PSORIATIC ARTHRITIS (O FITZGERALD AND P HELLIWELL, SECTION EDITORS)

Classification Criteria: Peripheral Spondyloarthropathyand Psoriatic Arthritis

William J. Taylor & Philip C. Robinson

Published online: 23 February 2013# Springer Science+Business Media New York 2013

Abstract Recent proposals for re-classification ofspondyloarthropathies according to the predominance of pe-ripheral and axial manifestations and for non-radiographicankylosing spondylitis to be re-named axial spondyloarthritisare reviewed. It is argued that such proposals are less likely toadvance knowledge in the study of spondyloarthopathies andthat accurate classification criteria for defined diseases, forexample psoriatic arthritis, remain as necessary now as theyever did. The CASPAR criteria remain the best performingclassification criteria for psoriatic arthritis.

Keywords Psoriatic arthritis . Spondyloarthritis .

Classification criteria . Peripheral spondyloarthropathy

Introduction

Disease nosology, terminology, and classification are evolvingprocesses, greatly dependent upon ever-better understandingof pathology and aetiology. Such changes often occur becauseof advances in technology that result in novel perspectives andnew data. Recently, a significant shift in the understanding ofankylosing spondylitis (AS) has been facilitated by the use ofmagnetic resonance imaging (MRI), which has enabled thepossibility of detecting objective changes of sacroiliitis andspondylitis before such changes are visible on conventionalradiography.

Non-radiographic ankylosing spondylitis is not exactly anovel concept, because it is well-recognised that symptomsattributable to the disease can be present for many yearsbefore radiographic changes. Yet the requirements of themodified New York (mNY) classification criteria for AS[1], which include radiographic changes, meant that clinicalresearch into this disease was largely limited to patients withradiographic disease. Therefore, what we knew about ASwas mainly confined to this group of patients. One questionwhich arises, then, is whether non-radiographic AS is adifferent disease or the same disease at an earlier point inits natural history. We shall review evidence that seems tosupport both positions and ultimately argue that clarificationcan only come with more, rather than less, precision in theclassification of these disorders.

The Assessment of SpondyloArthritis International Society(ASAS) formally known as the Assessments in AnkylosingSpondylitis working group, has developed new classificationcriteria that go beyond the need for radiographic sacroiliitisand have suggested the term “axial spondyloarthritis”(axSpA) to designate the disease identified by these classifi-cation criteria [2]. Because spondyloarthropathies do not al-ways involve the spine, a complementary approach was alsotaken to define “peripheral spondyloarthritis” (pSpA) [3••].This paper reviews the logical basis and the implications ofthese new classification criteria, with particular reference topsoriatic arthritis (PsA). We argue that these classificationcriteria actually have the potential to obscure advances inknowledge and suggest that there are more advantages intrying to distinguish particular diseases than there are in tryingto amalgamate diseases into a single disorder.

A Question of Perspective

The degree to which granularity is useful is highly depen-dent on the purpose of the observer. From the moon, theearth is a unitary body, with only land and water apparently

This article is part of the Topical Collection on Psoriatic Arthritis

W. J. Taylor (*)Department of Medicine, University of Otago Wellington,Mein Street, Wellington, New Zealande-mail: will.taylor@otago.ac.nz

P. C. RobinsonUniversity of Queensland Diamantina Institute,Princess Alexandra Hospital, Ipswich Road, Woolloogabba,Queensland 4102, Australiae-mail: philip.robinson@uq.edu.au

Curr Rheumatol Rep (2013) 15:317DOI 10.1007/s11926-013-0317-3

separable. To distinguish the earth from other objects inspace it does not help the observer on the moon to knowthat there are many distinguishable countries on earth. Formany years, it was sufficient to only be able to identify“arthritis” to recommend treatment, whereas in the modernera, distinguishing between different diseases that presentwith arthritis is crucial for correct therapy.

So we need to understand the purpose of the concept ofSpA. Moll andWright originally introduced the term seroneg-ative polyarthritis or seronegative spondarthritis to emphasizethe profound differences between a set of conditions andrheumatoid arthritis [4]. The important diseases that formedthe SpA group were AS, psoriatic arthritis (PsA), reactivearthritis (ReA), and enteropathic arthritis associated with in-flammatory bowel disease (EnA) [5]. Later, cases of patientswith features consistent with SpA but without manifestationsthat would enable classification into one of these defineddisease groups were identified as “undifferentiated SpA” [6].

