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8 Measures of outcome in ankylosing spondylitis and other spondyloarthritides
8 Measures of outcome in ankylosing spondylitis and other spondyloarthritides D. M. F. M. van der Heijde MD, PhD Associate Professor of Rheumatology
Sj. van der Linden MD, PhD Professor of Rheumatology
Department of Internal Medicine, Division of Rheumatology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands
This chapter describes core sets that can be used in the assessment of ankylosing spondylitis and other spondyloarthritides. Various core sets are described for the evaluation of disease-controlling antirheumatic therapy, symptom-modifying antirheumatic drugs and physical therapy, or for use in clinical record keeping. These core sets describe domains and also give advice on specific instruments. The value of spinal mobility and acute-phase reactants in the assessment of ankylosing spondylitis in AS are described in more detail. The available radiological scoring methods are discussed.
Key words: core set; outcome; ankylosing spondylitis; psoriatic arthritis; reactive arthritis; spondyloarthritis; spondyloarthropathy; acute-phase reactants; ESR; CRP; spinal mobility; radiological scoring methods.
Outcome is a general term, often opposed by the term 'process'. However, various definitions for outcome are in use. 'Outcome' can be seen as the final result of the disease, where 'process' stands for what is happening along the way. Radiographic damage is seen by many as a measure of outcome. However, if Fries' definition for outcome: 'the suffering or loss of health experienced by an individual as a result of the process of the disease' is used, radiographic damage would be no measure of outcome (Fries, 1983). A more neutral term is 'endpoint'; it is especially feasible to use this term in the context of a clinical trial. However, in this chapter the terms outcome and endpoint will be used interchangeably. Measures of outcome can be classified in various groups depending on the point of interest: (1) disease activity versus structural damage, (2) patient versus physician-oriented, (3) specific versus general, (4) for use in the evaluation of disease controlling anti-rheumatic therapy (DC-ART), Bailli#re's Clinical Rheumatology-Vol. 12, No. 4, November 1998 ISBN 0-7020-2464-3 0950-3579/98/040683 + 11 $12.00/00
683 Copyright © 1998, by Bailliere Tindall All rights of reproduction in any form reserved
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symptom-modifying anti-rheumatic drugs (SMARD), physical therapy or in clinical practice, (5) measuring various aspects of outcome according to underlying constructs such as the five Ds" death, disability, discomfort, (drug) toxicity, (dollar) costs. Of course there is overlap, and there are cross-links between these categories (Fries et al, 1982; Edmonds et al, 1993; van der Heijde et al, 1997). A good evaluation of the overlap of categories (2) and (3) has been described by Bakker et al (1993). For the purpose of this chapter we will focus mainly on categories (1) and (4). Some measures of outcome assess disease activity (i.e. morning stiffness), others structural damage (i.e. radiographic changes) and others a combination of both (i.e. functional disability). The decision to use measures of outcome for various settings was made first by the international ASsessments in Ankylosing Spondylitis (ASAS) working group (van der Heijde et al, 1997). The focus of this chapter will be on ankylosing spondylitis (AS) and only a brief overview will be given for other types of spondyloarthritides (SPA). Within AS a distinction should be made between patients with axial involvement only and those with extraspinal involvement such as peripheral arthritis, inflammatory bowel disease (IBD) or uveitis. With this concept as a starting point, the group of SpA could be considered as one group with various ways of presentation. For example, for the subgroup of psoriatic arthritis (PsA) patients with peripheral arthritis the measures of outcome for extraspinal AS could be applied, and for the group of PsA patients with axial involvement only the measures of outcome for spinal AS could be applied.
Available measures of outcome for AS in the literature
Over 100 assessments of outcome for use in AS were described in the literature up to 1995 (Bakker et al, 1993; van der fIeijde et al, 1997). Therefore, there is a need to reduce the number of assessments to be actually used in AS and to agree upon a common well accepted core set of endpoints. An overview of the lack of standardization was described earlier (van der Linden and van der Heijde, 1995). There are several reasons as to why a core set is really needed. First, (too) many variables are included in research projects, and this leads to statistically significant differences between groups by chance alone. Moreover, investigators may choose to publish selectively only those variables that show the most impressive results. In addition, variables that have proven to be insensitive to change are still being used. Because every investigator may select from a large range of available measures, comparisons between various studies are very hard. This also makes the performance of a meta-analysis very difficult if not impossible. Another problem is that measures are not standardized. Many ways exist to assess spinal mobility, and even if everyone selects the Schober index, as an example, there are several ways to perform this test.
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How to select a core set of measures?
A core set is defined as the minimum set of variables which should be included in each study (Boers et al, 1994). There are three main ways of selecting a group of measures of outcome to be included in a core set: by a consensus procedure by experts, and on statistical grounds, or a combination of these two. In fact, purely on statistical grounds is not possible: only those instruments that have been used in studies can be used for the statistical analyses. Selection of the instruments is therefore an important step which is usually done by consensus procedures by the investigators. This selection should be done because it is not feasible to include a large number of assessments in one study, not even if this study was especially designed to evaluate the various instruments. A sensible way to reduce the number of available measures to a more comprehensive group is by combining instruments into domains. These domains are intended to measure the same underlying concept such as 'spinal mobility' or 'functional capacity'. After selecting the domains which should be included in the core set, a selection of specific measures can be made. An example of both approaches (consensus and statistical) will be discussed below. Consensus approach: selection of a core set of domains by ASAS
In 1995 the ASAS working group was formed (van der Heijde et al, 1997). Participants from 21 countries in Europe, North and South America, Asia and Australia took part in this initiative. The group comprised experts in the field of AS, (clinical) epidemiologists, representatives of the pharmaceutical industry and AS patients. The group decided to define core sets for three different settings: (1) for the evaluation of DC-ART, (2) for the evaluation of SMARD and physical therapy, and (3) for use in clinical record keeping. By nominal group discussions and plenary sessions during several workshops, domains for each of these three settings were selected (Table 1) (van der Heijde et al, 1997). During later steps a selection of specific variables was Table 1. Core set for studies on DC-ART, SM-ARD/physical therapy, and for clinical record keeping endorsed by ASAS, OMERACT and ILAR (van der Heijde et al, 1997). DC-ART
SM-ARD/physical therapy
Clinical record keeping
Physical function Pain Spinal mobility Spinal stiffness* Patient global assessment Peripheral joints/entheses Acute phase reactants (AUC)* Spine radiograph Hip radiograph* Fatigue*
Physical function Pain Spinal mobility Spinal stiffness Patient global assessment
Physical function Pain Spinal mobility Spinal stiffness Patient global assessment Peripheral joints/entheses Acute-phase reactants
AUC = area under the curve, acute-phase reactants assessed as a cumulative measure over time. * Domains not definitely included in the core set but have been put on the research agenda.
