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original article

Tofacitinib or Adalimumab versus Placebo in Rheumatoid Arthritis

Ronald F. van Vollenhoven, M.D., Ro Fleischmann, M.D., !tanle "ohen, M.D., #un $ong %ee, M.D., Ph.D., &uan A. 'arc(a Meijide, M.D., ! l)e *agner, M.D., !ar)a Forejtova, M.D., !amuel +. ,willich, M.D., David 'ruben, Ph.D., Tamas -onc., M.D., 'ene V. *allenstein, Ph.D., !riram -rishnaswami, Ph.D., &ohn D. $radle , M.D., and $ethanie *il)inson, Ph.D., for the /RA% !tandard 0nvestigators1
Abstr act Bac g!o"nd
From -arolins)a 0nstitute, !toc)holm 2R.F.V.34 Metro5le6 "linical Research "en7 ter, Dallas 2R.F., !.".34 !eoul 8ational 9niversit , !eoul, !outh -orea 2#.$.%.34 +os5ital 8uestra !e:ora de la #s5eran.a, !antiago de "om5ostela, !5ain 2 &.A.'.M.34 0nternistische !chwer5un)t5ra6is f;r Rheumatologie, +alle 2!.*.3, and the De7 5artment of Medicine <, 9niversit of %ei5.ig, %ei5.ig 2!.*.3 = both in 'erman 4 Revmatologic) ustav 8o. >, Prague, ".ech Re5ublic 2!.F.34 Pfi.er, 'roton, "T 2!.+.,., D.'., '.V.*., !.-., &.D.$., $.*.34 and Pfi.er, 8ew ?or) 2T.-.3. Address re7 5rint re@uests to Dr. *il)inson at Pfi.er 0nc., AA> #astern Point Rd., $ldg. BC M! C<DE7<>FG, 'roton, "T EDHAE, or at bethanie.wil)insonI5f i.er.com. 1The investigators in the /ral Rheuma7 toid Arthritis Phase H Trials !tandard 2/RA% !tandard3 stud are listed in the !u55lementar A55endi6, available at 8#&M.org. This article was u5dated on &une <G, <EFH, at 8#&M.org.
N Engl J Med 2012;367:508-19. DOI: 10.1056/NEJMoa1112072
Copyright 2012 Massachusetts Medical Society.

Tofacitinib 2"P7DBE,>>E3 is a novel oral &anus )inase inhibitor that is being investi7 gated for the treatment of rheumatoid arthritis.
Me#$od%

0n this F<7month, 5hase H trial, GFG 5atients who were receiving stable doses of methotre6ate were randoml assigned to > mg of tofacitinib twice dail , FE mg of tofacitinib twice dail , AE mg of adalimumab once ever < wee)s, or 5lacebo. At month H, 5atients in the 5lacebo grou5 who did not have a <EJ reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either > mg or FE mg of tofacitinib twice dail 4 at month D, all 5atients still receiving 5lacebo were switched to tofacitinib in a blinded fashion. The three 5rimar outcome measures were a <EJ im5rovement at month D in the American "ollege of Rheumatolog scale 2A"R <E34 the change from baseline to month H in the score on the +ealth Assessment KuestionnaireL Disabilit 0nde6 2+AK7D03 2which ranges from E to H, with higher scores indicating greater disabilit 34 and the 5er7 centage of 5atients at month D who had a Disease Activit !core for <C7joint counts based on the er throc te sedimentation rate 2DA!<C7AM#!RN3 of less than <.D 2with scores ranging from E to B.A and higher scores indicating greater disease activit 3.
&e%"l#%

At month D, A"R <E res5onse rates were higher among 5atients receiving > mg or FE mg of tofacitinib 2>F.>J and ><.DJ, res5ectivel 3 and among those receiving adalimumab 2AG.<J3 than among those receiving 5lacebo 2<C.HJ3 2POE.EEF for all com5arisons3. There were also greater reductions in the +AK7D0 score at month H and higher 5ercentages of 5atients with a DA!<C7A2#!R3 below <.D at month D in the active7treatment grou5s than in the 5lacebo grou5. Adverse events occurred more fre@uentl with tofacitinib than with 5lacebo, and 5ulmonar tuberculosis devel7 o5ed in two 5atients in the FE7mg tofacitinib grou5. Tofacitinib was associated with an increase in both low7densit and high7densit li5o5rotein cholesterol levels and with reductions in neutro5hil counts.
'oncl"%(on%

0n 5atients with rheumatoid arthritis receiving bac)ground methotre6ate, tofacitinib was significantl su5erior to 5lacebo and was numericall similar to

The 8ew #ngland &ournal of Medicine

adalimumab in efficac . 2Funded b Pfi.er4 /RA% !tandard "linicalTrials.gov number, 8"TEEC>HHC>.3

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Tofacitinib or Adalimumab in Rheumatoid Arthritis

heumatoid arthritis is a common autoimmune disease of the musculos)ele7 tal s stem that is associated with consider7 able1-3 morbidit and diminished @ualit of life. Treatment of rheumatoid arthritis is based on con7 ventional or biologic 2or both3 disease7 modif ing drugs, of which methotre6ate is the most 4widel used. For 5atients who have an

su55ort were 5rovided b an em5lo ee of "om5lete Medical "ommunications who was fund7 ed b Pfi.er. The final 5rotocol, amendments, and informed7consent documentation were a55roved b a central or local institutional review board or an inde5endent ethics committee. The stud was conducted and anal .ed according to the 5rotocol, which is available with the full te6t of this article

inade@uate re7

s5onse to methotre6ate, antiLtumor necrosis fac7 tor 2T8F3 biologic agents have 5roved to be effec7 5-7 tive as second7line treatment.

"onventional

disease7modif ing drugs are small, orall active molecules, whereas biologic 5roducts are, b defi7 nition, large 5roteins that are available onl as 5ar7 enteral agents. The develo5ment of a novel oral an7 tirheumatic agent with safet and adverse7event 5rof iles and eff icac that are similar to those of biologic agents would be of clinical interest. Tofacitinib 2"P7DBE,>>E3 is being investigated as a targeted immunomodulator and disease7 modif 7 ing thera5 for rheumatoid arthritis. Tofacitinib is a novel, small7molecule, oral selective inhibitor of &anus )inase 2&A-3 F and &A-H and, to a lesser e6tent, &A-<. &A-s mediate signal7transduction activit b the surface rece5tors for multi5le c to7 )ines, including interleu)ins <, A, D, G, B, F>, and 8,9 <F. These c to)ines are integral to

l m5hoc te

activation, 5roliferation, and function4 inhibition of their signaling ma result in the modulation 8-11 of multi5le as5ects of the immune res5onse.

