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Impact of imaging in established rheumatoid arthritis
Best Practice & Research Clinical Rheumatology Vol. 17, No. 5, pp. 783–790, 2003 doi:10.1016/S1521-6942(03)00064-0, www.elsevier.com/locate/jnlabr/yberh
5 Impact of imaging in established rheumatoid arthritis De´sire´e van der Heijde
MD, PhD
*
Professor of Rheumatology University Hospital Maastricht, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
Joint damage visualized on radiographs is still the hallmark of rheumatoid arthritis. With increasing duration of disease, there is an increasing relationship between joint damage and functional status. There are also other imaging techniques such as magnetic resonance imaging and ultrasound. The role of these techniques in clinical trials and clinical practice is discussed. Structural damage is an important measure of outcome for showing aspects of disease modification resulting from antirheumatic therapy. Recommendations are presented on how the results could be reported in an optimal way to ensure the correct presentation of data and comparability of the results. Joint damage is a clear sign of severe disease. More data become available that joint damage is related to several aspects of outcome, such as functional status, work disability and mortality. The significance and clinical implication of a certain magnitude of change in the modified Sharp score is discussed. Key words: imaging; radiographs; rheumatoid arthritis; outcome.
Joint damage visualized on radiographs is considered to be the hallmark of rheumatoid arthritis (RA). Currently, the standard method for assessing structural damage is radiography. Radiographs can be used to assess the amount of destruction at a single point in time, or a series of films can be used to assess the progression of the disease. It is a simple and cheap way to assess structural damage and can serve as a permanent record. Several drugs have proven to be able to retard radiographic progression substantially. The armamentarium for treating patients with RA effectively has expanded tremendously over the past few years. Therefore it is increasingly important to assess the progression of structural damage in individual patients in clinical practice and, if necessary, to adjust therapy accordingly. If outcome is defined as ‘burden of disease’, damage seen on radiographs is not an outcome. However, it is considered as a valid surrogate marker for outcome because of the high face validity and the proven link with functional capacity, an important outcome for patients. ADVANTAGES AND DISADVANTAGES OF RADIOGRAPHY A clear advantage of radiography is that it is widely available in all hospitals, without waiting time, and it is cheap, well standardized, and can easily be interpreted by * Tel.: þ 31-43-387-5026; Fax: þ31-43-387-5006. E-mail address: [email protected] (D. van der Heijde). 1521-6942/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
784 D. van der Heijde
rheumatologists. The technique is especially valuable for imaging cortical and trabecular bone, but has very limited usefulness for imaging soft-tissue structures. Another disadvantage is the exposure to radiation, although this is usually quite low. A real disadvantage is the fact that the three-dimensional joint structures are converted into a two-dimensional image. Consequently, there is superimposition of overlying structures. This disadvantage can be overcome only by multiplanar techniques such as computer tomography (CT) or magnetic resonance imaging (MRI). However, a tomographic technique results in a large number of images, which need to be combined for interpretation; this requires a larger storage capacity. Plain films combine a lot of information on a single film. In the case of a CT, there is also a much higher exposure to radiation compared with plain radiography. Plain films are based on a fast technique; many joints can be assessed in a short period of time. This contrasts especially with MRI, in which the imaging time is a limitation in the number of joints that can be assessed.
THE VALUE OF MRI AND ULTRASOUND IN RHEUMATOID ARTHRITIS There is growing interest in the use of new imaging techniques in the assessment of RA. The most promising techniques are MRI and ultrasound (US). These techniques can be applied in both clinical research and clinical practice. MRI is able to provide detailed information on the structure and functioning of the joints and their surroundings; in RA, this technique is able to pick up early changes in bone and cartilage, including erosions and—perhaps most importantly—a quantification of inflamed synovium and tenosynovitis. Most data are available from patients with early RA. It has been shown in several studies that MRI is more sensitive than conventional radiography for picking up early erosive changes.1 In clinical practice, MRI and US could play a role in making a diagnosis, prognostication and evaluation of the course of the disease. What would be the best position for these techniques still leads to contradictory opinions. Most people agree that the role for MRI and US seems to lie especially in the diagnostic process.1 – 3 In early RA, the presence of erosions could confirm the diagnosis and play a role in prognostication. In established RA, evaluation of the presence of synovitis in cases that are difficult to distinguish by clinical appraisal might also be useful. Moreover, tenosynovitis can be readily diagnosed. MRI is certainly a good method for evaluating complicated joints, such as the wrist, because these joints suffer largely from overprojection in conventional radiography. Boers has written a critical editorial on the question of whether MRI fulfils the criteria for a useful clinical measurement.3 These criteria are: (1) what do the MR abnormalities (and their changes) mean; and (2) can they be measured reliably. The first question is still not answered. More data are becoming available that show a relationship in time between bone oedema and erosion, and recently between synovitis and erosions.4 By relating individual MRI lesions over 2 years to radiographic erosions, it was shown that only one out of the four so-called erosions detected on MRI became radiographic erosions.5 So we do not know the true nature of those MRI lesions that do not progress to radiographic erosions. In another study comparing MRI lesions and CT erosions, MRI lesions did not always correspond to any lesion on the CT image, and most of the MRI lesions were larger in volume than the corresponding lesions on CT.6 An additional important issue is that the relationship between MRI and long-term outcome is unknown. A lot of work has been done on the development of a valid
Impact of imaging 785
scoring system for MRI.7 A lot of progress has definitely been made, but the scoring system still needs further validation. McQueen has a more positive view and sees a role for MRI in diagnosis and prognostication but also in monitoring responses to therapy.2 Before we are able to implement such an approach in a large number of patients, we also need more information on the cost-effectiveness. Recently, Goldbach-Mansky et al summarized the current position of MRI and emphasized that it might still be too premature to use MRI for assessing the efficacy of drugs in a clinical trial, but that, with evolving technique and knowledge, MRI might become a powerful tool for examining the physiology of bone damage, and remodelling, as well as for evaluating response to therapy.6 US is a less costly technique than MRI, although the costs of high-quality, highresolution systems are still considerable, and it is a misconception that low-cost units are ideal for use in the clinical setting.8 The advantages of US over other imaging techniques are that it requires less housing space, is patient-friendly, has the ability to scan in multiple planes, lacks ionizing radiation, has high spatial resolution, and is capable of real-time examination.8 The two main roles for US could be the extension of physical examination in the clinical setting and assessing outcome in research studies, but the precise role of ultrasound is yet to be fully defined.8 Again, a major advantage seems to be in the diagnosis of soft-tissue abnormalities. US can help to distinguish between synovitis and other causes of joint swelling, and is sensitive for detecting tendon and bursal disease. The main disadvantage is that the results are examiner-dependent.
