Review. The new ASAS classification criteria for axial and peripheral spondyloarthritis: promises and pitfalls. Sarah Lipton1 & Atul Deodhar*1

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1 The ew ASAS classificatio criteria for axial ad peripheral spodyloarthritis: promises ad pitfalls Spodyloarthritis (SpA), if ot diagosed ad treated early, ofte leads to sigificat morbidity. Ufortuately, diagosis ad implemetatio of therapy are frequetly delayed, i may cases by years. The Assessmet of SpodyloArthritis Iteratioal Society has recetly developed ew criteria for classificatio of both axial ad peripheral SpA. The ew criteria were formulated with the aim of ehacig desig of cliical trials, ad ultimately leadig to earlier ad more effective diagosis ad treatmet i the cliical settig. This paper reviews the process of the developmet of both sets of criteria, ad discusses their potetial advatages ad disadvatages. Keywords: akylosig spodylitis axial spodyloarthritis dactylitis ethesitis HLA-B7 iflammatory bowel disease-related arthritis psoriatic arthritis reactive arthritis sacroiliitis spodylitis Spodyloarthritis (SpA) is a umbrella term applied to a group of rheumatic diseases with features i commo with ad distict from other iflammatory arthritides, particularly rheumatoid arthritis. SpA ecompasses akylosig spodylitis (AS), reactive arthritis, psoriatic arthritis, iflammatory bowel disease-related arthritis ad udifferetiated SpA. Features that lik these etities are a associatio with HLA-B7, a characteristic patter of peripheral arthritis that is asymmetric, oligoarticular ad predomiates i the lower extremities, ad possible sacroiliitis, spodylitis, ethesitis, dactylitis ad iflammatory eye disease []. Estimated prevalece of akylosig spodylitis i Europe is %, ad of SpA is %, which is higher tha rheumatoid arthritis []. Data from Natioal Health ad Nutritio Examiatio Survey (NHANES) suggest that prevalece of SpA i the USA may be as high as.4% [3]. AS, with typical oset at a youg age, without treatmet or with delayed treatmet, is associated with tremedous symptomatic burde ad loss of fuctio durig years that are ormally productive [4]. Opportuities for early treatmet are hampered by delayed diagosis; a average delay of 8 years betwee oset of symptoms ad time of diagosis has bee reported [5]. Reasos for the delay i diagosis are myriad ad iclude lack of a pathogomoic cliical feature or laboratory test. Low back pai afflicts most patiets with AS, but is extremely commo i the geeral populatio, ad ofte the iflammatory origis of back pai are ot carefully sought i practice [4]. Furthermore, radiographic sacroiliitis, which has historically bee a corerstoe of diagosig AS, may take several years to develop [6]. The eed for early diagosis ad treatmet was less crucial i the past, whe therapeutic optios were quite limited. This has chaged with the developmet of TNF-α ihibitors that are used effectively to treat AS ad arrest progressio of peripheral arthritis i other SpA [7]. A major challege over recet decades has bee the lack of diagostic or classificatio criteria, which could help with early establishmet of diagosis to allow for timely ad proper treatmet, ad facilitate cliical trial desig, respectively. The developmet of the Assessmet of SpodyloArthritis Iteratioal Society (ASAS) classificatio criteria for both axial ad peripheral SpA has bee a welcome advace i this regard. This article discusses the ew criteria ad their potetial promises ad pitfalls. Evolutio of the ew criteria As metioed earlier, oe of the challeges i diagosig AS is that low back pai, its cardial cliical symptom, is extremely commo i the geeral populatio. Accordig to recet NHANES data, chroic low back pai is see i 9% of Americas [3]. The modified New York criteria for classificatio of AS were developed i 984 [8]. They required fulfillmet of at least oe cliical criterio plus presece of radiographic sacroiliitis. While the iclusio of iflammatory back pai (IBP) as a cliical criterio replaced the less specific symptom of low back pai that had bee used i the Rome ad prior New York criteria, reliace o radiographic sacroiliitis left the remaiig problem of lack of sesitivity whe 0.7/IJR..6 0 Future Medicie Ltd It. J. Cli. Rheumatol. (0) 7(6), Sarah Lipto & Atul Deodhar* Divisio of Arthritis & Rheumatic Diseases, Orego Health & Sciece Uiversity, Mail Code OP-09, 38 SW Sam Jackso Park Road, Portlad, OR 9739, USA *Author for correspodece: Tel.: Fax: deodhara@ohsu.edu part of ISSN

