Arthritis & Rheumatism

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1 ARTHRITIS & RHEUMATISM Volume 38 Number 6, Jue 1995, pp , America College of Rheumatology Arthritis & Rheumatism Official Joural of the America College of Rheumatology AMERICAN COLLEGE OF RHEUMATOLOGY PRELIMINARY DEFINITION OF IMPROVEMENT IN RHEUMATOID ARTHRITIS DAVID T. FELSON, JENNIFER J. ANDERSON, MAARTEN BOERS, CLAIRE BOMBARDIER, DANIEL FURST, CHARLES GOLDSMITH, LINDA M. KATZ, ROBERT LIGHTFOOT, JR., HAROLD PAULUS, VIBEKE STRAND, PETER TUGWELL, MICHAEL WEINBLATT, H. JAMES WILLIAMS, FREDERICK WOLFE, ad STEPHANIE KIESZAK Objective. Trials of rheumatoid arthritis (RA) treatmets report the average respose i multiple outcome measures for treated patiets. It is more cliically relevat to test whether idividual patiets improve with treatmet, ad this idetifies a sigle primary efficacy measure,. Multiple defiitios of improvemet are curretly i use i differet trials. The goal of this study was to promulgate a sigle defiitio for use i RA trials. From the Committee o, Outcome Measures i Rheumatoid Arthritis Cliical Trials, a subcommittee of the Committee o Health Care Research, America. College of Rheumatology. David T. Felso, MD, MPH, Jeifer J. Aderso, PhD: Bosto Uiversity Arthritis Ceter, Bosto, Massachusetts; Maarte Boers, MD, PhD, MSc: Uiversity Hospital, Maastricht, The Netherlads; Claire Bombardier, MD: Wellesley Hospital, Uiversity of Toroto, Toroto, Otario, Caada; Daiel Furst, MD: Virgiia Maso Medical C eter, Seattle, Washigto; Charles Goldsmith, PhD: McMaster Uiversity, Hamilto, Otario, Caada; Lida M. Katz, MD, MPIH: Food ad Drug Admiistratio, Rockville, Marylad; Robert :Lightfoot, Jr., MD: Uiversity of Ketucky, Lexigto; Harold Paulus, MD: Uiversity of Califoria at Los Ageles; Vibeke Strad, MD: Staford Uiversity, Staford, Califoria; Michael Weiblatt, :MD: Brigham ad Wome s Hospital, Bosto, Massachusetts; H. James Williams, MD: Uiversity of Utah, Salt Lake City; Frederick Wolfe, MD: Arthritis Ceter, Wichita, Kasas; Stephaie Kieszak, MA: America College of Rheumatology, Atlata, Georgia. The opiios ad assertios cotaied herei are the private views of the authors ad are ot to be costrued as official or as a reflectio of the views of the Food ad Drug Admiistratio. Address reprit requests to America College of Rheumatology, 60 Executive Park South, Suite 1, Atlata, GA 329. Submitted for publicatio September 2, 1994; accepted i revised form December 6, Methods. Usig the America College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested differet defiitios of improvemet, usig a 3-step process. First, we performed a survey of rheumatologists, usig actual patiet cases from trials, to evaluate which defiitios correspoded best to rheumatologists impressios of improvemet, elimiatig most cadidate defiitios of improvemet. Secod, we tested remaiig defiitios to determie which maximally discrimiated effective treatmet from placebo treatmet ad also miimized placebo respose rates. With 8 cadidate defiitios of improvemet remaiig, we tested to see which were easiest to use ad were best i accord with rheumatologists impressios of improvemet. Results. The followig defiitio of improvemet was selected: % improvemet i teder ad swolle joit couts ad % improvemet i 3 of the 5 remaiig ACR core set measures: patiet ad physicia global assessmets, pai, disability, ad a acutephase reactat. Additioal validatio of this defiitio was carried out i a comparative trial, ad the results suggest that the defiitio is statistically powerful ad does ot idetify a large percetage of placebo-treated patiets as beig improved. Coclusio. We preset a defiitio of improvemet which we hope will be used widely i RA trials. Recet work by our committee i cocert with the iteratioal rheumatology commuity has led to 727