M e t hod s
The authors who are em5lo ees of Pfi.er designed the stud in collaboration with the academic au7 thors. Data were collected b an em5lo ee of -endle 0nternational, a clinical research organi7 .ation, and were anal .ed b an author who is an em5lo ee of Pf i.er. The f irst author wrote the initial draft of the manuscri5t with subse@uent revisions 5rovided b all authors4 all the authors vouch for the com5leteness of the data and anal7 ses and made the decision to submit the manu7 scri5t for 5ublication. *riting assistance and editorial
The 8ew #ngland &ournal of Medicine

at 8#&M.org. All 5atients 5rovided written in7 formed consent.

) a # ( e n # %

rent treatment with other antirheumatic agents, including biologic agents4 5rior treatment with adalimumab4 lac) of res5onse to 5rior anti7T8F biologic treatment4 and current infection or evi7 dence of active or inade@uatel treated infection with Mycobacterium tuberculosis.
*#"d+ De%(gn and ,!ea#-en#

Patients were eligible for enrollment if the were FC ears of age or older and had received a diag7 nosis of active rheumatoid arthritis, as def ined according to the American "ollege of Rheumatol7 og 2A"R3 FBCG Revised 1 "riteria. Active disease was def ined as the 5resence of D or more tender or 5ainful joints 2of DC joints e6amined3 and D or more swollen joints 2of DD joints e6amined3 and either an er throc te sedimentation rate 2#!R3 greater than <C mm 5er hour 2*estergren meth7 od3 or a "7 reactive 5rotein level e6ceeding G mg 5er liter. Patients were receiving G.> to <> mg of meth7 otre6ate wee)l and had an incom5lete res5onse 2def ined as suff icient residual disease activit to meet entr criteria3. -e e6clusion criteria were cur7

The /ral Rheumatoid Arthritis Phase H Trials !tan7 dard 2/RA% !tandard3 stud , was a randomi.ed, 5hase H clinical trial conducted in FF> centers worldwide between &anuar HE, <EEB, and Februar FE, <EFF, to investigate the clinical efficac of to7 facitinib as com5ared with 5lacebo. All 5atients were ta)ing bac)ground methotre6ate and, b means of an interactive voice7res5onse s stem, were randoml assigned, in a APAPAPFPF ratio, to one of five regimensP > mg of tofacitinib twice dail , FE mg of tofacitinib twice dail , AE mg of adalimumab administered b subcutaneous injection once ever < wee)s, 5lacebo for H months or D months fol7 lowed b > mg of tofacitinib twice dail , and 5la7 cebo for H months or D months followed b FE mg of tofacitinib twice dail . Patients in the 5lacebo grou5 who did not have a <EJ reduction in the number of swollen and tender joints after H months 2considered as not having had a res5onse3 were randoml assigned to either > mg or FE mg of tofacitinib. After D months, all 5atients assigned to 5lacebo were switched in a blinded fashion to either > mg or FE mg of tofacitinib. Patients ran7 doml assigned to tofacitinib or adalimumab who did not have a res5onse to treatment continued

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with the same regimens for the duration of the tri7 al. All 5atients self7administered injections of either adalimumab or 5lacebo once ever < wee)s and also too) 5lacebo or tofacitinib 5ills twice dail .
Mea%"!e% o. E..(cac+

e6aminations were 5erformed at scheduled visits.

*#a #(%# (cal /na l+%( %

The three 5rimar eff icac end 5oints, for which the eff icac of tofacitinib was com5ared with 5lacebo, were the 5ercentage of 5atients at month D who met the criteria for an A"R res5onse 2de7 f ined as a <EJ reduction in the number of tender and swollen joints, as well as im5rovement in at least three 13 of the other f ive A"R com5onents3 4 the mean change from baseline to month H in 5h s7 ical function status, as assessed with the use of the +ealth Assessment KuestionnaireL Disabilit 0nde6 2+AK7D03 2with higher scores indicating 14 greater disabilit 3 4 and the 5ercentage

To 5reserve the t 5e 0 error rate, the three 5rimar eff icac end 5oints were assessed se@uentiall as followsP the 5ercentage of 5atients with an A"R 13 <E res5onse, the mean

change from baseline in

of 5a7

tients who had a Disease Activit !core of less than <.D at month D 2with scores ranging from E to B.A and higher scores indicating greater disease ac7 15 tivit 3. The Disease Activit !core for the

5rimar

eff icac end 5oint is based on a <C7joint count for swollen joints and for tender joints, the 5atientQs global assessment of disease activit , and the er throc te sedimentation rate 2DA!<C7AM#!RN3. !econdar end 5oints included com5arisons of the two doses of tofacitinib 2> mg and FE mg3 with 5lacebo over time with res5ect to the 5er7 centage of 5atients who met the criteria for A"R <E, A"R >E, and A"R GE res5onses 2indicating re7 ductions from baseline of at least <EJ, >EJ, and GEJ, res5ectivel , in the number of tender and swollen joints, as well as im5rovement in at least three of the other f ive A"R com5onents3 and with res5ect to changes from baseline in the +AK7D0 score and DA!<C7 A2#!R3.
*a.e#+ /%%e%%-en#%

Another 5rimar objective was to assess the safe7 t of tofacitinib as com5ared with 5lacebo during the F<7month stud 5eriod. The incidence and severit of all adverse events were recorded, and clinical laborator tests, assessment of vital signs, and 5h sical

the +AK7D0 score, and the 5ercentage of 5atients with a DA!<C7 A2#!R3 below <.D 2Fig. !F in the !u55lementar A55endi6, available at 8#&M.org3. The t 5e 0 error rate was 5reserved for the 5rimar end 5oints when statistical signif icance was de7 termined4 no 5reservation of the t 5e 0 error rate was a55lied for the secondar end 5oints. P values of E.E> or less were considered to indicate statis7 tical signif icance. The full anal sis set for efficac and safet in7 cluded all 5atients who underwent randomi.ation and who received at least one dose of stud drug. The normal a55ro6imation for the difference in binomial 5ro5ortions was used to test the su5e7 riorit of each of the two tofacitinib regimens over 5lacebo with res5ect to A"R <E res5onse rates and the 5ercentage of 5atients with a DA!<C7A2#!R3 of less than <.D. 0m5utation of no res5onse was used to account for missing data in the calculation of these two end 5oints and was a55lied to 5atients who discontinued the stud drug for an reason 2including 5atients who were lost to follow7u5 before month D3, as is standard in man clinical trials involving 5atients with rheumatoid arthritis. +owever, in this trial, the im5utation of no res5onse was also a55lied to 5atients who did not have a <EJ reduction in the number of tender and swollen joints at month H, regardless of treatment assignment4 5atients in the active7treatment grou5s who did not meet the criteria for this res5onse continued with the same
>FE