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made based on aspects of feasibility (is this instrument achievable in this particular setting?) and relevance (is this instrument relevant to answer the study question in the particular setting in which the measurement is to be done?). The preliminary selection of specific variables for DC-ART is presented in Table 2. Further research needs to be done on aspects of truth (is the measure truthful, does it measure what is intended, is the result unbiased?) and discrimination (does the measure discriminate between situations of interest?) (Boers et al, 1998). The ASAS core sets were endorsed during the OMERACT IV conference (Cancun, 1998). Therefore they are now ASAS/OMERACT/ILAR core sets (van der Heijde et al, in press, b). Table 2. Specific instruments for each domain in core set for DC-ART (van der Heijde et al, in press, b). Domain
Instrument
Function Pain
BASFI or Dougados VAS-last week-spine-at-night-due to AS and VAS-last week-spine-due to AS Chest expansion and modified Schober and occiput to wall VAS-last week Number of swollen joints (44 joint count) AP + Lat Lumbar and Lat Cervical spine andX-pelvis (SI and hips) Duration of morning stiffness-spine-last week ESR See spine
Spinal mobility
Patient global Peripheral joints X-ray spine
Stiffness Acute-phase reactants X-ray hips Fatigue Research agenda
CRP Severity of morning stiffness-spine-last week Scoring method X-rays BASDAI, BASMI and other indices Fatigue, entheses
VAS = visual analogue scale. Example: How was the pain in your spine due to AS on average last week? To be answered on a 100 mm horizontal VAS. S t a t i s t i c a l a p p r o a c h : s e l e c t i o n of a c o r e s e t b y c l u s t e r a n a l y s i s
Another approach was taken by Catin et al (in press). They performed a cluster analysis on the data of 423 patients with axial AS with active disease after a period of stopping NSAIDs. The following assessments were taken into account: patient global assessment (visual analogue scale, VAS), physician global assessment (VAS), pain (VAS), spinal pain, night pain, morning stiffness, CRP, platelet count, haemoglobin, Dougados' functional index (D-FI), Bath Ankylosing Spondylitis Functional Index (BASFI), modified Schober test, finger-to-floor distance, occiput-to-wall distance, chest expansion, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The conclusion from the authors is that at least four domains are relevant to evaluate the symptomatic severity of axial involvement of
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AS: (1) patient's subjective perception (such as pain, global assessment or functional impairment), (2) inflammatory symptoms (such as night pain or morning stiffness), (3) metrology (such as the modified Schober test) and (4) laboratory data (such as platelets). Comparison of these results with those obtained by the consensus procedure from the ASAS group shows remarkable similarities, especially if it is taken into account that peripheral joints and radiographs could not be selected in Dougados' study because they had selected patients with axial involvement only and radiographs were not available for this data set. There is also considerable overlap with the recommendations given by Bellamy in his book on clinical metrology of musculoskeletal diseases (all measures with an asterisk are included in the ASAS core set): (1) pain*, stiffness*; (2) chest expansion*, finger-to-floor distance, limitation of flexion of lumbar spine (Schober test*); (3) patient global assessment*; (4) articular index*, physician global assessment':', occiput-to-wall distance*, quality of sleep (Bellamy, 1993).
Is assessing spinal mobility clinically relevant? This is a difficult question to answer, and the answer might differ in different stages of the disease. It also depends heavily on how the spinal mobility is measured. Posing this question to the ASAS group revealed a large range of answers: 30-87% of the respondents considered a specific assessment of spinal mobility to be a relevant measure. Only 30% of the respondents thought that assessing a modified Schober in three 10 cm segments was relevant, and 33% indicated the same for measuring cervical rotation by a gravity action goniometer. On the other hand, 87% of the respondents considered assessing chest expansion as relevant, and 83% replied so for measuring the modified Schober in a 10 cm segment. So even small changes in the way in which specific measure is assessed (i.e. two modified Schober tests) make a large difference in how relevant this measure is considered to be by experts. Hence, the measure assessing spinal mobility--but also the setting in which this measure is applied--determines the clinical relevance. Especially in trials of short duration, assessing spinal mobility is not very useful because these measures are usually insensitive to change over a limited time frame. In clinical practice, however, this can be an important measure in following patients over longer periods of followup. It provides the opportunity to give advice to correct a wrong posture (i.e. kyphosis). Spinal mobility is a combination of structural damage and disease activity. In trials it can be of great importance to give baseline data on spinal mobility of the population under study to make judgements on the severity of disease of the patients included and to be able to compare the trial patients with your own. The measures provisionally selected by the ASAS group on the basis of feasibility and relevance, combined with the elimination of redundancy, could be used as a guideline. These currently include chest expansion, the modified Schober based on a 10 cm segment, and the occiput-to-wall distance.
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Are biological parameters of any value in the assessment of AS patients? Recently, the literature on the use of ESR and CRP in ankylosing spondylitis was reviewed by Stucki and Ruof (in press). They concluded that acutephase, reactants do not comprehensively represent the disease process in AS, and thus do not have the same validity of content as a measure of disease activity as is the case in rheumatoid arthritis. Levels of ESR and CRP are generally lower than in rheumatoid arthritis and vary only to some degree with changes in disease activity. Many 'active' AS patients have normal or only slightly increased acute-phase reactants not allowing for further improvement. Both measures showed some discriminative power in cross-sectional studies, but currently too few data are available on discrimination during long-term follow-up. Also, not enough data are available to judge the predictive validity of the acute-phase reactants. Comparing both ESR and CRP, neither measure is clearly superior in terms of validity based on the currently existing data. Therefore, when selecting an acute-phase reactant, feasibility aspects might play an important role in the decision as to which one to use. Advantages for ESR are lower costs, easiness to perform, standardized test, promptness of results; advantages for CRP are that sera can be stored and used in a central laboratory. Spoorenberg et al (in press, b) compared the discriminative power of ESR and CRP for dividing patients into groups with high and with low disease activity. This was done in a cross-sectional study of 191 patients with AS. Separate analyses were done for patients with axial involvement only and patients with peripheral joint involvement and/or IBD. Comparing receiver operator curves (ROCs) (curves relating sensitivity [-- true positive] to 1-specificity [= true negative]) provided no clear differences between both acute-phase reactants. The predictive values were low, ranging from 0.15 to 0.69, and, on average, as much as 29% of the patients were misclassified as having high or low disease activity based on the CRP or ESR levels. ESR and CRP levels were higher in AS patients with peripheral joint involvement and/or IBD, but the results of the comparison between ESR and CRP were otherwise similar for these patients and for patients with axial involvement only. During the OMERACT IV meeting in Cancun, 1998, it was recommended that ESR should be used whenever possible and that no further cross-sectional research was needed to compare ESR and CRP (van der Heijde et al, in press, c). However, more research should be done on the predictive value and the discriminative power of ESR in longitudinal studies.
