt conventionl synthetic DMARDs (csdmards) nd dose escltion, most commonly with IFX nd ADA bdmard use my lso be limited by intrvenous or subcutneous dministrtion, which is inconvenient nd ssocited with infusion/ injection-site rections, substntil costs, 22 nd complince issues if doses re reduced becuse of fer of dverse effects or ctul intolernce. 23 is n orl Jnus kinse (JAK) inhibitor for the tretment of RA. 5 mg twice dily (BID) nd, more recently, once-dily dosing re pproved for use in the United Sttes in dults with modertely to severely ctive RA nd n indequte response/intolernce to MTX nd cn be dministered lone or with csdmards. 24 ACR published updted 2015 tretment guidelines recommending tofcitinib (nd bdmards) for RA-estblished ptients who hve indequte response to csdmards. 5 In current prctice, nd supported by U.S. pyer ccess, TNFi (prticulrly ADA nd ETN) re commonly used fter csdmards. For ptients with indequte responses to their first bdmards, ACR recommends non-tnfi bdmards before TNFi nd tofcitinib; however, this is supported by very low-level evidence. In this study, U.S. dministrtive clims dt were used to compre ptient chrcteristics, tretment ptterns, nd costs in RA ptients receiving tofcitinib or common bdmards following 1 previous bdmard. Methods Study Design This study ws retrospective cohort nlysis of ptients ged 18 yers (t index) with RA (Interntionl Clssifiction of Diseses, Ninth Revision, Clinicl Modifiction [ICD-9-CM] codes 714.0x-714.4x nd ) nd 1 clim for tofcitinib (selected first) or bdmard between November 1, 2012, nd October 31, 2014, in the Truven MrketScn Commercil nd Medicre Supplementl dtbses. Intrvenous nd subcutneous bdmards included TNFi (ADA, ETN, IFX, CZP, nd GOL) nd non-tnfi (ABA, RTX, TCZ, nd ANK) bdmards. The index event ws the first tofcitinib or bdmard use t which ptients hd continuous enrollment 12 months before nd 12 months fter index tretment nd fulfilled other selection criteri. Primry bseline period ws 12 months preindex; however, vrible-length pre-index, using the erliest continuous enrollment vilble through index, nd ny preindex (i.e., ll vilble clims) periods, were explored. Excluded ptients hd nother inflmmtory condition for which bdmards re used (Crohn s disese [555.xx], ulcertive colitis [556.xx], nkylosing spondylitis [720.0x], psorisis [696.1x], nd psoritic rthritis [696.0x]) in the 12-month preindex period or t index nd previous use of index mediction or filled > 1 bdmard or bdmard with tofcitinib t index. This nlysis focused on ptients with 1 previous nonindex bdmard t ny time before index, since significnt proportion of ptients received bdmards before the 12-month preindex period. An imblnce in the number of ptients with 2 previous bdmards ws lso observed prticulrly for ADA nd ETN, which were most common in bdmard-nïve ptients. Comprisons Among ptients who received 1 bdmard pre-index, those who initited tretment with tofcitinib were compred with those inititing ADA, ETN, or ABA (the most common bdmards used in these ptients). Assessments Ptient Chrcteristics. Ptient chrcteristics included bseline demogrphics, 12-month pre-index use of DMARDs nd other RA-relted medictions, rheumtologist visits, Qun- Chrlson Comorbidity Index (CCI) 25 nd clims-bsed index of RA severity (CIRAS) scores, 26 use of bdmards ny time before index, nd number of dys from erliest dignosis in the vrible-length bseline period to index. Tretment Ptterns. Monotherpy ws defined s the bsence of select csdmards (MTX, sulfslzine, hydrochloroquine, or leflunomide) within 90 dys post-index. For monotherpy ptients, ddition of select csdmards in the 12-month postindex period ws evluted Journl of Mnged Cre & Specilty Phrmcy JMCP December 2016 Vol. 22, No. 12

3 Tretment persistence ws defined s continuing index mediction without 60-dy gp fter the prescription dys supply hd run out through to the end of the 12-month postindex period Erly switch ws defined s the initition of tofcitinib or nonindex bdmard (including the bdmards previously listed) during or before 60-dy gp in index tretment. Delyed switch ws defined s the initition of tofcitinib or nonindex bdmard fter gp in index therpy 60 dys. Proportion of dys covered (PDC) ws derived by clculting the number of dys covered by the prescription fills during the denomintor period. 