treatment, whereas 5atients who were receiving 5lacebo were switched to tofacitinib in a double7 blind fashion. The im5utation7of7no7 res5onse anal sis assumes that 5atients who did not have a res5onse to treatment b month H will not have a res5onse during the remainder of the trial = even if the subse@uentl meet the criteria for an A"R <E res5onse. Thus, in this trial, the a55lication of im5uta7 tion of no res5onse 2referred to as Rim5utation of no res5onse with advancement 5enalt S3 was more conservative than in 5rior anal ses, because historicall the a55lication has not assumed that treatment has failed in 5atients receiving 5lacebo. An anal sis was also 5erformed in which the ad7 vancement 5enalt was removed to allow an new res5onse to active treatment after month H to be observed 2referred to as Rim5utation of no re7 s5onse without advancement 5enalt S3. For these anal ses, the 5lacebo grou5 at month D com5rised 5atients who were still receiving 5lacebo and 5a7

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Tofacitinib or Adalimumab in Rheumatoid Arthritis

,a0le 1. De-og!a1$(c and 'l(n(cal '$a!ac#e!(%#(c% a# Ba%el(ne2 /cco!d(ng #o ,!ea#-en# 3!o"1.4 7a!(a0le Female se6 = no. 2J3 *hite race = no. 2J3T Age = r Mean duration of rheumatoid arthritis = r Region of origin = JV 8orth America %atin America #uro5e Rest of world Tender and swollen joints = mean no.W Tender !wollen Mean +AK7D0 score Mean DA!<C7A2#!R3 Mean #!R = mmXhr Mean DA!<C7H2"RP3Y Mean "RP = mgXliter Positive for rheumatoid factor = J Positive for anti7""P = J Prior thera5 = no. of 5atients 2J3 T8F inhibitor 8on7T8F inhibitor biologic Disease7modif ing drug other than methotre6ate "oncomitant thera5 = no. of 5atients 2J3 'lucocorticoids %i5id7lowering medication AF 2GH.<3 F 2F.C3 HF 2>B.D3 H 2>.C3 F<D 2DF.C3 C 2H.B3 F<B 2DA.<3 FE 2>.E3 F<> 2DF.H3 FE 2A.B3 A 2G.F3 A 2G.F3 HE 2>H.D3 > 2B.D3 < 2H.C3 <B 2>>.C3 F< 2>.B3 < 2F.E3 FEB 2>H.A3 FA 2G.E3 A 2<.E3 FF> 2>G.<3 FD 2G.C3 H 2F.>3 FFA 2>>.B3 <D.D FD.B F.> D.D ><.G >.D <E.H GF.A GD.A <C.F FD.A F.A D.H A<.B >.H FF.D DE.C D<.E <C.> FD.G F.> D.D AC.D >.A FA.B DD.C GF.H <D.F F>.C F.> D.> AB.B >.A FG.H DD.< DA.E <D.G FD.A F.> D.A AC.> >.H FG.> DC.< GA.C <C.D H.D >F.C FD.F <C.C >.C AA.< <F.F <A.> H.B >H.B FG.D <A.B F.> >>.G FG.B <>.> <.B >H.B FG.D )lace0o 5ollo6ed 0+ 8N 9 56: AH 2GD.C3 AE 2GF.A3 >>.>UFH.G D.B )lace0o 5ollo6ed 0+ 8N 9 52: HB 2G>.E3 H> 2DG.H3 >F.BUFH.G B.E ,o.ac(#(n(02 8N 9 20;: FGA 2C>.H3 F>F 2GA.E3 >H.EUFF.B G.D ,o.ac(#(n(02 8N 9 201: FDC 2CH.D3 FAH 2GF.F3 ><.BUFF.C G.A

/dal(-"-a02 ,o.ac(#(n(02 5 8N 9 20;: FD< 2GB.A3 FAC 2G<.>3 ><.>UFF.G C.F

1 PlusLminus values are means U!D. There were no significant differences among the grou5s at baseline. ADA denotes adalimumab, ""P c clic citrullinated 5e5tide, "RP "7reactive 5rotein, DA!<C7A Disease Activit !core for <C joint counts, DA!<C7H2"RP3 DA!<C based on the "RP level, DA!<C7A2#!R3 DA!<C based on the er throc te sedimentation rate 2#!R3, +AK7D0 +ealth Assessment KuestionnaireLDisabilit 0nde6, and T8F tumor necrosis factor. T Race was self7re5orted. V A total of <F countries were included in the stud 4 the geogra5hic brea)down is based on the number of 5atients who had <EJ im5rove7 ment in the American "ollege of Rheumatolog scale 2A"R <E3 at month F. The 5ercentages of 5atients in each region were <A.>J in 8orth America, <.BJ in %atin America, >A.<J in #uro5e, and FC.AJ in the rest of the world. W A total of DC s5ecific joints were e6amined for tenderness or 5ain, and DD s5ecific joints were e6amined for swelling. +igher values indicate greater levels of disease activit . Y The DA!<C7H2"RP3 value is based on three variablesP tender7joint counts, swollen7joint counts, and "RP levels. Values range from E to B.A, with higher values indicating greater disease activit .

tients who had been switched from 5lacebo to to7 facitinib, > mg or FE mg twice dail , at month H. For each eff icac end 5oint, the com5arison with 5lacebo was 5erformed with the two7sided al5ha level for signif icance set at E.E> or, e@uiva7 lentl , the one7sided al5ha level set at E.E<>. For the

A"R <E anal sis, we calculated a sam5le si.e that we estimated would give the stud more than BEJ 5ower to detect a difference in res5onse rates of at least <EJ, assuming a res5onse of HEJ in the 5lacebo grou5s. For the anal sis of the +AK7D0, we estimated that the sam5le si.e would give the