Radiological scoring methods in AS For rheumatoid arthritis, radiographic changes are an important endpoint measure and several validated widely used scoring methods are available
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(van der Heijde, 1996). The situation is quite different for ankylosing spondylitis (Calin, 1996). Radiographic evidence of sacroiliitis is a prerequisite for the classification criteria of AS according to the (modified) New York criteria (van der Linden et al, 1984). However, radiographic changes are not a well established measure of outcome, although it was judged as an important area of outcome (Table 1). Which scoring method is preferable depends heavily on the aim of the study, for example, a study on the natural history of the disease, on prognosis, on the effectiveness of therapy. Several advantages of radiographs compared to other measures such as, for example, spinal mobility, are: (1) they reflect the history of pathology, and are, in fact, a result of a cumulative process of inflammation over time, (2) they provide a permanent record necessary for serial evaluation of the disease, /3) they can be randomized and blinded for objective scoring (Dawes; 1988; van der Heijde, 1996). To prove that drugs can modify the course of the disease, halting of progression of radiographic changes is a prerequisite (Edmonds et al, 1993). The situation is more complex in AS than in RA. It is not certain that all changes that can be seen on radiographs are indeed a consequence of the inflammatory disease process. Perhaps some changes should be looked upon as a result of healing (such as sclerosis, syndesmophytes). It could be hypothesized that syndesmophytes prevent the vertebrae from collapse due to osteoporosis. An important research issue would be to unravel the various pathophysiological processes and the associated changes on the radiographs. Thereafter, an appropriate selection could be made from all the abnormalities that could be included in a scoring method. AS is predominantly an axial disease affecting the (whole) spine and sacroiliac joints, but large axial joints (hips and shoulders) and peripheral joints can also be affected. Scoring systems for peripheral joints could be adapted from those developed for RA. However, based on the relative frequency of involvement, specific scoring systems for the spine and sacroiliac joints should be used. In the development and evaluation of a scoring method many issues need to be addressed, such as which abnormalities should be scored, which joints should be included, which views should be taken, the order in which radiographs should be scored, how the data should be presented, how inter/intra-observer variation should be assessed, how sensitivity to change should be assessed, the optimum number of readers for assessing radiographs, which score should be used if multiple readers are used, the issues around quality assurance, international training and validation set of radiographs and automated scoring of radiographs. These issues are outside the scope of this chapter and have been described in two recent papers (van der Heijde and Spoorenberg, in press; van der Heijde et al, in press, a).
Available scoring methods Two scoring methods are published in full papers: the first was the Stoke Ankylosing Spondylitis Spinal Score (SASSS) published by Taylor and
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colleagues (1991), and further validated by Averns et al (1996). This is a detailed scoring system, including the lateral view of the lumbar spine. Both the anterior and dorsal sites of the vertebrae from the lower border of Th12 to the upper border of $1 are scored for squaring, erosions, osteophytes and syndesmophytes. The range of the scores for this system is 0-72. There was a moderate to good intra- and interobserver reliability in the hands of the developers of the SASSS. They could also demonstrate sensitivity to change over a 1-year period in a trial on sulphasalazine, although this was not quantified but statistically based on P values only. Their findings were based upon radiographs scored in chronological order. Spoorenberg et al (in press, a) applied this method also to the lateral cervical spine. This group found a good intra- and interobserver reliability only for the anterior site of both the cervical and lumbar spine, but not for the dorsal site (Spoorenberg et al, in press, a). They scored radiographs of 187 patients with a 1-year interval in pairs without information on sequence. They found only in a low percentage of patients change which exceeded measurement error and therefore can be looked upon as 'real' change; moreover this change was in two directions. In conclusion, SASSS can be scored reliably, at least at the anterior site of the spine, but sensitivity to change needs to be investigated further. The second scoring method published was that by Kennedy et al (1995). However, this method has recently been modified and is now called the Bath Ankylosing Spondylitis Radiology Index (BASRI) (Calin et al, in press). This is a global grading system with a range from 0 to 4 for anterior and lumbar spine, lateral cervcial spine, SI joints and hips. The BASRIs(pine) part of this index, includes the lumbar, cervical spine and (average score of the two) SI joints, and ranges from 2 to 12 (the minimum score is 2 because, by definition, AS patients have to have abnormal SI joints). The BASRIh(ips) part is the BASRI for the hips only and BASRIt(otal) is the sum of BASRIs and BASRIh. Also, these authors showed good intra- and interobserver reliability. They were able to detect a statistically significant change in a group of 31 patients over a 2- but not a 1-year period. The change was from 7.0 to 7.9 for BASRI (P value <0.05). Spoorenberg et al (in press, a) assessed the BASRI in the same group of 187 patients for whom they had assessed the SASSS. BASRI showed good intra- and interobserver reliability, but, again, change exceeded measurement error in a very small percentage of patients only, and again in both directions: improvement and deterioration. Therefore, as with SASSS, BASRI can be scored reliably, but, again, sensitivity to change needs to be evaluated further. In conclusion, two scoring methods exist that are feasible and show good reproducibility (SASSS for the anterior site only). Data on discrimination (differences between groups of patients and sensitivity to change over time) are, however, scarce and should be evaluated further. The choice of the scoring method depends mainly on the purpose of the study. At present, no definite choice between the two can be made on the basis of currently available data. Other imaging techniques, such as MRI and scintigraphy, have been applied to AS, mainly for the sacroiliac joints. The application of these methods to AS is under development and, so far, no quantitative scoring methods are available. In particular, MRI may prove to be valuable
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in the future because of the possibility of quantification of the inflammatory process and its consequences.