2 728 FELSON ET AL the developmet of a uiform core set of outcome measures for rheumatoid arthritis (RA) trials (1). While this core set represets a advace i defiig ad stadardizig the outcomes to be measured i RA trials, it has ot chaged the focus of trial reportig ad aalysis, i.e., average improvemet for each of the outcomes measured. Usually cliical trials i RA report the average (mea or media) improvemet experieced by treated patiets, with the average improvemet with oe treatmet compared with the average improvemet with aother. Ufortuately, this curret practice is problematic: moderate average improvemet of patiets udergoig a treatmet may occur because all patiets improved modestly or because half of the patiets experieced dramatic improvemet ad the other half o improvemet at all. Further, testig for sigificat results i each of 7 core set measures icreases the likelihood of detectig a differece betwee therapies whe o real differece exists (a Type I error) ad makes it difficult to iterpret the differece betwee therapies whe just 1 or 2 outcome measures are sigificatly differet (Are 2 therapies differet if 1 of such outcomes shows sigificat differeces betwee treatmet groups? Two of 7? etc.). The availability of a sigle defiitio of respose i RA trials would resolve this problem. It would be a sigle primary ed poit for aalysis. Problems associated with multiple testig would dimiish. If a uiform defiitio of improvemet were used, the percetage of patiets improvig could be compared across trials, with the caveat that patiets i differet trials are differet ad may ot be equally likely to improve give the same therapy. Furthermore, patiets are iterested i the likelihood that they themselves will improve, ot i the average respose of similar patiets beig treated. Also, a focus o which patiets improve i trials could lead to ivestigatios that characterize what types of patiets improve with differet therapies. Curret practice does ot allow this, sice idividual patiets are ot well characterized by reports of trials. Last, as will be show below, relyig o a sigle defiitio of improvemet that icorporates iformatio from several outcome measures ca substatially ehace the statistical power of a trial. EXISTING DEFINITIONS OF IMPROVEMENT Defiitios of improvemet have bee developed previously. First, the America Rheumatism Associatio (ow the America College of Rheumatol- ogy [ACR]) defied remissio i RA (2), but remissio occurs so rarely i trials that it has ot bee a useful outcome measure for trials. Usig data from multiceter RA trials, Paulus et a1 (3) developed a defiitio of improvemet based o a set of measures that discrimiated well betwee active secod-lie drug treatmet ad placebo ad that limited placebo respose to -5%. This defiitio requires respose i at least 4 of 6 selected measures. These iclude a % improvemet i morig stiffess, erythrocyte sedimet,atio rate (ESR), joit tederess score, ad joit swellig score ad improvemet by at least 2 grades o a 5-grade scale (or from grade 2 to grade 1) for patiet ad physicia global assessmets of curret disease severity. This defiitio of improvemet is cliically reasoable ad workable i the cotext of trials, but it has bee used icosistetly. Although it was developed with statistical discrimiatio i mid, it may ot correspod to the patiet s or cliicia s perceptio of cliical improvemet. I additio, it relies o global severity scales that are uique to trials from the Cooperative Systematic Studies of the Rheumatic Diseases (a 5-poit adjectival scale), ad are ot widely used elsewhere. The 5-poit adjectival scale may ot be as sesitive to chage as a 7-poit scale or a 10-cm visual aalog scale (4). Furthermore, elemets icluded i the Paulus improvemet criteria do ot correspod to the curret core set: morig stiffess, a measure ofte isesitive to chage, is icluded, ad measuremet of physical fuctio is excluded. Joit couts, morig stiffess, ad ESR are equally weighted i the Paulus criteria, whereas studies of cliicia perceptio of improvemet suggest that joit couts are emphasized more heavily (5). Dutch ivestigators (6) have suggested a idex (the Disease Activity Score [DAS]) to be used i evaluatig improvemet. This score, while ot easy to compute, has the advatage of drawig from several differet outcome measures to assess disease activity, with measures weighted toward joit couts. The ivestigators i may trials have created their ow defiitios of improvemet. For example, amog 15 trials of RA treatimets (other tha osteroidal atiiflammatory drugs) published i 1992 (refereces available from the authors), oly 6 used improvemet or respose criteria ad each used a differet defiitio of improvemet, with oly 1 usig the Paulus criteria. This heterogeeity prevets comparisos of rates of improvemet across trials ad provides a powerful argumet i favor of a stadardized, widely used defiitio of improvemet.