REPORTING OF RADIOGRAPHIC DATA IN CLINICAL TRIALS The literature contains many words which indicate that the underlying pathophysiological process leading to structural damage has stopped. These are summarized in the report from a round-table conference (in alphabetical order): arrest, delay, halt, inhibit, prevent, reduce, retard, slow and stop.9 The differences in meaning are only small. The participants of the round-table conference felt that all of these words apply to the results obtained on a group level. Each of these words can be used if a statistically significant difference between two treatment groups is present. A recommendation on the reporting of joint damage in clinical trials is summarized in Table 1.9 The analysis on a group level should also be the primary analysis of a clinical trial. Radiographic data are often (very) skewed to the left; a large proportion of patients show no or minimal progression while a minority show a lot of change. Therefore, a non-parametric statistical test will mostly be the appropriate way to analyse the data. As the data are skewed, means and SDs are not suitable as the only way to present the data as these are largely dependent on the minority of patients with major progression. Means and standard deviations calculated in a skewed distribution are extremely sensitive to subtle changes at the upper extreme. A better way to present the data is by medians and interquartile range (IQR), best visualized in box-whisker plots. In fact, here the data are presented as percentages of patients with a certain amount of progression. The most important disadvantage of percentiles in comparison with means and SDs is that percentiles are descriptive statistics that relate only to the localization in the distribution and neglect the majority of the variable’s values. Presenting both percentiles and mean and SD gives a complementary overview of the data. It is also important to know the proportion of patients in which no progression of structural damage has occurred. This analysis can be compared with the proportion of patients achieving a clinical response, assessed, for example, by the ACR20.
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Table 1. Preliminary guidelines for presentation of radiographic results in clinical trials (Bethesda meeting).9 Radiographs of hands and feet Erosions and narrowing of joint space Smallest detectable difference (SDD) as quality control Preferably two or more observers Kappa and/or ICC, and SDD for inter-observer agreement Average score of observers If one observer Kappa and/or ICC for intra- and inter-observer agreement SDD for intra-observer agreement Presentation of absolute numbers Primary endpoint: total score (erosions and joint space narrowing combined) Secondary endpoints: erosions, joint space narrowing Primary analysis: group level Reporting of mean, SE/SD Box-whisker plot (median, percentiles, outliers) Secondary analysis: patient level % of patients with progression .0.5 for two observers, .0 for one observer % of patients with progression .SDD
The dichotomization of the data reduces the statistical power of a trial, and is therefore advised as a secondary analysis.9 An important issue is the choice of the cut-off level. The most obvious cut-off seems to be zero, but this does not take into account measurement error, which is always present. Measurement error is especially vital for within-group comparisons, which the presentation of a percentage of patients with progression below a certain amount is. In between-group comparisons, this measurement error is present in both groups to the same amount and can therefore be neglected. Ideally, we wish to know the minimal clinically important change in radiographic damage that would influence outcome in the longterm. As this is not available, and it will probably take some time before we have the data, the advice has been to use the smallest detectable difference (SDD) based on measurement error as a cut-off value.9 – 11 This is a kind of arbitrary cut-off, but changes equal to or smaller than this SDD can be detected by panels of rheumatologists and are judged to be clinically relevant in several clinical situations.12
CORRELATION WITH OUTCOME Structural damage visualized on plain films is characteristic for RA. On a group level, there is a linear progression over the course of the disease, although there is a wide variation among individual patients.13 – 15 However, it is relevant to try to prevent structural damage only if there is a clear relation between joint damage on plain films and outcome pertinent to the patient. Functional disability is of major importance for patients. There is clear evidence now that there is a close relationship between joint damage and function. This evidence has been nicely reviewed by Scott et al.14 Throughout the course of disease, there is a strong link between disease activity and functional capacity, assessed by the Health Assessment Questionnaire (HAQ).