M e a s u r e s of o u t c o m e in other s p o n d y l o a r t h r i t i d e s
No consensus yet exists on the assessment of other spondyloarthritides (SPA) such as psoriatic arthritis (PsA) and reactive arthritis (ReA). Mostly an overlap of measures used for RA and for AS are used. In a large multicentre trial on AS, PsA and ReA a group of measures that could be applied to all three subgroups (pain, patient global, physician global, morning stiffness) were assessed besides specific measures for each subgroup (Dougados et al, 1995). All the patients fulfilled the ESSG classification criteria for SpA. In a secondary analysis the subgroups were analysed according to the presentation of the disease: axial involvement only, oligo-articular and polyarticular disease. This could also be a good way to select which core set to use: for patients with axial involvement only the core set for AS could be used; for patients with oligo- and polyarticular involvement the core set for AS or for RA could be used.
Practice points •
international core set available of outcome measures in AS
•
assessing spinal mobility is not valuable in short-term studies
•
assessing spinal mobility is important to follow patients in clinical practice
•
the value of ESR and CRP in AS is not well established ESR is preferred on the basis of feasibility
•
radiological scoring methods are available
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Summary Recently, core sets of endpoints in ankylosing spondylitis have been defined by the international ASAS working group and are endorsed by OMERACT and ILAR. These include, for use in SM-ARD and physical therapy trials, physical function, pain, spinal mobility, spinal stiffness and patient global assessment. In addition to these, peripheral joints and entheses, and acutephase reactants should be assessed for clinical record keeping and in a DC-ART trial. In a DC-ART trial radiographs of hips and spine should also be added. Fatigue is still on the research agenda as to whether this should be included and if so what instrument should be used. Specific instruments are suggested for all the domains. Spinal mobility is especially helpful in the description of the population under study. The responsiveness depends heavily on the duration of disease and on the duration of the intervention. Too little is known about the responsiveness of the large number of instruments used to assess spinal mobility. The acute-phase reactants ESR and CRP behave very similarly in crosssectional studies. However, they are not very suitable for classifying patients as having active or inactive disease. Too little is known about the value of the acute-phase reactants in longitudinal studies. Two radiological scoring methods exist. The BASRI is a global grading system, and the SASSS is a more detailed scoring system. Both show good intra- and interobserver reliability, but, again, not enough data are available to address the issue of discrimination (between groups and during followup). For use in the other spondyloarthritides, core sets of either AS or RA could be applied--depending on the symptoms and signs of the group under study (i.e. axial and/or peripheral involvement).
References *Averns HL, Oxtoby J, Taylor HG et al (1996) Radiological outcome in ankylosing spondylitis: use of the Stoke Ankytosing Spondylitis Spine Score (SASSS) British Journal of Rheurnatology 35: 373-376. Bakker C, Boers M & van der Linden S (1993) Measures to assess ankylosing spondylitis: taxonomy, review and recommendations. Journal of Rheumatology 20: 1724-1730. Bellamy N (1993) Musculoskeletal Clinical Metrology, pp 177-183. Dordrecht, Boston, London: Kluwer Academic Publishers. Boers M, Brooks P, Strand CV & Tugwell P (1998) The OMERACT filter for outcome measures in rheumatology. Journal of Rheumatology 25: 198-199. Boers M, Tugwell P, Fetson DT et al (1994) World Health Organization and International League of Associations for Rheumatology core endpoints for symptom modifying antirheumatic drugs in rheumatoid arthritis clinical trials. Journal of Rheurnatology 41 (supplement): 86-89. *Calin A (1996) Radiology and spondylarthritis. BailIi~res Clinical Rheumatology 10: 455-476. *Calin A, Mackay K & Brophy S (in press) A new dimension to outcome: the Bath Ankylosing Spondylitis Radiology Index [BASRI]. Journal of Rheumatology.
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Calin A, Nakache J-P, Gueguen A et al (in press) Outcome variables in ankylosing spondylitis: evaluation of their relevance and discriminant capacity. Journal of Rheumatology. Dawes PT (1988) Radiological assessment of outcome in rheumatoid arthritis. BritishJournal of Rheumatology 27 (supplement 1): 21-36. Dougados M, van der Linden Sj, Leirisalo Repo M e t al (1995) Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebo-controlled study. Arthritis and Rheumatism 38: 618-627. Edmonds JP, Scott DL, Furst DE & Paulus HE (1993) New classification of antirheumatic drugs. The evolution of a concept. Journal of Rheumatology 20: 585-587. Fries JF (1983) Toward an understanding of patient outcome measurement. Arthritis and Rheumatism 26: 697-704. Fries JF, Spitz PW & Young DY (1982) The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. Journal of Rheumatology 9: 789-793. van der Heijde DM (1996) Plain X-rays in rheumatoid arthritis: overview of scoring methods, their reliability and applicability. Bailli~resClinicalRheumatology 10: 435-453. *van der Heijde D & Spoorenberg A (in press) Plain radiographs as an outcome measure in ankylosing spondylitis. Journal of Rheumatology. van der Heijde D, Bellamy N, Calin A et al (1997) Preliminary core sets for endpoints in ankylosing spondytitis. Journal of Rheumatology 24: 2225-2229. van der Heijde DMFM, Boers M & Lassere M (in press, a) Methodological issues in radiographic scoring methods in rheumatoid arthritis. Journal of Rheumatology. '."van der Heijde D, Calin A, Dougados M et al (in press, b) Selection of specific instruments for each domain in core sets for CD-ART, SM-ARD, physical therapy and clinical recordkeeping in ankylosing spondytitis. Journal of Rheumatology. van der Heijde D, van der Linden SJ, Dougados M e t al (in press, c) Ankylosing spondylitis: plenary discussion and results of voting on selection of domains and some specific instruments. Journal of Rheumatology. Kennedy LG, Jenkinson TR, Mallorie PA et al (1995) Ankylosing spondylitis: the correlation between a new metrology score and radiology. British Journal of Rheumatology 34: 767-770. van der Linden S & van der Heijde DM (1995) Ankylosing spondylitis and other B27 related spondylarthropathies. Bailli~resClinicalRheumatology 9: 355-373. van der Linden S, Valkenburg HA & Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis and Rheumatism 27: 361-368. *Spoorenberg A, de Vlam K, van der Heijde D et al (in press, a) Comparison of intra- and interobserver reliability, and sensitivity to change of SASSS and BASRI in cohort of 187 ankylosing spondylitis patients. Journal of Rheumatology. Spoorenberg A, van der Heijde D, de Klerk E et al (in press, b) ESR vs. CRP in relation to disease activity in a study of 191 ankylosing spondylitis patients. Journal of
RheumatoIogy. Stucki
G & Ruof J (in press) Validity aspects of ESR and CRP in ankylosing spondylitis.
Journal of Rheumatology. *Taylor HG, Wardle T, Beswick EJ & Dawes PT (1991) The relationship of clinical and laboratory measurements to radiological change in ankylosing spondylitis. BritishJournal of Rheumatology 30: 330-335.