3 ~ ACR PRELIMINARY DEFINITION OF RA IMPROVEMENT 729 ACR DEFINITION OF IMPROVEMENT 7 ~- step 2) Cadidate defilard patlet,mprwemet Aalysis of survey 1 lsuiof rheum robglsts Slrg defiitios corms lpapei pahes with lpomed best to - I 1 RA Whoimproved rheumatologists ad who did ot impressios of 1-1 patiet impiovemefj step 1 Step 2-1 Fh:ch i m ~ ~ e m e ~ t Step 5 step 4 step 3 Redudat del Ms Figure 1. Process of choosig America College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA) improvemet. As part of a ACR committee whose objective was to develop uiform :stadards for RA trial measuremets, we created a. defiitio of improvemet usig elemets of the ACR core set. To achieve that goal, we drew o cliicaj impressios of which RA patiets improve, to idetify what measures cliicias emphasize i evaluatig patiet improvemet. We combied this with a statistical approach similar to that used by Paulus et a1 (3), with additioal trial data to allow compariso of a variety of improvemet defiitios. Our statistical approach focused o the defiitio of improvemet that best discrimiates betwee active drug-treated ad placebo-treated patiets. The overall process is depicted i Figure l. METHODS Physicia survey (Figure 1, step 1). The first step was to assess how rheumato1ogi:sts decide whether a patiet has improved. Survey studies (5) had suggested that rheumatoiogists regard a patiet as improved if the teder or swolle joit cout improves by -% or if other outcomes improve by a larger percet. However, earlier studies combied data o cliicias ad ocliicias, did ot iclude all elemets of the ACR core set, ad diid ot ecessarily use data from real patiets. We therefore surveyed rheumatologists, usig paper patiets selected from real cliical trials by stratified radom samplig to iclude a large umber of survey patiets ear expected thresholds for improvemet (45% improvemet i at least 3 outcomes). The 89 rheumatologists to whom the survey was set cosisted of Outcome Measures i Rheumatoid Arthritis Cliical Trials (OMERACT) committee members, participats, ad others chose because of their cosiderable RA cliical ad/or cliical trial experiece. Sixty-eight (76.4%) retured the surveys, ad all surveys retured were usable. The ages of the respodets raged from 31 to 69 years (media 47 years), 15% were female, ad the media umber of hours of patiet care per week was 17, with 62% of the respodets medical school based. For each elemet of the core set (e.g., teder joit cout), data at baselie ad at 6 moths were provided ad the percet chage was oted. We asked survey respodets whether each paper patiet had improved or ot. Sice the survey was also desiged to evaluate patiet worseig, oly 43 of 69 patiets i the survey provided useful iformatio o improvemet. The other 26 patiets were substatially below expected thresholds for improvemet. As a validatio of our assumptios about which patiets from the survey would provide useful data regardig improvemet, oe of these latter 26 patiets were desigated as improved by more tha 14% of survey respodets. Aalysis of physicia survey (Figure 1, step 2). I the survey results, we focused o patiets characterized as improved by at least 80% of the surveyed rheumatologists. We chose the cutoff of 80% because we were iterested i patiets whom almost all rheumatologists would characterize as improved. We the examied the extet to which these same patiets were characterized as improved accordig to various possible defiitios of improvemet, as show below. We also looked at the percet of false-positives, i.e., patiets ot idetified as improved by 280% of rheumatologists but classified as improved by the improvemet defiitio. We decided that all cadidate defiitios of improvemet with chi-square values <6 (which correspods to P = 0.01) or false-positive rates >25% would be excluded from further cosideratio. Chagig these thresholds did ot chage the relative performace of improvemet defiitios i the survey. Aalysis of trial data (Figure 