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However, with increasing duration of disease, the relationship between joint damage and HAQ is becoming stronger.16 In an early RA cohort, it could be demonstrated that there is a close association between structural damage and HAQ after correction for disease activity.17 In the same cohort, disease activity was stable over a course of 9 years, the HAQ deteriorated slowly, and joint damage developed progressively. This indicates that worsening of the patient could best be picked up by assessing joint damage. Interesting data also became available from a cohort of patients in remission. In this cohort, functional disability was most strongly related to the presence of pain and, to a lesser extent, to disease activity, radiographic joint damage and duration of disease.18 At the moment, it is widely accepted that, by preventing joint destruction, functional capacity can be positively influenced. It has also been shown that radiographic progression predicts total joint replacement even after controlling for disease activity and disease severity.19 There is also limited information on the link between radiographic damage and other outcomes. Work disability is a significant problem in patients with RA. This is already occurring early in the course of disease and is rising with increasing duration of disease.20 An important observation was made in patients included in a clinical trial which studied the effect of addition of infliximab to methotrexate. There was a decrease in employment, both full-time and part-time, by increasing structural damage. In the lowest quartile of radiographic damage, 54% of the patients were employed (42% full-time), gradually diminishing by each quartile of joint damage to only 29% (15% full-time) of the patients with the highest radiographic scores (data on file, Centocor). There are few data on the relationship between joint destruction and mortality. From many publications, it is clear that there is an increased mortality in patients with RA.21 This is limited mainly to the group of patients with severe disease. Poor functional status is a well-known predictor of increased mortality risk.22 Most of the cohorts evaluating mortality do not have information on structural damage. In a cohort followed for 5 years, functional limitations, age and co-morbidities were better predictors for mortality than were radiographic and laboratory data.23 In another cohort with a follow-up of 14 years, erosions at baseline was related to mortality.24 Progression of radiographic damage predicted mortality after correction for demographic data and measures of disease activity in another study.25 Although the direct evidence is limited, there is also circumstantial proof through the causal relationship between disease activity, functional status and radiographic damage. Moreover, severe joint damage and mortality are both outcomes of severe disease. Mortality is strongly related to co-morbidities.21 In particular, cardiovascular comorbidity is associated with severe RA.26 Due to the inter-relationship of all these factors with severe disease, it will be hard, if ever possible, to untangle joint damage as an independent risk factor. It is worthwhile to mention the high mortality rate in patients with atlantoaxial subluxation. In a Norwegian study, the mortality was eight times higher compared with patients without atlantoaxial subluxation.27 Structural damage at the atlantoaxial site is, in turn, associated with erosiveness of the peripheral joints. A large proportion of patients have some kind of cervical involvement, and this increases with duration of disease, although it can already be present early in the course of the disease. In a Dutch cohort, 9.8% of the patients had a horizontal subluxation after 3 years of disease and 14.8% after 6 years. All of these patients had radiographic damage in hands and feet, and 80% also in their large joints.28 In another study by Winfield et al, 100 patients with early disease were followed for 9.5 years.29 In total, 54% of the patients had some cervical spine involvement. These authors related the cervical spine involvement to
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the erosive changes in hands and feet. Twenty-six of the 34 patients with subluxation had a progressive, erosive disease, four patients had a static disease, and four were nonerosive. Nine patients had a progressive cervical subluxation, and all of these patients had progressive erosive disease. So, there is also a strong relationship between erosive disease in hands and feet and cervical involvement. Patients with static erosive or nonerosive disease are unlikely to have (progressive) cervical spine involvement.
WHAT MAGNITUDE OF INHIBITION IS CLINICALLY RELEVANT? As discussed earlier, long-term follow-up of other outcomes such as, for example, functional disability and loss of work, is required to define the minimal clinically important change for joint damage. However, collection of these long-term data takes several years, so it is useful to look for circumstantial evidence. Structural joint damage in clinical trials is assessed in small joints. However, there is a good correlation between the damage in small joints and the damage in large joints.30 Therefore, an observed reduction in disease progression in small joints is porbably a reflection of the course of disease in large joints. Moreover, there is an association between structural joint damage and physical function that is stronger with increasing duration of disease.16 Lastly, it is important to consider that RA is a chronic disease, so it can be expected that, without treatment, patients will continue to show progressive structural damage. If we use the Sharp –van der Heijde scoring method as an example, the scoring range is 0 –448.31 However, it is extremely rare for patients to have complete destruction of all joints in both hands and feet, and therefore have the maximum score. Scores of about 100 indicate that major destruction has already occurred. Maximum scores in trials are rarely higher than about 60% of the scoring range.32 It has been defined in several cohorts (before the use of biologicals and high-dose methotrexate) that the progression of radiographic damage assessed by the Sharp –van der Heijde method was about 7.5 – 8 units per year.14 Given the chronicity of the disease, this would lead to significant joint destruction in about 10 –12 years. If this could be reduced by half, it would take over 20 years to achieve this level of destruction. This is a major maintenance of a status with still acceptable destruction. Usually, the increase in progression represents an increase in erosions and joint space narrowing in several joints. However, let us imagine that it all occurs in just one or two joints. This means that, if untreated, every 2 years there would be two or three completely destroyed joints in hands or feet. Moreover, as damage in these joints probably also represents an increase in damage in the large joints, this has major implications for the patient. Following the same line of reasoning, it is also a relevant difference if the progression in the control group in a clinical trial can be diminished from, for example, four to one or zero in the active treatment group. Furthermore, recent research has shown that clinical experts consider an increase of less than 5 Sharp – van der Heijde points to be a clinically meaningful change.12
Practice points † MRI and US are helpful in making a diagnosis of synovitis and tenosynovitis † joint damage in hands and feet is well correlated with damage in large joints
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† structural damage has a good relation with long-term outcome such as functional status † small changes in joint damage over a short period of time are relevant in the long course of the disease † recommendations on the presentation of radiographic data are available † cervical spine abnormalities are frequently seen in established RA and are related to mortality
Research agenda † the role of MRI and US in a clinical setting and in research † the relationship between MRI and US, with long-term outcome † the minimum progression in joint damage that still has an impact on long-term outcome
SUMMARY Radiography is still the most important imaging technique in the long-term evaluation of RA in clinical practice. MRI and US have promising applications, especially in making a diagnosis. Both MRI and US give unsurpassed information on the soft tissues involved in RA, mainly synovium, bursa and tendons. This is a significant addition to the imaging armamentarium in the clinical setting. The exact place of these imaging techniques still needs to be fully defined, as does the meaning of MRI abnormalities for long-term outcome. Radiography is the primary imaging technique in clinical trials for establishing the disease-modifying possibilities of drugs. It is important to follow international recommendations on the reporting of the results of the trial. Longitudinal studies have shown that there is a good relationship between joint damage visualized on plain films and several aspects of outcome, such as functional status, work disability and mortality. As RA is a chronic, long-standing disease, seemingly small changes over a period of 1 year might still have major implications in the final outcome of the disease.