2 Lipto & Deodhar Europea SpA Study Group classificatio criteria for SpA Iflammatory spial pai Syovitis Asymmetric predomiat lower limb Plus oe more of the followig: Alterate buttock pai Sacroiliitis Positive family history Psoriasis Iflammatory bowel disease Urethritis or cervicitis or acute diarrhea occurrig withi moth before the oset of arthritis Figure. Europea Spodyloarthropathy Study Group criteria. SpA: Spodyloarthritis. applied to patiets early i their disease course [9]. The Amor ad Europea Spodyloarthropathy Study Group (ESSG) criteria (Figure & Table ) were developed i the 990s [0,]. While the modified New York criteria solely addressed classificatio of AS, the Amor ad the ESSG criteria addressed the etire spectrum of SpA, icludig udifferetiated disease, which had previously bee igored i may studies owig to lack of a workable defiitio. The ESSG criteria have etry coditios i that they require the presece of iflammatory spial pai or syovitis. The Amor criteria are a list of twelve variables, with o madatory features required for classificatio. The Amor criteria perform slightly better tha ESSG i classificatio of early SpA, which may be attributable to the Amor iclusio of respose to NSAIDs ad HLA-B7 typig []. The ew ASAS classificatio criteria for axial SpA Developmet of the ew criteria (see Figure ) bega with 0 experts i SpA (all ASAS members) reviewig cliical data of 7 real patiets who had preseted to a rheumatology departmet i Berli (Germay). The patiets were selected based o a history of chroic back pai of ukow origi ad a possible diagosis of SpA. Cliical data icluded geder, age, duratio of back pai, cliical history, laboratory tests ad imagig results, ad were preseted to the experts i the format of paper patiets. I terms of imagig, iformatio about sacroiliitis o plai radiographs was provided accordig to the modified New York criteria. Additioally, all patiets uderwet sacroiliac joit MRI, ad MRI fidigs were coveyed as presece or absece of active iflammatio [3]. Paper patiets were first preseted ad classified without MRI iformatio ad cadidate criteria were formulated based o cliical reasoig, icludig review of imagig data. Oe of the iterestig fidigs durig the process of developig cadidate criteria was the large proportio of patiets (96%) who lacked defiite radiographic sacroiliitis ad were hece cosidered to have oradiographic axial SpA. I additio, MRI was foud to play a substatial role i classificatio. I % of patiets, the experts classificatio chaged oce MRI iformatio was preseted. It was also felt that the ew criteria Table. Spodyloarthropathies Amor Criteria 990. Cliical characteristic Score Lumbar pai at ight or lumbar morig stiffess Asymmetric oligoarthritis Buttock pai (or bilateral alteratig buttock pai) () Sausage-like toe or digit(s) Heel pai or other well-defied ethesities Iritis Nogoococcal urethritis/cervicitis withi moth of oset Acute diarrhea withi moth of arthritis oset Psoriasis, balaitis or iflammatory bowel disease (Croh s or ulcerative colitis) Sacroiliitis (bilateral grade or uilateral grade 3) HLA-B7(+) or (+) family history of a spodyloarthropathy Rapid (<48 h) respose to NSAIDs Diagosis of a spodyloarthropathy requires a score of 6. Data take with permissio from []. 676 It. J. Cli. Rheumatol. (0) 7(6) future sciece group

3 The ew ASAS classificatio criteria for axial & peripheral spodyloarthritis: promises & pitfalls should allow for classificatio based o cliical criteria aloe, ad the umber ad combiatio of cliical features were selected based o a balace of sesitivity ad specificity. Sets of cadidate criteria were comprised maily of positive imagig plus oe cliical feature, or IBP plus two cliical features [3]. The cadidate criteria were the validated i a idepedet prospective iteratioal study of 649 patiets from 5 ceters. Iclusio requiremets were a history of chroic back pai (at least 3 moths duratio) of ukow etiology that bega before 45 years of age, with or without peripheral symptoms. I a effort to prevet selectio bias, patiets were erolled i a strictly cosecutive matter. I additio to history, physical examiatio ad laboratory