Classification criteria for the SpA group as a wholewere first proposed by Amor [7] and the EuropeanSpondyloarthropathy Study Group (ESSG) [8]. Theseenabled study of individuals who did not fulfil classifi-cation criteria for more definable SpA, for example themNY criteria for AS. One such study, of 102 patientsdiagnosed by Spanish rheumatologists as having “possibleSpA” showed that 49 % met the Amor criteria for SpA and70 % met the ESSG criteria [9]. Half of these patients werefollowed for five years and most (29/52) were eventuallydiagnosed with a different condition. Only 6/52 patientsmet Amor’s or the ESSG criteria at baseline and at fiveyears but did not have a more specific SpA; these weredesignated as undifferentiated SpA (uSpA). Thus, for mostpatients with possible SpA the disease evolved into somethingelse or into a more definable SpA and only 11 % remainedundifferentiated. This suggests that “undifferentiated SpA” isunlikely to be a distinct disease and more likely to be an earlierphase of a more defined condition. Another cohort study ofpatients with peripheral arthritis as their main manifestationsuggested that patients with PsA had a worse clinical outcomeover two years than those with ReA, and that patients withuSpA had a somewhat intermediate outcome [10]. The crucialusefulness of the SpA concept is probably recognition ofpatients who are seen at an early stage, who have not yetexpressed the complete phenotype, to signal the need forongoing monitoring of the patient and possible appropriateintervention.

Classification Criteria

The purpose of classification criteria is to identity a relative-ly (depending upon purpose) homogenous group of patients(usually) for clinical research purposes [8]. In rheumatic

diseases, it is rare that a pathological gold-standard for diagno-sis exists; this is both the reason for classification criteria andalso the major problem with classification criteria. Generally,classification criteria are developed in order to mimic as closelyas possible a “gold-standard” diagnostic test for the condition itis supposed to identify. That is, the existence of the condition ispre-supposed, a gold-standard diagnostic procedure exists, andsteps are taken to derive criteria to classify cases with knownerror in comparison with the gold-standard procedure. In manyrheumatic diseases, the physician’s opinion is taken to be thediagnostic gold-standard. Classification criteria cannot be usedto justify the existence of a condition, because this is entirelycircular reasoning. In the case of classification criteria foraxSpA and pSpA, the external-standard against which thecriteria were developed were not axSpA or pSpA, but SpA inthe judgment of the clinical rheumatologist. The label of axialor peripheral was applied only by virtue of the entry criteria forthe derivation study—pSpA patients had to have peripheralmanifestations without chronic back pain that commences be-fore age 45 years; axSpA patients had to have chronic backpain that started before the age of 45 years [2]. This actuallymeans that the criteria identify SpA in people (by definition)with or without back pain, respectively, but do not necessarilyidentify the conditions of axSpA or pSpA. There is littleevidence that rheumatologists in ordinary clinical practice di-agnosed the conditions of axSpA or pSpA before the introduc-tion of the classification criteria that define them. This is puttingthe cart before the horse.

Spondyloarthritis Classification Criteria

If one examines SpA classification sets with the precedingcontext in mind one can consider the value of classificationcriteria which are intended to cover the whole concept ofSpA. There are two well-established general sets of SpAcriteria, the Amor and the European SpondylarthropathyStudy Group (ESSG) criteria and the more recently pro-posed Assessment of Spondyloarthritis International Society(ASAS) criteria for axSpA and pSpA which, when com-bined, resemble the Amor and ESSG criteria in that theyattempt to capture the entire range of SpA [2, 3••, 7, 11].

The Amor Criteria and the ESSG Criteria

The Amor and ESSG criteria were developed to enableclassification of SpA which did not meet sets of criteria forindividual phenotypes and specifically classified uSpA [7,11]. There was recognition that some patients did not meetclassification criteria for specific diseases but clearly hadfeatures that resembled the SpA typology.

The Amor criteria were developed from 1,219 SpA pa-tients and 157 other rheumatic disease controls [11]. The

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gold-standard used was clinician judgment of SpA. The setof criteria has no entry restrictions but requires a cumulativescore of six based on 12 differently weighted itemsencompassing clinical items, pelvic radiographs, humanleucocyte antigen (HLA)-B27, and/or family history andresponse to non-steroidal anti-inflammatory drugs. Thecriteria, when tested on a prospective group, were found tohave sensitivity of 90.0 % and specificity of 86.6 %.