REFERENCES 1. Conaghan PG, McGonagle D, Wakefield R & Emery P. New approaches to imaging of early rheumatoid arthritis. Clinical and Experimental Rheumatology 1999; 17(6 supplement 18): S37–S42. 2. McQueen FM. Magnetic resonance imaging in early inflammatory arthritis: what is its role? Rheumatology 2000; 39: 700 –706. 3. Boers M. Value of magnetic resonance imaging in rheumatoid arthritis? The Lancet 2000; 356: 1458–1459. 4. Conaghan PG, O’Connor P, McGonagle D et al. Elucidation of the relationship between synovitis and bone damage: a randomized magnetic resonance imaging study of individual joints in patients with early rheumatoid arthritis. Arthritis and Rheumatism 2003; 48: 64–71. 5. McQueen FM, Benton N, Crabble J et al. What is the fate of erosions in early rheumatoid arthritis? Tracking individual lesions using x-rays and magnetic resonance imaging over the first two years of the disease. Annals of the Rheumatic Diseases 1998; 57: 350–356. 6. Goldbach-Mansky R, Woodburn J, Yao L & Lipsky P. Magnetic resonance imaging in the evaluation of bone damage in rheumatoid arthritis: a more precise image or just a more expensive one. Arthritis and Rheumatism 2003; 48: 585– 589.
790 D. van der Heijde 7. Conaghan PG, Edmonds J, Emery P et al. Magnetic resonance imaging in rheumatoid arthritis: summary of OMERACT activities, current status, and plans. Journal of Rheumatology 2001; 28: 1158–1162. 8. Wakefield RJ, Gibbon WW & Emery P. The current status of ultrasonography in rheumatology. Rheumatology 1999; 38: 195–198. 9. van der Heijde D, Simon L, Smolen J et al. How to report radiographic data in randomized clinical trials in rheumatoid arthritis: guidelines from a roundtable discussion. Arthritis and Rheumatism 2002; 47: 215–218. 10. Lassere M, Boers M, van der Heijde D et al. Smallest detectable difference in radiological progression. Journal of Rheumatology 1999; 26: 731 –739. 11. Lassere MN, van der Heijde D, Johnson K et al. Robustness and generalizability of smallest detectable difference in radiological progression. Journal of Rheumatology 2001; 28: 911– 913. 12. Bruynesteyn K, van der Heijde D, Boers M et al. Detecting radiological changes in rheumatoid arthritis that are considered important by clinical experts: influence of reading with or without known sequence. Journal of Rheumatology 2002; 29: 2306–2312. 13. Wolfe F & Sharp JT. Radiographic outcome of recent-onset rheumatoid arthritis: a 19-year study of radiographic progression. Arthritis and Rheumatism 1998; 41: 1571–1582. * 14. Scott D, Pugner K, Kaarela K et al. The link between joint damage and disability in rheumatoid arthritis. Rheumatology 2000; 39: 122–132. 15. Plant MJ, Jones PW, Saklatvala J et al. Patterns of radiological progression in early rheumatoid arthritis: results of an 8 year prospective study. Journal of Rheumatology 1998; 25: 417 –426. 16. Drossaers-Bakker KW, de Buck M, van Zeben D et al. Long-term course and outcome of functional capacity in rheumatoid arthritis: the effect of disease activity and radiologic damage over time. Arthritis and Rheumatism 1999; 42: 1854–1860. * 17. Welsing PM, van Gestel AM, Swinkels HL et al. The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis. Arthritis and Rheumatism 2001; 44: 2009–2017. 18. Molenaar ET, Voskuyl AE & Dijkmans BA. Functional disability in relation to radiological damage and disease activity in patients with rheumatoid arthritis in remission. Journal of Rheumatology 2002; 29: 267–270. 19. Wolfe F & Choi HK. RA patients with radiographic progression are at increased risk for total joint replacement, even after controlling for disease activity and disease severity. Arthritis and Rheumatism 2001; 46: 730. abstract. 20. Felts W & Yelin E. The economic impact of the rheumatic diseases in the United States. Journal of Rheumatology 1989; 16: 867–884. 21. Gabriel SE, Crowson CS, Kremers HM et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis and Rheumatism 2003; 48: 54–58. 22. Yelin E, Trupin L, Wong B & Rush S. The impact of functional status and change in functional status on mortality over 18 years among persons with rheumatoid arthritis. Journal of Rheumatology 2002; 29: 1851–1857. 23. Callahan LF, Pincus T, Huston JW et al. Measures of activity and damage in rheumatoid arthritis: depiction of changes and prediction of mortality over five years. Arthritis Care and Research 1997; 10: 381 –394. 24. Chehata JC, Hassell AB, Clarke SA et al. Mortality in rheumatoid arthritis: relationship to single and composite measures of disease activity. Rheumatology 2001; 40: 447–452. 25. Choi HK & Wolfe F. Radiologic progression and mortality. Arthritis and Rheumatism 2001; 46: 1014. abstract. 26. Choi HK, Hernan MA, Seeger JD et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. The Lancet 2002; 359: 1173–1177. * 27. Riise T, Jacobsen BK & Gran JT. High mortality in patients with rheumatoid arthritis and atlantoaxial subluxation. Journal of Rheumatology 2001; 28: 2425–2429. 28. Kuper HH, van Leeuwen MA, van Riel PL et al. Radiographic damage in large joints in early rheumatoid arthritis: relationship with radiographic damage in hands and feet, disease activity, and physical disability. British Journal of Rheumatology 1997; 36: 855–860. 29. Winfield J, Young A, Williams P & Corbett M. Prospective study of the radiological changes in hands, feet, and cervical spine in adult rheumatoid disease. Annals of Rheumatic Diseases 1983; 42: 613 –618. * 30. Drossaers-Bakker K, Kroon H, Zwinderman A et al. Radiographic damage of large joints in long-term rheumatoid arthritis and its relation to function. Rheumatology 2000; 39: 998– 1003. 31. van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. Journal of Rheumatology 1999; 26: 743–745. * 32. Strand V & Sharp JT. Radiographic data from recent randomized controlled trials in rheumatoid arthritis: what have we learned? Arthritis and Rheumatism 2003; 48: 21 –34.