30 The numertor consisted of dys supply covered by rrys for ech fill during the denomintor period nd djusted for mximum 15-dy overlp in dys supply. The denomintor ws the time from index mediction fill/dministrtion to the end of the 12-month post-index period. PDC ws cpped t 1. In the study cohort, 81% of index mediction prescriptions hd 28-dy supply, nd 13% hd n 84-dy supply cross ADA, ETN, nd subcutneous ABA groups. For tofcitinib, 87% hd 30-dy supply, nd 11% hd 90-dy supply. Totl dys supply for tofcitinib, ADA, ETN, nd subcutneous ABA ws the dys supply rounded to the nerest 28-dy period. Rounding ws implemented to ddress likely inccurte dys supply bsed on the nlysis of index mediction prescription dys supply nd for consistency with dosing recommendtions, s well s to stndrdize cross monthly supplies (i.e., 28 dys [bdmards] vs. 30 dys [tofcitinib]). ABA infusion used 28-dy supply. Weekly dose ws determined for index clims during the follow-up period nd clculted by dividing the totl dose per prescription by the totl dys supply multiplied by 7 dys. Consistent with previous publictions, 31,32 dose escltion ws defined s ny increse in n verge weekly dose to 40 mg per week for ADA nd 100 mg per week for ETN. An increse of t lest double the recommended dose for tofcitinib (i.e., 20 mg per dy) nd subcutneous ABA (i.e., 250 mg per week) ws considered dose escltion. Dose escltion for intrvenous ABA occurred if the lst dose ws 100 mg greter thn the first dose. 32 Costs. All-cuse nd RA-relted helth cre resource use nd costs were evluted during the 12-month pre- nd post-index periods. RA-relted visits included those with ICD-9-CM code 714.xx in ny position on the clim nd ny bdmard dministrtion-relted visit (using ssocited Helthcre Common Procedure Coding System codes regrdless of RA dignosis, but excluding n osteoporosis dignosis [ICD-9-CM code 733.0]) if observed in the bsence of n RA dignosis (i.e., not be clssified s RA relted). RA-relted prescriptions included csdmards nd bdmards, COX-2 inhibitors, nonselective nonsteroidl nti-inflmmtory drugs, opioids, nd glucocorticoids. Costs included ptient nd helth pln-pid mounts. Costs were djusted using the nnul medicl cre component of the Consumer Price Index to reflect infltion between 2011 (erliest pre-index period) nd Sttisticl Anlyses Simple sttisticl nlyses were performed using pirwise t-sttistics (continuous vribles) or chi-squred sttistics (binry vribles) for ll vribles considered cliniclly relevnt in compring ech bdmard mediction t index versus tofcitinib. These vribles included demogrphy, enrollment history, clinicl chrcteristics, previous RA-relted tretments, nd use of monotherpy regimen (Appendix, vilble in online rticle). The behvior of the t-test ws compred with nonprmetric test (i.e., Wilcoxon), prticulrly for dt tht were likely to be skewed. The t-test ws robust nd chosen for simplicity nd comprbility with the djusted nlyses. Adjusted nlyses were performed using generlized liner models. Ech model included cliniclly relevnt vribles. For cost-relted dependent vribles, the model lso included the corresponding 12-month pre-index cost. Binry vribles were nlyzed with logit link. Cost vribles were nlyzed s gmm-distributed dt with log link. Other vribles were treted s normlly distributed with n inverse link. Pirwise t-sttistics nd chi-squre sttistics were lso pplied to the dependent vribles s n initil check, compring the bdmards t index versus tofcitinib. For independent vribles, P vlues 0.05 were noted for the reltive importnce of tht independent vrible. For ech vrible, when compring index mediction, P vlues were significnt fter pplying the multiple comprison procedure due to Hochberg, versus tofcitinib, using the 0.05 significnce level, unless otherwise noted. 33 For djusted nd undjusted nlyses, missing vlues were ignored. All P vlues were 2-sided. Results Ptients From November 2012 to October 2014, 1,252 ptients initited tofcitinib or bdmards nd met the initil study selection criteri (Figure 1). Overll, 392 (31.3%) ptients received index tretment with tofcitinib, nd 178 (14.2%), 118 (9.4%), nd 191 (15.3%) ptients initited with ADA, ETN, nd ABA, respectively. The remining 373 (29.8%) ptients were treted with CZP (n = 57; 4.6%), IFX (n = 59; 4.7%), RTX (n = 88; 7.0%), TCZ (n = 95; 7.6%), GOL (n = 70; 5.6%), nd ANK (n = 4; 0.3%), nd re not reported on further. Although ptient demogrphics nd clinicl chrcteristics were similr between ptients receiving tofcitinib nd the 3 most common bdmards, there were differences, such s tofcitinib ptients were older thn ADA ptients (P = ) nd hd lower proportion of Medicre supplementl ptients thn ABA ptients (P = ). A greter proportion of Vol. 22, No. 12 December 2016 JMCP Journl of Mnged Cre & Specilty Phrmcy 1459