Sj. van der Linden MD, PhD Professor of Rheumatology
Department of Internal Medicine, Division of Rheumatology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands
This chapter describes core sets that can be used in the assessment of ankylosing spondylitis and other spondyloarthritides. Various core sets are described for the evaluation of disease-controlling antirheumatic therapy, symptom-modifying antirheumatic drugs and physical therapy, or for use in clinical record keeping. These core sets describe domains and also give advice on specific instruments. The value of spinal mobility and acute-phase reactants in the assessment of ankylosing spondylitis in AS are described in more detail. The available radiological scoring methods are discussed.
Key words: core set; outcome; ankylosing spondylitis; psoriatic arthritis; reactive arthritis; spondyloarthritis; spondyloarthropathy; acute-phase reactants; ESR; CRP; spinal mobility; radiological scoring methods.
Outcome is a general term, often opposed by the term 'process'. However, various definitions for outcome are in use. 'Outcome' can be seen as the final result of the disease, where 'process' stands for what is happening along the way. Radiographic damage is seen by many as a measure of outcome. However, if Fries' definition for outcome: 'the suffering or loss of health experienced by an individual as a result of the process of the disease' is used, radiographic damage would be no measure of outcome (Fries, 1983). A more neutral term is 'endpoint'; it is especially feasible to use this term in the context of a clinical trial. However, in this chapter the terms outcome and endpoint will be used interchangeably. Measures of outcome can be classified in various groups depending on the point of interest: (1) disease activity versus structural damage, (2) patient versus physician-oriented, (3) specific versus general, (4) for use in the evaluation of disease controlling anti-rheumatic therapy (DC-ART), Bailli#re's Clinical Rheumatology-Vol. 12, No. 4, November 1998 ISBN 0-7020-2464-3 0950-3579/98/040683 + 11 $12.00/00
683 Copyright © 1998, by Bailliere Tindall All rights of reproduction in any form reserved
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symptom-modifying anti-rheumatic drugs (SMARD), physical therapy or in clinical practice, (5) measuring various aspects of outcome according to underlying constructs such as the five Ds" death, disability, discomfort, (drug) toxicity, (dollar) costs. Of course there is overlap, and there are cross-links between these categories (Fries et al, 1982; Edmonds et al, 1993; van der Heijde et al, 1997). A good evaluation of the overlap of categories (2) and (3) has been described by Bakker et al (1993). For the purpose of this chapter we will focus mainly on categories (1) and (4). Some measures of outcome assess disease activity (i.e. morning stiffness), others structural damage (i.e. radiographic changes) and others a combination of both (i.e. functional disability). The decision to use measures of outcome for various settings was made first by the international ASsessments in Ankylosing Spondylitis (ASAS) working group (van der Heijde et al, 1997). The focus of this chapter will be on ankylosing spondylitis (AS) and only a brief overview will be given for other types of spondyloarthritides (SPA). Within AS a distinction should be made between patients with axial involvement only and those with extraspinal involvement such as peripheral arthritis, inflammatory bowel disease (IBD) or uveitis. With this concept as a starting point, the group of SpA could be considered as one group with various ways of presentation. For example, for the subgroup of psoriatic arthritis (PsA) patients with peripheral arthritis the measures of outcome for extraspinal AS could be applied, and for the group of PsA patients with axial involvement only the measures of outcome for spinal AS could be applied.
Available measures of outcome for AS in the literature
Over 100 assessments of outcome for use in AS were described in the literature up to 1995 (Bakker et al, 1993; van der fIeijde et al, 1997). Therefore, there is a need to reduce the number of assessments to be actually used in AS and to agree upon a common well accepted core set of endpoints. An overview of the lack of standardization was described earlier (van der Linden and van der Heijde, 1995). There are several reasons as to why a core set is really needed. First, (too) many variables are included in research projects, and this leads to statistically significant differences between groups by chance alone. Moreover, investigators may choose to publish selectively only those variables that show the most impressive results. In addition, variables that have proven to be insensitive to change are still being used. Because every investigator may select from a large range of available measures, comparisons between various studies are very hard. This also makes the performance of a meta-analysis very difficult if not impossible. Another problem is that measures are not standardized. Many ways exist to assess spinal mobility, and even if everyone selects the Schober index, as an example, there are several ways to perform this test.
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How to select a core set of measures?
A core set is defined as the minimum set of variables which should be included in each study (Boers et al, 1994). There are three main ways of selecting a group of measures of outcome to be included in a core set: by a consensus procedure by experts, and on statistical grounds, or a combination of these two. In fact, purely on statistical grounds is not possible: only those instruments that have been used in studies can be used for the statistical analyses. Selection of the instruments is therefore an important step which is usually done by consensus procedures by the investigators. This selection should be done because it is not feasible to include a large number of assessments in one study, not even if this study was especially designed to evaluate the various instruments. A sensible way to reduce the number of available measures to a more comprehensive group is by combining instruments into domains. These domains are intended to measure the same underlying concept such as 'spinal mobility' or 'functional capacity'. After selecting the domains which should be included in the core set, a selection of specific measures can be made. An example of both approaches (consensus and statistical) will be discussed below. Consensus approach: selection of a core set of domains by ASAS
In 1995 the ASAS working group was formed (van der Heijde et al, 1997). Participants from 21 countries in Europe, North and South America, Asia and Australia took part in this initiative. The group comprised experts in the field of AS, (clinical) epidemiologists, representatives of the pharmaceutical industry and AS patients. The group decided to define core sets for three different settings: (1) for the evaluation of DC-ART, (2) for the evaluation of SMARD and physical therapy, and (3) for use in clinical record keeping. By nominal group discussions and plenary sessions during several workshops, domains for each of these three settings were selected (Table 1) (van der Heijde et al, 1997). During later steps a selection of specific variables was Table 1. Core set for studies on DC-ART, SM-ARD/physical therapy, and for clinical record keeping endorsed by ASAS, OMERACT and ILAR (van der Heijde et al, 1997). DC-ART
SM-ARD/physical therapy
Clinical record keeping
Physical function Pain Spinal mobility Spinal stiffness* Patient global assessment Peripheral joints/entheses Acute phase reactants (AUC)* Spine radiograph Hip radiograph* Fatigue*
Physical function Pain Spinal mobility Spinal stiffness Patient global assessment
Physical function Pain Spinal mobility Spinal stiffness Patient global assessment Peripheral joints/entheses Acute-phase reactants
AUC = area under the curve, acute-phase reactants assessed as a cumulative measure over time. * Domains not definitely included in the core set but have been put on the research agenda.