5 Impact of imaging in established rheumatoid arthritis De´sire´e van der Heijde
MD, PhD
*
Professor of Rheumatology University Hospital Maastricht, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
Joint damage visualized on radiographs is still the hallmark of rheumatoid arthritis. With increasing duration of disease, there is an increasing relationship between joint damage and functional status. There are also other imaging techniques such as magnetic resonance imaging and ultrasound. The role of these techniques in clinical trials and clinical practice is discussed. Structural damage is an important measure of outcome for showing aspects of disease modification resulting from antirheumatic therapy. Recommendations are presented on how the results could be reported in an optimal way to ensure the correct presentation of data and comparability of the results. Joint damage is a clear sign of severe disease. More data become available that joint damage is related to several aspects of outcome, such as functional status, work disability and mortality. The significance and clinical implication of a certain magnitude of change in the modified Sharp score is discussed. Key words: imaging; radiographs; rheumatoid arthritis; outcome.
Joint damage visualized on radiographs is considered to be the hallmark of rheumatoid arthritis (RA). Currently, the standard method for assessing structural damage is radiography. Radiographs can be used to assess the amount of destruction at a single point in time, or a series of films can be used to assess the progression of the disease. It is a simple and cheap way to assess structural damage and can serve as a permanent record. Several drugs have proven to be able to retard radiographic progression substantially. The armamentarium for treating patients with RA effectively has expanded tremendously over the past few years. Therefore it is increasingly important to assess the progression of structural damage in individual patients in clinical practice and, if necessary, to adjust therapy accordingly. If outcome is defined as ‘burden of disease’, damage seen on radiographs is not an outcome. However, it is considered as a valid surrogate marker for outcome because of the high face validity and the proven link with functional capacity, an important outcome for patients. ADVANTAGES AND DISADVANTAGES OF RADIOGRAPHY A clear advantage of radiography is that it is widely available in all hospitals, without waiting time, and it is cheap, well standardized, and can easily be interpreted by * Tel.: þ 31-43-387-5026; Fax: þ31-43-387-5006. E-mail address: [email protected] (D. van der Heijde). 1521-6942/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
784 D. van der Heijde
rheumatologists. The technique is especially valuable for imaging cortical and trabecular bone, but has very limited usefulness for imaging soft-tissue structures. Another disadvantage is the exposure to radiation, although this is usually quite low. A real disadvantage is the fact that the three-dimensional joint structures are converted into a two-dimensional image. Consequently, there is superimposition of overlying structures. This disadvantage can be overcome only by multiplanar techniques such as computer tomography (CT) or magnetic resonance imaging (MRI). However, a tomographic technique results in a large number of images, which need to be combined for interpretation; this requires a larger storage capacity. Plain films combine a lot of information on a single film. In the case of a CT, there is also a much higher exposure to radiation compared with plain radiography. Plain films are based on a fast technique; many joints can be assessed in a short period of time. This contrasts especially with MRI, in which the imaging time is a limitation in the number of joints that can be assessed.
THE VALUE OF MRI AND ULTRASOUND IN RHEUMATOID ARTHRITIS There is growing interest in the use of new imaging techniques in the assessment of RA. The most promising techniques are MRI and ultrasound (US). These techniques can be applied in both clinical research and clinical practice. MRI is able to provide detailed information on the structure and functioning of the joints and their surroundings; in RA, this technique is able to pick up early changes in bone and cartilage, including erosions and—perhaps most importantly—a quantification of inflamed synovium and tenosynovitis. Most data are available from patients with early RA. It has been shown in several studies that MRI is more sensitive than conventional radiography for picking up early erosive changes.1 In clinical practice, MRI and US could play a role in making a diagnosis, prognostication and evaluation of the course of the disease. What would be the best position for these techniques still leads to contradictory opinions. Most people agree that the role for MRI and US seems to lie especially in the diagnostic process.1 – 3 In early RA, the presence of erosions could confirm the diagnosis and play a role in prognostication. In established RA, evaluation of the presence of synovitis in cases that are difficult to distinguish by clinical appraisal might also be useful. Moreover, tenosynovitis can be readily diagnosed. MRI is certainly a good method for evaluating complicated joints, such as the wrist, because these joints suffer largely from overprojection in conventional radiography. Boers has written a critical editorial on the question of whether MRI fulfils the criteria for a useful clinical measurement.3 These criteria are: (1) what do the MR abnormalities (and their changes) mean; and (2) can they be measured reliably. The first question is still not answered. More data are becoming available that show a relationship in time between bone oedema and erosion, and recently between synovitis and erosions.4 By relating individual MRI lesions over 2 years to radiographic erosions, it was shown that only one out of the four so-called erosions detected on MRI became radiographic erosions.5 So we do not know the true nature of those MRI lesions that do not progress to radiographic erosions. In another study comparing MRI lesions and CT erosions, MRI lesions did not always correspond to any lesion on the CT image, and most of the MRI lesions were larger in volume than the corresponding lesions on CT.6 An additional important issue is that the relationship between MRI and long-term outcome is unknown. A lot of work has been done on the development of a valid
Impact of imaging 785
scoring system for MRI.7 A lot of progress has definitely been made, but the scoring system still needs further validation. McQueen has a more positive view and sees a role for MRI in diagnosis and prognostication but also in monitoring responses to therapy.2 Before we are able to implement such an approach in a large number of patients, we also need more information on the cost-effectiveness. Recently, Goldbach-Mansky et al summarized the current position of MRI and emphasized that it might still be too premature to use MRI for assessing the efficacy of drugs in a clinical trial, but that, with evolving technique and knowledge, MRI might become a powerful tool for examining the physiology of bone damage, and remodelling, as well as for evaluating response to therapy.6 US is a less costly technique than MRI, although the costs of high-quality, highresolution systems are still considerable, and it is a misconception that low-cost units are ideal for use in the clinical setting.8 The advantages of US over other imaging techniques are that it requires less housing space, is patient-friendly, has the ability to scan in multiple planes, lacks ionizing radiation, has high spatial resolution, and is capable of real-time examination.8 The two main roles for US could be the extension of physical examination in the clinical setting and assessing outcome in research studies, but the precise role of ultrasound is yet to be fully defined.8 Again, a major advantage seems to be in the diagnosis of soft-tissue abnormalities. US can help to distinguish between synovitis and other causes of joint swelling, and is sensitive for detecting tendon and bursal disease. The main disadvantage is that the results are examiner-dependent.