4 FIGURE 1 Cohort Selection 1 clim for tofcitinib or bdmards between November 1, 2012, nd October 31, 2014 N = 240,320 (100.0%) Continuous enrollment during 1-yer pre- nd post-index periods n= 84,339 (35.1%) RA dignosis during pre-index period n = 37,583 (15.6%) Aged 18 yers on index dte n = 36,752 (15.3%) Without dignosis for select conditions n = 32,198 (13.4%) Without index mediction during pre-index period nd with only 1 bdmard or tofcitinib on index n = 9,193 (3.8%) With 1 previous bdmard during pre-index period n = 1,252 (0.5%) n = 392 (31.3%) ADA n = 178 (14.2%) ETN n = 118 (9.4%) ABA n = 191 (15.3%) Other bdmards n = 373 (29.8%) ABA = btcept; ADA = dlimumb; bdmard = biologic disese-modifying ntirheumtic drug; ETN = etnercept; RA=rheumtoid rthritis. tofcitinib ptients received bdmards in the 12-month preindex period versus those receiving ADA, ETN, nd ABA (ll P < ; Tble 1). TNFi were the most common bdmards t ny time preindex cross ll groups. A greter proportion of ADA, ETN, nd ABA ptients received TNFi t ny time pre-index versus tofcitinib ptients (ll P < 0.05). A greter proportion of tofcitinib ptients received non-tnfi bdmard t ny time pre-index versus ADA, ETN, nd ABA ptients (ll P < 0.05). Most ptients receiving tofcitinib, ADA, ETN, nd ABA received tretment with csdmards in the 12-month preindex period. MTX ws the most common csdmard in the 12-month pre-index period (Tble 1). Twelve-Month Post-index Tretment Ptterns Overll, 53.1% (208/392) of ptients received tofcitinib s monotherpy versus 48.3% (86/178), 48.3% (57/118), nd 41.4% (79/191; P = ) of ptients receiving ADA, ETN, nd ABA, respectively. The remining ptients received combintion therpy with csdmards, most commonly MTX (70.2%). Of ptients who initited tofcitinib s monotherpy, 24.0% (50/208) received csdmard in the 12-month post-index period versus 34.9% (30/86), 29.8% (17/57), nd 39.2% (31/79; P = ) of ptients inititing ADA, ETN, nd ABA monotherpy regimens, respectively. A similr proportion of ptients inititing tofcitinib (42.6%; 167/392), ADA (37.6%; 67/178), ETN (42.4%; 50/118), nd 1460 Journl of Mnged Cre & Specilty Phrmcy JMCP December 2016 Vol. 22, No. 12

5 TABLE 1 Ptient Demogrphics nd Bseline Chrcteristics in the 12-Month Pre-index Period (Unless Noted Otherwise) n = 392 ADA n = 178 P Vlue ADA vs. ETN n = 118 P Vlue ETN vs. ABA n = 191 P Vlue ABA vs. Age in yers, men [SD] 54.6 [11.7] 51.5 [15.2] [13.7] [12.6] Femle, n (%) 328 (83.7) 156 (87.6) (84.8) (83.8) Geogrphic region, n (%) South 168 (42.9) 62 (34.8) 45 (38.1) 72 (37.7) North Centrl 91 (23.2) 50 (28.1) 37 (31.4) 56 (29.3) West 66 (16.8) 38 (21.4) 22 (18.6) 31 (16.2) Northest 60 (15.3) 25 (14.0) 14 (11.9) 27 (14.1) Unknown 7 (1.8) 3 (1.7) 5 (2.6) Dt provider, n (%) Employer 284 (72.5) 141 (79.2) 91 (77.1) 150 (78.5) Helth pln 108 (27.6) 37 (20.8) 27 (22.9) 41 (21.5) Insurnce, n (%) Commercil 327 (83.4) 142 (79.8) 99 (83.9) 142 (74.4) Medicre supplementl 65 (16.6) 36 (20.2) 19 (16.1) 49 (25.7) Time in dys between erliest RA dignosis observed to index dte, men [SD] [423.4] [389.6] [340.7] [360.6] CCI score, men [SD] 1.5 [1.0] 1.4 [1.1] [1.2] [1.0] CIRAS score, men [SD] 4.6 [1.4] 4.8 [1.6] [1.5] [1.4] Rheumtologist visits, men [SD] 5.0 [3.2] 4.2 [2.7] [3.1] [3.6] bdmard use, n (%) 304 (77.6) 106 (59.6) < (49.2) < (47.6) < bdmard use (ny time pre-index), n (%) 392 (100.0) 178 (100.0) 118 (100.0) 191 (100.0) TNFi 288 (73.5) 163 (91.6) < (85.6) (92.7) < ADA 100 (25.5) N/A N/A 76 (64.4) < (32.5) CZP 18 (4.6) 1 (0.6) (4.2) (4.7) ETN 109 (27.8) 127 (71.4) < N/A N/A 69 (36.1) IFX 37 (9.4) 25 (14.0) (11.9) (17.3) GOL 24 (6.1) 10 (5.6) (5.1) (2.1) Non-TNFi bdmard 104 (26.5) 15 (8.4) < (14.4) (7.3) < RTX 21 (5.4) 4 (2.3) (5.1) (5.2) TCZ 26 (6.6) (1.6) ABA 57 (14.5) 11 (6.2) (7.6) N/A N/A ANK 0 0 N/A 2 (1.7) (0.5) csdmard use, n (%) b 305 (77.8) 127 (71.4) (78.8) (79.6) MTX 209 (53.3) 93 (52.3) (60.2) (56.5) Sulfslzine 22 (5.6) 18 (10.1) (9.3) (10.5) Hydroxychloroquine 72 (18.4) 39 (21.9) (22.0) (19.9) Leflunomide 74 (18.9) 24 (13.5) (17.0) (17.8) Other csdmard 29 (7.4) 11 (6.2) (9.3) (6.3) Pin mediction use, n (%) Opioids 131 (33.4) 61 (34.3) (34.8) (39.8) NSAIDs 214 (54.6) 103 (57.9) (49.2) (44.5) Corticosteroids 275 (70.2) 117 (65.7) (73.7) (71.2) Top 5 medictions, n (%) Prednisone 237 (60.5) 103 (57.9) (67.0) (64.9) MTX sodium 206 (52.6) 93 (52.3) (60.2) (56.5) Acetminophen/hydrocodone bitrtrte 157 (40.1) 74 (41.6) (45.8) (47.1) Folic cid 144 (36.7) 70 (39.3) (44.1) (37.7) Azithromycin 87 (22.2) 50 (28.1) (22.0) (23.6) Significnt t 0.05 fter pplying the Hochberg procedure. b Ptients could receive > 1 csdmard. ABA = btcept; ADA = dlimumb; ANK = nkinr; bdmard = biologic disese-modifying ntirheumtic drug; CCI = Chrlson Comorbidity Index; CIRAS = climsbsed index of RA severity; csdmard = conventionl synthetic disese-modifying ntirheumtic drug; CZP = certolizumb pegol; ETN = etnercept; GOL = golimumb; IFX = infliximb; MTX = methotrexte; N/A = not pplicble; NSAID = nonsteroidl nti-inflmmtory drug; RTX = rituximb; SD = stndrd devition; TCZ = tocilizumb; TNFi = tumor necrosis fctor inhibitor. Vol. 22, No. 12 December 2016 JMCP Journl of Mnged Cre & Specilty Phrmcy 1461