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stud more than BEJ 5ower to detect a differ7 ence of at least E.H 5oints, assuming a standard deviation of E.G>. The change from baseline in +AK7D0 scores was e65ressed as least7s@uares means. For this anal sis, we used a mi6ed7effect longitudinal model, which included an effects of treatment and follow7u5 visits. 0n addition, variabilit as a result of 5atient effect was included. !econdar end 5oints with binar variables were anal .ed in the same wa as A"R <E res5onses, and continuous end 5oints were anal .ed in the same wa as the changes in +AK7D0 scores. !afet data were summari.ed descri5tivel and as least7s@uares means for selected variables. For7 mal testing of the observed differences in safet measures was not 5art of the statistical anal sis 5lan, in 5art because such testing is 5oorl defined and misleading for uncommon events.

changes from baseline in DA!<C7A2#!R3 and +AK7D0 scores over time 2PZE.E> for all com7 5arisons3. The magnitude of these res5onses was sustained to month F< and was numericall simi7 lar among the three active7treatment grou5s 2Fig.

R e sult s
)a#(en#%

The majorit of the GFG 5atients in the full anal 7 sis set were women 2range among the f ive stud grou5s, G>.E to C>.HJ3 and white 2range, DG.H to GA.EJ3 and the mean duration of rheumatoid ar7 thritis ranged from D.B to B.E ears 2Table F3. A total of >>D 5atients 2GG.>J3 com5leted the F<7month stud 2Fig. !< in the !u55lementar A55endi63.
E..(cac+

A signif icantl greater 5ercentage of 5atients re7 ceiving active treatment than those receiving 5la7 cebo met the criteria for an A"R <E res5onse at month DP >F.>J in the >7mg tofacitinib grou5, ><.DJ in the FE7mg tofacitinib grou5, and AG.<J in the AE7mg adalimumab grou5, as com5ared with <C.HJ in the 5lacebo grou5 2POE.EEF for all com7 5arisons3 2Fig. FA3. The mean change from base7 line in the +AK7D0 score at month H 2Fig. F$3 and the 5ercentage of 5atients with a DA!<C7A2#!R3 below <.D at month D 2Fig. F"3 were also signif i7 cantl greater with the active treatments than with 5lacebo. *ith res5ect to secondar eff icac end 5oints, signif icantl greater res5onses were seen with the active treatments than with 5lace7 bo with res5ect to A"R >E and A"R GE res5onses and the

5(g"!e 1 8.ac(ng 1age:. )!(-a!+ E.. (cac+ /nal+%e%. Panel A shows the numbers and 5ercentages of 5atients with at least a <EJ im5rovement in the American "ollege of Rheumatolog scale 2A"R <E3. The bar gra5h on the left shows the results of the anal sis with im5utation of no res5onse with the advancement 5enalt 4 if 5atients did not have a res5onse to thera5 b month H, the treatment was considered to be a failure even if the had a res5onse after month H. POE.EEF for the com5ar7 ison of each active7treatment grou5 with 5lacebo. The bar gra5h on the right shows the results of the anal sis with im5utation of no res5onse without the advance7 ment 5enalt , which are the actual res5onse rates at month D in the active7 treatment grou5s4 if 5atients did not have a res5onse to thera5 b month H but had a res5onse after month H, treatment was not considered to be a failure. The res5onse without the advancement 5enalt in the 5lacebo grou5 cannot be calculated be7 cause 5atients in that grou5 who did not have a res5onse b month H were switched to tofacitinib. Panel $ shows the change in +ealth Assessment KuestionnaireL Disabilit 0nde6 2+AK7D03 scores 2which range from E to H, with higher scores indicating greater disabilit 3 from baseline to month H. A total of BC 5atients in the 5lacebo grou5, FCC in the >7mg tofacitinib grou5, FC> in the FE7mg tofacitinib grou5, and FBE in the adalim7 umab grou5 were included in this anal sis. POE.EEF for the com5arison of each active7treatment grou5 with 5lacebo. Panel " shows the numbers and 5ercent7 ages of 5atients with a Disease Activit !core for <C7joint counts based on the er throc te sedimenta7 tion rate 2DA!<C7 AM#!RN3 of less than <.D. !cores on the DA!<C7A2#!R3 range from E to B.A, with higher scores indicating more disease activit . As in Panel A, the bar gra5h on the left shows the results of the anal sis with im5utation of no res5onse with the advancement 5enalt , and the bar gra5h on the right

shows the results of the anal sis with im5utation of no res5onse without the advancement 5enalt . For the bar gra5h on the left, POE.E> for the com5arison of the >7 mg tofacitinib grou5 and of the adalimumab grou5 with the 5lacebo grou5, and POE.EEF for the com5arison of the FE7mg tofacitinib grou5 with the 5lacebo grou5. Data are e65ressed as means, with T bars indicating the standard error.

!H and !A in the !u55lementar A55endi63. A ra57 id res5onse to active treatment was observed4 a signif icant difference in A"R <E and A"R >E re7 s5onses with each tofacitinib treatment as com7 5ared with 5lacebo was noted after F month 2PZE.EEF for all com5arisons3 2Fig. !H in the !u57 5lementar A55endi63.
*a.e#+

Table < summari.es the changes from baseline in laborator measurements. After an initial de7 crease in neutro5hil counts at month H with all active treatments 2decrease of E.G<[FEH 5er

cubic millimeter with > mg tofacitinib, E.GD[FEH 5er cu7

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Tofacitinib or Adalimumab in Rheumatoid Arthritis

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cubic

millimeter with 5lacebo3, neutro5hil counts remained relativel stable through month
F<. The incidence of mild neutro5enia 2F>EE to FBBB neutro5hils 5er cubic millimeter3 and mod7 erate7to7severe neutro5enia 2>EE to FABB neutro7 5hils 5er cubic millimeter3

was low across all treatment grou5s 2Table <3. /ne 5atient 2in the >7mg tofacitinib grou53 had less than >EE neutro7

5hils 5er cubic millimeter at month F, a level that was not conf irmed on retesting. %evels of low7 densit li5o5rotein 2%D%3 cholesterol and of high7 densit li5o5rotein 2+D%3 cholesterol during months E to H increased from baseline to a great7 er e6tent in the tofacitinib grou5s than in the adalimumab and 5lacebo grou5s. A total of H.BJ of 5atients in the >7mg tofacitinib grou5, D.>J in the FE7mg tofacitinib grou5, E.FJ in the adalim7 umab grou5, and E.BHJ in the 5lacebo grou5 had
august B, <EF<