REPORTING OF RADIOGRAPHIC DATA IN CLINICAL TRIALS The literature contains many words which indicate that the underlying pathophysiological process leading to structural damage has stopped. These are summarized in the report from a round-table conference (in alphabetical order): arrest, delay, halt, inhibit, prevent, reduce, retard, slow and stop.9 The differences in meaning are only small. The participants of the round-table conference felt that all of these words apply to the results obtained on a group level. Each of these words can be used if a statistically significant difference between two treatment groups is present. A recommendation on the reporting of joint damage in clinical trials is summarized in Table 1.9 The analysis on a group level should also be the primary analysis of a clinical trial. Radiographic data are often (very) skewed to the left; a large proportion of patients show no or minimal progression while a minority show a lot of change. Therefore, a non-parametric statistical test will mostly be the appropriate way to analyse the data. As the data are skewed, means and SDs are not suitable as the only way to present the data as these are largely dependent on the minority of patients with major progression. Means and standard deviations calculated in a skewed distribution are extremely sensitive to subtle changes at the upper extreme. A better way to present the data is by medians and interquartile range (IQR), best visualized in box-whisker plots. In fact, here the data are presented as percentages of patients with a certain amount of progression. The most important disadvantage of percentiles in comparison with means and SDs is that percentiles are descriptive statistics that relate only to the localization in the distribution and neglect the majority of the variable’s values. Presenting both percentiles and mean and SD gives a complementary overview of the data. It is also important to know the proportion of patients in which no progression of structural damage has occurred. This analysis can be compared with the proportion of patients achieving a clinical response, assessed, for example, by the ACR20.
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Table 1. Preliminary guidelines for presentation of radiographic results in clinical trials (Bethesda meeting).9 Radiographs of hands and feet Erosions and narrowing of joint space Smallest detectable difference (SDD) as quality control Preferably two or more observers Kappa and/or ICC, and SDD for inter-observer agreement Average score of observers If one observer Kappa and/or ICC for intra- and inter-observer agreement SDD for intra-observer agreement Presentation of absolute numbers Primary endpoint: total score (erosions and joint space narrowing combined) Secondary endpoints: erosions, joint space narrowing Primary analysis: group level Reporting of mean, SE/SD Box-whisker plot (median, percentiles, outliers) Secondary analysis: patient level % of patients with progression .0.5 for two observers, .0 for one observer % of patients with progression .SDD
The dichotomization of the data reduces the statistical power of a trial, and is therefore advised as a secondary analysis.9 An important issue is the choice of the cut-off level. The most obvious cut-off seems to be zero, but this does not take into account measurement error, which is always present. Measurement error is especially vital for within-group comparisons, which the presentation of a percentage of patients with progression below a certain amount is. In between-group comparisons, this measurement error is present in both groups to the same amount and can therefore be neglected. Ideally, we wish to know the minimal clinically important change in radiographic damage that would influence outcome in the longterm. As this is not available, and it will probably take some time before we have the data, the advice has been to use the smallest detectable difference (SDD) based on measurement error as a cut-off value.9 – 11 This is a kind of arbitrary cut-off, but changes equal to or smaller than this SDD can be detected by panels of rheumatologists and are judged to be clinically relevant in several clinical situations.12
CORRELATION WITH OUTCOME Structural damage visualized on plain films is characteristic for RA. On a group level, there is a linear progression over the course of the disease, although there is a wide variation among individual patients.13 – 15 However, it is relevant to try to prevent structural damage only if there is a clear relation between joint damage on plain films and outcome pertinent to the patient. Functional disability is of major importance for patients. There is clear evidence now that there is a close relationship between joint damage and function. This evidence has been nicely reviewed by Scott et al.14 Throughout the course of disease, there is a strong link between disease activity and functional capacity, assessed by the Health Assessment Questionnaire (HAQ).