6 FIGURE 2 All-Cuse Totl, Phrmcy, nd Medicl Costs in the 12-Month Pre-index nd Post-index Periods for Ptients Receiving, ADA, ETN, nd ABA A. Twelve-Month Pre-index Period Men [SD] All-Cuse Costs Pre-index ($) 80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 Tofcitnib ADA ETN ABA 0 Totl Costs B. Twelve-Month Post-index Period 80,000 Men [SD] All-Cuse Costs Post-index ($) 70,000 60,000 50,000 40,000 30,000 20,000 10,000 Phrmcy Costs Medicl Costs Tofcitnib ADA ETN ABA 0 Totl Costs Phrmcy Costs Medicl Costs Note: Clims t index were considered s post-index costs. All-cuse costs included mbultory nd ER visits, inptient dmissions, nd prescriptions for ny reson. Significnt t 0.05 fter pplying the Hochberg procedure. ABA = btcept; ADA = dlimumb; ER = emergency room; ETN = etnercept; SD = stndrd devition. ABA (43.5%; 83/191) were persistent during the 12-month post-index period. Men persistence (dys) ws not significntly different for tofcitinib (219.9) versus ADA (221.3), ETN (232.9), nd ABA (232.6). Differences remined nonsignificnt in djusted nlyses. A greter proportion of ptients receiving ADA (10.1%; 18/178; P = ) nd ETN (10.2%; 12/118; P = ) switched erly to tofcitinib or nonindex bdmard versus those receiving tofcitinib (5.1%; 20/392); neither were significnt when djusting for multiple comprisons. A similr proportion of ptients (rnge: 13.6%-18.9%) hd 1462 Journl of Mnged Cre & Specilty Phrmcy JMCP December 2016 Vol. 22, No. 12

7 TABLE 2 RA-Relted Totl, Phrmcy, nd Medicl Costs in 12-Month Pre-index nd Post-index Periods A. Twelve-Month Pre-index Period Totl costs, men [SD]/medin, $ Phrmcy costs, men [SD]/medin, $ (n = 392) 20,784 [20,727]/16,623 10,014 [11,100]/6,634 bdmards 9,706 [11,088]/6,401 ADA (n = 178) 12,581 [14,115]/8,211 7,299 [8,875]/2,298 7,088 [8,858]/2,200 P Vlue ADA vs. ETN (n = 118) < ,750 [11,455]/4, ,460 [9,105]/ ,202 [9,133]/0 P Vlue ETN vs. ABA (n = 191) < ,490 [15,392]/7,471 < ,076 [7,780]/349 < ,872 [7,759]/0 P Vlue ABA vs. < < < Select csdmards b 272 [373]/ [234]/ [178]/100 < [263]/ Other csdmard medictions [208]/0 [224]/0 [485]/0 [70]/0 bdmard dministrtion costs, men [SD]/medin, $ Medicl costs, men [SD]/medin, $ 4,496 [13,331]/0 10,770 [20,552]/1, [3,074]/0 5,282 [11,634]/1,087 < [2,709]/0 < ,290 [7,448]/1,110 < ,655 [6,240]/0 < ,414 [14,880]/1, Inptient dmissions 2,693 [12,012]/0 1,702 [7,735]/ ,466 [5,505]/ ,188 [8,655]/ Ambultory visits 8,077 3,580 < ,824 < , [16,495]/1,499 [7,437]/1,015 [5,191]/1,006 [12,651]/1,262 Office visits 601 [728]/ [399]/ [395]/ [381]/ Outptient visits 7,476 [16,418]/810 3,063 [7,325]/437 < ,288 [5,084]/465 < ,680 [12,582]/ ER visits 123 [927]/0 194 [1,340]/ [853]/ [792]/ Urgent helth cre visits 0 0 N/A 4 [34]/ [208]/ Home helth cre visits 14 [136]/ [74]/ [405]/ Other unclssified services B. Twelve-Month Post-index Period Totl costs, men [SD]/medin, $ Phrmcy costs, men [SD]/medin, $ 7,339 [16,393]/755 24,793 [13,320]/24,072 19,804 [9,467]/21,186 16,318 [9,372]/16,602 bdmards 3,178 [7,782]/0 2,869 [7,258]/421 28,046 [13,708]/27,538 24,237 [12,713]/24,272 < ,079 [5,043]/ ,376 [11,906]/28,213 < ,140 [10,651]/25,251 < ,531 [12,540]/ ,800 [17,357]/28, ,282 [13,657]/13, < < < < ,915 [12,653]/24,041 < ,789 [10,543]/24,778 < ,959 [13,646]/13,604 < Select csdmards b 247 [383]/ [529]/ [290]/ [332]/ Other csdmard medictions [293]/0 [231]/0 [596]/0 [391]/0 bdmard dministrtion costs, men [SD]/medin, $ Medicl costs, men [SD]/medin, $ 1,184 [5,811]/0 1,050 [5,510]/ ,144 [4,645]/ ,888 [16,011]/0 < ,989 [11,366]/965 3,809 [7,997]/ ,236 [7,350]/ ,518 [20,189]/4,021 < Inptient dmissions 1,481 [7,171]/0 833 [4,190]/ ,305 [5,872]/ ,103 [11,693]/ Ambultory visits 3,508 [8,951]/878 2,976 [6,955]/ ,931 [4,345]/ ,415 [17,453]/2,604 < Office visits 565 [601]/ [355]/ [367]/ [353]/ Outptient visits 2,942 [8,818]/324 2,492 [6,810]/ ,467 [4,186]/ ,886 [17,394]/2,103 < ER visits 181 [1,355]/0 96 [603]/ [382]/ [440]/ Urgent helth cre visits 0 [9]/0 3 [27]/ [22]/ [2,374]/ Home helth cre visits 12 [101]/0 1 [10]/ [99]/ [180]/ Other unclssified services 2,750 [8,299]/303 2,395 [6,803]/ ,390 [4,180]/ ,795 [17,405]/2,025 < Significnt t 0.05 fter pplying the Hochberg procedure. b MTX, sulfslzine, hydrochloroquine, nd leflunomide. ABA = btcept; ADA = dlimumb; bdmard = biologic disese-modifying ntirheumtic drug; csdmard = conventionl synthetic disese-modifying ntirheumtic drug; ER = emergency room; ETN = etnercept; MTX = methotrexte; RA = rheumtoid rthritis; SD = stndrd devition. Vol. 22, No. 12 December 2016 JMCP Journl of Mnged Cre & Specilty Phrmcy 1463