testig that icluded HLA-B7 ad CRP, patiets uderwet plai radiographs of the pelvis. Sacroiliitis was graded for each sacroiliac joit separately (grades 0 4). MRI of the sacroiliac joits was required i the first 0 patiets i each ceter, while MRI of the spie was optioal. MRI fidigs were recorded as the presece or absece of active iflammatio, omittig chroic chages such as erosios ad fatty degeeratio [4]. Diagosis by a expert physicia (axial SpA or o SpA) was used as the gold stadard. Followig data aalysis ad presetatio, the fial criteria were determied by vote of ASAS members. The fial criteria iclude a imagig arm ad a cliical arm: by applyig the fial criteria, a patiet with chroic back pai of oset at before the age of 45 years ca be classified as havig axial SpA if there is sacroiliitis o imagig (by radiographs or MRI) alog with at least oe other SpA feature, or if imagig evidece of sacroiliitis is abset, positive HLA-B7 alog with at least two other SpA features [4]. The ew criteria performed well i the validatio study. Sesitivity was 8.9% ad specificity was 84.4%. The ew criteria also outperformed the ESSG ad Amor criteria, eve after icorporatig sacroiliitis o MRI ito the earlier criteria [5]. Promises & pitfalls of the ew axial SpA criteria Oe of the otable aspects of these criteria is the icorporatio of the emergig cocept of oradiographic axial SpA. This refers to patiets with sigs ad symptoms of axial disease who lack the radiographic damage to the sacroiliac joits to meet the modified New York criteria [6]. This etity may be part of the same spectrum of disease as AS (see Figure 3). Ivestigators of the Germa Spodyloarthritis Iceptio Cohort (GESPIC) future sciece group The Assessmet of SpodyloArthritis Iteratioal Society classificatio criteria for axial SpA (i patiets with back pai 3 moths ad age at oset <45 years Sacroiliitis o imagig plus SpA feature or HLA-B7 plus other SpA features Figure. Axial spodyloarthritis classificatio criteria. Active (acute) iflammatio o MRI, highly suggestive of sacroiliitis associated with SpA or defiite radiographic sacroiliitis accordig to the modified New York criteria. Iflammatory back pai, arthiritis, ethesitis (head), uveitis, dactylitis, psoriasis, Croh s disease (ulcerative colitis), good respose to NSAIDs, family history of SpA, HLA-B7 ad elevated CRP. SpA: Spodyloarthritis. Data take with permissio from [4]. sought to prospectively study the disease course of patiets with early axial SpA ad idetify predictors of outcome. They compared patiets with established early AS ad patiets with oradiographic SpA (the latter diagosis had to be determied by the treatig rheumatologist, ad was carried out prior to the publicatio of the ew criteria). Cliical maifestatios, presece of HLA-B7 ad levels of disease activity were foud to be quite similar betwee the groups [7]. The iclusio of MRI, give equal weight as radiographic sacroiliitis, i the criteria is a crucial advacemet. Advatages of MRI iclude multiplaar imagig, absece of ioizig radiatio ad superior tissue cotrast resolutio [8]. MRI is highly sesitive for detectio of sacroiliitis, maily via demostratio of boe marrow edema represetig early stages of iflammatio. This is usually best see o fat suppressed T-weighted or short tau iversio recovery (STIR) sequeces, by which icreased water cotet (represetig cellular ifiltratio or replacemet of boe marrow fat) heightes sigal itesity. Alterative techiques requirig cotrast agets iclude fat-suppressed T-weighted images followig the gadoliium admiistratio, with heighteed sigal itesity represetig chages i tissue perfusio. Potetial disadvatages of cotrast admiistratio, however, iclude cost, requiremet of itraveous access ad potetial risk of ephrogeic systemic fibrosis [6]. The ability to detect sacroiliitis by MRI durig early stages of disease, well before detectio by radiographs is possible, has bee demostrated [9]. Furthermore, oe study demostrated the utility of boe marrow edema surroudig the sacroiliac joits o MRI i predictig subsequet developmet of AS [0]. The defiitio of a positive MRI, or active sacroiliitis by MRI, applied i the ew criteria was determied by cosesus by rheumatologists ad 677