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However, with increasing duration of disease, the relationship between joint damage and HAQ is becoming stronger.16 In an early RA cohort, it could be demonstrated that there is a close association between structural damage and HAQ after correction for disease activity.17 In the same cohort, disease activity was stable over a course of 9 years, the HAQ deteriorated slowly, and joint damage developed progressively. This indicates that worsening of the patient could best be picked up by assessing joint damage. Interesting data also became available from a cohort of patients in remission. In this cohort, functional disability was most strongly related to the presence of pain and, to a lesser extent, to disease activity, radiographic joint damage and duration of disease.18 At the moment, it is widely accepted that, by preventing joint destruction, functional capacity can be positively influenced. It has also been shown that radiographic progression predicts total joint replacement even after controlling for disease activity and disease severity.19 There is also limited information on the link between radiographic damage and other outcomes. Work disability is a significant problem in patients with RA. This is already occurring early in the course of disease and is rising with increasing duration of disease.20 An important observation was made in patients included in a clinical trial which studied the effect of addition of infliximab to methotrexate. There was a decrease in employment, both full-time and part-time, by increasing structural damage. In the lowest quartile of radiographic damage, 54% of the patients were employed (42% full-time), gradually diminishing by each quartile of joint damage to only 29% (15% full-time) of the patients with the highest radiographic scores (data on file, Centocor). There are few data on the relationship between joint destruction and mortality. From many publications, it is clear that there is an increased mortality in patients with RA.21 This is limited mainly to the group of patients with severe disease. Poor functional status is a well-known predictor of increased mortality risk.22 Most of the cohorts evaluating mortality do not have information on structural damage. In a cohort followed for 5 years, functional limitations, age and co-morbidities were better predictors for mortality than were radiographic and laboratory data.23 In another cohort with a follow-up of 14 years, erosions at baseline was related to mortality.24 Progression of radiographic damage predicted mortality after correction for demographic data and measures of disease activity in another study.25 Although the direct evidence is limited, there is also circumstantial proof through the causal relationship between disease activity, functional status and radiographic damage. Moreover, severe joint damage and mortality are both outcomes of severe disease. Mortality is strongly related to co-morbidities.21 In particular, cardiovascular comorbidity is associated with severe RA.26 Due to the inter-relationship of all these factors with severe disease, it will be hard, if ever possible, to untangle joint damage as an independent risk factor. It is worthwhile to mention the high mortality rate in patients with atlantoaxial subluxation. In a Norwegian study, the mortality was eight times higher compared with patients without atlantoaxial subluxation.27 Structural damage at the atlantoaxial site is, in turn, associated with erosiveness of the peripheral joints. A large proportion of patients have some kind of cervical involvement, and this increases with duration of disease, although it can already be present early in the course of the disease. In a Dutch cohort, 9.8% of the patients had a horizontal subluxation after 3 years of disease and 14.8% after 6 years. All of these patients had radiographic damage in hands and feet, and 80% also in their large joints.28 In another study by Winfield et al, 100 patients with early disease were followed for 9.5 years.29 In total, 54% of the patients had some cervical spine involvement. These authors related the cervical spine involvement to
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the erosive changes in hands and feet. Twenty-six of the 34 patients with subluxation had a progressive, erosive disease, four patients had a static disease, and four were nonerosive. Nine patients had a progressive cervical subluxation, and all of these patients had progressive erosive disease. So, there is also a strong relationship between erosive disease in hands and feet and cervical involvement. Patients with static erosive or nonerosive disease are unlikely to have (progressive) cervical spine involvement.
WHAT MAGNITUDE OF INHIBITION IS CLINICALLY RELEVANT? As discussed earlier, long-term follow-up of other outcomes such as, for example, functional disability and loss of work, is required to define the minimal clinically important change for joint damage. However, collection of these long-term data takes several years, so it is useful to look for circumstantial evidence. Structural joint damage in clinical trials is assessed in small joints. However, there is a good correlation between the damage in small joints and the damage in large joints.30 Therefore, an observed reduction in disease progression in small joints is porbably a reflection of the course of disease in large joints. Moreover, there is an association between structural joint damage and physical function that is stronger with increasing duration of disease.16 Lastly, it is important to consider that RA is a chronic disease, so it can be expected that, without treatment, patients will continue to show progressive structural damage. If we use the Sharp –van der Heijde scoring method as an example, the scoring range is 0 –448.31 However, it is extremely rare for patients to have complete destruction of all joints in both hands and feet, and therefore have the maximum score. Scores of about 100 indicate that major destruction has already occurred. Maximum scores in trials are rarely higher than about 60% of the scoring range.32 It has been defined in several cohorts (before the use of biologicals and high-dose methotrexate) that the progression of radiographic damage assessed by the Sharp –van der Heijde method was about 7.5 – 8 units per year.14 Given the chronicity of the disease, this would lead to significant joint destruction in about 10 –12 years. If this could be reduced by half, it would take over 20 years to achieve this level of destruction. This is a major maintenance of a status with still acceptable destruction. Usually, the increase in progression represents an increase in erosions and joint space narrowing in several joints. However, let us imagine that it all occurs in just one or two joints. This means that, if untreated, every 2 years there would be two or three completely destroyed joints in hands or feet. Moreover, as damage in these joints probably also represents an increase in damage in the large joints, this has major implications for the patient. Following the same line of reasoning, it is also a relevant difference if the progression in the control group in a clinical trial can be diminished from, for example, four to one or zero in the active treatment group. Furthermore, recent research has shown that clinical experts consider an increase of less than 5 Sharp – van der Heijde points to be a clinically meaningful change.12
Practice points † MRI and US are helpful in making a diagnosis of synovitis and tenosynovitis † joint damage in hands and feet is well correlated with damage in large joints
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† structural damage has a good relation with long-term outcome such as functional status † small changes in joint damage over a short period of time are relevant in the long course of the disease † recommendations on the presentation of radiographic data are available † cervical spine abnormalities are frequently seen in established RA and are related to mortality
Research agenda † the role of MRI and US in a clinical setting and in research † the relationship between MRI and US, with long-term outcome † the minimum progression in joint damage that still has an impact on long-term outcome
SUMMARY Radiography is still the most important imaging technique in the long-term evaluation of RA in clinical practice. MRI and US have promising applications, especially in making a diagnosis. Both MRI and US give unsurpassed information on the soft tissues involved in RA, mainly synovium, bursa and tendons. This is a significant addition to the imaging armamentarium in the clinical setting. The exact place of these imaging techniques still needs to be fully defined, as does the meaning of MRI abnormalities for long-term outcome. Radiography is the primary imaging technique in clinical trials for establishing the disease-modifying possibilities of drugs. It is important to follow international recommendations on the reporting of the results of the trial. Longitudinal studies have shown that there is a good relationship between joint damage visualized on plain films and several aspects of outcome, such as functional status, work disability and mortality. As RA is a chronic, long-standing disease, seemingly small changes over a period of 1 year might still have major implications in the final outcome of the disease.