8 delyed switch to tofcitinib or nonindex bdmard. Overll switch rte ws similr for ptients receiving tofcitinib (25.0%) versus ADA (27.5%), ETN (23.7%), nd ABA (24.6%); pre-index bdmard nd TNFi use were ssocited with significntly higher rtes of switching in djusted nlyses. Men (stndrd devition) PDC ws similr for ptients receiving tofcitinib (0.55 [0.30]), ADA (0.57 [0.30]), nd ETN (0.59 [0.31]) but ws significntly lower for ABA ptients (0.44 [0.39]; P = ) versus tofcitinib ptients. The proportion of ptients with PDC 0.8 rnged from 29.1% to 36.4%. In djusted nlyses, ABA use ws ssocited with significntly lower men PDC versus tofcitinib; however, there ws no significnt difference versus tofcitinib in the proportion of ptients with PDC 0.8 in undjusted nd djusted nlyses. Incresing ge ws ssocited with significntly higher PDC (s ws commercil insurnce coverge) nd proportion of ptients with PDC 0.8. Dose escltion ws more common mong ADA ptients (15.3%; 26/170) versus tofcitinib ptients (7.4%; 27/366; P = ). There were no significnt differences in dose escltion between tofcitinib ptients nd ETN (2.7%; 3/110) nd ABA (7.0%; 13/186) ptients. Costs Twelve-Month Pre-index Costs. ptients hd greter pre-index ll-cuse totl costs versus ADA nd ETN ptients (P < 0.05), medicl costs versus ETN ptients (P = ), nd phrmcy costs versus ptients receiving bdmards (ll P < 0.05; Figure 2A). ptients hd greter pre-index RA-relted totl nd phrmcy costs versus ptients receiving bdmards (ll P < 0.05) nd greter pre-index RA-relted medicl costs versus ADA nd ETN ptients (both P < ; Tble 2A). Phrmcy costs comprised 48.2% of the totl RA-relted costs for tofcitinib ptients versus 58.0%, 56.0%, nd 37.6% of the RA-relted totl costs for ADA, ETN, nd ABA ptients, respectively. Most RA-relted phrmcy costs were ttributed to the cost of bdmards nd their dministrtion (Tble 2A). RA-relted medicl costs comprised 51.8% of the totl costs for tofcitinib ptients versus 42.0%, 44.0%, nd 62.4% of the totl costs for ADA, ETN, nd ABA ptients, respectively. Most RA-relted medicl costs were ttributed to mbultory visits (Tble 2A). Twelve-Month Post-index Costs. Totl undjusted post-index men ll-cuse costs were similr for ptients receiving tofcitinib nd bdmards. Post-index ll-cuse phrmcy costs for tofcitinib ptients were lower versus ADA ptients but higher versus ABA ptients (both P < 0.001), while post-index llcuse medicl costs were lower for tofcitinib ptients versus ABA ptients (P = ; Figure 2B). In djusted nlyses, the totl post-index men (95% confidence intervl [CI]) ll-cuse cost ws significntly lower for tofcitinib versus ADA, ETN, nd ABA (Tble 3A). While CCI score, 3 csd- MARDs pre-index, rheumtologist visits pre-index, nd totl costs pre-index were ssocited with significntly higher llcuse totl costs, the South nd West regions were ssocited with lower costs (vs. Northest region; Tble 3B). ptients hd significntly lower undjusted postindex RA-relted totl costs versus ADA nd ABA ptients, significntly lower phrmcy costs versus ADA nd ETN ptients, nd significntly lower medicl costs versus ABA ptients (ll P < 0.05; Tble 2B). Post-index RA-relted phrmcy costs ccounted for most of the totl costs for ptients receiving tofcitinib (79.9%), ADA (86.4%), nd ETN (87.2%) nd > 50% of the totl cost for ABA ptients. Most RA-relted phrmcy costs for tofcitinib ptients were ttributed to the cost of tofcitinib followed by the cost of bdmards nd their dministrtion (Tble 2B). For ptients receiving bdmards, RA-relted costs ssocited with bdmards nd their dministrtion comprised most of the phrmcy costs (Tble 2B). Most post-index RA-relted medicl costs for ptients receiving tofcitinib nd bdmards were ttributed to mbultory visits (Tble 2B). In djusted nlyses, totl post-index men (95% CI) RA-relted costs were significntly higher for ADA, ETN, nd ABA versus tofcitinib (Tble 3A). Furthermore, commercil coverge, rheumtologist visits pre-index, nd RA-relted costs preindex were ssocited with significntly higher RA-relted totl costs, while the