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new engl and jour nal

of

medicine

,a0le 2. *a.e#+ and @a0o!a#o!+ Da#a.4 7a!(a0le Placebo 28 ] FEC3 Adverse events = no. 2J3 Patients with treatment7emergent adverse events Patients with serious adverse events Patients with serious infection events Discontinuation of stud drug owing to adverse event
\H

Mon#$% 0A3 > mg 28 ] <EA3 FE mg 28 ] <EF3 AE mg 28 ] <EA3

Mon#$% 3A6 Placebo 28 ] >B3 Tofacitinib, > mg, Tofacitinib, Placebo 28 ] <C3

Tofaciti

>F 2AG.<3 < 2F.B3 F 2E.B3 H 2<.C3

FED 2><.E3 F< 2>.B3 H 2F.>3 FA 2D.B3

BA 2AD.C3 FE 2>.E3 A 2<.E3 FE 2>.E3

FE> 2>F.>3 > 2<.>3 E FE 2A.B3

FD 2<G.F3 < 2H.A3 E E

G 2<>.E3 E E F 2H.D3

Mon#$ 32 Mean '$ange .!o- Ba%el(ne 8eutro5hil count = FE +emoglobin = gXdl "holesterol level = J %ow7densit li5o5rotein +igh7densit li5o5rotein !erum creatinine = mgXdl E.<DU<.DE \F.>>UF.BG EUE.EF F<.FCUF.BA F<.FGUF.AC E.EAUE.EF FC.BHUF.B> FE.B>UF.AB E.E>UE.EF H.D<UF.BF >.DAUF.AG E.E<UE.EF

Mon#$ 62 Mean '$ange .!o- Ba%el(ne

Xmm

\E.<AUE.FG
E.EAUE.G>

\E.G<UE.F<
\E.F<U<.HC

\E.GDUE.FH
E.HDUE.C<

\F.<>UE.F<
8A 8A 8A 8A E.<DUE.CC FE.E>UH.DF >.BFU<.GG E.EAUE.E< Mon#$ 6

8A

E.ECUE.BF

Mon#$ 3 Placebo 28 ] BC3 8eutro5enia = no. of 5atients 2J3T Mild, F>EE to FBBB cellsXmmH > mg 28 ] FCD3 FE mg 28 ] FCH3 AE mg 28 ] FCG3 Placebo 28 ] E3

Tofacitinib, > mg, Tofacitinib, Placebo 28 ] ><3

Tofaciti

< 2<.E3
F> 2C.F3

Moderate to severe, >EE to FABB cellsXmmH E Decreased hemoglobin, \F.E to \H.E gXdl = B 2B.<3 no. of 5atients 2J3V

H 2F.D3 < 2F.F3

F> 2C.<3 Mon#$ 0A3

H 2F.D3 H 2F.D3
FE 2>.H3 8A

> 2<.G3 E
H 2>.C3 Mon#$% 3A6

8A 8A

Placebo 28 ] FE>3 Aminotransferase levels = no. of incidentsX total no. 2J3W A!T^F[ 9%8 A!T^H[ 9%8 A%T^F[ 9%8 A%T^H[ 9%8

> mg 28 ] <EH3

FE mg 28 ] <EF3

AE mg 28 ] <EA3

Placebo 28 ] AD3

Tofacitinib, > mg, Tofacitinib, Placebo 28 ] <C3

Tofacitin

FFXFAH 2G.G3 ACXFAH 2HH.D3 ACXFAH 2HH.D3 HDXFAH 2<>.<3 FX< 2>E.E3 FXA 2<>.E3 FX< 2>E.E3 <XA 2>E.E3 E FXA 2<>.E3 E E FCXFGH 2FE.A3 >CXFGH 2HH.>3 ABXFGH 2<C.H3 ACXFGH 2<G.C3

HXBC 2H.F3 E AXF<E 2H.H3 E

HXBC 2H.F3 E GXF<E 2>.C3 E

1 PlusLminus values are least7s@uares means U!# in all cases e6ce5t for hemoglobin values, which are means U!D. A 5atient ma have had more than one adverse event, so the individual totals ma not add u5 to the overall total number of events. To convert the values for creati7 nine to micromoles 5er liter, multi5l b CC.A. A%T denotes alanine aminotransferase, A!T as5artate aminotransferase, 8A not assessed, and 9%8 u55er limit of the normal range. T Potentiall life7threatening neutro5enia is defined as less than >EE neutro5hils 5er cubic millimeter. V A severe decreased hemoglobin is also defined as an actual level of greater than G g 5er deciliter but less than C g 5er deciliter. W For A%T and A!T, we recorded the number of incidents in which values were higher than the 9%8. More than one incident ma be recorded for the same 5atient.

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Tofacitinib or Adalimumab in Rheumatoid

Mon#$% 3A6 Tofacitinib, FE mg,

Mon#$% 6A12 Tofacitinib, > mg, Tofacitinib, FE mg,

The 8ew #ngland &ournal of Medicine

Tofacitinib, FE mg, Tofacitinib, !witched from Placebo 28 ] <E3 B 2A<.B3 HXBC 2H.F3 E AXF<E 2H.H3 E > mg 28 ] FCD3

!witched from Placebo orTofacitinib, Tofacitinib Adalimumab Rheumatoid Tofacitinib, Adalimumab, > mg, in Tofacitinib, FE mg, Tofacitinib, 28 <F3 FE mg AE]mg !witched from !witched from > mg 28 ] FCH3 28 ] FCG3 Placebo Placebo 28 ] FDG3 28 ] >E3 28 ] A<3

Tofacitinib, Adalimumab, FE mg AE mg 28 ] FGA3 28 ] FGC3

E E E 2<H.H3 HBXF<E 2H<.>3 HCXF<E 2HF.G3 <CXF<E BXF>A 2>.C3 E BXF>A 2>.C3

DG 2H<.C3 FE 2A.B3 < 2F.E3

<CXBC 2<C

<X> 2AE. > 2<.>3 A<XF>A 2<G.H3 >GXF>A 2HG.E3 HGXF>A 2<A.E3 HXFA 2<F.A3

HXD 2>E.E3 <XD 2HH.H3 FXD 2FD.G3 Mon#$ 62 Mean '$ange .!o- Ba%el(ne

E >XFA 2H>.G3 DXFA 2A<.B3 Mon#$ 122 Mean '$ange .!o- Ba%el(ne \E.CFUE.FH

%D%\E.<HUE.BD cholesterol levels that were below FEE mg 5er deciliter 2<.D mmol 5er liter3 at baseline and that increased to FHE mg 5er deciliter 2H.A mmol 5er liter3 or higher in months E to H. The mean \<.FCUH.EF chang7 es from baseline in serum creatinine level E.EHUE.E< were small in magnitude across the treatment grou5s. The changes at month D were E.ED mg 5er deciliter 2>.H _mol 5er liter3 with Tofacitinib, FE mg, FE!witched mg of from tofacitinib, E.E> Placebo mg 5er deciliter 2A.A _mol 5er liter3 with > 28 ] A<3 mg