4 Lipto & Deodhar Preradiographic stage (udifferetiated axial SpA) Back pai (MRI: active sacroiliitis) Radiographic stage (akylosig spodylitis) Back pai Radiographic sacroiliitis Back pai Sydesmophytes Time (years) Figure 3. Spectrum from spodyloarthritis to akylosig spodylitis. Data take with permissio from [9]. SpA: Spodyloarthritis. radiologists comprisig the ASAS/OMERACT trials MRI workig group. Amog the active iflammatory lesios detectable by MRI, the clear presece of either boe marrow edema o STIR or osteitis o T postgadoliium imagig was deemed a requiremet i defiig active sacroiliitis. The presece of structural lesios (such as fat depositio, sclerosis, erosios ad boy akylosis), while likely to reflect previous iflammatio, were ot felt to sufficietly defie a positive MRI i the absece of boe marrow edema or osteitis []. The superior sesitivity of MRI was supported i the evaluatio of the ASAS paper patiets. Oly.8% of patiets had defiite sacroiliitis accordig to the modified New York criteria, but 38% of them were foud to have sacroiliitis o MRI [3]. It should be oted, however, that boe marrow edema of the sacroiliac joits is ot perfectly specific for iflammatio, as it ca be preset i other settigs that iclude mechaical stress []. Thus, iappropriate use of the sacroiliac joit MRI i a youg patiets with chroic back pai of mechaical origi has a dager of misdiagosis. Aother potetial limitatio of the criteria is the exclusio of spial MRI, which could have improved sesitivity as well as specificity [0]. Ability to classify someoe with oradiographic axial SpA, eve i the absece of positive MRI, usig the cliical arm (i.e., positive HLAB7 with at least two SpA features) is oe of the advatages of the ew axial SpA criteria. However, sice the prevalece of HLA-B7 amogst white Caucasias withi the USA is kow to be 7.5%, some people could get misclassified if they have soft sigs/symptoms of SpA alog with positive HLA-B7 by chace. This misclassificatio would icrease if the perso comes from a ethic group that has a eve higher prevalece of HLA-B7 (such as some Native America populatios). This pitfall should be kept i mid whe classifyig people usig the cliical arm of the criteria. 678 It. J. Cli. Rheumatol. (0) 7(6) The axial SpA criteria ad defiitio of a positive MRI were studied i a iceptio cohort comparig patiets with IBP to cotrol patiets. All of the patiets with IBP were classified as havig axial SpA, with more patiets meetig the imagig arm of the criteria tha the HLA-B7 arm (83 vs 6%, respectively). Both arms showed good diagostic utility but were less valuable for predictio of radiographic progressio. This might be due to limited specificity of the ASAS defiitio of a positive MRI at baselie, or it may be that MRI evidece of sacroiliitis may ot truly be a good progostic marker. Progostic utility may also be limited by iclusio of mild boe marrow edema i the defiitio of a positive MRI, ad a role for additioal progostic factors idepedet of MRI fidigs []. As discussed above, the disease burde of oradiographic SpA is quite similar to that of AS. It is, therefore, imperative to establish a mode of early ad effective diagosis ad treatmet of this etity. The ew criteria are expected to ehace desig of future cliical trials ad observatioal studies [3]. This may have direct therapeutic implicatios, supported by evidece of efficacy of ati-tnf agets i patiets with oradiographic SpA [4,5]. While desiged for classificatio ad ot diagostic purposes, the criteria may have a role i diagosis i the settig of a rheumatology cliic. Whe they were applied i this settig to patiets with udiagosed back pai, pretest probability of axial SpA of 60% icreased to a post-test probability of 89%, with a positive l ikelihood ratio of 5.3 [4]. Cautio must be exercised, however, i the extrapolatio of classificatio criteria to the cliic. While the diagostic performace of the ew criteria i the outpatiet rheumatology cliic was good, it was ot perfect. Fulfillmet of classificatio criteria, which work well i the study of groups of patiets, does ot ecessarily traslate directly to a diagosis i a idividual patiet [6]. As oted above, oe other aspect of delay i diagosis that remais a challege is facilitatig referral to the rheumatologist of appropriate patiets with back pai ad a high pretest probability of axial SpA. It is ot yet clear whether the criteria could have utility i such referral cliic settigs, ad while this remais uaswered there is risk of misuse of them as diagostic criteria [5]. This risk is proouced whe classificatio criteria are applied i a populatio with a low pretest probability of disease [9] ad could lead to iappropriate use of ati-tnf agets to treat patiets with chroic mechaical back pai. future sciece group