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made based on aspects of feasibility (is this instrument achievable in this particular setting?) and relevance (is this instrument relevant to answer the study question in the particular setting in which the measurement is to be done?). The preliminary selection of specific variables for DC-ART is presented in Table 2. Further research needs to be done on aspects of truth (is the measure truthful, does it measure what is intended, is the result unbiased?) and discrimination (does the measure discriminate between situations of interest?) (Boers et al, 1998). The ASAS core sets were endorsed during the OMERACT IV conference (Cancun, 1998). Therefore they are now ASAS/OMERACT/ILAR core sets (van der Heijde et al, in press, b). Table 2. Specific instruments for each domain in core set for DC-ART (van der Heijde et al, in press, b). Domain
Instrument
Function Pain
BASFI or Dougados VAS-last week-spine-at-night-due to AS and VAS-last week-spine-due to AS Chest expansion and modified Schober and occiput to wall VAS-last week Number of swollen joints (44 joint count) AP + Lat Lumbar and Lat Cervical spine andX-pelvis (SI and hips) Duration of morning stiffness-spine-last week ESR See spine
Spinal mobility
Patient global Peripheral joints X-ray spine
Stiffness Acute-phase reactants X-ray hips Fatigue Research agenda
CRP Severity of morning stiffness-spine-last week Scoring method X-rays BASDAI, BASMI and other indices Fatigue, entheses
VAS = visual analogue scale. Example: How was the pain in your spine due to AS on average last week? To be answered on a 100 mm horizontal VAS. S t a t i s t i c a l a p p r o a c h : s e l e c t i o n of a c o r e s e t b y c l u s t e r a n a l y s i s
Another approach was taken by Catin et al (in press). They performed a cluster analysis on the data of 423 patients with axial AS with active disease after a period of stopping NSAIDs. The following assessments were taken into account: patient global assessment (visual analogue scale, VAS), physician global assessment (VAS), pain (VAS), spinal pain, night pain, morning stiffness, CRP, platelet count, haemoglobin, Dougados' functional index (D-FI), Bath Ankylosing Spondylitis Functional Index (BASFI), modified Schober test, finger-to-floor distance, occiput-to-wall distance, chest expansion, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The conclusion from the authors is that at least four domains are relevant to evaluate the symptomatic severity of axial involvement of
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AS: (1) patient's subjective perception (such as pain, global assessment or functional impairment), (2) inflammatory symptoms (such as night pain or morning stiffness), (3) metrology (such as the modified Schober test) and (4) laboratory data (such as platelets). Comparison of these results with those obtained by the consensus procedure from the ASAS group shows remarkable similarities, especially if it is taken into account that peripheral joints and radiographs could not be selected in Dougados' study because they had selected patients with axial involvement only and radiographs were not available for this data set. There is also considerable overlap with the recommendations given by Bellamy in his book on clinical metrology of musculoskeletal diseases (all measures with an asterisk are included in the ASAS core set): (1) pain*, stiffness*; (2) chest expansion*, finger-to-floor distance, limitation of flexion of lumbar spine (Schober test*); (3) patient global assessment*; (4) articular index*, physician global assessment':', occiput-to-wall distance*, quality of sleep (Bellamy, 1993).
Is assessing spinal mobility clinically relevant? This is a difficult question to answer, and the answer might differ in different stages of the disease. It also depends heavily on how the spinal mobility is measured. Posing this question to the ASAS group revealed a large range of answers: 30-87% of the respondents considered a specific assessment of spinal mobility to be a relevant measure. Only 30% of the respondents thought that assessing a modified Schober in three 10 cm segments was relevant, and 33% indicated the same for measuring cervical rotation by a gravity action goniometer. On the other hand, 87% of the respondents considered assessing chest expansion as relevant, and 83% replied so for measuring the modified Schober in a 10 cm segment. So even small changes in the way in which specific measure is assessed (i.e. two modified Schober tests) make a large difference in how relevant this measure is considered to be by experts. Hence, the measure assessing spinal mobility--but also the setting in which this measure is applied--determines the clinical relevance. Especially in trials of short duration, assessing spinal mobility is not very useful because these measures are usually insensitive to change over a limited time frame. In clinical practice, however, this can be an important measure in following patients over longer periods of followup. It provides the opportunity to give advice to correct a wrong posture (i.e. kyphosis). Spinal mobility is a combination of structural damage and disease activity. In trials it can be of great importance to give baseline data on spinal mobility of the population under study to make judgements on the severity of disease of the patients included and to be able to compare the trial patients with your own. The measures provisionally selected by the ASAS group on the basis of feasibility and relevance, combined with the elimination of redundancy, could be used as a guideline. These currently include chest expansion, the modified Schober based on a 10 cm segment, and the occiput-to-wall distance.
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Are biological parameters of any value in the assessment of AS patients? Recently, the literature on the use of ESR and CRP in ankylosing spondylitis was reviewed by Stucki and Ruof (in press). They concluded that acutephase, reactants do not comprehensively represent the disease process in AS, and thus do not have the same validity of content as a measure of disease activity as is the case in rheumatoid arthritis. Levels of ESR and CRP are generally lower than in rheumatoid arthritis and vary only to some degree with changes in disease activity. Many 'active' AS patients have normal or only slightly increased acute-phase reactants not allowing for further improvement. Both measures showed some discriminative power in cross-sectional studies, but currently too few data are available on discrimination during long-term follow-up. Also, not enough data are available to judge the predictive validity of the acute-phase reactants. Comparing both ESR and CRP, neither measure is clearly superior in terms of validity based on the currently existing data. Therefore, when selecting an acute-phase reactant, feasibility aspects might play an important role in the decision as to which one to use. Advantages for ESR are lower costs, easiness to perform, standardized test, promptness of results; advantages for CRP are that sera can be stored and used in a central laboratory. Spoorenberg et al (in press, b) compared the discriminative power of ESR and CRP for dividing patients into groups with high and with low disease activity. This was done in a cross-sectional study of 191 patients with AS. Separate analyses were done for patients with axial involvement only and patients with peripheral joint involvement and/or IBD. Comparing receiver operator curves (ROCs) (curves relating sensitivity [-- true positive] to 1-specificity [= true negative]) provided no clear differences between both acute-phase reactants. The predictive values were low, ranging from 0.15 to 0.69, and, on average, as much as 29% of the patients were misclassified as having high or low disease activity based on the CRP or ESR levels. ESR and CRP levels were higher in AS patients with peripheral joint involvement and/or IBD, but the results of the comparison between ESR and CRP were otherwise similar for these patients and for patients with axial involvement only. During the OMERACT IV meeting in Cancun, 1998, it was recommended that ESR should be used whenever possible and that no further cross-sectional research was needed to compare ESR and CRP (van der Heijde et al, in press, c). However, more research should be done on the predictive value and the discriminative power of ESR in longitudinal studies.