\E.BFUE.<>

of tofacitinib, and E.E< mg 5er deciliter 2F.C E.F>UE.C> _mol 5er liter3 with adalimumab. Most instances of decreased hemoglobin were mild to moderate in severit 4 decreased hemoglobin FE.BDUF.>A was 5otentiall life7 threatening in one 5atient E.E>UE.EF in the FE7mg tofaci7 tinib grou5 at months F, H, D, and F<, as well as in one 5atient in the Mon#$ >7mg 6 tofacitinib grou5 and one 5atientTofacitinib, in the mg adalimumab grou5 at month F<. A > greater 28 ] FGE3 5ercentage of 5atients in the >7mg and

E G 2FD.G3 Mon#$% 3A6 Mon#$% 6A12

E FG 2FE.E3

The 8ew #ngland &ournal of Medicine

> /d<e!%e and In.ec#(on E<en#% O<e! #$e 'o"!%e o. 12 Mon#$%2 /cco!d(ng #o ,!ea#-en# *eB"ence.4 ,a0le 3. *e!(o"%
)lace0o 5ollo6ed 0+ ,o.ac(#(n(02 5 -g 8N 9 56: )lace0o 5ollo6ed 0+ ,o.ac(#(n(02 10 -g 8N 9 52: ,o.ac(#(n(02 5 -g 8N 9 20;: ,o.ac(#(n(02 10 -g 8N 9 201: /dal(-"-a02 ;0 -g 8N 9 20;: $one marrow failure disorders Atrioventricular bloc) Acute m ocardial infarction "ardiac failure congestive, m o7 Acute m ocardial infarction, com5lete infarction, m ocardial ischemia

MedD&/ *+%#e- O!gan 'la%% $lood and l m5hatic s stem

8ew #ngland &ournal of "ardiacThe disorders Downl oaded #ar and lab rinth disorders from nejm.o #ndocrine disorders rg on # 8ove e disorders mber 'astrointestinal disorders FE, <EFH. 'eneral For disorders and admin7 5erson n al use +e5atobiliar disorders e onl . n 8o g infestations 0nfections and other l uses withou j t 5ermis m e sion. d 0njur , 5oisoning, and 5roce7 "o5 right `
H D Massachusett G 4 !ociet D . All

Vertigo Autoimmune th roiditis Retinal detachment !alivar 7gland calculus 0leus %iver disorder "holelithiasis !ialoadenitis 'astroenteritis 0m5aired healing "holelithiasis, cholec stitis "ellulitis 2two 5atients3, her5es 5neumonia 2two 5atients3, Anal 5ol 5, diverticular 5erfora7 P re6ia

Abdominal hernia, hema7 tion, 5e5tic ulcer hemo "hest 5ain istration site conditions "holec stitis acute infective
T h e

Arthritis bacterial, cellulitis, clos7 $reast abscess, breast celluli7 .oster, locali.ed n in 5ulmonar tuberculosis sal5ingo7oo5horitis, se5tic 2two 5atients3, urinar

w
Femur fracture, humerus fracture Femur fracture, fibular fracture, Femur fracture, joint dislo7 dural com5lications lower7limb fracture, multi5le fractures, tendon disorder, tendon ru5ture

g
Diabetes mellitus disorders Rheumatoid arthritis,T s5inal column stenosis 8euroma !alivar 7gland neo5lasm, hair static renal7cell carcinoma, $ursitis, rheumatoid arthritis,T s5ond lolisthesis

Metabolism and nutrition Musculos)eletal and connec7 tive tissue disorders 8eo5lasm benign, malignant, c sts and 5ol 5s

l a

"holesteatoma, cervi6 carcinoma, 8onLsmall7cell lung cancer and uns5ecified, inc benign nonLsmall7cell lung cancer

FE7mg tofacitinib grou5s than in the adalimumab or 5lacebo grou5 had as5artate aminotransferase levels one or more times the u55er limit of the normal range at month H. Alanine aminotrans7 ferase levels that were one or more times the u57 5er limit of the normal Dr range were recorded most fre@uentl in the FE7 ug 0gA mg tofacitinib grou5. %esse6 than >J of 5atients ne5h 5o in the active7treatment grou5s had ro5a as5artate sur th e amino7 transferase aminotransferase or alanine dur + u55er levels that were three or more ing times the D 5re <3. limit of the normal range 2Table R e g7 e e Treatment7emergent adverse events 2i.e., n 5 ad7 verse events that develo5ed after random as7 a + 7 l e E to H occurred v signment3 during months in a e ><.EJ of the 5atients in f d the >7mg tofacitinib i n grou5 2FED 5atients3, AD.CJ in the FE7mg tofa7 citinib grou5 2BA 5atients3, >F.>J in the adali7 mumab grou5 2FE> 5atients3, and AG.<J in the 5lacebo grou5 2>F 5atients3 2Table <3. During months D to F< 2b which time all 0ntersti "er 5atients who were initiall randoml assigned tial vi6 to 5lacebo had been switched to lung active dis disease treatment3, treatment7 emergent ord adverse events "hroni er, c occurred in AH.DJ of the 5atients initiall me obstruc tro assigned to the >7mg tofaci7 tinib grou5 tive2CB rrh 5ulmo 5atients3, AF.CJ of those ini7 agi tiall assigned nar a, to the FE7mg tofacitinib grou5 2CA 5atients3, disease, and AE.GJ of those in the adalim7 o umab grou5 5ain 2CH 5atients3 2Table <3. The most fre@uentl P the re5orted s stem organ class 2accord7 ing to r / Medical Dictionar for Regulator Activities u v MMedDRAN classification, version FH.F3 in r a r i oc7 which treatment7emergent adverse events i g curred from months E to F< was infections and o infestations4 for months E to H, the rates of treat7 ment7emergent D adverse events in this s stem or7 gan class were FCJ in the P>7mg u s tofacitinib grou5, l a m in r FGJ in the FE7mg tofacitinib grou5, FDJ o t the adalimumab grou5, and BJ in n the h a r 5lacebo grou5. Treatment7emergent adverse r i events occur7 ring in more a than <J of 5atients in an treatment grou5 are, summari.ed according to MedDRA 5re7 ferred terms in Table !F in the !u55lementar A55endi6. The rates of serious adverse and 8ervous s stemevents disorders serious infectious eventsPregnanc in months E to H were , 5uer5erium, and numeri7 call higher with tofacitinib than with 5erinatal conditions 5lacebo or adalimumab Re5roductive 2Table <3. s 0n months D stem and breast to F<, the rates of serious disorders adverse events were A.BJ in the Renal and urinar disorders >7mg tofacitinib grou5, H.EJ in the FE7mg to7 Res5irator , thoracic, and facitinib grou5, and H.AJ in the adalimumab mediastinal disorders grou5, and the rates of serious infectious events
The 8ew #ngland &ournal of Medicine