5 The ew ASAS classificatio criteria for axial & peripheral spodyloarthritis: promises & pitfalls The ew ASAS classificatio criteria for peripheral SpA The process of developig the ew criteria for peripheral SpA (see Figure 4) was similar to that for axial SpA. Two sets of cadidate criteria were formulated based o cliical reasoig ad the tested i 35 paper patiets, adjusted ad validated. Patiets without back pai ad with peripheral maifestatios that usually bega before the age of 45 years, but without a established diagosis, were icluded. Two hudred ad sixty six patiets from 4 ceters were recruited. Agai, i a effort to miimize selectio bias patiets were erolled i a strictly cosecutive maer, ad agai cliical diagosis (SpA or o SpA) by a ASAS rheumatologist was used as the gold stadard. A fial set of criteria showig the best balace of sesitivity (77.8%) ad specificity (8.9%) was decided upo. It cosists of peripheral arthritis (usually lower limb predomiat ad asymmetric) ad/or ethesitis ad/or dactylitis) plus additioal features. These additioal features may iclude oe or more of the followig: psoriasis, iflammatory bowel disease, precedig ifectio, HLA-B7, uveitis ad sacroiliitis o imagig. Alteratively, they may iclude two or more of the followig: arthritis, ethesitis, dactylitis, history of previous IBP ad family history of SpA [7]. These ew criteria, aki to the criteria for axial SpA, performed better tha versios of the Amor ad ESSG criteria (which were modified to iclude MRI fidigs), particularly i terms of sesitivity [7]. Additioally, a combiatio of the ew criteria for axial ad peripheral SpA was compared to the modified versios of the Amor ad ESSG criteria i the etire ASAS populatio of 975 patiets. The balace of sesitivity ad specificity of the combied ew criteria was foud to be superior to both of the older criteria sets. These figures for the combied ew criteria were sesitivity of 79.5% ad specificity of 83.3%, compared with 79. ad 68.8%, respectively for the modified ESSG criteria, ad 67.5 ad 86.7%, respectively, for the modified Amor criteria [7]. Promises & pitfalls of the ew peripheral SpA criteria The criteria for peripheral SpA call for a reorgaizatio of iter-related diseases ito groups based o cliical maifestatios rather tha uderlyig idividual disease etities (see Figure 5 ). To some experts, referred to as lumpers, this is appropriate because they cosider differet SpA etities as variable expressio of the major features of the same disease. Uifyig future sciece group features ivoked i support of this approach iclude associatio with HLA-B7, commo groud i therapies employed ad potetially shared pathogeic mechaisms. A geetic lik is suggested by fidigs that iclude a higher frequecy of psoriasis i patiets with Croh s disease tha i cotrols [8]. It is hoped that the ew criteria will allow for cliical trials to examie diagostic ad therapeutic itervetios i a defied cliical s ubgroup, regardless of the uderlyig etiology []. Oe of the advatages of the ew peripheral criteria is the iclusio of mooarthritis ad polyarthritis i additio to oligoarthritis, leadig to icreased sesitivity of the criteria. Aother advatage is that fewer cliical features are required to fulfill the ew criteria. A otable distictio betwee these ad the ESSG criteria is that ethesitis ad dactylitis are icluded as etry criteria alog with arthritis, so a patiet who presets with ethesitis ad/or dactylitis but without arthritis could be classified. The additio of HLA-B7 is also cosidered a advatage, sice all spodyloarthritides share associatio with this gee [9]. O the other had, splitters assert that differeces betwee the idividual disease etities that ca cause peripheral SpA are sigificat eough to warrat separate cosideratio i classificatio criteria. They cite differeces i cliical presetatio, etiology ad geetics that should be recogized. Aother cocer is that i the settig of a trial it may be challegig to iterpret outcome measures that have bee validated i oe subset of