North Centrl region nd the South (Northest s reference) were ssocited with lower costs (Tble 3B). Discussion is the first orl JAK inhibitor pproved for RA. Although network met-nlysis of rndomized controlled tril dt demonstrted similr efficcy for tofcitinib versus bdmards in improving RA signs nd symptoms in ptients with indequte response to TNF inhibitors, 34 limited rel-world dt re vilble. In this study, we compred ptient chrcteristics, tretment ptterns, nd costs in RA ptients receiving tofcitinib versus ADA, ETN, nd ABA, fter 1 bdmard in U.S. clims dtbse. persistence nd dherence were t lest comprble versus bdmards, with lower djusted totl RA-relted costs. However, significnt differences between tretment cohorts, prticulrly with regrd to 12-month pre-index bdmard use nd RA-relted costs in fvor of bdmards, were observed, which my suggest chnneling bis for tofcitinib. Future nlyses will be required, idelly under similr ccess nd prescribing conditions nd incorporting dt with clinicl informtion, to ssess severity nd outcomes. Although this nlysis focused on ptients who received 1 previous bdmard, tofcitinib ptients were more likely to receive bdmard in the 12-month pre-index period versus 1464 Journl of Mnged Cre & Specilty Phrmcy JMCP December 2016 Vol. 22, No. 12

9 TABLE 3 Adjusted Anlyses for All-Cuse nd RA-Relted Totl Costs in the 12-Month Post-index Period ADA ETN ABA A. Adjusted 12 Month Post-index All-Cuse nd RA-Relted Totl Costs All-cuse totl costs, $ Men 36,945 42,221 42,219 43,042 95% CI 33,462-40,790 37,755-47,214 37,156-47,970 38,483-48,141 RA-relted totl costs, $ Men 23,568 29,278 26,885 30,477 95% CI 21,258-26,130 26,058-32,896 23,594-30,634 27,154-34,206 All Cuse RA Relted Coefficient P Vlue Coefficient P Vlue B. Coefficients from Generlized Liner Models for Anlysis of 12 Month Post-Index All-Cuse nd RA-Relted Totl Costs Intercept < < Age Region Northest (reference) North Centrl South < West Unknown Sex 1 (reference) Insurnce type of index clim Medicre (reference) Commercil Length of pre-index period Qun-CCI score during 12 months pre-index CIRAS score during 12 months pre-index Number of dys between first RA dignosis nd index csdmard count during 12 months pre-index 0 (reference) Index mediction (reference) ADA < ETN ABA < Use of 1 select csdmard during 90 dys post-index No (reference) Yes Number of rheumtologist visits during 12 months pre-index Unique number of opioid prescriptions during 12 months pre-index TNFi use during whole dtbse pre-index No (reference) Yes bdmard use before 12 months pre-index No (reference) Yes Totl costs during 12 months pre-index < < Significnt t 0.05 fter pplying the Hochberg procedure. ABA = btcept; ADA = dlimumb; bdmard = biologic disese-modifying ntirheumtic drug; CCI = Chrlson Comorbidity Index; CI = confidence intervl; CIRAS = clims-bsed index of RA severity; csdmard = conventionl synthetic disese-modifying ntirheumtic drug; ETN = etnercept; RA = rheumtoid rthritis; TNFi = tumor necrosis fctor inhibitor. Vol. 22, No. 12 December 2016 JMCP Journl of Mnged Cre & Specilty Phrmcy 1465

10 bdmard ptients, potentilly indicting differences in disese severity between groups; bdmard ptients were possibly more likely to hve previous tretment response or remission. Disese severity ws ssessed by CIRAS score, in the bsence of outcome mesures; however, the vlidity of CIRAS s robust proxy hs been questioned. 35 Pre-index RA-relted costs my be better indictor of severity nd were significntly higher for tofcitinib. This finding is interesting given the significntly higher undjusted medicl costs versus ADA nd ETN. In ddition, tofcitinib ptients hd higher previous prescription nd dministrtion costs nd n incresed likelihood of receiving non-tnfi bdmard, further suggesting more complicted cses compred with the bdmard groups. Thus, there is likely significnt chnneling bis with tofcitinib, but this would hve bised ginst tofcitinib. A substntil proportion of ptients strted monotherpy with tofcitinib or bdmard, despite most receiving csdmard in the 12-month pre-index period. A greter proportion of ptients received tofcitinib monotherpy versus bdmard monotherpy, nd mong these monotherpy ptients, tofcitinib ws ssocited with the lowest proportion of ptients who initited csdmards in the 12-month follow-up period. This is supported by dt from the Corron registry, where 43.2% of tofcitinib ptients received monotherpy versus 27.3% of ptients receiving bdmards. 