1 #v ent s are list ed acc ord ing to the s s te m org an cla sse s in the Me dic al Di cti on ar y for Re gul ato ry c ti!i tie s 2M ed DR A3, ver sio n FH. F, an d acc ord ing to R5r efe rre d ter ms .S T 0n ve sti ga tor s

were F.EJ in the >7mg tofacitinib grou5, F.>J in

n engl j med HDG4D nejm.org august B, <EF<

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The 8ew #ngland &ournal of Medicine

e n e w e n g l a n d j o u r n a l of m e d the FE7mg tofacitinib grou5, T h and E.>J in we 5resent were calculated with the adalimumab grou5 2Table <3. Throughout the the use of a more conservative trial, serious infections occurred in G of <EA im5utation7 of7no7res5onse 5atients 2H.AJ3 in the >7mg tofacitinib grou5, C anal sis that automaticall of <EF 5a7 tients 2A.EJ3 in the FE7mg tofacitinib con7 sidered a 5atient who did grou5, and not have a res5onse at H of <EA 5atients 2F.>J3 in the adalimumab H months to have had no res5onse during the trial, grou5. All the serious adverse events and serious infec7 tious events recorded during this stud are listed in Table H. Discontinuation of treatment owing to adverse events in months E to H occurred most fre@uentl in the >7mg tofacitinib grou5 2D.BJ of the 5atients in that grou53, as com5ared with >.EJ of the 5atients in the FE7mg tofaci7 tinib grou5, A.BJ of the 5atients in the adalimu7 mab grou5, and <.CJ of the 5atients in the 5lacebo grou5 2Table <3. Two deaths were re5ortedP one in the >7mg tofacitinib grou5, FA da s after the 5atient com5leted the treatment, and one in the adalimumab grou5 2Table !< in the !u55lemen7 tar A55endi63. There were two cases of 5ulmo7 nar tuberculosis 2both in the FE7mg tofacitinib grou53 and no cases of e6tra5ulmonar tubercu7 losis or other major o55ortunistic infections 2Table !H in the !u55lementar A55endi63.

!is c us sion
The /RA% !tandard trial was a 5hase H stud in which tofacitinib, a novel, orall available antirheu7 matic agent, was com5ared both with 5lacebo and with an antiLT8F biologic agent 2adalimumab3. This trial is 5art of a large 5hase H 5rogram to stud tofacitinib in multi5le randomi.ed clinical trials4 one other trial is also re5orted in this issue 1" of the "ournal. 0n the trial re5orted here,

results

showed that tofacitinib, when administered with bac)ground methotre6ate, was su5erior to 5lacebo with res5ect to all clinical outcomes. The magni7 tude of the eff icac res5onses over the F<7month stud 5eriod was similar with the three active treat7 ments 2> mg and FE mg of tofacitinib given twice dail and AE mg of adalimumab given once ever < wee)s3. Therefore, in this stud 5o5ulation and with res5ect to the efficac outcomes re5orted here, the clinical efficac of tofacitinib was numericall similar to that observed with adalimumab, an antiL T8F biologic agent. 0t should be noted that the A"R <E eff icac data

even if that 5atient later had a res5onse b month D without an infections 2es5eciall re7 s5irator and urinar change in thera5 . This anal sis was necessar to account for the tract infections34 and gas7 trointestinal side The n e w e n g l a n d j o u r n a l of m e d switch to active treat7 ment in a double7blind fashion of 5atients effects. There were two cases of 5ulmonar initiall assigned to 5lacebo. Although the rationale for this t 5e tuberculosis 2described in detail in Table !H in of anal sis was agreed on b scientists and regulators, we the !u55lementar A55endi63. recogni.e that it is challenging to com5are the results of this "hanges in laborator values that were ob7 trial with those of other trials that used the more usual served with both doses of tofacitinib, as com7 im5utation7 of7no7res5onse a55roach. 5ared with 5lacebo, included small increases in The inclusion of adalimumab allowed us to es7 timate the serum creatinine levels and increases in mean relative efficac and safet of tofacitinib. A formal noninferiorit levels of %D% and +D% cholesterol. The effects com5arison among the active treatments, although of obvious of tofacitinib on li5id 5rofiles are still not interest, was thought to be 5remature because little was )nown com5letel understood. Although li5id levels about the efficac of tofacitinib at the time the trial was designed. stabili.ed after 0n addition, concern over what constitutes a clinicall significant H months, an unfavorable overall effect difference 2noninferiorit margin3, as well as the 5reference of cannot be e6cluded. 'iven the duration and si.e the rheumatolog communit to use multi5le measures to assess of the stud , the im5lications of the elevations the overall eff icac of a com7 5ound, made a h 5othesis7driven in %D% cholesterol for the ris) of cardiac events a55roach dif7 f icult. and of neutro5enia for the ris) of infections The ris) of adverse events, including serious adverse events could not be assessed. %onger7term monitoring and serious infectious events, was greater in 5atients treated with of 5atients receiving tofacitinib is ongoing. The tofacitinib than in those who received 5lacebo, at month H. 5ercentages of 5atients with adverse events in Patients receiving tofacitinib must be monitored b their each MedDRA categor were similar across the 5h sician for such events. 8otable adverse events included active treatments, and the 5ercentages of c to5enia, which ma be attributable to the inhibition of &A-<4 5atients who re5orted se7
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Tofacitinib or Adalimumab in Rheumatoid