SpA but ot others, ad treatmet resposes may be misiterpreted [8]. Emergig data regardig treatmet of idividual etities may also be overlooked by the criteria ad ot addressed i cliical trials. Oe example of this is the recet work supportig combiatio atibiotics i the maagemet of Chlamydia-iduced reactive Arthritis or ethesitis or dactylitis Plus of: Psoriasis Iflammatory bowel disease Precedig ifectio HLA-B7 Uveitis Sacroiliitis o imagig (radiographs or MRI) or Plus of the remaiig: Arthritis Ethesitis Dactylitis Iflammatory back pai i the past Positive family history for SpA Figure 4. Peripheral spodyloarthritis classificatio criteria. SpA: Spodyloarthritis. Data take with permissio from [7]

6 Lipto & Deodhar SpA Split of the uified spodyloarthritides (classificatio of cliical maifestatios) Peripheral Axial Extra-articular Akylosig spodylitis Iter-related diseases lumped together as spodyloarthritides (uified classificatio of idividual diagoses) Psoriatic arthritis Reactive arthritis Arthropathy of iflammatory bowel disease Udifferetiated SpA Juveile SpA Figure 5. Iter-relatioship betwee the ew split of spodyloarthritis accordig to the Assessmet of SpodyloArthritis Iteratioal Society classificatio criteria ad the preset family of disorders. SpA: Spodyloarthritis. Data take with permissio from []. arthritis [30]. Sice the CASPAR criteria for the classificatio of psoriatic arthritis (PsA) already exist, it is ulikely that these ew peripheral SpA criteria would be used i cliical trials desiged specifically o PsA patiets [3]. Aother potetial drawback is the exclusio of patiets with disease iitiatio after the age of 45 years, which is ot ucommo i peripheral SpA. It also remais uclear what degree of spial ivolvemet should allow for classificatio of a patiet with peripheral ivolvemet, ad similarly what degree of peripheral ivolvemet is allowed i classificatio of axial SpA. Oe or both sets of criteria may be fulfilled at differet poits i disease course, ad this could hamper the cosistecy of classificatio i cliical trials []. The same cautios metioed above regardig misuse of classificatio criteria, which have bee validated i a group of patiets, for diagosis i a idividual patiet i iappropriate cliical settigs (i.e., low pretest probability) also apply. Coclusio A major challege obstructig the effective treatmet of SpA has bee delay i diagosis. The ew ASAS classificatio criteria provide promise for icorporatio of data ito meas of improvig ad streamliig cliical trial desig, which will hopefully lead toward earlier diagosis ad iitiatio of proper therapy for idividual patiets. The criteria for axial SpA icorporate the cocept of oradiographic axial SpA ad a role for MRI i evaluatio of SpA. They perform favorably whe compared to the older Amor ad ESSG criteria. The reorgaizatio of peripheral SpA etities proposed by the ew criteria is viewed by some as a advace ad by others as detrimetal. Advaces 680 It. J. Cli. Rheumatol. (0) 7(6) iclude the icreased emphasis o ethesitis ad dactylitis, ad the iclusio of HLA-B7. The decisio to ot distiguish betwee idividual etities may cause cofusio i the iterpretatio of outcome measures ad treatmet resposes, ad may ot iclude available data o specific etities. Cocers that apply to both sets of criteria iclude the potetial misuse as diagostic criteria i idividual patiets with low pretest probability of SpA. Possible overlap ad chage over time betwee degrees of axial ad pe ripheral ivolvemet may also pose challeges. Future perspective Over the comig years work will likely focus o validatig these criteria further ad assessig their value i the settig of cliical trials. Goals for future study iclude further clarifyig the etity of oradiographic axial SpA ad defiig the role for MRI i the diagosis, cliical follow-up ad evaluatig the progosis of axial SpA. Further study ad discussio will also cotiue surroudig what is the most apt scheme for categorizig the various forms of peripheral SpA, ad how much overlap i therapy amog the differet etities should be cosidered appropriate. As cliical trial data emerge ad outcome measures are aalyzed the criteria may require further refiemet. Future work will also address the utility of these criteria whe traslated ito various cliical settigs ad will help address whether they should play a role i diagosis of idividual patiets. Overall, despite some cocers ad potetial limitatios, they represet a importat step forward i the pursuit of effective methods of early diagosis ad of meaigful cliical research i the area of SpA. future sciece group