1, steps 3 ad 4). Oce the survey results had elimiated some of the possible defiitios of improvemet, we tured to statistical aalysis of trial data. The goal was to select the improvemet defiitio(s) that best discrimiated active secod-lie drugs from placebo. We assembled a data set of 5 placebocotrolled trials of secod-lie drugs, icludig 1 trial of gold (7) ad 4 of methotrexate (refs ad Schmid FR et al: upublished observatios). Oe of these (Schmid FR et al: upublished observatios) was a small upublished trial, ad its exclusio does ot affect aalytic results. Sice we wished to choose regimes that offered as large as possible a efficacy differece betwee drug ad placebo, we excluded 1 auraofi arm i 1 trial, sice evidece (11,12) suggests it is relatively weak. Six of the 7 ACR core set measures were icluded i these trials, but like may completed RA trials, 4 of the 5 trials did ot iclude a assessmet of fuctioal status. We substituted grip stregth, a measure whose chage correlated moderately (r = 0.45 with chage i Arthritis Impact Measuremet Scales physical fuctio i 1 trial [7] ad r = 0.64 i aother study [13]) ad which loads with fuctioal status i factor aalyses of trial data, suggestig that it measures a similar costruct (4). The data set cotaied 8 patiets, but 3 patiets (177 active drug-treated/l43 placebo-treated) remaied after exclusio of patiets with missig data for at least 1 elemet of the core set (or for grip stregth). Additioal aalysis of the 1 trial with data o fuctio suggests that the results would likely ot have chaged if such data were available i all trials. After selectig the improvemet defiitio based

4 7 FELSON ET AL Table 1. Descriptio of cadidate defiitios for improvemet applied to the 43 patiet profiles, ad results of rheumatologist survey* Outcome measures Survey results Swolle Physicia Patiet Chi- No. (%) false- Criterio Physical Teder joit joit global global square positives, of code Defiitio type disability Pai ESR cout cout assessmet assessmet value 25 Pa Pb PC Wa Wb wc Ea Eb Ec Ed Ee Ef Eg Eh Ei Ej Ek El Em E Eo EP Oa Ob OC Od Ja Jb Da Db Dc Dd De Df Dg Dh I1 I2 I3 17 Paulus (4/6) Paulus (4/6) Paulus (5/7) WHO (4/5) WHO (415) WHO (5/7) Equal (5/7) Equal (6/7) Equal (4/7) Equal (5/7) Equal (417) Equal (517) Equal (3/7) Equal (4/7) Equal (5/7) Equal (3/7) Equal (4/7) Equal (5/7) Equal (3/7) Equal (417) Equal (3/7) Equal (417) OMERACT (417) OMERACT (5/7) OMERACT (417) OMERACT (5/7) Joit cout (212) Joit cout (2/2) DAS 3 (2 SEM) DAS 3 (4/3 SEM) DAS 3 (1 SEM) DAS 4 (2 SEM) DAS 4 (4/3 SEM) DAS 4 (1 SEM) Liear DAS3 Liear DAS4 Idex (0.5 uits) Idex (0.5 uits) Idex (0.5 uits) Idex (0.5 uits) 5 IT (25) (25)(req.)S (req.)s (req.)$. (req.)s (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) (24) 5 I I I ll T ll ~ ~ ~ ~~ ~~~~~ * Defiitios show i boldface were selected for the ext stage of aalysis. ESR = erythrocyte sedimetatio rate; WHO = World Health Orgaizatio; OMERACT = Outcome Measures i Rheumatoid Arthritis Cliical Trials; DAS = Disease Activity Score. Either 1 of 2 items i row may be couted. t Item is required. Item is i DAS. IT Item is i the idex. t t t t D 0 (i o its performace i placebo-cotrolled trials, we tested it i a large compariso trial data set of methotrexate ad auraofi, i which methotrexate had bee show to be more efficacious ( = 274 patiets with complete data) (12). I aalyzig trial data, we calculated the percetage of active drug-treated patiets who were idetified as improved by each cadidate improvemet defiitio ad the percetage of placebo-treated patiets who were characterized as improved by each defiitio. For each improvemet defiitio, we also evaluated the statistical power i discrimiatig active drug from placebo groups. The first stage of assessig cadidate defiitios etailed selectig the most statistically powerful. Of those with roughly equal power, we the chose the oes that idetified the fewest placebo-treated patiets as improved. Because of the imprecisio of estimates, we relied further o the aalysis of the comparative: trial (methotrexate versus auraofi) ad attempted to be geerous i our estimates of equivalece, so as ot to elimiate a defiitio of improvemet because of isufficiet data. Ease of use, credibility (Figure 1, step 5). From those defiitios remaiig, we made our fial choice. As a group