rious adverse events, severe adverse events, and either tem5orar or 5ermanent discontinuations in both tofacitinib grou5s were similar to those in the adalimumab grou5. Patients from our stud could continue ta)ing tofacitinib as 5art of a long7term e6tension trial. !erious adverse events re5orted from the long7 term stud were similar to those re5orted for this stud and were most commonl infection events. To date, one 5atient from this stud re5orted l m7 5homa in the long7term e6tension trial. The rate of l m5homas or other l m5ho5roliferative disorders in the tofacitinib rheumatoid arthritis 5rogram as of A5ril FD, <EF<, was E.EG 5er FEE 5atient7 ears 2B>J conf idence interval, E.EH to E.F>3. This rate for tofacitinib is consistent with the rates re5orted for all 5atients with rheumatoid arthritis and for those treated with biologic disease7 modif ing
&e.e!ence % 1. !trand V, !ingh &A. 0m5roved health7 related @ualit of life with effective dis7 ease7modif ing antirheumatic drugsP evi7 dence from randomi.ed controlled trials. Am & Manag "are <EEG4FHP!u55l BP!<HG7 !<>F. 2. +ochberg M", &ohnston !!, &ohn A-. The incidence and 5revalence of e6tra7 articular and s stemic manifestations in a cohort of newl 7 diagnosed 5atients with rheumatoid arthritis between FBBB and <EED. "urr Med Res /5in <EEC4<APADB7 CE. 3. $reedveld F. The value of earl inter7 vention in RA = a window of o55ortunit . "lin Rheumatol <EFF4HEP!u55l FP!HH7!HB. ;. /QDell &R. Thera5eutic strategies for rheumatoid arthritis. 8 #ngl & Med <EEA4 H>EP<>BF7DE<. 5. $athon &M, "ohen !$. The <EEC American "ollege of Rheumatolog rec7 ommendations for the use of nonbiologic and biologic disease7modif ing antirheu7 matic drugs in rheumatoid arthritisP where the rubber meets the road. Arthritis Rheum <EEC4>BPG>G7B. 6. !aag -', Teng '', Pat)ar 8M, et al. American "ollege of Rheumatolog <EEC recommendations for the use of nonbio7 logic and biologic disease7modif ing anti7 rheumatic drugs in rheumatoid arthritis. Arthritis Rheum <EEC4>BPGD<7CA.
7.

17,18

drugs. "lose monitoring of the long7term safet of tofacitinib continues to be carried out. 0n conclusion, in this randomi.ed, 5hase H trial involving 5atients with rheumatoid arthritis who had an incom5lete res5onse to methotre6ate, the efficac of > mg or FE mg of tofacitinib given twice dail was significantl su5erior to that of 5lacebo and numericall similar to that of adalimumab. The safet of tofacitinib should be evaluated in a larger number of 5atients who have received treat7 ment for longer durations.
!u55orted b Pf i.er. Disclosure forms 5rovided b the authors are available with the full te6t of this article at 8#&M.org. *e than) the 5atients who were involved in this stud 4 the stud team, s5ecif icall &ill -. %undberg, Ann ". !orrels, !arah Ri5le &ones, Allison '. $raile , Dr. Richard &. Riese, and "huan7 bo ,ang4 and Martin 'oulding, Ph.D., of "om5lete Medical "ommunications, who was funded b Pf i.er.

!molen &!, %andewa R, $reedveld F", et al. #9%AR recommendations for the management of rheumatoid arthritis with s nthetic and biological disease7modif 7 ing antirheumatic drugs. Ann Rheum Dis <EFE4DBPBDA7G>. M#rratum, Ann Rheum Dis <EFF4GEPF>FB.N 8. Flanagan M#, $lumen)o5f TA, $ris7 sette *+, et al. Discover of "P7DBE,>>EP a 5otent and selective &anus )inase 2&A-3 inhibitor for the treatment of autoim7 mune diseases and organ trans5lant re7 jection. & Med "hem <EFE4>HPCADC7CA. 9. Me er DM, &esson M0, %i b, et al. Anti7 inf lammator activit and neutro5hil reductions mediated b the &A-FX&A-H inhibitor, "P7DBE,>>E, in rat adjuvant7 induced arthritis. & 0nf lamm 2%ond3 <EFE4 GPAF. 10. !ewgobind VD, Kuaedac)ers M#, van der %aan %&, et al. The &a) inhibitor "P7 DBE,>>E 5reserves the function of "DA"D<>Fo6PH regulator T cells and in7 hibits effector T cells. Am & Trans5lant <EFE4FEPFGC>7 B>. 11. 'horeschi -, &esson M0, %i b, et al. Modulation of innate and ada5tive im7 mune res5onses b tofacitinib 2"P7 DBE,>>E3. & 0mmunol <EFF4FCDPA<HA7 AH. 12. Arnett F", #dworth !M, $loch DA, et al. The American Rheumatism Associa7

tion FBCG revised criteria for the classif i7 cation of rheumatoid arthritis. Arthritis Rheum FBCC4HFPHF>7<A. 13. Felson DT, Anderson &&, $oers M, et al. American "ollege of Rheumatolog P 5reliminar def inition of im5rovement in rheumatoid arthritis. Arthritis Rheum FBB>4HCPG<G7 H>. 1;. Fries &F, !5it. P, -raines R', +olman +R. Measurement of 5atient outcome in arthritis. Arthritis Rheum FBCE4<HPFHG7A>. 15. Fransen &, van Riel P%. The Disease Activit !core and the #9%AR res5onse criteria. "lin #65 Rheumatol <EE>4<HP !u55lP!BH7!BB. 16. Fleischmann R, -remer &, "ush &, et al. Placebo7controlled trial of tofacitinib monothera5 in rheumatoid arthritis. 8 #ngl & Med <EF<4HDGPAB>7 >EG. 17. !imon TA, !mitten A%, Fran)lin &, et al. Malignancies in the rheumatoid ar7 thritis abatace5t clinical develo5ment 5rogramP an e5idemiological assessment. Ann Rheum Dis <EEB4DCPFCFB7<D. 18. *olfe F, Michaud -. $iologic treat7 ment of rheumatoid arthritis and the ris) of malignanc P anal ses from a large 9nited !tates observational stud . Arthritis Rheum <EEG4>DP<CCD7B>.
Copyright 2012 Massachusetts Medical Society.

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