7 The ew ASAS classificatio criteria for axial & peripheral spodyloarthritis: promises & pitfalls Fiacial & competig iterests disclosure The authors have o relevat affiliatios or fiacial ivolvemet with ay orgaizatio or etity with a fiacial iterest i or fiacial coflict with the subject matter or materials discussed i the mauscript. This icludes employmet, cosultacies, hooraria, stock owership or optios, expert testimoy, grats or patets received or pedig, or royalties. No writig assistace was utilized i the productio of this mauscript. Executive summary Spodyloarthritis Features likig this group of diseases iclude associatio with HLA-B7, peripheral arthritis that is typically asymmetric ad lower limb predomiat, ad possibly iclude sacroiliitis, spodylitis, ethesitis, dactylitis ad iflammatory eye disease. Diagosis, ad hece the implemetatio of proper treatmet, is ofte delayed by years. Radiographic sacroiliitis, historically the corerstoe of diagosis, ca take years betwee 5 ad 0 years from the start of symptoms to develop. New features of the Assessmet of SpodyloArthritis Iteratioal Society axial spodyloarthritis criteria The cocept of oradiographic axial spodyloarthritis. Recogitio of a role of MRI i idetificatio of sacroiliitis. New features of the Assessmet of SpodyloArthritis Iteratioal Society peripheral spodyloarthritis criteria Diseases grouped by cliical features rather tha by idividual disease etities. Iclusio of dactylitis ad ethesitis as etry criteria. Iclusio of mooarthritis ad polyarthritis i additio to oligoarthritis. Coclusio While the ew criteria represet a step forward i may ways, there are some cocers that remai; further study is required to establish their role i spodyloarthritis classificatio ad diagosis i a idividual patiet. These criteria appear to perform well whe compared with older sets of criteria for spodyloarthritis, ad it is hoped that they will be used to ehace the desig of cliical trials. I most cliical settigs, cautio must be exercised whe attemptig to employ classificatio criteria as diagostic tools. Refereces 8 Papers of special ote have bee highlighted as: of iterest va der Lide S, Valkeburg HA, Cats A. Arthritis Rheum. 7(4), (984). 9 Rudwaleit M, Kha MA, Sieper J. The challege of diagosis ad classificatio i early akylosig spodylitis: do we eed ew criteria? Arthritis Rheum. 5(4), (005). Sieper J, Rudwaleit M, Kha MA, Brau J. Cocepts ad epidemiology of spodyloarthritis. Best Prac. Res. Cli. Rheumatol. 0(3), (006). Brau J, Sieper J. Akylosig spodylitis. Lacet 369(9570), (007). 3 Reveille JD, Witter JP, Weisma MA. Prevalece of axial spodyloarthritis i the Uited States: estimates from a cross-sectioal survey. Arthritis Care Res. 64(6), (0). 0 O Shea F, Saloe D, Ima R. The challege of early diagosis i akylosig spodylitis. J. Rheumatol. 34, 5 7 (007). 5 Feldtkeller E, Kha MA, va der Heijde D, va der Lide S, Brau J. Age at disease oset ad diagosis delay i HLA-B7 egative vs. positive patiets with akylosig spodylitis. Rheumatol. It. 3(), 6 66 (98). 6 Mau W, Zeidler H, Mau R et al. Cliical features ad progosis of patiets with possible akylosig spodylitis. Results of a 0-year follow-up. J. Rheumatol. 5, 09 4 (998). 4 7 Kha MA. Update o spodyloarthropathies. A. Iter. Med. 36, (00). future sciece group 3 SpodyloArthritis iteratioal Society classificatio criteria for axial spodyloarthritis (part I): classificatio of paper patiets by expert opiio icludig ucertaity appraisal. A. Rheum. Dis. 68, (009). 4 Rudwaleit M, va der Heijde D, Ladewé R et al. The developmet of assessmet of SpodyloArthritis Iteratioal Society classificatio criteria for axial spodyloarthritis (part II): validatio ad fial selectio. A. Rheum. Dis. 68, (009). 5 Rudwaleit M. New approaches to diagosis ad classificatio of axial ad peripheral spodyloarthritis. Curr. Opi. Rheumatol., (00). Discusses limitatios of older criteria; proposes developmet of ew criteria. Dougados M, va der Lide S, Juhli R et al. The Europea spodyloarthropathy study group prelimiary criteria for the classificatio of spodyloarthropathy. Arthritis Rheum. 