5 ACR PRELIMINARY DEFINITION OF RA IMPROVEMENT 73 1 of experieced trialists, we ralked the face validity (cliical reasoableess ad ease of use) of the remaiig defiitios o a 1-8 scale with 8 the highest, ad the tabulated the raks. Also, we retured to the rheumatologist survey ad raked each defiitio by its kappa statistic (aother measure of agreemet betwee the rheumatologists impressio of improvemet ad the defitio s classificatio of improvemet). These 2 rakigs were multiplied, ad the defiitio with the best score was selected. RESULTS The survey. Of the 43 paper survey patiets that were the focus of our ivestigatio of improvemet, 18 were thought by 280% of the respodets to have improved ad 25 were ot. We tested possible criteria for improvemet (Table 1). These were selected because they were used i trials, because they were recommeded i publicatios, by members of our committee, or by the iteratioal commuity, or because they were variatios o used or recommeded defiitios. There were 7 groupls of cadidate improvemet defiitios. The first group was derived from the Paulus criteria (3) ad substituted improvemet i pai or physical disability for the Paulus criterias improvemet i morig stiffess. This group of defiitios was referred to as Paulus. Aother group of defiitios of improvemet required improvemet i the teder ad swolle joit couts, as well as i a proportio of other core set elemets. Because of similar recet prelimiary World Health Orgaizatio recommedatios developed by 1 of the authors (Dr. Furst), we desigated this group of improvemet defiitios as WHO. A third group (called Equal) weighted each of the core set elemets equally ad tested equal percet improvemets i all core set elemets. For example, oe defiitio was % improvemet i 5 of 7 of the core set elemets, aother % improvemet i 5 of 7, ad aother % i 4 of 7, etc. For the fourth group, developed from OMER- ACT meetig surveys (ad therefore called OMER- ACT), we used evidecle that cliicias emphasized improvemet i joit couts ad developed improvemet defiitios with 2210% improvemet i teder or swolle joit couts or at least % improvemet i the other measures (improvemets i joit cout ot required). Yet aother group of defiitios of improvemet (called Joit Cout) focused oly o joit cout 10 I I I I I I Percetage improved i placebo group Figure 2. Performace of cadidate criteria i placebo-cotrolled trials. See Table I for defiitios of criterio codes. measures defiig improvemet as improvemet i teder ad/or swolle joit couts. The sixth group evaluated the recommeded improvemet defiitios usig the DAS (6), a idex, ad tried out differet cutpoits for improvemet as well as a liearized versio (calculated usig the liear regressio estimate of log [esrl over the iterval 0- ad of the square root of teder joit cout over the iterval 15-45). There are 2 versios of the DAS: 1 usig 2 joit cout measures ad the ESR ad the other usig the same 3 measures plus patiet global assessmet. For the last group (called Idex), we costructed pooled idices of improvemet, dividig the chage i each outcome measure by its chage stadard deviatio (the latter derived from all trial patiets) to create a effect size for each outcome measure, ad the averagig effect sizes. A chage of 0.5 effect size uits was used as the cutoff for improvemet. Of the possible defiitios of improvemet tested, 17 met the previously defied threshold i the survey, low false-positivity rate ad high chi-square value. These 17 defiitios appear i boldface i Table 1. They iclude all improvemet defiitios i groups 1 (Paulus) ad 2 (WHO), ad selected defiitios i 32 64