The ESSG criteria study recruited 403 SpA patients and674 control rheumatology patients and used as their gold-standard clinician judgment of SpA [7]. The entry criteriaare either inflammatory spinal pain or synovitis (asymmetricor predominantly in the lower limbs). These two entrycriteria cover the two major manifestations of axial andperipheral SpA respectively and the patient, in addition,requires one more SpA feature from a list of seven whichincludes psoriasis, inflammatory bowel disease, andenthesopathy. They noted that adding HLA-B27 did notchange the performance of their set of criteria, and, there-fore, this was not included. This gave sensitivity of 78.4 %and specificity of 89.6 %. Both the Amor and the ESSGcriteria have also been modified to include MRI, a modifi-cation which substantially improves sensitivity [2, 3••].

The ASAS SpA Sets of Criteria

The ASAS group has proposed separate sets of criteria foraxSpA and pSpA. These were developed initially by clinicalreasoning and then modified on the basis of the study results[2, 3••, 12]. The developers stated they wanted to comparethe new sets with the established Amor and ESSG classifi-cation. When tested with the ASAS patient set the axSpA sethas sensitivity of 82.9 % and specificity of 84.4 %. ThepSpA set has sensitivity of 77.8 % and specificity of 82.2 %.When combined as a set of criteria to classify all SpA theyhave sensitivity of 79.5 % and specificity of 83.3 %.

Issues with the SpA Criteria Construction

There has been much discussion about issues related to sets ofSpA criteria [8, 13•, 14, 15]. Some of these issues relate toweaknesses of particular sets of criteria, but there are generalissues also; SpA is a heterogeneous disease with significantchallenges to the development of appropriate criteria.

Use of criteria with no or broad requirements enableclassification of patients without symptoms or evidence ofjoint pathology. This could be regarded as indicating lack ofvalidity, although this depends somewhat on the observers’perspective of the disease construct used. For example,using the ESSG criteria, a patient with iritis, psoriasis, andHLA-B27 can be classified as ESSG SpA, whereas theASAS pSpA criteria are satisfied by enthesitis and HLA-B27. Therefore the population prevalence of HLA-B27 can

affect the proportion classifiable by use of the criteria, asdemonstrated by Bakland and colleagues in Norway, wherethe prevalence of HLA-B27 is 16 % [16•]. This issue is notrestricted to peripheral SpA, because the axSpA criteria alsoenable classification without objective evidence of disease[12].

The ESSG criteria were developed with few assumptionsof which items would be important for classification where-as the ASAS pSpA criteria were developed from pre-specified sets of items. These sets were then modified onthe basis of the results of the study. Development of criteriaitems primarily on the basis of their sensitivity and specific-ity seems an inherently more robust method of constructingcriteria, which are then modified to be feasible in practice.Otherwise pre-existing ideas about what is important forclassification may excessively affect the outcome of thederivation study.

General Concerns about SpA Classification Criteria

There are issues inherent to SpA that make the construction ofclassification criteria challenging. The foremost is the lack ofthe biological understanding of SpA. For example, we knowthe phenotypes of SpA are related and can even change fromone to another, but how related are they? What is the basis fortheir shared relationship? Is SpA one disease with differentmanifestations, or are SpA more distinct diseases with pheno-typic overlap, phenocopies of a type [17••]? Because of thisproblem, in all sets criteria clinician judgment is the gold-standard. This judgment is affected by the clinician’s under-standing of the essence of SpA, which is likely to vary amongclinicians, one reason why classification criteria are necessaryfor clinical studies in the first place. However it doesmean thatthe same criteria can have variable sensitivity and specificitydepending on the cohort tested. The sensitivity and specificityof the Amor and ESSG criteria were good when the criteriawere tested on their development cohort (Table 1) but whenthese two sets of criteria were applied to the ASAS pSpAcohort their sensitivity and specificity decreased (Table 2).What is this telling us? Although it is logically inevitable thatcriteria are more accurate for the cohort from which they werederived, it also seems likely that the patient cohorts are some-how different. This could result from different study designsor different populations fromwhich the cohorts were sampled.But, in fact, the studies were designed similarly and patientswere recruited from secondary care rheumatology clinics. Onepossible difference, very difficult to confirm, might be differ-ent allocation of the gold-standard, directly affected by theconcept with the disease of the clinician making the diagnosis.Seemingly the only way to make progress on this issue is toimprove our understanding of the biology of SpA. Suchunderstanding is more likely to progress with more rather thanfewer precisely defined disease categories.