34(), 8 7 (99). Amor B, Dougados M, Mijiyawa M. Criteria of the classificatio of spodyloarthropathies. Rev. Rhum. Mal. Osteoartic. 57, (990). Zeidler H, Amor B. The Assessmet i Spodyloarthritis Iteratioal Society (ASAS) classificatio criteria for peripheral arthritis ad for spodyloarthritis i geeral: the spodyloarthritis cocept i progress. A. Rheum. Dis. 70(), 3 (0). Cocise review of the history ad curret state of spodyloarthropathy classificatio ad helpful discussio of the ew criteria. Rudwaleit M, Ladewé R, va der Heijde D et al. The developmet of assessmet of Compares the performace of the ew criteria to older criteria. Colbert RA. Early axial spodyloarthritis. Curr. Opi. Rheumatol., (00). Summarizes the uderstadig of oradiographic axial spodyloarthritis. Rudwaleit M, Haibel H, Baraliakos X et al. The early disease stage i axial spodyloarthritis: results from the Germa Spodyloarthritis iceptio cohort. Arthritis Rheum. 60(3), (009). 68

8 Lipto & Deodhar Prospective study of disease course of patiets i the GESPIC cohort. Foud that the disease burde of spodyloarthritis is similar to that of akylosig spodylitis, suggestig that they are part of the same disease spectrum. 8 Grigorya M, Roemer FW, Mohr A, Geat HK. Imagig i spodyloarthropathies. Curr. Rheumatol. Reports 6, 0 09 (004). 9 Oostvee J, Revo R, de Boer J, va de Laar. Early detectio of sacroiliitis o magetic resoace imagig ad subsequet developmet of sacroiliitis o plai radiography: a prospective logitudial study. J. Rheumatol. 6, (999). 0 Demostrates that MRI ca be employed to idetify sacroiliitis earlier tha plai radiography. Beett AN, McGoagle D, O Coor P et al. Severity of baselie magetic resoace imagig evidece sacroiliitis ad HLA-B7 status i early iflammatory back pai predict radiographically evidet akylosig spodylitis at eight years. Arthritis Rheum. 58(), (008). Rudwaleit M, Jurik AG, Herma KG et al. Defiig active sacroiliitis o magetic resoace imagig (MRI) for classificatio of axial spodyloarthritis: a cosesual approach by the ASAS/OMERACT MRI group. A. Rheum. Dis. 68, (009) Aydi SZ, Maksymowych WP, Beett AN, McGoagle D, Emery P, Marzo-Ortega H. Validatio of the ASAS criteria ad defiitio of a positive MRI of the sacroiliac joit i a iceptio cohort of axial spodyloarthritis followed up for 8 years. A. Rheum. Dis. 7, (0). Beett AN, Marzo-Ortega H, Emery P, McGoagle D; Leeds Spodyloarthropathy Group. Diagosig axial spodyloarthropathy. The ew assessmet i Spodyloarthritis Iteratioal Society criteria: MRI eterig cetre stage. A. Rheum. Dis. 68(6), (009). Helpful discussio of the icreasig role of MRI ad the sigificace of its iclusio i the ew criteria. Barkam N, Kee H, Coates LC et al. A radomized cotrolled trial of ifliximab shows cliical ad MRI efficacy i patiets with HLA-B7 positive very early akylosig spodylitis. Arthritis Rheum. 56(Suppl.), L (007). Haibel H, Rudwaleit M, Listig J et al. Efficacy of adalimumab i the treatmet of axial spodyloarthritis without radiographically defied sacroiliitis: results of a twelve-week radomized, double-blid, placebo-cotrolled trial followed by a ope-label extesio up to week fifty-two. Arthritis Rheum. 58, (008). It. J. Cli. Rheumatol. (0) 7(6) 6 Huder GG. The use ad misuse of classificatio ad diagostic criteria for complex diseases. A. Iter. Med. 9(5), (998). Clarifies the differece betwee classificatio ad diagostic criteria. 7 Rudwaleit M, va der Heijde D, Ladewé R et al. The assessmet of SpodyloArthritis Iteratioal Society classificatio criteria for peripheral spodyloarthritis ad for spodyloarthritis i geeral. A. Rheum. Dis. 70(), 5 3 (0). 8 Nash P, Mease PJ, Brau J, va der Heijde D. Seroegative spodyloarthropathies: to lump or split? A. Rheum. Dis. 64(Suppl. II), ii9 ii3 (005). Explores the argumets for lumpig ad for splittig. 9 Castillo-Gallego C, Aydi SZ, Marzo-Ortega H. Cliical utility of the ew ASAS criteria for spodyloarthritis ad the disease activity score. Curr. Rheumatol. Reports 3, (0). 30 Carter JD, Espioza LR, Ima RD et al. Combiatio atibiotics as a treatmet for chroic Chlamydia-iduced reactive arthritis. Arthritis Rheum. 6(5), (00). 3 Taylor W, Gladma D, Helliwell P et al. Classificatio criteria for psoriatic arthritis: developmet of ew criteria from a large iteratioal study. Arthritis Rheum. 54(8), (006). future sciece group