6 732 FELSON ET AL Table 2. Face validity ad survey performace of the 8 cadidate defiitios of improvemet that had the most statistical power ad desigated the fewest placebo-treated patiets as improved Face Face validity Improvemet validity Survey X survey defiitio* rak? kappa kappa Paulus, Pc WHO, Wc Equal, Eg Equal, Ec Equal, Ea Equal, Eb Omeract, Ob Idex, I * See Table 1 for defiitios of criterio codes. t Scored o a scale of 1-8, with 8 beig the highest face validity. each of the other groups. The WHO ad Paulus groups of defiitios, those usig the DAS, Idex 3 (with 2 joit couts), ad 1 of the joit cout improvemet criteria all had high chi-square values, suggestig that cliical perceptios of patiet improvemet rely heavily o joit cout improvemet. Noetheless, the tedecy for the DAS ati joit cout improvemet defiitios to have high false-positive rates suggests that cliicias evaluate more tha just joit cout i characterizig patiets as beig improved. At least 1 improveimet defiitio from each group was icluded i the ext stage of aalysis, but 2 that met the threshold were omitted because they were duplicative (Ef is similar to Ed ad Oc is similar to Oa) (see Table 1 for defiitios of criterio codes). I additio, at the request of committee members ad for completeess, 5 additioal variatios of the remaiig 15 cadidate defiitios (2 i the Idex group [I2 ad 171, 1 i the DAS group [Dd], ad 2 i the Equal group [Ec ad Eg]) were evaluated i the ext stage with the aticipatio that they might do well i discrimiatig active drug- from placebotreated patiets, givig a total of. We plaed that later selectio of a Table 3. America College of Rheumatology prelimiary defiitio of improvemet i rheumatoid arthritis * >% improvemet i teder joit cout Required i- 2% improvemet i swolle joit cout Swolle joit coutt Disease activity measure Teder joit coutt Patiet s assessmet of pai Patiet s global assessmet of disease activity Physicia s global assessmet of disease activity Patiet s assessmet of physical fuctio 7. Acute-phase reactat value + 2% improvemet i 3 of followig 5: Patiet pai assessmet Patiet global assessmet Physicia global assessmet Patiet self-assessed disability Acute-phase reactat (ESR or CRP) Method of assessmet ACR teder joit cout, a assessmet of 28 or more joits. The joit cout should be doe by scorig several differet aspects of tederess, as assessed by pressure ad joit maipulatio o physical examiatio. The iformatio o various types of tederess should the be collapsed ito a sigle teder-versus-oteder dichotomv. ACR swoll& joit cout, a assessmet of 28 or more joits. Joits are classified as either swolle or ot swolle. A horizotal visual aalog scale (usually 10 cm) or Likert scale assessmet of the patiet s curret level of pai. The patiet s overall assessmet of how the arthritis is doig. Oe acceptable method for determiig this is the questio from the AIMS istrumet: Cosiderig all the ways your arthritis affects you, mark X o the scale for how well you are doig. A achored, horizotal, visual aalog scale (usually 10 cm) should be provided. A Likert scale respose is also acceptable. A horizotal visual aalog scale (usually 10 cm) or Likert scale measure of the physicia s assessmet of the patiet s curret disease activity. Ay patiet self-assessmet istrumet which has bee validated, has reliability, has bee prove i RA trials to be sesitive to chage, ad which measures physical fuctio i RA patiets is acceptable. Istrumets which have bee demostrated to be sesitive i RA trials iclude the AIMS, the HAQ, the Quality (or Idex) of Well Beig, the MHIQ, ad the MACTAR. A Westergre erythrocyte sedimetatio rate or a C-reactive protei level. * ACR = America College of Rheumatology; ESR = erythrocyte sedimetatio rate; CRP = C-reactive protei; AIMS = Arthritis Impact Measuremet Scales; RA = rheumatoid arthritis; HAQ = Health Assessmet Questioaire; MHIQ = McMaster Health Idex Questioaire; MACTAR = McMaster Toroto Arthritis Patiet Preferece Disability Questioaire. t For details o which joits, see refs. 14 ad 15.