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Construction of criteria for an entity such as SpA ischallenging because it is an heterogeneous disorder, andtherefore sets of criteria introduced with the purpose ofincluding “all” SpA will end up including a very heteroge-neous group [18], whereas including only one of the phe-notypic entities that is more homogenous, for example ASor PsA, as with the modified New York or CASPAR criteria,will lead to a more homogenous group [1, 19]. The approachchosen (either broadly inclusive or sub-type specific) willdepend on the intended purpose of the criteria. If one wishesto study biological phenomena, for example immune cells orgenes, then a very homogenous patient set defined by moreprecise criteria is desirable. But if one wants to include alarge heterogeneous group for epidemiological purposes orto test the effect of a drug across broader categories ofdisorders, then a more inclusive set of criteria may be moreappropriate. It is possible that the use of broad inclusivecriteria will enable the description of prognostic factorswhich differentiate divergent outcomes. Nevertheless allcriteria must be properly constructed and tested in practicebefore their usefulness can be determined.

Peripheral SpA and axial SpA

The only logical reason for the concept of pSpA is theconcept of axSpA. It is therefore necessary to review infurther detail the basis for axSpA and how this relates toexisting concepts of the diseases regarded as SpA. Onepossible concept of SpA is shown in Fig. 1a, in which eachcircle represents a clearly recognisable disease and that thesediseases overlap, to illustrate that some patients may seem to

have more than one disease. In fact, it is more plausible thatsuch overlap patients have a single disease which has fea-tures of more than one disorder. For example, patients withPsA and AS could be labelled with either disease but havefeatures of each. There could be an argument that particularradiographic, genetic or clinical features might help distin-guish such overlapping cases [20], but the essential point isthat a specific diagnosis is possible and that a broad termsuch as axSpA is actually not necessary for such patients.

In this concept, radiographic AS is regarded as a subset ofAS, because, clearly, patients with AS do not have radiograph-ic changes at the earliest moment of the disease. Such casesmay now be recognised by characteristic MRI abnormalities.However, the question which arises is whether such cases arenecessarily destined to become radiographic AS or whetherthey will always remain non-radiographic, in which caseshould they really be regarded as having AS? There are datato suggest that only 60% of patients developmNYAS after tenyears of observation [21, 22]. There are, therefore, cases of“undifferentiated SpA” that appear similar to nr-axSpA but donot evolve into radiographic (mNY)AS. Such a situation couldbe imagined in Fig. 1b.

Here, the complete range of SpA is bounded by therectangle but includes cases that are “undifferentiated”. Inaddition, the concepts of peripheral and axSpA are intro-duced as mutually exclusive types of SpA that together formthe complete range of SpA. Here axSpA encompasses all ofthese disorders: radiographic AS, non-radiographic AS, anddisorders that have axial manifestations but are never des-tined to be AS; this last category we have already specifiedas “undifferentiated SpA”. It is difficult to distinguish whatelse axSpA could be. Because understood terms are already

Table 1 Characteristics of SpA classification criteria based on the patient cohort used to construct and/or validate the criteria

Criteria Controls Sensitivity (%) Specificity (%) Ref.

Amor Other rheumatic diseases 90.0 86.6 [11]

ESSG Other rheumatic diseases 87.0 87.7 [7]

ASAS axSpA Other rheumatic diseases 82.9 84.4 [12]

ASAS pSpA Other rheumatic diseases 77.8 82.2 [3••]

ASAS SpA Other rheumatic diseases 79.5 83.3 [3••]

ESSG European Spondylarthropathy Study Group; ASAS Assessment of SpondyloArthritis International Society

Table 2 Characteristics of the overall and peripheral SpA classification criteria in the ASAS pSpA patient set only

Criteria Controls Sensitivity (%) Specificity (%) Ref.