36 Use of bdmards with csdmards my be more likely following reports of enhnced efficcy with some TNFi when combined with MTX TCZ hs demonstrted comprble sfety nd efficcy s monotherpy or combintion therpy, with trend towrds better outcomes with combintion therpy in some cses. 37,40,41 TCZ monotherpy hs lso been linked with lower tretment retention versus combintion therpy. 41 Persistence ws similr for ptients receiving tofcitinib nd bdmards nd comprble with previous dt in ptients receiving bdmards nd non-ra therpies. 42,43 Adherence, evluted using PDC, ws similr to previous reports for TNFi in RA. Men PDC vlues of 0.57 for ETN nd 0.64 for IFX hve been reported in Medicid ptients, 44 while dherence of 0.52 hs been reported in n inception cohort of ptients with phrmcy clims for ETN nd ADA in n insurnce clims dtbse of self-insured employer helth plns. 45 Adherence ws consistent with the rnge (35%-72%) reported by Yew et l. (2009) in their nlysis of phrmcy clims cross 6 chronic mediction clsses. 43 Furthermore, men PDC vlues were similr for ptients receiving tofcitinib, ADA, nd ETN but significntly lower with ABA versus tofcitinib. Although not possible to discern here, differences in dherence my be ttributed to severl fctors, including sfety nd efficcy profiles, frequency nd route of dministrtion, nd cost of tretment. Indequte therpy behviour, ssocited with incresed risk of RA flre, ws observed in ptients with RA who hd chieved remission with DMARDs nd hd mild or no disese ctivity/disbility. 46 Differences in route of dministrtion exist between ADA, ETN, nd ABA Wheres ADA nd ETN re dministered subcutneously, ABA is often dministered by intrvenous infusion nd ws pproved for subcutneous dministrtion in Men RA-relted costs for bdmard dministrtions over the 12-month post-index follow-up for the ABA cohort ws $10,000 versus pproximtely $1,000 for comprtors. Orl nd subcutneous routes of dministrtion offer ptients more flexibility nd convenience thn intrvenous infusion, since medictions cn be dministered t home t time selected by the ptient nd could led to improved dherence. In choice-bsed conjoint survey miled to 1,400 Humn members with RA, the most frequently selected route of dministrtion ws orl (0.754), followed by self-injection (0.492) nd intrvenous infusion (0.263). 47 In ddition, single center British study of 100 RA ptients reported tht those receiving TNFi preferred subcutneous dministrtion over intrmusculr or intrvenous dministrtion nd preferred home dministrtion versus n outptient/inptient setting. 48 Literture compring dherence nd persistence for orl versus injectble nd infusible products is chllenging nd limited. Some evidence exists tht discontinution or nondherence rtes re higher for the most common infusible bdmard, IFX, versus self-injectble bdmards (e.g., ETN nd ADA ). Other literture report similr or better tretment persistence/dherence with IFX The evlution of subcutneous versus orl versions of MTX found no difference in the proportion of ptients discontinuing tretment t 1 yer. 56 In other therpeutic res previously dominted by injectble therpies where orl options re being introduced, there is emerging evidence, sometimes conflicting, regrding the benefits of orl therpy on tretment persistence/ dherence Route of dministrtion my ply role in RA tretment initition. Primry nondherence to bdmards hs been reported in nerly 40% of RA ptients within 6 months fter being prescribed bdmard. 60 Thus, understnding the impct of route of dministrtion on DMARD initition nd dherence is criticl. Dose escltion ws reltively uncommon mong tofcitinib-treted ptients, which is not surprising given tht 5 mg BID is the pproved dose in the United Sttes, nd dose escltion is not permitted. 24 Dose escltion ws significntly more common for ptients receiving ADA versus tofcitinib, which is consistent with the fct tht it is lbel permitted. 18 Totl djusted RA-relted costs in the 12-month post-index period were significntly lower for ptients receiving tofcitinib versus bdmards, despite significntly higher pre-index costs. Totl RA-relted costs post-index were highest for ptients receiving ABA. These results dovetil with dt on TNFi cycling Journl of Mnged Cre & Specilty Phrmcy JMCP December 2016 Vol. 22, No. 12