7 ACR PRELIMINARY DEFINITION OF RA IMPROVEMENT more of both placebo-treated ad active drug-treated patiets as improved. The 2 cadidate defiitios discrimiatig best betwee active ad placebo treatmets were 2 that did ot perform well i the physicia survey, Idex defiitio I7 ad Equal defiitio Eg. Defiitios with the most power, that desigated the fewest placebo-treated patiets as improved, were chose (see Figure 2). These were Paulus defiitio Pc, WHO defiitio Wc, Equal defiitios Ea, Eb, = Ec, ad Eg, OMERACT defiitio Oa, ad Idex defiitio 17. Most cadidate defiitio groups remaied represeted i this fial list, although defiitios of improvemet based solely o joit cout = 32 improvemet ad those based o the DAS were elimiated. These latter defiitios had less power tha the oes selected ad were especially likely to character = 64 ize placebo-treated patiets as improved. We the scored each of the 8 remaiig cadidate defiitios of improvemet for face validity ad I I I I I I multiplied the face validity score by the survey kappa score (Table 2). This procedure idetified 1 defiitio that clearly scored better tha the others, ad this Percetage of Aureofl patlets improved defiitio, WHO defiitio Wc, was selected as the defiitio for improvemet (Table 3). It should be oted that ot oly did this defiitio do well i the survey (chi-square 18. I, o false-positives [Table I]), but, i the aalysis of trial data, it discrimiated well betwee placebo ad active treatmet ad idetified few placebo-treated patiets as improved. Next, we tested this defiitio i aother cliical trial data set, a multiceter trial of methotrexate versus auraofi. I this trial, mea improvemets i idividual measures were, i geeral, much greater for methotrexate-treated patiets tha for patiets receivig auraofi (12). The defiitio selected ad others like it i the WHO series performed as well as or better tha ay other types of defiitios i discrimiatig betwee methotrexate ad auraofi (Figure 3). As i placebo trials, joit cout- ad DAS-based defiitios idetified as improved a large percetage of patiets who received the weaker therapy. The Equal defiitio ad the Paulus defiitios characterized more methotrexate-treated ad more auraofi-treated patiets as improved tha did the defiitio selected. Figure 3. Performace of the lewly developed criteria i comparig methotrexate ad auraofi. See Table 1 for defiitios of criterio codes. improvemet defiitio would reicorporate survey results, so that the added defiitios that did ot do well i the survey would be appropriately pealized. Aalyzig trial data. Usig the previously described set of 5 placebo-cotrolled cliical trials, we evaluated the proportio of active drug-treated patiets desigated as impiroved ad the proportio of placebo-treated patiets as ot improved for each of the remaiig defiitios of improvemet (see Figure 2). Curves of equal powex- (isopower lies) are superimposed o the plot. Ay 2 poits o the same isopower curve are defiitios with equal discrimiatig power, i.e., the trial sample sizes eeded for those 2 defiitios to detect differeces betwee active drugad placebo-treated patiets as sigificat (Ztailed a = 0.05, power 80%) are the same. I the lowest curve 64 patiets per treatmet group are eeded, while for the other 2 lies, sample sizes of 32 ad per group, respectively, are required. For example, Equal defiitio Eb ad DAS defiitio Da have similar discrimiatio i these trial data, but they differ i the proportio of placebo-treated ad active drug-treated patiets they idetify as improved, with Da idetifyig DISCUSSION Based o this aalysis usig several differet approaches to evaluatig potetial defiitios of improvemet i RA, we suggest that improvemet for cliical trial patiets be defied as 2% improvemet