Amor criteria Other rheumatic diseases 55.6 86.7 [3••]

Modified Amor criteria (with MRI) Other rheumatic diseases 67.5 86.7 [3••]

ESSG criteria Other rheumatic diseases 66.7 72.0 [3••]

Modified ESSG criteria (with MRI) Other rheumatic diseases 79.1 68.8 [3••]

ASAS pSpA criteria Other rheumatic diseases 77.8 82.2 [3••]

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available for describing the constituents of axSpA, is therereally any advantage in introducing this new term? Further-more, we have seen above that persistent “undifferentiatedSpA” is actually uncommon, suggesting that the condition ismore likely to be an earlier phase of a more definable disease.This leaves AS, for which there is a much clearer phenotypeand understanding. There is a definite disadvantage in com-bining the three conditions under a single name—it is impos-sible to study whether, or the extent to which, non-radiographic AS or undifferentiated SpA evolves into radio-graphic AS or other disorders unless each condition is prop-erly classified and defined.

There is the possibility that the 10 % of cases ofundifferentiated SpA that remain undifferentiated is actuallya disease distinct from AS. It is also necessary to considerwhether axSpA is a useful label to apply to those instances ofother (non-AS) SpA that happen to have axial involvementand therefore fulfil axSpA criteria. If cases of (persistent)undifferentiated SpA with axial involvement, AS, and otherdefinable cases of SpA (reactive arthritis, psoriatic arthritis,enteropathic arthritis) with axial involvement are all classifiedas axSpA, it prevents sensible study of these different disor-ders (even in order to show that they are or are not different).

At a pragmatic level, the currently constructed classifica-tion criteria for axSpA may have insufficient specificity for

the purpose of enrolment into clinical trials. With specificityof approximately 80 %, there may be issues with the includ-ed population, as was seen in the ABILITY-1 trial, namelylack of efficacy for those with normal CRP and negativeMRI. This group did no better than placebo [12, 23•, 24].The European Medicines Agency (EMA) has approvedadalimumab for axSpA only for those with a raised CRPor positive MRI findings [25]. Such patients may be morelikely to have “true” pre-radiographic AS, again raising thepossibility that axSpA is merely describing AS at a milder orearlier phase.

There are additional practical problems. It is specified thatpatients with inflammatory-type back pain should be classi-fied as axSpA, even if they also have peripheral disease. AsZeidler and Amor point out, it is not clear how to handle casesfor whom spinal symptoms change over time, leading toinconsistent classification in longitudinal studies [26].

The overall conclusion is that classification of patients asaxSpA is not a useful concept.

Psoriatic Arthritis and pSpA or axSpA

Psoriatic arthritis may involve peripheral joints and/oraxial joints. Asymptomatic radiographic sacroiliitis iscommon in psoriatic arthritis patients who were identifiedby virtue of active peripheral arthritis [27]. Thus, psoriaticarthritis cannot be easily classified as either axSpA or pSpA,but may fit into either group. Is it prudent that the disease becompletely re-defined on the basis of whether spinal symp-toms predominate?

Notwithstanding the problems of the classification criteriadiscussed above, the performance of the pSpA criteria andCASPAR criteria were directly compared in an early arthritiscohort [28••]. This showed that the CASPAR criteria [19] aremuch more sensitive for detecting PsA (88.7 %) than theASAS pSpA criteria (52 %) but are very poor at detectingSpA in general (sensitivity 5.3 %). This is not surprising,because CASPAR was never designed for that purpose. Buteven the ASAS pSpA criteria have unsatisfactory sensitivityfor early SpA (48.7 %) as do the ESSG and Amor criteria forSpA (sensitivity of 48.7 % and 26.3 %, respectively). Overall,this study supports the ongoing use of CASPAR when theintention is to identify psoriatic arthritis, but it leaves thequestion of how to identify early SpA still unanswered.

Conclusions

Advances in classification criteria will come from an itera-tive process of proposing new sets of criteria and testingthem in real situations, and from advances in our knowledgeof how these diseases interrelate. For most purposes, the

Fig. 1 Possible concepts of SpA

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advantages of the new ASAS pSpA and axSpA criteria areoutweighed by their disadvantages.

Acknowledgements This work was supported by the facilities of theUniversity of Otago and University of Queensland. Dr Taylor is amember of GRAPPA; Dr Robinson is an associate member of ASAS.

Conflict of Interest Dr Taylor has consulted for Metabolex.Dr Robinson declares that he has no conflict of interest.

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