11 Limittions This study hs some limittions to consider. Clims dt re collected for pyment processing only; therefore, clim does not indicte tht the ptient took the mediction. Similrly, no clim period my not indicte nondherence but temporry tretment discontinution. Coding errors could lso ffect the bility to detect ll relevnt helth cre resource use. Furthermore, there were no medicl history, clinicl severity, outcome indictors, or resons for discontinution in these clims dt. Clims nlyses of bdmards in RA typiclly require 6- to 12-month pre-index enrollment period. 31,32,44,62-64 While we required 12 months pre-index enrollment, we found tht significnt proportion of RA ptients hd bdmards before the 1-yer pre-index period, thus, we used ll vilble history. Becuse we did not require enrollment beyond 1 yer, nd the dt were vilble on Jnury 1, 2009, it is possible tht we hve underestimted previous bdmard use cross tretment groups. However, it should be noted tht men (SD) enrollment ws 1,116 (353) dys, nd there were no significnt differences cross tretment groups. In ssessing tretment ptterns, n djustment for dys supply ws implemented to ddress the inccurcy of the dys supply field nd vrying interprettion of the dys supply for monthly prescriptions for injectble versus orl therpies. Similr issues hve been described in other therpeutic res. The most frequent dys supply vlue for n orl second-genertion ntipsychotic (SGA) is 30 dys versus 28 dys for longcting injectble SGA. In this exmple, 2-dy discrepncy in dys supply for the long-cting SGA resulted in significntly fewer ptients with tretment gp. 65 In our study, this issue ws ddressed by djusting the dys supply to the nerest 28-dy supply. This hd little impct on the bdmards, since 94% of those prescriptions were 28-dy or 84-dy supplies nd not requiring djustment. In contrst, for tofcitinib, the djusted dys supply would be less thn using ctul dys supply for which 98% of tofcitinib prescriptions were 30-dy or 90-dy supplies, which likely lowered the persistence nd dherence vlues to mke more robust comprison. As newly vilble tretment option, tofcitinib prescriptions could be influenced by chnneling bis, whereby ptients re more likely to receive tofcitinib if they hve previously hd n indequte response/ intolernce to csdmards nd bdmards. Furthermore, s we selected tofcitinib ptients first, we my hve introduced selection bis with regrd to bdmard experience. Conclusions In this cohort of RA ptients with 1 previous bdmard, more ptients inititing tretment with tofcitinib versus the bdmards received monotherpy nd styed on monotherpy (P < 0.05 for ABA). Persistence nd dherence were generlly similr for tofcitinib versus bdmards. Totl djusted RA-relted costs post-index were lower for tofcitinib versus bdmards, despite significntly higher pre-index costs. While these dt support tofcitinib, further nlysis is wrrnted given the significnt differences observed between tretment groups, which suggests chnneling bis. Authors JAMES HARNETT, PhrmD, MS, nd CONNIE CHEN, PhrmD, Pfizer, New York, New York; ROBERT GERBER, PhrmD, nd DAVID GRUBEN, PhD, Pfizer, Groton, Connecticut; nd ANDREW S. KOENIG, DO, Pfizer, Collegeville, Pennsylvni. AUTHOR CORRESPONDENCE: Jmes Hrnett, PhrmD, MS, Pfizer, 235 E. 42nd St., New York, NY Tel.: ; Fx: ; E-mil: jmes.hrnett@pfizer.com. DISCLOSURES This study ws sponsored by Pfizer. Hrnett, Gerber, Gruben, Koenig, nd Chen re employees nd shreholders of Pfizer. Some dt reported in this mnuscript hve been previously presented t the Acdemy of Mnged Cre Nexus 2015; Orlndo, Florid; October 26-29, 2015, nd ws submitted in bstrct form to the Europen Legue Aginst Rheumtism Congress; London, United Kingdom; June 8-11, All uthors were involved in the conception nd design of this study. Hrnett nd Gruben were involved in dt collection nd nlysis. All uthors interpreted the dt, criticlly reviewed nd revised the mnuscript, nd red nd pproved the finl mnuscript. ACKNOWLEDGMENTS Editoril support, under the direction of the uthors, ws provided by Kren Irving, Complete Medicl Communictions, nd funded by Pfizer. REFERENCES 1. Mysoedov E, Crowson CS, Kremers HM, Therneu TM, Gbriel SE. Is the incidence of rheumtoid rthritis rising? Results from Olmsted County, Minnesot, Arthritis Rheum. 2010;62(6): Birnbum H, Pike C, Kufmn R, Mrynchenko M, Kidolezi Y, Cifldi M. Societl cost of rheumtoid rthritis ptients in the U.S. Curr Med Res Opin. 2010;26(1): Kwtkr AA, Jcobsen SJ, Levy GD, Medhekr SS, Venktsubrmnim KV, Herrinton LJ. Direct medicl expenditure ssocited with rheumtoid rthritis in ntionlly representtive smple from the medicl expenditure pnel survey. Arthritis Cre Res (Hoboken). 2012;64(11): Smolen JS, Breedveld FC, Burmester GR, et l. Treting rheumtoid rthritis to trget: 2014 updte of the recommendtions of n interntionl tsk force. Ann Rheum Dis. 2016;75(1): Vol. 22, No. 12 December 2016 JMCP Journl of Mnged Cre & Specilty Phrmcy 1467

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