Radiological scoring methods in AS For rheumatoid arthritis, radiographic changes are an important endpoint measure and several validated widely used scoring methods are available
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(van der Heijde, 1996). The situation is quite different for ankylosing spondylitis (Calin, 1996). Radiographic evidence of sacroiliitis is a prerequisite for the classification criteria of AS according to the (modified) New York criteria (van der Linden et al, 1984). However, radiographic changes are not a well established measure of outcome, although it was judged as an important area of outcome (Table 1). Which scoring method is preferable depends heavily on the aim of the study, for example, a study on the natural history of the disease, on prognosis, on the effectiveness of therapy. Several advantages of radiographs compared to other measures such as, for example, spinal mobility, are: (1) they reflect the history of pathology, and are, in fact, a result of a cumulative process of inflammation over time, (2) they provide a permanent record necessary for serial evaluation of the disease, /3) they can be randomized and blinded for objective scoring (Dawes; 1988; van der Heijde, 1996). To prove that drugs can modify the course of the disease, halting of progression of radiographic changes is a prerequisite (Edmonds et al, 1993). The situation is more complex in AS than in RA. It is not certain that all changes that can be seen on radiographs are indeed a consequence of the inflammatory disease process. Perhaps some changes should be looked upon as a result of healing (such as sclerosis, syndesmophytes). It could be hypothesized that syndesmophytes prevent the vertebrae from collapse due to osteoporosis. An important research issue would be to unravel the various pathophysiological processes and the associated changes on the radiographs. Thereafter, an appropriate selection could be made from all the abnormalities that could be included in a scoring method. AS is predominantly an axial disease affecting the (whole) spine and sacroiliac joints, but large axial joints (hips and shoulders) and peripheral joints can also be affected. Scoring systems for peripheral joints could be adapted from those developed for RA. However, based on the relative frequency of involvement, specific scoring systems for the spine and sacroiliac joints should be used. In the development and evaluation of a scoring method many issues need to be addressed, such as which abnormalities should be scored, which joints should be included, which views should be taken, the order in which radiographs should be scored, how the data should be presented, how inter/intra-observer variation should be assessed, how sensitivity to change should be assessed, the optimum number of readers for assessing radiographs, which score should be used if multiple readers are used, the issues around quality assurance, international training and validation set of radiographs and automated scoring of radiographs. These issues are outside the scope of this chapter and have been described in two recent papers (van der Heijde and Spoorenberg, in press; van der Heijde et al, in press, a).
Available scoring methods Two scoring methods are published in full papers: the first was the Stoke Ankylosing Spondylitis Spinal Score (SASSS) published by Taylor and
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colleagues (1991), and further validated by Averns et al (1996). This is a detailed scoring system, including the lateral view of the lumbar spine. Both the anterior and dorsal sites of the vertebrae from the lower border of Th12 to the upper border of $1 are scored for squaring, erosions, osteophytes and syndesmophytes. The range of the scores for this system is 0-72. There was a moderate to good intra- and interobserver reliability in the hands of the developers of the SASSS. They could also demonstrate sensitivity to change over a 1-year period in a trial on sulphasalazine, although this was not quantified but statistically based on P values only. Their findings were based upon radiographs scored in chronological order. Spoorenberg et al (in press, a) applied this method also to the lateral cervical spine. This group found a good intra- and interobserver reliability only for the anterior site of both the cervical and lumbar spine, but not for the dorsal site (Spoorenberg et al, in press, a). They scored radiographs of 187 patients with a 1-year interval in pairs without information on sequence. They found only in a low percentage of patients change which exceeded measurement error and therefore can be looked upon as 'real' change; moreover this change was in two directions. In conclusion, SASSS can be scored reliably, at least at the anterior site of the spine, but sensitivity to change needs to be investigated further. The second scoring method published was that by Kennedy et al (1995). However, this method has recently been modified and is now called the Bath Ankylosing Spondylitis Radiology Index (BASRI) (Calin et al, in press). This is a global grading system with a range from 0 to 4 for anterior and lumbar spine, lateral cervcial spine, SI joints and hips. The BASRIs(pine) part of this index, includes the lumbar, cervical spine and (average score of the two) SI joints, and ranges from 2 to 12 (the minimum score is 2 because, by definition, AS patients have to have abnormal SI joints). The BASRIh(ips) part is the BASRI for the hips only and BASRIt(otal) is the sum of BASRIs and BASRIh. Also, these authors showed good intra- and interobserver reliability. They were able to detect a statistically significant change in a group of 31 patients over a 2- but not a 1-year period. The change was from 7.0 to 7.9 for BASRI (P value <0.05). Spoorenberg et al (in press, a) assessed the BASRI in the same group of 187 patients for whom they had assessed the SASSS. BASRI showed good intra- and interobserver reliability, but, again, change exceeded measurement error in a very small percentage of patients only, and again in both directions: improvement and deterioration. Therefore, as with SASSS, BASRI can be scored reliably, but, again, sensitivity to change needs to be evaluated further. In conclusion, two scoring methods exist that are feasible and show good reproducibility (SASSS for the anterior site only). Data on discrimination (differences between groups of patients and sensitivity to change over time) are, however, scarce and should be evaluated further. The choice of the scoring method depends mainly on the purpose of the study. At present, no definite choice between the two can be made on the basis of currently available data. Other imaging techniques, such as MRI and scintigraphy, have been applied to AS, mainly for the sacroiliac joints. The application of these methods to AS is under development and, so far, no quantitative scoring methods are available. In particular, MRI may prove to be valuable
Measures of outcome in spondyloarthritides 691
in the future because of the possibility of quantification of the inflammatory process and its consequences.
M e a s u r e s of o u t c o m e in other s p o n d y l o a r t h r i t i d e s
No consensus yet exists on the assessment of other spondyloarthritides (SPA) such as psoriatic arthritis (PsA) and reactive arthritis (ReA). Mostly an overlap of measures used for RA and for AS are used. In a large multicentre trial on AS, PsA and ReA a group of measures that could be applied to all three subgroups (pain, patient global, physician global, morning stiffness) were assessed besides specific measures for each subgroup (Dougados et al, 1995). All the patients fulfilled the ESSG classification criteria for SpA. In a secondary analysis the subgroups were analysed according to the presentation of the disease: axial involvement only, oligo-articular and polyarticular disease. This could also be a good way to select which core set to use: for patients with axial involvement only the core set for AS could be used; for patients with oligo- and polyarticular involvement the core set for AS or for RA could be used.