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790 D. van der Heijde 7. Conaghan PG, Edmonds J, Emery P et al. Magnetic resonance imaging in rheumatoid arthritis: summary of OMERACT activities, current status, and plans. Journal of Rheumatology 2001; 28: 1158–1162. 8. Wakefield RJ, Gibbon WW & Emery P. The current status of ultrasonography in rheumatology. Rheumatology 1999; 38: 195–198. 9. van der Heijde D, Simon L, Smolen J et al. How to report radiographic data in randomized clinical trials in rheumatoid arthritis: guidelines from a roundtable discussion. Arthritis and Rheumatism 2002; 47: 215–218. 10. Lassere M, Boers M, van der Heijde D et al. Smallest detectable difference in radiological progression. Journal of Rheumatology 1999; 26: 731 –739. 11. Lassere MN, van der Heijde D, Johnson K et al. Robustness and generalizability of smallest detectable difference in radiological progression. Journal of Rheumatology 2001; 28: 911– 913. 12. Bruynesteyn K, van der Heijde D, Boers M et al. Detecting radiological changes in rheumatoid arthritis that are considered important by clinical experts: influence of reading with or without known sequence. Journal of Rheumatology 2002; 29: 2306–2312. 13. Wolfe F & Sharp JT. Radiographic outcome of recent-onset rheumatoid arthritis: a 19-year study of radiographic progression. Arthritis and Rheumatism 1998; 41: 1571–1582. * 14. Scott D, Pugner K, Kaarela K et al. The link between joint damage and disability in rheumatoid arthritis. Rheumatology 2000; 39: 122–132. 15. Plant MJ, Jones PW, Saklatvala J et al. Patterns of radiological progression in early rheumatoid arthritis: results of an 8 year prospective study. Journal of Rheumatology 1998; 25: 417 –426. 16. Drossaers-Bakker KW, de Buck M, van Zeben D et al. Long-term course and outcome of functional capacity in rheumatoid arthritis: the effect of disease activity and radiologic damage over time. Arthritis and Rheumatism 1999; 42: 1854–1860. * 17. Welsing PM, van Gestel AM, Swinkels HL et al. The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis. Arthritis and Rheumatism 2001; 44: 2009–2017. 18. Molenaar ET, Voskuyl AE & Dijkmans BA. Functional disability in relation to radiological damage and disease activity in patients with rheumatoid arthritis in remission. Journal of Rheumatology 2002; 29: 267–270. 19. Wolfe F & Choi HK. RA patients with radiographic progression are at increased risk for total joint replacement, even after controlling for disease activity and disease severity. Arthritis and Rheumatism 2001; 46: 730. abstract. 20. Felts W & Yelin E. The economic impact of the rheumatic diseases in the United States. Journal of Rheumatology 1989; 16: 867–884. 21. Gabriel SE, Crowson CS, Kremers HM et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis and Rheumatism 2003; 48: 54–58. 22. Yelin E, Trupin L, Wong B & Rush S. The impact of functional status and change in functional status on mortality over 18 years among persons with rheumatoid arthritis. Journal of Rheumatology 2002; 29: 1851–1857. 23. Callahan LF, Pincus T, Huston JW et al. Measures of activity and damage in rheumatoid arthritis: depiction of changes and prediction of mortality over five years. Arthritis Care and Research 1997; 10: 381 –394. 24. Chehata JC, Hassell AB, Clarke SA et al. Mortality in rheumatoid arthritis: relationship to single and composite measures of disease activity. Rheumatology 2001; 40: 447–452. 25. Choi HK & Wolfe F. Radiologic progression and mortality. Arthritis and Rheumatism 2001; 46: 1014. abstract. 26. Choi HK, Hernan MA, Seeger JD et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. The Lancet 2002; 359: 1173–1177. * 27. Riise T, Jacobsen BK & Gran JT. High mortality in patients with rheumatoid arthritis and atlantoaxial subluxation. Journal of Rheumatology 2001; 28: 2425–2429. 28. Kuper HH, van Leeuwen MA, van Riel PL et al. Radiographic damage in large joints in early rheumatoid arthritis: relationship with radiographic damage in hands and feet, disease activity, and physical disability. British Journal of Rheumatology 1997; 36: 855–860. 29. Winfield J, Young A, Williams P & Corbett M. Prospective study of the radiological changes in hands, feet, and cervical spine in adult rheumatoid disease. Annals of Rheumatic Diseases 1983; 42: 613 –618. * 30. Drossaers-Bakker K, Kroon H, Zwinderman A et al. Radiographic damage of large joints in long-term rheumatoid arthritis and its relation to function. Rheumatology 2000; 39: 998– 1003. 31. van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. Journal of Rheumatology 1999; 26: 743–745. * 32. Strand V & Sharp JT. Radiographic data from recent randomized controlled trials in rheumatoid arthritis: what have we learned? Arthritis and Rheumatism 2003; 48: 21 –34.