8 734 FELSON ET AL i teder ad swolle joit couts ad 2% improvemet i at least 3 of the followig 5 ACR core set measures: pai, patiet ad physicia global assessmets, self-assessed physical disability, ad acutephase reactat. Our work suggests that this defiitio correspods closely to cliicias impressio of patiet improvemet sice it emphasizes joit couts, ad furthermore, it discrimiates powerfully betwee active ad placebo treatmet, idetifyig few placebotreated patiets as beig improved. This defiitio of improvemet provides a sigle outcome measure that ca be used i all RA trials. The defiitio of improvemet ca characterize the respose of idividual patiets to therapy, ad usig it, ivestigators ca profile those likely to respod to a therapy. Our aalyses suggest that this defiitio of improvemet icreases the power of cliical trials sice it draws o iformatio from multiple differet outcome measures. Therefore, the sample size eeded to demostrate differeces betwee therapies may decrease, makig it possible for some trials that previously would have bee cosidered to be uderpowered to have sufficiet patiets to compare treatmets. For example, for the comparative trial aalyzed i Figure 3, betwee ad 32 patiets per treatmet group would be required usig this improvemet defiitio (80% power, a = 0.05, 2-sided), versus at least 80 patiets per group if the trial were aalyzed i the curret ad traditioal way, evaluatig I of the 7 core set measures. Ultimately, if the improvemet criteria are widely used i a stadardized maer, it may be possible to rak the efficacy of differet therapies based o the percetage of patiets who improve. Sice our data aalysis focused o defiig improvemet based o the differeces betwee edof-trial ad start-of-trial scores, we recommed that patiets be evaluated as improved or ot improved based o their scores at trial s ed (or at the time they drop out) compared with etry scores. Util ow, improvemet criteria have ofte relied o chages i joit cout to determie whether a patiet has improved. Compared with more comprehesive measures, defiitios that deped oly o joit cout geerally do ot discrimiate as well betwee active drug-treated ad placebo-treated patiets, ad usually idetify more placebo-treated patiets as beig improved. We hope that our defiitio of improvemet satisfies a middle groud i that it relies heavily o joit cout improvemet while icorporatig data from other measures. There are limitatios both to our approach to defiig improvemet ad to our defiitio. First, our aalysis of how well improvemet defiitios distiguished active drug-treated from placebo-treated patiets,was limited by the absece of fuctioal status data i our data sets. We had to rely o grip stregth istead. Aalyses with smaller data sets that did cotai fuctioal status suggest that the results would have bee similar. Noetheless, it is essetial that these improvemet criteria be validated with data sets that cotai iformatio o fuctioal status chage. I geeral, validatio i other prospectively measured data sets would be of great value. I additio, the use of oe sigle measure to evaluate the respose to therapy i rheumatoid arthritis may be overly simplistic. Some treatmets affect joit cout improvemet more tha improvemet i acute-phase reactats, ad (others do the opposite. To igore the spectrum of improvemet iduced by a particular treatmet would be a mistake, ad we recommed that the chage i each outcome still be reported, but that the primary outcome for trials be improvemet as reported here. I summary, we suggest a defiitio for improvemet i rheumatoid arthritis that correspods closely to rheumatologists ow impressios of patiet improvemet ad also discrimiates betwee active drug- ad placebo-treated patiets, which suggests that its use will ehace the statistical power of future trials. ACKNOWLEDGMENT The authors are idebtsed to members of the ACR Committee o Health Care Research for their critical commets. REFERENCES Felso DT, Aderso JJ, Boers M, Bombardier C, Cheroff M, Fried B, Furst D, Goldsmith C, Kieszak S, Lightfoot R, Paulus H, Tugwell P, Weiblatt M, Widmark R, Williams HJ, Wolfe F: The America College of Rheuratology prelimiary core set of disease activity measures for rh eumatoid arthritis cliical trials. Arthritis Rheum 36:729-7, 1993 Pials RS, Masi AT, Larse RA, ad the Subcommittee for Criteria of Remissio i Rheumatoid Arthritis of the America Rheumatism Associatio Diagostic ad Therapeutic Criteria Committee: Prelimiary criteriar for cliical remissio i rheumatoid arthritis. Arthritis Rheum 24: , 1981 Paulus HE, Egger MJ, Ward JR, Williams HJ, ad the Cooperative Systematic Studies of the Rheumatic Diseases Group: Aalysis of improvemet i idividual rheumatoid arthritis patiets treated with disease-modifyig atirheumatic drugs, based o the fidigs i patiets treated with placebo. Arthritis Rheum 33: , 1990

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