Practice points •
international core set available of outcome measures in AS
•
assessing spinal mobility is not valuable in short-term studies
•
assessing spinal mobility is important to follow patients in clinical practice
•
the value of ESR and CRP in AS is not well established ESR is preferred on the basis of feasibility
•
radiological scoring methods are available
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Summary Recently, core sets of endpoints in ankylosing spondylitis have been defined by the international ASAS working group and are endorsed by OMERACT and ILAR. These include, for use in SM-ARD and physical therapy trials, physical function, pain, spinal mobility, spinal stiffness and patient global assessment. In addition to these, peripheral joints and entheses, and acutephase reactants should be assessed for clinical record keeping and in a DC-ART trial. In a DC-ART trial radiographs of hips and spine should also be added. Fatigue is still on the research agenda as to whether this should be included and if so what instrument should be used. Specific instruments are suggested for all the domains. Spinal mobility is especially helpful in the description of the population under study. The responsiveness depends heavily on the duration of disease and on the duration of the intervention. Too little is known about the responsiveness of the large number of instruments used to assess spinal mobility. The acute-phase reactants ESR and CRP behave very similarly in crosssectional studies. However, they are not very suitable for classifying patients as having active or inactive disease. Too little is known about the value of the acute-phase reactants in longitudinal studies. Two radiological scoring methods exist. The BASRI is a global grading system, and the SASSS is a more detailed scoring system. Both show good intra- and interobserver reliability, but, again, not enough data are available to address the issue of discrimination (between groups and during followup). For use in the other spondyloarthritides, core sets of either AS or RA could be applied--depending on the symptoms and signs of the group under study (i.e. axial and/or peripheral involvement).
References *Averns HL, Oxtoby J, Taylor HG et al (1996) Radiological outcome in ankylosing spondylitis: use of the Stoke Ankytosing Spondylitis Spine Score (SASSS) British Journal of Rheurnatology 35: 373-376. Bakker C, Boers M & van der Linden S (1993) Measures to assess ankylosing spondylitis: taxonomy, review and recommendations. Journal of Rheumatology 20: 1724-1730. Bellamy N (1993) Musculoskeletal Clinical Metrology, pp 177-183. Dordrecht, Boston, London: Kluwer Academic Publishers. Boers M, Brooks P, Strand CV & Tugwell P (1998) The OMERACT filter for outcome measures in rheumatology. Journal of Rheumatology 25: 198-199. Boers M, Tugwell P, Fetson DT et al (1994) World Health Organization and International League of Associations for Rheumatology core endpoints for symptom modifying antirheumatic drugs in rheumatoid arthritis clinical trials. Journal of Rheurnatology 41 (supplement): 86-89. *Calin A (1996) Radiology and spondylarthritis. BailIi~res Clinical Rheumatology 10: 455-476. *Calin A, Mackay K & Brophy S (in press) A new dimension to outcome: the Bath Ankylosing Spondylitis Radiology Index [BASRI]. Journal of Rheumatology.
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Calin A, Nakache J-P, Gueguen A et al (in press) Outcome variables in ankylosing spondylitis: evaluation of their relevance and discriminant capacity. Journal of Rheumatology. Dawes PT (1988) Radiological assessment of outcome in rheumatoid arthritis. BritishJournal of Rheumatology 27 (supplement 1): 21-36. Dougados M, van der Linden Sj, Leirisalo Repo M e t al (1995) Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebo-controlled study. Arthritis and Rheumatism 38: 618-627. Edmonds JP, Scott DL, Furst DE & Paulus HE (1993) New classification of antirheumatic drugs. The evolution of a concept. Journal of Rheumatology 20: 585-587. Fries JF (1983) Toward an understanding of patient outcome measurement. Arthritis and Rheumatism 26: 697-704. Fries JF, Spitz PW & Young DY (1982) The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. Journal of Rheumatology 9: 789-793. van der Heijde DM (1996) Plain X-rays in rheumatoid arthritis: overview of scoring methods, their reliability and applicability. Bailli~resClinicalRheumatology 10: 435-453. *van der Heijde D & Spoorenberg A (in press) Plain radiographs as an outcome measure in ankylosing spondylitis. Journal of Rheumatology. van der Heijde D, Bellamy N, Calin A et al (1997) Preliminary core sets for endpoints in ankylosing spondytitis. Journal of Rheumatology 24: 2225-2229. van der Heijde DMFM, Boers M & Lassere M (in press, a) Methodological issues in radiographic scoring methods in rheumatoid arthritis. Journal of Rheumatology. '."van der Heijde D, Calin A, Dougados M et al (in press, b) Selection of specific instruments for each domain in core sets for CD-ART, SM-ARD, physical therapy and clinical recordkeeping in ankylosing spondytitis. Journal of Rheumatology. van der Heijde D, van der Linden SJ, Dougados M e t al (in press, c) Ankylosing spondylitis: plenary discussion and results of voting on selection of domains and some specific instruments. Journal of Rheumatology. Kennedy LG, Jenkinson TR, Mallorie PA et al (1995) Ankylosing spondylitis: the correlation between a new metrology score and radiology. British Journal of Rheumatology 34: 767-770. van der Linden S & van der Heijde DM (1995) Ankylosing spondylitis and other B27 related spondylarthropathies. Bailli~resClinicalRheumatology 9: 355-373. van der Linden S, Valkenburg HA & Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis and Rheumatism 27: 361-368. *Spoorenberg A, de Vlam K, van der Heijde D et al (in press, a) Comparison of intra- and interobserver reliability, and sensitivity to change of SASSS and BASRI in cohort of 187 ankylosing spondylitis patients. Journal of Rheumatology. Spoorenberg A, van der Heijde D, de Klerk E et al (in press, b) ESR vs. CRP in relation to disease activity in a study of 191 ankylosing spondylitis patients. Journal of
RheumatoIogy. Stucki
G & Ruof J (in press) Validity aspects of ESR and CRP in ankylosing spondylitis.
Journal of Rheumatology. *Taylor HG, Wardle T, Beswick EJ & Dawes PT (1991) The relationship of clinical and laboratory measurements to radiological change in ankylosing spondylitis. BritishJournal of Rheumatology 30: 330-335.